Strong and Confined Acids Control Five Stereogenic Centers in Catalytic Asymmetric Diels-Alder Reactions of Cyclohexadienones with Cyclopentadiene.

Santanu Ghosh,Diana Yepes,Markus Leutzsch,Sayantani Das,Frank Neese,Chandra Kanta De,Benjamin List,Giovanni Bistoni

doi:10.1002/anie.202000307

Santanu Ghosh, Diana Yepes + Show 6 more

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https://doi.org/10.1002/anie.202000307

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Abstract

We describe a highly enantioselective Diels–Alder reaction of cross‐conjugated cyclohexadienones with cyclopentadiene, in which five stereocenters are effectively controlled by a strongly acidic and confined imidodiphosphorimidate catalyst. Our approach provides tricyclic products in excellent stereoselectivity. We also report methods to convert the obtained products into useful intermediates and a computational study that aids in gaining deeper insight into the reaction mechanism and origin of stereoselectivity.

Highlights

The Diels–Alder reaction is widely appreciated as one of the most powerful methods in chemical synthesis for its operational simplicity and for the construction of molecular complexity and several contiguous stereocenters in a single step.[1,2] Despite the remarkable progress in advancing catalytic asymmetric variants of the Diels–Alder reaction,[3,4,5] the use of cross-conjugated 4,4-dialkyl-substituted cyclohexadienones as dienophiles, even with their high synthetic potential, is still extremely rare (Figure 1)
Previous catalytic approaches towards challenging cyclohexadienone Diels–Alder reactions have been reported by Takagi and co-workers using a chiral phosphoric acid (CPA) catalyst and by Corey and co-workers, who reported a single example of using a highly activated chiral oxazaborolidine Lewis acid catalyst.[7]
We show that strong and confined imidodiphosphorimidates (IDPi) enable a broadly useful and general catalytic Diels– Alder reaction of cross-conjugated, 4,4-dialkyl-substituted cyclohexadienones with cyclopentadiene

Summary

Introduction

The Diels–Alder reaction is widely appreciated as one of the most powerful methods in chemical synthesis for its operational simplicity and for the construction of molecular complexity and several contiguous stereocenters in a single step.[1,2] Despite the remarkable progress in advancing catalytic asymmetric variants of the Diels–Alder reaction,[3,4,5] the use of cross-conjugated 4,4-dialkyl-substituted cyclohexadienones as dienophiles, even with their high synthetic potential, is still extremely rare (Figure 1). Previous catalytic approaches towards challenging cyclohexadienone Diels–Alder reactions have been reported by Takagi and co-workers using a chiral phosphoric acid (CPA) catalyst and by Corey and co-workers, who reported a single example of using a highly activated chiral oxazaborolidine Lewis acid catalyst.[7] both of these studies required electronically biased dienones, high catalyst loadings (20– 40 mol %), and gave only moderate enantioselectivities.

Results

Conclusion