DOI: 10.1002/adsc.200700032 A Simple Organocatalytic Enantioselective Cyclopropanation of a,b-Unsaturated Aldehydes Ramon Rios, a Henrik SundØn, a JanVesely, a Gui-Ling Zhao, a Pawel Dziedzic, a and Armando Córdova a, * a DepartmentofOrganicChemistry,ArrheniusLaboratory,StockholmUniversity, SE-10691Stockholm,Sweden Fax:(+ 46)-8-154-908;e-mail:acordova@organ.su.se Received:December19,2006 SupportinginformationforthisarticleisavailableontheWWWunderhttp://asc.wiley-vch.de/home/. Abstract: A highly chemo- and enantioselective or- ganocatalytic cyclopropanation of a,b-unsaturated aldehydes with bromomalonate and 2-bromoacetoa- cetate esters is presented. The reaction is catalyzed by chiral amines and gives access to 2-formylcyclo- propanesinhighyieldsandupto99% ee. Keywords: asymmetric catalysis; cyclopropanes; domino reactions; halomalonates; organocatalysis; a,b-unsaturatedaldehydes The cyclopropane motif has long been an interesting targetfororganicchemists.Thecyclopropaneringisa constituent in more than 4000 natural isolated [1] and 100 biologically active agents. In addition, cyclopropyl derivatives are attractive as intermediates in complex molecule synthesis, [2] as synthetic building blocks, [3] and as templates for the construction of conforma- tionally restricted amino acids and peptides. [4] Hence, the importance of cyclopropyl derivatives has inspired chemists to develop asymmetric methods for their synthesis. [5] For example, in the last few years high levels of asymmetric induction have been achieved in- volving metal-catalyzed intermolecular cyclopropana- tionsofelectron-richolefins. [6] Intherealmoforgano- catalysis, there are a few examples of enantioselective cyclopropanations. [7–11] For instance, Aggarwal and Gaunt pioneered the use of catalyst-bound ylides in enantioselective intermolecular cyclopropanation re- actions. [7b] Moreover, Gaunt developed a very elegant catalytic intramolecular cyclopropanation using modi- fied Cinchona alkaloids as organocatalysts. [10] Cincho- na alkaloid derivatives have also been used by Connon and co-workers as catalysts for the asymmet- ric cyclopropanation of nitroalkenes. [8] Most recently, MacMillan and co-workers disclosed a novel enantio- selective cyclopropanation rection between stabilized ylides and a,b-unsaturated aldehydes using a 2-car- boxylic acid dihydroindole as the catalyst. [11] Encour- aged by these studies and our previous experience on the combination of enamine and iminium catalysis, [12] we envisioned a chiral amine-catalyzed domino reac- tion between halomalonates or 2-halo-b-keto esters and enals would be a simple asymmetric entry to 2- formylcyclopropanes[Eq.(1)]. [13] Herein, we report the highly enantioselective cata- lytic asymmetric reaction between bromomalonates or 2-bromoacetoacetate esters and a,b-unsaturated al- dehydes that gives the corresponding 2-formylcyclo- propanes in high yields and diasteromeric ratios and excellentasymmetricinduction(93–99% ee). After an extensive screening of catalysts and differ- ent solvents for the asymmetric cyclopropanation of cinnamic aldehyde 1a,wefoundthatthattheaddition of 1 equivalent of Et 3 N was crucial in order to obtain high yields. In Table1, selected results from the screening of reaction conditions for the enantioselec- tive transformation between enal 1a and diethyl bro- momalonate 2a are shown. We found that chiral amines 4–9 catalyzed the asymmetric formation of the corresponding 2-formyl- cyclopropanes 3a with up to > 25:1 dr (trans/cis) and ee valuesrangingfrom9–99%.Chiralamines 8 [14] and 9 were the most efficient catalysts under our reaction conditions and catalyzed the formation of 3a with high chemo-, diastereo- and enantioselectivity (en- 1028 #2007Wiley-VCHVerlagGmbH&Co.KGaA,Weinheim Adv. Synth. Catal. 2007, 349,1028–1032 COMMUNICATIONS