Stereoselective Total Synthesis of Zaragozic Acid A based on an Acetal [1,2] Wittig Rearrangement

Abstract

A simultaneous creation of the C4 and C5 quaternary carbon centers by an acetal [1,2] Wittig rearrangement of O‐glycoside 1 derived from L‐arabino‐γ‐lactone is the key feature in the construction of the 2,8‐dioxabicyclo[3.2.1]octane core structure of zaragozic acid A (2).

Stereoselective Total Synthesis of Zaragozic Acid A based on an Acetal [1,2] Wittig Rearrangement

“…Previous work suggested that the carbanion rearrangement of an O-glycoside such as 5 a should produce the [1,2] rearrangement product with high diastereoselectivity and in good yield. [7,9] In contrast to this expect- [10] in 54 % yield. (Scheme 3).…”

“…Disconnection of the C6 side chain A, unraveling of the C1 acetal, and cleavage of the C1ÀC1' bond led to lactone B and an alkyl anion equivalent zaragozic acid A / squalestatin S1 (1) core C. [6] Our interest in the carbanion rearrangement of the sugar derivatives led us to consider a strategy for lactone B starting from the C-glycoside D, namely an acetal [1,2] Wittig rearrangement product of the O-glycoside E. The preceding paper describes the synthesis of this class of highly functionalized C-glycosides based on a rearrangement protocol. [7] Furthermore, we planned to construct a C5' À C6' bond in segment C using the original ether [1,2] Wittig rearrangement. [8] Our synthesis begins from the O-glycoside 5 a ( E), which can be prepared from the hemiketal 3 derived from larabino-g-lactone [9] and the protected ethynylvinylmethanol 4 (racemate; Scheme 2).…”

Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals

“…19 As a preparative alternative to di-tert-butyl acetal 7e, solutions of carboxylic acids 1, such as benzoic acid in dichloromethane, have been reacted with a cyclohexane solution of tert-butyl trichloroacetimidate [Me 3 COC(=NH)CCl 3 ], which is obtained on the addition of potassium tert-butoxide in tert-butyl alcohol-diethyl ether to trichloroacetonitrile. [69][70][71] In this manner, after 14 hours and only in the presence of boron trifluoride-diethyl ether complex, tert-butyl benzoate was formed in 92% yield. 69 Likewise, carboxylic acids 1, as well as phenols 16, can be reacted with O-tert-butyl-N,N¢-diisopropylisourea [Me 3 COC(=Ni-Pr)NHi-Pr] to provide the corresponding tert-butyl esters or ethers, respectively, in high yields.…”

Total Synthesis of the Squalene Synthase Inhibitor Zaragozic Acid C

“…Since then the Evans 30) and Armstrong 31,32) groups have accomplished the total syntheses of zaragozic acid C, while the efforts of the groups of Heathcock, 33,34) and Tomooka and Nakai 35) culminated in successful total syntheses of zaragozic acid A. These approaches are summarized in Chart 1.…”