Erythronolide aldol reaction

The next step to erythronolide A is the coupling of fragments A and B. Asymmetric aldol reaction of aldehyde 2 with a lithium enolate generated from... 

The C27-C35 segment 238 was prepared from 32 (O Scheme 30), which is the synthetic intermediate of erythronolide A. Oxidative cleavage of 32 gave aldehyde 251, which was subjected to aldol reaction with TBDMS-enol ether and TiCl4 to provide 252. Hydrolysis of thioester and deacetalization with TFA were accompanied by furanose-to-p)ranose interconversion and... 

The conversion of 235 to erythronolide A is still under investigation but will most probably involve the protection of the C-9 carbonyl, oxidation of the olefin to the aldehyde, and thiopropionate aldol reaction (a la Woodward). 

Ketone (27) and reagents related to it have been used in synthesis. In equation (SO) is shown an application of the magnesium enolate in Still s synthesis of monensin the facial selectivity in this case is S 1 and the reaction proceeds in 85% yield.67 The lithium enolate of (27) has been employed in a synthesis of the C-l.C-7 segment of erythronolide A (equation 51) the facial selectivity in this case is 6 1.68 Ketone (31) was used in a synthesis of the basic nucleus of crassin acetate (equation 52).69 The aldol reaction of (31) with (32), derived from geraniol, occurs in 58% yield to give only one isomer. Four further... 

Reagent (27) has been used in a synthesis of the C-l,C-7 segment of erythronolide A, as shown in equation (108).144 Addition of the lithium enolate of (27) to chiral aldehyde (165) provides aldols (166) and (167) in a ratio of approximately 6 1. [The initial report that this aldol reaction gives a stereoisomer ratio of approximately 15 1 was subsequently found to be in error (ref. 144b).]... 

Paterson s synthesis is based on a short and eflScient asymmetric route to the simplified erythronolide derivative 120 (R=TBS) by using an Evans aldol reaction for the preparation of the C2-C4 and Cg-Cjo fragments. 

In anticipation of the final carbon-carbon bond construction that is required to prepare the intact seco acid of erythronolide B using a directed aldol reaction to form the C(10)-C(l 1) bond, it was first necessary to prepare the requisite chiral aldehyde 80. Although the synthesis of 80 had been previously reported, we elected to devise an alternative route to access this material that commenced with the addition of the chiral boron enolate 37 0 to propionaldehyde to furnish 81 (Scheme 12). The sequential protection of the secondary hydroxyl group and removal of the chiral auxiliary gave 82, which was then converted to 80 by over-reduction followed by reoxidation under Swem conditions. 

Upon examination of the reactions outlined in Schemes 9, 11, and 12, it is evident that the present route to the seco acid of erythronolide B is remarkably concise, involving a longest linear sequence of a mere 14 chemical operations from the commercially available 2-ethylfuran (64). Even counting the steps required for the preparation of the aldehyde 80, the total number of operations is only 19. We anticipate that the analogous aldol reaction of the enolate derived from 79 with the... 

The other aspect of the aldol condensation to be considered in using this reaction for the construction of compounds such as erythronolide-A is diastereoface selection. That is, in many cases one will want to carry out aldol condensations on aldehydes already having one or more chiral centers. The carbonyl faces in these molecules are diastereotopic, rather than enantiotopic, and there... 

Carreira has demonstrated that the hydroxy-directed nitrile oxide cycloaddition reaction is a general synthetic approach to polyketide fragments, with the intermediate isoxazolines functioning as latent, masked aldol adducts [65], The 1,3-dipolar cycloadditions have been shown to tolerate a large variety of alcohol substrates, including aliphatic allylic, homoallylic, and cyclic allylic alcohols [65-67], A demonstration of the versatility of the approach was reported in the synthesis of erythronolide A (58, Scheme 18.12) [67], This synthetic effort took advantage of two sequential hydroxy-directed nitrile oxide cycloadditions to provide fragments 55 and 57, both of which were obtained with excellent yields and diastereoselectivity (dr2 98 2). 

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