Researchers have explored the use of lithio tris(methylthio)methane as a versatile reagent for the diastereoselective addition to sulfinimines. This approach enables the synthesis of various amino acid derivatives, including thioesters, esters, anilides, and amides, with high stereoselectivity. The method provides a valuable tool for the asymmetric synthesis of chiral compounds and offers opportunities for peptide synthesis.
Summary
- 🔬 Nonracemic sulfinimines are widely used for the synthesis of chiral amine-containing compounds, including amino acids.
- 🔬 Previous methods used Et2AlCN or 1,3-dithiane as a formyl anion equivalent, limiting the scope of transformations.
- 🔬 Lithio tris(methylthio)methane (LiC(SMe)3) is a readily accessible reagent that serves as a hydroxy, thio, and aminocarbonyl equivalent.
- 🔬 Addition of LiC(SMe)3 to sulfinimines derived from aryl and alkyl aldehydes results in diastereoselective products with high stereoselectivity.
- 🔬 The addition reaction occurs from the face opposite the sulfinimine, directed by the bulky sulfinyl group.
- 🔬 The sulfinamido trithioformates obtained can be transformed into various amino acid derivatives, such as thioesters, esters, anilides, and amides.
- 🔬 The method allows for the synthesis of dipeptides and tripeptides by reacting the trithioformate with amino acid esters.
The synthesis of α-amino acids in enantiopure form is of great interest in various fields, including structural biology and medicinal chemistry. This study explores the use of lithio tris(methylthio)methane (LiC(SMe)3) as a versatile reagent for the diastereoselective addition to sulfinimines, providing a useful method for the synthesis of amino acid derivatives.
The researchers first investigated the addition of LiC(SMe)3 to sulfinimines derived from aryl aldehydes. The reaction resulted in high diastereoselectivity, producing the corresponding sulfinamido thioformates. The method was found to be general, with various substitutions on the aryl ring allowing for the synthesis of different sulfinamido thioformates.
The addition of LiC(SMe)3 was then extended to sulfinimines derived from alkyl aldehydes. The reaction yielded separable mixtures of diastereomers, providing access to a wide range of sulfinamido thioformates. The proximity of heteroatom oxygen in the sulfinimine was found to influence the outcome of the addition reaction.
The researchers also demonstrated the transformation of sulfinamido trithioformates to various amino acid derivatives. Treatment of the trithioformates with AgNO3 resulted in the formation of sulfinamido thioesters, methyl/ethyl esters, anilides, and amides. The transformation maintained the stereochemistry of the chiral centers and allowed for the synthesis of substituted vinyl glycine esters and dipeptides.
Overall, this study highlights the utility of LiC(SMe)3 as a versatile reagent for the diastereoselective addition to sulfinimines, enabling the synthesis of diverse amino acid derivatives with high stereoselectivity. The method offers opportunities for the asymmetric synthesis of chiral compounds and peptide synthesis with potential applications in structural biology and medicinal chemistry.
- Gangarajulu Kesavulu, Biguvu Balachandra, and Kavirayani R. Prasad*
- Publication Date: July 5, 2023
- https://doi.org/10.1021/acs.orglett.3c01969
