Toward the Total Synthesis of Onchidin,a Cytotoxic Cyclic Depsipeptide from a Mollusc

The total synthesis of onchidin ( 1 ), a cytotoxic, C₂‐symmetric cyclic decadepsipeptide from a marine mollusc, according to the published structure, is described. A novel β‐amino acid, (2S,3S)‐3‐amino‐2‐methyl‐7‐octynoic acid (AMO), was efficiently prepared in high yield with high diastereo‐ and enantioselectivity based on a catalytic asymmetric three‐component Mannich‐type reaction with a chiral zirconium catalyst. The formation of sterically unfavorable N‐methyl amide and hindered ester bonds were successfully demonstrated, and final macrocyclization was achieved at a secondary‐amide site. Completion of the synthesis of 1 suggested that a revision of the structure of the natural product is required. Two diastereomers were also synthesized as candidates for the actual structure of onchidin. Furthermore, efficient solid‐phase methods were employed for the combinatorial synthesis of other derivatives to clarify the real structure of onchidin. The solid‐phase assembly of a pentadepsipeptide containing all the building blocks was established followed by dimeric cyclization in solution.     

Structure of cymbidine A, a monomeric peptidoglycan-related compound with hypotensive and diuretic activities, isolated from a higher plant, Cymbidium goeringii (Orchidaceae)

The structure of a new monomeric peptidoglycan-related compound with hypotensive and diuretic activities, cymbidine A (1) isolated from the orchid Cymbidium goeringii, was elucidated mainly by spectroscopic analysis. The structure of 1 was shown to involve four amino acids (D-alanin, meso-diaminopimelic acid, D-gultamic acid, and L-valine) and two amino sugars (N-acetylglucosamine and 1,6-anhydro-N-acetylmuramic acid). The sequence of the amino acids and amino sugars was determined by the analysis of 2D NMR data. The absolute stereochemistries of the three amino acids (D-Ala, D-Glu and L-Val) were determined by the modified Marfey's method, and the (6S,10R) configurations of meso-diaminopimelic acid in 1 were indicated on the basis of the CD analysis. The absolute stereochemistry of 1,6-anhydro-N-acetylmuramic acid was also determined by CD data.     

Synthesis and NMR studies of cyclopeptides containing a sugar amino Acid

[structure: see text] Cyclopeptides containing Glucuronic acid methylamine (Gum) alternating with Gly, L-Ala, D-Ala, L-Phe, D-Phe, L-Lys, or D-Lys were synthesized by a combination of solid-phase synthesis and solution chemistry. A more effective pathway to synthesize the sugar amino acid Gum in higher yields and in a shorter period of time was developed. Gum is employed in the benzylated and deprotected form. The cyclopeptides were characterized by NMR and the structure of one deprotected cyclic peptide solved.     

Enantioselective synthesis of an unnatural bipyridyl amino acid and its incorporation into a peptide

The synthesis of a bipyridyl amino acid, 2-amino-3-(4′-methyl-2,2′-bipyridin-4-yl) propanoic acid, is described. A short three step synthesis from commercially available 4,4′-dimethyl-2,2′-bipyridine provides the amino acid in 65% enantiomeric excess (ee). An enzyme-mediated chiral resolution increases the ee to 95% in two additional steps. The amino acid was incorporated into a 22 amino acid peptide composed predominantly of alanine. The peptide was found to be 88% α-helical in aqueous solution at 1°C by circular dichroism (CD) spectropolarimetry, indicating a high helical propensity for this amino acid. This amino acid can provide a means to incorporate a metal into structure-forming peptides.     

IB-01212, a new cytotoxic cyclodepsipeptide isolated from the marine fungus Clonostachys sp. ESNA-A009

IB-01212, a new cytotoxic cyclodepsipeptide featuring C2 symmetry, was isolated from the mycelium extract of Clonostachys sp. ESNA-A009. The amino acid sequence of the compound was determined by spectroscopy techniques. The absolute configuration of the amino acids was determined by a combination of the Marfey and menthol methods. The structure, which was confirmed by comparison of the analytical data for the natural product with a sample obtained by solid-phase peptide synthesis, was revealed to be a cyclic dimer formed by two chains of L-N,N-Me2Leu-L-Ser-L-N-MeLeu-L-N-MePhe bound by the two esters formed between the carboxylic acid of the L-N-MePhe and the hydroxyl function of the L-Ser. IB-01212 is highly cytotoxic to different tumor cell lines.     

含有络合功能基的非天然氨基酸的设计、合成及在生物活性肽中的应用

设计合成了一类侧链带有络合基团的非天然氨基酸, 即侧链带有N,N-二羧甲基氨甲基、N,N-二酰胺甲基氨甲基和N,N-二羟乙基氨甲基的苯丙氨酸衍生物, 并将这类非天然氨基酸用于促性腺激素释放激素(LHRH)类似物的固相合成. 高效液相色谱分析结果表明, 粗肽的纯度较好, 易于纯化; 用电喷雾质谱测定了多肽的分子量. 这些非天然氨基酸可作为其它肽类药物合成的构建单元.     

Novel formal synthesis of cephalotaxine via a facile Friedel-Crafts cyclization

[structure: see text]. A novel formal synthesis of cephalotaxine (CET), the parent structure of the antileukemia Cephalotaxus alkaloids, was achieved via a facile Friedel-Crafts cyclization of the amino (or amido) spiro-cyclopentenone precursor (A) mediated by a protic acid leading to tetracyclic ketone B. A remarkable stereoelectronic effect of the methylenedioxy substituent (R) and an interesting skeletal isomerization of the CET core ring system (B, X = H2) were observed.     

An unnatural amino acid that induces beta-sheet folding and interaction in peptides

This paper introduces a unique amino acid that can readily be incorporated into peptides to make them fold into beta-sheetlike structures that dimerize through beta-sheet interactions. This new amino acid, Orn(i-PrCO-Hao), consists of an ornithine residue with the beta-strand-mimicking amino acid Hao [J. Am. Chem. Soc. 2000, 122, 7654-7661] attached to its side chain. When Orn(i-PrCO-Hao) is incorporated into a peptide, or appended to its N-terminus, the Hao group hydrogen bonds to the three subsequent residues to form a beta-sheetlike structure. The amino acid Orn(i-PrCO-Hao) is readily used in peptide synthesis as its Fmoc derivative, Fmoc-Orn(i-PrCO-Hao)-OH (3). Fmoc-Orn(i-PrCO-Hao)-OH behaves like a regular amino acid in peptide synthesis and was uneventfully incorporated into the peptide o-anisoyl-Val-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe (4) through standard automated Fmoc solid-phase peptide synthesis, with DIC and HOAt as the coupling agent for Fmoc-Orn(i-PrCO-Hao)-OH and o-anisic acid and HATU as the coupling agent for all other couplings. A second synthetic strategy was developed to facilitate the preparation of peptides with N-terminal Orn(i-PrCO-Hao) residues, which avoids the need for the preparation of Fmoc-Orn(i-PrCO-Hao)-OH. In this strategy, Boc-Orn(Fmoc)-OH is used as the penultimate amino acid in the peptide synthesis, and i-PrCO-Hao-OH (2) is used as the final amino acid. N-Terminal Orn(i-PrCO-Hao) peptide H-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe.TFA (5) was prepared in a fashion similar to that for 4, using DIC and HOAt as the coupling agent for i-PrCO-Hao-OH and HATU as the coupling agent for all other couplings. 1H NMR transverse-ROESY, coupling constant, and chemical shift studies establish that peptide 4 forms a dimeric beta-sheetlike structure in CDCl3 solution. The 1H NMR studies also suggest that the ornithine unit adopts a well-defined turn conformation. Analogous 1H NMR studies of peptide 5 indicate that this TFA salt folds but does not dimerize in CD3OD solution. Collectively, these synthetic and spectroscopic studies establish that the amino acid Orn(i-PrCO-Hao) induces beta-sheet structure and interactions in peptides in suitable organic solvents. Unlike the Hao amino acid, which acts as a prosthetic to replace three residues of the peptide strand, the Orn(i-PrCO-Hao) amino acid acts as a splint that helps enforce a beta-sheetlike structure without replacing the residues and their side chains. This feature of Orn(i-PrCO-Hao) is important, because it allows the creation of beta-sheet structure with minimal perturbation of the peptide sequence.     

3-Nitro-l,2,4-triazol-l-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP) as a condensing reagent for solid-phase peptide synthesis

Solid-phase oligopeptide synthesis has been well developed and most short oligopeptides can now be easily synthesized. However, when a desired oligopeptide forms a secondary structure or includes less reactive amino acids such as aminoisobutyric acid, its terminal amino groups become less reactive and synthesis of the desired oligopeptides becomes difficult. To expand the number of synthetic peptide sequences, we have developed efficient coupling conditions using 3-nitro-l,2,4-triazol-l-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP) as a highly reactive condensing reagent on an unswellable solid support. PyNTP demonstrated higher reactivity than conventional condensing reagents and the optical purity of the synthesized oligopeptides was sufficiently high for application to general oligopeptide synthesis.     

Application of divergent multi-component reactions in the synthesis of a library of peptidomimetics based on γ-amino-α,β-cyclopropyl acids

The multi-component condensation of organozirconocene, aldimine and zinc carbenoid was applied to the stereoselective synthesis of cyclopropane amino acid derivatives. These compounds served as scaffolds for the preparation of a 46-member library. The C- and N-termini of the cyclopropane amino acid derivatives were diversified by condensations with ten amines and ten acylating agents, respectively. To improve yields and accelerate library synthesis, most products were prepared under microwave irradiation and purified by polymer-bound scavengers and SPE methodology. All compounds were analyzed by LC-MS and a representative selection was fully characterized.     

A novel [60]fullerene amino acid for use in solid-phase peptide synthesis

[see structure]. A fullerene derivative containing a free amino group has been condensed with N-Fmoc-L-glutamic acid alpha-tert-butyl ester to give a C60-functionalized amino acid. The carboxylic end of this amino acid has been deprotected in acidic conditions, and the resulting acid has been used for solid-phase peptide synthesis. The final peptide, cleaved from the resin, was very soluble in water solutions and showed antimicrobial activity against two representative bacteria.     

An efficient synthesis of a novel analog of octreotide with an unnatural l-lysine-like tetrazolyl amino acid

A new cyclic octreotide-like octapeptide was prepared by incorporation of an unnatural tetrazolyl amino acid, an analog of Fmoc-l-lysine, into the peptide chain. The new tetrazolyl amino acid, (S)-2-{[2-(9H-fluoren-9-yl)acetoxy]amino}-6-(1H-tetrazol-1-yl)hexanoic acid, was obtained by azidation of Fmoc-l-lysine trifluoroacetate with sodium azide in the presence of triethyl orthoformate in glacial acetic acid. The linear peptide sequence was prepared using efficient Fmoc/t-Bu solid-phase peptide synthesis (SPPS). Cyclization of the octapeptide was carried out via oxidation with iodine. The structure and purity of the cyclic octapeptide were confirmed by LC–MS, MALDI-TOF MS/MS analysis as well as 1D/2D ¹H and ¹³C NMR spectroscopy.     

Alpha,alpha-disubstituted glycines bearing a large hydrocarbon ring: peptide self-assembly through hydrophobic recognition

A method was developed for synthesizing alpha,alpha-disubstituted glycine residues bearing a large (more than 15-membered) hydrophobic ring. The ring-closing metathesis reactions of the dialkenylated malonate precursors proceed efficiently, particularly when long methylene chains tether both terminal olefin groups. Surprisingly, the amino groups of these alpha,alpha-disubstituted glycines are inert to conventional protective reactions (e.g., N-tert-butoxycarbonyl (Boc) protection: Boc(2)O/4-dimethylaminopyridine (DMAP)/CH(2)Cl(2); N-benzyloxycarbonyl (Z) protection: Z-Cl/DMAP/CH(2)Cl(2)). Curtius rearrangement of the carboxylic acid functionality of the malonate derivative after ring-closing metathesis leads to formation of an amine functionality and can be catalyzed by diphenylphosphoryl azide. However, only the intermediate isocyanates can be isolated, even in the presence of alcohols such as benzyl alcohol. The isocyanates obtained by Curtius rearrangement in an aprotic solvent (benzene) were isolated in high yields and treated with 9-fluorenylmethanol in a high-boiling-point solvent (toluene) under reflux to give the N-9-fluorenylmethoxycarbonyl (Fmoc)-protected aminomalonate derivatives in high yield. These hydrophobic amino acids can be incorporated into a peptide by Fmoc solid-phase peptide synthesis and the acid fluoride activation method. The stability of the monomeric alpha-helical structure of a 17-amino-acid peptide was enhanced by replacement of two alanine residues with two hydrophobic amino acid residues bearing a cyclic 18-membered ring. The results of sedimentation equilibrium studies suggested that the peptide assembles into hexamers in the presence of 100 mM NaCl.     

Thiophene backbone amide linkers, a new class of easily prepared and highly acid-labile linkers for solid-phase synthesis

Solid-phase synthesis is of tremendous importance for small-molecule and biopolymer synthesis. Linkers (handles) that release amide-containing products after completion of solid-phase synthesis are widely used. Here we present a new class of highly acid-labile backbone amide linkers (BAL handles) based on 3,4-ethylenedioxythiophene (EDOT), which we have termed T-BAL. These thiophene linkers are synthesized in three convenient steps from commercially available EDOT. In the linker design, the spacer was introduced to the EDOT core either via a carbon-carbon bond or via a thioether linkage. Introduction of the spacer via a C-C bond was performed by a chemoselective Negishi coupling without transient protection of the aldehyde group to provide the T-BAL1 handle. Introduction via a thioether linkage was performed by a facile nucleophilic aromatic substitution between the brominated EDOT aldehyde and unprotected mercapto acids to provide T-BAL2 and T-BAL3 handles. The minimal use of protecting groups gave the corresponding linker molecules in few synthetic steps and in good yields. After anchoring of the linker to a polymeric support, introduction of the first amino acid was achieved by reductive amination, giving a secondary amine. A following acylation of the secondary amine with a symmetrical amino acid anhydride resulted in a backbone amide linkage between the handle and the growing substrate (e.g., peptide chain). After solid-phase synthesis, the substrates could be released from the resin by either low acid conditions using 1% TFA in CH2Cl2 or high acid conditions such as 50% TFA in CH2Cl2. Peptide thioesters could be released from the T-BAL1 handle under very mild conditions using aqueous acetic acid. Tert-butyl based protecting groups, tert-butyl esters, tert-butyl ethers, and Boc groups, as well as dimethyl acetals were relatively stable to these mild conditions for release of the peptides.     

Introduction of a triazole amino acid into a peptoid oligomer induces turn formation in aqueous solution

Peptoids are a non-natural class of oligomers that are composed of repeating N-substituted glycine units and are capable of folding into helices that mimic peptide structure and function. In this letter, we report the concise synthesis of a 1,5-substituted triazole amino acid (Tzl) and its subsequent incorporation into a short peptoid. The Tzl amino acid was shown to induce turn formation in aqueous solution, thus expanding the structural repertoire available to peptoid chemists.     

Rigid dipeptide surrogates: syntheses of enantiopure quinolizidinone and pyrroloazepinone amino acids from a common diaminodicarboxylate precursor

A versatile and practical approach for synthesizing azabicyclo[X.Y.0]alkane amino acids of different ring sizes from a common diaminodicarboxylate precursor has been developed as a means for mimicking different peptide conformations. (2S,9S)-1-tert-Butyl 10-benzyl 5-oxo-2-[N-(PhF)amino] 9-[N-(BOC)amino]dec-4-enedioate (18) was first prepared in 83% yield by the Horner-Wadsworth-Emmons olefination of N-(PhF)aspartate beta-aldehyde 8 with pyroglutamate-derived beta-keto phosphonate 12 (PhF = 9-phenylfluoren-9-yl). The practicality of this approach for making azabicyclo[X.Y.0]alkane amino acids was then illustrated by the first synthesis of enantiopure quinolizidin-2-one amino acid 6 in seven steps and 40% overall yield from L-pyroglutamic acid. Hydrogenation of delta-keto alpha,omega-diaminosebacate 18, followed by lactam cyclization and protection, gave quinolizidin-2-one amino acid 6 as a single diastereomer. The versatility of this approach was next demonstrated by the synthesis of both ring-fusion isomers of pyrroloazepin-2-one amino acid 6 in 11 steps and 13% overall yield from pyroglutamic acid. Hydride reduction of 18, followed by methanesulfonate displacement, gave 5-alkylproline 22. Protective group manipulations, lactam cyclization, and removal of the ester group afforded readily separable pyrroloazepinone amino acids (7S)- and (7R)-7 in a 1:2 diastereomeric ratio. By introducing two new azabicycloalkane amino acids using our olefination approach, we have expanded the diversity of these important heterocycles for studying the conformational requirements for peptide biological activity.     

DOTAGA-anhydride: a valuable building block for the preparation of DOTA-like chelating agents

A DOTA derivative that contains an anhydride group was readily synthesized by reacting DOTAGA with acetic anhydride and its reactivity was investigated. Opening the anhydride with propylamine led to the selective formation of one of two possible regioisomers. The structure of the obtained isomer was unambiguously determined by 1D and 2D NMR experiments, including COSY, HMBC, and NOESY techniques. This bifunctional chelating agent offers a convenient and attractive approach for labeling biomolecules and, more generally, for the synthesis of a large range of DOTA derivatives. The scope of the reaction was extended to prepare DOTA-like compounds that contained various functional groups, such as isothiocyanate, thiol, ester, and amino acid moieties. This versatile building block was also used for the synthesis of a bimodal tag for SPECT or PET/optical imaging.     

Enantioselective total synthesis of (+)-largazole, a potent inhibitor of histone deacetylase

An enantioselective total synthesis of the cytotoxic natural product (+)-largazole (1) is described. It is a potent histone deacetylase inhibitor. Our synthesis is convergent and involves the assembly of thiazole 3-derived carboxylic acid with amino ester 4 followed by cycloamidation of the corresponding amino acid. The synthesis features an efficient cross-metathesis, an enzymatic kinetic resolution of a beta-hydroxy ester, a selective removal of a Boc-protecting group, a HATU/HOAt-promoted cycloamidation reaction, and synthetic manipulations to a sensitive thioester functional group.     

"@-Tides": the 1,2-dihydro-3(6H)-pyridinone unit as a beta-strand mimic.

The cyclic amino acid surrogate 1 was designed to mimic the extended conformation of a peptide unit and to provide hydrogen bond donor and acceptor functions conducive to beta-sheet formation. A convenient synthesis of this unit and solution and solid-phase methods for its incorporation into an oligomer alternating with peptide units have been devised. The resulting "@-tides", as these oligomers have been designated, show a high propensity for self-association in comparison to oligopeptides; insights into the structure and dynamical properties of their antiparallel dimers have been obtained by NMR.     

Stereoselective Synthesis of Unsaturated and Functionalized l-NHBoc Amino Acids, Using Wittig Reaction under Mild Phase-Transfer Conditions

The stereoselective synthesis of a new amino acid phosphonium salt was described by quaternization of melting triphenylphosphine with the γ-iodo NHBoc-amino ester, derived from l-aspartic acid. The deprotection of the carboxylic acid function to afford the phosphonium salt with a free carboxylic acid group was achieved by a palladium-catalyzed desallylation reaction. This phosphonium salt was used in the Wittig reaction with aromatic or aliphatic aldehydes and trifluoroacetophenone, under solid-liquid phase-transfer conditions in chlorobenzene and in the presence of K(3)PO(4) as weak base, to afford the corresponding unsaturated amino acids without racemization. Thus, the reaction with substituted aldehydes allows to graft various functionalized groups on the lateral chain of the amino acid, such as trifluoromethyl, cyano, nitro, ferrocenyl, boronato, or azido. In addition, the reaction of the amino acid Wittig reagent with α,β-unsaturated aldehydes leads to amino acids bearing a diene on the lateral chain. Finally, this amino acid phosphonium salt appears to be a new powerful tool for the preparation of unsaturated and non-proteinogenic α-amino acids, directly usable for the synthesis of customized peptides.