Total Synthesis of Cyclosporine: Access to N-Methylated Peptides via Isonitrile Coupling Reactions

Wu, Xiangyang; Stockdill, Jennifer L.; Wang, Ping

doi:10.1021/ja100517v

Cited by 95 publications

(69 citation statements)

References 31 publications

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“…We continued our exploration in this method of amide formation using varying amines and thioacids (19,28,29). Coupling of solid-support glutamine 8 and leucine-derived thioacid 11 (19) under mediation by t-BuNC and HOBt, followed by cleavage from resin, provided dipeptide 12 in 94% yield (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Coupling of solid-support glutamine 8 and leucine-derived thioacid 11 (19) under mediation by t-BuNC and HOBt, followed by cleavage from resin, provided dipeptide 12 in 94% yield (Fig. 2, Eq.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, entry 3 establishes the dominance of the thio-FCMA pathway, indicating a possible low-yielding acyl activation pathway by HOBt itself, independent of isonitrile mediation or adventitious oxidative activation. Entry 4 demonstrates that, at least under the more discriminating SPPS conditions, we are able to effectively avoid oxidative acylation and there are no discernable acyldonating properties by thioacids, themselves, with respect to amine nucleophile.We continued our exploration in this method of amide formation using varying amines and thioacids (19,28,29). Coupling of solid-support glutamine 8 and leucine-derived thioacid 11 (19) under mediation by t-BuNC and HOBt, followed by cleavage from resin, provided dipeptide 12 in 94% yield (Fig.…”

mentioning

confidence: 99%

“…The potentialities of the isonitrile-mediated amidation method were foreshadowed via its application to the synthesis of cyclosporine (19). The power of the method was particularly well demonstrated in the context of our recent total synthesis of oxytocin (OT) (20), wherein isonitrile mediation was used in each of the peptide bond constructions, leading to the synthesis of the hormone in high yield and excellent purity.…”

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confidence: 99%

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Solid-phase peptide synthesis and solid-phase fragment coupling mediated by isonitriles

Wang

2013

Proc. Natl. Acad. Sci. U.S.A.

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The synthesis of polypeptides on solid phase via mediation by isonitriles is described. The acyl donor is a thioacid, which presumably reacts with the isonitrile to generate a thio-formimidate carboxylate mixed anhydride intermediate. Applications of this chemistry to reiterative solid-phase peptide synthesis as well as solid-phase fragment coupling are described.A mide bond formations are arguably among the most important constructions in organic chemistry (1, 2). The centrality of the amide linkage, as found in polypeptides and proteins, in the maintenance of life hardly needs restatement. Numerous strategies, resulting in a vast array of protocols to synthesize biologically active polypeptides and proteins, have been demonstrated (3, 4). Central to reiterative polypeptide bond formations was the discovery and remarkable development of solid-phase peptide synthesis (SPPS) (5, 6). The extraordinary impact of SPPS in fostering enhanced access to homogeneous polypeptides is clear to everyone in the field.As we have described elsewhere, by classical, mechanistic reasoning, we were led to conjecture about some hithertounexplored possibilities relevant to the chemistry of isonitriles (7)(8)(9)(10)(11)(12)(13)(14). It was anticipated that isonitriles might be able to mediate the acylation of amines, thus giving rise to amides (15). Early experiments focused on free carboxylic acids as the acylating agents. As our studies progressed, it was found that the combination of thioacids, amines, and isonitriles leads to the efficient formation of amide bonds under stoichiometric or nearstoichiometric conditions (7-13, 16, 17). Although there remain unresolved issues of detail and nuance, the governing mechanism for amide formation under these conditions involves reaction of the thioacid, 1, with an isonitrile, 2, to generate a thio-formimidate carboxylate mixed anhydride (thio-FCMA), 3, which is intercepted by the "acyl-accepting" amine to generate amide, 5, and thioformamide, 6 (Fig. 1). The efficiency of the amidation was further improved through the use of hydroxybenzotriazole (HOBt) (18), which could well give rise to HOBt ester 7, although this pathway has not been mechanistically proven.The potentialities of the isonitrile-mediated amidation method were foreshadowed via its application to the synthesis of cyclosporine (19). The power of the method was particularly well demonstrated in the context of our recent total synthesis of oxytocin (OT) (20), wherein isonitrile mediation was used in each of the peptide bond constructions, leading to the synthesis of the hormone in high yield and excellent purity. This nonapeptide is involved in a range of biological functions including parturition and lactation (21,22). Signaling of OT to its receptor (OTR) is apparently an important factor in quality maintenance of various CNS functions (23). The ability to synthesize such modestly sized, but bio-impactful peptides in both native (wild-type) form, and as strategically modified variants, is one of the current missions of our labo...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Solid-phase peptide synthesis and solid-phase fragment coupling mediated by isonitriles

Wang

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Danishefsky et al have also demonstrated the reaction of thioacid and isonitrile as a possible way to access amides efficiently. 30,152 The chemistry was explored to synthesize Nmethylated peptides also (Scheme 68).…”

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confidence: 99%