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Synfacts 2019; 15(07): 0709
DOI: 10.1055/s-0039-1689933
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (+)-Biotin

Contributor(s):
Erick M. Carreira
,
Michael Schneider
Baggiolini EG. * Lee HL, Pizzolato G, Uskoković MR. Hoffmann-La Roche Inc., Nutley, USA
Synthesis of d-Biotin from l-Cystine via Intramolecular [3+2] Cycloaddition.

J. Am. Chem. Soc. 1982;
104: 6460-6462
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Further Information

Publication History

Publication Date:
17 June 2019 (online)

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Key words

(+)-biotin - disulfide cleavage - dipolar cycloaddition - nitrone-olefin cycloaddition

Significance

(+)-Biotin is a vitamin involved in several biological processes including acetyl-CoA carboxylase mediated carboxylation of acetyl-CoA to malonyl-CoA. (+)-Biotin forms one of the strongest known non-covalent interactions with the protein streptavidin. In biotechnology, this binding is widely used for the labeling of proteins and small molecules and protein purification. Starting from l-cystine dimethyl ester, Baggiolini and co-workers reported an elegant synthesis of (+)-biotin, which features a highly diastereoselective intramolecular dipolar cycloaddition.


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Comment

Acylation of l-cystine dimethyl ester with 5-hexynoyl chloride (A) afforded amide B. Treatment of B with zinc in AcOH under air atmosphere led to disulfide cleavage and subsequent cyclization to furnish C. DIBAL-H reduction of the ester moiety followed by condensation of the resulting aldehyde with hydroxylamine E gave nitrone F. Nitrone-olefin cycloaddition was induced by refluxing F in toluene. Reductive N–O cleavage followed by treatment with methyl chloroformate (H) afforded carbamate I. Ba(OH)2-mediated amide hydrolysis led to concomitant urea formation. Dehydroxylation of J in two steps followed by global deprotection furnished (+)-biotin.


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