Discoveries from the Abyss: The Abyssomicins and Their Total Synthesis

Abstract

Abyssomicin C is a recently discovered antibiotic with promising antibacterial activity, high structural complexity, and a novel mechanism of action. We give an account of our abyssomicin campaign and some of the discoveries that were borne of our total synthesis efforts, including a new Lewis acid templated Diels-Alder­ reaction, the previously undescribed atrop-abyssomicin C, a facile Brønsted acid-catalyzed isomerization of abyssomicin C, and clarification of the likely biosynthetic origin of abyssomicin D.

1 Introduction

2 Retrosynthetic Analysis

3 Initial Forays

4 A Novel Diels-Alder Reaction and Process Development

5 Fragment Coupling and Ring-Closing Metathesis Studies

6 The Structures of the Abyssomicins: Implications for Their Synthesis, Biosynthesis, and Biological Activity

7 Conclusion

Key words

antibiotics - atropisomerism - Diels-Alder reactions - metathesis - total synthesis

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  This catalyst was recommended to us by Professor K. B. Sharpless.

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20

In ref. 9b, we disclosed that isomerization between 1 and 1a occurs at 180 ˚C in 1,2-dichlorobenzene. However, it is not clear whether this is occurring thermally or mediated by trace amounts of HCl released by the solvent at elevated temperature.

21

The identity of iso-abyssomicin C was later confirmed; personal communication with Professor E. J. Sorensen.