Asymmetric Synthesis of Chiral N-Sulfinyl 3-Alkyl- and 3-Arylpiperidines by α-Alkylation of N-Sulfinyl Imidates with 1-Chloro-3-iodopropane

Abstract

α-Alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane successfully led to 2-substituted N-tert-butanesulfinyl-5-chloropentanimidates in acceptable diastereomeric ratios (dr 67/33 to 72/28) and good yields (74-86%). Subsequent reduction with NaBH(4) led to the corresponding 2-substituted N-tert-butanesulfinyl-5-chloropentylamines, which could be cyclized to a range of new chiral 3-substituted N-tert-butanesulfinylpiperidines using NaH in DMSO. Finally, the N-tert-butanesulfinylpiperidines could be efficiently deprotected to enantiomerically pure 3-alkyl- and 3-arylpiperidine hydrochlorides.

Mannich-Type Reaction of α-Sulfanyl N-tert-Butanesulfinylimidates: Diastereoselective Access to α-Mercapto-β-amino Acid Derivatives

“…To improve yield and diastereoselectivity, we focused on the replacement of the oxygen of the carbonyl group of mercaptoacetate with chiral tert -butanesulfinylamides . As chiral equivalents of esters or amides, N - t BS imidates/amidines have been used in diastereoselective α-functionalizations such as alkylation, hydroxylation, fluorination, sulfenylation, and nucleophilic addition to compounds bearing polarized π-bonds, such as aldehydes, imines, nitrosoarenes, N -aryl- N -diphenylphosphinyldiazenes, and 1,4-addition acceptors suggesting the possibility of diastereoselective synthesis of α-mercapto-β-amino acid derivatives via a Mannich-type reaction using α-sulfanyl N - t BS imidates and N -tosyl imines.…”

Iridium-catalyzed asymmetric hydrogenation of racemic α-substituted lactones to chiral diols

“…10 By using the catalyst ( S )- 1d , we synthesized (–)-preclamol, 11 which is a candidate drug for the treatment of neurological disorders such as Parkinson's disease. 12 The hydrogenation of rac - 2g (1.65 g) catalyzed by ( S )- 1d afforded the diol ( S )- 3g (89% yield and 93% ee), which was subsequently transformed to (–)-preclamol by activation with methanesulfonyl chloride, substitution/cyclization with n -propylamine, and demethylation with hydrobromic acid (84% yield over three steps, Scheme 3).…”

Heterocyclic Chemistry – A Mature Area in Its Infancy!

“…The construction of the piperidine moiety can be taken as an arbitrary example to give a snapshot how greatly bond forming methodology has advanced beyond the classical approach of donor–acceptor interactions, e.g. realized in substitution reactions with halides or additions to carbonyl compounds by nitrogen nucleophiles. Such an electronic prerequisite can be overcome in concerted reactions, and thus various strategies via [4+2]‐cycloadditions have been successfully applied towards the piperidine core .…”