Synthesis of the HCV protease inhibitor Vaniprevir (MK-7009) using ring-closing metathesis strategy

A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.     

Synthesis of alkyne-bridged cyclic tripeptides toward constrained mimics of vancomycin

The synthesis of a range of highly constrained cyclic tripeptides has been performed using either an intramolecular Sonogashira coupling or a macrolactamization as the final ring-closing reaction. Our approach gives access to rigidified 15-membered peptidic macrocycles based on the central ring system of vancomycin. Tripeptides 3a-c and dipeptide 11 were cyclized via an intramolecular Sonogashira reaction, and the cyclic peptides 4a-c and 15a were obtained in 6-23% yield. In contrast, macrolactamization of 12 and 17 resulted in the desired peptidic macrocycles 15b and 18 with 54-61% yield. Modeling studies hint at a distorted triple bond, which explains the low yield of the Sonogashira-based cyclization. Moreover, modeling data also showed that this class of peptidic macrocycles formed a cavity-like structure in which guest molecules may bind.     

Synthesis of linear tripeptides for right-hand segments of complestatin

This paper concerns a synthetic study of the right-hand segment of complestatin, an inhibitor of gp120-CD4 receptor. The effective synthesis of four important precursors for the right-hand segment of complestatin is described. Two of them are the precursor tripeptides for macrolactamization to the right-hand segment of complestatin at the last step and the other two are the precursor tripeptides for ring-closing reaction using Suzuki and Stille coupling, respectively, to the right-hand segment of complestatin at the last step. These compounds and the synthetic procedure will serve for both the synthesis of the right-hand segment and total synthesis of complestatin in the near future. In addition, consideration of the smooth acidic isomerization of complestatin to chloropeptin was carried out by density functional theory (DFT) calculation.     

Step-wise and pre-organization induced synthesis of a crossed alkene-bridged nisin Z DE-ring mimic by ring-closing metathesis

This paper describes two approaches for the synthesis of a crossed alkene-bridged mimic of the thioether ring system of the nisin Z DE-fragment. The first approach comprised the stepwise total synthesis featuring a cross metathesis and a macrolactamization on a solid support followed by a ring-closing metathesis in solution. Via this route the title compound was obtained in an overall yield of 7% (85% on average for 16 reaction steps). In the second approach, the linear precursor peptide was subjected to ring-closing metathesis and the bicyclic peptide with the correct side chain connectivity pattern was obtained in yields up to 95%. The preferred formation of the bicyclic crossed alkene-bridged mimic of the DE-ring suggests a favorable pre-organization of the linear precursor peptide.     

Flexible total synthesis of biphenomycin B

A total synthesis of the biaryl antibiotic biphenomycin B is reported which makes use of three independent building blocks (key steps were a clean Suzuki-Miyaura coupling of a free acid iodide, a novel 4-hydroxyornithine synthesis, and a high-yielding macrolactamization); a practical deprotection protocol allowed isolation of the target compound with excellent recovery and purity.     

Total synthesis of halipeptin A, a potent anti-inflammatory cyclodepsipeptide from a marine sponge

Total synthesis of halipeptin A, a potent anti-inflammatory cyclodepsipeptide, was achieved through proline-catalyzed asymmetric α-oxidation, diastereoselective aldol reaction, silver cyanide-mediated esterification, and macrolactamization.     

Total synthesis of arenamide A and its diastereomer

Arenamide A and its diastereomer have been synthesized in a convergent fashion. The key steps involved in this synthesis are Sharpless asymmetric epoxidation, C–C bond formation, and macrolactamization.     

Synthesis of cyclic dimeric methyl morpholinoside—a common synthetic precursor to cyclic dinucleotide analogs

An eight-step synthesis of cyclic dimeric methyl morpholinoside (c-di-MM), a common synthetic precursor to a number of cyclic dinucleotide analogs is reported. The synthesis of c-di-MM proceeds through a morpholine monomer prepared from readily available inexpensive starting materials and culminates with a key macrolactamization reaction to provide the macrocycle in 15% overall yield.     

Total synthesis of janadolide

The first total synthesis of janadolide, a new cyclic polyketide-peptide hybrid possessing a tert-butyl group, is described. The synthesis of an unsaturated hydroxycarboxylic acid was effected via the lithiation of vinyl iodide followed by addition to a Weinreb amide with a tert-butyl group and stereoselective 1,2-reduction. The cyclic structure was constructed by macrolactamization at the amide bond between the proline moiety and fatty acid moiety.     

Total syntheses of arenamides A,B and C

Total syntheses of the three arenamides A–C, NFκB inhibitors, are described for the first time. The key steps involved in the synthesis are a Crimmin’s aldol, Wittig olefination and a macrolactamization reaction.     

Expedient synthesis of a stereoisomer of acremolide B

A highly straightforward strategy for the synthesis of the acremolide class of lipodepsipeptides has been developed. Synthetic highlights include a cross-metathesis to couple the C1-C7 and the C8-C12 fragments, an esterification to introduce the dipeptide unit, a macrolactamization to build the macrolide core, and two stereoselective allylations/crotylations to control all four stereogenic centers of the C1-C12 polypropionate segment.     

Efficient solid-phase-based total synthesis of the bisintercalator TANDEM

[reaction: see text] In this article, the first solid-phase-based total synthesis of TANDEM, a synthetic analogue of triostin A, is described. In initial studies, the synthesis incorporated depsipeptide formation, introduction of chromophores, and disulfide bond formation on the solid phase, prior to a final solution-phase macrolactamization, to give the target molecule. Although pure TANDEM was obtained in an overall yield comparable to those for all syntheses to date, the yield of the final cyclization was low (11%). A more efficient approach involved removal from the solid phase prior to disulfide bond formation. The resulting linear peptide underwent macrolactamization under mild conditions and high dilution. Final disulfide bond formation was essentially quantitative and gave the target molecule, TANDEM, in an overall yield of 18%. The final compound was assessed for its ability to bind to 5'-TpA sequences on DNA by DNase I footprinting. This efficient synthesis sets the stage for a study of the structure-activity relationship of TANDEM and the natural product triostin A, with analogues containing "point mutations" at every site within the cyclic compounds.     

Total synthesis of emericellamides A and B

The total synthesis of emericellamides A and B is reported. A convergent, flexible strategy employing peptide chemistry, asymmetric alkylations, and culminating in macrolactamization is described. The previously reported structure of both compounds is confirmed.     

Total synthesis of ustiloxin D.

The total synthesis of ustiloxin D, a highly potent inhibitor of microtubule assembly, has been achieved. Notable features are the use of nucleophilic aromatic substitution (SNAr) for the construction of a chiral tertiary alkyl-aryl ether linkage, Sharpless asymmetric aminohydroxylation for the formation of the beta-hydroxytyrosine moiety, macrolactamization, and regioselective methylation.     

Total syntheses of 28,29-diepi-arenamide A, 29-epi-arenamide A, and 28-epi-arenamide A

This communication describes the synthesis of stereochemical analogs of arenamide A, a 19-membered cytotoxic depsipeptide isolated from the fermentation broth of a marine bacterial strain Salinispora arenicola. The key steps are diastereoselective aldol reaction, Mitsunobu reaction, and HATU mediated macrolactamization.     

Solid‐phase Total Synthesis of (−)‐Apratoxin A and Its Analogues and Their Biological Evaluation

Two approaches for the solid‐phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer‐support, macrolactamization of 10 , followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid‐phase peptide synthesis by using amino acids 13 – 15 and 18 . The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O‐methyl tyrosine can be replaced by 7‐azidoheptyl tyrosine without loss of activity. The 1,3‐dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.     

Combinatorial synthesis of RGD model cyclic peptides utilizing a palladium-catalyzed carbonylative macrolactamization on a polymer support

A combinatorial synthesis of 24-member RGD models was accomplished on polymer-support. Ortho-, meta-, and para-iodobenzylamines loaded on an aldehyde linker by reductive amination were coupled with RGD sequences and various omega-amino acids by a split-and-pool method. Palladium-catalyzed carbonylative macrolactamization of the polymer-supported cyclization precursors, followed by acid cleavage, provided conformationally restricted RGD model cyclic peptides.     

Total synthesis of (-)-stevastelin B

The total synthesis and an unambiguous structure confirmation of stevastelin B 1, a novel 15-membered cyclic depsipeptide, are described; the fatty acid moiety in 1, prepared stereoselectively from L-quebrachitol was converted into the amino carboxylic acid, whose macrolactamization by Shioiri's procedure effectively constructed the cyclic structure of 1.     

A double ring-closing olefin metathesis approach to [3]catenanes

A [3]catenane with peripheral olefinic macrocycles was conveniently synthesized via a double ring-closing olefin metathesis. Highlights of this work include the synthesis of a 65-membered macrocycle featuring two phenanthroline ligands, a Cu(I)-templated synthesis of a [3]pseudorotaxane, and the key double ring-closing olefin metathesis to afford the desired [3]catenane in 71% yield.     

Sweetening cyclic peptide libraries

Enzymatic macrolactamization of linear glycosidated peptides provides access to an important class of drug-like molecules. The work presented in this issue [1] shows that it may be possible to make complex libraries of glycosidated cyclic peptides by incorporating glycosidated amino acids into linear peptides via solid-phase peptide synthesis followed by thioesterase-mediated peptide cyclization.