Chemical Synthesis of Natural Product Peptides:  Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides

and, John M. Humphrey†; Chamberlin, A. Richard

doi:10.1021/cr950005s

Cited by 1,115 publications

(583 citation statements)

References 174 publications

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“…14 A cocatalyst screen revealed that 1-hydroxybenzotriazole (HOBt), 4-(dimethylamino) pyridine (DMAP), imidazole and pentafluorophenol (PFPOH) are effective at promoting the reaction, affording the desired amide products. (1) Experiments that probe the scope of useful amine partners are summarized in Table 1. A variety of primary and secondary amines partake in the reaction (entries 1-5, Table 1) to afford the desired amide in good to excellent yields.…”

mentioning

confidence: 99%

Nucleophilic Carbene and HOAt Relay Catalysis in an Amide Bond Coupling: An Orthogonal Peptide Bond Forming Reaction

2007

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The ubiquity of amides throughout organic, biological and materials chemistry mandates the development of more efficient methods for their synthesis. 1 Conventional amide bond formation utilizes acids and amines as coupling partners and relies on stoichiometric activating agents for the acid functionality. 2,3 A recent survey of process scale reactions cites a "...pressing need for the development of catalytic environmentally friendly acylation processes." 4,5 We 6 and others 7 have recently illustrated that nucleophilic carbenes 8 catalyze an internal redox reaction whereby alpha reducible aldehydes provide alpha reduced ester derivatives under catalytic conditions. 9 Surprisingly, among the many nucleophiles reported to participate in this process are only two amines: we 6a have shown that aniline participates and Scheidt 7b has shown that a vinylogous imide could be used. 10 Clearly, the salient features of this redox manifold, a waste free catalyzed acylation, provide a strong impetus to identify a general solution to the problem of NHC catalyzed amidation. Herein, we report one such solution relying on relay catalysis by a nucleophilic carbene and a common peptide cocatalyst such as 1-hydroxy-7-azabenzotriazole 11 (HOAt).Outside of aniline, our efforts at using amines as nucleophilies in the alpha redox reaction were met with uniform failure. Since we had established that phenols are competent partners, we hypothesized that the use of a cocatalyst such as HOAt could provide a relay shuttle. 12,13 HOAt should participate in the redox chemistry to generate activated ester which would undergo the in situ amidation thereby regenerating the catalyst. The viability of a concerted catalytic system using N-heterocyclic carbenes and HOAt to generate amides was investigated utilizing 2,2-dichloro-3-phenylpropanal as the redox substrate and benzyl amine as the nucleophile. The desired chemical transformation took place to afford the benzyl amide 2a in 93% yield (eq 1). In the absence of HOAt, only minor amidation product is observed. 14 A cocatalyst screen revealed that 1-hydroxybenzotriazole (HOBt), 4-(dimethylamino) pyridine (DMAP), imidazole and pentafluorophenol (PFPOH) are effective at promoting the reaction, affording the desired amide products.

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confidence: 99%

Nucleophilic Carbene and HOAt Relay Catalysis in an Amide Bond Coupling: An Orthogonal Peptide Bond Forming Reaction

2007

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“…As discussed by Humphrey and Chamberlin, racemization during coupling of N-methyl amino acids can be a problem, especially if the α-nitrogem atom is protected by the Boc group [26]. In this study, the Fmoc protocol was employed and at least in the case of the thioredoxin reductase peptide fragment, racemization was not observed as evidenced by the single peak in the HPLC chromatogram ( Figure 3A).…”

Section: Tandem Cleavage and Cyclization Protocol For Peptides Contaimentioning

confidence: 78%

A viable synthesis of N‐methyl cysteine

Ruggles¹,

Flemer²,

Hondal³

2008

Biopolymers

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While a number of methods exist for the production of N-methyl amino acid derivatives, the methods for the production of N-methyl cysteine (MeCys) derivatives are suboptimal as they either have low yields or lead to significant sulfhydryl deprotection during the synthetic protocol. This paper focuses on the generation of MeCys and its subsequent use in Fmoc solid-phase peptide synthesis for the generation of N-methyl cystine containing peptides. Various methods for amino methylation of cysteine, in the presence of acid labile or acid stable sulfhydryl protecting groups, are compared and contrasted. Production of MeCys is best attained through formation of an oxazolidinone precursor obtained via cyclization of Fmoc-Cys(StBu)-OH. Following oxazolidinone ring opening, iminium ion reduction generates Fmoc-MeCys(StBu)-OH with an overall yield of 91%. The key to this procedure is using an electronically neutral Cys-derivative, as other polar Cys-derivatives gave poor results using the oxazolidinone procedure. Subsequently, the Fmoc-MeCys(StBu)-OH building block was used to replace a Cys residue with a MeCys residue in two peptide fragments that correspond to the active sites of glutaredoxin and thioredoxin reductase. The examples used here highlight the use of a MeCys(StBu) derivative, which allows for facile on-resin conversion to a MeCys(5-Npys) residue that can be subsequently used for intramolecular disulfide bond formation with concomitant cleavage of the peptide from the solid support.

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“…25 Metilni N-sulfonilimidat 43 reakcijom s cikličkim aminom 44, uz NaCN kao katalizator, daje N-sulfonilamidin 45 (shema 20). 26 Reakcija se odvija u metanolu pri 50 °C.…”

Section: 39 10unclassified

1,3-Dipolarna cikloadicija (II. dio): Trokomponentne Cu(I) katalizirane klik-reakcije

et al. 2015

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Chemical Synthesis of Natural Product Peptides: Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides

Cited by 1,115 publications

References 174 publications

Nucleophilic Carbene and HOAt Relay Catalysis in an Amide Bond Coupling: An Orthogonal Peptide Bond Forming Reaction

Nucleophilic Carbene and HOAt Relay Catalysis in an Amide Bond Coupling: An Orthogonal Peptide Bond Forming Reaction

A viable synthesis of N‐methyl cysteine

1,3-Dipolarna cikloadicija (II. dio): Trokomponentne Cu(I) katalizirane klik-reakcije

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