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Article

Total Synthesis of the Thiopeptide Antibiotic Amythiamicin D

Supporting Info

Rachael A. Hughes,^† Stewart P. Thompson,^† Lilian Alcaraz,^‡ and Christopher J. Moody*^†^§

Contribution from the School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom, Department of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, United Kingdom, and Medicinal Chemistry Department, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, United Kingdom

J. Am. Chem. Soc., 2005, 127 (44), pp 15644–15651

DOI: 10.1021/ja0547937

Publication Date (Web): October 18, 2005

†

University of Exeter.

‡

AstraZeneca.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

University of Nottingham.

, c.j.moody@nottingham.ac.uk

Abstract

The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels−Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels−Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N−H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels−Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.

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