Anti-Selective Aldol Reactions with Titanium Enolates of N-Glycolyloxazolidinethiones

Abstract

[reaction: see text] A highly diastereoselective anti aldol addition utilizing a variety of N-glycolyloxazolidinethiones has been developed. Enolization of an N-glycolyloxazolidinethione with titanium (IV) chloride and (-)-sparteine followed by addition of an aldehyde activated with additional TiCl(4) resulted in highly anti-selective aldol additions, typically with no observable syn isomers. Allyl-protected glycolates demonstrated the highest levels of selection and yields, although O-benzyl and O-methyl glycolyloxazolidinethiones also performed well.

Application of Oxazolidinethiones and Thiazolidinethiones in Aldol Additions

“…Various oxazolidinethione and thiazolidinethione auxiliaries have been used for acetate-type aldol additions in an attempt to identify a suitable combination of auxiliary and metal enolate. The first examples were reported by Nagao and Fuijita using the tin (II) enolate of oxazolidinethione (28) and thiazolidinethione (30) [20]. The diastereoselectivity for these acetate aldol additions was quite good, but the need to use tin (II) triflate (a reagent that is somewhat difficult to handle) as the Lewis acid led others to look for alternative enolization methods (Scheme 7.16).…”

“…Anti-selective aldol additions of N-glycolyloxazolidinethiones (50) can be obtained (Scheme 7.21) when the aldol additions are conducted by the generation of the enolate with 3-4 equiv of titanium tetrachloride and 1 equiv of (−)-sparteine [30]. The anti-aldol adducts 51 are produced with consistently high selectivities and good yields, (typically <3% of the syn-adducts).…”

Fluorinated peptidomimetics: synthesis, conformational and biological features

“…up to 8:1 depending on the N-acyl group), the subsequent exocyclic cleavage of the oxazolidin-2-one auxiliary could not be performed, despite intensive efforts. We therefore turned our attention to oxazolidin-2-thiones [25], whose cleavage was reported to occur much more smoothly [26].…”

Chiral Glycolate Equivalents for the Asymmetric Synthesis of α-Hydroxycarbonyl Compounds

“…Deprotonation of the glycolate imide with LDA furnished a chiral enolate that underwent alkylation with alkyl halides to give 45 (Table 5). Three examples of the alkylated product 45 prepared by this method were reported with excellent de's (92-94%) and in reasonable yields (68-87% tive cleavage of the intermediates with lithium borohydride gave 2-benzyloxy alcohols (46)(47)(48) in yields ranging between 82-85%. Diols were also prepared using either a single hydrogenolysis step (palladium on carbon) as in the case of 46, or preceding hydrogenolysis by oxidative cleavage with ozone followed by borohydride reduction in the case of 47, or with prior acylation with propanoyl chloride in the case of 48.…”

“…The best results in terms of yield and selection were observed using the allyl-protected glycolates. 48 A selection of results and conditions of such aldol reactions are shown in Table 7. 49 Overall, these versatile methods for the formation of -hydroxy acids are clearly excellent and have been used extensively owing to their ready availability of starting materials.…”