δ-Amino β-Keto Esters, a Designed Polyfunctionalized Chiral Building Block for Alkaloid Synthesis. Asymmetric Synthesis of (R)-(+)-2-Phenylpiperidine and (−)-SS20846A

Abstract

[formula: see text] delta-Amino beta-keto esters 3 and 11 are designed polyfunctionalized chiral building blocks for alkaloid synthesis and are prepared in one step from the corresponding sulfinimine (N-sulfinyl imine). Concise highly enantioselective four-step syntheses of 2-phenylpiperidine (7) and SS20846A (14) from 3 and 11, respectively, are described.

Diastereoselective synthesis of 6-functionalized 4-aryl-1,3-oxazinan-2-ones and their application in the synthesis of 3-aryl-1,3-aminoalcohols and 6-arylpiperidine-2,4-diones

“…Treatment of 4-aryl-6-(iodomethyl)-1,3-oxazinan-2-ones 10c,d with an aqueous solution of sodium hydroxide under reflux in ethanol afforded the 6-arylpiperidine-2,4-diones 15 in 82-86% yield after recrystallisation (Scheme 5). 6-Arylpiperidine-2,4-diones have been prepared as analogues of VMAT2 antagonists, 26 and represent key intermediates for further synthetic transformations to 6-aryl-4-hydroxypiperidin-2-ones, 27 4-hydroxypipecolic acids, 28 (R)-(+)-2-phenylpiperidine, 29 and biomimetic NADH models. 30 27 Relatively few methods for the synthesis of 6-arylpiperidine-2,4-diones have been reported in the literature.…”

“…Alternatively, β-aryl-β-amino acid derivatives can be reacted with metal enolates of alkyl acetates or with Meldrum's acid in the presence of pyridine to afford the corresponding δ-amino-β-keto esters which are subsequently cyclized under basic conditions to give 6-arylpiperidine-2,4-diones. 29,31 Analogously, a number of 6-arylpiperidine-2,4-diones were obtained by reaction of chiral Nsulfinyl imines with lithium or TMS dienolates of 2,2,6-trimethyl-1,3-dioxin-4-one. 32 An early efficient preparation of 1-tert-butyl-6-phenylpiperidine-2,4-dione involved the addition of N-benzylidene-tert-butylamine to diketene.…”

Asymmetric synthesis of alkaloids using polyfunctionalized chiral building blocks

“…Polyfunctionalized chiral building blocks, which we define as molecules having at least one stereogenic center and more than one chemically differentiated functional group, have played significant roles in asymmetric synthesis and the synthesis of biologically and pharmacologically active molecules [1]. Examples include carbohydrates, amino acids, hydroxy acids, and terpenes.…”

“…phosphonate synthesis and ␦-amino ␤-ketoesters [1] and isoquinolones [7] for alkaloid synthesis. Recent applications of the latter two building blocks are presented here.…”

Regioselective synthesis of substituted piperidine-2,4-diones and their derivatives via Dieckmann cyclisations

“…The mixture was then heated under reflux for 3 h, allowed to cool to 20 C, evaporated, and the residue was purified by flash chromatography (9:1 ethyl acetate:hexane) to give (R)-6f (0.36 g, 56%) as a white solid, mp 163e166 C (lit. 37 166e168 C); ½a 25 D þ119. …”