Synthesis of Cyclic Depsipeptides and Peptides via Direct Amide Cyclization

The 2,2-disubstituted 2H-azirin-3-amines 7 (2,2-disubstituted 3-amino-2H-azirines) were used as amino-acid synthons in the preparation of medium-sized cyclic depsipeptides and peptides derived from salicylic acids 6 and anthranilic acid 19 , respectively (Schemes 2--4 and 5, resp.). The combination of the ‘azirine/oxazolone method’ for the synthesis of linear peptides containing α,α-disubstituted α-amino acids and the acid-catalyzed amide cyclization in DMF at 60° proved to be an excellent preparative route to ten-membered cyclic depsipeptides and peptides. In the case of the anthranilic-acid derivative, a transannular ring-closure reaction was observed ( 24 → 25 ). Larger rings proved to be extremely sensitive to hydrolysis.     

Synthesis of cyclic peptides via O-N-acyl migration

We describe here a novel and convenient synthesis of head-to-tail cyclic peptide avoiding racemization. Linear depsipeptides including a serine residue as the key element for ester bond formation and acyl transfer were synthesized on 2-chlorotrityl chloride resin. After cleavage from the resin, intramolecular head-to-tail cyclization was performed in solution by C-terminal activation of urethane protected O-acyl serine residue. After removal of the N^α-serine protecting group, the final step consisted in O-N-acyl migration reaction on the ‘switch’ or ‘click’ element to restore native cyclic peptides.     

Rapid, high-yield, solid-phase synthesis of the antitumor antibiotic sansalvamide A using a side-chain-tethered phenylalanine building block

A 10-step solid-phase synthesis of the cytotoxic depsipeptide sansalvamide A (1) has been accomplished in an overall yield of 67% with >95% purity employing polymer-bound phenylalanine building block 2. Both the N- and C-termini of 2 are extended followed by on-resin head-to-tail macrocyclization of the linear peptide in a high yield. This should be a general stategy for the synthesis of diverse libraries of cyclic peptides and depsipeptides that contain exclusively phenylalanine and other hydrophobic side chains.     

Synthesis of Natural and Unnatural Cyclooligomeric Depsipeptides Enabled by Flow Chemistry

Flow chemistry has been successfully integrated into the synthesis of a series of cyclooligomeric depsipeptides of three different ring sizes including the natural products beauvericin ( 1 a ), bassianolide ( 2 b ) and enniatin C ( 1 b ). A reliable flow chemistry protocol was established for the coupling and macrocyclisation to form challenging N‐methylated amides. This flexible approach has allowed the rapid synthesis of both natural and unnatural depsipeptides in high yields, enabling further exploration of their promising biological activity.     

Nonribosomal cyclic peptides: specific markers of fungal infections

Some cyclic peptides and depsipeptides are synthesized in microorganisms by large multienzymes called nonribosomal peptide synthetases. The structures of peptide products originating in this way are complex and diverse and are microorganism-specific. This work proposes the use of fungal cyclic peptides and depsipeptides as extremely specific markers of fungal infections. Since a reliable molecular tool for diagnosing fungal infections at an early stage is still missing, we present mass spectrometry as a new, modern, broadband (with respect to fungal strain) and specific tool for clinical mycologists. More than 40 different fungal species can be rapidly characterized according to specific families of cyclic peptides, and in some cases, a particular fungal strain can be identified on the basis of its cyclopeptide profile. This paper is also aimed at initiating discussion on the biological role of these secondary metabolites, especially of those synthesized by medically important strains. Proven cytotoxic, anti-inflammatory or immunosuppressive activities of some cyclic peptides indicate that these molecules may contribute to the synergistic array of fungal virulence factors and support microbial invasion during fungal infection. In addition to an overview on recent mass spectrometric protocols for cyclic peptide sequencing, the structures of new peptides from Paecilomyces and Pseudallescheria are presented.     

Mo(CO)(6)-mediated carbamoylation of aryl halides

A simple method for the synthesis of amides has been developed by molybdenum-mediated carbamoylation of aryl halides. Whereas the conventional palladium-catalyzed three-component coupling reaction requires a large excess of gaseous carbon monoxide, the incorporation of carbon monoxide in this Mo-mediated carbamoylation reaction is so efficient that it requires only a slight excess amount of carbon monoxide in the form of its molybdenum complex, Mo(CO)(6). The reaction is applicable for the synthesis of a wide variety of not only secondary and tertiary amides but also primary amides by using aqueous ammonia.     

Synthesis of phosphinopeptides via the Mannich ligation

Phosphinopeptides are a class of unnatural peptides containing a tetrahedral phosphorus atom and have potential for use as enzyme inhibitors. A series of phosphinopeptides were synthesized via the Mannich-type reaction of aryldichlorophosphines, aldehydes, and N-protected amino amides or peptide amides and subsequent aminolysis with amino esters or peptide esters. The current method named the Mannich ligation is an efficient route to synthesis of phosphinopeptides through convergent condensation.     

A new strategy for solid-phase depsipeptide synthesis using recoverable building blocks

The technique of choice for synthesis of small-scale depsipeptides is on a solid support. However, if expensive monomers have to be incorporated, solid-phase synthesis can quickly turn out to be unattractive because of its low atom economy. Herein, we describe a new type of recoverable and reuseable alpha-hydroxy acid building block for solid-phase synthesis and its application in the synthesis of a number of small cyclic depsipeptides. [structure: see text]     

Total synthesis of emericellamides A and B

A concise total synthesis of emericellamides A and B, two cyclic depsipeptides exhibiting antibacterial and cytotoxic activities, is reported. A Paterson anti-aldol reaction and a hydroxy directed 1,3-anti reduction were applied for construction of the polypropionate unit with the required stereochemistry in emericellamides A and B. An FDPP mediated macrolactamization was used to construct the macrocycle of emericellamides A and B.     

Oligooxatetraazacoronands (review)

Information on methods of synthesis and the physicochemical and chemical properties of tetraazamacroheterocycles from classes of crown ethers, viz., amides and thioamides, urethanes, azomethines, formazans, and depsipeptides, that contain two or more oxygen atoms in their loops is correlated. The unique characteristics of their complexing with various groups of metals are noted.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 867–882, July, 1987.     

New Methods of Synthesis of Phosphoryl and Thiophosphoryl Halides from Organylchlorophosphonium Hexachlorophosphorates

A new method of synthesis of phosphonic and thiophosphonic chlorides is offered, based on treatment of acyclic and cyclic organylchlorophosphonium hexachlorophosphorates with dimethylformamide, dimethylacetamide, or dimethylthioacetamide. The method involves no formation of phosphoryl chloride and thiophosphoryl chloride, which facilitates isolation of the target products. The reactions of alkenylchlorophosphonium hexachlorophosphorates with amides and thioamides results in incorporation of the PCl₆ ^- anion into an insoluble chloroiminium salt which is easily separated by filtration. Removal of the solvent leaves almost pure phosphonic or thiophosphonic chlorides.     

Stereoselective Synthesis of Enamides through Palladium-Catalyzed Oxidative Amidation of Conjugated Olefins with 2-Pyridones

A palladium-catalyzed oxidative amidation of conjugated olefin with 2-pyridone is described. A series of E-Enamides were synthesized in a highly stereocontrolled manner. The reaction also accommodates other cyclic and acyclic amides. Z-Enamides were predominantly prepared for primary amides probably due to the presence of an intramolecular hydrogen bond. Gram-scale synthesis of enamide and the following oxidative annulation with diphenylacetylene demonstrates the synthetic utility of this reaction.     

Biomimetic synthesis of esters of natural amino acids

A method for the synthesis of Gly, Ala, Phe, and Thr esters is proposed and considered as being a stage of possible biomimetic synthesis of peptides. The methyl esters of the said amino acids are obtained via intervention of 2‐hydroxypropyl phosphonate. The resulting aminoacyl phosphonates reacts with methanol to produce the amino acid methyl esters, with the release of phosphoric acid. The reaction is carried out at room temperature in water. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:252–255, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20427     

Solid-phase synthesis of biaryl cyclic peptides containing a histidine-tyrosine linkage

A solid-phase strategy for the synthesis of biaryl cyclic peptides containing a side-chain to side-chain His-Tyr linkage was developed. The key step was the macrocyclization of a linear peptidyl resin incorporating a 5-bromohistidine and a 3-boronotyrosine via the formation of the biaryl bond by means of a microwave-assisted Suzuki-Miyaura reaction. This method allowed direct access to biaryl cyclic peptides containing a 3- or 5-amino acid ring and bearing the histidine residue at the N- or the C-terminus, being especially conducive for analogues in which this amino acid is located at the C-terminus. This study also served to establish a strategy for the synthesis of biaryl cyclic peptides derived from the two hemispheres of the natural biaryl bicyclic peptides aciculitins.     

Miscellaneous applications of ferrocene‐based peptides/amides

This article provides a critical review of the different applications of ferrocene‐based peptides/amides in biological as well as in non‐biological systems. Ferrocene‐based peptides/amides find many applications in different fields such as materials science, medicine, organic synthesis, bio‐organometallic and biological chemistry, asymmetric catalysis, nonlinear optics, in polymer science as redox active polymers and dendrimers, in molecular recognition as biosensors and in electrochemistry). Extensive research is being done on ferrocene‐based peptides/amides but we will highlight the various applications of ferrocene‐based peptides/amides for the period 2006–2010. The main factors that govern the potential biological and non‐biological applications are an electroactive core, a conjugated linker that can act as a chromophore and lower the oxidation potential of the ferrocene part, an amino acid or peptide derivative that can interact with other molecules via hydrogen bonding or any secondary bonding, and symmetric and asymmetric substitution on the ferrocene moiety. Copyright © 2011 John Wiley & Sons, Ltd.     

New, simple method for synthesis of cystine peptides

A report is given on the conversion of S-trityl-cysteine-containing protected peptides to cystine peptides by a reaction with iodine in methanol. The new method permits the synthesis of symmetrical, open-chain unsymmetrical, and especially cyclic cystine peptides.     

Synthesis of functional derivatives ofN-carboxamidomethyl- andN-phthalimidomethyl-a-amino acids and peptides by reaction of amides and nitriles of α-amino acids with formaldehyde and primary amides or phthalimide

A direct method for the synthesis of functional derivatives ofN-carboxatnidomethyl- and N-phthalimidomethyl-a-amino acids by the reaction of nitriles and amides of -amino acids (including peptides) with formaldehyde and NH-compounds (amides and imides) in DMF in the presence of TsOH was developed. The reactions of the compounds synthesized with acetic anhydride, tosyl chloride, and phcnylalanine benzylamide in the presence of dicyclohexylcarbodiimide affording the corresponding N-acyl and N-sulfonyl derivatives or peptides containing carboxamido- and phthalimidomethyl substituents at the terminal N-atom of the peptide chain, were studied.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1480–1488, June, 1996.     

Efficient Synthesis of Cryptophycin‐52 and Novel para‐Alkoxymethyl Unit A Analogues

Cryptophycins are a family of highly cytotoxic, cyclic depsipeptides. They display antitumour activity that is largely maintained for multi‐drug‐resistant tumour cells. Cryptophycins are composed of four building blocks (units A–D) that correspond to the respective amino and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres in a short, efficient and reliable synthesis and contributes to an easier and faster synthesis of cryptophycins. The first two stereogenic centres are introduced by a catalytic asymmetric dihydroxylation, whereas the remaining two stereogenic centres are introduced with substrate control of diastereoselectivity. The stereogenic diol function also serves as the epoxide precursor. The approach was used to synthesise the native unit A building block as well as three para‐alkoxymethyl analogues from which cryptophycin‐52 and three analogous cryptophycins were prepared. Macrocyclisation of the seco‐depsipeptides was based on ring‐closing metathesis.     

Synthese cyclischer Depsipeptide durch direkte Amid-Cyclisierung: 12gliedrige Depsipeptide mit alternierender Sequenz von α-Hydroxy- und α-Aminosäuren

Synthesis of Cyclic Depsipeptides via Direct Amide Cyclization: Cyclic Depsipeptides with 12-Ring Atoms and Alternating Sequence of α-Hydroxy and α-Amino Adds The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine (1; R¹ = R² = R³ = R⁴ = Me) with α-hydroxy-carboxylic acids, followed by selective hydrolysis of the terminal dimethylamide group yields the dipeptide analogues 15a and 18b (Schemes 3 and 4). After protection of the OH group (→ 16a and 19 , resp.), coupling with the C-terminus-protected derivatives 14 and 18a , respectively, by a modified 1,1′-carbonyldiimidazole procedure followed by hydrolysis gives the linear depsipeptides 17c and 20 , respectively. Treatment with HCl gas in toluene at 100° leads to the cyclic depsipeptides 21 and 22 in very good yield. The two model reactions show that the ‘azirine/oxazolone-method’, combined with the ‘direct amide cyclization’, is a versatile procedure for the synthesis of cyclic depsipeptides containing α,α-disubstituted α-amino acids.