Highly Selective Acetate Aldol Additions Using Mesityl-Substituted Chiral Auxiliaries

Abstract

[reaction: see text] Highly diastereoselective acetate aldol additions using chlorotitanium enolates of mesityl-substituted N-acetyloxazolidinethione and N-acetylthiazolidinethione auxiliaries are reported. These additions proceed in high yields and diastereoselectivities (93:7 to 98:2) for aliphatic, aromatic, and ,-unsaturated aldehydes. Double diastereoselective acetate aldol additions are also reported and are found to proceed in high yields and diastereoselectivities (90:10 to 97:3).

Application of Oxazolidinethiones and Thiazolidinethiones in Aldol Additions

“…A subsequent report from the Evans lab demonstrated that ''Evans'' syn-aldol adducts (10) (Scheme 7.7) are also obtained through the chlorotitanium enolates using titanium tetrachloride as the Lewis acid and diisopropylethylamine or TMEDA as the base [4]. Concurrently, Thornton reported the selective formation of the ''non-Evans'' syn-diastereomer (12) Evans model, was proposed to explain the dominant formation of the ''non-Evans'' syn-isomer [18]. The chlorotitanium enolates offer some potential benefits.…”

“…Thiazolidinethiones can also be prepared by exposure of the amino alcohol to sulfuric acid followed by treatment with potassium O-ethyl xanthate and aqueous base [11] or by exposure of the β-chloro amine salt to carbon disulfide and aqueous base (Scheme 7.4) [12].…”

“…A super-quat type auxiliary was developed by Phillips (36, Scheme 7.18) [25], while Sammakia has exploited the t-leucine derived thiazolidinethione as well as an oxygenated t-leucine analog (38a,b; Scheme 7.18) [26]. Crimmins reported a mesityl-substituted oxazolidinethione and thiazolidinethione for acetate aldol additions (40, Scheme 7.18) [12], and Olivo ( these more highly hindered auxiliaries provides fairly consistent and high levels of diastereoselectivity.…”

Stereoselective Acetate Aldol Reactions

“…This is the case of thiazolidinethione (196) Evans oxazolidinone auxiliary fails to give high selectivities in acetate aldol reactions, Sammakia speculated that the boron-mediated reaction from 196 ((3) in Scheme 1.67) proceeded through an open transition state, but a more common cyclic chairlike transition state was not ruled out (XLII and XLIII, respectively, in Scheme 1.69) [159a]. On the other hand, the opposite stereochemistry obtained in the titanium-mediated reactions led Phillips [157a] and Crimmins [158] to propose a chelated chairlike or a non-chelated boatlike transition states (XLIV and XLV, respectively, in Scheme 1.69) to account for the observed stereocontrol.…”

“…[158] reported that N-acetyl oxazolidinethiones (192) and (193) underwent highly diastereoselective additions to aliphatic, α, β-unsaturated, and aromatic aldehydes, affording aldols (194) and (195) in high yields and diastereoselectivities ((1) and (2) in Scheme 1.67), whereas Sammakia [159], Crimmins [158,160], and Olivo [161] described that boron and titanium enolates from N-acetyl thiazolidinethiones (196)(197)(198) provided high levels of stereocontrol with a wide range of aldehydes, affording aldols (199)(200)(201) in high yields ( (3)(4)(5) in Scheme 1.67) [162]. This chemistry has been widely applied to the synthesis of natural products [163], as can be illustrated by two concurrent reports on the total synthesis of cyanolide A (202).…”