Accepted Manuscript Title: Marine cytotoxic jaspine b and its stereoisomers: biological activity and syntheses Author: Miroslava Martinková, Jozef Gonda PII: DOI: Reference:

S0008-6215(16)30006-4 http://dx.doi.org/doi: 10.1016/j.carres.2016.01.009 CAR 7119

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Carbohydrate Research

Received date: Revised date: Accepted date:

18-11-2015 11-1-2016 20-1-2016

Please cite this article as: Miroslava Martinková, Jozef Gonda, Marine cytotoxic jaspine b and its stereoisomers: biological activity and syntheses, Carbohydrate Research (2016), http://dx.doi.org/doi: 10.1016/j.carres.2016.01.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Marine cytotoxic jaspine B and its stereoisomers: biological activity and syntheses Miroslava Martinková , Jozef Gonda Institute of Chemical Sciences, Department of Organic Chemistry, P. J. Šafárik University, Moyzesova 11, Sk-040 01 Košice, Slovak Republic

ARTICLE INFO Artical history: Received Accepted Available online

Keywords: Sphingolipids; Anhydrophytosphingosines; Jaspine B; Cytotoxic activity; Stereoselective synthesis, Asymmetric synthesis

Graphical Abstract

Jaspine B and its stereoisomers: synthesis and biological activity Miroslava Martinková,* Jozef Gonda Institute of Chemical Sciences, Department of Organic Chemistry, P. J. Šafárik University, Moyzesova 11, 040 01 Košice, S Republic

 Corresponding author. Tel.: +421 55 2342329; fax: +421 55 6222124; e-mail address: [email protected] (M. Martinková).

1 Page 1 of 88

ABSTRACT

Conformationally constrained sphingolipids such as anhydrophytosphingosines represented by jaspine B (also known as pachastrissamine) and its stereoisomers have become an attractive and timely target for total synthesis due to their significant biological activity as well as the unique structures. This review article describes the biological activity and chemistry of the natural jaspine B and its seven stereoisomers.

Contents

1. Introduction 2. Synthetic approaches toward jaspine B and its stereoisomers Syntheses of anhydrophytoshphingosines using the Chiron approach

2.1.

2.1.1. Syntheses from serine scaffolds 2.1.2. Syntheses from phytosphingosines 2.1.3. Syntheses from carbohydrates and their derivatives 2.1.4. Syntheses from tartaric acid derivatives 2.1.5. Syntheses from other chiral substrates 2.2.

Syntheses anhydrophytoshingosines from achiral substrates

2.3.

Syntheses anhydrophytosphingosines from racemic substrates

2.4.

Syntheses of racemic anhydrophytosphingosines

3. Miscellaneous 4. Conclusion References

1. Introduction Sphingolipids

(SLs),

a

conspicuous

class

of

natural

products

including

sphingomyelins, cerebrosides and more complex glycosphingolipids are essential components of eukaryotic cells. Besides pivotal structural roles in the membrane construction, they also serve as a source for bioactive metabolites such as sphingosine-1-phosphate (SIP), sphingosine (Sph) and ceramide (Cer) that are involved in various significant cell signalling pathways and processes.1 Membrane 2 Page 2 of 88

sphingolipids were discovered as far back as 1884 by J. L. W. Thudichum2 who first defined the chemical composition of the brain, and over the past 20 years much has been learned about their chemistry and biology. The biosynthesis of SLs has been very well documented by several reviews,1,3 especially by Overkleeft’s and Aerts’s groups,1d and its first necessary step utilizes the decarboxylative condensation of the amino acid L-serine and palmitoyl CoA, via the action of serine palmitoyltransferase (SPT),1c,3 an essential enzyme for the regulation of sphingolipid levels in cells, to produce a precursor for the construction of the key D-erythro-sphinganine 14 (Fig. 1). On the other hand, defects in their metabolism have led to the formation of numerous inherited metabolic disorders resulting in a sphingolipid substrate accumulation.1d The principal backbone of sphingolipids is based on the structurally related class of lipophilic compounds very often termed the sphingoid bases. This family involve the aliphatic amino alcohols with long hydrocarbon side chains where three C18 derivatives ‒ sphinganine 1,4 D-erythro-sphingosine 24b,5 and D-ribo-phytosphingosine 34b,5b,6 are predominant in nature (Fig. 1). Among them, 1 has been found in many organisms as an early intermediate in the de novo pathway leading to sphingolipds including 2 and 3.

D-erythro-Sphingosine

2 is the major core unit in mammal SLs,

and both 1 and 2 were found to inhibit protein kinase C.7 As mentioned above, sphingosine 2 itself as well as its derivatives such as sphingosine-1-phosphate and ceramide have been implicated as mediators in various cell signalling pathways.1 The natural sphinganine 1, sphingosine 2

and related members of the mammalian

sphingolipid family are the (2S,3R)-configured, but sphingoid bases produced by invertebrates and various microbes possess various configuration.4b,8 It should be noted that 2 is not easily available from natural sources and is prepared via chemical synthesis, in contrast to D-ribo-phytosphingosine 3 (Fig. 1), that is readily accessible on an industrial scale through fermentation processes.9,10 Among the mentioned naturally occurring sphingoid bases, 3 originally isolated from the mushroom Amanita muscaria,11 represents the most abundant member of phytosphingosine family that is more frequent in plants and fungi.1e Recent studies in Saccharomyces cerevisiae have confirmed the key role of 3 in heat stress response.12 In humans, amide-linked derivatives of 3 (phytoceramides)1a occupy the uppermost layer of the epidermis (skin) and thus contribute to the generation of the water permeability barrier to prevent lethal dehydratation.1d It should be noted, there have been further structural and compositional variations of the sphingoid bases produced by various living 3 Page 3 of 88

organisms and this biodiversity has been excellently documented by the several reviews.1g,1i,4b,8 Apart from the open chain forms, phytosphingosines also possess cyclic anhydro structures. One such naturally occurring anhydrophytosphingosine molecule is jaspine

B (4) (also known as pachastrissamine, Fig. 1) that has been isolated independently from two marine sponges (Pachastrissa sp.13a and Jaspis sp.13b) together with its oxazolidine congener, jaspine A (5, Fig. 1).13b It is highly likely that jaspine B (4) is biosynthetically derived from D-ribo-phytosphingosine considering the same number of carbon atoms in the backbone, as well as the same stereochemical C-2/C-3 amino alcohol motif (phytosphingosine numbering, see Fig. 1) for both, 3 and 4. The structure of 4 was determined by the extensive spectroscopic studies13 including NOE experiments13a to be unprecedented sphingolipid related cyclic molecule, which is characterized by the presence of a (2S,3S,4S)-configured tetrahydrofuran skeleton with the amino, hydroxyl and C14 alkyl chain functionalities. All these structural features have been revealed to be crucial for its biological activity (vide infra). Jaspine B (4) has been reported to exhibit a significant in vitro cytotoxicity against several different cancer cell lines such as A-549,13,14a-b,14h P-388,13a HT-29,13a MeL-28,13a,14c MCF-7,14b,14d-f KB,14b HCT-116,14f-h,14k U2OS,14g MDA-231,14f,14i,14k

HeLa,14f,14i

CNE,14i MGC-803,14e EC-9706,14e PC-3,14h,14k A-375,14j WM-115,14j Caco-2,14f Jurkat,14f SNU-638,14k and Caki-114k with IC50 in the micromolar to sub-micromolar ranges. Andrieu-Abadie’s studies14c have shown that 4 induced apoptosis on melanoma cells (murine B16 and human MeL-28). This effect is due to its potent inhibitory activity against sphingomyelin synthase (SMS), an essential enzyme involved in the biosynthesis of sphingomyelins.1c-d With the aim to elucidate the structure-activity relationships in 4 and its congeners, the role of the configuration of stereocentres on the tetrahydrofuran backbone on the biological profile has been investigated.14a,14d,14g,15 Delgado and co-workers14a and also Génisson et al.14g confirmed that the absolute configuration of the tetrahydrofuran core is the decisive factor for the cytotoxic properties. ent-Jaspine B (ent-4), for instance, was found to display a lower activity against some aforementioned cell lines [HTC-116 (ent-4),14g U2OS (ent-4),14g MCF-7 (ent-4.TFA,14d ent-4.HCl14f), MDA-MB-231 (ent-4.HCl),14f HCT-116 (ent-4.HCl),14f Caco-2 (ent-4.HCl),14f Jurkat (ent-4.HCl),14f HeLa (ent4.HCl)14f]. Furthermore, compounds 6 (A-549,14a,14l MCF-7,14d,14l DU-145,14l A4 Page 4 of 88

172,14l PLC/PRF/5,14l 786-O14l and DLD-114l), ent-6.HCl (MDA-MB-231, MCF-7, HCT-116, Caco-2, Jurkat, HeLa),14f 7 (A-549,14a MDA-MB-231,14f MCF-7,14f HCT116,14f Caco-2,14f Jurkat,14f HeLa14f) and ent-8 (A-54914a) were less potent than jaspine B, but still retained the activity. To promote these aforementioned findings concerning the SAR, other studies focused on the side-chain modified analogues of jaspine B, compounds (9-16)14e,15a-b as well as the core ring-modified derivatives (17-23)14h,14i,15c of 4 have been developed (Fig. 2). Among the analogues of 4, the sulphur and selenium derivatives 17 and 18, respectively, exhibited significant activity compared with the natural jaspine B against HCT-116, A-549, PC-3 cancer cell lines.14h Also, the aza-analogue 19 and carbocylic derivatives 20-2214k (Fig. 2) were shown to be potent inhibitor of the growth of B-16, A-375, WM-115 cells (for 19)14i and HCT116, SNU-638, MDA-MB-231, PC-3, Caki-1 (for 20-22)14k at very low concentrations. According to the recently Liu’s study, 1,2,3-triazole-jaspine B hybrids 16 (Fig. 2) were found to indicate excellent cytotoxicity (EC-9706, MGC-803 and MCF-7).14e It should be noted, that there are three reports encompassing the cytotoxicity of jaspine B (4),14b,14g its TFA salt,14b also antipode (ent-4),14g further 4.HCl,14f ent-4.HCl,14f ent-6.HCl14f and 7.HCl14f towards non-cancer cell lines, namely NiH 3T314b,14f and GM-637.14g Further biological screening realized by Fujii et al.16a revealed that jaspine B and all its isomers inhibit both forms of sphingosine kinase (SphK1 and SphK2) with moderate to high activities, at which compounds ent7 and 8 (Fig. 1) exhibited the most potent inhibitory profile. The same authors also have demonstrated that SphK inhibitory activity depends on the length of the hydrocarbon side chain and the naturally C14 carbon functionality was found to be the most optimal.16b Kim and co-workers14k also reported inhibitory activity of 20 against SphKs. Their obtained results revealed that the appropriate length of the alkyl unit is evidently requisite to maintain the biological profile. Truncated or side-chain elongated analogues 21 and 22, respectively, were less potent than 20 and surprisingly, the ring oxygen atom of 4 seems to be unnecessary.14k On the other hand, jaspine A (5) was toxic at concentrations as low as 0.1 μg/mL in the Artemia salina bioassay as well as the ethanolic extract from the sponge Jaspis sp. containing both jaspines 4 and 5 displayed cytotoxicity against KB cancer cell line (IC95 = 10 μg/mL),13b none further report on the biological properties besides Debitusʼs work has been published so far. Jaspine A was also screened for cytotoxic

5 Page 5 of 88

activity on A549 tumor cells, but its cytotoxic potency was not demonstrated due to poor solubility of 5 in DMSO.13b

2. Synthetic approaches toward jaspine B and its stereoisomers

The significant biological activity, simple, but unique structural features and limited availability of the natural anhydrophytosphingosines have resulted in the development of numerous total syntheses of 4, as well as its stereoisomers (Figs. 3-6). In 2008, Davies et al.17a reviewed the isolation, characterization, stereochemical assignment, and syntheses of jaspine B together with the construction of 2-epi-jaspine B (6). In last seven years a number of synthetic chemists have undertaken studies on the preparation of jaspine B and its analogues employing different approaches and various starting materials, however, the most straightforward routes still appear to be those utilizing the Chiron approach, especially carbohydrates and serine scaffolds (vide infra) since they encompass a part of the chiral moieties that are seen in the final anhydrophytosphingosines.

2.1.

Syntheses of anhydrophytoshphingosines

using the Chiron

approach

2.1.1. Syntheses from serine scaffolds

Starting from serine scaffolds such as Garner aldehydes (24 and ent-24) and D-serine methyl ester, several independent synthetic approaches to anhydrophytosphingosines have been published. In 2009, Fujii, Ohno and co-workers18 accomplished a synthesis of jaspine B (4), in which palladium(0)-catalyzed bis-cyclization of bromoallenes 26a and 26b, possessing hydroxyl and benzamide groups as internal nucleophiles for the successive cascade reaction, was employed as the key transformation (Scheme 1).18 The erythro-alkynol 25a was stereoselectively prepared from (S)-Garnerʼs aldehyde 24 using the known pocedure19 in 78% yield and with diastereomeric ratio of > 20:1. Its treatment with MsCl and Et3N furnished the corresponding mesylate, whose reaction with CuBr.Me2S/LiBr20 (Taddeiʼs protocol) afforded the desired (S,aR)bromoallene 26a (59%). Exposure of 26 to acidic hydrolysis (TFA) resulted in 6 Page 6 of 88

cleavage of the N,O-isopropylidene and Boc groups. The liberated amino functionality was reprotected applying BzCl/Et3N to form amide 27 (56%). Optimized reaction conditions (Cs2CO3, Pd(PPh3)4, THF/MeOH (10:1), 50 °C) of the subsequent Pd(0)-catalyzed cascade cyclization18 of 26a afforded the require bicyclic product 28 with very good yield of 89%. With the aim to compare the difference in reactivity between diastereomeric allenes 26a and 26b, authors also prepared epimeric bromoallene 26b by the similar reaction sequence (Scheme 2).18

The obtained results of the cyclization step demonstrated that both allenes 26a and 26b afforded the same product 28 to allow the utilization of an epimeric mixture of bromoallenes for the construction of tetrahydrofuran derivative 28. To complete the total synthesis, hydroboration (9-BBN) of 28 followed by oxidative treatment gave alcohol 29 (80%) with the requisite stereochemistry as the sole isomer. Activation of 29 as its triflate (Tf2O, Et3N) and subsequent displacement with a cuprate derived from C13H27MgBr/CuI furnished product 30 (80%) possessing an aliphatic side chain. Finally, 4 was obtained in 80% yield by acid hydrolysis of 30 (Scheme 1).18 The spectroscopic data and optical rotation of the synthetic jaspine B were in accord with those reported in the literature for the natural compound13a (see Table 3). A year later, the same scientific group reported a stereodivergent synthesis of jaspine B (4) based on the aforementioned elaborated Pd(0)-catalyzed cyclization route using in this case propargylic substrates such as carbonates 34 and chlorides bearing the long alkyl chains (Scheme 3).21 The construction of the carbonates syn-34 and anti-34 commenced with the addition of pentadec-1-yn-1-yllithium 31 to aldehyde 24 gave the corresponding alkynol syn-3219 in 83% yield and with diastereomeric ratio of >95:5. Modification of syn-32 into carbonate syn-33 (94%) was achieved by treatment with ClCO2Me in pyridine and in the presence of DMAP. Subsequent deprotection of the acetonide and Boc groups in syn-33 followed by benzoylation (BzCl/DIPEA) resulted in the formation of the amide syn-34 (74%). In a parallel fashion, Garnerʼs aldehyde 24 was transformed into anti-34 via the diastereomeric alcohol anti-3219,21 (Scheme 3).

For the preparation of propargyl chlorides syn-36 and anti-36 (Scheme 3), alcohols 32 were chosen as the starting points and were treated with Ph3PCl2 and imidazole in 7 Page 7 of 88

several solvents. The use of DMF, MeCN, THF and CH2Cl2 as solvents produced the corresponding syn-35 with high diastereoselectivities (95:5) as well as increased the yields of syn-35 (from 9% for DMF to 30% for CH2Cl2). The isomeric anti-35 was prepared from anti-33 (Ph3PCl2, imidazole, CH2Cl2) in 47% and with diastereomeric ratio of syn:anti > 5:95. In both cases, the reaction was performed with net retention of configuration.21 Amides syn-36 and anti-36 were obtained using the same reaction conditions as described for the transformation of compounds 33 into 34 (Scheme 3).21 Both, propargyl carbonates 34 and chlorides 36 were then subjected to Pd(0)catalyzed bis-cyclization and furnished the required bicyclic tetrahydrofurans (E)/(Z)37 along with the undesired oxazoline products cis/trans-38. Reaction of syn-34 with Pd(PPh3)4 in THF afforded the corresponding bicyclic derivatives 37 in yield of 69% and with high selectivity (E:Z > 95:5). The diastereomeric carbonate anti-34 provided under the same conditions 37 in low yield (< 20%) but with high selectivity (E:Z > 95:5) and with SN2 product 38 (60%). In the case of substrates 36, after optimization of the reaction conditions (Pd(PPh3)4, Cs2CO3, THF/MeOH = 10:1), propargyl chloride syn-36 afforded the corresponding cascade products 37 in 89% yield and excellent selectivity (E:Z > 95:5). On the other hand, using the same conditions as described for syn-36, anti-36 gave 37 in 55% yield with moderate selectivity (E:Z = 13:87) together with products 38 (32%), revealing the effectiveness of syn-36 as a precursor of bicyclic structures. The obtained results demonstrated a difference in reactivity between the diastereoisomeric substrates and the cyclization of the propargylic substrates with syn configuration was shown to be more efficient (Scheme 4).21 To accomplish the synthesis of jaspine B, catalytic hydrogenation (H2, (Ph3P)3RhCl, EtOH/C6H6) of (E)-37 resulted in the formation of the saturated derivative 3018 (82%, for 30, see also Scheme 1), whose treatment with DIBAl-H yielded the protected jaspine B derivative 39. Its debenzylation with the heterogeneous catalyst Pd(OH)2/C produced jaspine B (4) in 86% yield (Scheme 4).21 Its spectroscopic data and optical rotation matched the known values reported for the same compound18 (see also Table 3).

In the same year, Fujii, Ohno and co-workers22 published a stereodivergent synthesis of jaspine B (4) and its three diastereoisomers, namely compounds 6, 7 and ent-8. The naturally occurring stereoisomer 4 was elaborated via bis-tosylation of the common precursor molecule 41b, prepared from (S)-Garnerʼs aldehyde 24 through a two-step 8 Page 8 of 88

sequence. The Wittig reaction of 24 with a non-stabilized ylide afforded a mixture of the known olefins 4023 (92%) with high Z-selectivity (Z:E = 13:1). Subsequent dihydroxylation of 40 (OsO4, MNO) gave the corresponding diols 41a and 41b in 91% yield and with diastereomeric ratio of 23:77. The derivative 41b was then treated with TsCl in the presence of Et3N and Me3N.HCl to give the bis-tosylate 42, whose acid hydrolysis provided the desired product 43 possessing tetrahydrofuran core as the result of the intramolecular nucleophilic displacement of the -OTs functionality at C-4 by the liberated primary alcohol group at C-1. The final deprotection of 43 afforded jaspine B (4) (Scheme 5).22 The material had spectroscopic data and optical rotation in good agreement with those published in the literature.18,21

As illustrated in Scheme 6, for the preparation of 2-epi-jaspine B (6), the common intermediate 41b was chosen as a starting material. Removal of the isopropylidene moiety in 41b with p-TsOH in MeOH gave the protected D-ribo-phytosphingosine 44.14a,24 Its regioselective monotosylation prompted spontaneous cyclization of the formed intermediate 45 to yield the N-Boc-2-epi-jaspine B (46)14a,24 in 91% yield. Deprotection of the carbamate group with TFA afforded target molecule 6 (Scheme 6).22 A similar approach for the construction of 6, which included ring closure readily effected through the selective tosylation of the primary hydroxyl group, was previously used by Overkleeftʼs24 and also Delgadoʼs groups.14a

For the preparation of 3-epi- and 2,3-di-epi-jaspine B diastereoisomers 7 and ent-8, respectively, regio- and stereospecific ring-opening of the orthoester 48 assisted by a nucleophilic attack of the neighboring carbamate functionality was used as the key step. This transformation produced the protected D-xylo-phytosphingosine 50 as the common precursor for both anhydrophytosphingosines 7 and ent-8. To achieve the synthesis of 3-epi-jaspine B (7), triol 44 was selectively silylated with TIPSCl to give the corresponding ether 47. Its treatment with MeC(OMe)3 in the presence of catalytic amounts of BF3.OEt2 provided compound 49 (96%) via activation of a transient orthoester into the oxonium cation 48 and subsequent nucleophilic attack of the Boc oxygen regioselectively to the C-3 position. Protection of the carbamate nitrogen with a Boc group and hydrolysis of the oxazolidinone under basic conditions produced derivative 50 as the 3-epimer of 47. Bis-tosylation of 50 followed by desilylation of 9 Page 9 of 88

the generated product 51 provided the desired tetrahydrofuran derivative 52 (70%). 3epi-Jaspine B (7) was obtained in 89% yield after removal of the remaining protecting groups (Scheme 7).

2,3-Di-epi-jaspine B (ent-8) was obtained from the common intermediate 50 through a four-step sequence as seen in Scheme 8.22 Desilylation of 50 under standard conditions (TBAF, THF) furnished the known derivative 53.14a Its subsequent selective monotosylation followed by treatment of the generated derivative 54 with base (K2CO3) gave compound 55. Its hydrolysis with TFA resulted in the formation of ent-8 (Scheme 8). Koskinen and Passiniemi25 have reported a short synthetic route toward jaspine B and its three diastereomers 6, 7 and ent-8 from (S)-Garnerʼs aldehyde 24 through a palladium(0)-mediated cyclization and olefin cross-metathesis reaction as the key transformations. Iodide 59 was coupled with aldehyde 24 by treatment with n-BuLi and additives (HMPT, DMPU) or chelating metals/Lewis acids to give the corresponding adducts anti-60a and syn-60b (for anti/syn-selectivities, see Table 2), which were sepateated by column chromatography. The known iodide 5926 was prepared from propargyl alcohol 56 in 51% overall yield over three steps (Scheme 9).25

Alcohols 60a and 60b were independently treated with BnBr and NaH to afford benzyl ethers 61a and 61b. Their desilylation (TBAF, THF) furnished allyl derivatives 62a and 62b, which were subsequently acetylated producing the corresponding acetates 63a and 63b. Deprotection of the N,O-isopropylidene fragment with FeCl3/SiO2 in CHCl3 provided compounds 64a and 64b (Scheme 9).25 The open-chain allyl acetates anti-64a and syn-64b afforded after Pd(0)-mediated intermolecular cyclization25 the desired tetrahydrofuran derivatives 65a/65b and 66a/66b in very good combined yields: for 65a/65b (87%), for 66a/66b (89%) and with moderate to good selectivities (65a:65b ~ 2:1, 66a:66b ~ 9:1). After chromatographical separation, all prepared diastereoisomers 65a-b and 66a-b were 10 Page 10 of 88

then subjected to the olefin cross-metathesis (OCM) reaction with tetradec-1-ene using Grubbsʼ-second generation catalyst. The catalytic hydrogenation (H2, Pd/C) of the coupled products 67-70 followed by deprotection (HCl, MeOH) furnished jaspine B (4) and its three stereoisomers 6, 7 and ent-8 in the form of free bases, respectively (Scheme 10).25

In 2013, Fujii, Ohno and co-workers16b published the improved sterodivergent synthesis of the four anhydrophytosphingosine molecules 4, 6, 7 and ent-8 from (S)Garnerʼs aldehyde 24 via an indium-mediated acetoxyallylation and OCM reaction as the key steps. For the indium-mediated reductive coupling reaction between aldehyde 24 and 3-bromoprop-1-enyl acetate was adopted Trombiniʼs protocol,27 which afforded after hydrolysis (K2CO3, MeOH/H2O) the common scaffold 71 in 77% yield (Scheme 11). Its transformation to jaspine B (4) was achieved over 6 steps in 34% overall yield. Exposure of 71 to TsCl, Et3N, and Me3N.HCl produced bis-tosylate derivative 72 (79%). Compound 72 was converted into the tetrahydrofuran derivative 73 by treatment with p-TsOH in MeOH. Cleavage of the tosyl moiety in 73 and the subsequent protection of the free amino functionality with CbzCl afforded the corresponding carbamate 74 in 84% yield over two steps. The OCM reaction of 74 with tetradec-1-ene in the presence of Grubbss II catalyst followed by the final catalytic hydrogenation (H2, Pd/C) gave jaspine B (4) (Scheme 11).16b In order to obtain 2-epi-jaspine B (6), removal of the isopropylidene moiety of the common diol 71 with p-TsOH in MeOH was accomplished to provide compound 75 (84%). The deprotected primary hydroxyl group in 75 was selectively tosyated (TsCl, Et3N, Me3N.HCl) and the resulting product was treated with base (K2CO3) in MeOH to give the cyclization derivative 76 in 80% yield over to steps. The subsequent OCM reaction, heterogeneous hydrogenation, and deprotection of the Boc group resulted in the formation of the target molecule 6 (Scheme 12).16b The key transformation for the preparation of 3-epi-jaspine B (7) was stereoinversion process at the C-3 position in 77 involving thionyl chloride as an activating reagent.

Bis-silylated derivative 77 was regioselectively obtained from 71 (TBDPSCl, imidazole, CH2Cl2) in excellent 94% yield. Reaction of 77 with SOCl2 was formed the 11 Page 11 of 88

oxazolidinone 78 (83%), whose the nitrogen atom was protected with a nosyl group to produce compound 79. Cleavage of the silyl protecting groups (TBAF) and cyclic carbamate under basic conditions afforded the corresponding triol 80. Its treatment with MeC(OMe)3 in the presence of BF3.OEt2 gave the tetrahydrofuran core 81 (86%) through the known protocol24 utilizing the orthoester production. Following the same conditions described for the OCM transformation in Scheme 11, the reaction of 81 with tetradecen-1-ene followed with the sequential removal of the protecting groups furnished 3-epi-jaspine B (7) (Scheme 12).16b The cyclic carbamate 78 was chosen as the starting material for the preparation of ent8 (Scheme 13).16b Its protection with Boc2O and the subsequent desilylation provided compound 82 (95%, over two steps). Selective tosylation of the primary hydroxyl group in 82, followed by cleavage of the oxazolidinone skeleton (K2CO3, MeOH) gave the desired tetrahydrofuran 83 in 66% yield. Finally, OCM reaction, then catalytic hydrogenation and deprotection of the Boc group generated the final molecule of ent-8 (Scheme 13).16b

Shaw et al.14b have reported a stereoselective approach toward jaspine B (4) from (S)Garnerʼs aldehyde 24 using a diastereoselective iodocyclization as the key step. The nucleophilic addition of vinylmagnesium bromide to 24 afforded a separable mixture of the anti/syn allylic alcohols 8428 in 91% combined yield (anti-84a:syn-84b = 6:1) The secondary hydroxyl group in anti-84a was protected as benzyl ether 8529 (91%) using BnBr and NaH in DMF. Its OCM reaction with pentadec-1-ene afforded the desired products 86 (92%) with high E-selectivity (E:Z = 94:6). The acetonide group in 86 was removed by acid hydrolysis (p-TsOH, THF) to yield amino alcohols 87. The subsequent iodocyclization reaction (NIS, I2) provided compounds 88 possessing tetrahydrofuran skeleton in combined 90% yield and with diastereomeric ratio of 10:1, adopting the model developed by Chamberlin’s group30 for the predominant formation of 88a. After optimization of the reaction conditions, the reductive deiodination of 88a using n-Bu3SnH/ABCN (1,1'-azobis(cyclohexanecarbonitrile)) afforded two compounds 89 and 9014a in 32% and 42% yields, respectively. The resulting derivative 89 was then subjected to the catalytic hydrogenation to give the desired N-Boc-jaspine B (90). The cis relationship of the substituents around the tetrahydrofuran core in 90 was confirmed by NOE experiments.14b Treatment of 90 12 Page 12 of 88

with TFA in CH2Cl2 provided the corresponding TFA salt of 4, which after neutralization delivered the target jaspine B (Scheme 14).14b

At the same time, Panda and Jana31 published the stereoselective synthesis of jaspine B and its 2-epimer 6 from Garner’s aldehyde 24 by different synthetic routes. To achieve the preparation of 4, addition of vinylmagnesium bromide to 24, followed by separation of the major diastereoisomer anti-84a28 and N,O-isopropylidene deprotection produced diol 91 in 70% yield over two steps. The key iodocyclization reaction of 91 furnished the product 92 via the regioselective 5-exo-tet process in very good yield (90%) and with high diastereoselectivity (dr > 95:5). The acetonide formation in 92 was achieved with 2,2-DMP in the presence of CSA to yield 93 (95%). Reaction of 93 with vinylmagnesium bromide in the presence of Cu and HMPA afforded derivative 94, which was subjected to OCM reaction with tridec-1ene in the presence of Grubbs II catalyst 95 to give olefins 96 (82%). Catalytic heterogeneous hydrogenation of 96 furnished compound 97. Its treatment with 6 N HCl followed by neutralization provided jaspine B (4) in 29% overall yield (Scheme 15).31

To accomplish the construction of 2-epi-jaspine B (6), the Wittig olefination of Garnerʼs aldehyde 24 with the stabilized ylide (Ph3P=CHCO2Et) resulted in the formation of (E)-α,β-unsaturated ester 9832 exclusively in 90% yield. The Sharpless asymmetric dihydroxylation of 98 gave diol 99 (95%) with dr > 95:5, which was regioselectively tosylated and afforded the corresponding derivative 100. Its treatment with PPTS in MeOH provided the cyclic product 101 as the result of two reactions: the acetonide ring opening and intramolecular nucleophilic displacement of the Otosyl group by the liberated primary hydroxyl functionality. The incorporation of the isopropylidene moiety was achieved with 2,2-DMP in the presence of BF3.OEt2 to yield compound 102. During this transformation, the transesterification has been also performed. Reduction of 102 with LiBH4 afforded alcohol 103, which after oxidation and the subsequent Wittig reaction furnished alkene 104. The following OCM reaction of 104 with tetradec-1-ene, using Grubbs II catalyst 95, produced olefins 105 in 95% yield. Hydrogenation of 104 followed by hydrolysis of the saturated derivative

13 Page 13 of 88

106, and neutralization delivered 2-epi-jaspine B (6) in 15.6% overall yield (Scheme 16).31 In 2011, Fujii, Oishi and co-workers16a communicated the stereoselective construction of four stereoisomers of jaspine B ent-4, ent-6, ent-7 and 8 from (R)-Garner’s aldehyde ent-24 utilizing the approach published previously.22 By adopting Azuma’s protocol,23 transformation of ent-24 to olefin ent-(Z)-40 followed by dihydroxylation with OsO4 gave the corresponding diol ent-41b in 62% yield together with its diastereoisomer ent-41a (19%). Exposure of ent-41b to TsCl (Et3N, Me3N.HCl) produced di-O-tosylate ent-42 (88%), which was treated with p-TsOH to afford cyclic product ent-43. Removal of the tosyl group in ent-43 provided ent-4 in 79% yield (Scheme 17).16a With the aim to obtain ent-6, after deprotection of the acetonide group, the regioselective tosylation of ent-44 (87%) stimulated spontaneous cyclization to provide ent-46 (88%). Its treatment with TFA in CH2Cl2 generated the target molecule ent-6 in 79% yield (Scheme 17).16a The prepared compound ent-44 served as the starting point for the preparation of ent-7 according to the same reaction sequence used in Scheme 7.22 The reaction of ent-44 with TIPSCl and imidazole in DMF formed derivative ent-47, which was transformed to oxazolidinone ent-49 through orthoester formation.24

Protection of the nitrogen atom of the cyclic carbamate with a Boc group followed by alcoholysis produced ent-50 in 70% yield over two steps. Similar to the preparation of ent-4, the synthesis of di-O-tosyl derivative ent-51, its desilylation and TBAI-induced cyclization resulted in the formation of ent-52 (65%). The final two-step deprotection afforded the desired compound ent-7 (88%, Scheme 18).16a

The elaborated ent-50 was then converted into 4-epi-jaspine B (8) using the same strategy as described in Scheme 8.22 This sequence involved desilylation, selective monotosylation, treatment with a base and final deprotection to furnish 8 in 48% overall yield starting from ent-50 (Scheme 18).16a In 2013, Fujii, Ohno et al.16b published the synthesis of 8 from ent-83,16b which was obtained from (R)-Garnerʼs aldehyde ent-24 using procedures identical with those described for the synthesis of 83 but yields of the reaction steps are not given (for 83, see Scheme 13). Compound ent-83 was converted into 8 via three steps (OCM 14 Page 14 of 88

reaction, catalytic hydrogenation and deprotection) in overall yield of 44% using the same sequence as employed in Scheme 13. In 2012, Lee33 communicated a total synthesis of the antipode of 2-epi-jaspine B (ent6) wherein a three-component tandem OCM-intramolecular SN2' substitution-OCM sequence in the one-pot manner was involved. For this approach,

D-serine

methyl

ester 107 was chosen as a chiral starting material. Its transformation to the known alcohol 108 was accomplished via eight steps applying modifications of the combined literature protocols.34 The reaction of 108 with allyl chloride in the presence of Grubbs II catalyst 95 afforded the corresponding cyclic derivative 110a and 110b in 62% yield and with high diastereoselectivity (110a:110b = 10:1) through a generation of the intermediate 109, which was subjected to intramolecular nucleophilic substitution. Author further has found that treatment of 108 with the sequential addition of allyl chloride and tetradec-1-ene, using the same conditions as for the tandem transformation, produced the derivative 111 in 45% overall yield from 108 with high E-selectivity (E:Z = 10:1). Catalytic hydrogenation of 111 followed by the saponification of the resultant oxazolidinone 112 gave the final product ent-6 (Scheme 19).33 Spectral data of ent-6 matched the values present in the literature35 for its antipode 2-epi-jaspine B (6).

2.1.2. Syntheses from phytosphingosines

Among various synthetic approaches published after Daviesʼs review (2008), Delgado et al. 14a as well as Kim and co-workers,37 have estimated the potential of using the NBoc phytosphingosine structures as the starting materials. Delgadoʼs group14a has accomplished the facile synthesis of jaspine B (4) and its three diastereoisomers 6, 7 and ent-8 from the phytosphingosines 113,36 44,22,24,36 11423,36

and 53,22,36

respectively. Compounds 44, 114 and 53 were converted into the corresponding tetrahydrofuran derivatives 46,22,24 116 and 55,22 respectively, through the formation of the corresponding monotosylated derivatives 45,22 115, 5422 spontaneous cyclization of which was promoted by the used conditions (TsCl, pyridine/CH2Cl2). Regioselective protection of the primary hydroxyl group in 113 (TsCl, Et3N, DMAP, CH2Cl2) resulted in the isolation of the tosylate 117, which was then treatment with base to afford product 90.14b All the prepared cyclic products 90, 46, 116 and 55 gave

15 Page 15 of 88

after deprotection the final anhydrophytosphingosines 4, 6, 7 and ent-8, respectively (Scheme 20).14a

Kimʼs37 total synthesis of jaspine B and its 2-epimer 6, published in 2012, commenced from the common starting material 118,14h which was prepared from Dribo-phytosphingosine 4414a,24 in two steps with 90% overall yield.14h Mesylation of the oxazolidinone 118 (MsCl, pyridine) followed by treatment of 119 with BF3.OEt2 furnished the bicyclic derivative 12014g,15b in 90% yield via deprotection of the trityl moiety and concomitant cyclization. The obtained material had the same sense of optical rotation with comparable magnitude {[α]D24 = +57.5 (c 0.5, CHCl3)} to those reported in the literature14g,15b {lit.14g [α]D20 = +65.0 (c 0.8, CHCl3), lit.15b [α]D20 = +66.5 (c 1.2, CHCl3)}. However, its

13

C NMR values, especially data for THF

carbons are not concordant with previous report (lit.15b 83.2 (C-2), 80.9 (C-3), 73.3 (C-5), 57.1 (C-4), lit.37 (77.2, 73.3, 63.9, 57.1 ppm, for numbering, see Scheme 21). Hydrolysis of 120 with KOH afforded the target anhydrophytosphingosine 4 (Scheme 21).37 To obtain 2-epi-analogue 6, compound 118 was converted into diol 121 by treatment with BF3.OEt2. Regioselective tosylation of the primary alcohol functionality in 121 readily induced ring closure to provide compound ent-112.14h,37 Subsequent base-mediated deprotection of the oxazolidinone skeleton of ent-112 furnished 2-epi-jaspine B (6) (Scheme 21).

2.1.3. Syntheses from carbohydrates and their derivatives

Generally, simple carbohydrates are very often utilized as the chiral starting materials for the construction of various natural compounds due to their optical purity and the stereodiversity as well as the highly oxygenated character and high degree of functionality. Therefore, several simple sugar molecules (D-glyceraldehyde, D-ribose, D-xylose, D-glucose, D-mannose)

and their related derivatives (L-ascorbic acid,

D-

isoascorbic acid, D-galactal) have been involved for the total syntheses of jaspine B (4) and its stereoisomers. Chattopadhyay and Vichare38 have published a simple stereoselective synthesis of jaspine B (4) from 2,3-O-cyclohexylidene-D-glyceraldehyde 12239 as the source of 16 Page 16 of 88

chirality. Its nitroaldol reaction with nitromethane resulted in the formation of the easily separable adducts 123a and 123b in the combined 91% yield and with high anti-selectivity (syn-123a:anti-123b = 2:98). The free secondary hydroxyl group in 123a was protected as silyl ether 124 (TBDMSCl, Et3N). The Nef reaction of 124 generated the highly unstable aldehyde 125, which was immediately treated with C14H29MgBr to form derivative 126 as the sole diastereoisomer. Desilylation of the benzoylated product 127 afforded alcohol 128. The stereochemistry of the C-3 position was inverted through an oxidation-reduction sequence. PCC oxidation of 128 followed by reduction of ketone 129 furnished 130 exclusively in 83% yield over two steps. Exposure of 130 to BzCl produced 131 whose acid hydrolysis afforded diol 132. Its regioselective benzoylation and subsequent mesylation of the resulting compound 133 yielded 134. SN2 displacement of -OMs with NaN3 gave azide 135, which after cleavage of the benzoate ester functionalities provided triol 136 in 72% yield over three steps. Monotosylation of the primary alcohol group of 136 followed by base treatment of 137 gave tetrahydrofuran 138. The final catalytic hydrogenation resulted in the formation of the target jaspine B (Scheme 22)38 whose optical rotation was in good agreement with those reported.16b,18,21 No spectroscopic data were published by authors for this synthetic jaspine B.

Rao et al.40 have published a stereoselective approach to 2-epi-jaspine B (6) from the known protected D-ribofuranose 139 (prepared from D-ribose in two steps),41 which was initially treated with benzylamine to give ribosylamine 140 (yield of this transformation not reported). Its reaction with vinylmagnesium bromide provided exclusively erythro-isomer 141 (72%), formation of which can be explained through the generation of a seven membered transition state or Felkin-Anh model.40 Exposure of 141 to CbzCl produced the corresponding carbamate 142 in 98% yield. Subsequent ozonolysis of 142 followed by reduction with NaBH4 afforded amino alcohol 143 whose treatment with NaH gave the corresponding oxazolidinone 144. Desilylation of 144 (TBAF, THF) and oxidative fragmentation of the resulting diol 145 furnished aldehyde, which was immediately subjected to the Wittig olefination (C13H27PPh3Br, n-BuLi) to yield olefin 146. Acid hydrolysis of 146 removed the acetonide and carbamate moiety to provide 147 in 94% yield. Its catalytic hydrogenation followed by protection with Boc2O gave 4414a,24 in 95% yield over two steps. Selective 17 Page 17 of 88

tosylation of the primary alcohol functionality of 44 prompted intramolecular cyclization to furnish the known tetrahydrofuran 46.14a,22,24 Removal of the Boc group with TFA afforded 6.TFA, which was converted into the known diacetate 14824 (Scheme 23).40 It had the spectroscopic data and optical rotation in accord with those reported in the literature for the same compound.24 In 2011, the group of Sartillo-Piscil and co-workers42 applied a high 1,3-trans stereoselectivity in the nucleophilic substitution at the anomeric position, controlled by an amino functionality at C-3 and β-fragmentation of the primary alkoxy radical in tetrahydrofuran derivative 157 presumable favoured by an intramolecular interaction between the semifilled p-orbital (SOMO) of 157 and –NH group, to the construction of ent-6 (Scheme 24). Their synthesis started with the preparation of the protected 3amino-3-deoxy-α-D-ribofuranose 151 from the known α-D-xylofuranose 14943 in two steps with 58% overall yield. This strategy involved oxidation of the secondary alcohol group of 149 to produce ulose 150, and its treatment with bezylamine and subsequently with NaBH4 to afford the desired amine 151.

Its exposure to allyltrimethylsilane in the presence of BF3.OEt2 provided fully functionalized tetrahydrofuran compound 152a in 66% yield and with high transselectivity (trans-152a:cis-152b = 91:9). Benzylation of 152a, subsequent OCM reaction of 153 (92%) with tridec-1-ene and Grubbs II catalyst 95 followed by catalytic hydrogenation furnished the corresponding derivative 154 in 70% yield over two steps. Desilyation of 154 afforded alcohol 155, which was submitted to the reaction with N-hydroxyphthalimide under Mitsunobu conditions44 to produce 156. Its treatment with Bu3SnH/AIBN45 resulted in the formation of the truncated analogue 158. The global deprotection of 158 was achieved via hydrogenation (H2, Pd(OH)2/C to give the target molecule ent-6 (Scheme 24).42 Liu et al.46 have reported the formal synthesis of jaspine B, in which the regio- and stereoselective epoxide ring-opening and the inversion of stereochemistry at the C-3 position through an oxidation-reduction protocol were involved as the key transformations. D-Xylose as the chiral starting material was initially converted into the known 1,2-O-isopropylidene derivative 159.47 Its tosylation gave bis-tosylated product 160 whose acid-induced furan ring generation followed by epoxide formation led to 161 (94%). Subsequent stereoselective opening of the epoxide skeleton48 of 161 18 Page 18 of 88

produced compound 162. Oxidation of the secondary hydroxyl group in it with IBX followed by reduction (KBH4) resulted in the formation of alcohols 162 and 163 in the combined 86% yield and with very good diastereoselectivity (162:163 = 1:12). This diastereomeric mixture was separated after benzylation step to give the desired derivative 164 in 85% yield. Acid hydrolysis of 164 afforded the corresponding aldehyde 165 (Scheme 25).46 Jaspine B 4 can be constructed from 165 according to the known synthetic protocols.14i,49 In 2010, the research group of Rao and co-workers14d communicated their synthesis of two jaspine B stereoisomers 2,3-di-epi-jaspine B (ent-8) and ent-4.TFA from 1,2-Oisopropylidene-α-D-glucofuranose 167, which was initially converted into derivative 16814d in 74% yield. The corresponding azide 170 was formed through tosylate 169. Deprotection of the acetonide moiety of 170 under acid hydrolysis provided diol 171 (86%) whose oxidative fragmentation with NaIO4 afforded aldehyde 172 (yield and also its spectroscopic data are not reported). Subsequent Wittig olefination with a nonstabilized ylide, derived from the salt C13H27PPh3Br employing t-BuOK as the base, produced olefin 173. Global reduction of 173 was achieved via catalytic hydrogenation (H2, Pd/C) furnished ent-8 in 92% yield. The obtained material had spectroscopic data in accord with those published,14a,16b,22,25 but the optical rotation was opposite in sign; lit.14d[α]D28 = +3.1 (c 0.005, CHCl3), lit.14a [α]D25 = ‒2.5 (c 0.71, CHCl3), lit.16b [α]D25 = ‒3.0 (c 0.98, CHCl3), lit.22 [α]D25 = ‒1.17 (c 0.99, CHCl3), lit.25 [α]D = ‒2.8 (c 0.94, CH2Cl2, temperature not reported). Its treatment with Ac2O and Et3N in the presence of DMAP gave N,O-diacetyl derivative 174 (Scheme 26).14d To accomplish the construction of ent-4, authors transformed compound 168 to derivate 175 using Mitsunobu conditions. Subsequent hydrolysis with LiOH resulted in the formation of alcohol 176, whose mesylation and subsequent treatment of the resultant 177 with NaN3 afforded azide 178 in 63% yield. Hydrolysis of the acetonide function of 178 provided diol 179, which was treated with NaIO4 to generate aldehyde 180. Its Wittig reaction according to the same conditions described for 173 gave alkene 181. The final catalytic hydrogenation furnished ent-4 as the corresponding TFA salt (Scheme 27).14d

Sartillo-Piscil and co-workers50 have reported a five-step formal synthesis of ent-4 from the know 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 182.51 Its benzylation 19 Page 19 of 88

under standard conditions (BnBr, NaH) provided the fully protected derivative 183 in 98% yield. Application of SHOWO50 protocol to 183, which involved acid hydrolysis of the 5,6-O-isopropylidene moiety with concomitant oxidative fragmentation of the liberated diol and subsequent Wittig reaction, gave compound 184 as a mixture of the corresponding alkenes in 86% overall yield and with good Z-selectivity (Z:E = 9:1). After separation of 184, the major (Z)-184 was converted into tetrahydrofuran 185 employing Robinsʼs conditions52 (Et3SiH, BF3.OEt2). Transformation of 185 to azide 186 was achieved by treatment with trifluoromethanesulfonyl chloride (CF3SO2Cl) followed by reaction with NaN3 in DMF in the presence of TBAF to provide 186 in 69% over two steps (Scheme 28).50 The synthesis of the target compound ent-4 can be realized via the widely reported global reduction.14i,49 In 2012, Rao and co-workers53 published a total synthesis of ent-4 in the form of diacetate 194 employing the diastereoselectively formed allylamine 18754 as a key intermediate, which was previously prepared from

D-glucose

(Scheme 29). The

corresponding derivative 188, readily obtained from 187, was modified into alcohol 189 via ozonolysis of the vinyl group of 188 and subsequent reduction (NaBH4). Treatment of 189 with NaH caused intramolecular cyclization to give oxazolidinone 190. Acid-mediated deprotection of the acetonide group furnished diol 191. Its oxidative cleavage generated aldehyde, which was submitted to the Wittig olefination to afford (Z)-alkene 192 in 90% yield. Cleavage of the cyclic carbamate fragment of 192 resulted in the formation of 193. Global reduction was then accomplished via hydrogenation, which was followed by protection of the liberated amino group with Boc2O to give ent-113. The known sequence24 involving selective tosylation of the primary alcohol functionality of ent-113 prompted intramolecular cyclization to provide compound ent-90. Its acid hydrolysis afforded ent-4, but no data are reported for this molecule. As an additional confirmation of structure, isolated ent-4 was converted to its diacetyl derivative 194 (94%, Scheme 29).53 The spectroscopic data and optical rotation value matched known data present in the literature for the same compound.55b Reissigʼs group56 has reported a stereodivergent construction of jaspine B (4) and its stereoisomers ent-4, 6 and ent-6 in which addition of the lithiated glucose-derived alkoxyallenes to pentadecanal and gold-catalyzed 5-endo-cyclization were used as the key transformations. The starting alkoxyallene 195,57 prepared on gram scale in two 20 Page 20 of 88

steps, was treated with n-BuLi and subsequently added to pentadecanal to give a separable mixture of diastereomeric alcohols 196 and 197 in 57% yield and with diastereomeric ratio of 57:43. Au(I)-catalyzed cyclization58 of both allenyl alcohols 196 and 197 afforded the corresponding dihydrofurans 198 and 199, which were isolated in 41% and 31% yields, respectively. To achieve a synthesis of 4 and ent-6, the electrophilic bromination of 199 with NBS followed by substitution with NaN3 were conducted and provided azidotetrahydrofuranones. Their diastereoselective reduction (L-selectride) resulted in the formation of derivatives 200 and 13838 in the combined 66% yield over three steps (dr = 60:40). Due to the similar Rf values of 200 and 138, these structures were converted into easily separable carbonates 201 (53%) and 202 (40%). Final hydrogenolysis of 201 and 202 furnished the target molecules ent-6 and 4, respectively (Scheme 30).56 According to the same protocol described in Scheme 30, 2-epi-jaspine B (6) and ent-4 were built up from dihydrofuran 198 in the similar yields.56 However, no spectroscopic data and optical rotation values for isolated jaspine B stereoisomers 6 and ent-4 were given in Reissig’s work. In 2011, Rao et al.60 published a stereoselective synthesis of jaspine B (4) from Lascorbic acid 203, which was initially elaborated into chiral epoxide 204 employing the known synthetic protocol.61 Its regioeselective opening with n-tridecylmagnesium bromide in the presence of CuCN produced alcohol 205 as the sole product in 92% yield. Acid hydrolysis of the acetonide skeleton of 205 afforded the corresponding triol 206. Subsequent selective protection-deprotection sequence involved silylation of 206 to give 207, its treatment with 2,2-DMP to generate the isopropylidene derivative 208 and desilylation to form derivative 209. Swern oxidation of 209 followed by condensation of in situ formed aldehyde with BnNH2 furnished imine 210, which was immediately treated with vinylmagnesium bromide to give 211 exclusively in 80% yield over three steps. The newly constructed stereochemistry in 211 was determined according to earlier observation obtained during the construction of 141 (Scheme 23).40 After protection of 211, ozonolysis of the terminal double bond in 212 and subsequent NaBH4 reduction resulted in 213 (85%). Catalytic hydrogenation of 213, followed by reprotection of the liberated amino functionality with Boc2O provided compound 214. The primary hydroxyl group in 214 was transformed into O-mesylate, which was then reacted with p-TsOH in MeOH to give tetrahydrofuran 90.14a Removal of the Boc group of 90 with TFA afforded the corresponding salt of jaspine 21 Page 21 of 88

B (4.TFA)13a whose treatment with Ac2O in the presence of Et3N produced ent19424,59 (Scheme 31).60 The group of Rao and co-workers62 has communicated the formal synthesis of 3-epijaspine B (7) in the form of diacetate 228 utilizing D-isoascorbic acid 215 as the chiral starting material (Scheme 32). The synthesis commenced from the known ester 216 prepared from 215 according to literature procedure.63 Its reduction with LiAlH4 generated alcohol 217 in 95% yield. Swern oxidation of 217, followed by the Wittig olefination (Ph3P=CHCO2Et) produced a mixture of α,β-unsaturated esters 218 with good E-selectivity (E:Z = 9:1), in the combined yield of 92%. The acid hydrolysis of (E)-218 with 80% aq AcOH gave diol 219, whose NaH-mediated intramolecular oxaMichael addition regioselectively resulted in the formation of the inseparable derivatives 220a and 220b (ca. 10:1 ratio, 96%). Their mesylation and subsequent reaction with NaN3 yielded the corresponding azides 221a and 221b. The global reduction of 221 generated the crude amino alcohols, which after the protection with Boc2O furnished chromatographically separated derivatives 222 and 223. Their structures were confirmed by 1D and 2D NMR spectroscopic analysis.62 Alcohol functionality of the major compound 222 was oxidized and the resultant crude aldehyde 224a was submitted to the olefination (C12H25PPh3Br, t-BuOK) to form Z-alkene 225 in low 23% yield over two steps. The same product 225 was obtained also from 223 in 21% yield and it can be explained according to the mechanism proposed by Daviesʼs group17a via formation of enolate of 224b, its retro-Michael addition to generate α,βunsaturated aldehyde62 and subsequent cyclization, which would produce favoured 224a. The final catalytic hydrogenation of 225 resulted in 11614a,64 (Scheme 32).62 The spectroscopic data of 116 were in good agreement with those reported.14a,64 In order to improve the overall yield of the aforementioned strategy toward 7, the authors have realized a modified synthetic route, which employed azides 221. Its DIBAl-H reduction provided alcohols 226 (98%). Their oxidation, followed by Wittig reaction furnished olefin 227 in 55% yield over two steps, whose structure was confirmed by 2D NMR analysis including NOESY experiments.62 Hydrogenation of 227 and the subsequent protection with Boc2O gave 116 (96%), which was then treated with TFA and acetylated to generate 22864 {thick syrup, [α]D25 = +11.2 (c 1.1, CHCl3), lit.64 mp 70‒71 °C, [α]D25 = ‒11.9 (c 0.21, CHCl3)} (Scheme 32).62 Stereochemistry of the tetrahydrofuran core in 228 was determined by NMR studies (NOESY).62 It had the 22 Page 22 of 88

spectral values identical with those reported,64 but the optical rotation was opposite in sign. Most recently, Shaw et al.14l published a total synthesis of 2-epi-jaspine B (6) employing stereocontrolled iodocycloetherification of the functionalized alcohol 230 as the key transformation. The starting allylic substrate was prepared from 3,4,6-tri-Obenzyl-D-galactal 229 according to the known literature protocol.65 Initially, the compound 230 was treated with I2 to undergo exo-trig iodocyclization to give an inseparable mixture of diastereomeric products 231a and 231b. To explain the mechanism of iodocycloetherification, the authors adopted the well documented models developed by Chamberlin’s group30 for the iodonium ions A and B of their corresponding substrates (Scheme 33). The OBn group at the C-6 position in the alcohol 230 is spatially in close proximity to olefinic C-3 carbon and triggered the diastereofacial cyclization by involving a favoured C4-H in-plane conformer to generate stabilizing interactions between the developing positive charge and benzyloxy oxygen lone pairs as illustrated in the complex B. Thus, the most stable iodonium ion was produced preferentially affording the tetrahydrofuran 231b after the attack of the internal nucleophile. On the other hand, the production of minor derivative 231a could be elucidated by considering the disfavored OBn moiety inplane conformer A. Its instability is presumably caused by an unfavourable steric interaction between the eclipsed allylic fragment -R and the terminal methylenic centre that would allow stabilization of the incipient positive charge by oxygen lone pairs on C4-OBn. Subsequent reaction of the aforementioned derivatives with I2 in the presence of Ph3P and imidazole resulted in the formation of two chromatographically separable olefins 232a (15%) and 232b (36%) in a ratio of 1:3.6 (determined by HPLC analysis). The configuration of the newly constructed stereocentre at the C-2 position on the tetrahydrofuran skeleton was determined by NOESY experiments of the major diastereoisomer 232b, which revealed cis-relationship between H-2 and H-3 protons.14l Olefin cross-metathesis of 232a with tetradec-1-ene using Grubbs II catalyst provided alkene 233 in 60 % yield. The alcohol functionality in 233 was transformed into O-mesylate, which was then reacted with NaN3 to afford product 234 in 70% yield over two steps. Compound 234 was submitted to the global reduction to give the target 2-epi-jaspine B (6) (Scheme 33).14l We have recently reported a stereoconvergent synthesis of jaspine B (4)14f and its five stereoisomers, namely ent-4,66 ent-6,64 7,64 814f and ent-866 in the form of their HCl 23 Page 23 of 88

salts from the simple carbohydrates such as

D-xylose,

66

14f

L-arabinose

and

D-

mannose.64 For the construction of 414f and 814f was also employed dimethyl

L-

tartrate. Our elaborated approach relies on a [3,3]-heterosigmatropic rearrangement, which was utilized for the incorporation of the new stereogenic centre bearing an amino functionality, a Wittig olefination for the formation of the carbon backbone and the acid-promoted building up of a tetrahydrofuran skeleton. Jaspine B (4) and its 4-epi-analogue 8 were synthesized from L-arabinose and/or dimethyl L-tartrate.14f L-Arabinose was initially converted into scaffold 240 via 12 reaction steps in 14% overall yield accompanied by the execution of suitable functional group interconversions and selective protection-deprotection protocols. This sequence included the conversion of the starting sugar into alcohol 235, which was inverted through an oxidation-stereoselective reduction strategy, affording the corresponding

L-lyxofuranose

236 (100% de). After protection of the secondary

hydroxyl of 236, the O-trityl group was removed to give 237. Benzoylation of 237, followed by cleavage of the acetonide moiety resulted in 238. Sodium metaperiodate (NaIO4) fragmentation of the vicinal diol in 238 and subsequent NaBH4 treatment provided compound 239. The following 1,3-O-isopropylidene formation and removal of the O-benzoyl fragment furnished the desired building block 240. Because we required great amounts of 240, we then adopted the known more economic three-step sequence67 starting from dimethyl L-tartrate (Scheme 34).14f IBX oxidation of 240, followed by HWE olefination afforded a separable mixture of α,β-unsaturated esters (E)-241 and (Z)-242 in the combined yield of 93% (E:Z = 88:12 ratio). After separation, the major isomer 241 was then used for further transformations. Watching the sequence in Scheme 35, it was submitted to the reduction with DIBAl-H to produce allyl alcohol 243. Its mesylation, followed by nucleophilic displacement with KSCN led to the thiocyanate 244 in 90% yield in two steps. On the other hand, the treatment of 245 with trichloroacetonitrile and NaH gave trichloroacetimidate 245. With both substrates 244 and 245 in hand, we examined individual [3,3]-sigmatropic rearrangements (Scheme 35).

The thermal reaction of 244 was carried out in heptane at 70 °C and 90 °C and afforded the corresponding isothiocyanates 246 and 247 as a separable mixture of diastereoisomers in very good yields (85-91%) and with satisfactory selectivity 24 Page 24 of 88

(246:247 = 90:10 ratio, ∆, 70 °C, 8 h, 85%). The application of microwave energy at the same temperatures requires the shorter reaction times and provided the rearrangement products with yields and selectivities similar to the thermal driven reaction (246:247 = 86:14 ratio, MW, 70 °C, 1.5 h, 91%). Upon Overman rearrangement (o-xylene, in the presence of K2CO3), this reaction afforded two trichloroacetamides 248 and 249 in very good yields (75-90%), but unfortunately no diastereoselectivity was observed (248:249 = 54:46 ratio).

The obtained rearranged products 246, 248 and 247, 249 were then converted into the oxazolidinones 254 and 255, respectively. The corresponding isothiocyanates 246 and 247 were through a two-step procedure transformed to carbamates 250 and 251, respectively. The single crystal X-ray analysis of 250 revealed (S) configuration of the installed stereocentre in 246. Ozonolysis of 250 and 251 followed by a reductive work up resulted in alcohols 252 (81%) and 253 (87%). Their NaH-mediated cyclization furnished

the

desired

common

derivatives

254

and

255

(Scheme

36).

Trichloroacetamides 248 and 249 afforded the same compounds 254 and 255 via a three-step approach involving ozonolysis with subsequent reduction and the final elaboration of generated 256 (86%) and 257 (90%) with DBU. The prepared materials had physical and spectroscopic properties in excellent accord with those found for the structures 245 and 255 previously obtained from isothiocyanates 246 and 247 confirming (S)-configured stereocentre with nitrogen in the major Overman product 248.

Both oxazolidinones 254 and 255 were then modified into the final jaspine B (4) and its 4-epi-analogue 8, respectively (Scheme 37). For this purpose, compounds 254 and 255 were subjected to the acid hydrolysis with p-TsOH in MeOH to give diols 258 (92%) and 259 (93%). Their treatment with TrCl, followed by benzylation of the resultant products 260 and 261 afforded the fully protected derivatives 262 and 263. After detritylation, the primary hydroxyl group in generated 264 and 265 was oxidized to produce crude aldehydes, which were treated with a non-stabilized Wittig reagent, derived from tridecyltriphenylphosphonium bromide and LHMDS as a base, providing barely separable mixtures of olefins 266 and 267 (Z:E = 88:12 for 266, Z:E = 86:14 for 267) with 83% and 91% yields, respectively, due to very similar Rf values. 25 Page 25 of 88

Subsequent catalytic hydrogenation of 266 and 267 with 10% Pd/C yielded 268 and 269, which were then N-debenzylated to provide the corresponding phytosphingosines 270 and 271. Their exposure to 6 M HCl resulted in cleavage of the cyclic carbamate fragment and concomitant cyclization afforded the HCl salts of 4 and 8. The optical rotation value for 4.HCl showed very good concordance with that previously reported.59b Both salts were submitted to the acetylation with Ac2O in pyridine to afford the corresponding N,O-diacetates ent-194 (81%) and ent-174 (85%, Scheme 37).14f Again, the spectroscopic data and optical rotation were in good agreement with data present in the literature for the same compound ent-194.24,56 In the case of ent174, NMR data matched the known values for its antipode.14d,66

In 2014, our group66 communicated a total synthesis of further two jaspine B stereoisomers, namely ent-4 and ent-8 from D-xylose, which was initially converted into the scaffold ent-24068 through nine reaction steps in 47% overall yield (Scheme 38). The known 1,2-O-isopropylidene-α-D-xylofuranose 159,47 prepared from

D-

xylose in 90% yield on a multi-gram scale, was treated with TrCl to give derivative 269, whose benzylation afforded the fully protected compound 270. Its detritylation followed by protection of the liberated alcohol 271 with BzCl in pyridine resulted in 272. Acid hydrolysis gave diol 273, which after oxidative fragmentation with NaIO4 provided ent-239. The isopropylidene formation in ent-239 and subsequent treatment of 274 with K2CO3 in MeOH furnished the require building block ent-240.

Substrates for the key [3,3]-sigmatropic rearrangements were constructed from the corresponding scaffold ent-240 according the same reaction sequence described in Scheme 35. Elongation of the side chain in ent-240 was achieved through an oxidation-HWE olefination sequence to furnish a mixture of esters (E:Z = 88:12, 88% over two steps), from which the major isomer ent-(E)-241 was then reduced to give the alcohol ent-243 (Scheme 39). Subsequent protocol involving mesylation/KSCN treatment resulted in the formation of thiocyanate ent-244 (85%). Application of the standard conditions such as trichloroacetonitrile and NaH to the alcohol ent-243 afforded imidate ent-245. The aza-Claisen rearrangement of ent-244 led to the construction of the corresponding isothiocyanates ent-246 and ent-247 in very good yields (86-96%) and with the satisfactory selectivity (ent-246:ent-247 = 88:12, ∆, 70 26 Page 26 of 88

°C, 8 h, 90%). Overman reaction of the allylic trichloroacetimidate ent-245 resulted in the formation of amides ent-248 and ent-249 and was found to show stereoselectivities and yields similar to those observed in the rearrangement of its antipode 245 (ent-248:ent-249 = 52:48, MW, 150 °C, 1.5 h, 89%). In a similar fashion (see Scheme 36), the isolated products ent-246, ent-248 and ent-247, ent-249 were submitted to the transformations based on the functional group interconversions, providing the desired oxazolidinones ent-254 and ent-255 (Scheme 40). Configuration of the newly installed stereocentre with nitrogen in ent-246 and ent-247 was determined by single crystal X-ray crystallographic analysis of ent-250, which was derived from the major isothiocyanate ent-246.

To confirm the stereochemistry in ent-248 and ent-249, chemical correlations of these compounds to the aforementioned cyclic carbamates ent-254 and ent-255, were carried out (Scheme 40). During transformation of ent-248 to ent-256 and ent-249 to ent-257, smaller amounts of ent-254 (35%) and ent-255 (11%) were isolatated as a result of the intramolecular cyclization due to the reaction conditions (NaBH4 in MeOH).

For the transformation of the common oxazolidinones ent-254 and ent-255 to the target ent-4 and ent-8 (Scheme 41), respectively, the same synthetic strategy as illustrated in Scheme 37 was employed. The spectroscopic data and the specific rotation of 194 were in good agreement with those reported in the literature for the same compound.53,55b Moreover, the structure of 194 was unambiguously assigned by single crystal X-ray analysis (Fig. 7)66 (for the crystal structures of ent-194 see: Refs. 55b and 59a and the corresponding Figs. 8-9, respectively).

We have also reported a stereoselective synthesis of 2-epi-jaspine B enantiomer (ent6) and 3-epi-jaspine B (7), where D-mannose was chosen as a starting chiral pool.64 In this approach, the known 2,3:5,6-di-O-isopropylidene-D-mannofuranose 27251 was subjected to a Wittig reaction with the stabilized ylide (Ph3P=CHCO2Et) affording a separable mixture of α,β-unsaturated esters (E)-273 and (Z)-274 in the combined yield 27 Page 27 of 88

of 98% and with good E-selectivity (E:Z = 91:9). The remaining hydroxyl group in (E)-273 was protected as TBDMS ether 275 (98%). Its reduction with DIBAl-H furnished the corresponding alcohol 276, which was then converted into the required aza-Claisen substrates 277 (CCl3CN, DBU) and 278 using the standard reaction procedures14f,66 (Scheme 42).

Overman rearrangement of 277 (Scheme 42) realized under microwave irradiation conditions in o-xylene in the presence of K2CO3 and provided a barely separable mixture of diastereoisomers 279 and 280 in 81% yield due to very similar Rf values (279:280 = 33:67 ratio for 170 °C, MW, 1 h). On the other hand, the allylic thiocyanate 278 was rearranged in n-heptane using both the conventional thermal protocol and microwave heating giving the corresponding isothiocyanate 281 and 282 (281:282 = 82:18 ratio, 53% for ∆, 90 °C, 25 h) in modest yields (47-56%). During these experiments we recovered the starting material 278 in approximately 39-47% yields, which was then reused for the repeated rearrangements. Conversion of a mixture of trichloroacetamides 279 and 280 to the corresponding N-Boc derivatives 283 and 284 was achieved through two steps involving a basic hydrolysis followed by treatment with Boc2O (Scheme 43).

After their chromatographic separation, ozonolysis of both compounds and subsequent reductive work up resulted in the formation of alcohols 285 and 286, which were then treated with NaH to give the cyclic products 287 and 288 in 86% and 97% yields, respectively. Crystallographic analysis of 287 confirmed the stereochemistry of the newly incorporated stereocentre bearing amine functionality. The chemical correlation of the major isothiocyanate 281 to common oxazolidinone 287 was executed. Thus, exposure of 281 to MeONa, followed by MNO treatment furnished carbamate 289 in lower 39% yield over two steps. Subsequent modification of the terminal double bond in 289 resulted in 290 (80%), whose NaH-induced ringclosure yielded 287 (92%). The obtained cyclic carbamates 287 and 288 were then converted into the target jaspine B diastereoisomers 7 and ent-6, respectively, according to the synthetic strategy illustrated in Scheme 44.64 After PMB protection of the oxazolidinone core in 287 and 288, the O-TBDMS group of the resulting 28 Page 28 of 88

products 291 and 292 was removed to give derivatives 293 (93%) and 294 (98%). Acid hydrolysis of the terminal isopropylidene ring in 293 and 294 furnished the requisite triols 295 and 296. Their oxidative fragmentation resulted in the corresponding aldehydes, which were immediately coupled with the Wittig reagent (generated from C13H27PPh3Br) affording barely separable mixtures of olefins 297 (Z:E = 90:10) and 298 (Z:E = 92:8) due to very similar Rf values Subsequent hydrogenation of 297 and 298 produced the saturated compounds 299 and 300, which after deprotection with CAN provided the protected phytosphingosines 301 and 302. The final treatment of both cyclic carbamates with 6 M HCl resulted in the formation of 7.HCl and ent-6.HCl (Scheme 44). For the confirmation of their cyclized structure, the salts were converted into the N,O-diacetate 22862 and ent-148 (for its antipode, see: Refs. 24, 40, 59) and N-Boc derivatives 11614a {lit.64 [α]D25 = ‒28.1 (c 0.21, CHCl3); lit.14a [α]D25 = ‒31.7 (c 1.09, CHCl3)} and ent-4616a (for its enantiomer, see: Refs. 14a, 24). The spectroscopic data of these four compounds matched values present in the literature for the same compounds in the case of 116, 228 and ent-46 or the corresponding antipode in the case of ent-148. For comparisons, ent-46 lit.64 [α]D25 = ‒10.0 (c 0.23, CHCl3), lit.16a [α]D25 = ‒7.76 (c 0.29, CHCl3)}, for values of ent-148 and148, see Table 3. 1H NMR NOE analysis conducted on 7.HCl, ent-148 and 228 confirmed the relative stereochemistry on the tetrahydrofuran skeleton.

2.1.4. Syntheses from tartaric acid derivatives In 2008, Ichikawa and co-workers69 reported a stereocontrolled synthesis of jaspine B (4), in which [3,3]-sigmatropic rearrangement of the chiral allylic cyanate 311 was utilized to install the desired amino functionality. Their synthesis commenced with the known derivative 303 prepared from L-tartaric acid.70 Reaction of 303 with triflic anhydride followed by SN2 displacement with tridec-1-yn-1-yllithium resulted in 304 in 61% yield after two steps. Reduction of the triple bond in 304 and subsequent desilylation provided compound 209,60 which was subjected to one-pot Swern oxidation-HWE olefination to afford α,β-unsaturated ester 305 (85%). Its DIBAl-H reduction and subsequent oxidation (4-acetamido-TEMPO/NCS) of the resultant allylic alcohol 306 produced the corresponding aldehyde 307. Addition of Et2Zn to 307 applying modified Nugentʼs conditions (in the presence of ligand 308)71 furnished alcohol 309 in 80% yield and with diastereomeric ratio > 95:5. The 29 Page 29 of 88

stereochemistry of the newly incorporated stereocentre in 309 was established using the Mosher-Kusumi MTPA ester analysis method.72 Compound 309 was further submitted to the reaction with trichloroacetyl isocyanate followed by treatment with K2CO3 in MeOH to give product 310, which after dehydration (Ph3P, CBr4, Et3N) afforded

cyanate

311.

Its

[3,3]-sigmatropic

rearrangement

generated

the

corresponding isocyanate 312, which was converted into carbamate 313 in 82% yield after two steps. After deprotection of the acetonide moiety, the formed diol then reacted with NaH to furnish the oxazolidinone derivative 314. Ozonolysis of 314 yielded lactol 315 (94%) whose acetylation and reduction of the resultant compound 316 with Et3SiH led to 120.14g,37 Finally, basic hydrolysis of the cyclic carbamate skeleton in 120 resulted in jaspine B (4), which was then transformed to diacetate ent194 (Scheme 45).69 NMR data of the material ent-194 matched known values reported in the literature for the same compound.14f,24,59 Fadnavisʼs group73 has published a stereoselective construction of 2-epi-jaspine B (6) from diethyl

D-tartrate

317 via 12 reaction steps in 27% overall yield. After

transformation of 317 to cyclic derivative 318, it was then reacted with NaN3 to afford the requisite azide 319. After benzylation of the secondary alcohol in 319, global reduction of the produced compound 320, followed by protection of the liberated amine functionality with Boc2O provided 321 in 90% overall yield. Formation of an acetonide in 321 afforded the N,O-isopropylidene derivative 322 whose Dess-Martin oxidation

and

subsequent

Wittig

olefination

with

the

stabilized

ylide

(Ph3P=CHCO2Et) furnished α,β-unsaturated ester 323 as the sole product. Its acid hydrolysis furnished the protected amino alcohol 324, which was through the diastereoselective intramolecular Michael addition74 converted into tetrahydrofuran 325 as the single diastereomer (determined by 13C NMR spectra, carbon C-2 displays a characteristic peak at 78.5 ppm for anti-isomer, for syn product C-2 was at 70 ppm) and the results were in accord with the mechanism proposed by Daviesʼs group,17a which predicts formation of the thermodynamically favourable 2,3-anti adduct upon the attack of the generated oxyanion species during the intramolecular Michael reaction and was postulated as an outcome of the revision of Dataʼs synthesis of jaspine B17a (for greater clarity, see Ref. 17a, chapter “Synthesis with inconsistent data”). The reduction of 325 with DIBAl-H gave a crude aldehyde, which was treated with a ylide generated from the phosphonium salt (C12H25PPh3Br), employing n-BuLi as a base to give olefin 326 in 73% yield. Final catalytic hydrogenation of 326 in the 30 Page 30 of 88

presence of TFA generated TFA salt of 2-epi-jaspine B (6.TFA)40 (Scheme 46).73 The spectroscopic data and optical rotation values were in good agreement with those published in the literature.40 In 2011, Prasad and Penchalaiah75 reported a total synthesis of ent-4 from the known alcohol 32676 derived from diethyl

L-tartrate

ent-317, in which a Williamson

etherification and OCM reaction were employed as the key transformations. Compound 326 was initially converted into derivative 327 via two steps in 70% overall yield using the synthetic protocol published in the literature.77 After protection of the secondary hydroxyl functionality with a MOM group in 327, the acetonide group was then removed to give diol 328 in 62% yield over two steps. Compound 328 was treated with TsCl and generated bis-tosylated product 329, which underwent the intramolecular Williamson etherification under acid hydrolysis to provide tetrahydrofuran 330. Subsequent SN2 displacement with BnNH2 afforded the corresponding derivative 331, which was submitted to OCM reaction with tridec-1ene and Grubbs I catalyst to result in the formation of alkene 332 in 78% yield. Finally, the global reduction of 332 in the presence of TFA gave ent-4.TFA (93%) followed by treatment with methanolic NaOH furnished ent-4 (Scheme 47).75 The spectroscopic data of ent-4 fully agreed with those of the natural product isolated by Kurodaʼs group.13a

2.1.5. Syntheses from other chiral substrates Hou et al.78 have communicated a total synthesis of ent-8 and ent-4 from the common starting material (3R,4R)-hexa-1,5-diene-3,4-diol 333,79 in which the construction of key tetrahydrofuran skeletons via a SN2 substitution/cyclization and 5-endo-tet cyclization of oxirane 338 and aziridine 344, respectively, was utilized. To obtain ent8, mono-silylation of the C2 symmetrical compound 333 was conducted and the resulting product 334 was subjected to a Sharpless asymmetric epoxidation to provide 335 in 76% yield. Its stereochemistry was in accord with a previous report (dr > 19:1).80 Exposure of 335 to MOMCl and Hünigʼs base produced MOM-ether 336, which after deprotection of the TBDMS group and subsequent OCM reaction (tetradec-1-ene, Grubbs II catalyst) resulted in 327 in 61% overall yield. Its catalytic hydrogenation afforded the saturated derivative 338. Since attempted 5-endo-tet 31 Page 31 of 88

cyclization in 338 to form directly a THF core turned out to be ineffective, the authors decided to prepare 340 through a sequence of the nucleophilic displacement, followed by cyclization, adopting strategy, which was used previously by Brittonʼs group.81 The treatment of 328 with LiI furnished the corresponding iodide 329, which was modified into 340 employing microwave irradiation thermal conditions. Subsequent protocol involving tosylation of 340, SN2 substitution with NaN3 and final reduction to afford 2,3-di-epi-jaspine B (ent-8) in 51% yield over three steps (Scheme 48).78 The NMR data were in good agreement with those present in the literature for the same compound.14a,16b ent-Jaspine B (ent-4) was synthesized from the same starting material 333. The epoxid-ring formation in 333 was achieved according to the conditions published by Takano et al.82 to give 341, wherein the two hydroxyl groups were silylated to provide 342. Compound 342 was then converted into aziridine 344 in 58% overall yield by treatment of 342 with LiI, followed by substitution of the formed iodide 343 with NaN3, and subsequent Staudinger type reaction. Exposure of 344 to CbzCl in the presence of Et3N produced carbamate 345, which underwent the cyclization directly during deprotection of the TBDMS groups under acid hydrolysis (HF/MeCN) and furnished the desired tetrahydrofuran ent-74 in 67% yield. Its cross-metathesis with tetradec-1-ene and final hydrogenolysis accomplished the construction of ent-4 (Scheme 49).78 The natural product 4 could be prepared according to the aforementioned strategy employing ent-333 and (+)-DIPT.

In 2013, the group of Britton83 developed a short, eight-step total synthesis of jaspine B (4), in which a diastereoselective aldol reaction between the protected hydantoin 349 and optically enriched α-chloroaldehyde provided the key intermediate 350 bearing all desired stereogenic centres (Scheme 50). Their synthesis started from the optically pure (R)-2-chlorohept-6-enal 347 (99% ee), which was prepared by the asymmetric chlorination of hept-6-enal 346 according to MacMillanʼs procedure, using the chiral catalyst 348.84 After optimization of reaction conditions, the following aldol transformation between 347 and the known hydantoin 34985 resulted in the formation of chlorohydrines in the combined yield of 68% and with diastereomeric ratio of 10:1:1:1.83 The desired adduct 350 was isolated in 52% yield. Its optimized cyclization83 provided a mixture of two products, the unprotected chlorohydrin 351 32 Page 32 of 88

and the corresponding γ-lactone 352 (351:352 = 1:2.7, 60%). After chromatographic separation, the OCM reaction of 352 with undec-1-ene in the presence of Grubbs II catalyst and subsequent hydrogenation afforded 353 in 43% overall yield. The reduction of the lactone functionality in 353 with DIBAl-H, followed by treatment of the generated lactol 31569 with Et3SiH in the presence of BF3.OEt2 furnished oxazolidinone 120,14g,37 whose alkaline hydrolysis produced the target jaspine B (4) (Scheme 50).83 The NMR data and optical rotation were in accord with those published in the literature.13b,24

2.2.

Syntheses anhydrophytosphingosines from achiral substrates

Of the methods that do not rely on the Chiron approach, organocatalytic aldol reaction, Sharpless asymmetric dihydroxylation and epoxidation, and Pd-catalyzed dynamic kinetic asymmetric transformation were employed for the construction of homochiral building blocks applicable in the total syntheses of jaspine B and its stereoisomers. Enders and co-workers86 have accomplished a total synthesis of jaspine B (4) from 2,2-dimethyl-1,3-dioxan-5-one 354 using a diastereo- and enantioselective (R)proline-catalyzed aldol reaction for introducing asymmetry (Scheme 51). The desired product 355 was prepared via aldol reaction between the known dioxanone 35487 and pentadecanal in 59% yield with de > 99% (95% ee). Silylation of the secondary alcohol functionality in 355, followed by diastereoselective reduction of the carbonyl moiety in the resultant derivative 356 produced anti-1,3-diol 357 (de > 98%), which was obtainable on multi-gram scale. Exposure of 357 to MsCl in the presence of DMAP gave mesylate 358, which was then reacted with NaN3 to provide azide 359. Removal of the O-TBDMS group in 359 and subsequent tosylation of the liberated hydroxyl in 360 furnished compound 361. Acid-mediated opening of the 1,3-dioxane skeleton generated intermediate 362, whose intramolecular nucleophilic substitution resulted in 138.38,56 The reduction of 138 was achieved via catalytic hydrogenation to afford jaspine B (Scheme 51).86

33 Page 33 of 88

In 2010, Génisson’s group15b reported an enantioselective synthesis of jaspine B from (E)-4-(benzyloxy)but-2-en-1-ol 363. Its one-pot transformation involving a Sharpless asymmetric epoxidation, followed by the asymmetric anti-aminohydroxylation process afforded the corresponding regioisomers 364 and 365 in 95% yield (364:365 = 65:35 ratio). Alternatively, the same products (364:365 = 80:20, 83%) were obtained from the epoxyalcohol 366 prepared according to the known procedure from allylic

alcohol

363.88

Reaction

of

both

products

364

and

365

with

methylchloroformate and subsequent treatment with KOH in MeOH resulted in the formation of the separable oxazolidinones 367 and 368. At this stage, their structure has been assigned by X-ray analysis of the minor cyclic carbamate 368. Oxidation of the remaining hydroxyl group in dominant stereoisomer 367 gave the desired aldehyde 369 in 89% yield. Addition of the TIPS-acetylene-derived organocerium reagent to aldehyde 369 afforded 370 (65%) as the single isomer. Mesylation of the secondary alcohol functionality, followed by treatment of the resultant compound 371 with BnNH2, Et3N in DMSO provided tetrahydrofuran 372 in 71% over two steps via the SN2-type intramolecular cyclization.15a The one-pot desilylation/bromination protocol89 was employed for the transformation of 372 to bromide 373. The Pdcatalyzed coupling reaction of 373 with dodec-1-yne furnished diyne 374 (32%), which was then subjected to the catalytic hydrogenation to yield the saturated derivative 375. A two-step deprotection sequence involving removal of the PMB group of 375 and hydrolysis of the oxazolidinone moiety in 12014g,37,83 accomplished the synthesis of jaspine B (Scheme 52). 15b In this work authors15b have also demonstrated the synthesis of jaspine B from the vinylic building block 378, which was constructed from the same aldehyde 369 (Scheme 53). Addition of the organocerium reagent generated from vinylmagnesium bromide to 369 resulted in alcohol 376 (100% de, 51% yield, its structure determined by X-ray analysis), which after mesylation and subsequent spontaneous cyclization of the produced mesylate 377 afforded 378 in overall yield of 87% after two steps. The olefin cross-metathesis of 378 with tetradec-1-ene in the presence of Grubbs II catalyst furnished the corresponding alkene Δ1'-(E)-379a together with the isomerized minor derivative Δ2'-(E)-379b (Δ1'-379a:Δ2'-379b = 70:30, 72%).15b To complete the synthesis, the double bond of the mixture of olefins 379a/379b was subjected to the catalytic hydrogenation, which gave derivative 375 (94%). Using the

34 Page 34 of 88

same two-step sequence (375→120→4) as described in Scheme 52, compound 375 was converted into jaspine B (4) (Scheme 53).15b

2.3.

Syntheses anhydrophytosphingosines from racemic substrates

Castillón et al.90 have communicated a divergent asymmetric synthesis of jaspine B (4) and its three diastereomers, namely 2-epi-jaspine B (6), 3-epi-jaspine B (7) and 2,3-di-epi-jaspine B (ent-8) based on racemic 2-vinyloxirane 380, which was initially converted into derivative 382 via a palladium-catalyzed dynamic kinetic asymmetric transformation (Pd/(S,S)-DACH-naphthyl 381)91 in 99% yield, with excellent enantioselectivity (99% ee). Subsequent OCM reaction of 382 using Grubbs II catalyst 95 afforded olefin 383 in 99% yield and high (E)-selectivity (E:Z > 98:2). Substrate-controlled dihydroxylation of 383 employing (DHQ)2PYR as the ligand resulted in the formation of a separable mixture of diols 384 and 385 in the combined yield of 80% and with diastereomeric ratio of 5.2:1.92 These aforementioned products 384 and 385 were then utilized for the construction 4, 6 and 7, ent-8, respectively, by the following sequences. Regioselective monotosylation of the major diastereomer 384, followed by basic treatment of the crude reaction product provided tetrahydrofuran derivative 386 (61% over two steps) as a result of the intramolecular SN2 reaction and partial methanolysis of the phthalimido moiety. Removal of the protecting group furnished the desired jaspine B (Scheme 54).90 In order to obtain 6, the primary hydroxyl group of 384 was selectively protected as the TBDPS ether, whose reaction with thionyl chloride and subsequent oxidation (RuCl3/NaIO4) resulted in 387 possessing a cyclic sulfate moiety as the leaving group.92 The formation of 388 was achieved via desilylation step inducing 5-endo-tet cyclization and subsequent treatment with acid to remove the sulfate group. The final reaction with MeNH2 then afforded the target molecule of 2-epi-jaspine B (6) (Scheme 54).

The similar reaction sequence as employed for the conversion of 384 to 4 and 384 to 6 was applied to 385 to provide 7 and ent-8, respectively. 2,3-Di-epi-jaspine B (ent-8) was prepared in two steps in 53% overall yield, which involved tosylation of 385 and deprotection of the phthalimido functionality in the resultant cyclic derivative 389 (Scheme 55).90 To obtain the compound 7, initial silylation of 385 was carried out and afforded 390 whose reaction with SOCl2 and subsequent oxidation (RuCl3/NaIO4) 35 Page 35 of 88

resulted in 391 (yield not reported). Its cyclization, followed by sulfate hydrolysis provided 392, which after removal of the protecting group yielded 7 (Scheme 55). In 2013, the group of Génisson and co-workers14g accomplished a total synthesis of jaspine B (4) and its antipode ent-4 from the racemic aziridino-γ-lactone 394. Their racemic route relied on the regioselective ring-opening of the aziridine skeleton of 394 and subsequent intramolecular cyclization to build up the cis amino alcohol motif present in 4, and the supercritical fluid chromatography (SCF), which was employed for resolution of the racemic oxazolidinone (±)-375. The aforementioned 2,3aziridino-γ-lactone (±)-394 was derived from D-erythronolactone 393 through a twostep protocol.15c Based on the published mechanism,93 the initial treatment of (±)-394 with methyl carbonochloridate generated the corresponding aziridinium (compound 395, see the proposed mechanism in Scheme 56) whose a ring-opening reaction with the nucleophilic chloride ion afforded chlorocarbamate 396 (see Scheme 56). Its intramolecular cyclization provided (±)-397 in 79% yield. The obtained derivative (±)-397

was

subjected

to

the

modified

Julia

olefination94

with

2-

95

(tetradecylsulfonyl)benzo[d]thiazole to furnish a mixture of the enol ethers (±)-398 (from 49% to 55%, E:Z = 2:1). During this transformation, hemiketal (±)-399 (from 23% to 8%) was also isolated as a result of the sensitivity of (±)-398 to hydration. Purification on basic alumina instead of silica gel slightly increased the isolated yield of (±)-398 and eliminated the formation of (±)-399. Subsequent homogeneous catalytic hydrogenation using (Ph3P)3RhCl resulted in (±)-375, which after the resolution by the chiral SCF96 led to the isolation of enantiomerically pure forms of 375. Isolated antipodes (+)-375 and (‒)-375 underwent to known steps15b involving deprotection of the N-PMB group to afford (+)-120 and (‒)-120, and their final treatment with KOH in EtOH/H2O, which yielded jaspine B (4) and its enantiomer ent-4, respectively (Scheme 56).14g The spectroscopic data and optical rotation of 4 were in accord with those reported.15b The NMR values and also obtained data for the optical rotation of ent-4 matched those present in the literature for the same compound.75 2.4.

Syntheis of racemic anhydrophytosphingosines

Génisson et al.14g have also published the synthesis of the racemic jaspine B (±)-4. For its construction utilized compound (±)-375. Using the same reaction sequence as 36 Page 36 of 88

described for the conversion (+)-375 to 4 or (‒)-375 to ent-4 (Scheme 56), the racemic oxazolidinone 375 was submitted to oxidative cleavage of the p-methoxybenzyl moiety to give (±)-120 in 71% yield. Saponification of the carbamate resulted in the formation of (±)-4 (Scheme 56). Reissig and co-workers56 have communicated the preparation of (±)-4 and (±)-6 from methoxyallene 400, which was obtained from propargyl alcohol in two steps using known procedure97 (Scheme 57). Exposure of 400 to n-BuLi and subsequent treatment with pentadecanal led to the product (±)-401 (yield not reported), which was immediately submitted to 5-endo cyclization (t-BuOK, DMSO) to afford dihydrofuran (±)-402 in 74% yield over two steps. The oxidative azidation98 of the racemic 402 provided a direct access to α-azidofuranones, which after reduction with L-Selectride gave the corresponding azides (±)-138 and (±)-200 in 62% overall yield and with diastereomeric ratio of 40:60. The spectroscopic data of (±)-138 and (±)-200 were in accord with the values of the enantiomerically pure compounds 138 and 200 (see Scheme 30). Authors have assumed that the observed diastereoselectivity of the reduction step

is likely due to stereoelectronic effects of the α-azido functionality, which overcame the steric hindrance of the alkyl chain. Similar observations have been published in the literature99 for the reduction of carbonyl moiety possessing an electronegative group in α-position. Subsequent catalytic hydrogenation of (±)-138 and (±)-200 resulted in an inseparable mixture of (±)-4 and (±)-6 (Scheme 41).56 These results were useful for the construction of the enantiopure jaspine B 4 and its stereoisomers (see Scheme 30).56

3. Miscellaneous

To allow recapitulation, Table 3 includes optical rotation values of jaspine B (4), 2epi-jaspine B (6), 3-epi-jaspine B (7), 4-epi-jaspine B (8), their antipodes ent-4, ent-6, ent-7, ent-8 as free bases or salts and also the corresponding acetylated jaspine B derivatives 148, ent-148, 174, ent-174, 194, ent-194 and 228. With the aim to compare, in this table are also added [α]D data for the natural product 4 isolated from two independent sources.13

37 Page 37 of 88

Since isolation of jaspine B in 2003 (or pachastrissamine in 2002), there have been published three X-ray crystallographic structures of jaspine B derivatives, namely 19466 and ent-194,55b,59a which are illustrated in Figures 7-9.

4. Conclusion

The cytotoxic jaspine B (4) was discovered by two independent research groups. The first of them isolated 4 from the marine sponge Pachastrissa sp. and named it pachastrissamine while the second group found this anhydrophytosphingosine in the sponge genus Jaspis and referred to it as jaspine B. The significant biological activity, simple, but unique structural features and limited availability of the natural anhydrophytosphingosines have resulted in the development of numerous total syntheses of 4 as well as its stereoisomers. In 2008, Davies and co-workers reviewed the isolation, characterization, stereochemical assignment, and syntheses of jaspine B together with the construction of 2-epi-jaspine B (6). In last seven years a number of synthetic chemists have undertaken studies on the preparation of jaspine B, its stereoisomers and also modified analogues employing different approaches and various starting materials. Not surprisingly, the majority of communicated approaches to jaspine B derivatives relies on the Chiron approach, especially serine scaffolds and carbohydrates. Since 2008, there have been reported 19 independent total syntheses of jaspine B (4)14a,14b,14f,14g,15b,16b,18,21,22,25,31,37,38,56,60,69,83,86,90 and one formal,46 11 of 2epi-jaspine B (6),14a,14l,16b,22,25,31,37,40,56,73,90 7 of 3-epi-jaspine (7),14a,16b,22,25,62,64,90 2 of 4-epi-jaspine B (8),14f,16a 8 of ent-414d,14g,16a,53,56,66,75,78 together with one formal construction,50 5 of ent-6,16a,33,42,56,64 1 of ent-716a and 8 of ent-8.14a,14d,16b,22,25,66,78,90 Due to the significant cytotoxic activity, 4 as well as several its analogues are expected to be promising lead structures for novel anticancer agents based on their ability to modulate the metabolism of sphingolipids in cancer cells. Although much synthetic and biological effort in the field of anhydrophytosphingosines and their related compounds has been done, many challenges in this research still remain.

Acknowledgements The present work was supported by the Grant Agency (Grant No. 1/0168/15 and No. 1/0398/14) of the Ministry of Education, Slovak Republic. It was also supported by the Slovak Research and Development Agency (Grant No. APVV-14-0883). 38 Page 38 of 88

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17. For recent review on syntheses of jaspine B (4) and 2-epi-jaspine B (6), see: (a) Abraham, E.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Tetrahedron: Asymmetry 2008, 19, 1027–1047 and references cited therein, and also see: (b) Ballereau, S.; Baltas, M.; Génisson, Y. Curr. Org. Chem. 2011, 15, 953‒986. 18. Unuki, S.; Yoshimitsu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2009, 11, 4478‒4481. 19. Herold, P. Helv. Chim. Acta 1988, 71, 354‒362. 20. DʼAniello, F.; Mann, A.; Schoenfelder, A.; Taddei, M. Tetrahedron 1997, 53, 1447‒1456. 21. Unuki, S.; Yoshimitsu, Y.; Oishi, S., Fujii, N.; Ohno, H. J. Org. Chem. 2010, 75, 3831‒3842. 22. Yoshimitsu, Y.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2010, 75, 3843‒3846. 23. Azuma, H.; Tamagaki, S.; Ogino, K. J. Org. Chem. 2000, 65, 3538‒3541. 24. van den Berg, R. J. B. H. N.; Boltje, T. J.; Verhagen, C. P.; Litjens, R, E. J. N.; van der Marel. G. A.; Overkleeft, H. S. J. Org. Chem. 2006, 71, 836‒839. 25. Passiniemi, M.; Koskinen, A. M. P. Org. Biomol. Chem. 2011, 9, 1774‒1783 and references cited therein. 26. Pearson, W. H.; Postich, M. J. J. Org. Chem. 1994, 59, 5662‒5671. 27. Lombardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004, 60, 11725‒11732. 28. (a) Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979‒2984; (b) Sudhakar, N.; Kumar, A. R.; Prabhakar, A.; Jagadeesh, B.; Rao, B. V. Tetrahedron Lett. 2005, 46, 325‒327. 29. Ghosal, P.; Shaw, A. K. Tetrahedron Lett. 2010, 51, 4140‒4142. 30. Chamberlin, A. R.; Mulholland, R. L., Jr.; Kahn, S. D. Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 672‒677. 31. Jana, A. K.; Panda, G. RSC Adv. 2013, 3, 16795‒16801. 32. Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2001, 2136‒2157. 33. Lee, D. Synlett 2012, 23, 2840‒2844. 34. (a) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto, Y. Angew. Chem. Int., Ed. Engl. 1994, 33, 652‒654; (b) 41 Page 41 of 88

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55. (a) Ribes, C.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron 2006, 62, 5421‒5425; (b) Ramana, C. V.; Giri, A. G.; Suryawanshi, S. B.; Gonnade, R. G. Tetrahedron Lett. 2007, 48, 265‒268. 56. Schmiedel, V. M.; Stefani, S.; Reissig, H.-U. Beilstein J. Org. Chem. 2013, 9, 2564‒2569. 57. Hausherr, A.; Orschel, B.; Scherer, S.; Reissig, H.-U. Synthesis 2001, 1377‒1385. 58. Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485‒4488. 59. (a) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.; Sánchez-Fernández, E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2007, 18, 2510–1513; (b) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sánchez-Fernández, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 1665–1673. 60. Rao, G. S.; Rao, B. V. Tetrahedron Lett. 2011, 52, 6076‒6079. 61. Elie, A.; Purushotham, V.; Robert, W. L.; Haribansh, K. S.; Amarendra, B. M.; David, C. J.; Racha, S.; Raymond, P. P. J. Org. Chem. 1988, 53, 2598‒2602. 62. Rao, G. S.; Sudhakar, N.; Rao, B. V.; Basha, S. J. Tetrahedron: Asymmetry 2010, 21, 1963‒1970. 63. Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.; Wu, D. C. J.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53, 2598‒2602. 64. Martinková, M. Pomikalová, K.; Gonda, J.; Vilková, M. Tetrahedron 2013, 69, 8228‒8244. 65. Sagar, R.; Reddy, L. V. R.; Shaw, A. K. Tetrahedron: Asymmetry 2006, 17, 1189‒1198. 66. Martinková, M.; Mezeiová, E.; Gonda, J.; Jacková, D.; Pomikalová, K. Tetrahedron: Asymmetry 2014, 25, 750‒766. 67. Sánchez-Sancho, F.; Valverde, S.; Herradón, B. Tetrahedron: Asymmetry 1996, 7, 3209–3246. 68. Sato, H.; Maeba, T.; Yanase, R.; Yamaji-Hasegawa, A.; Kobayashi, T.; Chida, N. J. Antibiot. 2005, 58, 37‒49. 69. Ichikawa, Y.; Matsunaga, K.; Masuda, T.; Kotsuki, H.; Nakano, K. Tetrahedron 2008, 64, 11313‒11318. 70. Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52, 3337‒3342. 71. Nugent, W. A. Chem. Commun. 1999, 1369‒1370. 43 Page 43 of 88

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Figure 1. Structures of three predominant sphingoid bases and related anhydrophytosphingosines.

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Figure 2. Some selected synthetic analogues of jaspine B (4).

Figure 3. Reported approaches to jaspine B (4) and its enantiomer ent-4 after Daviesʼs review.17a

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Figure 4. Reported approaches to 2-epi-jaspine B (6) and its enantiomer ent-6 after Daviesʼs review.17a

Figure 5. Reported approaches to 3-epi-jaspine B (7) and its enantiomer ent-7 after Daviesʼs review.17a

Figure 6. Reported approaches to 4-epi-jaspine B (8) and its enantiomer ent-8 after Daviesʼs review.17a

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Figure 7. Martinková et al.66. ORTEP structure of N,O-acetylated derivative 194 showing the crystallographic numbering (for greater clarity, see: CCDC No. 967930).

Figure 8. Ramana et al.55b ORTEP structure of N,O-acetylated jaspine B (ent-194) (for greater clarity, see: CCDC No. 617243).

Figure 9. Davies et al.59a Chem 3D representation of the X-ray structure of ent-194 (for greater clarity, see: CCDC No. 616170).

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Scheme 1. Fujii, Ohno et al.18 Reagents and conditions: (a) (i) ethynyltrimethylsilane, n-BuLi, HMPA, THF, ‒78 °C; (ii) TBAF, THF, 0 °C; (b) (i) MsCl, Et3N, THF, ‒78 °C→(‒)60 °C; (ii) CuBr.Me2S, LiBr, THF, 65 °C; (c) TFA, MeOH, 50 °C, then BzCl, Et3N, CH2Cl2, 0 °C; (d) Pd(PPh3)4, Cs2CO3, THF/MeOH (10:1), 50 °C; (e) 9-BBN, THF, 0 °C→rt, then 15% NaOH, 30% H2O2; (f) (i) Tf2O, Et3N, CH2Cl2, ‒78 °C; (ii) C13H27MgBr, CuI (20 mol %), THF, ‒78 °C→(‒)10 °C; (g) 20% H 2SO4, CH2Cl2, 120 °C, seal tube.

Scheme 2. Fujii, Ohno et al.18 Reagents and conditions: (a) (i) ethynyltrimethylsilane, EtMgBr, CuI, Me2S, THF, ‒78 °C→rt; (ii) TBAF, THF, 0 °C; (b) (i) MsCl, Et 3N, THF, ‒78 °C→(‒)60 °C; (ii) CuBr.Me2S, LiBr, THF, 65 °C; (c) TFA, MeOH, 50 °C, then BzCl, Et 3N, CH2Cl2, 0 °C; (d) Pd(PPh)4, Cs2CO3, THF/MeOH (10:1), 50 °C.

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Scheme 3. Fujii, Ohno et al.21 Reagents and conditions: (a) for syn-32: 31, ZnBr2, Et2O, ‒78 °C→rt, for anti-32: 31, HMPA, THF, ‒78 °C→0 °C; (b) ClCO 2Me, pyridine, DMAP, CH2Cl2; (c) TFA, MeOH, 50 °C, then BzCl, DIPEA, CH2Cl2, 0 °C; (d) Ph3PCl2, imidazole, CH2Cl2, 0 °C→rt.

Scheme 4. Fujii, Ohno et al.21 Reagents and conditions: (a) Table 1; (b) (Ph3P)3RhCl, C6H6/EtOH, 50 °C; (c) DIBAl-H, CH2Cl2, 0 °C→rt; (d) H2, Pd(OH)2/C, EtOAc, 50 °C.

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Scheme 5. Fujii, Ohno et al.22 Reagents and conditions: (a) C15H31PPh3Br, LHMDS, THF, ‒78 °C→rt; (b) OsO4, MNO, t-BuOH/H2O (1:1), rt; (c) TsCl, Et3N, Me3N.HCl, CH2Cl2, rt; (d) p-TsOH.H2O, MeOH, 70 °C; (e) Mg, MeOH, rt.

Scheme 6. Fujii, Ohno et al.22 Reagents and conditions: (a) p-TsOH.H2O, MeOH, rt; (b) TsCl, Et3N, DMAP, CH2Cl2, rt; (c) TFA, CH2Cl2, rt.

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Scheme 7. Fujii, Ohno et al.22 Reagents and conditions: (a) TIPSCl, imidazole, DMF, rt; (b) MeC(OMe)3, BF3.OEt2, CH2Cl2, rt; (c) (i) Boc2O, Et3N, DMAP, CH2Cl2, rt; (ii) NaOMe, MeOH, rt; (d) TsCl, Et3N, Me3N.HCl, CH2Cl2, rt; (e) TBAF, THF, rt; (f) (i) Mg, MeOH, rt; (ii) TFA, CH 2Cl2, rt.

Scheme 8. Fujii, Ohno et al.22 Reagents and conditions: (a) TBAF, THF, rt; (b) TsCl, Et3N, Me3N.HCl, CH2Cl2, ‒78 °C; (c) K2CO3, MeOH, rt; (d) TFA, CH2Cl2, rt.

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Scheme 9. Koskinen and Passiniemi.25 Reagents and conditions: (a) I2, KOH, MeOH/H2O, 0 °C→rt; (b) KO2CN=NCO2K, AcOH, MeOH (c) TBDMSCl, imidazole, DMF, 0 °C→rt; (d) 24, Table 2, ‒78 °C→(‒)95 °C; (e) BnBr, NaH, THF, TBAI, reflux; (f) TBAF, THF, rt.; (g) Ac 2O, DMAP, Et3N, CH2Cl2, rt; (h) FeCl3/SiO2, CHCl3, rt.

Scheme 10. Koskinen and Passniemi.25 Reagents and conditions: (a) Pd(PPh3)4, PPh3, THF, 55 °C; (b) tetradec-1-ene, Grubbs II catalyst, CH2Cl2, 45 °C; (c) (i) H2 (1 atm), Pd/C, MeOH, rt; (ii) HCl, MeOH, 0 °C→rt.

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Scheme 11. Fujii, Ohno et al.16b Reagents and conditions: (a) (i) 3-bromoprop-1-enyl acetate, In, DMF, 0 °C; (ii) K2CO3, MeOH/H2O (4:1), rt; (b) TsCl, Et3N, Me3.HCl, CH2Cl2, rt; (c) p-TsOH.H2O, MeOH, reflux; (d) (i) Mg, MeOH, rt; (ii) CbzCl, NaHCO3, THF/H2O (1:1), rt; (e) (i) tetradec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (ii) H2, 10% Pd/C, EtOH, rt.

Scheme 12. Fujii, Ohno et al.16b Reagents and conditions: (a) p-TsOH.H2O, MeOH, rt; (b) (i) TsCl, Et3N, Me3N.HCl, CH2Cl2, ‒78 °C; (ii) K2CO3, MeOH, rt; (c) (i) tetradec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (ii) H2, Pd/C, EtOH, rt; (iii) TFA, CH2Cl2, rt; (d) TBDPSCl, imidazole, CH2Cl2, ‒20 °C; (e) SOCl2, THF, reflux; (f) NsCl, NaH, THF, rt; (g) TBAF, THF, then KOH aq, THF, rt; (h) MeC(OMe)3, BF3.OEt2, CH2Cl2, rt; (j) (i) tetradec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (ii) PhSH, Cs2CO3, then KOH aq, MeCN, rt; (h) H2, Pd/C, EtOH, rt.

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Scheme 13. Fujii, Ohno et al.16b Reagents and conditions: (a) (i) Boc2O, Et3N, DMAP, THF, rt; (ii) 3HF.Et3N, THF, reflux; (b) (i) TsCl, Et3N, Me3N.HCl, CH2Cl2, ‒78 °C; (ii) K2CO3, MeOH, rt; (e) (i) tetradec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (ii) H2, Pd/C, EtOH, rt; (iii) TFA, CH2Cl2, rt.

Scheme 14. Shaw et al.14b Reagents and conditions: (a) vinylmagnesium bromide, THF, ‒78 °C; (b) BnBr, NaH, DMF, 0 °C→rt; (c) pentadec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (d) p-TsOH, MeOH, 0 °C; (e) NIS, I2, THF, 0 °C→rt; (f) n-Bu3SnH, ABCN, toluene, reflux; (g) H2, Pd/C, MeOH, 95%; (h) TFA/CH2Cl2 (1:4), 0 °C; (j) 2.5 M NaOH/MeOH, CH2Cl2, 0 °C→rt.

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Scheme 15. Panda and Jana.31 Reagents and conditions: (a) (i) vinylmagnesium bromide, THF, ‒78 °C; (ii) p-TsOH, MeOH, 0 °C→rt; (b) I2, K2CO3, MeCN, 0 °C; (c) 2,2-DMP, (±)-CSA, CH2Cl2, 0 °C→rt; (d) vinylmagnesium bromide, Cu/HMPA, THF, ‒30 °C; (e) tridec-1-ene, 95, CH2Cl2, 45 °C; (f) H2, Pd/C, EtOAc, 50 psi, rt; (g) 6 N HCl/MeOH, 0 °C→rt, then 2 M aq KOH, CH 2Cl2, rt.

Scheme 16. Panda nad Jana.31 Reagents and conditions: (a) Ph3P=CHCO2Et, C6H6, 0 °C→rt; (b) ADmix-α; MeSO2NH2, t-BuOH/H2O (1:1), 0 °C; (c) TsCl, Et3N, CH2Cl2, 0 °C; (d) PPTS, MeOH, 0 °C; (e) 2,2-DMP, BF3.OEt2, acetone, 0 °C→rt; (f) LiBH4, THF, 0 °C→rt; (g) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ‒78 °C; (ii) Ph3PCH3Br, KHMDS, THF, ‒78 °C; (h) tetradec-1-ene, 95, CH2Cl2, 45 °C; (j) H2, Pd/C, EtOAc, 50 psi, rt; (k) 6 N HCl/MeOH, 0 °C→rt, then 2 M aq KOH, CH 2Cl2, rt.

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Scheme 17. Fujii, Oishi et al.16a Reagents and conditions: (a) C15H31PPh3Br, LHMDS, THF, ‒78 °C; (b) OsO4, MNO, t-BuOH/H2O (1:1), 0 °C→rt; (c) TsCl, Et3N, Me3N.HCl, rt, (d) p-TsOH.H2O, MeOH, 70 °C; (e) Mg, MeOH, rt; (f) p-TsOH.H2O, MeOH, 0 °C→rt; (g) TsCl, Et3N, DMAP, CH2Cl2, 0 °C→rt; (h) TFA, CH2Cl2, 0 °C→rt.

Scheme 18. Fujii, Oishi et al.16a Reaction and conditions: (a) TIPSCl, imidazole, DMF, 0 °C→rt; (b) MeC(OMe)3, BF3.OEt2, CH2Cl2, 0 °C→rt; (c) (i) Boc2O, Et3N, DMAP, THF, 0 °C→rt; (ii) NaOMe, MeOH, 0 °C→rt; (d) TsCl, Et 3N, Me3N.HCl, CH2Cl2, rt; (e) TBAF, THF, 0 °C→rt; (f) (i) Mg, MeOH, rt; (ii) TFA, CH2Cl2, 0 °C→rt; (g) TBAF, THF, 0 °C→rt; (h) (i) TsCl, Et 3N, Me3N.HCl, CH2Cl2, ‒78 °C; (ii) K2CO3, MeOH, 0 °C→rt; (j) TFA, CH2Cl2, 0 °C→rt.

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Scheme 19. Lee.33 Reagents and conditions: (a) eight steps, Ref. 34; (b) (i) allyl chloride, 95, CH2Cl2, 45 °C; (ii) tetradec-1-ene, 95, CH2Cl2, 45 °C; (c) H2 (1 atm), Pd/C, EtOAc, rt; (d) aq KOH, EtOH, reflux.

Scheme 20. Delgado, Casas et al.14a Reagents and conditions: (a) TsCl, pyridine/CH2Cl2 (1:1), rt; (b) TsCl, Et3N, DMAP, CH2Cl2, 0 °C→rt; (c) K2CO3, MeOH, 0 °C→rt; (d) TFA, CH2Cl2, rt.

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Scheme 21. Kim, Lee et al.37 Reagents and conditions: (a) (i) TrCl, DMAP, CH2Cl2/pyridine, rt; (ii) NaH, DMF, rt; (b) MsCl, pyridine, rt; (c) BF 3.OEt2, toluene/MeOH, rt; (d) aq KOH, EtOH, reflux; (e) BF3.OEt2, toluene/MeOH, rt; (f) TsCl, DMAP, pyridine, reflux.

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Scheme 22. Chattopadhyay and Vichare.38 Reagents and conditions: (a) MeNO2, aq K2CO3, rt; (b) TBDMSCl, Et3N, CH2Cl2, rt; (c) K2CO3, MeOH, aq KMnO4, MgSO4, 0 °C; (d) C14H29MgBr, THF, ‒50 °C; (e) BzCl, pyridine, DMAP, 0 °C→rt; (f) TBAF, THF, rt; (g) PCC, CH 2Cl2, rt; (h) K-Selectride, THF, ‒78 °C; (j) BzCN, Et3N, CH2Cl2, 0 °C→rt; (k) 90% aq TFA, CH2Cl2, 0 °C; (l) MsCl, Et3N, DMAP, CH2Cl2, 0 °C→rt; (m) NaN3, DMF, 100 °C; (n) K2CO3, MeOH, rt; (o) TsCl, pyridine, DMAP, 0 °C; (p) H2, 10% Pd/C, MeOH/CH2Cl2, rt.

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Scheme 23. Rao and Rao.40 Reagents and conditions: (a) BnNH2, MeOH, reflux; (b) vinylmagnesium bromide, THF, ‒78 °C→rt; (c) CbzCl, NaHCO3, MeOH, 0 °C→rt; (d) (i) O3, MeOH, ‒78 °C, then DMS; (ii) NaBH4, MeOH, 0 °C; (e) NaH, THF, 0 °C; (f) TBAF, THF, 0 °C; (g) (i) NaIO 4, MeOH/H2O, 0 °C; (ii) C13H27PPh3Br, n-BuLi, THF, ‒40 °C; (h) 6 N HCl, EtOH, reflux; (j) (i) H 2, Pd/C/Pd(OH)2/C (1:1), MeOH, rt; (ii) Boc2O, Et3N, CH2Cl2; (k) TsCl, Et3N, DMAP, CH2Cl2, rt; (l) TFA, CH2Cl2, rt; (m) Ac2O, Et3N, CH2Cl2, 0 °C→rt.

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Scheme 24. Sartillo-Piscil, Quintero et al.42 Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, ‒78 °C; (b) BnNH2, TiCl4, THF, 0 °C, then NaBH4, MeOH, ‒30 °C; (c) allyltrimethylsilane, BF3.OEt2, CH2Cl2, 0 °C→rt; (d) BnBr, NaH, THF, 0 °C→reflux; (e) (i) tridec-1-ene, 95, toluene, reflux; (ii) H2, Pd(OH)2/C, MeOH, rt; (f) TBAF, THF, rt; (g) Ph3P, DEAD, N-hydroxyphthalimide, THF, 0 °C→rt; (h) Bu3SnH, AIBN, toluene, reflux; (j) H2, Pd(OH)2/C, AcOH, MeOH, rt.

Scheme 25. Liu et al.46 Reagents and conditions: (a) acetone, H2SO4, rt, then Na2CO3, rt; (b) TsCl, pyridine, CH2Cl2, rt; (c) AcCl, MeOH, reflux, then K2CO3, rt; (d) NaN3, NH4Cl, H2O/EtOH, reflux; (e) (i) IBX, EtOAc, reflux; (ii) KBH4, EtOH, rt; (f) BnBr, K2CO3, THF, reflux; (g) 0.05 M HCl/dioxane, 80 °C; (h) Refs. 14i, 49.

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Scheme 26. Rao et al.14d Reagents and conditions: (a) (i) NaH, THF, 0 °C; (ii) diethyl carbonate, reflux; (b) TsCl, Et3N, DMAP, CH2Cl2, 0 °C→rt; (c) NaN3, DMF, 90 °C; (d) 60% aq AcOH, concd HCl, rt; (e) NaIO4, MeOH/H2O, rt; (f) C13H27PPh3Br, t-BuOK, THF, ‒40 °C→rt; (g) H2, 10% Pd/C, MeOH, rt; (f) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C→rt.

Scheme 27. Rao et al.14d Reagents and conditions: (a) Ph3P, DIAD, p-nitrobenzoic acid, THF, 0 °C→rt; (b) LiOH.H2O, THF/H2O, rt; (c) MsCl, Et3N, CH2Cl2, 0 °C→rt; (d) NaN3, DMF, 120 °C; (e) 60% aq AcOH, concd HCl, rt; (f) NaIO4, MeOH/H2O, rt; (g) C13H27PPh3Br, t-BuOK, THF, ‒40 °C→rt; (h) H2, Pd/C, MeOH/TFA, rt.

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Scheme 28. Sartillo-Piscil et al.50 Reagents and conditions: (a) BnBr, NaH, (solvent and temperature not reported); (b) (i) H5IO6, EtOAc, rt; (ii) C13H27PPh3Br, n-BuLi, THF, 0 °C; (c) Et3SiH, BF3.OEt2, CH2Cl2, 0 °C→rt; (d) (i) CF3SO2Cl, CH2Cl2, DMAP, 0 °C; (ii) NaN3, TBAF, DMF, rt; (e) Refs. 14i, 49.

Scheme 29. Rao et al.53 Reagents and conditions: (a) Ref. 54; (b) CbzCl, NaHCO3, MeOH, 0 °C→rt; (c) (i) O3, CH2Cl2, ‒78 °C, then DMS, ‒78 °C→rt; (ii) NaBH 4, MeOH, 0 °C; (d) NaH, THF, 0 °C→rt; (e) TFA/H2O (3:2), 0 °C→rt; (f) (i) NaIO4, MeOH/H2O, aq NaHCO3, 0 °C; (ii) C13H27PPh3Br, n-BuLi, THF, 0 °C; (g) 4 M NaOH aq, EtOH, reflux; (h) (i) H 2, Pd/C/Pd(OH)2/C (1:1), EtOH, rt; (ii) Boc2O, Et3N, CH2Cl2, 0 °C; (j) TsCl, pyridine, CH2Cl2, rt; (k) (i) TFA, CH2Cl2, 0 °C→rt; (ii) Ac2O, Et3N, DMAP, CH2Cl2, rt.

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Scheme 30. Reissig et al.56 Reagents and conditions: (a) n-BuLi, THF, ‒40 °C, then pentadecanal, ‒78 °C; (b) AuCl, pyridine, CH2Cl2, rt; (c) (i) NBS, THF/H2O/MeCN, ‒30 °C→(‒)15 °C; (ii) NaN3, (Oct)3MeNI, CH2Cl2/H2O, rt; (iii) L-selectride, THF, ‒78 °C; (d) NaH, CbzCl, DMAP, Bu 4NI, CH2Cl2, 0 °C→rt; (e) H2, Pd/C, CH2Cl2/MeOH, rt.

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Scheme 31. Rao and Rao.60 Reagents and conditions: (a) Ref. 61; (b) C13H27Br, Mg, CuCN, THF, ‒20 °C; (c) 80% aq AcOH, rt; (d) TBDMSCl, imidazole, CH 2Cl2, rt; (e) 2,2-DMP, p-TsOH, CH2Cl2, rt; (f) TBAF, THF, 0 °C; (g) (i) DMSO, (COCl)2, Et3N, CH2Cl2, ‒78 °C; (ii) BnNH2, CH2Cl2, 4 Å MS, 0 °C; (iii) vinylbromide, Mg, THF, ‒20 °C→rt ; (h) CbzCl, NaHCO3, MeOH, 0 °C→rt; (j) (i) O3, CH2Cl2, ‒78, °C, then DMS; (ii) NaBH4, MeOH, 0 °C; (k) (i) H2, Pd/C/Pd(OH)2/C (1:1), EtOH, rt; (ii) Boc2O, Et3N, CH2Cl2, rt; (l) (i) MsCl, Et3N, DMAP, CH2Cl2, 0 °C→rt; (ii) p-TsOH, MeOH, rt, then NaHCO3; (m) TFA, CH2Cl2, 0 °C→rt; (n) Ac2O, Et3N, CH2Cl2, 0 °C→rt.

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Scheme 32. Rao at al.62 Reagents and conditions: (a) Ref. 63; (b) LiALH4, THF, 0 °C→rt; (c) (i) DMSO, (COCl)2, CH2Cl2, DIPEA, ‒78 °C; (ii) Ph3P=CHCO2Et, CH2Cl2, 0 °C; (d) 80% aq AcOH, 0 °C→rt; (e) NaH, THF, ‒40 °C; (f) (i) MsCl, Et 3N, DMAP, CH2Cl2, 0 °C→rt; (ii) NaN3, DMF, 120 °C; (g) (i) LiAlH4, THF, 0 °C→rt; (ii) aq NaOH, Boc2O, 0 °C; (h) BAIB/TEMPO, CH2Cl2, rt; (j) C12H25PPh3Br, t-BuOK, THF, ‒40 °C; (k) H2, 10% Pd/C, EtOH, rt; (l) DIBAl-H, CH2Cl2, 0 °C→rt; (m) (i) BAIB/TEMPO, CH2Cl2, rt; (ii) C12H25PPh3Br, t-BuOK, THF, ‒40 °C; (n) (i) H2, 10% Pd/C, EtOH, rt; (ii) Boc2O; Et3N, CH2Cl2, 0 °C; (o) (i) TFA, CH2Cl2, 0 °C→rt; (ii) Ac2O, Et3N, DMAP, CH2Cl2, 0 °C→rt.

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Scheme 33. Shaw et al.14l Reagents and conditions: (a) Ref. 65; (b) I2, CH2Cl2, rt; (c) I2, Ph3P, imidazole, toluene, 45 °C; (d) tetradec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (e) (i) MsCl, Et3N, CH2Cl2, 0 °C; (ii) NaN3, DMF, 100 °C; (f) H2, Pd/C, MeOH, rt.

Scheme 34. Martinková et al.14f Reagents and conditions: (a) (i) TrCl, DMAP, pyridine, 40 °C→rt; (ii) 2,2-DMP, acetone, CSA, rt; (b) (i) IBX, MeCN, reflux; (ii) NaBH4, EtOH, 0 °C→rt; (c) (i) BnBr, DMF, NaH, TBAI, 0 °C→rt; (ii) CSA, CH2Cl2/MeOH (2:1), rt; (d) (i) BzCl, DMAP, pyridine, 0 °C→rt; (ii) 80% TFA, 0 °C; (e) (i) NaIO4, MeOH/H2O (1:1), rt; (ii) NaBH4, MeOH/CH2Cl2, 0° C→rt; (f) (ii) 2,2-DPM, CH2Cl2, p-TsOH, rt; (ii) K2CO3, MeOH, 0 °C→rt; (g) Ref. 67, 16% (over three steps).

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Scheme 35. Martinková et al.14f Reagents and conditions: (a) (i) IBX, MeCN, reflux; (ii) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C→rt; (b) DIBAl-H, CH2Cl2, –50 °C→rt; (c) (i) MsCl, Et3N, CH2Cl2, 0 °C→rt; (ii) KSCN, MeCN, 0 °C→rt; (d) NaH, Cl 3CCN, NaH, THF, 0 °C→rt; (e) n-heptane, ∆ and MW (both at 70 and 90 °C); (f) o-xylene, K2CO3, ∆ (at 140 °C) and MW (at 130, 150 and 170 °C).

Scheme 36. Martinková et al.14f Reagents and conditions: (a) (i) MeONa, MeOH, 0 °C→rt, 97% from both 246 and 247; (ii) MNO, MeCN, rt; (b) (i) O3, MeOH or MeOH/CH2Cl2, –78 °C; (ii) NaBH4, MeOH or MeOH/CH2Cl2, –78 °C→rt; (c) NaH, THF, 0 °C→rt, 99% for 254 from 252, 92% for 255 from 253; (d) (i) O3, MeOH/CH2Cl2, –78 °C; (ii) NaBH4, MeOH/CH2Cl2, –78 °C→rt; (e) DBU, CH2Cl2, 0 °C→rt, 95% for 254 from 256, 96% for 255 from 257.

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Scheme 37. Martinková et al.14f Reagents and conditions: (a) p-TsOH, MeOH, rt; (b) TrCl, DMAP, pyridine, 60 °C; (c) BnBr, NaH, DMF, TBAI, 0 °C→rt; (d) p-TsOH, CH2Cl2/MeOH, rt; (e) (i) IBX, MeCN, reflux; (ii) LHMDS, C13H27PPh3Br, THF, rt; (f) H2, 10% Pd/C, EtOH, rt; (g) H 2, 10% Pd/C, EtOH, 35% HCl, 60 °C; (h) 6 M HCl, reflux; (j) Ac2O, pyridine, DMAP, rt.

Scheme 38. Martinková et al.66 Reagents and conditions: (a) TrCl, DMAP, Et3N, DMF, rt; (b) BnBr, NaH, DMF, TBAI, 0 °C→rt; (c) p-TsOH, CH2Cl2/MeOH, rt; (d) BzCl, pyridine, DMAP, 0 °C→rt; (e)

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TFA/H2O, 0 °C→rt; (f) (i) NaIO4, MeOH/H2O, rt; (ii) NaBH4, EtOH/H2O, 0 °C→rt; (g) 2,2-DMP, CH2Cl2, p-TsOH, rt; (h) K2CO3, MeOH, 0 °C→rt.

Scheme 39. Martinková et al.66 Reagents and conditions: (a) (i) IBX, CH3CN, reflux; (ii) (EtO)2P(O)CH2COOEt, NaH, THF, –10 °C; (b) DIBAl-H, CH2Cl2, –50 °C; (c) (i) MsCl, Et3N, CH2Cl2 0 °C→rt, (ii) KSCN, CH3CN, 0 °C→rt; (d) NaH, CCl3CN, THF, 0 °C; (e) n-heptane, ∆ and MW, (both at 70 and 90 °C); (f) o-xylene, K2CO3, ∆ (at 140 °C) and MW (at 130, 150 and 170 °C).

Scheme 40. Martinková et al.66 Reagents and conditions: (a) (i) MeONa, MeOH, 0 °C→rt, 98% from both ent-246, 98% from ent-247; (ii) MNO, MeCN, rt; (b) (i) O3, EtOH or EtOH/CH2Cl2, –78 °C; (ii) NaBH4, EtOH or EtOH/CH2Cl2, –78 °C→rt; (c) NaH, THF, 0 °C→rt, 95% for ent-254 from ent-252, 93% for ent-255 from ent-253; (d) (i) O3, MeOH/CH2Cl2, –78 °C; (ii) NaBH4, MeOH/CH2Cl2, –78 °C→rt, ent-254, 35%, ent-255, 11%; (e) DBU, CH2Cl2, 0 °C→rt, 95% for ent-254 from ent-256, 93% for ent-255 from ent-257.

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Scheme 41. Martinková et al.66 Reagents and conditions: (a) p-TsOH, MeOH, rt; (b) TrCl, DMAP, pyridine, 60 °C; (c) BnBr, NaH, DMF, TBAI, 0 °C→rt; (d) p-TsOH, CH2Cl2/MeOH, rt; (e) (i) IBX, MeCN, reflux; (ii) LHMDS, C13H27PPh3Br, THF, rt; (f) H2, 10% Pd/C, EtOH, rt; (g) H 2, 10% Pd/C, EtOH, 35% HCl, 60 °C; (h) 6 M HCl, reflux; (j) Ac 2O, pyridine, DMAP, rt.

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Scheme 42. Martinková et al.64 Reagents and conditions: (a) Ph3P=CHCO2Et, CH2Cl2, benzoic acid, reflux; (b) TBDMSCl, imidazole, DMF, rt; (c) DIBAl-H, CH2Cl2, –15 °C; (d) CCl3CN, DBU, CH2Cl2, 0 °C→rt; (e) (i) MsCl, Et3N, CH2Cl2, 0 °C→rt; (ii) KSCN, MeCN, rt; (f) o-xylene, K2CO3, Δ and MW (both at 150 and 170 °C); (g) n-heptane, Δ (at 90 °C) and MW (at 90, 120, 150 and 170 °C).

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Scheme 43. Martinková et al.64 Reagents and conditions: (a) (i) NaOH, EtOH/H2O, rt; (ii) Boc2O, Et3N, CH2Cl2, rt; (b) (i) O3, MeOH/CH2Cl2, –78 ºC; (ii) NaBH4, –78 ºC→rt; (c) NaH, THF, 0 ºC→rt, 86% from 285, 92% from 290; (d) (i) MeONa, MeOH, 0 ºC→rt, 52%; (ii) MNO, MeCN, rt, 75%.

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Scheme 44. Martinková et al.64 Reagents and conditions: (a) PMBCl, NaH, DMF, TBAI, 0 ºC→rt; (b) TBAF, THF, 0 ºC→rt; (c) AcOH/H2O, rt; (d) (i) NaIO4, MeOH/H2O, rt; (ii) C13H27PPh3Br, LHMDS, THF, rt; (e) 10% Pd/C, EtOH, rt; (f) CAN, MeCN/H2O, rt; (g) 6 M HCl, reflux; (h) Boc2O, Et3N, THF, rt; (j) Ac2O, pyridine, DMAP, rt.

75 Page 75 of 88

Scheme 45. Ichikawa et al.69 Reagents and conditions: (a) (i) Tf2O, 2,6-lutidine, CH2Cl2, ‒78 °C; (ii) tridec-1-yne, n-BuLi, THF/DMPU (6:1), ‒20 °C; (b) (i) H2, Pd/C, EtOAc, rt; (ii) TBAF, MeCN, rt; (c) (i) (COCl)2, DMSO, Et3N, THF, ‒78 °C; (ii) (Et2O)2P(O)CH2CO2Et, NaH, ‒20 °→(‒)78 °C; (d) DIBAl-H, CH2Cl2, ‒20 °C; (e) 4-acetamido-TEMPO, NCS, CH2Cl2/H2O, TBACl, rt; (f) Et2Zn, 308, toluene/hexane (6:1), 0 °C; (g) (i) CCl3CONCO, CH2Cl2, 0 °C; (ii) 1 M aq K2CO3, MeOH, rt; (h) PPh3, CBr4, Et3N, CH2Cl2, ‒20 °C; (j) di-n-butyltin maleate, MeOH, ‒20 °C→rt; (k) (i) Dowex 50W-X8, MeOH, reflux; (ii) NaH, THF, rt; (l) O3, CH2Cl2/MeOH, ‒78 °C, then DMS; (m) Ac2O, pyridine, 0 °C; (n) Et3SiH, TMSOTf, CH2Cl2, ‒20 °C→0 °C; (o) 1 M aq KOH, EtOH, reflux; (p) Ac2O, pyridine, rt.

76 Page 76 of 88

Scheme 46. Fadnavis at al.73 Reagents and conditions: (a) SOCl2, Et3N, CH2Cl2, 0 °C→rt; (b) NaN3, DMF, rt; (c) BnBr, Ag2O, CH2Cl2, rt; (d) (i) LiAlH4, THF, 0 °C→reflux; (ii) 1 M aq NaOH, Boc2O, rt; (e) 2,2-DMP, p-TsOH, CH2Cl2, rt; (f) (i) DMP, CH2Cl2, rt; (ii) Ph3P=CHCO2Et, CH2Cl2, rt; (g) pTsOH, MeOH, rt; (h) NaH, THF, 0 °C→rt; (j) (i) DIBAl-H, THF, ‒78 °C; (ii) C12H25PPh3Br, n-BuLi, THF, ‒78 °C→rt; (k) H2, Pd(OH)2/C, MeOH, TFA, rt.

Scheme 47. Prasad and Penchalaiah.75 Reagents and conditions: (a) Ref. 77; (b) (i) MOMCl, DIPEA, CH2Cl2, 0 °C→rt; (ii) PPTS, MeOH, rt; (c) TsCl, DMAP, CH 2Cl2, 0 °C→rt; (d) PPTS, MeOH, reflux; (e) BnNH2, 150 °C; (f) tridec-1-ene, Grubbs I catalyst, CH2Cl2, reflux; (g) H2, Pd(OH)2/C, MeOH, TFA, rt; (h) 2.5 M NaOH/MeOH, CH2Cl2, rt.

77 Page 77 of 88

Scheme 48. Hou et al.78 Reagents and conditions: (a) TBDMSCl, imidazole, CH2Cl2, 0 °C→reflux; (b) Ti(i-OPr)4, (+)-DIPT, TBHP, CH2Cl2, 3 Å, ‒30 °C→(‒)20 °C; (c) MOMCl, DIPEA, CH 2Cl2, 0 °C→reflux; (d) (i) TBAF, THF, rt; (ii) tetradec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (e) H2, 10% Pd/C, MeOH, rt; (f) LiI, AcOH, THF, rt; (g) MeOH, propylene oxide, 120 °C, MW; (h) (i) TsCl, pyridine, 0 °C→50 °C; (ii) NaN3, DMF, 100 °C; (iii) H2, 10% Pd/C, THF/MeOH, rt.

Scheme 49. Hou et al.78 Reagents and conditions: (a) Ti(i-OPr)4, (‒)-DIPT, TBHP, CH2Cl2, ‒30 °C→(‒)20 °C; (b) TBDMSCl, imidazole, CH2Cl2, 0 °C→reflux; (c) LiI, AcOH, THF, rt; (d) (i) NaN 3, DMF, 40 °C; (ii) Ph3P, toluene, reflux; (e) CbzCl, Et3N, CH2Cl2, 0 °C→rt; (f) HF/H2O/ MeCN, rt; (g) (i) tetradec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (ii) H2, 10% Pd/C, MeOH, TFA, rt.

78 Page 78 of 88

Scheme 50. Britton et al.83 Reagents and conditions: (a) 348, Cu(TFA)2, LiCl, Na2S2O8, H2O, MeCN, 0 °C→rt; (b) LHMDS, THF; ‒78 °C; (c) H2O/MeOH (1:1.2), MW, 100 °C; (d) (i) undec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (ii) H2, Pd(OH)2/C, EtOAc/MeOH, rt; (e) DIBAl-H, CH2Cl2, ‒55 °C; (f) Et3SiH, BF3.OEt2, CH2Cl2, ‒78 °C→rt; (g) 1 M aq KOH, EtOH, reflux.

79 Page 79 of 88

Scheme 51. Enders et al.86 Reagents and conditions: (a) pentadecanal, (R)-proline, CHCl3, rt; (b) TBDMSOTf, 2,6-lutidine, CH2Cl2/THF, ‒20 °C; (c) L-Selectride, THF, ‒78 °C; (d) MsCl, DMAP, CH2Cl2, 0 °C→(‒)10 °C; (e) NaN3, 18-crown-6, DMF, 100 °C; (f) TBAF, THF, 0 °C→rt; (g) TsCl, DMAP, CH2Cl2, 0 °C; (h) Amberlyst 15, THF/MeOH, rt; (j) H2, Pd/C, CH2Cl2, rt.

Scheme 52. Génisson et al.15b Reagents and conditions: (a) (i) Ti(Oi-Pr)4, (‒)-DET, TBHP, 4 Å, CH2Cl2, ‒23 °C; (ii) resin-supported Ph3P, CH2Cl2, ‒23 °C→rt; (iii) Ti(Oi-Pr)4, PMBNH2, CH2Cl2, rt, 95%, 364:365 = 65:35; (b) Ref. 88; (c) Ti(Oi-Pr)4, PMBNH2, CH2Cl2, reflux, 83%, 364:365 = 80:20; (d) (i) MeOCOCl, K2CO3, THF, rt; (ii) 10% KOH/MeOH, rt; (e) DMP, CH2Cl2, rt; (f) TIPSCCLi/CeCl3, THF, ‒78 °C; (g) MsCl, Et3N, CH2Cl2, 0 °C→rt; (h) BnNH2, Et3N, DMSO, 80 °C; (j) NBS, AgF, MeCN, rt; (k) dodec-1-yne, Pd(PPh3)2Cl2, CuI, i-Pr2NH, THF, rt; (l) H2, Pd(OH)2/C, EtOAc/MeOH, rt; (m) CAN, MeCN/H2O, rt; (n) 10% KOH/MeOH, 85 °C.

80 Page 80 of 88

Scheme 53. Génisson et al.15b Reagents and conditions: (a) vinylmagnesium bromide/CeCl3, THF, ‒78 °C; (b) MsCl, Et3N, CH2Cl2, 0 °C→rt; (c) tetradec-1-ene, Grubbs II catalyst, CH2Cl2, reflux; (d) H2, Pd(OH)2/C, EtOAc/MeOH, rt; (e) Scheme 52 (steps m and n).

81 Page 81 of 88

Scheme 54. Castillón, Matheu et al.90 Reagents and conditions: (a) phthalimide/Na2CO3, 381, (η3C3H5PdCl)2, CH2Cl2, rt (Ref. 91); (b) tetradec-1-ene, 95, CH2Cl2, reflux; (c) K2OsO2(OH)4, (DHQ)2PYR, MeSO2NH2, K2CO3, NaHCO3, K3Fe(CN)6, rt (Ref. 92); (d) (i) TsCl, Et3N, DMAP, CH2Cl2, rt; (ii) Na2CO3, MeOH, rt; (e) MeNH2, 50 °C; (f) (i) TBDPSCl, Et3N, DMAP, CH2Cl2/DMF, 0 °C; (ii) SOCl2, Et2N, CH2Cl2, 0 °C; (iii) RuCl3.H2O, NaIO4, MeCN/CCl4/H2O (1:1:1), rt (Ref. 92); (g) (i) TBAF, THF, rt; (ii) H2SO4, THF, H2O, rt.

82 Page 82 of 88

Scheme 55. Castillón, Matheu et al.90 Reagents and conditions: (a) TsCl, pyridine, CH2Cl2, 0 °C→rt; (b) MeNH2, 50 °C; (c) TBDMSCl, Et3N, DMAP, CH2Cl2/DMF, 0 °C→rt; (d) (i) SOCl2, Et3N, CH2Cl2, 0 °C; (ii) RuCl3.H2O, NaIO4, MeCN/CCl4/H2O (1:1:1), rt; (e) (i) TBAF, THF/CH2Cl2, rt; (ii) H2SO4, THF, H2O, rt.

83 Page 83 of 88

Scheme 56. Génisson, Ballereau et al.14g Reagents and conditions: (a) Ref. 93; (b) ClCO2Me, MeCN, sealed tube, MW, 100 °C; (c) (i) 2-(tetradecylsulfonyl)benzo[d]thiazole, LiHMDS, THF, ‒78 °C; (ii) DBU, THF, rt; (d) H2, (Ph3P)3RhCl, C6H6/EtOH, 40 °C; (e) CAN, MeCN/H2O (9:1), rt; (f) KOH, EtOH/H2O (4:1), 85 °C.

84 Page 84 of 88

Scheme 57. Reissig et al.56 Reagents and conditions: (a) (i) n-BuLi, THF, ‒40 °C; (ii) pentadecanal, THF, ‒78 °C; (b) t-BuOK, DMSO, 60 °C; (c) (i) NaN3, CAN, MeCN/H2O, ‒25 °C; (ii) L-Selectride, THF, ‒78 °C; (d) H2, Pd/C, MeOH/CH2Cl2, rt.

Table 1. Selected conditions of Pd(0)-catalyzed bis-cyclization of propargylic susbtrates Entry

Substrate

Conditionsa

1 2 3 4

syn-34 anti-34 syn-36 anti-36

THF THF Cs2CO3, THF/MeOH (10:1) Cs2CO3, THF/MeOH (10:1)

Yieldb [%] 69 95:5 >95:5 >95:5 13:87

Yieldb 38 [%] NDc 60 trace 32

a

In the presence of Pd(PPh3)4, at 50 °C Isolated combined yields. c Not determined. b

Table 2. Selected conditions for the addition of 59 to Garnerʼs aldehyde 24 Entry

Additive

Conditionsa n-BuLi, toluene

Ratio 60a:60b 12:1

Yieldb [%] 55

1

HMPT

2

DMPU

n-BuLi, toluene

16.9:1

57

3

no additive

n-BuLi, toluene

4:1

63

4

ZnCl2

n-BuLi, toluene/Et2O

1:5.7

72

5

BF3.OEt2

n-BuLi, toluene

1:6

70

a b

At ‒95 °C. Isolated combined yields.

Table 3. Optical rotation values for jaspine B (4), 2-epi-jaspine B (6), 3-epi-jaspine B (7), 4-epi-jaspine B (8), their corresponding antipodes ent-4, ent-6, ent-7, ent-8 and acetylated derivatives 148, ent-148, 174, ent-174, 194, ent-194 and 228

Compound

natural jaspine B or pachastrissamine

synthetic jaspine B (4)

Literature Higa et al. (Ref. 13a) (pachastrissamine)

Optical rotation [α]D = +18.0 (c 0.1, EtOH)a

Debitus et al. (Ref. 13b) (jaspine B)

[α]D20 = +7.0 (c 0.1, CHCl3)

Fujii, Ohno et al. (Ref. 18) Fujii, Ohno et al. (Ref. 21) Fujii, Ohno et al. (Ref. 22) Koskinen et al. (Ref. 25) Fujji, Ohno et al. (Ref. 16b) Shaw et al. (Ref. 14b) Panda et al. (Ref. 31) Delgado, Casas et al. (Ref. 14a) Kim, Lee et al. (Ref. 37) Chattopadhyay et al. (Ref. 38)

[α]D25 = +19.7 (c 0.62, EtOH) [α]D25 = +18.9 (c 0.77, EtOH) [α]D25 = +14.8 (c 0.57, EtOH) [α]D = +18.4 (c 1.00, CH2Cl2)a [α]D25 = +15.6 (c 0.49, EtOH) [α]D17 = +8.6 (c 0.32, MeOH) [α]D22 = +9.42 (c 0.10, MeOH) [α]D25 = +8.7 (c 1.10, CHCl3) [α]D24 = +23.2 (c 1.0, MeOH) [α]D25 = +17.7 (c 0.38, EtOH)

85 Page 85 of 88

Enders et al. (Ref. 86) Génisson et al. (Ref. 15b) Castillón et al. (Ref. 90) Génisson, Ballereau et al. (Ref. 14g)

[α]D27 = +18.4 (c 0.48, MeOH) [α]D23 = +18.6 (c 1.0, MeOH) [α]D20 = +10.0 (c 0.48, CHCl3)b [α]D20 = +16.0 (c 0.45, EtOH)b [α]D23 = +20.2 (c 0.55, MeOH) [α]D20 = +20.9 (c 1.1, CHCl3) [α]D25 = +7.7 (c 0.6, CHCl3) [α]D20 = +18.8 (c 0.85, EtOH)

Shaw et al. (Ref. 14b) Rao et al. (Ref. 60)

[α]D28 = +12.9 (c 0.34, MeOH) [α]D26 = +16.1 (c 0.8, EtOH)

Martinková et al. (Ref. 14f)

[α]D23 = +2.8 (c 0.36, MeOH)

Rao et al. (Ref. 60) Martinková et al. (Ref. 14f) Ichikawa et al. (Ref. 69)

[α]D26 = ‒24.0 (c 0.6, CHCl3) [α]D22 = ‒29.2 (c 0.24, CHCl3) [α]D23 = ‒23.5 (c 0.40, CHCl3)

Fujii, Oishi et al. (Ref. 16a) Prasad et al. (Ref. 75) Hou et al. (Ref. 78) Génisson, Ballereau et al. (Ref. 14g)

[α]D25 = ‒9.61 (c 0.61, CHCl3) [α]D = ‒17.7 (c 0.4, EtOH)a [α]D20 = ‒7.0 (c 0.1, CHCl3) [α]D20 = ‒19.0 (c 0.8, EtOH)

Rao et al. (Ref. 14d) Prasad et al. (Ref. 75)

[α]D28 = ‒15.5 (c 0.008, MeOH) [α]D = ‒16.4 (c 0.4, EtOH)a

Martinková et al. (Ref. 66)

[α]D27 = ‒2.9 (c 0.28, MeOH)

Rao et al. (Ref. 53) Martinková et al. (Ref. 66)

[α]D26 = +26.8 (c 1.2, CHCl3) [α]D23 = +25.0 (c 0.14, CHCl3)

Fujii, Ohno et al. (Ref. 22) Koskinen et al. (Ref. 25) Fujji, Ohno et al. (Ref. 16b) Panda et al. (Ref. 31) Delgado, Casas et al. (Ref. 14a) Kim, Lee et al. (Ref. 37) Shaw et al. (Ref. 14l) Castillón et al. (Ref. 90)

[α]D25 = +14.5 (c 0.34, EtOH) [α]D = +23.0 (c 1.0, CH2Cl2)a [α]D25 = +14.1 (c 0.35, EtOH) [α]D22 = +14.9 (c 0.9, MeOH) [α]D25 = +14.8 (c 0.97, MeOH) [α]D24 = +38.4 (c 1.0, CHCl3) [α]D27 = +18.86 (c 0.28, MeOH) [α]D25 = +9.1 (c 0.1, CHCl3)

Rao et al. (Ref. 40) Fadnavis et al. (Ref. 73)

[α]D26 = +16.2 (c 1.1, EtOH) [α]D25 = +13.6 (c 1.0, EtOH)

Rao et al. (Ref. 40)

[α]D26 = ‒15.1 (c 1.2, CHCl3)

Reissig et al. (Ref. 56) Ichikawa et al. (Ref. 69) Britton et al. (Ref. 83)

4.TFA

4.HCl

ent-194

ent-4

ent-4.TFA

ent-4.HCl

194

2-epi-jaspine B (6)

6.TFA

86 Page 86 of 88

148 Fujii, Oishi et al. (Ref. 16a) Lee (Ref. 33) Sartillo-Piscil et al. (Ref. 42) Reissig et al. (Ref. 56)

[α]D25 = ‒8.78 (c 0.75, CHCl3) [α]D25 = ‒9.57 (c 0.21, MeOH) [α]D25 = ‒8.2 (c 1.0, CHCl3) [α]D29 = ‒5.2 (c 0.66, MeOH)

Martinková et al. (Ref. 64)

[α]D22 = ‒29.6 (c 0.48, MeOH)

Martinková et al. (Ref. 64)

[α]D24 = +17.7 (c 0.13, CHCl3)

Fujii, Ohno et al. (Ref. 22) Koskinen et al. (Ref. 25) Fujji, Ohno et al. (Ref. 16b) Delgado, Casas et al. (Ref. 14a) Castillón et al. (Ref. 90)

[α]D25 = ‒1.55 (c 0.43, CHCl3) [α]D = ‒3.2 (c 0.88, CH2Cl2)a [α]D25 = ‒2.66 (c 0.50, CHCl3) [α]D25 = ‒3.8 (c 0.71, CHCl3) [α]D25 = ‒1.8 (c 0.8, CHCl3)

Martinková et al. (Ref. 64)

[α]D24 = +9.0 (c 0.21, MeOH)

Rao et al. (Ref. 62) Martinková et al. (Ref. 64)

[α]D25 = +11.2 (c 1.1, CHCl3) [α]D25 = ‒11.9 (c 0.21, CHCl3)

Fujji, Oishi et al. (Ref. 16a)

[α]D25 = +1.48 (c 0.056, CHCl3)

Fujji, Oishi et al. (Ref. 16a)

[α]D25 = +2.33 (c 0.20, CHCl3)

Martinková et al. (Ref. 14f)

[α]D24 = ‒7.3 (c 0.46, MeOH)

Martinková et al. (Ref. 14f)

[α]D23 = ‒8.2 (c 0.15, CHCl3)

Fujii, Ohno et al. (Ref. 22) Koskinen et al. (Ref. 25) Fujji, Ohno et al. (Ref. 16b) Delgado, Casas et al. (Ref. 14a) Rao et al. (Ref. 14d) Hou et al. (Ref. 78) Castillón et al. (Ref. 90)

[α]D25 = ‒1.17 (c 0.99, CHCl3) [α]D = ‒2.8 (c 0.94, CH2Cl2)a [α]D25 = ‒3.0 (c 0.98, CHCl3) [α]D25 = ‒2.5 (c 0.71, CHCl3) [α]D28 = +3.1 (c 0.005, CHCl3) [α]D20 = ‒5.1 (c 0.15, CHCl3) [α]D25 = ‒0.7 (c 1.0, CHCl3)

ent-6

ent-6.HCl

ent-148

3-epi-jaspine B (7)

7.HCl

228

ent-7

4-epi-jaspine B (8)

8.HCl

ent-174

2,3-di-epi-jaspine B (ent-8)

87 Page 87 of 88

Martinková et al. (Ref. 66)

[α]D27 = +7.5 (c 0.52, MeOH)

Rao et al. (Ref. 14d) Martinková et al. (Ref. 66)

[α]D28 = +7.4 (c 0.002, CHCl3) [α]D23 = +9.9 (c 0.26, CHCl3)

ent-8.HCl

174 a b

Teperature was not reported. Two values for 4 were given in Ref. 38.

88 Page 88 of 88