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. 2017 Mar 29;139(12):4568-4573.
doi: 10.1021/jacs.7b01590. Epub 2017 Mar 15.

Evolution of an Efficient and Scalable Nine-Step (Longest Linear Sequence) Synthesis of Zincophorin Methyl Ester

Affiliations

Evolution of an Efficient and Scalable Nine-Step (Longest Linear Sequence) Synthesis of Zincophorin Methyl Ester

Liang-An Chen et al. J Am Chem Soc. .

Abstract

Because of both their synthetically challenging and stereochemically complex structures and their wide range of often clinically relevant biological activities, nonaromatic polyketide natural products have for decades attracted an enormous amount of attention from synthetic chemists and played an important role in the development of modern asymmetric synthesis. Often, such compounds are not available in quantity from natural sources, rendering analogue synthesis and drug development efforts extremely resource-intensive and time-consuming. In this arena, the quest for ever more step-economical and efficient methods and strategies, useful and important goals in their own right, takes on added importance, and the most useful syntheses will combine high levels of step-economy with efficiency and scalability. The nonaromatic polyketide natural product zincophorin methyl ester has attracted significant attention from synthetic chemists due primarily to the historically synthetically challenging C(8)-C(12) all-anti stereopentad. While great progress has been made in the development of new methodologies to more directly address this problem and as a result in the development of more highly step-economical syntheses, a synthesis that combines high levels of step economy with high levels of efficiency and scalability has remained elusive. To address this problem, we have devised a new synthesis of zincophorin methyl ester that proceeds in just nine steps in the longest linear sequence and proceeds in 10% overall yield. Additionally, the scalability and practicability of the route have been demonstrated by performing all of the steps on a meaningful scale. This synthesis thus represents by a significant margin the most step-economical, efficient, and practicable synthesis of this stereochemically complex natural product reported to date, and is well suited to facilitate the synthesis of analogues and medicinal chemistry development efforts in a time- and resource-efficient manner.

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Conflict of interest statement

Notes

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Summary of previous total syntheses of zincophorin (1) and zincophorin methyl ester (2).
Figure 2
Figure 2
(a) Leighton’s fragment coupling and end game strategy. (b) Krische’s fragment coupling and end game strategy.
Figure 3
Figure 3
(a) A new disconnection for a convergent and step-economical fragment coupling and end-game strategy. (b) Evans’ precedent for the proposed anti aldol fragment coupling strategy.
Figure 4
Figure 4
(a) Preparation of vinylboronate 13. (b) Synthesis of bromide 19. (c) Completion of the seven-step (LLS) synthesis of aldehyde 10.
Figure 5
Figure 5
An efficient and practicable six-step synthesis of ethyl ketone 11.
Figure 6
Figure 6
(a) The C(9) and C(11) OH protecting groups dramatically impacted on the success of the chiral enolate addition reaction in our first-generation synthesis. (b) In the present work, C(9)-protected substrate 29 was found to perform poorly in the enolate addition reaction, consistent with the results from our first-generation synthesis.
Figure 7
Figure 7
(a) The fragment coupling anti aldol addition reaction. (b) The aldol reaction with aldehyde 30 proceeds with the same 4:1 diastereoselectivity as observed by Evans. (c) The aldol reaction with aldehyde 32 proceeds with just 1.6:1 diastereoselectivity, implicating the remote alkene in aldehydes 10 and 32 as the source of the compromised selectivity.
Figure 8
Figure 8
(a) Stepwise ketone reduction and PMB ether deprotection was unsuccessful due to acetal formation. (b) One-pot sequential ketone reduction and PMB ether deprotection delivers zincophorin methyl ester in a single step from aldol product 9.

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