Revisiting Oxytocin through the Medium of Isonitriles

Wang, Ting

doi:10.1021/ja3063452

Cited by 20 publications

(25 citation statements)

References 57 publications

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“…Finally, aeration of 24 in pH 7 aqueous solution provided vasopressin 25 in 71% isolated yield. As in the recently reported case of oxytocin (20), the high field proton spectra of 24 and 25 were quite similar, thus suggesting a high order of preorganization, even in the absence of disulfide bond formation. We next evaluated the feasibility of a more challenging proposition, namely, the possibility of an iterative chemoselective solidphase fragment coupling (SPFC) via isonitrile-mediated amidation.…”

Section: % (supporting

confidence: 78%

“…After cleavage from resin, dipeptide 10 was obtained in 95% yield (Table 1, entry 1). The experiments summarized in Table 1 serve to clarify and integrate the findings herein, conducted under SPPS conditions, with the previously described (20,27) solutionbased amidation of thioacids. Previously, we had demonstrated a highly exploitable oxidatively activable pathway for enhancing the acyl-donating properties of thioacids (18).…”

Section: Resultsmentioning

confidence: 79%

“…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).…”

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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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confidence: 78%

Section: Resultsmentioning

confidence: 79%

mentioning

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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“…Next, we employed these conditions for direct, on-resin disulfide formation in the synthesis of the neurotransmitter, oxytocin ( 1 ), 6,27 a 9-mer peptide with one disulfide bond. We synthesized carboxy-oxytocin to facilitate analysis of the disulfide forming reaction.…”

Section: Resultsmentioning

confidence: 99%

“…3a Several important single-disulfide containing pharmaceuticals 5 are illustrated in Figure 1. Oxytocin ( 1 ) 6 is used clinically to induce parturition and lactation in nursing mothers and to decrease bleeding postpartum. 7 Desmopressin ( 2 ) is a vasopressin analog used in the treatment of nocturnal enuresis and blood clotting.…”

Section: Introductionmentioning

confidence: 99%

Direct palladium-mediated on-resin disulfide formation from Allocam protected peptides

et al. 2017

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The synthesis of disulfide-containing polypeptides represents a long-standing challenge in peptide chemistry, and broadly applicable methods for the construction of disulfides are in constant demand. Few strategies exist for on-resin formation of disulfides directly from their protected counterparts. We present herein a novel strategy for the on-resin construction of disulfides directly from Allocam-protected cysteines. Our palladium-mediated approach is mild and uses readily available reagents, requiring no special equipment. No reduced peptide intermediates or S-allylated products are observed, and no residual palladium can be detected in the final products. The utility of this method is demonstrated through the synthesis of the C-carboxy analog of oxytocin.

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Amine Activation: N‐Arylamino Acid Amide Synthesis from Isothioureas and Amino Acids

et al. 2017

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N-arylamino acid amides have been synthesized via a novel method based on N-arylamine activation into isothioureas followed by reaction with amino acids under iron catalysis. The activated N-arylamines are easily prepared using a three-component reaction with commercial reagents, tert-butylisocyanide and S-phenyl benzenethiosulfonate. The protocol shows a broad functional group compatibility, with respect to side chain functionality of the amino acid (e. g. aliphatic and aromatic OH, (hetero)aromatic NH, amide NH, thioether), and the chiral amino acids do not undergo epimerization. The mechanism of the new amide synthesis has been studied.

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Revisiting Oxytocin through the Medium of Isonitriles

Cited by 20 publications

References 57 publications

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

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

Direct palladium-mediated on-resin disulfide formation from Allocam protected peptides

Amine Activation: N‐Arylamino Acid Amide Synthesis from Isothioureas and Amino Acids

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