Zaragozic acid

BU2AIH, CH2CI2, -78°, 95% yield. /-BU2AIH, CH2CI2, toluene, 84% yield. Three pivaloates were cleaved from a zaragozic acid intermediate. The use of THE or ether as solvent failed to remove all three. 

Three other modifications of the standard conditions provide synthetically useful strategies for the preparation of dihydrofurans. One method, called the interrupted Feist-Benary reaction, utilizes milder reaction conditions to stop the final dehydration step. For example, Calter combined bromide 47 with dicarbonyl 48 to produce dihydrofuran 49 as a mixture of diastereomers. He examined the scope and diastereoselectivity of this process and applied this reaction toward the synthesis of the polycyclic core of the zaragozic acids. A method principally designed to yield practical syntheses of cyclic ketodiesters also furnished a dihydrofuran via a variation of the interrupted Feist-Benary reaction. ... 

Scheme 1. Sites of inhibition of cholesterol biosynthesis by Mevacor and zaragozic acid A.

Medicinal chemistry has frequently drawn inspiration and important new leads from the examination of natural products, and this was proven to be the case once more. In 1992, researchers at Merck and Glaxo announced, almost simultaneously, the independent discovery of the same new class of natural products from two different fungi. As a consequence, the same family of natural products has two names - the zaragozic acids (Merck)4 or the squalestatins (Glaxo).5 A typical member of the family, zaragozic acid A (squa-lestatin SI) (1) was shown to have a tremendous affinity for squalene synthase (K, = 79 pM for rat microsomal squalene synthase) and could even lower serum cholesterol levels in vivo in a population of marmosets.6... 

In the following sections and before we describe the synthesis of zaragozic acid A, we give a brief historical introduction to the dihydroxylation reaction, then describe the development of the Sharpless AD and some of its recent applications. 

Scheme 17. Retrosynthetic analysis of zaragozic acid A/squalestatin S1 (1).

The retrosynthetic analysis described above outlines a triply convergent strategy towards the synthesis of zaragozic acid A (1). The most pleasing aspect of the retrosynthetic strategy is the rapid and enantioselective manner in which the two-dimensional molecule... 

Scheme 18. Synthesis of zaragozic acid A (1) from key intermediate 73.

In total synthesis, model studies are frequently performed on simpler systems prior to the final assault on the target molecule. In the synthesis of zaragozic acid A (1), 2-methyl-1,3-dithiane (92) was employed as a simple model for the more elaborate dithiane 67. Deprotonation of 92 with n-butyllithium under standard conditions47 and addition of the aldehyde provides a mixture of two diastereoisomers, 93 and 94 (Scheme 22), in approximately equal amounts. One of the diastereoisomers (93) lacks the TMS group,... 

Zaragozic Acid A/Squalestatin S1 35.3.4 Synthesis of the Side Chains... 

Coupling of Key Intermediates and Completion of the Total Synthesis of Zaragozic Acid A/Squalestatin SI... 

Scheme 8.5 Synthesis of the bicydic acetal core of zaragozic acid C.

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