Propionate aldols, Evans aldol reaction

As the role of the common precursor 34 is critical, it has been synthesized in large scale by using an Evans syn aldol protocol [39], starting from the commercially available (i )-(-)-methyl 3-hydroxy-2-methyl propionate 1 . This compound was transformed in three steps to aldehyde 32 [40, 41] and used in an Evans aldol reaction with the dibutylboron enolate A. The Weinreb amide formation completed the construction of the common precursor 34 [42] (Scheme 7). From this precursor fragments C1-C8, C9-C14 and C15-C21 were synthesized (Scheme 8). 

As an extension of the Evans aldol reaction, the so-called Evans-Mettemich variation [17] adds two polyketide units to the growing polyketide chain (Scheme 2.114). It should be pointed out that here not the chiral auxiliary controls the stereoselectivity but the a-chiral center, which in turn was previously generated by addition to the Evans propionate. Using different metals and reaction conditions, three out of four possible stereoisomers can be generated and subsequent reduction of the keto carbonyl group can construct an additional chiral alcohol (vide infra). 

Impressive advances in catalytic, enantioselective propionate aldol addition reactions have also been documented since 1992. Mikami has described a Ti(lV) catalyst readily prepared from BINOL and TiC O Pr. A propionate aldol addition process by Evans utilizes complexes prepared with bisoxazoline ligands and Sn(II) and Cu(II). In analogy to the acetate aldol... 

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of apoptolidinone. This synthesis features three thiazolidinethione propionate aldol reactions for controlling the configuration of 6 of 12 stereogenio centers <05JA13810>. For example, addition of aldehyde 146 to the enolate solution of A -propionyl thiazolidinethione 145 produces aldol product 147 with excellent selectivity (>98 2) for the Evans syn isomer. Compound 145 also undergoes diastereoselective aldol addition with bisaryl aldehyde 148 to give the Evans syn product 149, which is converted to eupomatilone-6 in 6 steps <05JOC9658>. 

In addition to the advances in auxiliary-controlled acetate aldol addition reactions, a number of innovative solutions for the preparation of propionate-derived 1,2-anti products have also appeared using auxiliaries other than Evans oxazolidinone. The various successful approaches to anti aldol adducts stem from the design of novel auxiliaries coupled with the study of metal and base effects on the reaction stereochemistry. Masamune documented that the addition of optically active ester enolate 112 to aldehydes afforded anti aldol adduct 113 in superb yield and diastereoselectivity (Equation 10) [70]. After careful selection of the reaction conditions for the enolization of the ester [71], the aldol addition was successfully carried out with a broad range of substrates including aliphatic, aromatic, unsaturated, and functionalized aldehydes. An attractive feature of this process is the subsequent facile removal of the auxiliary (LiOH, THF/H2O) to afford the corresponding acid without concomitant deterioration of the configurational integrity of the products [70]. 

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