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. 2009 Jan 1;2009(1):33-42.
doi: 10.1055/s-0028-1083259.

Discoveries from the Abyss: The Abyssomicins and Their Total Synthesis

K C Nicolaou  1 , Scott T Harrison, Jason S Chen
Affiliations

Discoveries from the Abyss: The Abyssomicins and Their Total Synthesis

K C Nicolaou et al. Synthesis (Stuttg). .

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.

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Figures

Figure 1
Figure 1
Molecular structures of abyssomicins B (2), C (1), and D (3) and the postulated biosynthetic origins of abyssomicins B and D.
Figure 2
Figure 2
Retrosynthetic analysis of abyssomicin C (1).
Figure 3
Figure 3
Revised retrosynthetic analysis of the abyssomicin core structure 11.
Figure 4
Figure 4
Proposed mechanism of acid-mediated interconversion of abyssomicin C (1) and atrop-abyssomicin C (1a).
Figure 5
Figure 5
Overlay of the X-ray crystal structures of abyssomicin C (1, blue) and atrop-abyssomicin C (1a, yellow). [Reprinted with permission from the Journal of the American Chemical Society 2007, 129, 429-440. Copyright (2007) American Chemical Society.]
Figure 6
Figure 6
Kinetics of the reduction of abyssomicin C (1) and atrop-abyssomicin C (1a) by NADH analog 57. [Reprinted with permission from the Journal of the American Chemical Society 2007, 129, 429-440. Copyright (2007) American Chemical Society.]
Scheme 1
Scheme 1
Highlights of the Sorensen total synthesis of abyssomicin C (1).
Scheme 2
Scheme 2
Initial synthesis of key building blocks (±)-9 and (±)-23.
Scheme 3
Scheme 3
Attempted fragment couplings with epoxide 9.
Scheme 4
Scheme 4
Dieckmann condensation/epoxide opening cascade entry to the abyssomicin C core.
Scheme 5
Scheme 5
Ward’s enantioselective Diels-Alder synthesis of lactone 16.
Scheme 6
Scheme 6
Initial Diels-Alder-based construction of lactone 34.
Scheme 7
Scheme 7
Enantioselective synthesis of abyssomicin core structure 11.
Scheme 8
Scheme 8
Synthesis of aldehyde fragment 42.
Scheme 9
Scheme 9
Initial ring closing metathesis route to abyssomicin C (1).
Scheme 10
Scheme 10
Improved synthesis of the abyssomicin C skeleton by ring closing metathesis.
Scheme 11
Scheme 11
Biomimetic synthesis of abyssomicin D (3).
See this image and copyright information in PMC

References

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