Enantioselective Organocatalytic Cyclopropanation of Enals Using Benzyl Chlorides

Abstract

Herein we describe the first enantioselective cyclopropanation of enals using benzyl chlorides as bifunctional (nucleophilic and electrophilic) reagents. The reaction is simply catalyzed by chiral secondary amines to afford the formyl cyclopropane derivatives in good yields and with moderate to excellent stereoselectivities.  INTRODUCTIONCyclopropane subunits have always fascinated organic chemists because of their unusual structural properties and their wide presence in natural products and pharmaceuticals. The cyclopropane skeletal structure is often found in terpenes, pheromones, fatty acid metabolites, and unnatural amino acids; moreover, its derivatives present a plethora of biological activities such as insecticidal, antibiotic, antifungal, antitumor, and antiviral properties. For these reasons, many scientists are interested in developing new enantioselective methods for the construction of cyclopropanes.Since the seminal report of Simmons and Smith on the reaction of alkenes with diiodomethane in the presence of zinc dust to afford cyclopropanes in high yields, 1 several asymmetric versions of cyclopropanations were reported. These methodologies rely either on the use of stoichiometric amounts of chiral auxiliaries or promoters with allylic alcohols (or amines), α,β-

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…Yang, Rios, and co‐workers utilized 2‐nitrobenzyl chlorides 275 as bifunctional reagents to react with enals 42 in the synthesis of cyclopropanecarbaldehyde derivatives 277 with very high enantioselectivities via an asymmetric domino Michael addition/α‐alkylation reaction catalyzed by ( S )‐ 45 (Scheme ) . The presence of an ortho ‐nitro group in the benzene ring of the substrates 275 facilitated the benzylic sp 3 ‐C–H bond activation.…”

“…The presence of an ortho ‐nitro group in the benzene ring of the substrates 275 facilitated the benzylic sp 3 ‐C–H bond activation. The successive Michael addition to 42 provided the intermediated 276 , which subsequently underwent an α‐alkylation reaction to produce three diastereomers of the desired cyclopropanes ( 277a , 277b , and 277c ) …”

Synergistic catalysis: enantioselective cyclopropanation of alkylidene benzoxazoles by Pd(ii) and secondary amine catalysis. Scope, limitations and mechanistic insight

“…On the basis of the strong electron-withdrawing property of the benzoxazole moiety, we predicted a completely regioselective opening of the cyclopropanes. 8 To explain the origin of the regioselectivity of this reaction we propose the mechanism outlined in Scheme 7. At first, the nucleophilic addition of the NHC 9 to the aldehyde 8a leads to the enaminol, the so-called Breslow intermediate.…”

Diastereoselective Cyclopropanation through Michael Addition‐Initiated Ring Closure between α,α‐Dibromoketones and α,β‐Unsaturated Fischer Carbene Complexes

“…The synthesis of trisubstituted cyclopropanes with three stereogenic centres is mostly achieved using sulfur ylides and other sulfur‐based reagents, selenonium ylides, telluronium ylides, nitromethanes, benzyl chloride, oxazoline and other reagents . The preparation of cyclopropanes with three stereogenic centres and four different substituents is one of the most challenging tasks of the current cyclopropane synthesis.…”