Asymmetric synthesis of γ-chloro-α,β-diamino- and β,γ-aziridino-α-aminoacylpyrrolidines and -piperidines via stereoselective Mannich-type additions of N-(diphenylmethylene)glycinamides across α-chloro-N-sulfinylimines

Abstract

SummaryThe asymmetric synthesis of new chiral γ-chloro-α,β-diaminocarboxylamide derivatives by highly diastereoselective Mannich-type reactions of N-(diphenylmethylene)glycinamides across chiral α-chloro-N-p-toluenesulfinylaldimines was developed. The resulting (S S,2S,3S)-γ-chloro-α,β-diaminocarboxylamides were formed with the opposite enantiotopic face selectivity as compared to the (S S,2R,3R)-γ-chloro-α,β-diaminocarboxyl esters obtained via Mannich-type addition of analogous N-(diphenylmethylene)glycine esters across a chiral α-chloro-N-p-toluenesulfinylaldimine. Selective deprotection under different acidic reaction conditions and ring closure of the γ-chloro-α,β-diaminocarboxylamides was optimized, which resulted in Nα-deprotected syn-γ-chloro-α,β-diaminocarboxylamides, N-sulfinyl-β,γ-aziridino-α-aminocarboxylamide derivatives, a trans-imidazolidine, and an Nα,Nβ-deprotected syn-γ-chloro-α,β-diaminocarboxylamide.

Diastereoselective Mannich Reactions Using Fluorinated Ketones: Synthesis of Stereogenic Carbon–Fluorine Units

“…The configurations of 3ad and 3na were confirmed using X-ray crystallography, and by analogy, the same configuration was assigned to all major diastereoisomers 3 . The observed stereochemical outcome of the reaction can be explained by a chairlike transition state (Figure a), which has been suggested by Davis, Ellman, and other researchers to be involved in condensation reactions of metal enolates and imines. , The Z -fluoro­enolates of the α-fluoro ketones are believed to participate in the process; they attack the Si face of ( R )- N - tert -butyl­sulfinyl­imines, providing access to the major syn diastereoisomers. The absolute configuration of 3aa′ was established by X-ray crystallographic analysis, and by analogy, the same configuration was assigned to 3ba′ and 3ca′ .…”

Asymmetric synthesis of chloroisothreonine derivatives via syn-stereoselective Mannich-type additions across N-sulfinyl-α-chloroimines

“…According to the good results obtained in the diastereoselective synthesis of non-functionalized α-hydroxy-β-amino acid derivatives, 20c the addition of O-protected alkyl α-hydroxyacetates 3 across N-sulfinyl-α-chloroimines 4 was investigated (Scheme 1, Table 1) in view of providing access to γ-functionalized-α-hydroxy-β-amino acid building blocks, suitable for the synthesis of chloroisothreonine derivatives and functionalized heterocyclic compounds. Therefore, the O-protected alkyl α-hydroxyacetates 3, 20c α-chloro N-tert-butanesulfinylaldimines 4a-c, 19f,g and α-chloro N-p-toluenesulfinylaldimines 4d-e 14,17 were synthesized via (modified) literature procedures.…”

“…15 Also γ-chloro-α,β-diaminoand β,γ-aziridino-α-aminoacylpyrrolidines and -piperidines, as potential dipeptidyl peptidase (DPP) inhibitors, 16 were synthesized via stereoselective Mannichtype additions of N-(diphenylmethylene)glycinamides across α-chloro-N-sulfinylimines. 17 Chiral N-sulfinylimines have already proven to be valuable synthons for the preparation of a wide range of enantiopure aliphatic and cyclic amines. 18 In this study, α-chloro N-sulfinylaldimines were used as starting products as these imines are known for their good reactivity and stereoselectivity by incorporation of chiral directing groups.…”

Recent Developments in Asymmetric Aziridination

“…[25] As shown in Scheme 13, the process involved the Mannich-type reaction between chiral a-chloro-N-paratoluenesulfinyl aldimines and N-(diphenylmethylene)glycinamides in the presence of LiHMDS as a base. [25] As shown in Scheme 13, the process involved the Mannich-type reaction between chiral a-chloro-N-paratoluenesulfinyl aldimines and N-(diphenylmethylene)glycinamides in the presence of LiHMDS as a base.…”

“…Furthermore, a related methodology was applied by the same authors to the asymmetric synthesis of N‐ sulfinyl‐β,γ‐aziridino‐α‐aminocarboxylic amides 25. As shown in Scheme , the process involved the Mannich‐type reaction between chiral α‐chloro‐ N ‐ para ‐toluenesulfinyl aldimines and N ‐(diphenylmethylene)glycinamides in the presence of LiHMDS as a base.…”