Cu-mediated enamide formation in the total synthesis of complex peptide natural products.

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REVIEW

Cite this: Nat. Prod. Rep., 2014, 31, 514

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Cu-mediated enamide formation in the total synthesis of complex peptide natural products Takefumi Kuranaga, Yusuke Sesoko and Masayuki Inoue*

Covering: up to the end of 2013 Cu-mediated C(sp2)–N bond formation has received intense interest recently, and has been applied to the Received 25th September 2013

total synthesis of a wide variety of structurally complex natural products. This review covers the synthetic assembly of peptide natural products in which Cu-mediated enamide formation is the key transformation.

DOI: 10.1039/c3np70103d www.rsc.org/npr

1 1.1 1.2 1.3 1.4 2 2.1 2.2 2.3 2.4 3 3.1 3.2 4 4.1 4.2 4.3 4.3.1 4.3.2 4.3.3 4.4 5 6

The total syntheses of cyclopeptide alkaloids, pacidamycin D, and yaku'amide A exemplify the versatility of the Cu-catalyzed cross-coupling reaction in comparison to other synthetic methods.

Introduction Peptide natural products Enamides in peptide natural products Enamide synthesis Cu-mediated cross-coupling reactions Synthesis of cyclopeptide alkaloids Cyclopeptide alkaloids Synthesis background Total synthesis of paliurine F Total synthesis of ziziphine N Synthesis of pacidamycin D Uridylpeptide antibiotics Total synthesis of pacidamycin D Synthesis of yaku'amide A Yaku'amides A and B Dehydropeptide natural products Background for the synthesis of a,b-dehydroamino acids b-Elimination Horner–Wadsworth–Emmons reaction Conversion from a-ketoacid Total synthesis of yaku'amide A Conclusion References

1

Introduction

1.1

Peptide natural products

Peptide natural products possess diverse biological activities including insecticidal, antimicrobial, antiviral, antitumor, tumor

promotive, anti-inammatory, and immunosuppressive actions.1 The broad spectrum of biological activities arises from the structural diversity of these peptides. These peptides are mostly cyclic or branched cyclic compounds containing non-proteinogenic amino acids, small heterocyclic rings, and unusual modications in the peptide backbone. These structural features, together with their polyamide backbone, play pivotal roles in their biological functions. Some of these compounds serve as drugs or as lead compounds in drug development, while others have proven useful in studies directed toward the elucidation of biochemical pathways. 1.2

Enamides, which have a neighboring double bond at the amidenitrogen atom, are important structural motifs in peptide natural products such as cyclopeptide alkaloids (e.g., paliurine F 1, Fig. 1),2 uridylpeptide antibiotics (e.g., pacidamycin D 2),3 and dehydropeptides4 (e.g., yaku'amide A 3). Enamides comprise a macrocycle bridge in cyclopeptide alkaloids, as a junction between the peptide and nucleoside moieties in uridylpeptide antibiotics, and as a,b-dehydroamino acids in the backbone of dehydropeptides. Since double bonds inhibit the rotation of the C–C bond, enamides generally help to organize these compounds into their specic three-dimensional shape. Accordingly, these unsaturated natural products exhibit unique biological proles. Their unusual structural features and biological activities have spurred interest among synthetic chemists, and a number of total syntheses have been reported. This review covers the synthetic aspects of these natural products, and particularly focuses on the recent total syntheses of the three complex peptide natural products shown in Fig. 1. 1.3

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: [email protected]; Fax: +81-35841-0568; Tel: +81-3-5841-1354

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Enamides in peptide natural products

Enamide synthesis

Amides are generally synthesized by the condensation of the corresponding carboxylic acid and amine (Scheme 1a). To

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realize efficient amide bond formation, numerous powerful coupling reagents5 have been developed and applied. However, it is not possible to generate the enamide from the corresponding enamine, because the imine is in equilibrium with the enamine and is readily hydrolyzed with the release of ammonia. Therefore, alternative olenation methods (e.g., belimination and Horner–Wadsworth–Emmons reaction) have been generally used to synthesize enamides.4 However, direct olenation oen suffers from low functional group tolerance and low stereoselectivity in forming the E- or Z-double bond. Under these circumstances, the Cu-catalyzed cross-coupling reaction between an amide and alkenyl halide has emerged as a powerful tool for the efficient and stereoselective synthesis of enamides (Scheme 1b).6

1.4

Cu-mediated cross-coupling reactions

In 1991, Ogawa and co-workers reported a Cu-mediated crosscoupling reaction between alkenyl bromides and amides using a stoichiometric quantity of CuI in hexamethylphosphoric Takefumi Kuranaga was born in Miyazaki, Japan, in 1981. He received his B.Sc. degree from The University of Tokyo in 2006, where he also obtained his Ph.D. in 2011 under the supervision of Professor K. Tachibana. Aer six months of postdoctoral research with Professor M. Inoue at the same university, he was then appointed assistant professor in the research group of Professor M. Inoue. His research interests are natural product chemistry and synthetic organic chemistry.

Yusuke Sesoko was born in 1989 in Hyogo, Japan. He received his B.Sc. degree from the University of Tokyo in 2012. He is currently studying for a M.Sc. degree under the guidance of Professor M. Inoue at the same university. His current research is focused on the synthesis of yaku'amide and its derivatives.


triamide (HMPA) at 130 C (Scheme 2a).7 On the basis of this precedent, three groups independently reported catalytic Cumediated enamide formations. In 2000, Porco and co-workers established mild conditions for enamide formation. E-Alkenyl iodides were converted to the corresponding E-enamides using copper(I) thiophene carboxylate (CuTC) as a catalyst and Cs2CO3 as a base in N-methylpyrrolidone (NMP) at 90 C (Scheme 2b).8 An improved catalytic system based on Cu(CH3CN)4PF6, ligand 12 and Rb2CO3 in dimethylacetamide (DMA) was developed by the same group (Scheme 2c).9 In 2003, Buchwald et al. reported a versatile method for the synthesis of enamides using CuI, K2CO3 and diamine ligand 16 (Scheme 2d).10 In 2004, Ma and co-workers developed an alternative efficient system for the preparation of enamides. Aer screening a variety of amino acid ligands, they found that alkenyl halides were smoothly coupled with amides using CuI, N,N-dimethylglycine 20, and Cs2CO3 in dioxane (Scheme 2e).11 These three reactions enabled the stereoselective formation of the C(sp2)-N bond under milder conditions, and have been applied in numerous total syntheses of natural products.6,12 A possible mechanism of the Cu-catalyzed reaction is illustrated in Scheme 3.13 Initially, the active copper(I) species 23 reacts with amide 22 by the action of the base to form copper amidate 24. Then, oxidative insertion of copper amidate 24 into a vinyl halide 25 and subsequent reductive elimination affords enamide 26 via regeneration of catalyst 23.

2 Synthesis of cyclopeptide alkaloids 2.1

Cyclopeptide alkaloids

Cyclopeptide alkaloids have been isolated from the roots, leaves, and bark of a variety of plants, and over 200 compounds of this class have been reported to date.2 The peptide macrocyclic core of a 13-, 14-, or 15-membered ring contains an aromatic ring and is attached by a peptide side chain. The phenol moiety within the ring is connected to a hydroxy amino

Masayuki Inoue obtained his Ph.D. from The University of Tokyo in 1998, working under the supervision of Prof. K. Tachibana. Aer spending two years with Prof. S. J. Danishefsky at the Sloan-Kettering Institute for Cancer Research (1998– 2000), he joined the Graduate School of Science at Tohoku University as an assistant professor, and was promoted to associate professor in 2004. In 2007, he moved to the Graduate School of Pharmaceutical Sciences, The University of Tokyo as a full professor. His research interests include the total synthesis of structurally complex natural products, and synthesis, design and study of biologically important molecules.

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Fig. 1

Review

Enamides in peptide natural products.

Scheme 1 (a) Synthesis of an amide and enamide by dehydration. (b) Synthesis of an enamide by a Cu-mediated cross-coupling reaction.

acid by the C–O bond, and to an enamide or hydroxy ethylene spacer by the C–C bond (Fig. 2). In spite of these shared structural features, cyclopeptide alkaloids exhibit a wide range of biological activities. For instance, sanjoinines14 are reported to be effective inhibitors of calmodulin-induced activation of Ca2+ATPase, and provide a sedative action, while ziziphines15 show potent antiplasmodial activities. 2.2

Synthesis background

Over the past few decades, cyclopeptide alkaloids have attracted the attentions of a number of synthetic chemists due to their unusual structures and biological activities. In 1981, Schmidt

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Scheme 2

Syntheses of enamides.


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p-nitrophenyl selenide 33 by using tributylphosphine and p-nitrophenyl selenocyanate,17 and subsequent b-elimination was induced by H2O2-promoted oxidation, affording (Z)-enamide 34. Finally, a 4-step sequence, including the introduction of the side chain peptide, gave rise to ziziphene A (30). The generality of the pentauorophenyl ester macrocyclization/b-elimination strategy, developed by Schmidt et al., has been demonstrated in the construction of this class of natural products. Joulli´ e and co-workers utilized this method in their total syntheses of cyclopeptide alkaloids.18

2.3 Scheme 3

Possible reaction mechanism for enamide formation.

and co-workers reported the rst total synthesis of ziziphine A16 utilizing macrolactamization and the subsequent construction of the enamide using b-elimination. The Schmidt group’s synthetic route to ziziphine A is summarized in Scheme 4. Removal of the Cbz group of 31 under high-dilution conditions afforded the cyclized alcohol 32 through amide bond formation between the liberated amine and the pentauorophenyl ester. Then, alcohol 32 was converted to

Fig. 2

Structures of representative cyclopeptide alkaloids.


Total synthesis of paliurine F

In 2007, Evano et al. reported the rst example of the total synthesis of cyclopeptide alkaloids utilizing the Cu-mediated C(sp2)-N bond formation (Scheme 5).19 This coupling reaction was employed as an alternative approach to macrolactamization en route to paliurine F. Cu-mediated aryl ether formation20 was rst applied to fragment coupling. Proline derivative 35 and iodobenzene 36 were treated with CuI (10 mol%), 1,10-phenanthroline (20 mol%) and Cs2CO3 in toluene at 125 C to generate aryl ether 37. The Z-vinyl iodide was then stereoselectively installed by Stork–Zhao

Scheme 4

Schmidt's total synthesis of ziziphine A (1981).

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olenation,21 then the isoleucineamide moiety was attached by a 4-step manipulation to give the acyclic precursor 39. When iodoamide 39 was treated with catalytic CuI (10 mol %), ligand 16 (20 mol%) and Cs2CO3 in THF under high-dilution conditions at 60 C, the 13-membered ring was cyclized to afford 40 in 70% yield. This mild reaction proceeded without epimerization at the a-carbons of the two amino acids or isomerization of the Z-vinyl iodide. Furthermore, no dimerization or oligomerization was observed using these macrocyclization conditions. Having constructed the macrocyclic core, the Evano group then synthesized paliuline F (1) by the simple condensation of the peptidic side chain to 41.19 To evaluate the efficiency of their Cu-mediated macrocyclization strategy, the Evano group constructed a 13-membered core 4022 by other methods, such as the ene-enamide ring-closing metathesis of 42,23,24 the cyclodehydration of 44, and the oxidative amidation of 4525 (Scheme 6). Although macrocycle 40 was produced by these three reactions, the yields were lower, mainly due to the decomposition of the starting materials and/or macrocyclic enamide 40 under these reaction conditions.

Scheme 5

The Evano group's total synthesis of paliurine F (2007).

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In these studies, the Evano group demonstrated the superiority of the Cu-mediated intramolecular amidation strategy for the assembly of the macrocycles. In fact, the strategy was successfully applied to the total syntheses of related cyclopeptide alkaloids, which allowed them to investigate in detail the structure–activity relationship.22,26,27 2.4

Total synthesis of ziziphine N

In 2007, Ma and co-workers reported the total synthesis of ziziphine N (Scheme 7), using the Cu-mediated intermolecular cross-coupling.28 An intermolecular Cu-catalyzed reaction of vinyl iodide 46 and N-Alloc-L-proline amide 47 under the standard conditions reported by the Ma group11 (CuI, N,N-dimethylglycine 20, Cs2CO3, dioxane, 80 C) gave rise to enamide 48 in 75% yield. Cleavage of the silyl ether, followed by oxidation of the primary alcohol and removal of the Alloc group, afforded the acyclic amino acid 49. Pentauorophenyl diphenylphosphinate (FDPP)29 was then adopted to realize the macrocyclization,

Scheme 6

Cyclization of the 13-membered macrocycle.


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leading to the 13-membered ring 34. Finally, the total synthesis of ziziphine N (29) was completed via installation of the dipeptide side chain. This efficient synthesis again highlighted the versatility of the Cu-mediated reaction for coupling structurally complex fragments.


3 Synthesis of pacidamycin D 3.1

Uridylpeptide antibiotics

The emergence of multidrug-resistant Pseudomonas aeruginosa (MRPA) is a serious clinical problem due to the lack of effective pharmaceuticals against MRPA.30 To overcome this issue, the development of novel anti-P. aeruginosa agents is urgently required. Uridylpeptide antibiotics (Fig. 3) are of great interest because of their potent anti-P. aeruginosa activity.3 Mureidomycins (e.g., mureidomycin A, 50), isolated from Streptomyces avidoviridens SANK 60486, shows potent antibacterial activity against strains of P. aeruginosa.31 50 was demonstrated to be effective in a mouse infection model, indicating that uridylpeptides have strong potential as lead compounds for new MRPA drugs. Intriguingly, mureidomycins exert bactericidal action by inhibiting bacterial cell wall biosynthesis in a manner different to b-lactams and vancomycin. Pacidamycins (pacidamycin D, 2), which possess a tryptophan residue at their C-terminus instead of the tylosine residue of 50, are new anti-P. aeruginosa uridylpeptides isolated from the fermentation broth of a Streptomyces coeruleorubiduns strain.32 Although structure–activity relationship studies33,34 and biosynthetic

Scheme 7

Fig. 3

The Ma group’s total synthesis of ziziphine N (2007).

Structures of representative uridylpeptide antibiotics.


Scheme 8 Retrosynthetic analysis of pacidamycin D (2) and 30 hydroxypacidamycin D (51).

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studies35 have been conducted by several groups, it was not until 2011 that the rst total synthesis of a uridylpeptide antibiotic, pacidamycin D, was reported by Ichikawa and Matsuda et al.36

Scheme 9

Synthesis of the peptide fragment (54).

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3.2

Total synthesis of pacidamycin D

One of the most signicant challenges in the total synthesis of pacidamycin D (2) is the stereoselective construction of the chemically sensitive Z-oxyenamide moiety. Ichikawa and Matsuda et al. synthesized this Z-enamide via the Cu-mediated cross-coupling reaction at a late stage in the synthesis. Their retrosynthetic analysis is illustrated in Scheme 8. The Z-enamide would be constructed by Cu-mediated

Scheme 10 Synthesis of the iodide fragments 55 and 56.


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Table 1

NPR Optimization of the cross-coupling reaction of 54 and 56

Entry

Cul (eq.)

Ligand (eq.)

Time

Yield

1 2 3 4 5 6

0.2 0.2 0.2 0.2 0.8 0.8

16 71 72a 72b 72a 72b

7 7 7 7 9 10

Trace 16 30 32 70 86

Scheme 12 (a) Synthesis of 2 and 51 (2011). (b) Model study of deoxygenation. Scheme 11 Structure and proposed generation mechanism of

byproduct 74.


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Review Antibacterial activity of 2 and 51 a

1


MIC (mg mL ) Strain

2

51

P. aeruginosa PAO1 P. aeruginosa ATCC 25619 P.aeruginosa SR 27156 P. aeruginosa YY165 (DmexB)

64 16 16 16

32 16 16 8

a

MIC ¼ minimum inhibitory concentration

cross-coupling between highly functionalized peptide fragment 54 and Z-vinyl iodide 55 or 56. They rst planned to remove the extra 30 -hydroxy group of 53 aer coupling of 54 and 56. However, the 3-deoxygenation proved impossible, and thus predeoxygenated 55 was utilized for the total synthesis of pacidamycin D (vide infra).

The synthesis of peptide carboxamide fragment 54 is shown in Scheme 9. The amino acid 59, which was synthesized from Lthreonine (57),37 was condensed with pentauorophenyl ester 60 to afford peptide 61. Hydrogenation of 61 liberated the secondary amine, which was further condensed with N-Boc-alanine pentauorophenyl ester 63 in the presence of i-Pr2NEt in DMF to generate 64. Then, the carboxylic acid of 64 was converted to the corresponding carboxyamide 54 by treatment with O-(7-azabenzotriazole-1-yl)-N,N,N0 ,N0 -tetramethyluronium hexauorophosphate (HATU),38 NH4Cl, and N-methylmorpholine (NMM) in DMF. To stereoselectively synthesize the enamide linkage between the peptide and uridine substructures, Z-oxyvinyl iodide needed to be prepared as the substrate of the Cu-catalyzed cross coupling reaction. Iodonium dicollidinium triate (IDCT)39 efficiently realized the synthesis of the Z-oxyvinyl iodide fragments 55 and 56 (Scheme 10). Aer uridine (65) was converted to the exo-olen 67 in 6 steps, 67 was directly converted to Zoxyvinyl iodide 56 in 79% yield by treating with IDCT in CH2Cl2

Fig. 4 Structure of yaku'amide A (3) and yaku'amide B (77).

Fig. 5

Structure of micrococcin P1 (78), thiostrepton (79), antrimycin A (80), and phomopsin B (81).

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Scheme 13 Synthesis of DAla-DAbu moiety of lactocin S (2010).

Scheme 14

to promote the cross-coupling reaction, presumably because the non-productive Cu-peptide coordination reduced the activity of the catalyst. C(sp2)–N bond formation specically at the nitrogen atom of the primary amide in the presence of the secondary amide, urea, carbamate and indole nitrogen atoms demonstrated the high chemoselectivity of the present crosscoupling reaction. Ichikawa et al. observed the formation of undesired macrolactam 74 in addition to the desired adduct 53 upon applying ligand 16 in the cross-coupling reaction (Scheme 11). In accordance with the general reaction mechanism (Scheme 3), the amide–Cu(I) complex 73 would be the key reactive intermediate for the enamide formation. However, the subsequent oxidative insertion into vinyl iodide 56 is a slow process, so the competing nucleophilic addition of the activated nitrogen atom preferentially occurs to generate macrolactam 74. It was rationalized

The Castle group’s dehydropeptide synthesis.

at room temperature. Compound 55, the 30 -deoxy analogue of 56, was also synthesized. 30 -Deoxy-uridine compound 68 was prepared through a 4-step procedure,40 and then 68 was converted to the exo-olen 70 by protecting group manipulation and b-elimination of the primary hydroxy group. Then, the Zvinyliodide 55 was produced in 53% yield, by conducting the reaction in the presence of IDCT in MeCN at –20 C. Having synthesized the requisite fragments, the key Cumediated cross-coupling of peptide fragment 54 and iodide 56 was investigated (Table 1). First, the Buchwald group's conditions10 (20 mol% of CuI, 40 mol% of ligand 16, Cs2CO3, THF, 70 C, Table 1, entry 1) were applied to connect peptide 54 and iodide 56. However, a large amount of the iodide 56 was recovered, and only a trace amount of the desired product (53) was obtained. Therefore, Ichikawa and Matsuda et al. modied the bulkiness of the ligand (Table 1, entries 2–4). The use of the sterically larger ligand 72 resulted in an increased yield (Table 1, entries 3 and 4). Furthermore, the yield of 53 was dramatically improved with the use of 80 mol% CuI (Table 1, entries 5 and 6). A relatively large amount (80 mol%) of the catalyst was needed


Scheme 15 Syntheses of a,b-dehydroamino acids by dehydration and the Wandless group’s total synthesis of phomopsin B (81).

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Review Table 3

The Schmidt group’s a,b-dehydroamino acid syntheses


(1984)

Entry

R1

1

Yielda (%)

Z:E

Cbz

74

>10 : 1

2

Ac

86

>50 : 1

3

Ac

55

>20 : 1

4

Ac

82

>50 : 1

a

Scheme 16 The Nicolaou group's total synthesis of thiostrepton by the late stage introduction of the a,b-dehydroamino acids (2004).

that the use of bulky ligand 72a/b helped to kinetically suppress the approach of the amide to the t-butyl ester of 54, and allowed the yield of the desired product 53 to increase. Completion of the total synthesis of 2 and its analogue 51 is illustrated in Scheme 12a. With the cross-coupled product 53 with the C30 -hydroxy group in hand, Ichikawa and Matsuda's group rst synthesized 30 -hydroxypacidamycin D. Deprotection of the BOM, Boc, and t-butyl groups (BCl3)41 and two TBS groups (HF$NEt3)42 in two separate steps afforded 30 -hydroxypacidamycin D (51) from 53, a synthetic analogue of pacidamycin D. Then, they conducted a model study for the last stage deoxygenation of the 30 -hydroxy group of 53 (Scheme 12b). However, several attempts to deoxygenate the 30 -hydroxy group of the truncated model compound 75 under Barton and McCombie’s conditions43 led to a complex mixture of products, and the formation of the desired model compound 76 was not observed. Therefore, the reaction sequence was altered, and 30 deoxygenated iodide 55 was used for the synthesis of pacidamycin D (2). Specically, 30 -deoxy-iodide 55 and the peptide

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R2

Yield of Z-isomer.

fragment 54 were coupled under optimized conditions (80 mol % of CuI, 1.6 eq. of ligand 72a, Cs2CO3, in THF at 70 C) to produce the cross-coupled product 52 (69% yield). Finally, global deprotection of 52 using the same 2-step sequence as the synthesis of 51 delivered pacidamycin D (2). As shown in Table 2, synthetic pacidamycin D (2) showed potent activity against various strains of P. aeruginosa.36b Interestingly, an improvement in antibacterial activity was observed for articial analogue, 30 -hydroxypacidamycin D (51). These results provide an important chemical basis for the future design and synthesis of new uridylpeptide anti-MRPA agents.

Scheme 17

The Schmidt group's total synthesis of antrimycin Dv

(1992).


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Table 4 The Shinada group’s olefination reaction (2013)

Entry

Additive

T/ C

Yield (%)

(E)-106/(Z)-106

1 2 3 4 5 6

None Nal Kl LiCl MgBr2$OBt2 ZnCl2

rt 78 to 0 78 78 rt rt

97 93 84 59 99 27–62

4 : 96 72 : 28 95 16 : 84 87 : 13 66 : 34 to 80 : 20

4 Synthesis of yaku'amide A 4.1

Yaku'amides A and B

In 2010, two new linear peptides, yaku'amide A and B (3 and 77, Fig. 4), were isolated from a marine sponge Ceratopsion sp.44 The complete structures of yaku'amides A and B had been determined, except for the stereochemistry of the C4-methyl group in NTA. Both compounds feature four a,b-dehydroamino acids (residues 2, 4, 9, and 13), seven non-proteinogenic amino acids (residues 1, 5, 6, 7, 8, 10 and 12), an N-terminal acyl group (NTA), and a C-terminal amine (CTA). These two dehydropeptides show potent cytotoxicity against P388 murine leukemia cells. Furthermore, the growth-inhibitory activity of 3 against a panel of 39 human cancer cell lines (JFCR39)45 is distinct among the known anticancer drugs. Therefore, it is likely that 3 and 77 possess a new mode of action and that the a,b-dehydroamino acids play an important role in exerting the growth-inhibitory activity. 4.2

Dehydropeptide natural products

Although a,b-dehydroamino acids are not categorized as belonging to the 20 proteinogenic amino acids, they are found in numerous bioactive natural products (Fig. 5).4 Many of these dehydropeptides possess unique biological activities related to their unusual structure. As the C]C bond prevents rotation of the side chain, the a,b-dehydroamino acids have a large impact on the conformational behavior of their proximal residues. Therefore, a,b-dehydroamino acids potentially inuence the bioactive three-dimensional structure of the dehydropeptides.46 Micrococcin P1 (78)47 and thiostrepton (79),48 which have dehydrothreonine and alanine derivatives within their structures, exhibit noteworthy antibacterial activity by inhibiting protein biosynthesis in bacteria. Antrimycin A (80), which possesses an E-dehydroisoleucine residue, shows antibiotic activity against Mycobacterium smegmatis ATCC 607 and Mycobacterium tuberculosis H37Rv.49 Phomopsin B (81), which


Scheme 18 The Shin group's synthesis of a,b-dehydroamino acids (1985) and total synthesis of antrimycin Av (1994).

possesses an E-dehydroisoleucine–dehydroaspartic acid sequence, is a potent inhibitor of microtubule polymerization.50 4.3

Background for the synthesis of a,b-dehydroamino acids

4.3.1 b-Elimination. Together with their intriguing biological proles, dehydropeptides provide synthetic challenges due to their unusual structures. Among a number of synthetic methods,

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b-elimination would be the most straightforward approach to the a,b-dehydroamino acids. In particular, didehydroalanine (DAla) and didehydroaminobutenoic acid (DAbu) are readily prepared from serine and threonine derivatives via b-elimination of the hydroxy group, respectively. Vederas and co-workers reported the synthesis of the DAla-DAbu sequence 83 by the b-elimination of the corresponding dipeptide (82, Ser-Thr) in their total synthesis of the lantibiotic, lactocin S (Scheme 13).51,52 The development of methods for the exible synthesis of b-hydroxy amino acids allowed the preparation of the corresponding a,b-dehydroamino acids, other than didehydroalanine and didehydroaminobutenoic acid. Castle's group reported a regioselective aminohydroxylation/b-elimination strategy for the synthesis of dehydropeptides (Scheme 14).53 When enoate 84 was treated with catalytic OsO4 and benzyl 4-chlorobenzoyloxy carbamate (85),54 tertiary alcohol 86 was obtained as the sole product. Cbz deprotection by hydrogenation, followed by condensation of the liberated amine with Cbz-glycine, afforded dipeptide 87. Treatment of 87 with the Martin group’s sulfurane55 facilitated the desired dehydration, and dehydrovaline-containing peptide 88 was obtained in high yield. A number of reagents and systems have been developed for the activation of the b-hydroxy group and subsequent b-elimination. Generally, the sterically favorable Z-isomer is formed as a major isomer during the preparation of b-substituted dehydroamino acid derivatives. Since both Z- and E-isomers of the dehydroamino acid derivatives are found in peptide natural products, the stereoselective preparation methods for both regioisomers are required. Several practical routes to the Z- and E-a,b-dehydroamino acids are shown in Scheme 15. In 1999, Wandless et al. reported a stereoselective anti-elimination using SOCl2/DBU dehydration systems (Scheme 15a).56 Specically, the Z-didehydroaminobutenoic acid 91 was formed from the

Review L-threonine

derivative 89 via the cyclic sulfamidite 90, while the thermodynamically less stable E-isomer was generated from L-allo-threonine derivative 92. In 2003, Sai et al. reported an alternative approach to E-didehydroaminobutenoic acid.57 The syn-elimination of L-threonine derivative 93 was induced by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in the presence of CuCl2 to generate the (E)-95 isomer via 9458 (Scheme 15b). A short reaction time was found to be important for high E-selectivity because the produced E-dehydroamino acid slowly isomerized into the more stable Zisomer under these reaction conditions. Wandless et al. applied their dehydration approach to the Eselective synthesis of the dehydroisoleucine residue in phomopsin B (81) (96/97, Scheme 15c). The rst total synthesis of 81 was accomplished from 97 in 2007.59 b-Elimination reactions have been employed for the late stage introduction of multiple a,b-dehydroamino acid residues in highly complex peptide molecules such as micrococcin P1 (78)60 and thiostrepton (79).61 As shown in Scheme 16, the chemically labile dehydroamino acid residues were introduced during the last two steps in the Nicolaou group's total synthesis of thiostrepton.61d,62 4.3.2 Horner–Wadsworth–Emmons reaction. The Horner– Wadsworth–Emmons reaction was employed by the Schmidt group to prepare dehydroamino acid derivatives (Table 3). The N-protected dimethoxyphosphoryl glycinate 99 was condensed with various aldehydes or ketones to afford the corresponding dehydroamino acid (Z)-100 with high Z-selectivity.63 The Schmidt group realized the total synthesis of antrimycin Dv (103) using their method for the synthesis of dehydovaline (101 / 102, Scheme 17).64 A stereoselective synthesis of the less sterically favorable E-dehydroamino acid derivatives was reported by Shinada,

Scheme 19 (a) Structure of the fragments for the total synthesis of 3. (b) E/Z-Selective synthesis of a,b-unsaturated amino acid moieties utilizing the Cu-mediated enamide formation strategy.

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Ohfune and co-workers (Table 4).65 E-Dehydroamino acid 106 was stereoselectively generated from (a-diphenylphosphono) glycine reagent 104.66 They also demonstrated that the E/Zselectivity of the produced dehydroamino acids can be modulated by changing the metal salts. 4.3.3 Conversion from a-ketoacid. Shin and co-workers developed an efficient method for the assembly of the tripeptide sequence containing the b-disubstituted dehydroamino acid residue (Scheme 18a).67 First, the Cbz-protected a,b-dehydroamino acids 110 and 111 were prepared by condensation of carbamate 109 and a-ketoacids 107 and 108, respectively. Second, 110/111 was converted to the activated acid 112/113 by treatment with SOCl2. Finally, a N,N0 -dicyclohexylcarbodiimide

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(DCC)-mediated condensation between N-Boc-L-alanine and 112/113, followed by introduction of L-serine benzyl ester 117 in one pot, gave rise to tripeptide 118/119. Compound 118 was further utilized for the total synthesis of antrimycin Av (123, Scheme 18b). Boc removal of 118, followed by coupling with dipeptide 120, produced pentapeptide 122, which was converted to natural heptapeptide 123 through amino acid condensations at the N-terminus, followed by deprotection.68

4.4

Total synthesis of yaku'amide A

The highly unsaturated peptide structure and unusual biological prole of yaku'amide A (3) motivated Inoue and co-workers to

Scheme 20 (a) E/Z-Selective synthesis of dehydroisoleucine moieties. (b) Synthesis of C-terminal peptide 131.


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launch studies directed at its total synthesis. Since yaku'amide A (3) possesses multiple a,b-dehydroamino acids, the development of a new, efficient method for its stereoselective construction was imperative for its efficient construction. Inoue et al. utilized the Cu-mediated cross-coupling reaction as a powerful tool for the Eand Z-selective preparation of the a,b-dehydroamino acids in their total synthesis of 3.69,70 The synthetic strategy is summarized in Scheme 19. To determine the unknown C4-stereochemistry, the intent was to synthesize the two possible C4-isomers of yaku'amide A (3a and 3b), and then spectroscopically compare them with natural 3. The entire structure was retrosynthetically disassembled into eight fragments 124–131 (Scheme 19a). The two enantiomers 124a and 124b would be separately prepared for structural conrmation. The three dipeptides 125, 126, and 130 were designed to possess a,b-unsaturated carboxylic acids at their C-terminus, because these peptides would be nonepimerizable at the Ca carbons upon peptide condensation. All C(sp2)–N bonds in these three dipeptides, as well as in tetrapeptide 131, were formed by the Cumediated cross-coupling reaction. In the synthetic direction, the eight fragments were condensed in a stepwise fashion from the Cterminal tetrapeptide 131 through seven amide bond formations. Stereoselective synthesis of the E- and Z-dehydroisoleucine residues (residue 2, 4, and 9) was one of the major synthetic challenges in the total synthesis of 3. The assembly method in the Inoue group's synthesis is illustrated in Scheme 19b. First, the C(sp2)–N bond of 134 would be formed by the Cu-catalyzed crosscoupling reaction of primary amide 132 and alkenyl iodide 133 in a stereoselective fashion. Second, the cross-coupled product 134 would be converted to a,b-unsaturated carboxylic acid 135. Finally, the amine 136 would be condensed with 135 in a nonisomerizable manner to furnish the dehydropeptide 137. Stereoselective preparation of dipeptide fragments 125, 126, and 130, utilizing the Cu-mediated enamide formation is depicted in Scheme 20a. Aer screening the reagent systems for enamide formation, the Buchwald group's conditions10 were employed for the synthesis of these three dipeptide fragments, although careful tuning of the reaction conditions was necessary to achieve high-yielding transformations. When amide 138 and Z-alkenyl iodide 139 were treated with CuI (30 mol %), 16 (2 eq.), and Cs2CO3 (1.2 eq.) in dioxane (1 M) at 70 C, the hindered C–N bond was formed to afford Z-enamide 140 in 87% yield. Further application of these optimized conditions enabled the coupling reactions of 142/143 and 145/139 to generate E-enamide 144 (96%) and Z-enamide 146 (86%), respectively. These stereoselective constructions of the three hindered tetrasubstituted olens 140, 144 and 146 under mild conditions demonstrated the versatility of the present protocol. The bis-Boc protected dipeptide fragments 125, 126 and 130 were synthesized from the coupling adducts 140, 144 and 146, respectively (Scheme 20a). Enamide 140 was treated with TBAF to give the corresponding allylic alcohol, which was oxidized to carboxylic acid 141 by sequential reactions using Dess–Martin reagent71 and NaClO2.72 Next, the additional Boc group was introduced to the secondary amide of 141 by 3-step protective group manipulation to give dipeptide 125. The dipeptides 126 and 130 were prepared by applying the same six-step sequence.

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Review

The Cu-mediated coupling reaction between 147 and 148 efficiently assembled the C-terminal tetrapeptide 131 (Scheme 20b). When peptide 147 and iodide 148 (2 eq.) were treated with CuI (60 mol %), ligand 16 (4 eq.), and Cs2CO3 (1.2 eq.) in dioxane (0.7 M) at 90 C, peptide 131 was smoothly obtained in 61% yield. This reaction clearly showed the high applicability of intermolecular C(sp2)–N bond formation to the convergent synthesis of the complex peptide sequence. Having synthesized all the a,b-unsaturated amino acids containing peptide fragments, the condensation of these fragments was performed. The major obstacle to this was the isomerizable nature of the E- or Z-dehydroisoleucine acid under the condensation conditions. A model study uncovered the importance of the Boc-group at the secondary amide to prevent generation of the geometrical mixture (Scheme 21). While coupling between N-unsubstituted acid 141 and amine 149 under various conditions led to a 1 : 1 mixture of geometrical isomers 150, presumably through intermediary 151–153,73 amidation of N-substituted acid 125 with 149 afforded the adduct 154 as the sole isomer. Finally, the total synthesis of 3 was achieved by the sequential attachment of the fragments to the C-terminal peptide 131 (Scheme 22). In accordance with the results of the model study, the secondary amide-protected 125, 126, and 130 were utilized for the isomerization-free amidation. Removal of the Boc group of tetrapeptide 131 liberated the corresponding amine 155, which was then coupled with Z-dehydroisoleucine derivative 130 using benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium

Scheme 21 Model study for isomerization-free amidation of a,bdehydroisoleucine.


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Review

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deprotection and condensation with Z-dehydroisoleucine analogue 125 to deliver N-Boc protected 161. Tridecapeptide 161 was treated with TFA to liberate the corresponding amine 162, which was then condensed with the C4-epimeric NTA fragments 124a and 124b using (1-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexauorophosphate


hexauorophosphate (PyBOP)74 in the presence of 1-hydroxy-7azabenzotriazole (HOAt)75 and i-Pr2NEt to provide hexapeptide 156. Aer conversion of hexapeptide 156 to nonapeptide 157 by a six-step peptide elongation, 157 was then deprotected and coupled by the action of PyBOP and HOAt to the carboxylic acid 126 to yield 159. Undecapeptide 159 in turn underwent

Scheme 22

Total synthesis of the two possible isomers of 3 (2013).


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Review

(COMU)76 to give the two possible structures of yaku'amide A (3a and 3b, respectively) in stereochemically pure form. It was revealed that natural yaku'amide A possesses the C4 S-stereochemistry of 3a by comparing the NMR spectra of these synthetic two diastereomers with natural 3.69 The Cu-mediated enamide formations were effectively used for the stereoselective synthesis of dehydroisoleucines, as well as the convergent synthesis of the tetrapeptide. This versatile strategy should be useful for synthesizing various yaku'amide derivatives and other peptide natural products containing a,bdehydroamino acids.

5 Conclusion The synthetic approaches toward enamide-containing complex molecules, in particular the total synthesis of cyclopeptide alkaloids, pacidamycin D, and yaku'amide A, were reviewed. The Cumediated cross-coupling reaction realized convergent enamide formations, macrocyclizations and a,b-dehydroamino acid syntheses in the structural context of complex peptidic molecules. Because of its efficiency and high chemo- and stereoselectivity, the Cu-mediated enamide formation functions as a key method in the construction of peptide natural products with unsaturated structures, and is suitable for synthesizing various analogues to obtain insights into the structural and biological roles of the enamide structures within these natural products. The active interplay of these analogue syntheses and biological assays will provide valuable information on the activity prole of these peptide natural products, which can be essential for the evolution of natural lead compounds into efficient drugs.

6

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Nitropyrrole natural products: isolation, biosynthesis and total synthesis.

Total synthesis of halichondrin A, the missing member in the halichondrin class of natural products.

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules.

Studies on the synthesis of peptides containing dehydrovaline and dehydroisoleucine based on copper-mediated enamide formation.

Identification of an Auxiliary Leader Peptide-Binding Protein Required for Azoline Formation in Ribosomal Natural Products.

First total synthesis of the marine natural products clavulolactones II and III.

Biosynthesis and Total Synthesis Studies on The Jadomycin Family of Natural Products.

O-Glycosylation methods in the total synthesis of complex natural glycosides.

Natural products in synthesis and biosynthesis.

Natural products in synthesis and biosynthesis II.

Donor-acceptor substituted cyclopropane to butanolide and butenolide natural products: enantiospecific first total synthesis of (+)-hydroxyancepsenolide.

First total synthesis of antihypertensive natural products S-(+)-XJP and R-(-)-XJP.

Chemoenzymatic synthesis of thiazolyl peptide natural products featuring an enzyme-catalyzed formal [4 + 2] cycloaddition.

Total synthesis and related studies of large, strained, and bioactive natural products.

Flavoenzyme-catalyzed formation of disulfide bonds in natural products.

Automated genome mining of ribosomal peptide natural products.

Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation.

A strategy for complex dimer formation when biomimicry fails: total synthesis of ten coccinellid alkaloids.

Peptide Macrocyclization Inspired by Non-Ribosomal Imine Natural Products.

Design and synthesis of analogues of natural products.

Structure, Chemical Synthesis, and Biosynthesis of Prodiginine Natural Products.