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. 2009 Oct 21;131(41):15061-74.
doi: 10.1021/ja906056v.

Total synthesis and stereochemical assignment of (-)-ushikulide A

Barry M Trost  1 , Brendan M O'Boyle, Daniel Hund
Affiliations

Total synthesis and stereochemical assignment of (-)-ushikulide A

Barry M Trost et al. J Am Chem Soc. .

Abstract

We report the determination of the full stereostructure of (-)-ushikulide A (1), a spiroketal containing macrolide by total synthesis. Ushikulide A (1) was isolated from a culture broth of Streptomyces sp. IUK-102 and exhibits potent immunosuppressant activity (IC(50) = 70 nM). To embark upon an ushikulide A synthesis, a tentative assignment was made based on analogy to cytovaricin (2), a related macrolide isolated from a culture of Streptomyces diastatochromogenes whose full structure was previously established via synthesis and X-ray crystallography. This report delineates studies on several key steps, namely a direct aldol reaction catalyzed by the dinuclear zinc ProPhenol complex, a metal catalyzed spiroketalization, as well as application of an unprecedented asymmetric alkynylation of a simple saturated aldehyde with methyl propiolate to prepare the nucleophilic partner for a Marshall-Tamaru propargylation. These studies culminated in the first total synthesis and stereochemical assignment of (-)-ushikulide A and significantly extended the scope of the above-mentioned methodologies.

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Figures

Figure 1
Figure 1
Tentative Stereochemical Assignment of (–)-Ushikulide A
Figure 2
Figure 2
Comparison of Cytovaricin and Ushikulide A
Figure 3
Figure 3
NOE and Coupling Constant Analysis of the Spiroketal
Scheme 1
Scheme 1
Retrosynthetic Analysis of Ushikulide A
Scheme 2
Scheme 2
Preparation of Several Aldehyde Partners through a Crimmins Aldol Reaction
Scheme 3
Scheme 3
Preparation of the Alkyne Fragment
Scheme 4
Scheme 4
Attempted Diastereoselective Alkyne Addition
Scheme 5
Scheme 5
Modification of the Spiroketalization Substrate
Scheme 6
Scheme 6
Optimization of the Spiroketalization Reaction
Scheme 7
Scheme 7
Mechanism of the Spiroketalization Reaction
Scheme 8
Scheme 8
Completion of the Spiroketal Fragment
Scheme 9
Scheme 9
First Approach Toward the Aliphatic Fragment
Scheme 10
Scheme 10
Second Generation and Completion of the Aliphatic Fragment
Scheme 11
Scheme 11
An Alternative Aldol Disconnection in the Synthesis of the Aliphatic Fragment
Scheme 12
Scheme 12
Completion of the Synthesis
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