Simple indole alkaloids and those with a nonrearranged monoterpenoid unit.

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Simple indole alkaloids and those with a nonrearranged monoterpenoid unit Cite this: DOI: 10.1039/c5np00032g

Minoru Ishikura,*a Takumi Abe,a Tominari Choshib and Satoshi Hibinob

Covering: 2012 to 2013. Previous review: Nat. Prod. Rep., 2013, 30, 694–752 Received 30th March 2015

This review covers the literature on simple indole alkaloids and those with a nonrearranged monoterpenoid DOI: 10.1039/c5np00032g

unit from the beginning of 2012 up to the end of 2013, which includes newly isolated alkaloids, structure

www.rsc.org/npr

determinations, total syntheses and biological activities.

1 2 2.1 2.1.1 2.1.2 2.2 2.2.1 2.2.2 2.2.3 2.3 2.4 3

1

Introduction Simple indole alkaloids Non-tryptamines Indole phytoalexins Carbazoles Tryptamines Piperazinediones Pyrroloindoles b-Carbolines Bisindole alkaloids Peptide alkaloids References

2 Simple indole alkaloids 2.1

Non-tryptamines

Six new indole alkaloids, anthcolorins A (1), B (2), C (3), D (4), E (5), and F (6), were isolated from the MeOH extract of the fungal strain of Aspergillus versicolor, originally isolated from the sea

Introduction

This review covers the literature on simple indole alkaloids and those with a nonrearranged monoterpenoid unit from the beginning of 2012 to the end of 2013. In this series, marine natural products and peptide alkaloids have been also surveyed. As a result, there will be some overlap with marine alkaloids and peptide alkaloids containing the indole ring. Reviews on carbazole alkaloids,1–3 mitomycinoid alkaloids,4 akuammiline alkaloids,5 biomimetic syntheses of indersial alkaloids,6 the structure elucidation of indole–indoline-type alkaloids,7 the antimalarial activity of ellipticine,8 canthine alkaloids,9 the synthesis of harmicine,10 the catalytic asymmetric synthesis of pyrroloindoline alkaloids,11 welwitindolinones,12 the synthesis of strychnine,13 1H and 13C-NMR data of simple plumeran indole alkaloids,14 and prenylated indole alkaloids,15,16 have appeared. a

School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan. E-mail: [email protected]; Fax: +81 133 23 1245; Tel: +81 133 23 1245

b

Graduate School of Pharmacy & Pharmaceutical Sciences, Faculty of Pharmacy & Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

This journal is © The Royal Society of Chemistry 2015

Fig. 1

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urchin Anthocidaris crassispina. Compounds 2, 3, and 4 exhibited signicant cytotoxic activity against the murine P388 leukemia cell line (Fig. 1).17 Investigation of the chemical constituents of the fermentation broth of the plant endophytic fungus Pestalotiopsis podocarpi led to the isolation of a new indole alkaloid, 1-methoxy-1H-indol-3-ethanol (7) (Fig. 1).18 Two new indole alkaloids, peneciraistins E (8) and F (9), were isolated from saline soil-derived fungus Penicillium raistrickii (Fig. 1).19 Two new metabolites 10, 11 were isolated from the fungus Penicillium sp. Strain JMF034, obtained from deep-sea sediments of Suruga Bay, Japan (Fig. 1).20 Chemical investigation of two ground and freeze-dried marine sponge Trikentrion abelliforme samples collected from Australian waters resulted in the isolation of four new indole alkaloids, trikentramides A (12), B (13), C (14), and D (15). This

is the rst isolation of oxidized indole derivatives from a marine sponge (Fig. 2).21 Four new naturally occurring indole alkaloids, (Z)-3hydroxy-4-(3-indolyl)-1-hydroxyphenyl-2-butenone (16), (Z)-3hydroxy-4-(3-indolyl)-1-phenyl-2-butenone (17), and spirobacillenes A (18) and B (19), were obtained from the broth culture of the bacterial strain, Lysinibacillus fusiformis KMC003. Compound 18 exhibited a weak inhibitory effect against NO and POS production in the LPS-induced RAW 264.7 macrophage cell line (Fig. 3).22 Two new alkaloids, leucomidines A (20) and B (21), were isolated from the bark of Leuconotis griffithii, a member of the Apocynaceae family in Malaysia and Indonesia (Fig. 3).23 Fourteen new indole alkaloids 22–34 were isolated from an aqueous extract of the root of Isatis Indigotica, a biennial

Minoru Ishikura was born in Hokkaido, Japan. He graduated from the Graduate School of Pharmaceutical Sciences, Hokkaido University, and received his Ph. D. degree under the supervision of Professor Yoshio Ban in 1982. He then worked at the Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, and became a full professor in 2001. He spent the years 1985–1986 as a postdoctoral fellow at the University of California, San Diego with Professor Ernest Wenkert. His main research interests are the development of synthetic methods using organometallic reagents and the syntheses of bioactive natural products.

Tominari Choshi is a Professor of the graduate school of Pharmacy and Pharmaceutical Sciences, Fukuyama University. He was born in 1964, and graduated from Fukuyama University followed by the Graduate school of Pharmaceutical Sciences, Okayama University. He became a faculty member of Fukuyama University in 1992. He obtained his Ph. D. degree from Tohoku University in 1997 (Professor K. Fukumoto). He received the award for the young scientist of the Chugoku-Shikoku branch of the JPS in 2000. He was promoted to an Associate Professor in 2003, and then he became a Professor in 2011. Currently, he is a Professor in organic and medicinal chemistry. His research interests are in synthetic and medicinal chemistry including heterocyclic natural products.

Takumi Abe was born in Hokkaido, Japan. He graduated from the Graduate School of Pharmaceutical Sciences, Hokkaido University, and received his Ph. D. degree under the supervision of Professor Shunichi Hashimoto in 2007. He then worked at the Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido. He worked as a postdoctoral fellow with Prof. Kim D. Janda at the Scripps Research Institute, La Jolla (2009). He is interested in developing synthetic reactions catalyzed by transition metal complexes and their synthetic applications.

Satoshi Hibino is an emeritus Professor of the graduate school of Pharmacy and Pharmaceutical Sciences, Fukuyama University. He was born in 1945. He graduated from Osaka Pharmaceutical Sciences, followed by the Graduate School of Pharmaceutical Sciences, Tohoku University where he obtained his Ph. D. degree (Professor T. Kametani). Aer two years of a post doc (1975–1977) under Professor Steven M. Weinreb (PSU, USA) at the Chemistry Dept. of Fordham University, he worked at Tokyo Pharmaceutical University for ve years. He moved to Fukuyama University as an Associate Professor and then he was promoted to a Professor in 1986. His research interests are in synthetic organic chemistry in heterocycles including bioactive natural products.

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Fig. 2

Fig. 4

Fig. 3

herbaceous plant widely distributed in China. Compounds 25 are the rst natural products with the pyrrolo[2,3-b]indolo [5,5a,6-b,a]quinazoline system. Compounds 22–24 showed antiviral activity against the inuenza virus (Fig. 4).24 Two distinct synthetic strategies for spirobacillenes A (18) and B (19), were developed. In Taylor's synthesis of 18, spirocyclic cyclohexadienone 37 was constructed by the SnCl2mediated electrophilic spirocyclization reaction of alkyne 36. Then 37 was converted to 18 through epoxidation of the allylic alcohol followed by epoxide opening (Scheme 1).25 Tang's synthesis of 18 and 19 was achieved based on the proposed biogenetical pathway. Spirobacillene A (18) was obtained through the Ag2O-promoted biomimetic intramolecular phenol–enol oxidative coupling of 39 as a key step. I2-promoted intramolecular indole–enolate oxidative coupling of 38 led to 19 (Scheme 2).26 The asymmetric total synthesis of (+)-sattazolin (40), isolated from the soil bacteria Bacillus sp., was achieved through the Yb-catalyzed ring-opening of methyl glycidate 41 with


indole as a nucleophile. The absolute conguration was unequivocally established based on the synthesis (Scheme 3).27 The total synthesis of paspalinine (42) and the formal synthesis of paspalicine (43) were performed. Tricyclic triate 45 was derived from known ketone 44 in 6 steps. The construction of the indole ring 47 was performed through the Stille coupling of 45 with aniline 46, followed by Pd-mediated indole ring formation. Deprotection of the Boc group of 48 provided the known intermediate 49 for 43. Transformation of 48 to 42 was realized using the one-pot installation of the C13

Scheme 1 Reagents and conditions: (i) n-BuLi, THF, then 35; (ii) SnCl2, CH2Cl2; (iii) NaBH4, CeCl37H2O, CH2Cl2/MeOH; (iv) m-CPBA, NaHCO3, CH2Cl2; (v) Dess–Martin reagent, NaHCO3, CH2Cl2; (vi) p-TsOH, toluene; (vii) TFA, CH2Cl2.

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Scheme 2 Reagents and conditions: (i) PPTS, MeOH, THF, 0 C to rt; (ii) DMP, CH2Cl2, rt; (iii) silica gel; (iv) TBAF, AcOH, THF, rt; (v) Ag2O, CH2Cl2, rt; (vi) LHMDS, 40 C, THF, then I2, 78 C; (vii) PPTS, MeOH, rt; (viii) TBAF, AcOH, THF, rt.

Reagents and conditions: (i) 46, Pd(PPh3)4, CuCl, LiCl, 50 C; (ii) Pd(OCOCF3)2, NaOAc, DMSO, 60 C; (iii) HCl, THF, 45 C; (iv) t-BuOK, Alloc-Cl, THF, rt; (v) Pd(PPh3)4, PPh3, DME, rt, then DBU; (vi) CH2] CHC(OH)Me2, Grubbs' 2nd generation catalyst, CH2Cl2, reflux; (vii) K2OsO2(OH)4, (DHQD)2PHAL, K3Fe(CN)6, K2CO3, NaHCO3, t-BuOH/ H2O, 15 C; (viii) CPTS, MeOH, 5 C; (ix) DMP, NaHCO3, CH2Cl2, rt; (x) SiO2, 133 Pa, 90–100 C; (xi) KHMDS, PhSeCl, THF, 70 C to 15 C, then H2O2, NaHCO3, rt; (xii) SiO2, 133 Pa, 90–100 C. Scheme 4

Scheme 3 Reagents and conditions: (i) Yb(OTf)3, 41, CH2Cl2, 80 C; (ii) TBSCl, imidazole, DMF; (iii) (Boc)2O, DMAP, MeCN; (iv) N,O-dimethylhydroxylamine, n-BuLi, THF, 78 C; (v) isobutyllithium, THF, 78 C; (vi) silica gel, 80 C; (vii) TBAF, THF.

hydroxy group via an allylic selenoxide[2,3]sigmatropic rearrangement (Scheme 4).28 The rst synthesis of lecanindole D (50) was accomplished (Scheme 5). Triate 52 was obtained from epoxide 51 through the trans-diaxial ring opening of the epoxide followed by reductive cleavage of the cyclopropane ring to generate the enolate. Lecanindole D (50) was synthesized from 52 through the indole ring installation followed by deprotection of the TBS and Boc groups (Scheme 5).29 Terreusinone (53), featuring a pyrrolo[2,3-f]indole-4,8-dione framework, was isolated from the marine fungus Aspergillus terreus in 2003, and showed signicant UV-A protective properties. The total synthesis of (+)-53 was accomplished by a copper- and amine-free double Sonogashira reaction followed by hydroamination to simultaneously install both indole rings 54 (Scheme 6).30,31 Indoloquinoline alkaloids have received signicant attention because of their striking biological activities and their intriguing structures. A simple method for the synthesis of quindoline (56), indolo[3,2-b]quinoline alkaloid, was reported

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by two groups. Detert's strategy involved a two-fold palladiumcatalysed Buchwald–Hartwig reaction between the initially prepared cyclic benzoquinolineiodonium salt 57 and benzyl amine at 100 C (Scheme 7).32 Lopes' group developed the fact that the catalytic hydrogenation of the nitro group of 58 in MeOH containing a few drops of CHCl3 directly produced 56 (Scheme 8).33 Cryptolepine (59) exists in its salt form under acidic conditions. A four-step synthesis of 59 from N-sulfonylindole was developed through a tandem reductive cyclization/dehydration reaction followed by methylation (Scheme 9).34 The total synthesis of isocryptolepine (60) was accomplished by Hibino's and Butin's groups. Butin's approach featured a facile construction of the indole ring by the acidinduced reaction of 2-furylaniline with 2-nitrobenzaldehyde followed by the reductive cyclization of 2-nitrophenylindole (Scheme 10).35 Hibino's group achieved the total synthesis through the microwave-assisted tandem Curtius rearrangement of 2-indolylbenzoic acid with DPPA followed by the electrocyclic ring closure of isocyanate 61 (Scheme 11).36 This journal is © The Royal Society of Chemistry 2015

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Reagents and conditions: (i) TsOH, NaNO2, KI, MeCN, 0 C; (ii) m-CPBA, TfOH, CH2Cl2, 0 C; (iii) BnNH2, Pd2(dba)3/Xantphos, Cs2CO3, toluene, 100 C; (iv) t-BuOK, air, DMSO. Scheme 7

Scheme 5 Reagents and conditions: (i) LiAlH4, THF, 0 C to rt; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, rt; (iii) H2, Pd(OH)2, EtOH, rt; (iv) SO3– Py, Et3N, DMSO, rt; (v) Na/C8H19, THF, 78 C, then isoprene, ClC5H3N(NTf)2, HMPA, 78 to 10 C; (vi) 46, Pd(PPh3)4, CuCl, LiCl, DMSO, 50 C; (vii) Pd(OCOCF3)2, NaOAc, DMSO, 60 C; (viii) TBAF, AcOH, THF, rt; (ix) SiO2, 133 Pa, 90–110 C.

Four simple synthetic approaches to neocryptolepine (cryptotackieine) (62) were developed. The one-pot formation of indolo[2,3-b]quinoline core 63 was achieved starting with the alkylation of 63 with acetate 64, followed by two reductive cyclizations to form an a-carboline system (Scheme 12).37 The formal synthesis of 62 was achieved by a two-step synthesis of the known intermediate 65 through a one-pot reduction/cyclization/aromatization of 3-benzylindole (Scheme 13).38 A new one-pot strategy for 62 was developed based on the Rh(II)-catalyzed conversion of aryl azide 66 to an a-carboline system (Scheme 13).39 The one-pot formation of 62 was developed using the NBS-catalyzed reaction of indole-3-carbaldehyde with aniline. The reaction was supposed to proceed through the NBS-catalyzed formation of a 3-bromo-indolinium cation followed by attack by a secondary aniline and simultaneous cyclization (Scheme 14).40 A number of biological activities have been reported for indolo[2,1-b]quinazoline alkaloids. New tryptanthrin analogues

Scheme 8 Reagents and conditions: (i) n-BuLi, THF, 70 C, then CO2: (ii) sec-BuLi, 70 C; (iii) 2-nitrobenzaldehyde; (iv) Pd/C, H2, MeOH, CHCl3 (a few drops).

Reagents and conditions: (i) n-BuLi, THF, 78 C to rt; (ii) o-nitrobenzaldehyde, 78 C to rt; (iii) PPh3, MoO2Cl2(dmf)2, toluene, 110 C; (iv) aq. NaOH, MeOH, 80 C; (v) MeI, sulfolane, 55 C. Scheme 9

Scheme 6 Reagents and conditions: (i) Pd(OAc)2, [1,10 -(di-tert-butylphosphino)ferrocene], K2CO3, NMP; (ii) 55, toluene, 60 C; (iii) TBAF, THF, 0 C; (iv) Fremy's salt, acetone, H2O, KHPO4.


Scheme 10 Reagents and conditions: (i) HCl, AcOH, 30 C; (ii) Fe, AcOH, reflux; (iii) MeI, nitrobenzene; (iv) NH4OH, H2O.

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Scheme 11 Reagents and conditions: (i) DPPA, Et3N, toluene, 100 C;

(ii) 1,2-dichlorobenzene, 50 C; (iii) Tf2O, pyridine, CH2Cl2, rt; (iv) Et3SiH, Pd(OAc)2, dppp, DMF, 60 C; (v) MeOH, CH(OMe)3, CF3SO3H, MeNO2, 100 C; (vi) MeI, toluene, reflux; (vii) 28% aq. NH4OH. Scheme 15 Reagents and conditions: (i) CuI, DMSO, 80 C; (ii) oxone, MeCN, H2O, rt; (iii and iv) I2, TBHP, MeCN, 40 C.

Scheme 12 Reagents and conditions: (i) K2CO3, THF, rt; (ii) Fe, AcOH, reflux; (iii) DDQ, 1,4-dioxane, reflux; (iv) MeI, THF, reflux.

were synthesized and tested for their activity against Mycobacterium tuberculosis.41 Two approaches to tryptanthrin 67 using the one-pot oxidative dimerization of indole derivatives were developed. Wang's method involved copper-catalyzed oxidative dimerization of indole using CuI in DMSO at 80 C, which was supposed to involve Cu-catalyzed aerobic oxidation of indole, Cu-catalyzed decarboxylative coupling, and intramolecular cyclization (Scheme 15).42 Grundt reported the one-pot construction of 67 by the oxidative dimerization of indole-3-carbaldehyde with OXONE® in MeCN/H2O at room temperature (Scheme 15).43 A new I2/TBHP-mediated oxidative amination of indole was explored for the formation of 67 from readily available amine 68 (Scheme 15).44 The enantioselective synthesis of ()-(S)-phaitanthrin A (69) was developed by the amino acid salt-catalysed aldol condensation of 67 with acetone (Scheme 16).45 Tryptanthrin (67) was transformed into (+)-(S,S)-cruciferane (25) via a chiral auxiliarymediated asymmetric aldol reaction followed by the one-pot reductive cyclization/transamidation of 70 with NiCl2/NaBH4 (Scheme 16).46

Scheme 13 Reagents and conditions: (i) Ph3P, Ph2O, reflux; (ii) [Rh2(esp)2], ClCH2CH2Cl, 80 C; (iii) Na2CO3, H2O.

Scheme 14

Reagents and conditions: (i) aniline, NBS, rt.

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Scheme 16 Reagents and conditions: (i) acetone, L-phenylalanine potassium salt, CHCl3, p-bromoanisole, 0 C; (ii) 71, LHDMS, THF, 78 C; (iii) NiCl2, NaBH4, MeOH, 78 C to rt.


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Scheme 17 Reagents and conditions: (i) CsF, NaHCO3, MeCN, rt; (ii) MeCOOMe, LDA, THF, 78 C; (iii) NaBH4, MeOH, CHCl3; (iv) K2CO3, acetone; (v) LiCl, DMF, reflux.

The selective insertion of in situ-generated aryne 72 to the 3position nitrogen of 1,3-quinazoline was developed to prepare fused quinazolinone. Based on the one-pot protocol, phaithanthrins B (73) and C (74), 67, 69, and 25 were synthesized (Scheme 17).47 The formal synthesis of hapalindole O (75) was accomplished by the construction of Natsume's tetracyclic intermediate through the Sn-mediated coupling of indole 76 with TMS–enol 77 followed by ring-closure with methanolic HCl (Scheme 18).48 Hapalindoles J (78) and U (79) were synthesized from 76 and 80 based on the same strategy (Scheme 18).49 Formal synthesis of rac-chuangxinmycin (80), isolated from Actinoplanes tsinanensis n. sp., was accomplished. The known tricyclic intermediate 81 was assembled by a Ni-catalyzed intramolecular C–S cross coupling reaction (Scheme 19).50 A short synthesis of bruceollines D (82), E (83) and J (84) was achieved. The palladium-catalyzed cyclization of o-chloroaniline with dione produced 82, and subsequent DDQ oxidation of 82 gave 83. Enantioselective reduction of 83 with (+)-DIPCl provided (+)-84 (natural) (Scheme 20).51 The rst total synthesis of rac-16-hydroxy-16,22-dihydroapparacine (85) was achieved. The 1-azabicyclo[4.2.2]decane was assembled by diastereoselective addition of 2-lithioindole to ketone 86 followed by a cascade reaction involving phosphineimine generation/intramolecular N-allylation/aza-Wittig reaction/intramolecular Mannich reaction. The structure of 85 was revised to the 15S,16R-conguration (Scheme 21).52 The total synthesis of dictyodendrins B (87) and E (88) was reported. Palladium-catalyzed Larock indole annulation was used for the construction of 89, and the advanced intermediate



Scheme 18 Reagents and conditions: (i) SnCl4, CH2Cl2, 78 C; (ii) HCl, MeOH; (iii) NaH, PivCl, THF; (iv) PivCl, NaH, THF; (v) TsCl, DMAP, CH2Cl2, reflux.

Scheme 19 Reagents and conditions: (i) NiCl2, Zn, ethyl crotonate, pyridine, MeOH, 0 C to rt.

90 was assembled by Buchwald–Hartwig amination/C–H activation reaction (Scheme 22).53 The total syntheses of ve amaryllidaceae alkaloids, lycoranines A (92) and B (93), 2-methoxypratosine (94), oxoassoanine (95), and anhydrolycorinone (96), were reported. Two related

Scheme 20 Reagents and conditions: (i) Pd(t-Bu3P)2, AcOH, K3PO4, MgSO4, DMA, 125 C; (ii) DDQ, MeCN, H2O; (iii) (+)-DIPCl, THF, 42 C, 98% ee.

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Scheme 21 Reagents and conditions: (i) n-BuLi, THF, 78 C, then 86,; (ii) DIBAL, CH2Cl2, 78 C; (iii) TASF, ethylenediamine, THF, DMF, 50 C; (iv) 2-chloro-3-nitropyridine, KOH, K2CO3, tris[2-(2-methoxy) ethyl]amine, toluene, 20 C; (v) PPh3, THF, H2O, reflux; (vi) HCHO aq., PPTS.

approaches were developed for 92, 93, and 94 based on the Suzuki–Miyaura coupling reaction (Scheme 23).54 Oxoassoanine (95) and anhydrolycorinone (96) were synthesized by intramolecular biaryl coupling involving t-BuOK-initiated single electron transfer to the C–Br bond (Scheme 24).55 The halodecarboxylation of arenedicarxylic acid leading to a dihalogenated product was applied for the synthesis of kalbretorine (97). Treatment of dicarboxylic acid 98 with PhI(OAc)2 and KI produced diiodide 99, which was transformed into 97 in 3 steps (Scheme 25).56 Natural indolequinones, 5-methoxyindole-4,7-quinone (100) and 6-methoxyindole-4,7-quinone (101) were prepared from indoles through the oxidation of 7-boryated indoles derived by Ir-catalyzed C–H borylation (Scheme 26).57 rac-Cinchonaminone (102) was synthesized, which involved the assembly of indoline using the Rucatalysed cycloisomerization of 1,3-diene 103 as the key step (Scheme 27).58 The rst total synthesis of nostodione A (105), isolated from the cyanobacterium Nostoc commune, was completed. The reductive Heck reaction of 106 gave cyclopent[b]indole 107 with the Z-conguration, and the subsequent oxidation produced ketone 108 with the E-conguration through spontaneous isomerization (Scheme 28).59 A new method for the preparation of indole-2-carbaldehyde was developed using NIS-mediated amino cyclization of propargyl alcohol in an aqueous reaction medium. Aldehyde 111 was transformed into the known intermediate 110 for (R)-calindol (109) (Scheme 29).60 (E)-a-Indol-2-yl-b-aryl acrylate 113 was stereoselectively synthesized by the L-proline-catalyzed condensation of indol-2yl acetate with aryl aldehyde. Further chemical transformation

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Scheme 22 Reagents and conditions: (i) Pd(PPh3)4, K2CO3, THF, 65 C; (ii) 1-(2-bromoethyl)-4-methoxybenzene, KOH, DMF, 50 C; (iii) NBS, CH2Cl2; (iv) 91, Pd(OAc)2, (t-Bu3P)HBF4, t-BuONa, DMSO, 160 C; (v) Pd/C, H2, AcOEt; (vi) ClSO3CH2CCl3; (vii) BCl3, TBAI; (viii) Zn dust, HCOONH4; (ix) LiAlH4, AlCl3, THF, reflux; (x) Pd/C, H2, AcOEt, 50 C.

of 113 produced marine alkaloid, prenostodione (112) (Scheme 30).61 Diastereo- and enantioselective synthesis of the cyclopentene intermediate 118 for (+)-madindolines A (114) and B (115) was achieved using enantioselective desymmetrization of achiral cyclopentene 116 through Cu-catalyzed enantioselective methylation, followed by reaction of intermediary Zn–enolate with butylaldehyde to give 117, which was then converted to 118 (Scheme 31).62 The rst biomimetic transformation of (+)-vincadifformine (119) to ()-goniomitine (120) was achieved in 9 steps (Scheme 32).63


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Scheme 25 Reagents and conditions: (i) Pd(PPh3)4, KOAc; (ii) LiOH; (iii) PhI(OAc)2, KI, THF, 60 C; (iv) n-Bu4NBH4, SnCl2; (v) BBr3; (vi) BrCH2Cl, Na2CO3, Na2SO3. Scheme 23 Reagents and conditions: (i) R–CH(CN)Cl, BCl3, TiCl4; (ii) NaBH4; (iii) Et3N, PdCl2(dppf) CH2Cl2; (iv) [Ru(p-cymene)Cl2]2, Et2SiH2 or [Ir(OMe)COD]2, di-t-bpy, B2Pin2, HBPin; (v) NaOAc.

Scheme 26 Reagents and conditions: (i) [Ru(p-cymene)Cl2]2, Et2SiH2, toluene, 90 C; (ii) [Ir(OMe)COD]2, di-t-bpy, B2Pin2, HBPin, THF, 85 C; (iii) NaOAc, rt; (iv) H2O2, NaOH, THF, H2O, 0 C; (v) salcomine, O2, MeCN, rt.

Snyder's synthesis of (+)-scholarisine A (125) involved the assembly of the tricyclic cage core 128 by tandem radical cyclization/Keck allylation in [2.2.2]bicyle and the indole annulation

Scheme 24

Reagents and conditions: (i) t-BuOK, mesitylene, 100 C.

rac-Goniomitine (120) was synthesized using the Pd-catalyzed decarbonylative coupling of 121 with 122, followed by the one-pot oxidation/reduction/cyclization sequence (Scheme 33).64 ()-Mersicarpine (123), featuring a tetracyclic azepinoindole core, was synthesized through the DIBAH-promoted reductive ring expansion of oxime 124 to construct the azepinoindole core (Scheme 34).65 The enantioselective total synthesis of (+)-scholarisine A (125) was reported by two groups. In Smith's approach, the caged ring scaffold 127 was assembled by the Fischer indole annulation of ketone 126 using 1-benzyl-1-phenylhydrazine. Then 127 was transformed into (+)-125 through oxidative lactonization and intramolecular cyclization as the key tactics (Scheme 35).66,67


Scheme 27 Reagents and conditions: (i) 104, benzene, 80 C; (ii) 9-BBN, THF, 20 C, then H2O2, NaOH, H2O; (iii) TEMPO, NCS, Bu4NCl, CH2Cl2, H2O; (iv) Ph3PMeBr, NaN(TMS)2, THF, 78 C; (v) (1) Cy2BH, THF, 0 C, then H2O2, NaOH, H2O. (2) MOMCl, i-Pr2NEt, CH2Cl2. (3) NaOH, H2O, MeOH, reflux. (4) Boc2O, Et3N, DMAP, CH2Cl2; (vi) OsO4, NaIO4, dioxane; (vii) Zn, THF; (viii) CuCN, LiCl, BF3OEt2, THF, 78 C; (ix) Dess–Martin periodinane, CH2Cl2; (x) HCl, MeOH, 40 C.

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Scheme 28 Reagents and conditions: (i) Pd(OAc)2, PPh3, HCOOH, Et3N, DMF, 60 C; (ii) Shvo catalyst, acetone, 60 C; (iii) DDQ, MeCN, H2O, 0 C; (iv) TBAF, THF, 0 C.

Review

Scheme 31 Reagents and conditions: (i) Cu(OTf)2, phophoramidite ligand, Me2Zn, Et2O, 40 C, then butylaldehyde; (ii) DBU, toluene, 80 C; (iii) Zn(BH4)2, CH2Cl2, 40 C; (iv) TBSCl, KH, 18-crown-6, THF, rt; (v) Pd/C, EtOH, rt.

Scheme 29 Reagents and conditions: (i) NIS, MeCN, H2O, reflux; (ii) (R)-1-(1-naphthyl)ethylamine, NaBH4, MeOH.

via radical C–H arylation in 129 as the key features (Scheme 36).68 Indole-3-acetonitrile-4-methoxy-2-C-b-D-glucopyranoside (130), isolated from the roots of the plant Isatis indigotica, was

Scheme 30 Reagents and conditions: (i) L-proline, DMSO, rt; (ii) Boc2O, DMAP, CH2Cl2, rt; (iii) NaClO2, NaH2PO4, 2-methyl-2butene, t-BuOH, H2O; (iv) TFA, CH2Cl2.

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Scheme 32 Reagents and conditions: (i) NaBH3CN, AcOH, rt; (ii) TiCl3, MeOH, rt; (iii) Pd/C, HCOONH4, MeOH, reflux; (iv) 4 N HCl, 100 C.

synthesized using the Sonogashira coupling reaction of ethynyl-b-C-glycoside 131 followed by Cu-mediated indole annulation, leading to indole-C-glycoside core 132 (Scheme 37).69 The full details of the syntheses of PDE-I (133) and PDE-II (134), isolated from Streptomyces MD769-C6, have appeared, which involved a one-pot ve-step conversion of 135 to 136, including copper-mediated double aryl amination, elimination, deprotection of a Cbz group, and the formation of indole via removal of an Ns group followed by rearomatization (Scheme 38).70 Citrinadins A (137) and B (138) are members of a small family of spirooxindole alkaloids, isolated from a culture broth of Penicillium citrinum. The proposed stereochemical structures of citrinadins A (139) and B (145) were revised based on their enantioselective syntheses. The enantioselective synthesis of ()-citrinadin A (137) was achieved, which involved an asymmetric vinylogous Mannich


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Scheme 33 Reagents and conditions: (i) [PdCl(allyl)2], X-Phos, diglyme, 100 C; (ii) DPPA, DIAD, Ph3P, THF, 0 C; (iii) O3, NaHCO3, MeOH, 78 C, then Me2S, 78 C to rt; (iv) Zn, CaCl2, reflux; (v) sodium naphthalenide, THF, 20 C.


Scheme 35 Reagents and conditions: (i) 1-benzyl-1-phenylhydrazine, pyridine, HCl; (ii) AlCl3, toluene; (iii) Pd(OH)2/C, HCOONH4, MeOH; (iv) trifluoroacetylimidazole, THF; (v) MsCl, Et3N, CH2Cl2; (vi) tertbutylimino-tri(pyrrolidino)phosphorane, MeCN; (vii) K2CO3, MeOH; (viii) PhIO, CH2Cl2.

Scheme 36 Reagents and conditions: (i) allyltributylstannane, Et3B, benzene, air, THF, 50 C; (ii) TMG, TEMPO, THF, air 50 C; (iii) NaBH3CN, TFA, CH2Cl2, 0 C; (iv) AcOEt, 80 C; (v) 2-iodoaniline, PPTS, toluene, THF, 90 C; (vi) n-Bu3SnH, AHCN, toluene, 110 C. Scheme 34 Reagents and conditions: (i) DIBAH, CH2Cl2, 78 to 0 C, 0 C to rt; (ii) CbzCl, NaOH, H2O, 0 C; (iii) TPAP, NMO, MeCN, rt; (iv) Pd/C, H2, AcOEt; (v) air, rt; (vi) Me2S, rt.

addition of dienolate 140 to a chiral pyridinium salt establishing the initial chiral center, highly stereoselective epoxidation of 141 followed by ring-opening, and an oxidative rearrangement of indole 142 to furnish a spirooxindole (Scheme 39).71 The enantioselective synthesis of ()-citrinadin B (138) was completed using the key (+)-intermediate 144 derived from the [3 + 2] cycloaddition between rac-143 and ()-nitrone in the presence of L-proline. This was transformed to ()-138, which led to the revision of the originally proposed stereochemical assignment (Scheme 40).72 The welwitindolinone, possessing a bicyclo[4.3.1]decane ring system, is a unique family of oxyindole-containing


alkaloids, isolated from a series of marine and terrestrial cyanobacteria. Syntheses of N-methylwelwitindolinone C isothiocyanate (146), C3-hydroxy-N-methylwelwitindolinone C isothiocyanate (147), N-methylwelwitindolinone C isonitrile (148), C3-hydroxy-N-methylwelwitindolinone C isonitrile (149), and N-methylwelwitindolinone D isonitrile (150) were reported by three groups. Rawal's group reported the total synthesis of 146, 147, and 148 using tetracyclic intermediate 151, which was previously developed for the synthesis of N-methylwelwitindolinone D isonitrile (150) as the key compound. This compound (151) was transformed to ()-146 via electrophilic chlorination of hydrazine and oxidation of indole to oxindole with magnesium monoperoxyphthalate. Compound 146 was directly converted to 147 and 148 (Scheme 41).73

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Review

Scheme 37 Reagents and conditions: (i) PdCl2(PPh3)2, CuI, i-Pr2NEt, MeCN, 70 C; (ii) n-BuNH2, THF; (iii) K2CO3, MeI; (iv) Zn, AcOH; (v) CuI, DMF, 145 C; (vi) formalin, Me2NH, AcOH, dioxane; (vii) MeI, CH2Cl2; (viii) NaCN, EtOH, 80 C; (ix) Pd(OH)2/C, H2, MeOH, AcOEt.

Scheme 38

90 C.

Reagents and conditions: (i) CuI, CsOAc, Cs2CO3, DMSO,

Formal syntheses of 146–150 were completed by the independent synthesis of Rawal's intermediate 151. Ketoester 155 was converted to Rawal's intermediate 151 through Pd-catalyzed intramolecular enolate arylation and regioselective Pd-catalyzed p-allylic cyclization of benzoyloxy enone 156 (Scheme 42).74 In Garg's approach for 146–149, compound 158, obtainable by the nitrogen insertion reaction of 157, was developed as the key intermediate. The low efficiency of the nitrene insertion reaction of 157a was markedly improved by using 157b, with a deuterium atom at the C10 position, which minimized an undesirable competitive reaction based on the deuterium effect. Intermediate 158b was elaborated to natural products 146 and 148 over additional transformations. Furthermore, the aerobic oxidation of 146 and 148 under basic conditions

Nat. Prod. Rep.

Scheme 39 Reagents and conditions: (i) LDA, THF, 78 C; (ii) ZnCl2, THF, 78 C; (iii) pyridinium; (iv) 0.5 M HCl; (v) Cs2CO3, THF, MeOH, reflux; (vi) CF3CO3H, Na2CO3, CH2Cl2, 0 C; (vii) MeNH2, 100 C; (viii) PPTS, CH2Cl2, then Davis' oxaziridine; (ix) AcOH, CH2Cl2.

provided C3-hydroxylated 147 and 149, respectively (Scheme 43).75 The enantiospecic synthesis of (+)-N-methylwelwitindolinone D isonitrile (150) was achieved using the known tetracyclic intermediate 159. Cyclic carbamate 160 was assembled via oxidation of the indole ring followed by an intramolecular nitrene insertion reaction. Installing the tetrahydrofuran ring from ketone 162 was simply effected by exposure of 161 to TBAF in MeCN under air (Scheme 44).76 A rst asymmetric synthesis and determination of the absolute conguration of neoxaline (163) was accomplished by using optically pure furoindoline 164, prepared by the Katsuki– Sharpless asymmetric epoxidation of tryptophol. The reverse prenyl group was stereoselectively introduced at the C3a


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Scheme 41 Reagents and conditions: (i) NaBH(OMe)3, THF, EtOH, 0 C; (ii) N2H4, AcOH, EtOH 70 C; (iii) NCS, pyridine; (iv) MMPP, TFA, AcOH; (v) Dess–Martin periodinane, NaHCO3, CH2Cl2; (vi) NH2OH, pyridine, MeOH, 45 C; (vii) NCS, DMF, THF, 40 C, then Et3N,153; (viii) 154, toluene, 100 C; (ix) KHMDS, THF, 78 C, then 152.

Scheme 40 Reagents and conditions: (i) Pd(dba)3, Et3SiH, AcOH, toluene, rt; (ii) TBAF, THF; (iii) (COCl)2, DMSO, Et3N, CH2Cl2, 78 C; (iv) nitrone, L-proline, MeCN, CH2Cl2, rt; (v) (Me3SO)+I, NaH, THF, DMSO; (vi) TMSCl, NaI, THF, MeCN; (vii) Zn, AcOH, THF; (viii) Et2Zn, O2, toluene; (ix) (Boc)2O, Et3N, DMAP, CH2Cl2; (x) Pd/C, H2, THF; (xi) Me3OBF4, Na2CO3, CH2Cl2; (xii) Mg(ClO4)2, MeCN, 60 C.

position of 164 to give 165, which was then transformed to 163 through ring-opening of the tetrahydrofurane ring, ring formation, and indoline spiroaminal formation sequences (Scheme 45).77 The asymmetric syntheses of (+)-cis-trikentrins A (166) and B (167), an uncommon class of indole alkaloids, were accomplished employing Ni(II)-catalyzed asymmetric hydrovinylation as the key step. Treating 7-vinylindoles under ethylene in the presence of a Ni(II) catalyst and a phosphoramidite ligand provided hydrovinylation products 168 with excellent yields and ees, which were transformed to (+)-cis-166 and (+)-cis-167, respectively (Scheme 46).78 rac-cis-Trikentrin B (167), was synthesized using regioselective indole aryne cycloaddition with cyclopentadiene to install the cyclopentan ring via annulation at the 6,7-position of the indole ring. The aryne intermediate 171 was generated regioselectively by metal–halogen exchange at the 7-position of 5,6,7-tribromoindole 170 (Scheme 47).79


The total synthesis of rac-actinophyllic acid (173) was accomplished, which featured the one-pot construction of tetracyclic intermediate 174 through the cascade reaction of a carbocation generated from the TMSOTf-mediated ionization of indole with p-nucleophile enamido diene, followed by a spontaneous intramolecular cyclization of N-acyliminium ion (Scheme 48).80

Scheme 42 Reagents and conditions: (i) PEPPSI-IPr, t-BuONa, toluene, reflux; (ii) Pd2dba3, P(2-furyl)3, Bu3SnOMe, toluene, 100 C; (iii) NaHMDS, DMF, 40 C to rt; (iv) MeI, 40 C to rt; (v) LiAlH4, Et2O, rt; (vi) Dess–Martin, NaHCO3, CH2Cl2, rt.

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Scheme 43 Reagents and conditions: (i) AgOTf, PhI(OAc)2, bathophenanthroline, MeCN, 82 C; (ii) Ba(OH)2, H2, dioxane, 110 C; (iii) Dess–Martin reagent, TFA, CH2Cl2, rt; (iv) A, DMAP, DCE, 90 C; (v) LHDMS, air, THF, rt; (vi) HCOOH, Ac2O, THF, 0 C to rt; (vii) Burgess reagent, THF, benzene, rt; (viii) NaH, air, THF, rt.

Review

Scheme 45 Reagents and conditions: (i) t-BuOOH, (+)-DIPT, Ti(O-iPr)4, CH2Cl2, MS 4A, THF, 40 C; (ii) EDC, CuCl2, toluene, 45 C; (iii) TBAF, THF, 0 C; (iv) MeI, K2CO3, DMF; (v) MeAl, CH2Cl2, 78 C to rt; (vi) HF/pyridine, pyridine; (vii) hv, MeOH.

2.1.1 Indole phytoalexins. A new cruciferous indole phytoalexin, isocyalexin A (175), was isolated from UV-irradiated rutabaga root slices. Its synthesis was achieved from 3-nitroindole in 3 steps through methoxylation, reduction, formylation, and dehydration sequences. Antifungal activity

Scheme 44 Reagents and conditions: (i) AgOTf, PhI(OAc)2, bathophenanthroline, MeCN, 82 C; (ii) HCl, EtOH; (iii) Dess–Martin, NaHCO3, CH2Cl2; (iv) TBAF, air, MeCN, rt; (v) LiAlH4, THF, 78 C to 0 C; (vi) Ba(OH)2, H2O, dioxane, 110 C; (vii) IBX, TFA, DMSO; (viii) HCOOH, Ac2O, THF, 0 C to rt; (ix) Burgess reagent, THF, benzene, rt.

Nat. Prod. Rep.

Scheme 46 Reagents and conditions: (i) ethylene, 169, [(allyl) NiBr]2, NaB(Ar)4, CH2Cl2, 78 C; (ii) KH, TsCl, 18-crown-6, DME; (iii) 9-BBN, then H2O2; (iv) TPAP, NMO; (v) NaClO2, NaH2PO4; (vi) (COCl)2, DMF; (vii) AlCl3, CH2Cl2; (ii) t-BuOK, [Ph 3PMe]I; (iii) [(allyl)Pd]2, P(o-tol)3, AgOTf, ethylene; (iv) [(COD)Ir(PCy3) (py)] PF6, H2, CH2Cl 2; (v) TBAF, THF, reflux; (vi) Pd/C, H2, MeOH; (vii) PhI(OCOCF3)2, MeCN, rt; (viii) Mn(OAc)3, AcOH, reflux; (ix) (E)but-1-en-1-yltributylstannane, PdCl2(PPh3)2, LiCl, BHT, 15 C, (x) TBAF, THF, reflux.


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Reagents and conditions: (i) n-BuLi, cyclopentadiene, toluene, 78 C to rt; (ii) OsO4, NMO, THF, H2O, rt; (iii) NaIO4, THF, H2O, rt; (iv) NaBH4, THF, 0 C; (v) MsCl, Et3N, CH2Cl2, 0 C to rt; (vi) NaI, Zn powder, glyme, 90 C; (vii) TBAF, THF, rt; (viii) 172, Pd2(dba)3, AsPh3, MW, THF, 150 C. Scheme 47

against the root pathogen Rhizoctonia solani was observed (Scheme 49).81 The syntheses of indole phytoalexins, camalexin (176) and (S)-()-spirobrassinin (177), were reported. Camalexin (176) was synthesized starting with 3-iodoindole through the Matsuda borylation and Suzuki arylation with 2-bromothiazole 178 in a one-pot operation (Scheme 50).82 Stereoselective synthesis of (S)-()-spirobrassinin (177) was achieved by bromine-induced spirocyclization of derivative of brassinin (178) as a key step (Scheme 50).83 2.1.2 Carbazoles. Three new indolocarbazoles, fradcarbazoles A (179), B (180), and C (181), were isolated from a mutant strain of the marine-derived actinomycete Streptomyces fradiae 007M135. All compounds exhibited cytotoxicity and signicant inhibition of PKC-a (Fig. 5).84 Chemical investigation of the marine-derived actinomycetes strain Streptomyces sp. FMA resulted in the isolation of streptocarbazoles A (182) and B (183). Both compounds showed inhibition of the cell cycle and kinase and cytotoxicity against HeLa and P388 cell lines (Fig. 5).85 Two new indolo[3,2-a]carbazoles 184 and 185 were isolated from a deep-water collection of a sponge of the genus Asteropus. Compound 185 showed a minimum inhibitory concentration of 25 mg mL1 against Candida albicans and 50 mg mL1 against MRSA (Fig. 6).86 Four new nitrile-containing indole alkaloids deschloro 12-epi-scherindole W nitrile (186), 12-epi-scherindole W nitrile (187), 12-epi-scherindole I nitrile (188), and deschloro 12-epi-scherindole nitrile I (189) were isolated from the cultured cyanobacterium Fischerella sp. (SAG 46.79) (Fig. 6).87 The isolation of nine carbazole alkaloids, clausenawallines C (190), D (191), E (192), F (193), G (194), H (195), I (196), J (197), and K (198) were reported. Compounds 190–193 were obtained from the roots of Clausena wallichii. Compound 192 exhibited signicant antibacterial activity against MRSA and Staphylococcus aureus TISTR 1466 (Fig. 7).88 Compounds 194–198 were isolated from twigs of Clausena wallichii. The antibacterial activities of 194–198 against Gram-positive and Gram-negative bacteria were evaluated (Fig. 7).89


Scheme 48 Reagents and conditions: (i) TMSOTf, 2,6-(t-Bu)2pyridine, CH2Cl2, 78 C, then TBAF; (ii) (Boc)2O, DMAP, toluene; (iii) Pd2(dba)3, dppb, NDMBA, THF; (iv) ClCH2CHO, dichloroethane, 0 C; (v) t-BuONa, t-BuOH, THF, 0 C to rt; (vi) aq. HCl, MeOH, 65 C, then Pd/C, H2; (vii) IBX, DMSO, 50 C, then N-hydroxysuccinimide, 50 C, then aq. NaOH.

Ten new carbazole alkaloids, claulansines A (199), B (200), C (201), D (202), E (203), F (204), G (205), H (206), I (207), and J (208) were isolated from the stems of Clausena lansium. Compounds 199, 204, and 206–208 showed selective neuroprotective effects (Fig. 8).90 The asymmetric total synthesis of (+)-malbrancheamide B (209), isolated from a fungal strain Malbranchea aurantiaca RRC1813, was achieved through a diastereoselective domino sequence (tandem aldol condensation/alkene isomerization/ intramolecular aza Diels–Alder cycloaddition) as the key step. The diastereofacial selectivity of azadiene 210 in the cycloaddition step was effectively controlled by the chiral aminal auxiliary (Scheme 51).91 A new carbazole alkaloid, antipathine A (210), was isolated from the South China Sea black coral Antipathes dichotoma in 2009, and its structure was originally postulated to be 211. The rst total synthesis of 210 was achieved using Pd-catalyzed Buchwald–Hartwig coupling and Pd-mediated oxidative coupling to install the carbazole framework. Based on the synthesis, the originally proposed structure 211 was revised (Scheme 52).92 Murrayaquinone A (212) and murrayanine (213) were synthesized starting with o- or p-formylated 4-hydroxyl carbazoles. The key steps of synthesis of 212 involved a one-pot conversion of imine 214 via a cascade reduction/C–N bond cleavage sequence (route I), a one-pot replacement of OBn and Br groups in 215 by an OMe group (route II), and deprotection of the OBn group in 216 and further oxidation to quinone in a single operation (route III). Murrayanine (212) was derived from aldehyde 217 in three steps (Scheme 53).93

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Scheme 49 Reagents and conditions: (i) TFA, Tl(OAc)3, then I2, CuI, NaOMe, MeOH, DMF; (ii) Pd/C, H2, HCO2COCH3, HCOOH, MeOH; (iii) POCl3, Et3N, THF.

Fig. 5

Scheme 50 Reagents and conditions: (i) Pd(PPh3)4, HBPin, dioxane, Et3N, 80 C, then 196, PPh3, Na2CO3, H2O, 100 C; (ii) Br2, H2O, CH2Cl2, rt; (iii) PCC, MgSO4, CH2Cl2, rt; (iv) MeONa, MeOH, rt.

The two-step synthesis of murrayastine (218) was attained through the Pd-catalyzed Buchwald–Hartwig coupling followed by Pd-catalyzed oxidative coupling (Scheme 54).94 A compact route to murrayaquinone A (212) was developed starting with 219 through a one-pot tandem Buchwald–Hartwig/C–H arylation-ring-closing sequence (Scheme 54).95 Based on the Pd-catalyzed construction of carbazole core, the biomimetic total synthesis of pyrano[3,2-a]carbazole alkaloids, girinimbine (220), murrayacine (221), mahanimbine (222), murrayacinine (223), cyclomahanimbine (224), mahanimbidine (225), bicyclomahanimbidine (226), murrayazolinine (227), exozoline (228), and isocyclomahanimbine (229), was completed using carbazole 230 as a crucial intermediate (Scheme 55).96 The synthesis of (R)-()- and (S)-(+)-carquinostatin A (231) was reported. Diacetates (R)-()-233 and (S)-(+)-233, obtained by transesterication of racemic diol 232 with lipase-QLM followed by acetylation, were converted to (R)-()-231 (natural) and (S)-(+)-231, respectively (Scheme 56).97 Furoclausine-A (234) was synthesized based on a one-pot construction of a carbazole framework through the reaction of

Nat. Prod. Rep.

substituted anilines 236 with cyclohexadienyliumiron complexes 235 as the key step (Scheme 57).98 Carbazole 242, obtained from the reaction of 235 with aniline 241, served as the key intermediate in the synthesis of clausines H (237), K (238), and O (239), and 7-methoxy-Omethylmukonal (240) (Scheme 58).99

Fig. 6


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Reagents and conditions: (i) NaOMe, MeOH, 65 C; (ii) TsOH, CH2Cl2, 0 C; (iii) NaHCO3, toluene, reflux; (iv) DIBAL, 0 C; (v) SO3/pyridine, DMSO, i-Pr2NEt; (vi) i-Pr2NEt, PO(OMe)2CH2COOMe, LiCl, MeCN; (vii) NaBH4, LiI, THF, rt; (viii) toluenesulfonylhydrazide, EtOH; (ix) MsCl, pyridine; (x) toluene, 120 C; (xi) KI, Et3N, toluene, 120 C. Scheme 51

Fig. 7

The iron-mediated formation of carbazole was efficiently employed in the total synthesis of rac-lavanduquinocin (243) (Scheme 59).100 A facile method for the construction of a carbazole framework was developed based on the Pd-mediated Buchwald– Hartwig coupling of aniline with bromobenzene followed by

Fig. 8


Scheme 52 Reagents and conditions: (i) aniline, Pd(OAc)2, SPhos, Cs2CO3, toluene, 100 C; (ii) Pd(OAc)2, PivOH, 100 C.

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Scheme 54 Reagents and conditions: (i) Pd(OAc)2, XPhos, Cs2CO3, toluene, 111 C; (ii) Pd(OAc)2, K2CO3, PivOH, air, 120 C; (iii) 2-chloroaniline, Pd(OAc)2, (t-Bu3P)BF4, t-BuONa, toluene, 160 C, MW; (iv) BBr3, CH2Cl2, 78 C.

Scheme 53 Reagents and conditions: (i) NaBH3CN, MeOH, rt; (ii) PhI(OAc)2, MeOH, AcOH; (iii) MeONa, MeOH, CuI, DMF, 120 C; (iv) 1,3-propanediol, PTSA, toluene, reflux; (v) n-BuLi, MeI, 40 C; (vi) boric acid, H2O2, H2SO4, MeOH, reflux; (vii) Pd(OH)2, H2, MeOH; (viii) Tf2O, Et3N, CH2Cl2; (ix) Pd(PPh3)4, Bu3SnH, DMF, 80 C; (x) NaOMe, CuI, DMF, 120 C.

Pd-promoted intramolecular oxidative cyclization. The synthesis of 1,6-dioxygenated carbazole alkaloids, clausenine (244), 6-methoxymurrayanine (245), and clausine Z (246), clausenol (247), clausine G (248), and clausine I (249), was attained using carbazole 250 as a key intermediate (Scheme 60).101 The rst total synthesis of ekeberginine (251) was achieved using the Pd-mediated sequences (Scheme 61).102 An efficient synthesis of isomukonidine (252), clausines L (253) and V (254), mukonidine (255), glycosinine (256), and mukonal (257) was reported, using the gold-catalyzed cyclization of indolyl-2,3-allenol 258 to carbazole 259 as a key step (Scheme 62).103 The synthesis of 1-oxygenated carbazole alkaloids, clausine E (260) and mukonine (261), were achieved by anionic [4 + 2] annulation of lithiated furoindolones 262 with dimethyl maleate leading to carbazole 263 (Scheme 63).104 Carbazomycin G (264), featuring a unique quinol moiety, was isolated from Streptoverticillium ehimense H 1051-MY 10. Compound 264 is a racemate in nature. The synthesis of 264 was achieved from ketone 265 in 5 steps involving the solidphase CAN-SiO2-mediated oxidation of 265 and the HBF4-catalyzed Thiele acetylation of quinone 266 (Scheme 64).105

Nat. Prod. Rep.

The total syntheses of carbazomadurin A (267) and (S)(+)-carbazomadurin B (268), isolated from the microorganism Actinomadura madurae 2808-SV1, were completed. The key step was an allene-mediated 6p-electrocyclic reaction of 269 for the construction of the carbazole framework. The introduction of the alkenyl group at the C1 position was effected by the Suzuki coupling reaction in 270 (Scheme 65).106 The total syntheses of rac-noruleine (273) and rac-uleine (274) were accomplished through the DDQ-mediated dehydrogenative cyclization of 275, leading to the key intermediate of azocino[4,3-b]indole 276 (Scheme 66).107 The total synthesis of diterpenoid indole alkaloids anominine (277) and tubingensin A (278) was accomplished using 279 as a practical and a common intermediate for 277 and 278. Compound 279 was transformed to 277 in 9 steps, and 278 was obtained from 279 through Cu-mediated 6p-electrocyclization (Scheme 67).108 A new monoterpenoid alkaloid alstilobanine A (280), isolated from the leaves of the Malayan plant Alstonia angustiloba, was synthesized. The key b-lactone intermediate 283 was derived from indole 2-acetic acid ester 281 through an the intermolecular addition of the enolate of 281 to nitrosoalkene 282 and an intramolecular Romo cyclization (a formal ketene/ketone [2 + 2] intramolecular cycloaddition) reaction. The b-lactone 283 was transformed into rac-280 in 7 steps (Scheme 68).109 The total synthesis of calothrixins A (284) and B (285), isolated from lyophilized extracts of Calothrix cyanobacteria, was reported by four groups. The full details of the synthesis of 284 and 285 based on the Pd-catalyzed cross-coupling of indolylborate 286 and Cu-catalyzed 6p-electrocyclization as the key features were reported by Ishikura's group (Scheme 69).110 Kusurkar's synthesis of 285 involved Pd-catalyzed intramolecular CH/CI coupling in 288 for the construction of the indolophenanthridine moiety, and unexpected one-pot


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Scheme 56 Reagents and conditions: (i) BBr3; (ii) NaBH4; (iii) vinylacetate, Lipase QLM, i-Pr2O, 32 C; (iv) Ac2O, pyridine; (v) NBS, MeCN, 0 C; (vi) allyl pinacolborate, CsF, PdCl2(dppf), THF, 75 C; (vii) 2-methyl-2-butene, Grubbs' 2nd generation catalyst, CH2Cl2; (viii) LiAlH4, THF, 0 C; (ix) (PhSeO)2O, THF, 50 C.

2.2

Scheme 55 Reagents and conditions: (i) Ti(O-i-Pr)4, toluene, 78 C to rt; (ii) DDQ, MeOH, THF, H2O, rt; (iii) sunlight irradiation, toluene, 35 C; (iv) CSA (1.0 equiv.), toluene, rt; (v) CSA (0.2 equiv.), CDCl3, rt; (vi) 10% Pd/C, H2, MeOH, CH2Cl2; (vii) Oxone, NaHCO3, acetone, AcOEt, H2O, rt; (viii) CSA (1.0 equiv.), toluene, 100 C.

reduction of the CHO group and substitution of the OBn group by the OMe group in 287 (Scheme 70).111 Nagarajan's group achieved the syntheses of 284 and 285 using Pd-catalyzed intramolecular CH/CH coupling to construct 289, which was transformed to 284 and 285 (Scheme 71).112 A one-pot synthesis of 284 from enamine 290 was developed by Mohanakrishnan's group, which involved a FeCl3-mediated domino reaction. Treating 290 with FeCl3 in boiling DMF provided 285 through electrocyclization/oxidation/reduction of the nitro group/cyclization cascade (Scheme 72).113 The cycloaddition reaction of furoindole 279 with 3,4-pyridyne, generated from 3-bromopyridine in situ, produced pyridocarbazole 280, which was then converted to ellipticine (278) (Scheme 73).114


Tryptamines

A new carbamate- and cyano-containing alkaloid, aspeverin (294), was obtained from the culture of an algicolous Aspergillus versicolor dl-29 isolated from the marine green alga Codium fragile. Assay of 294 for growth inhibition against marine zooplankton and phytoplankton as well as four bacteria showed potent activities (Fig. 9).115 Two new alkaloids, calophyline A (295) and N-methylaspidodasycarpine (296), were isolated from the trunk bark of Winchia calophylla, growing in Yunnan Province and Hainan island, China. The compounds were evaluated for cytotoxicity against a small

Scheme 57 Reagents and conditions: (i) MeCN, rt; (ii) I2, pyridine, air, 90 C; (iii) amberlyst 15, chlorobenzene, 120 C; (iv) DDQ, MeOH, H2O, rt; (v) BBr3, CH2Cl2, 78 C.

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Scheme 58 Reagents and conditions: (i) MeCN, rt; (ii) I2, pyridine, 90 C; (iii) DDQ, MeOH, H2O, rt; (iv) BBr3, CH2Cl2, 30 C; (v) KCN, MnO2, MeOH, rt; (vi) KOH, EtOH, H2O, reflux.

Scheme 60 Reagents and conditions: (i) Pd(OAc)2, SPhos, Cs2CO3, toluene, reflux; (ii) Pd(OAc)2, AcOH, 115 C; (iii) LiAlH4, THF, 67 C; (iv) DIBAH, Et2O, 78 C; (v) MnO2, CH2Cl2, rt; (vi) BBr3, CH2Cl2, 78 C; (vii) Pd/C, H2, CH2Cl2, MeOH; (viii) LiAlH4, THF, 67 C; (ix) Pd/C, H2, CH2Cl2, MeOH; (x) DIBAH, Et2O, 78 C; (xi) MnO2, CH2Cl2, rt; (xii) AlCl3, dioxane, 101 C; (xiii) BBr3, CH2Cl2, 78 C.

Scheme 59 Reagents and conditions: (i) MeCN, air, rt; (ii) (1) Me3NO, acetone, 56 C, (2) 10% Pd/C, o-xylene, 145 C; (iii) NBS, CCl4, 77 C; (iv) dimeric p-allylnickel bromide, DMF, 70 C; (v) LiAlH4, Et2O, rt; (vi) CAN, MeCN, H2O, 0 C.

panel of human cancer cell lines (Fig. 9).116 Investigation of the chemical constituents of the seeds of Strychnos nux-vomica resulted in the isolation of two new indole alkaloids, strynuxlines A (297) and B (298), featuring an unprecedented 6/5/ 9/6/7/6 hexacyclic ring system. Both compounds were assayed for their cytotoxicity against ve human cancer cell lines (Fig. 9).117 A new indole alkaloid of the serotobenine family, calanthumindole (299), was isolated from Campylospermum calanthum (Ochnaceae), which is a small tree with yellow owers growing in the southern part of Cameroon. This compound is characterized by the presence of a fully unsaturated furan ring

Nat. Prod. Rep.

(Fig. 10).118 Chemical investigation of biologically active compounds led to the isolation of fumiquinazoline L (300) from the AcOEt extract of a gorgonian-derived Scopulariopsis sp. fungus. The structure and the absolute conguration were established by spectroscopic data and X-ray diffraction analysis (Fig. 10).119 Three new hydroxylated derivatives of

Scheme 61 Reagents and conditions: (i) bromobenzene, Pd(OAc)2, SPhos, Cs2CO3, toluene, reflux; (ii) Pd(OAc)2, K2CO3, PivOH, 115 C; (iii) LiAlH4, Et2O, CH2Cl2, rt; (iv) NBS, MeCN, rt; (v) DDQ, MeOH, H2O, THF, rt; (vi) bis[m-bromo(h3-prenyl)nickel], DMF, 55 C.


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Scheme 62 Reagents and conditions: (i) AuCl, toluene, rt; (ii) NBS, CCl4, rt; (iii) t-BuOK, DMSO, THF, O2, rt; (iv) KH, THF, rt, then n-BuLi, DMF, 30 C; (v) BBr3, CH2Cl2, 78 C; (vi) KH, THF, rt, then n-BuLi, CO2, 78 C; (vii) MeI, NaHCO3, DMF; (viii) BBr3, CH2Cl2, 78 C.


Scheme 65 Reagents and conditions: (i) TBAF, THF, 80 C; (ii) DDQ, CH2Cl2, rt; (iii) HCl, ethylene glycol, THF, 50 C; (iv) PhTf2, NaH, THF, 0 C; (v) BBr3, CH2Cl2, 78 C; (vi) SEMCl, i-Pr2NEt, CH2Cl2, 0 C; (vii) 258 or 259, Pd(PPh3)4, Na2CO3, DMF, 70 C; (viii) TBAF, HMPA, 100 C; (ix) NaBH4, MeOH, rt.

growth inhibitory or cytotoxic activity in antibacterial or antifungal assays (Fig. 10).120 Eight new alkaloids, 10-demethoxy-12-hydroxy-17,19-epoxygeissovelline (304), (Z)-10-demethoxy-12-hydroxygeissovelline (305), (E)-10-demethoxy-12-hydroxygeissovelline (306), geissospermidine (307), 10-methoxygeissospermidine (308), N-deScheme 63 Reagents and conditions: (i) t-BuOLi, TMEDA, THF, 60 C; (ii) KOH, H2O, MeOH, reflux; (iii) MeI, DBU; (iv) MeI, K2CO3, acetone.

pimprinine (5,30 -indolyl-2-methyloxazole), pimprinols A (301), B (302), and C (303), were isolated from rare actinomycetes, Streptomyces sp. Lv3-13, isolated from the rhizosphere soil of the plant Mespillus germanica. All compounds did not show

Reagents and conditions: (i) CAN, SiO2, MeCN, rt; (ii) Ac2O, HBF4, 70 C; (iii) CH2N2, CH2Cl2; (iv) MeLi, THF, 78 C to rt. Scheme 64


Scheme 66 Reagents and conditions: (i) DDQ, THF, DMSO, 50 C; (ii) MeLi, THF, 0 C; (iii) TFA, CH2Cl2, rt; (iv) NaAlH2(OC2H4OCH3)2, THF, 50 C; (v) MeI, K2CO3, acetone, MeOH.

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Scheme 69 Reagents and conditions: (i) n-BuLi, THF, 20 C, then BEt3; (ii) Pd2(dba)3CHCl3, P(o-Tol)3, THF, 60 C; (iii) TsOH, MeOH, CH2Cl2, rt; (iv) (CuOTf)2toluene, PCC, CH2Cl2, MeCN, 50 C; (v) Cu(OAc)2, PCC, CH2Cl2, reflux; (vi) Pd/C, H2, THF; (vii) OXONE, K2CO3, acetone, H2O.

Scheme 67 Reagents and conditions: (i) THF, 78 C; (ii) KHMDS, CS2, THF, 78 C, then MeI; (iii) n-Bu3SnH, AIBN, toluene, 110 C; (iv) TBAF, toluene, 110 C; (v) HClO4, THF, rt; (vi) MsCl, Et3N, CH2Cl2, 78 C to rt; (vii) (CuOTf)2toluene, MeCN, rt.

acetyl-N-butanoylgeissospermidine (309), 11-methoxygeissospermidine (310), and geissosreticulatine (311), were obtained from the leaves and bark of Geissospermum reticulatum

Scheme 68 Reagents and conditions: (i) LHMDS, THF, 78 C; (ii) 4-pyrrolidinopyridine, 2-bromo-N-propylpyridinium triflate, i-Pr2NEt, CH2Cl2, AcOH, rt.

Nat. Prod. Rep.

Scheme 70 Reagents and conditions: (i) NaOMe, CuI, DMF, 120 C; (ii) 2-iodoaniline, TsOH, THF, reflux; (iii) AcCl, Et3N, CH2Cl2, rt; (iv) Pd(OAc)2, PPh3, K2CO3; (v) CAN, MeCN, H2O, 0 C; (vi) Pd(OH)2, H2, MeOH.

Scheme 71 Reagents and conditions: (i) (COCl)2, AlCl3, CH2Cl2, 0 C, then aniline, K2CO3, THF; (ii) Pd(TFA)2, PhCOOH, O2, 120 C; (iii) Tf2O, pyridine, CH2Cl2, 40 C to rt, then Et3SiH, rt; (iv) TMSI, pyridine, sulforane, 70 C, then MeOH; (v) FeCl3, 2,6-dicarboxypyridine 1-oxide, TBHP, t-amyl alcohol, rt; (vi) PhCN, TBHP, NaOH, acetone, rt.


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Scheme 72


Reagents and conditions: (i) FeCl3 (3 equiv.), DMF, reflux.

Fig. 9

Scheme 73 Reagents and conditions: (i) 3-bromopyridine, LHMDS, THF, 15 C to reflux; (ii) t-BuONa, dioxane, sealed tube, 80 C.

A. Gentry (Apocyanaceae), a tree found throughout the Amazon rainforest of South America. Compounds 304–310 were aspidosperma-type alkaloids and 311 was an akuammiline-type alkaloid. The antiparasitic activities of the compounds were tested against Trypanozoma cruzi and Leishmania infantum (Fig. 11).121 The absolute conguration of 304 was established by vibrational circular dichroism (VCD) to be (+)-(2R,7R,15R,17S,19S) (Fig. 11).122 Two new alkaloids, melodinoxanine (312) and N-methylnortetraphyllicine (313), were isolated from the MeOH extract of the stems and leaves of Melodinus henryi growing in Yunnan, China. Compound 312 has an extra oxygen atom in the C-ring of a heteroyohimbine system (Fig. 12).123 A new cyano-substituted oxindole alkaloid, ervahainine A (314), was isolated from the EtOH extract of the powdered twigs and leaves of Ervatamia hainanensis (Fig. 12).124 A pair of enantiomers of indole alkaloid ()-315 and (+)-315, featuring dihydropyran and 1,2,4-thiadiazole rings, was isolated from an aqueous extract of the root of Isatis indigotica, a biennial herbaceous plant widely distributed in China (Fig. 12).125 Seven new secondary metabolites, nakijinamines A (316), B (317), F (318), G (319), H (320), and I (321), and 6-bromoconicamin (322), were isolated from an Okinawan marine sponge Suberites sp. (SS-1084). Compounds 316–318 showed antimicrobial activity and none of the compounds showed cytotoxicity (Fig. 13).126


Fig. 10

Seven new indole alkaloids, sartorymensin (323), tryptoquivaline O (324), 325, epi-scalin C (326), epi-scalin A (327), neoscalin A (328), and epi-neoscalin A (329), were isolated from the culture of the fungus Neosartorya siamensis (KUFC 6349). The absolute conguration of the previously reported tryptoquivalines L (330), H (331), and F (332) was revised. Compound 323 displayed a moderate in vitro growth inhibitory activity on the ve cell lines (Fig. 14).127 Anew tribrominated alkaloid, kororamide A (333), was obtained from the bryozoan Amathia tortuosa collected in northern New South Wales, Australia. This compound exists in a solution as a mixture of interconverting isomers, cis–trans isomers about the tertiary amide bond. This compound showed marginal growth inhibitory activity against the chloroquinonesensitive strain of Plasmodium falciparum (Fig. 15).128 Chemical investigation of the rhizome material of plant Alocasta macrorrhiza collected from the district of Guangzhou, China led to the isolation of ve new alkaloids, alocasins A (334), B (335), C (336),

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Fig. 11

Fig. 13

D (337), and E (338). All compounds were tested for cytostatic and antiproliferative activity (Fig. 15).129 Bioassay-guided fractionation of the CH2Cl2/MeOH extract from Plasmodium lita led to the isolation of four new thiazinederived alkaloids, thiaplakortones A (339), B (340), C (341), and D (342). Both compounds were tested against chloroquinesensitive and chloroquine-resistant Plasmodium falciparum lines. Compound 339 showed the most promising biological prole (Fig. 16).130 Seven new alkaloids containing 1-aminocyclopropane-1carboxylic acid moiety, tryptoquivaline K (330), and fumiquinazolines K (344), L (345), M (346), N (347), O (348), and P (349), were isolated from the fungus Aspergillus sp. obtained from the Mediterranean sponge Tethya aurantium. All

Fig. 12

Nat. Prod. Rep.

compounds were evaluated for their cytotoxicity against the murine lymphoma cell line L5178Y using the MTT method (Fig. 17).131 Seven new indole alkaloids, melodinines M (350), N (351), O (352), P (353), Q (354), R (355), and S (356), were isolated from Melodinus suaveolens. Melodinine M (350) is the rst Aspidosperma-type alkaloid with a dienone ring, and melodinines N (351) and O (352) are Aspidosperma-type alkaloids bearing a methyl group at C-10 (Fig. 18).132 Two new alkaloids containing the plumeran moiety, N1-benzoyl-12-demethoxycylindrocarine (357) and N1-cinnamoyl-12-demethoxycylindrocarine (358) were isolated from the MeOH extract of the stem bark of Aspidosperma cylindrocarpon. N1-cinnamoyl-12-demethoxycylindrocarine showed weak antimalarial activity against chloroquine-resistant strains of Plasmodium falciparum (Fig. 18).133 Six new indole-benzodiazepinediones, asperdiazepinones A (359), B (360), C (361), D (362), E (363), and F (364), and asperdiazepinone G (365), an enantiomer of the known (2R,3S,11R)aszonalenin, were isolated from the mycelial extract of the soil fungus Aspergillus sp. PSU-RSPG185. Asperdiazepinone B (360) showed weak antimalarial and noncytotoxic activities (Fig. 19).134 The biomimetic total synthesis of (+)-gelsemine (366) was achieved using an intramolecular enol–oxonium cyclization as a key step to assemble the small cage structure. The precursor 367 for one-pot enol–oxonium cyclization was obtained as an inseparable mixture of two diastereomers through condensation of oxyindole with piperidinoaldehyde, followed by an intramolecular Michael addition. Treating 367 with TsOH in


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Fig. 15

Fig. 16

Fig. 14

boiling CHCl3 afforded 368 through the spontaneous formation of E and F rings, and C3- and C7-stereocenters (Scheme 74).135 The total synthesis of rac-gelsemoxonine (369), a Gelsemium alkaloid including an azetidine ring embedded within a compact polycyclic scaffold, was reported. The synthesis was started from the construction of the azetidine ring through the ring contraction of spirocyclopropane isoxazolidine 370 to form b-lactam intermediate 371, which was further transformed to the azetidine intermediate 372. The late-stage construction of the oxindole 373 was achieved using a diastereoselective Heck cyclization (Scheme 75).136 Total syntheses of rac-marcfortine B (374) and ()-marcfortine C (375) were achieved by the Pd-catalyzed [3 + 2]


trimethylenemethane (TMM) cycloaddition between a TMM donor and oxindole, to construct the key spiriooxindole intermediate. Oxindole 378 was assembled by a diastereoselective TMM cycloaddition between 376 and 377, whereas cycloaddition between cyano-substituted TMM 379 and 380 produced oxindole 368 with high regioselectivity and enantioselectivity. Oxindoles 378 and 381 were transformed to rac374 and ()-375, respectively, through an intramolecular Michael addition and an oxidative radical cyclization involving the formation of a bicyclo[2.2.2]diazaoctane moiety (Scheme 76).137 Total syntheses of four spirocyclic oxindole alkaloids, corynoxine (383), corynoxine B (384), corynoxeine (385), and rynchophylline (386), were accomplished, which featured the assembly of tetracyclic spirooxindole intermediate 388 by the Tsuji–Trost allylic alkylation of a-keto ester 387 (Scheme 77).138

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Fig. 18

Fig. 17

Formal syntheses of ent-rynchophylline (ent-386) and entisorynchophylline (389) were reported. The enantioselective spirocyclization of oxazolopiperidone 390 produced tetracyclic intermediate 391, which was converted to the known intermediate 392 (Scheme 78).139 A marine alkaloid ammosamide B (393) was synthesized using a tandem Friedel–Cras reaction sequence to construct tricyclic pyrroloquinoline 394, which was converted to 393 through the introduction of a carbamoyl group at the C4 position and chlorination at the C7 position (Scheme 79).140 The biomimetic total synthesis of clavicipitic acid (395) was achieved, which involved the formation of tricyclic intermediate 396 through direct olenation to the C4 position of tryptophan via C–H activation, followed by Ag-promoted intramolecular allyl amination (Scheme 80).141 The total synthesis of fargesine (397), isolated from the root and stem of Evodia fargesii, was achieved by employing the Larock indole synthesis protocol as the key feature. Tricyclic intermediate 398 was assembled through the intramolecular Larock indole synthesis (Scheme 81).142 Synthetic efforts toward the synthesis of ()-indolactam V (399) were reported. Palladium-catalyzed intramolecular N-arylation reaction of (R)-401 provided a nine-membered ring

Nat. Prod. Rep.

Fig. 19


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Review


Scheme 75 Reagents and conditions: (i) TFA, MeCN, 80 C; (ii) proline, DMSO, rt; (iii) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O, then TMSCH2N2, CH2Cl2, MeOH, rt; (iv) TFAA, DBU, THF, rt; (v) Me3SnOH, 1,2-dichloroethane, 80 C; (vi) (COCl)2, DMF, CH2Cl2, rt, then N-(2-bromophenyl)hydroxylamine, NaHCO3, Et2O, CH2Cl2, 0 C; (vii) PdCl2(MeCN)2, 1,2,2,6,6-pentymethylpiperidine, HCO2H, DMF, 60 C; (viii) NaH, MeI, DMF, 0 C.

Scheme 74 Reagents and conditions: (i) LDA, THF, 78 C; (ii) SOCl2, pyridine, 0 C; (iii) LDA, THF, 78 C; (iv) LDA, PhSeCl, THF, 78 C, then NaIO4, NaHCO3, MeOH, THF, H2O; (v) Lindlar cat., H2, MeOH; (vi) TsOH, CHCl3, reflux; (vii) Pd/C, H2, MeOH; (viii) DIBAH, toluene, 78 C; (ix) Tebbe reagent, pyridine, THF, reflux.

product 402, whereas the same cyclization of (S)-401 resulted in the formation of proto-debrominated product 403 without the cyclization. Because of this unexpected stereospecicity of the cyclization reaction, only the synthesis of ()-epi-indolactam V (400) was accomplished (Scheme 82).143 The total synthesis of rugulovasine A (404) was accomplished using Uhle's ketone derivative 405 as the key intermediate derived from the intramolecular cyclization of 4-iodo-tryptophan. Spirocyclic butyrolactone 407 was assembled by the Reformatsky reaction of 405 followed by Ru-catalyzed double bond isomerization or formation of allenyl alcohol 406 by the Nozaki–Hiyama–Kishi reaction of 405, followed by Ru-catalyzed cyclocarbonylation (Scheme 83).144 The total synthesis of rac-alstonerine (408), a macroline alkaloid, was accomplished using the regioselective, stereospecic ring-opening of hydroxymethyl-substituted aziridine 409 with a sulfone-stabilized anion, to give lactone 410. racAlstonerine was synthesized from 410 through Me3Al-mediated transacylation/elimination, intramolecular Michael reaction,


and one-pot reduction/dehydration/Pictet–Spengler cyclization (Scheme 84).145 A convergent strategy for the enantioselective syntheses of ()-mersicarpine (412), ()-scholarisine G (413), (+)-melodinine (414), and ()-leuconoxine (415) was developed. Enantiomerically enriched cyclohexenone 417, obtainable from b-ketoester 416 through Pd-catalyzed asymmetric decarboxylative allylation and Suzuki-coupling, was diversied into alkaloids through controlled oxidation, reduction, and polycyclization sequences (Scheme 85).146 A hexacyclic iboga-type alkaloid, ()-voacangalactone (418), was isolated from the root bark of Voacanga africana, which is used as a traditional medicine in Africa. Its structure, including the absolute conguration, was established by spectroscopic analyses and asymmetric synthesis. Chiral aminocyclohexene 419, derived from the diastereoselective Diels–Alder addition of a chiral diene with an alkene, was used as a chiral building block. Further transformation of 419 via the construction of the isoquinuclidine ring and indole ring led to ()-418 (Scheme 86).147 Syntheses of ibogamine (420) and epiibogamine (421) were reported. The reductive Heck-type annulation was employed to construct the iboga scaffold in the nal step (Scheme 87).148,149 rac-Cleavamine (422) and rac-dihydrocleavamine (423) were synthesized involving the construction of the 1-azabicyclo[6.3.1] dodecane core by combining RCM with an intramolecular Heck cyclization. The RCM reaction of 424 using Grubbs' second generation catalyst produced azoninoindole 425, and the

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Scheme 77 Reagents and conditions: (i) Et3N, MeCN, rt; (ii) Pd(dppe), Cs2CO3, i-Pr 2NEt, THF; (iii) K2CO3, MeOH; (iv) Ph3P] CHOMe, THF, 78 C to rt; (v) TFA, TFAA, CH2Cl2; (vi) Pd/C, H2, AcOEt. Scheme 76 Reagents and conditions: (i) Pd(OAc)2, P(O-i-Pr)3, toluene, reflux; (ii) Me2SO4, K2CO3, acetone, reflux; (iii) KHMDS, THF, 0 C to rt; (iv) PMBCl, Bu4NI, K2CO3, acetone; (v) DIBAL, CH2Cl2, 0 C; (vi) KHMDS, CS2, THF, 78 C to rt; (vii) AIBN, n-Bu3SnH, benzene, reflux; (viii) Pd(dba)2, 382, toluene, 4 C; (ix) LiOt-Bu, n-BuLi, THF, 78 C, then Davis oxazoridine.

subsequent Heck cyclization led to advanced intermediate 426 for 422 and 423 (Scheme 88).150 The enantiopure synthesis of both enantiomes of norbalasubramide (428), containing an eight-membered ring, was reported. The key step was the one-pot generation of glycidic amide 430 from allylamine 429. The oxidation of 429 with NaCl2O produced an inseparable mixture of two diastereomers, 430a and 430b, through a tandem allylic oxidation/double bond epoxidation sequence. The synthesis of ()-428 (natural) and (+)-ent-428 (unnatural) was completed through the Cu-catalyzed

Nat. Prod. Rep.

intramolecular cyclization of 430 followed by deprotection (Scheme 89).151 The total synthesis of rac-lysergic acid (431) was accomplished. Tetracyclic framework 435 was assembled from diene 434, derived from allyl amine 433 with the requisite stereogenic center at the allylic position, and hemiaminal 432, through a ring-closing metathesis (D ring formation) followed by an intramolecular Heck reaction (C ring formation) (Scheme 90).152 Two different strategies were developed for the construction of a common tetracyclic intermediate 437 for the enantioselective synthesis of (+)-431. Strategy I featured the construction of 437 from diene 436 through ring-closing metathesis (D ring formation), followed by an intramolecular Heck reaction (C ring formation). In strategy II, 437 was assembled through Pd-catalyzed indole synthesis (B ring formation) with aldehyde 438 and


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Scheme 78 Reagents and conditions: (i) Et3SiH, TiCl4, CH2Cl2, reflux; (ii) DDQ, CH2Cl2, H2O, rt; (iii) IBX, DMSO, rt; (iv) NaClO2, NaH2PO4, MeCN, t-BuOH, H2O, 1-methyl-1-cyclohexene, rt, then Me3SiCl, MeOH, rt; (v) Na/Hg, NaH2PO4, MeOH; (vi) PhIO, CH2Cl2, rt; (vii) AlH3, THF, 78 C to 50 C, then MeOH, rt, then NaBH3CN, AcOH, rt.


Scheme 80 Reagents and conditions: (i) 2-methyl-3-buten-2-ol, Pd(OAc)2, AgOAc toluene, 100 C; (ii) AgOAc, toluene, 100 C; (iii) t-BuOK, DMSO, rt; (iv) Mg, MeOH; (v) KOH, MeOH, H2O, rt.

Scheme 81 Reagents and conditions: (i) Pd(OAc)2, PPh3, K2CO3, LiCl, DMF, 100 C; (ii) TFA, CH2Cl2, 0 C; (iii) HCHO, NaBH4, MeOH, rt; (iv) m-CPBA, CH2Cl2, 0 C; (v) NaOH, MeOH, rt.

Reagents and conditions: (i) BF3OEt2, toluene, 0 C; (ii) CAN, MeCN, rt; (iii) MeI, NaH, DMF, 0 C; (iv) Pd(OH)2, H2, THF, MeOH; (v) TFAA, THF, 0 C; (vi) m-CPBA, CHCl3, rt; (vii) POCl3, 100 C; (viii) PdCl2, CO, Et3N, MeOH, 100 C; (ix) TFAA, pyridine, 0 C; (x) NCS, pyridine, DMF, 80 C; (xi) NH3, MeOH, reflux. Scheme 79

2-iodoaniline 439, followed by an intramolecular Heck reaction (C ring formation) (Scheme 91).153 Trigonoliimines A (440), B (441), and C (442) were isolated from the leaves of trigonostemon lii, and 440 exhibits modest anti-HIV-1 activity. The unique structures of these, with an unprecedented polycyclic core, inspired several approaches. A short synthesis of 440 was accomplished using the TMSOFcatalyzed three-component Strecker-type reaction to construct the tetracyclic precursor 443 and the Houben–Hoesh


cyclization to close the unusual seven-membered ring 444 (Scheme 92).154 The highly enantioselective Michael addition of a-aryl-aisocyanoacetate to vinyl selenone catalysed by chichona alkaloid 446 was developed. An asymmetric total synthesis of (+)-440 was accomplished using the Michael adduct 445 as the chiral building block (Scheme 93).155 Trigonoliimine B (441) was synthesized starting with a,adisubstituted a-amino ester 447 as a pivotal intermediate, enabling the construction of the central tricyclic ring system (C, D, and E rings) in a straightforward manner (Scheme 94).156 A concise synthesis of rac-torigonoliimine C (442) was achieved. The key step was the Au-catalyzed addition of tryptophan to isatogen 449 derived by Pd-catalyzed cycloisomerization of

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Reagents and conditions: (i) n-BuLi, THF, 78 C to rt, then aq. HCl; (ii) Me3Al, toluene, reflux; (iii) 398, MW, toluene, 150 C; (iv) DBU, THF, rt; (v) KHDMS, THF, 78 C, then PhN(Tf)2, 78 C to rt; (vi) DIBAH, CH2Cl2, 78 C; (vii) sodium naphtharenide, THF, 78 C; (viii) MeI, i-Pr2NEt, THF, 78 C to rt. Scheme 84

The rst asymmetric synthesis of ()-melotenine A (451) was realized using enantioenriched amine 452, obtained by the stereoselective addition of allyl indium to N-sulnylimine. The

Scheme 82 Reagents and conditions: (i) XPhos precatalyst, t-BuONa, dioxane, 100 C; (ii) HCHO, NaBH3CN, AcOH, MeCN, 0 C; (iii) 3 M HCl, dioxane, H2O, 110 C.

alkyne 448, leading to 450. The synthesis was completed through a sequence of three reactions including removal of the NPhth groups with the concomitant reduction of the N–OH group, intramolecular imine formation, and N-formylation (Scheme 95).157

Reagents and conditions: (i) t-BuLi, THF, 78 C; (ii) propargyl bromide, CrCl3, LiAlH4, THF, HMPA, rt; (iii) (a-bromomethyl)acrylate, Zn, I2, THF, 50 C; (iv) Ru3(CO)12, 2,4,6-collidine, CO, 100 C; (v) Ru3(CO)12, Et3N, dioxane, 100 C; (vi) Cs2CO3, MeOH, THF; (vii) TMSOTf, 2,6-lutidine, CH2Cl2, 0 C. Scheme 83

Nat. Prod. Rep.

Scheme 85 Reagents and conditions: (i) O3, NaHCO3, CH2Cl2, MeOH, 78 C, then Ac2O, Et3N, 0 C to rt; (ii) Pd/C, H2, EtOH; (iii) KOH, EtOH; (iv) O2; (v) Me2S; (vi) Pd/C, H2, Ac2O, EtOH; (vii) O2; (viii) TFA, CH2Cl2, rt; (ix) t-BuOK, THF, 50 C, then AcOH, 78 C; (x) t-BuOK, THF, 50 C, then AcOH, 78 C; (xi) MsCl, Et3N, ClCH2CH2Cl, 75 C; (xii) DBU, 75 C; (xiii) Pd/C, H2, MeOH.


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Scheme 88 Reagents and conditions: (i) Grubbs' second generation catalyst, CH2Cl2, reflux; (ii) HCl, MeOH; (iii) 427; (iv) Mg, MeOH; (v) Pd2(dba)3, xantphos, K2CO3, toluene, Et3N, 80 C; (vi) PtO2, H2, AcOEt.

Scheme 86 Reagents and conditions: (i) CH2Cl2, rt; (ii) Cs2CO3, DMF, 100 C; (iii) KOH, EtOH, H2O, reflux; (iv) I2, sat. NaHCO3, rt; (v) 2-iodo4-methoxyaniline, Pd(PPh3)4, CuSO4, sodium ascorbate, Et3N, DMF, 80 C; (vi) NaAuCl4, EtOH, rt; (vii) (COCl)2, THF, then MeOH; (viii) TMSCl, NaI, MeCN, rt; (ix) BH3, THF, 0 C.

Scheme 87 Reagents and conditions: (i) K2CO3, MeCN, 70 (ii) Pd(OAc)2, PPh3, HCO2Na, DMF, MeCN.

C;

C and the E rings were assembled by the Mitsunobu reaction of alcohol 453 and subsequent heating with DBU, leading to 454. Closing the D ring (tetrahydroazepine ring) was realized by the addition of vinyl lithium to ketone (the Piers annulation) to give 455 (Scheme 96).158 The rst catalytic asymmetric synthesis of (+)-perophoramidine (456) was reported. The key feature was the catalytic asymmetric construction of two vicinal carbon quarternary centers with high enantioselectivity and diastereoselectivity by the Ni-catalyzed coupling of 3-bromooxindole and tryptamine to give 457, which was then transformed into (+)-456 (Scheme 97).159 Total syntheses of spiroquinazoline alkaloids, rac-spiroquinazoline (459), ()-alantryphenone (460), (+)-lapatin A (461), and ()-quinadoline B (462), containing a tricyclic pyrazino quinazolinedione bridged by an indoline-containing


Scheme 89 Reagents and conditions: (i) K2CO3, MeCN; (ii) NaCl2, NaH2PO4, 2-methylbut-2-ene, THF, t-BuOH, H2O, rt; (iii) Cu(OTf)2, MeCN, rt; (iv) TBAF, THF, reflux; (v) Li, liq. NH3, THF, 78 C.

substructure, were reported. The key step was the aza-Diels– Alder reaction of aminal-embodied olens 463 and 465 as dienophiles with azadienes 464 and 466, leading to the spiroquinazoline moiety (Scheme 98).160 The enantioselective total synthesis of ()-vincorine (467) was realized in nine steps from tryptamine. Tetracyclic intermediate 470 was assembled by employing a stereoselective Diels–Alder reaction catalysed by a secondary amine catalyst between vinylindole 468 and olen 469, followed by concomitant iminium cyclization. The nal seven-membered azepanyl ring construction was achieved through the radical cyclization of acyl telluride 471, followed by selective reduction of the allene (Scheme 99).161

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Scheme 92 Reagents and conditions: (i) TMSOTf, CH2Cl2; (ii) CF3SO3H, CH2Cl2; (iii) NH2NH2, EtOH, 60 C.

Scheme 90 Reagents and conditions: (i) NaBH3CN, AcOH, EtOH, reflux; (ii) Boc2O, NaHCO3, CH2Cl2, H2O, rt; (iii) Grubbs’ 2nd generation catalyst, toluene, 60 C; (iv) Pd(Ph3P)4, Ag2CO3, toluene, 100 C; (v) aq. NaOH, EtOH, 40 C.

Scheme 93 Reagents and conditions: (i) 446, MS 4A, toluene, 10 C; (ii) NaN 3, DMF, rt; (iii) HCl, MeOH; (iv) (indol-3-yl)acetaldehyde, NaBH(OAc) 3 , CH 2 Cl 2; (v) PPh 3, THF, H 2O, 60 C; (vi) RANEY®-Ni, MeOH, rt; (vii) PPTS, CH(OMe) 3, 60 C; (viii) POCl3, sulfolane, 80 C.

Scheme 91 Reagents and conditions: (i) K2CO3, MeCN, 60 C; (ii) Grubbs’ 2nd generation catalyst, TsOH, toluene, 50 C; (iii) LTMP, THF, 78 C to rt, then 2,6-di(t-Bu)phenol; (iv) Pd(OAc)2, PPh3, Ag2CO3, MeCN, 80 C; (v) KOH, EtOH, H2O; (vi) Pd(OAc)2, DABCO, DMF, 80 C; (vii) (Boc)2O, DMAP, MeCN, rt; (viii) HCl, dioxane, MeOH, H2O; (ix) HCHO, NaBH3CN, MeCN, rt; (x) LTMP, THF, 78 C to rt, then NH4Cl; (xi) Pd2(dba)3CHCl3, P(t-Bu)3HBF4, Cy2MeN, dioxane, 100 C.

Nat. Prod. Rep.

The construction of the vicinal quarternary carbon centers at the C7 and the C8 positions of cummunesin F (473) was realized by employing an internal cycloaddition of indole 474 with in situ-generated 2H-indol-2-one 475 by dehydrohalogenation of 3-bromooxindole, followed by concomitant ring-opening to give indolenine 476, which was transformed to rac-cummunesin F (473) (Scheme 100).162 Total syntheses of pyrroloquinoline alkaloids makaluvamines A (477) and D (478), damirone B (479), makaluvone (480), batzelline C (481), and isobatzelline C (482) were achieved, which featured a one-pot benzyne-mediated cyclization leading to tricyclic core framework 483. Trapping the in situgenerated anion 484 with a chlorinating or brominating agent produced 485 in a one-pot operation (Scheme 101).163 The rst total synthesis of zyzzyanones A (486), B (487), C (488) and D (489) was accomplished through the construction of pyrrole ring 492 by a Mn(OAc)3-mediated oxidative free radical


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Scheme 94 Reagents and conditions: (i) NaH, 1-azido-2-iodoethane, DMF, rt, then ethanolic HCl; (ii) NaBH(OAc)3, CH2Cl2; (iii) PPh3, THF, H2O, 60 C, then CaCl2, MeOH, 80 C; (iv) RANEY®-Ni, H2, MeOH; (v) CH(OMe)3, PPTS, 60 C; (vi) POCl3, sulfolane. Scheme 96 Reagents and conditions: (i) In0, allyl bromide, THF; (ii) HCl, dioxane, then Mg, MeOH; (iii) ethyl glyoxaldehyde, then LiAlH4; (iv) (Boc)2O, i-PrNEt2; (v) methyl acrylate, Hoveyda–Grubbs II catalyst; (vi) PPh3, DEAD, toluene, rt, then DBU, 80 C; (vii) CH3CHO, LDA, HMPA, THF; (viii) PtO2, H2, AcOEt; (ix) DDQ, toluene; (x) TMSOTf, Et3N; (xi) (Z)-3-bromo-1-iodopropene, K2CO3; (xii) Dess–Martin-iodinane; (xiii) n-BuLi, THF, 78 C; (xiv) PPh3, I2.

Scheme 95 Reagents and conditions: (i) PdCl2, MeCN, rt; (ii) AuCl(PPh3), AgSbF6, CH2Cl2, 0 C; (iii) 65% aq. NH2NH2, MeOH, reflux; (iv) Ti(O-i-Pr)4, THF, 75 C; (v) N-formylbenzotriazole.

cyclization of 490 with acetal 491. Two intermediates 493 and 494, resulting from the N-methylation of 492, were converted to 486–489 (Scheme 102).164 Two straightforward approaches to a spirooxindole alkaloid coerulescine (495), isolated from the blue canary grass Phalaris coerulescens, were developed. The rst route featured the onepot construction of tricyclic spirooxindole core 498 from oxiindole 496 with 2-bromoethylamine 497,165 and the second route involved the formation of precursor 500 from acrylate 499 and 497166 through an aza-Michael-initiated ring closure cascade (Scheme 103). Although the proposed structure of schizocommunin (501), featuring the cinnoline core, was prepared from cinnoline-3carboxaldehyde 502 and 2-oxyindole 503, the spectroscopic data were not consistent with those reported. The NMR spectra of product 504 obtained from quinazolinone 505 and isatine 506 were completely identical with those reported for natural product and the Z-conguration was established by X-ray


Scheme 97 Reagents and conditions: (i) Ni(OAc)2, 458, K3PO4, THF, rt; (ii) NsCl, NaH, THF, rt; (iii) N2H4, THF, MeOH, reflux; (iv) (Boc)2O, DMAP, Et3N, CH2Cl2; (v) LiAlH4, THF, 20 C; (vi) MeOBF4, NaHCO3, CH2Cl2, rt; (vii) K2CO3, Cs2CO3, PhSH, DMF; (viii) HCl, PCC, dioxane.

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Scheme 99 Reagents and conditions: (i) 472, HBF4, MeCN, 20 C; (ii) NaClO2, 2-methyl-2-butene, t-BuOH, THF; (iii) isobutyl chloroformate, N-methylmolpholine, THF, then diphenyl ditelluride, NaBH4, THF, then MeOH; (iv) TFA, rt; (v) 4-(tert-butylthio)but-2-ynal, NaBH(OAc)3, CH2Cl2, rt; (vi) 1,2-dichlorobenzene, 200 C; (vii) Pd/C, H2, THF, 15 C. Scheme 98 Reagents and conditions: (i) xylene, 130 C; (ii) HCl, AcOEt; (iii) Pd/C, H2, AcOEt; (iv) HCl, THF; (v) Pd/C, H2, THF; (vi) DBU, DMSO, 110 C; (vii) Pd/C, H2, MeOH; (viii) Pd/C, H2, THF, MeOH; (ix) i-PrNEt2, KI, MeCN, reflux.

crystallographic analysis. The structure of schizocommunin was revised to be 504 (Scheme 104).167 The Stevens' synthesis of makomakine (507) by the Ritter reaction of indolylacetonitrie 508 with a-pinene 509 was improved by employing Hg(OTf)2 to give makomakine (510) in 72% yield, which was then converted to aristoteline (507) (Scheme 105).168 The rst total synthesis of kottamide E (511), containing 5,6dibromoindole and the unusual 4-amino-1,2-dithiolane-4carboxylic acid, was achieved starting with the known indole 512 (Scheme 106).169 Synthesis of phidianidines A (513) and B (514), containing guanidine and a 1,2,4-oxadiazole ring, was reported by two groups. In Snider's approach, the 1,2,4-oxadiazole 518 was assembled by the condensation of acid chloride 516 with N-hydroxyguanidine 517 derived from diazide 515 in 3 steps. The synthesis of 513 and 514 was then completed by the elaboration of the guanidine from the azide in 518 (Scheme 107).170 Chamberland's group reported the shortest synthesis of 513 and 514, involving the construction of oxadiazole 521 from

Nat. Prod. Rep.

516 with N-hydroxyguanidine 520 derived from N,N0 -di-Bocguanidine 519 in 2 steps, followed by deprotection (Scheme 108).171 Eight new trace indolomonoterpenic alkaloids, stryvomicine (522), stryvomitine (523), isopseudostrychnine (524), 5-oxoburucine (525), 5-oxopseudostrychnine (526), 11-hydroxyl-icajine (527), 10-hydroxyl-icajine (528), and 5-hydroxyl-vomicine (529), were isolated from the seeds of Strychnos nux-vomica, widely distributed in China, India, and Sri Lanka. All compounds were tested for their neuroprotective activities on PC12 cells using MTT methods. Compounds 527 and 528 showed neuroprotective activities with IE50 values of 2.75 mM and 3.52 mM, respectively (Fig. 20).172 Three new aspidofractinines, N(1)-formylkopsininic acid (530), N(1)-formylkopsininic acid-N(4)-oxide (531), and 15-hydroxykopsamine (532), a new aspidospermatan, 14a-hydroxy-N(4)-methylcondylocarpine (533), and a new akuamiline, singaporentinidine (534), were isolated from the roots of Kopsia singapurensis (Fig. 21).173 A new monoterpenoid indole alkaloid, catharoseumine (535), was isolated from the whole plants of Catharanthus roseus. Compound 535 has a unique peroxy bridge bond, and exhibited cytotoxicity against the HL-60 cell line (Fig. 21).174


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Scheme 100 Reagents and conditions: (i) Ag2CO3, MeCN; (ii) TsCl, NaH, THF, 0 C, then MeOH, rt; (iii) TBSOTf, lutidine, CH2Cl2, rt, then KF, MeOH, rt; (iv) AlMe3, CH2Cl2, 0 C; (v) KHMDS, THF, 78 C, then ICH2CN, THF, 78 C to rt; (vi) LiAlH4, THF; (vii) NH3, NH4Cl, MeOH, rt, then NaBH3CN; (viii) Ac2O, Et3N, DMAP, CH2Cl2.

A new pyridine-containing Strychnos alkaloid, kopsiyunnanine-I (536), was obtained from the MeOH extract of the aerial part of Yunnan Kopsia arborea Blume, native to Yunnan Province in China. The structure was elucidated by chemical conversion from strychine via Wieland–Gumlich aldehyde (Scheme 109).175 Divergent total syntheses of ()-aspidophytine (537), (+)-cimicidine (538), and (+)-cimicine (539) were developed using pentacyclic intermediate 541 as a common intermediate, which was derived from the known ketone 540 through the Fischer indolization (Scheme 110).176 The enantioselective synthesis of ()-aspidophytine (537), which involved the enantioselective Pd-catalyzed decarboxylative allylation of thioether 542, was used for the formation of cyclohexanedione 543. The substructure of 537 was constructed through the assembly of the indole ring by the Heck-type cyclization of 544, followed by the formation of piperidine (D ring) and pyrrolidine (E ring) rings (Scheme 111).177 The formal synthesis of rac-aspidospermidine (545) was completed by the construction of Stork's ketone 547 through a transannular cyclization of functionalized nine-membered amino ketone 547, involving the cascade N-deprotection/C–N bond formation/nucleophilic substitution of enamine sequence (Scheme 112).178 The total synthesis of aspidospermidine (545) was reported. Pentacyclic framework 550 was assembled by a Lewis acidThis journal is © The Royal Society of Chemistry 2015


Scheme 101 Reagents and conditions: (i) LTMP, THF, 78 C; (ii) Cl(CCl2)Cl or Br(CCl2)Br, 0 C; (iii) DDQ, toluene, 0 C; (iv) TMSOTf, CH2Cl2, 0 C; (v) NaOH, MeOH, reflux; (vi) BBr3, CH2Cl2, 78 C; (vii) BBr3, CH2Cl2, 40 C; (viii) NH4Cl, EtOH, reflux.

mediated formal intramolecular [4 + 2] cyclization of cyclobutanone 548 with indole, involving the formation of 549 by regioselective ring cleavage of the cyclobutanone ring (Scheme 113).179 The syntheses of ()-aspidospermine (545), ()-tabersonine (551), and ()-vincadifformine (552) were accomplished. The key step was the diastereoselective synthesis of tricyclic intermediate 555 from N-sulnylimine 553 through an asymmetric domino Michael/Mannich/N-allylation sequence initiated by the Michael reaction of metallodienamine 554 with ethacrylate (Scheme 114).180 A detailed investigation of the reaction mechanism of Pd-catalyzed 2-alkylation of 1H-indole by invoking a norbornene-mediated cascade C–H activation was reported. Treating 1H-indole 557, norbornene (556), primary alkyl halides 558, and a base in the presence of a Pd(II) catalyst produced 2-alkylindoles 559. The syntheses of rac-aspidospermidine (545) and rac-goniomitine (120) were completed starting with 559 (Scheme 115).181 The synthesis of rhazinilam (560), a pyrrole-containing aromatic metabolite, starting with substituted pyrrole 561, and direct transformation of 560 to aspidospermidine (545) through a reductive transannular cascade sequence, was reported. The

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Scheme 104 Reagents and conditions: (i) Et3N, EtOH, reflux; (ii) DMSO, 120 C; (iii) AcOH, reflux.

Scheme 105 Reagents and conditions: (i) Hg(OTf)2, CH2Cl2, 40 C to

Scheme 102 Reagents and conditions: (i) Mn(OAc)3, MeCN, reflux;

rt, then 3 M NaOH in MeOH, then NaBH4, 0 C; (ii) 37% HCl.

(ii) NaH, MeI, DMF; (iii) NaN3, DMF; (iv) Pd black, HCOONH4, EtOH, reflux; (v) TFA, CH2Cl2; (vi) Et3N, HCOOEt, reflux.

key feature of this strategy is the conversion of a highly substituted pyrrole into an architecturally complex pyrrolidine, which is the reverse of a proposed biosynthesis that oxidatively degrades 545 to 560 (Scheme 116).182

Scheme 106 Reagents and conditions: (i) t-BuO2CCH2P(O) (OPh)2, NaH, THF, 78 C; (ii) TFA, CH2Cl2, then NaH, DPPA, THF; (iii) TMSCH2CH2OH, toluene, reflux; (iv) NaHMDS, MeO2CCOCl, THF, then TBAF, THF; (v) aq. NaOH, MeOH, THF; (vi) HBTU, Et3N, DMF.

Scheme 103 Reagents and conditions: (i) 497, NaH, THF, rt; (ii) TFA, CH2Cl2, rt, then Et3SiH; (iii) Pd/C, H2, MeOH, rt; (iv) Me2SO4, K2CO3, MeCN, rt; (v) 497, NaH, THF; (vi) Pd(OH)2/C, H2, EtOH; (vii) Me2SO4, K2CO3, MeCN, rt.

Nat. Prod. Rep.

Divergent syntheses of (+)-spegazzinine (562) and ()-aspidospermine (563) were developed using an intramolecular [4 + 2]/[3 + 2] cycloaddition cascade. The key intramolecular cycloaddition cascade was done by heating 1,3,4-oxazole 564, producing pentacyclic intermediate 565 as a single diastereomer, which was converted to 566 and 567 through reductive oxido bridge opening (Scheme 117).183 The total synthesis of Aspidosperma alkaloids, limaspermidine (568) and N-acetylaspidoalbidine (569), was completed by


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Scheme 107 Reagents and conditions: (i) Et3N, CH2Cl2, rt, then ClCH2CH2Cl, 80 C; (ii) HCOONH4, Zn, MeOH, rt; (iii) Et3N, AgNO3, DMF, 0 C to rt; (iv) TFA, CH2Cl2.


Fig. 20

Scheme 108 Reagents and conditions: (i) BrCN, NaHCO3, H2O, CH2Cl2, 0 C; NH2OH, K2CO3, EtOH, rt; (iii) CH2Cl2, rt; (iv) TFA, CH2Cl2, rt.

three groups. In Yang's synthesis, the key tetracyclic intermediate 571 was assembled by intramolecular cascade reductive cyclization of a-arylated cyclohexenone 570, involving the formation of the indole ring and the D ring (Scheme 118).184 The enantioselective synthesis of ()-568 and ()-569 were completed by Banwell's group. The key step was Pd-catalyzed enantioselective decarboxylative allylation of rac-572 leading to carbazoleone 573, featuring a quaternary carbon center with high enantioselectivity. Then, 573 was converted to ()-568 through RANEY®-Co-mediated reductive cyclization, conrming its absolute conguration (Scheme 119).185 The oxidative 1,3-alkyl shi process of phenol 575 leading to allenyl dienone 577 with a quaternary carbon center was developed by Canesi's group, which involved intramolecular trapping of phenoxonium ion 576 with an alkyne group. The resulting 577 was elaborated to form 569 through the formation


Fig. 21

of tricyclic ketone 578 followed by the Fischer indolization (Scheme 120).186 The rst enantioselective synthesis of ()-minovincine (579) was completed. The key feature is the one-pot construction of tetracyclic framework 582 from diene 580 through a [4 + 2] cycloaddition/b-elimination/hetero-conjugate addition cascade involving intermediary formation of 581 (Scheme 121).187

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Scheme 109 Reagents and conditions: (i) 1,2-ethanedithiol, BF3OEt2, AcOH; (ii) MsCl, Et3N, CH2Cl2, 0 C; (iii) LiEt3BH, CH2Cl2, rt; (iv) ethyl malonyl chloride, NaHCO3, CH2Cl2, rt; (v) TMSOTf, p-nitrobenzaldehyde, CH2Cl2, rt; (vi) Pb(OAc)4, benzene, rt; (vii) RANEY®-Ni, THF, reflux.

Review

Scheme 111 Reagents and conditions: (i) Pd2(dba)3CHCl3, (S,S)-Trost ligand, THF, 0 C; (ii) Pd(OAc)2, Cu(OAc)2, K2CO3, DMF, 140 C; (iii) TsCl, Bh4NHSO4, NaOH, CH2Cl2, rt; (iv) catecholborane, Wilkinson's catalyst, rt, then NaBO34H2O, 0 C to rt; (v) bromoethanol, K2CO3, EtOH, reflux; (vi) MsCl, i-Pr2NEt, CH2Cl2, 78 C; (vii) NaI, Cs2CO3, acetone, reflux; (viii) (PhSeO)2O, benzene, 65 C; (ix) HCHO, NaBH3CN, 70 C to rt; (x) NaOH, EtOH, 70 C, then K3[Fe(CN)6], NaHCO3, t-BuOH, H2O.

Scheme 112 Reagents and conditions: (i) t-BuOK, THF; (ii) NaIO4, RuCl3, MeCN, H2O; (iii) CH2N2; (iv) TFA, 90 C; (v) LiAlH4. Scheme 110 Reagents and conditions: (i) benzene, reflux, (ii) AcOH, 100 C; (iii) benzeneseleninic anhydride, CH2Cl2, 0 C; (iv) 37% aq. HCHO, NaBH3CN, AcOH, MeOH, 78 C; (v) 1 M NaOH, MeOH, 60 C; (vi) K3Fe(CN)6, NaHCO3, t-BuOH, H2O, rt; (vii) NaBH4, MeOH, 78 C to rt; (viii) propionic anhydride, pyridine, rt; (ix) 1 M NaOH, MeOH, 60 C; (x) K3Fe(CN)6, NaHCO3, t-BuOH, H2O, rt; (xi) BCl3, TABI, CH2Cl2, 78 C to rt.

The formal synthesis of (+)-kopsihainanine A (584) was achieved by the synthesis of the known intermediate 586 using the enantioselective Pd-catalyzed decarboxylated allylation of carbazolone 585 as the key step (Scheme 122).188 The formal synthesis of ()-aspidospermidine (545) and an asymmetric total synthesis of (+)-kopsihainanine A (584) were

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accomplished starting with 588, derived from the known carbazolone 573 (Scheme 123).189 Using the known enantioenriched carbazolone intermediate 592 obtainable from rac-carbazolone 591 by enantioselective Pd-catalyzed decarboxylative allylation, (+)-methyl N-decarbomethoxychanofruticosinate (590) was synthesized. The sevenmembered ring was assembled by the SmI2-mediated intramolecular Reformatsky reaction of 593, and the installation of the caged ring was attained by intramolecular oxidative coupling of enolate and indole in 594 with I2 as an oxidant (Scheme 124).190 An asymmetric total synthesis of the Akuammiline alkaloid ()-vincorine (595) was achieved using intramolecular oxidative


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Reagents and conditions: (i) EDC, 0 C; (ii) BnBr, NaH, DMF, rt; (iii) 1 N HCl, EtOH, reflux; (iv) TMSOTf, toluene, reflux; (v) NH2NH2, Na, (CH2OH)2, 160–210 C; (vi) LiAlH4, THF, rt; (vii) Pd(OH)2, H2, rt. Scheme 113

Scheme 115 Reagents and conditions: (i) PdCl2 (MeCN)2, indole, 556, K2CO 3, DMA, H2O, 70 C; PdCl 2, 3-sub indole, K2CO3, DMF, DMSO, H2O, 60 C; (ii) LHMDS, THF, 78 C to rt, then allyl bromide, 78 C to rt; (iii) 9-BBN, THF, 0 C to rt, then H2O2, NaOH, 0 C; (iv) DMP, NaHCO3, CH2Cl2, rt; (v) ethanolamine, NaBH4, EtOH, 0 C; (vi) DIBAH, CH2Cl2, 78 C; (vii) AcOH, THF, H2O, rt; (viii) MsCl, Et3N, CH2Cl2, 20 C, then t-BuOK, THF, 20 C to rt; (ix) NaBH4, EtOH, 0 C to rt; (x) DPPA, DIAD, PPh 3, THF, rt; (xi) LiAlH4, THF, 0 C to rt.

Scheme 114 Reagents and conditions: (i) LHMDS, THF, 78 C, then methyl ethacrylate, then allyl bromide; (ii) PtO2, H2, AcOEt; (iii) LDA, NCCO2Me, THF, 78 C.

coupling as the key step. Tetracyclic core structure 597 was assembled by treating the in situ-generated enolate anion from 596 with iodine as an oxidant, followed by spontaneous C–N bond formation. The total synthesis of 595 was achieved aer the formation of the E ring via intramolecular N-alkylation (Scheme 125).191 The intramolecular [4 + 2]/[3 + 2] cycloaddition cascade was extended for the total synthesis of kopsinine (598). The pentacyclic framework 600 was constructed as a single diastereomer by heating oxazolone 599 in o-dichlorobenzene at 180 C. The synthesis was performed through the late-stage formation of a bicyclo[2.2.2]octane system with SmI2-mediated transannular radical cyclization of dithiocarbonate 601 (Scheme 126).192 Chiral building block 604, obtained by chiral diether-mediated conjugate addition of lithium amide 602 to 603 followed by


Scheme 116 Reagents and conditions: (i) Pd(OAc)2, PivOH, t-BuONa, O2, DMF; (ii) Pd–C, H2,MeOH; (iii) AlCl3, H2O; (iv) Et3N, CH2Cl2; (v) NaOH; (vi) Boc2O, DMAP, THF; (vii) LiBHEt3, THF, then Ac2O; (viii) TFA, CH2Cl2; (ix) NaBH3CN, CH2Cl2, 0 C to rt; (ix) TFA, CH2Cl2.

alkylation of the lithium enolate, was used for an asymmetric formal synthesis of ()-kopsinine (598), which was completed by the construction of Natsume's pentacyclic intermediate (Scheme 127).193 A full account of the development of the base-mediated intramolecular cycloaddition of tryptamine-derived Zincke aldehyde 611 for the syntheses of strychnine (607),

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Scheme 119 Reagents and conditions: (i) Pd2(dba)3, 574, toluene, 70 C; (ii) HCO2H, rt; (iii) LiAlH4, THF, 20 C; (iv) K2OsO4, NMO, THF, H2O; (v) LiAlH4, Et2O, reflux; (vi) Na, liq. NH3, THF, 78 C; (vii) TBDPSCl, imidazole, CH2Cl2, rt; (viii) ClCH2COCl, Et3N, CH2Cl2, 0 C to rt; (ix) NaI, acetone, reflux, then AgOTf, THF, rt; (x) LiAlH4, THF, reflux.

Scheme 117 Reagents and conditions: (i) o-dichlorobenzene, 180 C; (ii) NH3, MeOH; (iii) TFAA, pyridine; (iv) NaCNBH3, HCl, MeOH; (v) NaBH4; (vi) LiAlH4; (vii) Pd/C, H2; (viii) Ac2O, pyridine, K2CO3, MeOH; (ix) 4-nitrobenzoic acid, DIAD, Ph3P; (x) TMSCH2N2, toluene, MeOH.

noruorocurane (608), dehydrodeacetylretuline (609), and valparicine (610) was reported, which included detailed discussion of the substrate scope and the reaction mechanism of the cycloaddition (Scheme 128).194

Scheme 120 Reagents and conditions: (i) PhI(OAc)2, hexafluoroisopropyl alcohol, rt; (ii) I2, NaHCO3, CHCl3; (iii) ethanolamine, THF, rt; (iv) MsCl, Et3N; (v) t-BuOK, benzene, 0 C; (vi) H2, Pd/C, EtOH; (vii) TFA, CH2Cl2, rt; (viii) LiAlH(O-t-Bu)3, THF, 0 C; (ix) PhNHNH2, toluene, 80 C; (x) AcOH, 118 C; (xi) LiAlH4, THF, rt; (xii) AcCl, NaHCO3, H2O, CH2Cl2.

Scheme 118 Reagents and conditions: (i) o-nitroiodobenzene, Pd(dba)3, DMSO; (ii) RANEY®-Co, H2, p-TsOH, MeOH, 40 C; (iii) ClCH2COCl, Et3N; (iv) NaI, acetone; (v) AgOTf, CH2Cl2; (vi) LiBH3(NH2), THF.

Nat. Prod. Rep.

2.2.1 Piperazinediones. Chemical investigation of Streptomyces sp. CHQ64 isolated from reeds rhizosphere soil collected from the mangrove conservation area of Guangdong province in China resulted in the isolation of three new alkaloids, indotertine A (612) and drimentines F (613) and G (614). Drimentine G (614) exhibited strong cytotoxicity against human cancer cell lines (HCT-8, Bel-7402, A549, and A2780) (Fig. 22).195 Four new diketopiperazine alkaloids, rel-(8R)-9-hydroxy-8-methoxy-18-epi-fumitremorgin C (615), rel-(8S)-19,20-dihydro-9,20-dihydroxy-8-methoxy-9,18-di-epi-


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Scheme 121 Reagents and conditions: (i) 583, CHCl3, 30 C; (ii) NIS, Pd(PhCN)2Cl2, Et3N, MeOH, MeCN, CO, 60 C; (iii) L-selectride, THF, 78 C to 0 C; (iv) TMSI, Et3N, CH2Cl2, 0 C; (v) 1,3-diiodopropane, NaHCO3, DMF, 35 C; (vi) TFA, CH2Cl2, 0 C to rt. Scheme 123 Reagents and conditions: (i) HCO2H, rt; (ii) LiAlH4, THF, 20 C, then HCl; (iii) K2Os42H2O, NMO, THF, H2O, then NaIO4; (iv) 1,2-ethandithiol, BF3OEt2, CH2Cl2; (v) RANEY®-Ni, H2, EtOH, 60 C; (vi) LiAlH4, Et2O, reflux; (vii) Na, liq. NH3, THF, 78 C; (viii) BH3, THF, 20 C; (ix) MsCl, Et3N, CH2Cl2, 0 C, then NaH, DMF, 0 C to rt; (x) LDA, Na2SO3, O2, 0 C to rt; (xi) AlCl3, toluene; (xii) sat. aq. Rochelle salt.

Scheme 122 Reagents and conditions: (i) Pd2(dba)3, 587, toluene, 50 C; (ii) HCO2H, rt; (iii) K2CO3, BnBr, acetone, 55 C.

fumitremorgin C (616), rel-(8S,19S)-19,20-dihydro-9,19,20trihydroxy-8-methoxy-9-epi-fumitremorgin C (617), and (3S,8S,9S,18S)-8,9-dihydroxyspirotryprostatin A (618), were isolated from the roots of the endophytic fungus Aspergillus fumigatus (Fig. 22).196 A new prenylated indole alkaloid, waikialoid A (619), was obtained from the fungus Aspergillus sp. isolated from a soil sample collected near Waikiki Beach, Hawaii. This compound inhibited biolm formation by Candida albicans with an IC50 value of 1.4 mM (Fig. 23).197 Two new spiro-polyketidediketopiperazine alkaloids, effusin A (620) and dihydrocryptoechinulin D (621), were obtained as racemates from a mangrove rhizosphere soil-derived fungus Aspergillus effuses H1-1. The enantiomers of the compounds were separated, and their structures were elucidated. Compound 621 showed remarkable cytotoxicity against P338 and HL-60 cells (Fig. 23).198 Cultivation of an endophytic fungus Eurotium rubrum, isolated from the inner tissue of the semi-mangrove plant Hibiscus tiliaceus, resulted in the isolation of a new


Scheme 124 Reagents and conditions: (i) 2-bromoacetyl chloride, NaOH, CH2Cl2; (ii) HBr, THF; (iii) TPAP, NMO, CH2Cl2; (iv) SmI2, THF; (v) BH3, THF, then HCl; (vi) pyridine-SO3, DMSO, Et3N, CH2Cl2; (vii) LHMDS, THF, 78 C, then I2, 40 C to rt; (viii) TMSCN, MeOH, THF; (ix) K2CO3, H2O2, MeOH; (x) HCl, MeOH.

dioxopiperazine alkaloid, 12-demethyl-12-oxo-eurotechinulin B (622) (Fig. 23).199 Three new alkaloids featuring an unusual epithiodiketopiperazine system, lepozines A (623), B (624), and C (625), were isolated from the AcOEt extract of an Aspergillus sp. strain isolated from a soil sample collected from sage rangeland south of Bridger, Montana (Fig. 24).200 A new aranotin-type diketopiperazine, bisdethiobis(methylsulfanyl)apoaranotin (626), was isolated from the fungus Aspergillus terreus strain

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Reagents and conditions: (i) N-benzyl-N-trimethylsilylamide, n-BuLi, toluene, 78 C, then 606, 78 C, then 603, 78 C to 40 C, then iodide, 78 C to 40 C; (ii) TBAF, THF, rt; (iii) MsCl, Et3N, CH2Cl2, rt; (iv) H2SO4, MeOH, reflux; (v) methyl acetate, LHMDS, THF, 78 C, then ketoester, 78 C to rt; (vi) NCCO2Me, LHMDS, THF, 78 C; (vii) HCO2H, Pd/C; (viii) ICH2CH2OH, Na2CO3; (ix) MsCl, Et3N; (x) t-BuOK, THF, HMPA, 78 C to rt. Scheme 127

Scheme 125 Reagents and conditions: (i) NaBH4, MeOH, 78 C to rt; (ii) TBSCl, imidazole, DMF; (iii) silica gel, 70 C, 0.2–0.3 mmHg; (iv) LHMDS, I2, THF, 40 C to rt; (v) KCN, H2O, DMF, 100 C; (vi) Ph3PCl2, CH2Cl2; (vii) TMSOTf, 2,6-lutidine, CH2Cl2, rt; (viii) K2CO3, KI, MeCN, 60 C; (ix) 37% aq. HCHO, NaBH3CN, MeCN, AcOH.

BCC465. This compound was subjected to studies of its antitubercular and antimalarial activities, and its cytotoxicity against three cancer cell lines (Fig. 24).201 Two new prenylated indole alkaloids, 5-chlorosclerotriamide (627) and 10-epi-sclerotriamide (628), were isolated from the

Scheme 126 Reagents and conditions: (i) o-dichlorobenzene, 180 C; (ii) NaCNBH3, AcOH, i-PrOH; (iii) NaH, CS2, MeI; (iv) 130 C, o-dichlorobenzene; (v) TBAF, THF; (vi) SmI2, THF, HMPA, rt; (vii) Lawesson reagent; (viii) RANEY®-Ni, EtOH, rt.

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deep-sea-derived fungus Aspergillus westerd FFSCS013 (Fig. 25).202 Two new prenylated indole alkaloids, 17-epi-notoamides Q (629) and M (630), were isolated from a marine-derived Aspergillus sp. fungus. The structures and the absolute congurations of 629 and 630 were determined from extensive NMR spectroscopic data as well as CD spectra (Fig. 25).203 Three

Scheme 128 Reagents and conditions: (i) EtOH, 80 C to rt, then 2 M NaOH; (ii) t-BuOK, THF, 80 C.


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Fig. 22

prenylated indole alkaloids, 6-epi-stephacidin A (631), N-hydroxy-6-epi-stephacidin A (632), and 6-epi-avrainvillamide (633), were identied by chemical investigation of the extract of Aspergillus taichungensis. The structures and the absolute congurations were elucidated by MS, NMR, CD, and X-ray data. When 631 was exposed to UV light in DMSO with drops of MeOH, (+)-versicolamides B (634) and C (635) were puried from the reaction mixture (Fig. 25).204 Total syntheses of prenylated indole alkaloids ()-stephacidin A (636) and (+)-notoamide B (637) were completed. The crucial step was the double radical cyclization in precursor 638 under reductive Bu3SnH conditions, affording the key polycyclic intermediate 639 as an inseparable mixture of two diastereomers, which then was subjected to further chemical transformations, leading to 636 and 637 (Scheme 129).205 The total synthesis of notoamide T (640) was achieved starting with the condensation of tryptophan 641 with hydroxyproline 642. In an effort to determine the biosynthetic pathway of stephacidins and notoamides, chemical conversion of 640 to stephacidin A (636), and bioconversion of 640 into 637 in Aspergills versicolor NRRL35600 were investigated (Scheme 130).206 The enantioselective synthesis of ()-maremycin A (643), featuring an oxindole core with a hydroxyl-bearing tetrasubstituted stereogenic center at C3, was completed. The key feature was the construction of spiro oxindole g-butyrolactone 645 by the enantioselective Michael addition of dioxindole 644 to crotonaldehyde in the presence of a secondary amine catalyst 646, followed by PCC oxidation. ()-Maremycin A (643) was accessed from 645 in 5 steps (Scheme 131).207


Fig. 23

The rst total synthesis of drimentines A (647), F (648), and G (649), and indotertine A (650) was reported. The key step is the construction of the core structure 653 through an intramolecular radical conjugate addition between 3-Br-pyrrroloindoline 639 and enone 651 using a photoredox catalyst under visible-light irradiation (blue LED). Alkaloids 647–649 were accessed from 653, and 649 was transformed into 650 (Scheme 132).208 The single-step asymmetric introduction of an isoprenyl group on C3a of a pyrroloindoline core was developed based

Fig. 24

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on the silver-promoted Friedel–Cras reaction. Treating bromopyrroloindole 658 and prenyl tributylstannane 659 in the presence of AgBF4 produced prenylated intermediate 660, which was then transformed into ()-ardeemin (655), ()-formylardeemin (656), and ()-acetylardeemin (657) (Scheme 133).209 The total synthesis of demethoxyfumitremorgin C (661) was completed using the Mg(ClO4)2-promoted intramolecular allyl amination of allylic alcohol as a key step. The cyclization reaction of 662 provided two diastereomers, 663a and 663b, which were transformed to (+)-661 (natural) and ()-epi-661, respectively (Scheme 134).210 The rst total synthesis of ent-()-azonazine (664), a hexacyclic dipeptide, was achieved. Oxidative free-radical cyclization of diketopiperazine 666 with PhI(OAc)2 was applied to construct the benzofuranoindoline ring system and the highly strained transannular 10-membered ring of 664 as the key step. Based on completion of the synthesis, the reported absolute conguration of (+)-(2R,10R,11S,19R)-665 was revised to (2S,10R,11S,19S)-664 (Scheme 135).211 The rst stereoselective total synthesis of brevianamide E (667), isolated from Penicillium brevicompactum, was reported, which featured the selective oxidative cyclization of 668 with DMDO to construct the pyrroloindoline 669 (Scheme 136).212

Fig. 25

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Full accounts of convergent syntheses of variecolortides A (670), B (671), and C (672) were reported. The key feature was the construction of the spirocyclic N,O-acetal moiety in 676 by a hetero-Diels–Alder reaction between heterodiene 674, formed by an intramolecular 1,5-hydrogen shi from 673 with exomethylene diketopiperazine 675 in aerated o-dichlorobenzene, followed by an oxidative unsaturation (Scheme 137).213 An improved method for sulfenylation of diketopiperazines using elemental sulphur (S8) and hexamethylsilazide bases (NaHMDS, LiHMDS and KHMDS) was applied for the syntheses of epicoccin G (677), 8,80 -epi-ent-rostrain B (678), gliotoxin (679), gliotoxin G (680), emethaicin E (681), and haematocin (682) (Scheme 138).214 2.2.2 Pyrroloindoles. Investigation into the extracts of the leaves of Alstonia pneumatophore resulted in the isolation of three new alkaloids, alsmaphorazines C (683), D (684), and E (685), containing a novel octahydropyrrolo[2,3-b]pyrrole unit (Fig. 26).215 A novel pyrroloindole terpenoid, scherindoline (686), was isolated from solid and liquid cultures of Neosartorya pseudoscheri. This compound showed in vitro growth inhibitory activity in six human and mouse cancer cell lines (Fig. 26).216 Pyrroloindoline alkaloids attract wide interest from the elds of chemistry, biosynthesis, and biology. In particular, from their

Scheme 129 Reagents and conditions: (i) HATU, i-PrNEt2, MeCN; (ii) H2O, 165 C, MW; (iii) LDA, THF, 78 C, then (PhS)2; (iv) n-Bu3SnH, ACCN, toluene, reflux; (v) H2O, 165 C, MW; (vi) SeO2, H2O2; (vii) DDQ, AcOEt; (viii) H2O, 165 C, MW.


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Scheme 130 Reagents and conditions: (i) HATU, i-PrNEt2, MeCN; (ii) Et3N, 2-hydropxypyridine, MeCN, reflux; (iii) TFA, CH2Cl2, 0 C to rt; (iv) Pd(PPh3)4, THF; (v) MsCl, i-PrNEt2, CH2Cl2, 0 C; (vi) KOH, MeOH, reflux; (vii) DDQ, dioxane.

structural perspective, a large number of strategies has been developed for the synthesis of pyrroloindoline alkaloids. Concise syntheses for the syntheses of 3-hydroxypyrroloindole alkaloids CPC-1 (687) and debromoustaminol B (688) were reported. The key step was the oxidative cyclization of tryptamine 689 with iodobenzene diacetate leading to a hexahydro-3-hydroxypyrroloindoline core (Scheme 139).217 A practical synthesis of oxindole-based spiro-isoxazoline 691 was developed using a [3 + 2] cycloaddition between 3-methyleneoxindole and hydroxyiminoyl chloride. rac-Flustraminol B (690) was synthesized using 3-hydroxy-3-cyanomethyl oxindole derived from 691 as a pivotal building block (Scheme 140).218 The total synthesis of rac-debromoustramine B (692) was achieved through the reaction of N-triethylindolylborate 693 with prenyl bromide as the key step, which involved the

Scheme 131 Reagents and conditions: (i) 633, 2-fluorobenzoic acid,

acetone, rt; (ii) PCC, CH2Cl2, rt; (iii) LDA, TsN3; (iv) Ph3P, H2O; (v) N-Boc-S-methyl-L-cysteine, HATU, i-Pr2NEt; (vi) HCO2H, rt; (vii) toluene, reflux.


Scheme 132 Reagents and conditions: (i) [Ir(ppy)2(dtbbpy)]PF6, blue LED, Et3N, DMF, rt; (ii) TFA; (iii) HATU, 654, i-Pr2NEt; (iv) TFA, then NH4OH; (v) CeCl3, MeMgBr; (vi) SOCl2, pyridine; (vii) Bi(OTf)3, KPF6.

formation of a C3-quaternary indolenine followed by spontaneous cyclization (Scheme 141).219 Debromoustramines B (692) and E (694) were synthesized using the intramolecular carbamoyl-alkene [2 + 2] cycloaddition as the key reaction. Cyclobutanone 695 was converted to 692 and 694 through the regioselective Beckman rearrangement (Scheme 142).220 The synthesis of debromoustramine B (692) was achieved using the [4 + 1] cycloaddition of indole isocyanate with bis(propylthio)carbene. The pyrroloindoline framework was assembled by treating azide 696 with carbene precursor 697 in benzene, which involved the in situ formation of isocyante from 696 via the Curtius rearrangement, and the in situ generation of carbene from 697 (Scheme 143).221 Syntheses of ()-692 and ()-694, and pseudophrynaminol (698) were reported, which featured the one-pot formation of enantioenriched 3,3-disubstituted oxindole from amide 699, bearing a chiral sulnyl amide group through the one-pot

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Scheme 133 Reagents and conditions: (i) AgBF4, Cs2CO3, CH2Cl2, 78 C; (ii) TMSCl, MeCN, 0 C; (iii) N-Fmoc-D-alanine, HATU, Et3N, DMF, 20 C; (iv) aq. HCHO, NaBH3CN, MeCN, AcOH, rt; (v) Et2NH, THF, 0 C to rt; (vi) n-BuLi, o-azidobenzoic acid, THF, 78 C; (vii) n-Bu3P, toluene; (viii) PDC, silica gel, CH2Cl2, rt; (ix) 8% aq. NaOH, MeOH, reflux.

Scheme 135 Reagents and conditions: (i) 3 M HCl, AcOEt, then aq. NaHCO3; (ii) BBr3, CH2Cl2, 0 C; (iii) PhI(OAc)2, LiOAc, CF3CH2OH, 30 C; (iv) AcOH, dioxane, H2O, MW, 65 C; (v) NaBH4, MeOH, 0 C; (vi) Tf2O, Et3N, AcOEt, 15 C; (vii) Pd(OH)2/C, H2, Et3N, MeOH, AcOEt; (viii) Ac2O, AcOH, rt.

Scheme 134 Reagents and conditions: (i) Mg(ClO4)2, MeCN, 80 C; (ii) TMSOTf, 2,6-lutidine, CH2Cl2, 0 C; (iii) Et3N, CH2Cl2, 0 C; (iv) Zn dust, MeOH, reflux; (v) TFA, CH2Cl2, 0 C.

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Cu-catalyzed arylation of o-bromoanilide/asymmetric alkylation sequence (Scheme 144).222 The asymmetric synthesis of pyrroloindoline 700 was accessed by the one-pot reaction of tryptamine and methyl vinyl ketone through Michael addition and intramolecular amination catalysed by chiral phosphoric acid 701. Pyrroloindoline 700 was transformed into ()-692 in 3 steps (Scheme 145).223 Transformation of ustrabromine to rac-ustramine A (702) was realized through an NBS-promoted oxidative cyclization/ alkyl migration cascade sequence (Scheme 146).224 rac-Esermethole (703) was synthesized from carboxylic acid 704 using an intramolecular carbamoylketene-alkene [2 + 2] cycloaddition and ring expansion of the cyclobutanone ring involving a Beckmann rearrangement (Scheme 147).225 An efficient route to the pyrrolidinoindole framework was developed using Rh-catalyzed domino hydroformylation/double cyclization of o-amino cinnamyl derivative 693, which was


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Scheme 136 Reagents and conditions: (i) TrtCl, Et3N, DMF; (ii) H-ProOMe, EDC, HOBt; (iii) DMDO, CH2Cl2, acetone, 78 C; (iv) HFIP, CH2Cl2; (v) i-PrNEt2, MeOH, 80 C.

Scheme 138 Reagents and conditions: (i) NaHMDS, S8, THF, rt; (ii) NaBH4, THF, MeOH, 0 C to rt, then MeI, rt; (iii) O2, TPP, hv, CH2Cl2, 45 C, then DBU, 45 to 0 C; (iv) Pd(OH)2/C, H2, MeOH; (v) NaBH4, THF, MeOH, 0 C to rt, then KI3; (vi) O2, TPP, CH2Cl2, 0 C, then Et3N; (vii) [CuH(PPh3)]6, benzene, then KI3, rt; (viii) LiHMDS, S8, THF, rt; (ix) LiHMDS, S8, THF, rt; (x) PhCH2COOH, DCC, DMAP, 0 C to rt; (xi) 1,3-propane dithiol, Et3N, MeCN, CH2Cl2, rt, then O2, MeOH, rt; (xii) AcOH, DCC, DMAP, 0 C to rt; (xiii) NaBH4, MeOH, pyridine, 0 C, then MeI, 0 C to rt.

Scheme 137

Reagents and conditions: (i) o-dichlorobenzene, 180 C.


successfully applied to the synthesis of CPC-1 (687) and desoxyeseroline (705) (Scheme 148).226 The enantioselective synthesis of ()-705 was achieved. The key step was the assembly of enantioenriched indolenine 707 through Cu-catalyzed enantioselective cyclopropanation of indole followed by N-deprotection/ring opening processes.

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Fig. 26

Scheme 141 Reagents and conditions: (i) t-BuOK, Et3B, dioxane, then prenyl bromide, rt; (ii) t-BuOK, prenyl bromide, dioxane, reflux; (iii) LiAlH4, THF, reflux.

Scheme 139 Reagents and conditions: (i) PhI(OAc)2, AcONa, TFE, 0 C; (ii) MeI, NaH, THF; (iii) KOH, MeOH, H2O; (iv) HCHO, NaBH4, MeOH; (v) prenyl bromide, K2CO3, acetone; (vi) KOH, MeOH, H2O.

Aminal ester 708, derived from hydrolysis of ester 707, was converted to ()-705 (Scheme 149).227 2.2.3 b-Carbolines. Five new alkaloids, voacalgines A (710), B (711), C (712), D (713), and E (714), were isolated from the bark of Vocanga grandifolia, a member of the Apocynaceae family distributed in Indonesia and India (Fig. 27).228

Scheme 140 Reagents and conditions: (i) Amberlyst A21, CH2Cl2, rt; (ii) KOAc, MeOH, H2O, MW, 100 C; (iii) prenyl bromide, Cs2CO3, MeCN, DMF, rt; (iv) H2O2, Cs2CO3, EtOH, H2O, rt; (v) AlH3NMe2Et, THF, 15 C; (vi) AlH3NMe2Et, THF, rt; (vii) HCHO, MeOH, then, NaBH3CN.

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Scheme 142 Reagents and conditions: (i) (COCl)2, benzene, reflux, then Et3N, reflux; (ii) MeNHOH, MS 3A, NaHCO3, EtOH, 50 C; (iii) p-TsCl, 4-pyrrolopyridine, CHCl3, reflux; (iv) Pd/C, H2, EtOH; (v) MgSO4, p-TsOH, toluene, 60 C; (vi) 5 N NaOH, MeOH, reflux; (vii) LiAlH4, THF, reflux; (viii) prenyl bromide, K2CO3, acetone, reflux.

Scheme 143 Reagents and conditions: (i) 697, benzene, reflux; (ii) LiAlH4, THF, reflux; (iii) NaH, MeI, THF; (iv) RANEY®-Ni, EtOH, rt; (v) LiAlH4, THF, reflux.


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Scheme 146 Reagents and conditions: (i) NaH, DMF, 0 C, then prenyl chloride; (ii) 32% aq. NaOH, EtOH, rt; (iii) NBS, THF, 0 C; NaBH4, MeOH, rt. Scheme 144 Reagents and conditions: (i) CuI, LiN(TMS)2, THF, reflux, then prenyl bromide, 0 C to rt; (ii) HCl, MeOH, dioxane; (iii) DIBAH, THF; (iv) Li, liq. NH3, THF: (v) CuI, LiN(TMS)2, THF, reflux, then bromide; (vi) Li, liq. NH3, THF.

Scheme 147 Reagents and conditions: (i) NsCl, Et3N, benzene, rt; (ii) MeNHOH, NaHCO3, MS 3A, EtOH, 50 C; (iii) p-TsCl, 4-pyrrolidinopridine, CHCl3, reflux; (iv) LiAlH4, THF, reflux.

Reagents and conditions: (i) 701, toluene, benzene, MS 4A, Ar, 20 C; (ii) n-BuLi, [MePPh3]Br, THF, rt; (iii) [RuH2(PPh3)4], toluene, reflux; (iv) red-Al, toluene, rt. Scheme 145

The isolation of indolotryptoline alkaloid xenocladoniamide F (715) from Streptomyces coelicolor M1146 was reported (Fig. 28).229 A new manzamine alkaloid featuring an 3-lactam as well as d-lactone rings, acantholactone (716), was isolated from the Indonesian sponge Acanthostronglyophora sp. (Fig. 28).230 The isolation of two new indole alkaloids, tabertinggine (717) and voatinggine (718), characterized by an unprecedented skeleton, was reported (Fig. 28).231 Five new alkaloids, dichotomines F (719), G (720), H (721), I (722), and J (723), were isolated from the roots of Chinese medicinal plant Stellaria dichotoma L. var. lanceolata (Fig. 29).232 Six new b-carboline alkaloid glycosides, ophiorrhisides A (724), B (725), C (726), D (727), E (728), and F (729), were isolated from Ophiorrhiza trichocarpon Blume collected in Thailand (Fig. 30).233 While searching for metabolites from the water-soluble fraction of an EtOH extract of the marine sponge Hyrtios


reticulatus, a new indole alkaloid, hyrtioreticulin F (730), was isolated (Fig. 31).234 Two new indole alkaloids, 5-oxodolichantoside (731) and deglycocadambine (732), were isolated from the twigs and leaves of Emmenopterys henryi (Fig. 31).235 In the screening for fruiting bodies of Mycena metata by means of HR-MALDI-MS imaging, a new alkaloid,

Scheme 148 Reagents and conditions: (i) Rh(acac)(CO)2, P(OPh)3, CO, H2, MeCN, 95 C; (ii) 1,3-dibromo-5,5-dimethylhydantoin, AIBN, CCl4, reflux; (iii) ZnMe2, toluene, reflux; (iv) red-Al, toluene, reflux; (v) Ti(O-iPr)4, MeOH, reflux.

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Fig. 28

Reagents and conditions: (i) CuOTf, 709, CH2Cl2, 0 C; (ii) TFA, CH2Cl2, (iii) NaOH, H2O, EtOH; (iv) Me2SO4, K2CO3, acetone; (v) MeNH2, MeOH; (vi) LiAlH4, THF. Scheme 149

6-hydroxymetatacarboline D (733), was isolated (Fig. 31).236 Chemical investigations of Alstonia macrophylla led to the isolation of 4 new indole alkaloids, 10-methoxydihydrosempervirine (734), N(1)-demethyl-7-methoxyikirydinium A (735), 17-carboxycompactivervine N-oxide (736), and 17-carboxyalstovine N-oxide (737) (Fig. 31).237 Investigation of the chemical constituents of the leaves and twigs of Ochrosia borbonica allowed the isolation of eight new alkaloids, 10-hydroxyisovallesiachotamine (738), 10-hydroxyisositsirikine (739), 10, 11-dimethoxysitsirikine (740), 10methoxyapoyohimbine (741), 10-hydroxyakuammidine (742), akuammidine 17-O-b-D-glucoside (743), 15a-hydroxyapparicine (744), 15a-hydroxy-10-methoxyapparicine (745) (Fig. 32).238

Fig. 27

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Ten new monoterpenoid indole alkaloids, meloyine (746), 19S-methoxytubotaiwine N4-oxide (747), 16,19-epoxyvincanol (748), 14b-hydroxymeloyunione (749), meloyunine (750), vincamenine N4-oxide (751), 16b,21b-epoxyvincadine (752), 14b-15b-20S-quebrachamine (753), 3-oxovoaphylline (754), and 2,7-dihydroxydihydrovoaphylline (755), were isolated from the leaves and twigs of Melodinus yunnanesis, distributed in the south of Yunnan and west of Guangxi, China (Fig. 33).239 The rst asymmetric synthesis of keramamine C (756), obtained from Okinawan marine sponge Amphimedon sp. was accomplished. The key step was asymmetric reduction of dihydro-b-carboline 757 using the Noyori asymmetric hydrogen transfer with (S,S)-TsDPEN-Ru(II) complex, leading to (1R)-tetrahydro-b-carboline. The absolute conguration at C1 in 756 was elucidated to be R (Scheme 150).240 The total synthesis of manzamine A (758), isolated from a sponge in the Okinawa Sea, was accomplished using late-stage cross-coupling of b-carboline 761 with pentacyclic triate 760 as

Fig. 29


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the key step. Diastereoselective Michael addition of the ketoester to a nitro olen followed by a three-component nitroMannich/lactamization cascade produced tricyclic intermediate 759, which was then converted to pentacyclic intermediate 760 (Scheme 151).241 Fascaplysin (762) and homofascaplysins B (763) and C (764), featuring the pyridodiindole system, exhibit a wide range of biological activities such as antibacterial, antifungal, antiviral, antimalarial, and anticancer. The two-step synthesis of 762, isolated from the sponge Fascaplysinosis sp. was developed. Homolytic benzoylation of b-carboline (Minisci reaction) under microwave irradiation, followed by pyridinium chloride-catalyzed cyclization produced 762 (Scheme 150).242 Two routes to 763 and 764, isolated from the Fijian sponge Fascaplysinosis reticulate, were developed based on photocyclization of 765. The rst is a one-pot photocyclization/photochemical dehydrogenation. The second is a two-step synthesis using

Fig. 31

Fig. 30 Fig. 32


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Scheme 150 Reagents and conditions: (i) POCl3, MeCN, benzene; (ii) (S,S)-TsDPEN, HCOOH, Et3N, DMF; (iii) (Boc)2O, DMAP, CH2Cl2; (iv) NH2NH2, EtOH; (v) NaBH3CN, AcOH, MeOH; (vi) 4 M HCl, dioxane.

Fig. 33

photocyclization and subsequent DDQ-mediated oxidation (Scheme 152).243 The total synthesis of a new indolotrypoline alkaloid, cladoniamide G (766), isolated from extracts of Streptomyces uncialis, was reported. The key step is one-pot generation of 766 by the condensation of 3,30 -bis-indole 767, derived from 5,50 dichloroindigo, with conjunctive electrophilic reagent 768 (Scheme 153).244 Indenotryptoline alkaloid, BE-54017 (769), isolated from Streptomyces sp. A54017, was accomplished using Os-promoted cis-dihydroxylation of maleimide 770 at a late-stage. Its absolute conguration was determined by comparison with independently derived BE-54017 from enatiopure cladoniamide A, which showed the absolute conguration of ()-756 (natural) was (4cS,7aR) (Scheme 154).245 A short synthesis of rac-deethyleburnamonine (771) was achieved through an indium-catalyzed tandem ring-opening/ Friedel–Cras alkylation reaction of 772 followed by N-alkylation (Scheme 155).246 An asymmetric synthesis of ()-dihydrocorynanthenol (773) was reported. The key step was the one-pot threecomponent catalytic asymmetric tandem Michael/Pictet– Spengler/lactamization reaction for the assembly of b-carboline intermediate 774 with high enantioselectivity (Scheme 156).247 The full details of the total syntheses of P-(+)-dispegatrine (776), (+)-spegartine (777), (+)-10-methoxyvellosimine (778), (+)-lochnerine (779), and (+)-sarpagine (780), and the rst total synthesis of lochvinerine (781) and (+)-lochneram (782) were

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reported. Pentacyclic ketone (783), obtainable from 5-methoxytryptophan by a known method, was used as the key common intermediate. Synthesis of (+)-776 was achieved by the thallium(III)-mediated oxidative coupling of (+)-779, and the axial chirality at the C9–C90 bond of dimer 779 was established as P (Scheme 157).248,249 The rst total synthesis of dichtomide I (784) and marinacarbolines A (785), B (786), C (787), and D (788) was accomplished using carboline 789 as a common intermediate that was previously developed for the synthesis of dichotomine C (Scheme 158).250 The asymmetric synthesis of ()-dichotomines A (790), B (791), C (792), and D (793) was achieved starting from L-tryptophan methyl ester and 2,3-O-isopropylidene-D-glyceraldehyde. The key intermediate 795 was derived from 794 by a chiral inversion at the C14 position of the side chain. Based on the total syntheses, the absolute conguration of the stereogenic center in ()-791, 792, and 793 was revised as R (Scheme 159).251 Enantioselective syntheses of ()-dichotomine A (790) and (+)-dichotomide II (796) were achieved starting with the known intermediate 789. The kinetic resolution of rac-alcohol by enantioselective esterication using Lipase QLM produced ()-alcohol and (+)-acetate. ()-Dichotomine A (790) and (+)-796 were obtained from ()-797 and (+)-798, respectively. The absolute conguration of (+)-796 was determined to be R (Scheme 160).252 A cascade one-pot method for the synthesis of rac-harmicine (799) was developed. An acid-catalyzed cascade reaction between tryptamine and 4-chlorobutyraldehyde produced rac-799 through tandem Schiff base formation/intramolecular N-alkylation/Pictet–Spengler reaction (Scheme 161).253


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Scheme 152 Reagents and conditions: (i) t-BuOOH, MW, TFA; (ii) pyridinium chloride, 200–210 C; (iii) hv, Cu(OAc)2, air-saturated acetone, pyridine; (iv) hv, acetone, pyridine; (v) DDQ, benzene, rt.

Scheme 151 Reagents and conditions: (i) KHMDS, 18-crown-6, THF,

94 C; (ii) HCHO, hex-5-en-1-amine, MeOH, reflux; (iii) AIBN, n-Bu3SnH, toluene, reflux; (iv) TMSCl, KI, 4A MS, MeCN, rt; (v) AgNO2, Et2O, rt; (vi) DIBAH, toluene, 78 C; (vii) Ti(i-PrO)4, Ph2SiH2, hexane, 0 C; (viii) TiCl3, THF, H2O, rt; (ix) 3-butenylmagnesium bromide, CeCl3, THF, 0 C; (x) TMSOTf, Et3N, Et2O, rt; (xi) Commins' reagent, KHDMS, THF, 78 C; (xii) Grubbs' first generation catalyst, CH2Cl2, reflux; (xiii) Pd(PPh3)4, 761, DMF, 60 C.

A formal synthesis of oxopropaline G (800), isolated from Streptomyces sp. G324, was reported. The known intermediate 801 was obtained by an iodine-promoted cascade of two electrophilic iodocyclization reactions on alkyne and alkene (Scheme 162).254 A formal synthesis of rac-tangutorine (802) was achieved by preparation of the known intermediate 803 using Cu(II)-mediated conjugate addition and organozinc/copper coupling (Scheme 163).255 The microwave-assisted Pictet–Spengler reaction between tryptamine and acetal was applied for the synthesis of rac-802 (Scheme 164).256 The direct N-acylation of imine with benzoic acid was developed for the preparation of a variety of heterocycles. This method was applied for the synthesis of evodiamine (804), isolated from Evodiae fructus. The advantage of this approach is the direct use of carboxylic acid in the generation of the N-acyliminium ion, using propylphosphonic acid anhydride 805 as an activator (Scheme 165).257


Scheme 153 Reagents and conditions: (i) NH2NH2H2O, NaOH, 80 C; (ii) Me2SO4; (iii) AcOEt, reflux.

Enantioselective syntheses of desbromoarborescidines A (806), B (807), and C (808), and the formal synthesis of (S)-deplancheine (809) were achieved using (S)-indolo[2,3-a] quinolizine as a key common intermediate (810), which was derived from amidolactone through a base-catalyzed rearrangement and diaselective intramolecular cyclization (Scheme 166).258 An intramolecular alkene hydroamination reaction was used for the synthesis of rac-806. The key step was the construction of the b-carboline core by the hydroamination of hydroxylamine 811 (Scheme 167).259

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Scheme 156 Reagents and conditions: (i) 775, EtOH, rt, then tryptamine, TFA, CH2Cl2, 50 C; (ii) LiAlH4, THF, reflux; (iii) (COCl)2, DMSO, Et3N, CH2Cl2, 78 C; (iv) Ph3PMeBr, BuLi, THF; (v) Pd/C, H2, MeOH, then 3 N HCl, H2, Pd/C, MeOH. Scheme 154 Reagents and conditions: (i) N-methylmaleimide, SnCl2, toluene, 110 C; (ii) Pd black, nitrobenzene, 200 C; (iii) MeI, KOH, DMF, rt; (iv) OsO4, pyridine, 40 C, then sat. NaHSO3, 50 C.

Scheme 155 Reagents and conditions: (i) Rh2esp2, CH2Cl2, rt; (ii) In(OTf)3, CH2Cl2, rt; (iii) TFA; (iv) NaCl, DMSO.

The synthesis of rac-807 was reported. Tetracyclic intermediate 812 was prepared through the one-pot In-promoted allylation of in situ-generated iminium, followed by RCM with Grubbs' catalyst (Scheme 168).260 A catalytic enantioselective synthesis of (+)-reserpine (813) was accomplished. The tetracyclic intermediate 814 was assembled by a thiourea-catalyzed diastereoselective formal aza-Diels–Alder reaction between dihydro-b-carboline and enantioenriched enone (Scheme 169).261 The total synthesis of rac-hirsutine (816) was achieved using phosphine-catalyzed [4 + 2] annulation as the key step. Cycloaddition between imine 817 and allenoate 818 in the presence

Nat. Prod. Rep.

of PBu3 provided tricyclic intermediate 819, which was converted to rac-816 through the formation of the C-ring via an intramolecular alkylation and diastereoselective addition of the malonate anion (Scheme 170).262 Enantioselective syntheses of dihyrocorynantheol (820), geissoschizol (821), and isogeissoschizol (822) were realized. Tetracyclic intermediate 824 was assembled through the Ru(II) (TsDPEN)-catalyzed asymmetric transfer hydrogenation of imine 823 followed by spontaneous lactamization, with discrimination between the two diastereotopic centers (Scheme 171).263 Eudistomidins G (825), H (826), and I (827) are new b-carboline alkaloids, isolated from the Okinawan marine tunicate Eudistoma glaucus. Asymmetric rst total syntheses of 825–827 were completed using the Noyori catalytic asymmetric hydrogen-transfer reaction of dihydro-b-carboline 828 as the key step (Scheme 172).264 The syntheses of eudistomins Y1 (829), Y2 (830), Y3 (831), Y4 (832), Y5 (833), Y6 (834), and Y7 (835), isolated from the Korean tunicate genus Eudistoma, were accomplished through a onepot reaction of tandem benzylic oxidation/aromatization as the key step. The key intermediate 1-acyl-b-carboline 838 was obtained by iodine-mediated oxidation of tetrahydro-b-carboline 836 or oxidation of 3,4-dihydro-b-carboline 837 with DBU in air (Scheme 173).265,266 Straightforward access to enantiopure 1-substituted tetrahydro-b-carboline alkaloids ()-N-methyltetrahydroharman (839), (+)-tetrahydroharman (840), komaroidine (841), and ()-N-acetylkomaroidine (842) was developed. Enantiopure 1-substituted b-carboline 844 was assembled by a stereoselective reduction of the oxazolidine ring of oxazolopiperidone lactam 843 derived from (R)-phenylglycinol (Scheme 174).267


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Scheme 158 Reagents and conditions: (i) NaOH, H2O, MeOH, rt; (ii) b-alanine methyl ester, DCC, DMAP, CH2Cl2, 20 C to rt; (iii) 1-ethoxyvinyltin, PdCl2(PPh3)2, Et4NCl, DMF, 100 C; (iv) 2 M HCl, MeOH, rt; (v) DCC, DMAP, CH2Cl2, 20 C to rt; (vi) tryptamine, DEPC, Et3N, DMF, 10 C to rt.

Scheme 157 Reagents and conditions: (i) (Z)-1-bromo-2-iodo-2butene, K2CO3, MeCN, rt; (ii) Pd(PPh3)4, PhOH, t-BuOK, THF, 75 C; (iii) Tl(OAc)3, BF3OEt2, MeCN, 40 C to 10 C; (iv) BBr3, CH2Cl2, 78 C; (v) MeI, MeOH, 40 C, sealed tube, then AgCl, MeOH.

Mitragynine (845), paynantheine (846), and speciogynine (847) were accessed through the thiourea-catalyzed enantioselective Pictet–Spengler reaction of amine 848 with aldehyde 849, leading to tricyclic intermediate 850 in 89% ee. Intermediate 850 was transformed into alkaloids 845–847 through the Tsuji– Trost reaction (Scheme 175).268


Scheme 159 Reagents and conditions: (i) TFA, AcOEt, 0 C; (ii) MsCl, DIPEA, CHCl3, 0 C; (iii) BzOH, DIPEA, CHCl3, 50 C; (iv) HCl, MeCN, H2O, rt; (v) Et3N, MeOH, reflux; (vi) NaOH, MeOH, H2O, 60 C, then AcOH, rt; (vii) K2CO3, n-BuOH, reflux.

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Scheme 162 Reagents and conditions: (i) I2, dichloroethane; (ii) Zn dust, AcOH; (iii) Na, naphthalene, THF; (iv) Pd/C, maleic acid, H2O. Scheme 160 Reagents and conditions: (i) 1-(ethoxyvinyl)tributyltin, PdCl 2(PPh3)2, Et4NCl, DMF, 100 C; (ii) HCl, MeOH, rt; (iii) NaBH4, MeOH, rt; (iv) vinylacetate, lipase QLM, t-BuOMe; (v) NaOH, H2O, dioxane, rt; (vi) NaOMe, MeOH, rt; (vii) TBDMSCl, imidazole, CH2Cl 2, rt; (viii) NH3, MeOH, sealed tube, 50 C; (ix) methyl cis-2iodoacrylate, CuI, DMEDA, Cs2CO3, toluene, 75 C; (x) TBAF, THF, rt.

Scheme 161

Reagents and conditions: (i) TFA, MeCN, 90 C.

Two concise approaches to annomontine (852), 1-(20 -aminopyrimidin-4-yl)-b-carboline alkaloid, were developed, which involved the Pictet–Spengler reaction between tryptamine and aldehyde, or inverse electron demand of the aza-Diels–Alder reaction (Scheme 176).269 The synthesis of nitramarine (853) and lavendamycin methyl ester (854) was achieved using the Povarov reaction (imino Diels–Alder reaction between imines and 1-vinyloxybutane) to construct quinolines 855 and the known intermediate 856 for 854 (Scheme 177).270 The enantiospecic total synthesis of (+)-eburnamonine (857), ()-aspidospermidine (545), and ()-quebrachamine (858) was achieved using esters 859, 860, and 861 as the key chiral building blocks derived from L-ethyl lactate. ()-Aspidospermidine (545) was obtained from 861 through the Pictet– Spengler reaction followed by in situ lactamization. (+)-Eburnamonine (857) was derived from 860, and ()-858 was synthesized starting with 859 through the Pictet–Spengler

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Scheme 163 Reagents and conditions: (i) CH2]CHMgBr, CuI, 70 C to 20 C; (ii) LiEt3BH, THF, 0 C: (iii) Ph3P, I2, imidazole, THF, rt; (iv) Zn, ethyl 2-(bromomethyl)acrylate, CuCN, TMSCl, 1,2-dibromoethane, DMF; (v) Grubbs' 2nd generation catalyst, toluene, 80 C; (vi) POCl3, toluene, 80 C; (vii) NaBH4, EtOH, 0 C; (viii) TFA, CH2Cl2, rt.

reaction and reductive ring opening of the quaternary salt (Scheme 178).271,272 g-Pyrone-containing indole alkaloid pleiomaltinine (862) was derived from the natural alkaloid pleiocarpamine. The key

Scheme 164 Reagents and conditions: (i) TFA, CH2Cl2, MW; (ii) NaBH4, CeCl3, MeOH.


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Scheme 165 Reagents and conditions: (i) propylphosphonic acid anhydride 805, i-Pr2NEt, toluene, 90 C.


Scheme 167 Reagents and conditions: (i) NaCNBH3, t-BuOH, MW, 120 C; (ii) TFA, CH2Cl2, rt; (iii) SOCl2, CH2Cl2, sealed tube, 40 C; (iv) NaOH, H2O, CH2Cl2, rt.

Reagents and conditions: (i) ClCOOEt, THF, then CH2]CHCH2Br, In; (ii) Grubbs' 2nd generation catalyst, CH2Cl2; (iii) NaH, DMSO; (iv) LiAlH4, THF. Scheme 168

Scheme 166 Reagents and conditions: (i) t-BuOK, THF, 78 C to 50 C; (ii) Ac2O, Et3N, DMAP, CH2Cl2, rt; (iii) NaBH4, MeOH, CH2Cl2, 10 C to 0 C; (iv) TFA, CH2Cl2, 10 C to 0 C; (v) AlH3, THF, rt; (vi) CHCl3, rt; (vii) AlH3, THF, rt; (viii) Burgess reagent, benzene, reflux.

feature was an acid-promoted pyrone annulation of b-carboline with 3-siloxy-4-pyrone (Scheme 179).273 2.3

Bisindole alkaloids

Two new bisindole alkaloids, cyclovinblastins A (863) and B (864), were isolated from the leaves of Catharanthus roseus, and evaluated for their cytotoxic activities (Fig. 34).274


A pair of polybrominated spiro-trisindole enantiomers, similisines A ((+)-865) and B (()-865), were isolated from the chloroform extract of Laurencia similis, collected in the South China sea. Compound (+)-865 exhibited moderate cytotoxic activity against HL-60 and JURKAT cell lines (Fig. 35).275 Six new alkaloids, trigolutes A (866), B (867), C (868), and D (869), and torigolutesines A (870) and B (871), were obtained from the EtOH extract of the twigs of Trigonostemon lutescens collected in the Guangxi Zhuang Autonomous Region of China. Compound 870 showed weak AChE inhibitory activity (Fig. 35).276 Three new dimeric carbazole alkaloids, bisgerayafolines A (872), B (873) and C (874), were isolated from the CHCl3 extract of the fruit pulp of Murraya koenigii, one of the most popular spice species. All compounds were evaluated for antioxidant, anti-a-glucosidase, DNA binding, and cytotoxic activities, and interactions with BSA (Fig. 36).277 Two new carbazole alkaloids, 875 and 876, were isolated from the sponge Penares sp., collected from the Vietnam waters (the South China Sea). Compound 875 showed moderate

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Scheme 169 Reagents and conditions: (i) 815, AcOH, toluene, rt; pyridinium fluoride, pyridine, THF, 0 C; (iii) Dess–Martin periodinane, CH2Cl2; (iv) piperidine, TsOH, toluene.

cytotoxicity against the human tumor cells HL-60 and HeLa (Fig. 37).278 Two new dimeric carbazole alkaloids, 877 and 878, along with one simple carbazole alkaloid 879, were obtained from the stems of Glycosmis pentaphylla (Fig. 37).279

Scheme 170 Reagents and conditions: (i) Bu3P, CH2Cl2, rt; (ii) SiO2; (iii) (COCl)2; (iv) BH3; (v) I2, PPh3; (vi) CH2(CO2Me)2, NaOMe; (vii) DIBAH; (viii) Ph3P]CH2; (ix) Pd/C, H2; (x) DIBAH; (xi) TMSCHN2.

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Scheme 171 Reagents and conditions: (i) HCO2H, Et3N, (R,R)-Ru(II) (TsDPEN), DMF, rt; (ii) (Boc)2O, DMAP; (iii) NaOH; (iv) ClCO2Et, Et3N, NaBH4; (v) TBSCl, imidazole; (vi) LDA, DMPU, 78 C, then CH3CHO; (vii) MsCl, Et3N, then DBU; (viii) DCC, CuCl, benzene; (ix) DIBAH, 40 C; (x) TBAF; (xi) K2CO3, MeOH, reflux; (xii) AlH3, THF, 0 C; (xiii) TBAF; (xiv) K2CO3, MeOH, reflux.

Five new bisindole alkaloids, goniomedines A (880) and B (881),280 goniomedinone (882), goniomedine A-methylene chloride (883), and goniomedine A-N-oxide (884)281 were isolated from the stem bark of Gonioma malagasy. Compound 881 is a natural alkaloid, and 880, 882, 883, and 884 are artifacts formed during the alkaloid-extraction process (Fig. 38). Three new bisindole alkaloids, perhentidines A (885), B (886), and C (887), were isolated from the stem-bark extract of Alstonia macrophylla and Alstonia angustifolia, widely distributed in Southeast Asia (Fig. 39).282 Five new vobasinyl-iboga-type bisindole alkaloids, tabernaricatines A (888), B (889), C (890), D (891), and E (892), and two new monomeric indole alkaloids, tabernaricatines F (893) and G (894), were isolated from the aerial parts of Tabernaemontana divaricate (Fig. 40).283 Two new bisindole alkaloids, geleganimines A (895) and B (896), were isolated from the aerial parts of Gelsemium


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Reagents and conditions: (i) HOBt, EDC, CH2Cl2, 0 C; (ii) POCl3, benzene, reflux; (iii) (S,S)–Ru(II) (TsDPEN), HCO2H, Et3N, rt; (iv) HCHO, NaBH3CN, MeCN, 40 C; (v) DBU, CH2Cl2, rt; (vi) paraformaldehyde, benzene, reflux.


Scheme 172

elegans, and are the rst bisindole alkaloids obtained from the genus Gelsemium. Compound 896 exhibited antiinammatory activity by suppressing lipopolysaccharideinduced pro-inammatory factors in BV2 microglial cells (Fig. 41).284 Bioassay-guided fractionation of the AcOEt extract of the whole culture of fungal strain Oidiodendron truncatum GW3-13 yielded two new epipolythiodioxopiperazines, chetracins B (897) and C (898), ve new diketopiperazines, chetracin D (899) and oidioperazines A (900), B (901), C (902), and D (903). Compounds 897, 898, and 899 showed potent cytotoxicity against ve human cancer cell lines in the nanomolar range, whereas 898 and 900 exhibited signicant cytotoxicity at a micromolar concentration (Fig. 42).285 Eight new indole alkaloids, melosuavines A (904), B (905), and C (906), an aspidosperma-scandine linkage, bisindole alkaloids melosuavines D (907), E (908), and F (909), possessing an aspidosperma–aspidosperma core, and melosuavines G (910) and H (911), featuring an aspidosperma–venalatonine core, were isolated from the twigs and leaves of Melodinus suaveolens. Compounds 904, 905, 907, 908, and 909 showed low micromolar cytotoxicity against one or more of ve human cancer cell lines (Fig. 43).286


Scheme 173 Reagents and conditions: (i) I2, K2CO3, AcOEt, 80 C; (ii) NaOH, H2O, EtH, 90 C; (iii) DBU, O2 in air, DMSO, rt; (iv) HBr, H2O, AcOH.

Scheme 174 Reagents and conditions: (i) benzene, reflux; (ii) LiAlH4, AlCl3, THF, 33 C; (iii) Pd(OH)2, H2; (iv) Na, liq. NH3; (v) AcCl.

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Scheme 177 Reagents and conditions: (i) aniline, MgSO4, CH2Cl2, reflux; (ii) I2, THF, reflux; (iii) LiOH, MeOH, H2O, rt; (iv) Cu, quinolone, 260 C. Scheme 175 Reagents and conditions: (i) 851, toluene, rt; (ii) (Boc)2O, DMAP, toluene, 40 C; (iii) AgOTf, CH2Cl2, rt; (iv) DMSO, 75 C; (v) [Pd(allyl)Cl]2, (CH2PPh3)2, i-Pr2NEt, Cs2CO3, THF, rt; (vi) MeOCH2PPh3Cl, t-BuOK, THF, 78 C; (vii) TFA, TFAA, CH2Cl2; (viii) H2, Pd/C, AcOEt.

Chemical investigation of the rust-coloured extra-suber layer of the stem bark of Strychnos nux-vomica allowed the isolation of three new bisindole alkaloids, strychnochrysine (912), demethoxyguiaavine (913), and Nb-methyl-longicaudatine (914). The specic antiplasmodial activity of all compounds was studied in vitro (Fig. 44).287

Scheme 176 Reagents and conditions: (i) TFA, rt; (ii) IB(X) TBAB, MeCN, rt; (iii) MW, 180 C; (iv) Pd/C, H2, MeOH.

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Four new aspidosperma–aspidosperma-type bisindole alkaloids, 3-oxovoafrine (915), and voacandimines A (916), B (917), and C (918), were isolated from the seeds and root bark of Voacaga africana, a tropical tree distributed in Africa (Fig. 45).288 Two new alkaloids, mekongenines A (919) and B (920), were isolated from the MeOH extract of twigs and leaves of Bousigonia mekongen distributed in southern China, Laos, and Vietnam. Compound 919 showed moderate cell growth inhibitory activity against ve human cell lines (Fig. 46).289 Two new alkaloids, trigolutesins A (921) and B (922), with a unique polycyclic system, and four new bisindole alkaloids, trigolutes A (923), B (924), C (925), and D (926), were isolated from the twigs of Trigonostemon lutescens collected in the Guangxi Zhuang Autonomous Region of China. The acetylcholinesterase inhibitory activities for all compounds were tested. Only 921 showed weak inhibitory activity (Fig. 47).290 Bioassay-guided fractionation of the AcOEt extract of the stem bark of Muntafara sessilifolia led to the isolation of six new vobasinyl-iboga bisindole alkaloids, tabernaelegantinals A (927), B (928), and E (929), and hydroxytabernaelegantines A (930), C (931), and D (932). Biological evaluation of all compounds against the in vitro development of the chloroquine-resistant strain FcB1 of Plasmodium falciparum established that 929 showed the highest activity (Fig. 48).291 A novel chlorinated bisindole alkaloid featuring an eightmembered ring, caulerchlorin (933), was isolated from the


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Fig. 34

Scheme 178 Reagents and conditions: (i) (MeO)2P(O)CH2CO2Me, NaH, THF, 0 C to rt; (ii) NiCl2, NaBH4, MeOH, 0 C; (iii) O3, CH2Cl2, MeOH, 78 C, then Me2S, 0 C; (iv) tryptamine, AcOH, reflux; (v) Pd/C, H2, MeOH; (vi) 40% H2SO4; LiAlH4, THF; (vii) tryptamine, TFA, CH2Cl2, 20 C; (viii) allylbromide, K2O3, DMF, 0 C to rt; (ix) Grubbs' 2nd generation catalyst, CH2Cl2, rt; (x) Pd/C, H2, EtOH, rt; (xi) TPAP, NMMO, CH2Cl2, rt; (xii) DIBAH, CH2Cl2, 78 C; (xiii) tryptamine, TFA, CH2Cl2, 0 C to rt; (xiv) allylbromide, K2CO3, DMF, 0 C to rt; (xv) Grubbs' 2nd generation catalyst, CH2Cl2, reflux; (xvi) H2, Pd/C, MeOH; (xvii) 6 N HCl, MeOH, rt; (xviii) MsCl, pyridine, 0 C; (xix) CHCl3, reflux; (xx) Na. liq. NH3, EtOH.

Scheme 179

Chinese green alga Caulerpa racemosa (Fig. 49).292 Two new heteroaromatic bisindole alkaloids, hyrtimomines D (934) and E (935), were isolated from an Okinawan marine sponge Hyrtios sp. collected off Kerama Island, Okinawa (Fig. 49).293 A new diketopiperazine dimer with N-1 to C-6 linkage, aspergilazine A (936), was isolated from the marine-derived fungus Aspergillus taichungensis ZHN-7-07, associated with the mangrove plant Acrostichum aureum. Evaluation of the antiviral activities of this compound on inuenza A virus indicated that A had weak activity (Fig. 49).294 An Aspergillus

Reagents and conditions: (i) HCl, MeCN, rt. Fig. 35


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Fig. 36

Fig. 38

Fig. 37 Fig. 39

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Fig. 42

Fig. 40

Fig. 41


versicolor (MF030) recovered from a sediment sample collected at a depth 60 m from the Bohai Sea in China yielded a new dimeric diketopiperazine alkaloid, brevianamide S (937). This compound exhibited signicant antibacterial activity against BCG. Although the potency of the anti-BCG activity is modest compared to the positive control isoniazid, the selectivity toward BCG is particularly noteworthy (Fig. 49).295 Investigation of the chemical constituents of the deep-seaderived Streptomyces sp. SCSIO 03032, taking advantage of a PCR-based screening approach, led to the isolation of four new bisindole alkaloids, spiroindimicins A (938), B (939), C (940), and D (941). The in vitro cytotoxicities of all four compounds were evaluated against 5 cancer cell lines. Compound 939 showed moderate cytotoxic activity (Fig. 50).296 Three new heteroaromatic alkaloids, hyrtimomines A (942), B (943), and C (944), were obtained from an Okinawan marine sponge Hyrtios sp. collected off Kerama Island, Okinawa. Compound 942 showed cytotoxicity against human epidermoid carcinoma KB cells and murine leukemia L1210 cells in vitro (Fig. 51).297

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Fig. 45

Fig. 43 Fig. 46

Fig. 44

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Fig. 47


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Fig. 49

mainly found in the Yunnan and Guangxi provinces of China. All the compounds were evaluated for cytotoxicity against human cell lines. Compounds 950 and 951 showed signicant inhibitory activity against cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480) (Fig. 53).299 The biomimetic synthesis of 2,5-bis(3-indolylmethyl)pyrazine (954) through the dimerization/oxidation of a-amino aldehyde 953 derived from L-tryptophan was reported (Scheme 180).300 The bacterial pigment violacein (956) was synthesized. Pyrrolidinone 957, resulting from a tandem RCM/isomerization/ nucleophilic addition, was converted to 956 through Ti-catalyzed tautomerization/aldol condensation between 957 and isatin (Scheme 181).301 Fig. 48

Four derivatives of tabernaelegantine, 30 -oxotabernaelegantines A (945) and B (946), and hydroxytabernaelegantines A (947) and C (948), and one 2-acyl monomeric indole, 19,20adihydroeleganine A (949), were isolated from the stem bark of Muntafara sessilifolia. Compound 947 was obtained as a mixture of 30 R and 30 S epimers, which are artifacts of extraction. All the compounds were evaluated in vitro for antiplasmodial activity against the chloroquine-resistant strain FcB1 of Plasmodium falciparum, and for cytotoxicity against the human lung cell line and the rat skeletal muscle cell line (Fig. 52).298 Four vobasinyl-iboga-type bisindole alkaloids, ervachinines A (950), B (951), C (952), and D (953), were isolated from the EtOH extract of the whole plant of Ervatamia chinensis, which is


Fig. 50

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Fig. 51

Dimeric indole alkaloid, yuehchukene (958), was synthesized by the dimerization of in situ-generated diene from 959 (Scheme 182).302 A bisindole alkaloid, ()-isatisine A (960), was isolated from the leaves of Isatis indigotica Fort., a herbaceous plant used in

Fig. 53

traditional Chinese Medicine. The total synthesis of ()-960 was reported two groups. A biomimetic approach was accomplished by Xie's group, involving benzylic ester rearrangement as a key biomimetic transformation. Intermediate 961 was transformed to 962 through CuCl-mediated tandem biomimetic oxidation/ benzylic ester rearrangement (Scheme 183).303 Ramana's group completed the synthesis of ()-960 starting with D-ribose, which featured four consecutive metal-promoted reactions at the late-stage, involving the Pd-catalyzed

Fig. 52

Nat. Prod. Rep.

Scheme 180 Reagents and conditions: (i) HNME(OMe), HATU, Et3N, CH2Cl2; (ii) LiAlH4, Et2O; (iii) Pd(OH)2, H2, MeOH, CH2Cl2, AcOH, then remove H2, then air, rt.


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Reagents and conditions: (i) Hoveyda–Grubbs 2nd catalyst, 5-benzyloxyindole, THF, reflux; (ii) LDA, PhSeBr, THF, 78 C; (iii) 35% H2O2, CH2Cl2, rt; (iv) isatin, Ti(O-i-Pr)4, toluene, reflux; (v) TFA, reflux. Scheme 181

Scheme 184 Reagents and conditions: (i) 2-iodonitrobenzene,

Pd(PPh3)Cl2, CuI, Et3N, THF, rt; (ii) Ac2O, pyridine, 0 C; (iii) Pd(MeCN)2Cl2, MeCN, rt; (iv) Indole, InCl3, MeCN, 80 C; (v) K2CO3, MeOH, rt; (vi) [RhCpCl2]2, K2CO3, acetone, 100 C; (vii) TiCl4, CH2Cl2, 0 C.

Sonogashira coupling, Pd-mediated nitroalkyne cycloisomerization, In-catalyzed indole addition, and Rh-catalyzed oxidative lactamization (Scheme 184).304 Biomimetic total syntheses of dimethylisoborreverine (963), isoborreverine (964), and inderoles A (965), B (966), and C (967) were completed using the dimerization of 968 by Lewis acid-promoted formal [3 + 2] cycloaddition and [4 + 2]

Scheme 182

Reagents and conditions: (i) TMSCl, DME, 100 C.

Reagents and conditions: (i) LDA; (ii) 2 N HCl, MeOH, rt; (iii) Pd(OH)2/C, H2; (iv) CuCl; (v) hv; (vi) CSA, CH2Cl2. Scheme 183


Scheme 185 Reagents and conditions: (i) BF3OEt2, CH2Cl2, rt; (ii) Na/ Hg, Na2HPO4, MeOH, rt; (iii) IBX, AcOEt, reflux; (iv) Me2NH, NaCNBH3, AcOH, MeOH, rt; (v) MeNH2, NaBH4, Fe(OTf)3, CH2Cl2, rt.

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Scheme 188 Reagents and conditions: (i) proline, MeCN, rt;

(ii) 6-bromoindole, I2, MeCN, reflux; (iii) N2H4, EtOH, rt.

Scheme 186 Reagents and conditions: (i) BF3OEt2, pyridine; (ii) HCl, MeOH; (iii) MeOTf, CHCl3, then TFA.

cycloaddition. Borreverines 963 and 964 were derived from [4 + 2] adduct 969, and formal [3 + 2] adduct 970 was transformed into inderoles 965, 966, and 967 (Scheme 185).305 The biomimetic synthesis of indersial alkaloids inderoles A (965) and B (966), desmethylinderole C (971), inderole C (967), isoborreverine (964), dimethylisoborreverine (963), and borreverine (972) was reported based on an acid-mediated dimerization of natural product borrerine (973), which began with acidic opening of 973 to iminium and diene (Scheme 186).306 Bisindolylmethanes are present in many natural products, exhibiting a broad range of biological activity. A platinumcatalyzed tandem indole annulation/arylation sequence was

Reagents and conditions: (i) indole, PtCl2, P(C6F5)3, Na2CO3, dioxane, 100 C; (ii) 160 C; (iii) POCl3, DMF. Scheme 187

Nat. Prod. Rep.

successfully developed for the construction of 2,30 -biindolylmethanes. Malassezin (974), isolated from cultures of the yeast Malassezia furfur, was synthesized (Scheme 187).307 A method for the preparation of unsymmetrical 3,3-biindolylmethan was developed using the proline-catalyzed condensation of barbituric acid 976 with aldehyde 977, followed by addition of indole, in which barbituric acid acted as a good leaving group. A natural product, 2,2-bis(60 -bromo-30 indolyl)ethylamine (975), isolated from the gulf of California, Tunicate Didemmum candidum, was synthesized (Scheme 188).308 A one-pot procedure for the preparation of 3,30 -bisindolylmethanes from nitrobenzene through the Bartoli indole synthesis was developed, in which quenching the reaction in the presence of an additional aldehyde with HCl produced bisindolylmethanes 978. Arundine, vibrindole, 3,30 -bisindolyl phenylmethane, tris(3-indolyl)methane, arsindoline,

Scheme 189 Reagents and conditions: (i) vinylmagnesium bromide, THF, 40 C to 0 C, then RCHO, then HCl; (ii) n-Bu3SnH, AIBN, toluene, reflux.


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Scheme 190 Reagents and conditions: (i) NBS, MeCN, rt; (ii) TsCl, NaH, THF, 0 C; (iii) LiAlH4, Et2O, CH2Cl2, rt; (iv) Cu, K2CO3, nitrobenzene, 170 C; (v) NBS, MeCN, rt, (vi) Boc2O, DMAP, rt.

Scheme 191 Reagents and conditions: (i) Boc2O, DMAP, MeCN, rt; (ii) DIBAH, Et2O, 78 C; (iii) methanesulfonic anhydride (0.75 equiv.), i-Pr2NEt, CH2Cl2, 0 C to rt.

streptindole, and arsindoline B were prepared (Scheme 189).309 Dimeric carbazole alkaloids, murrastifoline-A (979) and bismurrayafoline-A (980) were synthesized starting with mukonine (981). The Ullmann-type coupling of bromide 983 with murrayafoline-A (982) afforded 979, whereas the coupling of 984 with 982 afforded 980 through an unprecedented rearrangement (Scheme 190).310 The rst synthesis of oxydimurrayafoline (985) was completed by treating 981 with substoichiometric amounts of methanesulfonic anhydride in the presence of amine (Scheme 191).311 The total synthesis of biscarbazole alkaloids, murrafolines A (986), B (987), C (988), and D (989), was achieved. The Pd-catalyzed Sonogashira coupling of 990 with 991 produced biscarbazole 992 through the cascade Sonogashira coupling/ Claisen rearrangement/enolization/1,5-H shi/electrocyclic cyclization process. Murrafolines A (986) and C (988) were obtained from 992. Murrafolines B (987) and D (989) were


Scheme 192 Reagents and conditions: (i) Pd(PPh3)4, CuI, piperidine, rt; (ii) 30% Pd/C, H2, AcOEt; (iii) prenal, Ti(O-i-Pr)4, 78 C to rt; (iv) citral, Ti(O-i-Pr)4, 78 C to rt; (v) CSA, toluene, rt; (vi) LiAlH4, CH2Cl2, Et2O, rt.

derived from biscarbazoles 993 and 994, respectively (Scheme 192).312 The rst total synthesis of rac-dievodiamine (995), isolated from Evodia rutaecarpa, was realized using the Stille coupling reaction of two advanced indole intermediates 996 and 997 at the nal step (Scheme 193).313

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Scheme 195 Reagents and conditions: (i) I2, Cs2CO3, MeCN, rt; (ii) Nanaphthalenide, THF, 78 C; (iii) formalin, NaBH(OAc)3, MeCN, rt.

Scheme 193 Reagents and conditions: (i) ethynylmagnesium chloride, LiCl, toluene; (ii) Bu3SnH, AIBN, benzene; (iii) KOH, H2O, reflux; (iv) NIS, acetone; (v) PdCl2(PPh3)2, Et4NCl, CuI, DMF.

The enantioselective synthesis of cyclotryptamine alkaloid (+)-folicanthine (998), was reported. The key step was a chiral phosphoric acid-catalyzed enantioselective

Scheme 196 Reagents and conditions: (i) Pd2(dba)3CHCl3, dppe, THF, 70 C; (ii) Zn, AcOH, rt; (iii) ClCO2Me, K2CO3, THF, H2O, rt; (iv) BrCH2CO2Me, NaH, DMF, rt; (v) LiOH, THF, H2O, rt; (vi) (COCl)2, benzene, rt, then 85 C; (vii) Et3N, benzene, 90 C; (viii) MeNHOH, NaHCO3, MS 3A, EtOH, 50 C, then p-TsCl, 4-DMAP, CHCl3, 70 C; (ix) LiAlH4, THF, reflux; (x) 5 N NaOH, MeOH, reflux; (xi) LiAlH4, THF, reflux.

nucleophilic substitution of 3-hydroxyindole 999 with enamine 1000. The known intermediate 1001 was prepared (Scheme 194).314

Scheme 194 Reagents and conditions: (i) 1002, CH2Cl2, rt; (ii) n-Bu4NHSO4, KOH, MeI; (iii) NH2OH, pyridine, EtOH, rt; (iv) HgCl2, MeCN, 80 C; (v) t-BuOK, MeI, THF, rt; (vi) DMSO, HCl/AcOH, rt; (vii) BrCH2CO2Et, n-Bu4NHSO4, aq. NaOH, toluene, rt; (viii) CAN, MeCN, H2O; MeNH2, EtOH, 60 C.

Nat. Prod. Rep.

Scheme 197 Reagents and conditions: (i) ClCO2Et, aq. NaOH, CHCl3, 0 C; (ii) n-Bu4NHSO4, NaOH, CH2Cl2, rt, then (Boc)2O, 0 C; (iii) NBS, PPTs, CH2Cl2, rt; (iv) Zn, NiCl2, 2,20 -bipyridine, pyridine, MeCN, rt; (v) TMSI, MeCN, 0 C to rt; (vi) red-Al, toluene, rt to 90 C; (vii) aq. HCHO, NaBH(OAc)3, MeCN, rt.


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Reagents and conditions: (i) indole, (R)-1013, pH 7 buffer, EtOH, rt; (ii) CH(OMe)3, p-TsOH, 80 C, then BnBr, NaH, rt; (iii) HCl, AcOH, DMSO, rt; (iv) CH(OMe)3, p-TsOH, 80 C; (v) allyl bromide, NaH, DMF, rt; (vi) O3, PPh3, CH2Cl2, 78 C; (vii) 5% HCl, AcOH, 60 C. Scheme 200

Reagents and conditions: (i) nitroethylene, Mn(4-FBzO)2, 1009, MS 5A, toluene, 50 C; (ii) nitroethylene, Mg(OAc)2, benzoic acid, MS 5A, THF, 50 C; (iii) NiCl2, NaBH4, dimethyl dicarbonate, MeOH; (iv) LiEt3BH, toluene, 78 C to 40 C, then 4 M HCl in AcOEt, rt, then TFA, rt; (v) NaAlH(OCH2CH2OMe)2, toluene, reflux; aq. HCHO, NaBH(OAc)3, MeCN, rt. Scheme 198

A concise method for the formation of rac-folicanthine (998) was achieved using an I2-promoted regioselective C-2 amination reaction of tryptamine to provide dimeric product 1003 through C-2 amination/unexpected dimerization (Scheme 195).315 Total syntheses of rac-folicanthine (998) and rac-chimonanthine (1004) were achieved using a double intramolecular carbamoylketene [2 + 2] cycloaddition. A common intermediate 1005 was prepared from bis-carboxylic acid involving [2 + 2] cycloaddition of dienyl ketene and selective ring-expansion of bis-cyclobutanone sequences (Scheme 196).316 The nickel-catalyzed homocoupling reaction of tertiary alkyl bromide 1006 derived from tryptamine was successfully applied for the construction of bispyrrolo[2,3-b]indoline 1007

Scheme 199 Reagents and conditions: (i) bromine salt, catalyst, Na2CO3, toluene, 0 C; Co(PPh3)3Cl, acetone; (iii) TMSOTf, CH2Cl2; (iv) red-Al, toluene.


Scheme 201 Reagents and conditions: (i) allyl chloroformate, Et3N, THF, 0 C to rt; (ii) 1019, Pd2(dba)3CHCl3, dienol dicarbonate, (n-hex)4NBr, THF, 0 C; (iii) TFA, CH2Cl2, rt; (iv) NaH, DMF, 0 C, then BnBr, rt; (v) OsO4, NaIO4, 2,6-lutidine, dioxane, H2O, rt; (vi) NaBH4, MeOH, 0 C.

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Reagents and conditions: (i) V2O5, MeSO3H, H2O, 15 C; Boc-L-PheOH, DMT-MM, EtOH, neat, 230 C, under vacuum; (iii) N-Boc-Me-L-PheOH, HATU, Et3N, DMF; (iv) neat, 230 C, under vacuum; (v) Boc-L-Pro, DMT-MM, EtOH, neat, 230 C, under vacuum. Scheme 202

Review

Scheme 204 Reagents and conditions: (i) Rh2(OAc)4, MS4A, CH2Cl2, rt; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, 0 C; (iii) DIBAH, CH2Cl2, 78 C; (iv) DMP, pyridine, CH2Cl2, rt.

involving vicinal quaternary carbons, which was transformed to rac-chimonanthine (1004) and rac-folicanthine (998) (Scheme 197).317 Catalytic asymmetric syntheses of (+)-chimonanthine (1004) and (+)-folicanthine (998) were accomplished. The key step was the construction of the vicinal quaternary stereogenic carbon centers by sequential Michael reactions catalysed by a Mn(4-F-BzO)2/ligand and Mg(OAc)2/benzoic acid system. A one-pot double Michael reaction using Mn(4-FBzO)2/ligand showed only mild reactivity toward the second

Scheme 203 Reagents and conditions: (i) (CuOTf)2 toluene, CH2Cl2, rt; (ii) NaBH4, EtOH; (iii) 1027, Pd[P(o-tol)3]2, Na2CO3, DMF, 100 C, then 1 N HCl, MeOH.

Nat. Prod. Rep.

Scheme 205 Reagents and conditions: (i) 1033, 30% H2O2, 1,3-diisopropylcarbodiimide, DMAP, CH2Cl2, 0 C; (ii) Sc(OTf)3, toluene, 110 C; (iii) MeNH2, MeOH, then Boc2O, sat. NaHCO3, then CbzCl, Et3N, DMAP, CH2Cl2; (iv) NaBH4, MeOH; (v) NBS, DBU, CH2Cl2.


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Michael reaction, whereas sequential Michael reactions involving the rst Mn-catalyzed reaction and the second Mg-catalyzed reaction led to the key Michael adduct 1008 (Scheme 198).318 ()-Chimonanthine (1004) was synthesized using enantioselective bromocyclization of tryptamine and co-catalyzed homodimerization of chiral 3-bromopyrroloindole. Enantioselective cyclization of tryptamine to pyrroloindole 1010 was attained by using bromine salt and chiral phosphoric acid with 95% ee (Scheme 199).319 The formal synthesis of ()-chimonanthine (1004) was achieved by the construction of the known intermediate 1012. The key step was the asymmetric conjugate addition of indole to (Z)-isatylidene-3-acetaldehyde using the Jørgensen-Hayashi

Scheme 206 Reagents and conditions: (i) MeMgCl, THF, 78 C; (ii) TBSOTf, Et3N, DMAP, DMF, rt; (iii) OsO4, NMO, t-BuOH, acetone, H2O; (iv) Ac2O, DMAP, CH2Cl2, rt; (v) BF3OEt2, H2S, CH2Cl2, 78 C to rt; (vi) O2, MeOH, AcOEt, rt; (vii) La(OTf)3, MeOH, 45 C; (viii) I2, Et3N, AcOEt; (ix) MeI, K2CO3, acetone.



catalyst 1011, which provided adduct 989 bearing all-carbon quaternary stereocenters at the 3-position, with 92% ee (Scheme 200).320 The formal synthesis of ()-chimonanthine (1004), ()-folicanthine (998), ()-WIN64821 (1014), and ()-ditryptophenaline (1015) was reported. The key step was the construction of two vicinal quarternary carbon stereocenters of bisallyl oxindole 1016 by the Pd-catalyzed decarboxylative asymmetric allylic alkylation reaction in high regioselectivity and enantioselectivity (92% ee). The known intermediates 1017 and 1018 were derived from 1016 (Scheme 201).321 The synthesis of (+)-WIN 64821 (1014), ()-ditryptophenaline (1015), and (+)-naseseazine B (1020), was accomplished using direct the bio-inspired dimerization of tryptophan along the lines of the proposed biosynthetic pathway. Oxidation of tryptophan with V2O5 in MeSO3H and H2O produced three dimeric intermediates 1021, 1022, and 1023 for 1014, 1015, and 1020, respectively, in a one-step procedure (Scheme 202).322

Scheme 207 Reagents and conditions: (i) CuOAc, KOAc, toluene, 90 C; (ii) H2S, BF3OEt2, CH2Cl2, 78 C to rt; (iii) MeI, K2CO3, AcOEt; (iv) La(OTf)3, DMAP, MeOH, 50 C; (v) LiI, pyridine, 90 C; (vi) TfOH, CH2Cl2, 40 C.

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Reagents and conditions: (i) HATU, HOAT, Et3N, DMF; (ii) aq. HCHO, AcOH, NaBH3CN, MeOH; (iii) TMSOTf, i-PrNEt2, CH2Cl2.

Scheme 209 Reagents and conditions: (i) Tf2O, 3-cyanopyridine, MeCN, 85 C; (ii) NaBH3CN, THF; (iii) Pt/C, H2, THF; (iv) TFA, CF3CO2Na, H2O, 70 C; (v) LiAlH4, THF, 65 C; (vi) Tf2O, 2-chloropyridine, MeCN, rt; (vii) red-Al, 0 C.

Total synthesis of (+)-naseseazines A (1024) and B (1020) was reported, which featured the one-step construction of pyrroloindoline 1025 from a tryptophan derivative by copper-catalyzed arylation in high site- and diastereoselectivity. Pyrroloindoline 1025 was converted to (+)-1020 through a modied Larock indolization. (+)-Naseseazine A (1024) was derived from 1026 (Scheme 203).323 A Rh-catalyzed three-component reaction of 3-diazooxindole with indole and ethyl glyoxylate diastereoselectively provided 3,30 -bisindole 1029 through an zwitterion generation/Aldol addition sequence. Bisindole was converted to the known intermediate 1030 for rac-gliocladin C (1028) (Scheme 204).324 The formal synthesis of (+)-gliocladin C (1028) was accomplished by synthesis of the known chiral intermediate 1032. The key feature was a Sc(OTf)3-mediated oxidative rearrangement of hydroxyindolenine leading to rearrangement product 1031 (Scheme 205).325 Detailed accounts of the total syntheses of (+)-gliocladine C (1028), (+)-leptosin D (1035), (+)-T988C (1036), (+)-bionectin C (1037), and (+)-gliocladin A (bionectin C) (1038) were reported. The convergent syntheses were accomplished via the intermediate (+)-1034, involving stereoselective dihydroxylation of the C11–C11a double bond and stereoselective introduction of

Scheme 210 Reagents and conditions: (i) hv, MeCN; (ii) BnBr, K2CO3, DMF; (iii) (Boc)2O, DMAP, MeCN; (iv) N-selectride, THF; (v) LiOH, H2O, THF; (vi) NH4Cl, NH3, MeOH, sealed tube, then TMSCN; (vii) ClCO2Me, K2CO3, THF; (viii) CoCl2, NaBH4, MeOH; (ix) NH3, MeOH, sealed tube; (x) TMSI, MeCN.

Scheme 208

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Scheme 211 Reagents and conditions: (i) CuI, 1066, Cs2CO3, THF, 70 C; (ii) BCl3, CH2Cl2; (iii) HF, Et3N.

Fig. 54

sulfur groups at C3 and C11a, followed by oxidation (Scheme 206).326 The rst total synthesis of plectosphaeroic acids B (1039) and C (1040), isolated from the marine fungus Plectosphaerella cucumerica, was completed. The key features were Cu-mediated C–N cross coupling between the known pyrazinopyrroloindole 1042 and iodocinnabarinic acid diester 1041, and stereoselective introduction of the methylthio groups. The epitrisulde unit of (+)-1039 was formed by ring expansion of an epidisulde (Scheme 207).327,328 The rst total synthesis of nocardioazine B (1043) was accomplished, which relied on the condensation of two building blocks, 1044 and 1045, readily available from L- and D-tryptophan. The NMR spectra of the synthetic compound were


identical to those of the natural compound, but the optical rotation of synthetic ()-1043 was opposite to that of natural sample (+)-1043, whose absolute conguration was established (Scheme 208).329 A convergent strategy for the enantioselective syntheses of ()-N-methylaspidospermidine (1046), (+)-N-methylquebrachamine (1047), and (+)-dideepoxytabernaebovine (1048) was developed. The key feature was the construction of the pentacyclic intermediate employing a stereoselective double cyclization cascade involving the Bishler–Napieralski reaction en route. Electrophilic activation of lactam/rapid spirocyclization/cyclization of the vinyl group on to the indolenium produced diiminium 1049, which was then transformed into ()-1046 and (+)-1047. Dimerization of lactam 1051 with indole 1050 led to (+)-1048 through the formation of the C2–C150 bond (Scheme 209).330 Sponge metabolite dragmacidin E (1052) was synthesized from 7-hydroxyindole, involving the construction of a cycloheptanone ring by Witkop photocyclization in tryptophan (1053), followed by Dickmann cyclization (1054), the lactam ring opening (1055), spiroimidazolone ring formation (1056), pyrazinone ring formation (1057), and the late-stage installation of the guanidine (Scheme 210).331

2.4

Peptide alkaloids

Investigation into the chemical constituents of the roots of Psammosilene tunicoides, a well known medicinal herb in south

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China, led to the isolation of a new cyclic peptide, tunicyclin G (1058) (Fig. 54).332 Cyclic peptides calyxamides A (1059) and B (1060) were isolated from the marine sponge Discodermia calyx collected near Shikine-jima island, Japan. The absolute congurations of amino acids and the structures were determined by spectroscopic analyses and degradation experiments (Fig. 54).333 Pipestelide A (1061), containing brominated b-tyrosine and pipestelide B (1062) containing polypropionate with a Z-double bond, were isolated from the Pacic marine sponge Pipestela candelabra (Fig. 54).334 Full details of the total synthesis of pacidamycin D (1063), isolated from the fermentation broth of the Streptomyces coeruleorubiduns strain, were reported. The key step was the copper-catalyzed cross-coupling of tetrapeptide carboxamide 1064 with Z-oxyvinyl iodide 1065 (Scheme 211).335 The rst synthesis of cyclic peptides tunicyclins C (1067) and D (1068), isolated from the Chinese medicinal herb Psammosilene tunicoides, was achieved by Fmoc solid-phase peptide synthesis. Aer successful addition of amino acids to the resinbound peptide and the cleavage of the peptides from the resin, the resulting linear peptides 1069 and 1070 were transformed to 1067 and 1068, respectively (Scheme 212).336

Scheme 213

Reagents and conditions: (i) pyridine acetate buffer;

(ii) TFA, H2O.

Daptomycin (1071) is a lipodepsipeptide isolated from Streptomyces roseoporus and has potent bactericidal activity. Its total synthesis was achieved, which relied on macrocyclization via a serine ligation to assemble the 31-membered cyclic peptide. The macrocyclization was effected by dissolving peptide salicylaldehyde ester (1072) in pyridine acetate buffer, followed by treating with TFA/H2O (Scheme 213).337

3 References

Scheme 212 Reagents and conditions: (i) HBTU, DIPEA, DMF, rt; (ii) BOP, DIPEA, DMF, rt.

Nat. Prod. Rep.

1 A. W. Schmidt, K. R. Reddy and H. J. Kn¨ olker, Chem. Rev., 2012, 112, 3193. 2 J. Roy, A. K. Jana and D. Mal, Tetrahedron, 2012, 68, 6099. 3 I. Bauer and H.-J. Knolker, Top. Curr. Chem., 2012, 309, 203. This journal is © The Royal Society of Chemistry 2015

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