A flexible approach toward trisubstituted piperidines and indolizidines: synthesis of 6-epi-indolizidine 223A

The Journal of Organic Chemistry
Joel M Harris, Albert Padwa

Abstract

2,5,6-Trisubstituted piperidines are readily prepared by a combination of an aza-Achmatowicz oxidation of a furyl-substituted benzenesulfonamide followed by a conjugate addition to the resulting 2H-pyridone and subsequent addition of various nucleophiles to a transient N-sulfonyliminium ion. The stereochemistry of the conjugate addition product is the result of axial attack from the face opposite the diaxial substituents at C(2) and C(6). This can be attributed to steric hindrance between the pseudoaxially oriented 2,6-substituents and the equatorially approaching nucleophile, thereby leading to the exclusive formation of the kinetically favored axial 1,4-adduct. Indolizidine alkaloid 223A was isolated from a skin extract of a Panamanian population of the dendrobatid Dendrobates pumilio Schmidt (Dendrobatidae). Synthesis of the originally proposed structure of this alkaloid was achieved in 13 steps in 13.1% overall yield by using an aza-Achmatowicz oxidative rearrangement and a diastereoselective 1,4-conjugate addition as the key steps. The structure of the natural 223A alkaloid (5b) differs from that of the epi-isomer 5a synthesized in this study in the configuration at the 6-position of the indolizidine ring.

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Jun 7, 2002·Organic Letters·Joel M Harris, Albert Padwa

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Citations

Jan 26, 2013·Chemical Reviews·Bagher Eftekhari-SisAli Akbari
May 22, 2009·Organic Letters·Kevin ChengPatrick J Walsh
Sep 11, 2009·Organic Letters·Partha GhoshJeffrey Aubé
May 12, 2016·The Journal of Organic Chemistry·Zhilong Li, Rongbiao Tong
Dec 1, 2015·Chemistry : a European Journal·Hengtuo YangZiwei Gao
Sep 20, 2008·Organic & Biomolecular Chemistry·Claire A M CariouJohn S Snaith
Feb 26, 2005·Organic & Biomolecular Chemistry·Joseph P MichaelChristiaan W van der Westhuyzen
Jan 1, 2016·RSC Advances·Arun K Ghosh, Margherita Brindisi
Dec 3, 2010·Chemical Communications : Chem Comm·Laurent El KaïmSimon Wagschal
Feb 24, 2009·Organic Letters·Sezgin KirenAlbert Padwa
Jun 29, 2021·The Journal of Organic Chemistry·Qingzhao XingBinxun Yu
Nov 22, 2013·The Journal of Organic Chemistry·Alexey KuznetsovVladimir Gevorgyan
Sep 24, 2004·Journal of the American Chemical Society·Daisuke UraguchiMasahiro Terada
May 20, 2006·The Journal of Organic Chemistry·Renata Marcia de FigueiredoMathias Christmann

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