The Lichtenhaler retrosynthetic analysis of - -ACRL toxin

Julia-Lythgoe-Kocienski (E)-selective olefi nation 

Detailed mechanistic analysis can on occasion stifle the possibility of the unexpected, since frequently processes which appear mechanistically unsound or without precedent are discounted. 

In the coming section, we will detail how Lichtenhaler put such retro-synthetic thinking into practice in his synthesis of the (—)-ACRL toxin I. 

This paved the way for an Sn2 displacement with potassium thiophen-oxide, and sulfide oxidation to obtain phenylsulfone 5. Metallation of 5 was accomplished at —78°C with M-butyllithium in tetrahydrofuran (THF). The resulting a-phenylsulfonyl anion added readily to aldehyde 8 to afford a mixture of P-alkoxysulfones that underwent smooth O-acylation with acetic anhydride. The mixture of p-acetoxysulfones so formed was then reacted with 6% Na/Hg amalgam in methanol and ethyl 

After mercury(II)-assisted hydrolysis of the thioenol ether, aldehyde 3 was obtained. This was then subjected to the critical vinylogous aldol reaction needed to complete the carbon backbone of the natural product. The latter process furnished a 3.5 1 mixture of the y to ot addition products. The stereoselectivity observed in the installation of the C(5)-hydroxyl (natural product numbering) was only 2 1. Fortunately, the predominant isomer was the desired product 2. In retrospect, it can be seen that the level of selectivity attained conformed to the predictions of the Still model.4 

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Scheme 14.1 The Lichtenhaler retrosynthetic analysis of (—)-ACRL toxin I.

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