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Synthesis 2012(1): 144-150  
DOI: 10.1055/s-0031-1289631
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of the Indolo[2,3-a]quinolizidine Ring through the Addition of 2-Siloxyfurans to Imines and Intrinsic Reaction Coordinate Calculations

Yaneris Mirabal-Gallardoa, Maria D. P. C. Sorianoa, Julio Caballerob, Jans Alzate-Moralesb, Mario J. Simirgiotisc, Leonardo S. Santos*a
a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, Talca University, P.O. Box 747, Talca, Chile
Fax: +56(71)200448; e-Mail: lssantos@utalca.cl;
b Centre for Bioinformatics and Molecular Simulations, School of Bioinformatics, Talca University, P.O. Box 747, Talca, Chile
c Laboratory of Natural Products, Department of Chemistry, Faculty of Basic Sciences, University of Antofagasta, P.O. Box 170, Antofagasta, Chile
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Publication History

Received 9 September 2011
Publication Date:
01 December 2011 (online)

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Abstract

A concise asymmetric diastereoselective strategy for the synthesis of indolo[2,3-a]quinolizidine derivative 1 was developed using diastereoselective addition of 2-siloxyfurans 4 to imine 3 through chiral auxiliary induction. The addition of an ionic liquid as additive in the reaction favored the anti configuration in the major adduct. The stereochemical outcome of the anti/syn (threo/erythro) selectivity was rationalized based on transition state and IRC calculations at DFT (B3LYP) and MP2 theories. MP2 calculations was shown to be the method of choice in these systems, which orbital desymmetrizations were observed in the anti transition state of the addition of 4 to 3 and secondary orbital interactions allowed us to rationalize the production of the major anti-adduct 6. Furthermore, the work also suggested that 2-(triisopropylsiloxy)furan (4a) was the nucleophile of choice in this kind of Mannich reaction. Moreover, the strategy features the use of the Mitsunobu reaction to insert an amino group with the correct configuration into amine 2, key intermediate to achieve 1. The synthetic route can also be applied in the total synthesis of promising aza-β-carboline compounds.

Key words

azaeburnane - β-carbolines - chiral auxiliary - Mitsunobu reaction - intrinsic reaction coordinate calculations