How to Make Five Contiguous Stereocenters in One Reaction: Asymmetric Organocatalytic Synthesis of Pentasubstituted Cyclohexanes

Abstract

Give me five! An organocatalyzed two‐component domino reaction has been developed in which two new CC bonds and five stereocenters are created in a one‐pot fashion (see scheme; DABCO=1,4‐diazabicyclo[2.2.2]octane, TMS=trimethylsilyl). The striking features of this transformation are the high preference for one diastereomer (out of 32 possible isomers) and enantioselectivities of up to 94 %.

One‐Pot Catalytic Enantioselective Domino Nitro‐Michael/Michael Synthesis of Cyclopentanes with Four Stereocenters

“…These compounds can be used as scaffolds for further diversification. The importance of the transformation is additionally highlighted in that it correlates to the elegant protocols for cyclohexene and cyclohexane synthesis reported by the groups of Enders,6a,c Jørgensen,6b,d and Hayashi,6e as well as the cyclopentane synthesis developed by Wang's6f,g and our group6h.…”

“…The development of organocatalytic asymmetric one‐pot domino reactions is a rapidly growing research area 4–5. For example, the construction of highly functionalized carbocycles, such as cyclohexanes by Enders,6a,c Jørgensen,6b,d and Hayashi,6e as well as cyclopentanes by Wang6f,g and our group6h have recently been achieved by the employment of enantioselective amine catalysis 6. Inspired by these elegant reports, and our recently developed nitrocyclopropanation of enals [Eq.…”

Organocatalytic Enantioselective Henry Reactions

“…Concurrently, Jørgensen et al [53] developed the Michael addition of dinitroalkanes to α,β-unsaturated aldehydes followed by an intramolecular Henry reaction using catalyst 16 (Table 3). This was the first example of one-pot asymmetric formation of five contiguous streocenters by an intermolecular two-component reaction.…”

Iminium Activation in Catalytic Enantioselective Conjugate Additions

“…The high performance of the amine-catalyzed cascade processes in the formation of highly functionalized chiral compounds in an easy and stereocontrolled manner has been clearly demonstrated with a cleverly designed cascade nitro-Michel/nitroaldol cascade, as shown in Scheme 6.43 [93]. In this reaction, the use of a 2-substituted 1,3-dinitroalkane reagent in combination with an α,β-unsaturated aldehyde in the presence of O-TMS diarylprolinol 11b led to the direct formation of 2,4-dinitrocyclohexanols containing five stereogenic centers, and which were generated with a very high degree of stereocontrol.…”