Stereocontrolled Annulations of Indolo[2,3-a]quinolizidine-Derived Lactams with a Silylated Nazarov Reagent: Access to Allo and Epiallo Yohimbine-Type Derivatives

Federica Arioli; Maria Pérez; Celeste Are; Carolina Estarellas; F Javier Luque; Joan Bosch; Mercedes Amat

doi:10.1002/chem.201501912

Stereocontrolled Annulations of Indolo[2,3-a]quinolizidine-Derived Lactams with a Silylated Nazarov Reagent: Access to Allo and Epiallo Yohimbine-Type Derivatives

Chemistry. 2015 Sep 14;21(38):13382-9. doi: 10.1002/chem.201501912.

Authors

Federica Arioli¹, Maria Pérez¹, Celeste Are¹, Carolina Estarellas², F Javier Luque², Joan Bosch¹, Mercedes Amat³

Affiliations

¹ Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, 08028 (Spain).
² Department of Physical Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, 08028 (Spain).
³ Laboratory of Organic Chemistry, Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, 08028 (Spain). amat@ub.edu.

PMID: 26332232
DOI: 10.1002/chem.201501912

Abstract

The facial selectivity of double Michael addition reactions of the silylated Nazarov reagent 4 to unsaturated indolo[2,3-a]quinolizidine lactams 3 has been studied. Pentacyclic 3-H/15-H trans adducts 5 are generated from Nind -unsubstituted lactams, but the corresponding cis isomers 6 are formed when the indole nitrogen has a tert-butyloxycarbonyl (Boc) substituent. This reversal in the facial selectivity of the annulation has been rationalized by means of theoretical calculations, which indicate that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group. The synthetic usefulness of the pentacyclic Nazarov-derived adducts is demonstrated by their conversion into allo and epiallo yohimbine-type targets.

Keywords: Michael addition; alkaloids; density functional calculations; stereoselectivity; synthesis design.