Dynamic Kinetic Asymmetric Synthesis of Five Contiguous Stereogenic Centers by Sequential Organocatalytic Stetter and Michael−Aldol Reaction: Enantioselective Synthesis of Fully Substituted Cyclopentanols Bearing a Quaternary Stereocenter

Abstract

A synthesis of fully substituted cyclopentanes bearing a quaternary carbon center and five contiguous stereogenic centers has been achieved by sequential organocatalyzed Stetter and Michael-Aldol reactions of heteroaromatic aldehydes, nitroalkenes, and α,β-unsaturated aldehydes via the [1 + 2 + 2] annulation strategy with dynamic kinetic asymmetric transformation and excellent enantioselectivities (up to >99% ee).

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes

“…This strategy has been applied to a two-step protocol for the synthesis of highly substituted cyclopentenes and cyclopentanols (Scheme 43). 109 Different substitution patterns control the outcome of this reaction. Thus, when aryl aldehydes are used in the Stetter reaction, the subsequent Michael-aldol sequence preferentially forms the cyclopentene product.…”

Recent Advances in Organocatalytic Cascade Reactions toward the Formation of Quaternary Stereocenters

“…They also described the synthesis of a cyclopentenone with two contiguous stereogenic centers where one has a fluorine-bearing quaternary center. Although chloro derivatives did work in the presence of di(aryl)-substituted catalyst II, 3-fluoro-1,3-diphenylpropane (20) did not react with cinnamaldehyde (8) in the presence of this catalyst. Indeed, in this particular case, the reactivity was restored by replacing catalyst II with I.…”

“…In the field of cyclopentane synthesis, Hong and coworkers developed an organocatalytic Stetter and Michael/ aldol reaction sequence. 20 Starting from heteroaromaticsubstituted β-nitro ketones 30 and α,β-unsaturated aldehydes, a [1+2+2] annulation strategy, previously used by the same research group to synthesize cyclopentenes, 21 was used to afford fully substituted cyclopentanols 31 bearing a quaternary stereocenter (Scheme 8). In this case, it was crucial to have heteroaromatic aldehydes 28 as substrates to undergo the intermolecular Stetter reaction with nitroalkenes 29 in order to prepare the nitro ketone substrates 30.…”

Access to Oxoquinoline Heterocycles by N‐Heterocyclic Carbene Catalyzed Ester Activation for Selective Reaction with an Enone

“…Previous methods for this class of molecules require multiple synthetic steps and afford only racemic products. [9,10] Our laboratory is interested in organocatalytic activation of esters. In recent years, organocatalytic domino reactions have emerged as an effective strategy to assemble relatively sophisticated molecules.…”

“…[8] Cascade reactions using more than one type of organic catalysts (such as Nheterocyclic carbene and amine organic catalysts) have also been reported by the groups of Enders, Rovis, Jørgensen, Chen, and others. [9,10] Our laboratory is interested in organocatalytic activation of esters. [11] Esters are stable substrates with tunable reactivities.…”