Stereoselective approaches to 2,3,6-trisubstituted piperidines. An enantiospecific synthesis of quinolizidine (−)-217A

Abstract

The enantiospecific and diastereocontrolled total synthesis of alkaloid (-)-217A is described that employs a stepwise [3+3] annelation strategy and a piperidine 2,3-cyclopropanation-ring opening reaction as the key steps.

Ring Expansions of Activated Aziridines and Azetidines

“…Subsequent acid-catalyzed deprotection-cyclization furnished the desired tetrahydropyridine derivatives 382-385 in high yield (Scheme 97). This strategy was later exploited for the syntheses of (À)-monomorine [168] and quinolizidine (À)-217A [169]. Smith III and co-worker accomplished the total synthesis of (À)-indolizidine 223AB 391 utilizing a three-component linchpin coupling employing Ntosylaziridines 388, epoxides 387, and silyl dithianes 386 [170].…”

A Stereoselective Formal Synthesis of Quinolizidine (–)‐217A

“…Wittig olefination of aldehyde 9 with methyl(triphenylphosphoranylidene)acetate afforded ( E )‐ 10 in 96 % yield as a sole isomer and subsequent reduction of the resulting ester ( E )/( Z )‐ 10 furnished allyl alcohol ( E )/( Z )‐ 6 (93 %). The Ts‐protected chiral aziridine 7 was readily prepared from d ‐aspartic acid in a five‐step sequence according to the literature procedure with a slight modification of the Mitsunobu protocol (Ph 3 P vs. Bu 3 P, see Supporting Information [SI]).…”

“…The most recent contributors to the (–)‐217A are Harrity and co‐workers. The key feature of Harrity's synthesis is a stepwise [3+3] annulation to form the piperidine ring imbedded in the core structure of the natural product …”

Utilizing Palladium‐Stabilized Zwitterions for the Construction of N‐Heterocycles

“…Previous reports emerging from our laboratory have disclosed the Pd‐catalyzed [3+3] cycloaddition of TMM precursor 1 a with enantioenriched aziridines for the enantiospecific synthesis of piperidines . Specifically, the addition of Pd‐TMM to 2‐substituted N ‐Ts aziridines was effected by a combination of 10 mol % Pd(OAc) 2 , 60 mol % P(O i Pr) 3 and 20 mol % BuLi as reductant (Scheme ) .…”