Enantioselective desymmetrization of prochiral cyclohexanones by organocatalytic intramolecular Michael additions to α,β-unsaturated esters.

Adam D Gammack Yamagata,Robert S Paton,Linus Stegbauer,Swarup Datta,Darren J Dixon,Kelvin E Jackson

doi:10.1002/anie.201411924

Adam D Gammack Yamagata, Robert S Paton + Show 4 more

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https://doi.org/10.1002/anie.201411924

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Abstract

A new catalytic asymmetric desymmetrization reaction for the synthesis of enantioenriched derivatives of 2-azabicyclo[3.3.1]nonane, a key motif common to many alkaloids, has been developed. Employing a cyclohexanediamine-derived primary amine organocatalyst, a range of prochiral cyclohexanone derivatives possessing an α,β-unsaturated ester moiety linked to the 4-position afforded the bicyclic products, which possess three stereogenic centers, as single diastereoisomers in high enantioselectivity (83–99 % ee) and in good yields (60–90 %). Calculations revealed that stepwise C–C bond formation and proton transfer via a chair-shaped transition state dictate the exclusive endo selectivity and enabled the development of a highly enantioselective primary amine catalyst.

Highlights

A new catalytic asymmetric desymmetrization reaction for the synthesis of enantioenriched derivatives of 2-azabicyclo[3.3.1]nonane, a key motif common to many alkaloids, has been developed
As part of our research program directed towards the synthesis of various alkaloid natural products, including daphniphyllum and manzamine[2] targets, we sought to develop a new catalytic asymmetric method to access the morphan motif with high efficiency and selectivity
Retrosynthetic analysis revealed that a direct approach could exploit a desymmetrization[3] of prochiral ketone I by an intramolecular Michael addition reaction to an a,b-unsaturated ester under enamine catalysis.[4]

Summary

Introduction

A new catalytic asymmetric desymmetrization reaction for the synthesis of enantioenriched derivatives of 2-azabicyclo[3.3.1]nonane, a key motif common to many alkaloids, has been developed. We viewed this proposed desymmetrization reaction as a good opportunity to unveil new reactivity in organocatalysis whilst accessing key bicyclic building blocks that are useful for the synthesis of morphan-like natural product libraries.

Results

Conclusion