 = Johnson – Corey – Chaykovsky reaction = 
 
 The Johnson – Corey – Chaykovsky reaction ( sometimes referred to as the Corey – Chaykovsky reaction or CCR ) is a chemical reaction used in organic chemistry for the synthesis of epoxides , aziridines , and cyclopropanes . It was discovered in 1961 by A. William Johnson and developed significantly by E. J. Corey and Michael Chaykovsky . The reaction involves addition of a sulfur ylide to a ketone , aldehyde , imine , or enone to produce the corresponding 3 @-@ membered ring . The reaction is diastereoselective favoring trans substitution in the product regardless of the initial stereochemistry . The synthesis of epoxides via this method serves as an important retrosynthetic alternative to the traditional epoxidation reactions of olefins . 
 The reaction is most often employed for epoxidation via methylene transfer , and to this end has been used in several notable total syntheses ( See Synthesis of epoxides below ) . Additionally detailed below are the history , mechanism , scope , and enantioselective variants of the reaction . Several reviews have been published . 
 
 = = History = = 
 
 The original publication by Johnson concerned the reaction of 9 @-@ dimethylsulfonium fluorenylide with substituted benzaldehyde derivatives . The attempted Wittig @-@ like reaction failed and a benzalfluorene oxide was obtained instead , noting that " Reaction between the sulfur ylid and benzaldehydes did not afford benzalfluorenes as had the phosphorus and arsenic ylids . " 
 The subsequent development of ( dimethyloxosulfaniumyl ) methanide , ( CH3 ) 2SOCH2 and ( dimethylsulfaniumyl ) methanide , ( CH3 ) 2SCH2 ( known as Corey – Chaykovsky reagents ) by Corey and Chaykovsky as efficient methylene @-@ transfer reagents established the reaction as a part of the organic canon . 
 
 = = Mechanism = = 
 
 The reaction mechanism for the Johnson – Corey – Chaykovsky reaction consists of nucleophilic addition of the ylide to the carbonyl or imine group . A negative charge is transferred to the heteroatom and because the sulfonium cation is a good leaving group it gets expelled forming the ring . In the related Wittig reaction , the formation of the much stronger phosphorus @-@ oxygen double bond prevents oxirane formation and instead , olefination takes place through a 4 @-@ membered cyclic intermediate . 
 The trans diastereoselectivity observed results from the reversibility of the initial addition , allowing equilibration to the favored anti betaine over the syn betaine . Initial addition of the ylide results in a betaine with adjacent charges ; density functional theory calculations have shown that the rate @-@ limiting step is rotation of the central bond into the conformer necessary for backside attack on the sulfonium . 
 The degree of reversibility in the initial step ( and therefore the diastereoselectivity ) depends on four factors , with greater reversibility corresponding to higher selectivity : 
 Stability of the substrate with higher stability leading to greater reversibility by favoring the starting material over the betaine . 
 Stability of the ylide with higher stability similarly leading to greater reversibility . 
 Steric hindrance in the betaine with greater hindrance leading to greater reversibility by disfavoring formation of the intermediate and slowing the rate @-@ limiting rotation of the central bond . 
 Solvation of charges in the betaine by counterions such as lithium with greater solvation allowing more facile rotation in the betaine intermediate , lowering the amount of reversibility . 
 
 = = Scope = = 
 
 The application of the Johnson – Corey – Chaykovsky reaction in organic synthesis is diverse . The reaction has come to encompass reactions of many types of sulfur ylides with electrophiles well beyond the original publications . It has seen use in a number of high @-@ profile total syntheses , as detailed below , and is generally recognized as a powerful transformative tool in the organic repertoire . 
 
 = = = Types of ylides = = = 
 
 Many types of ylides can be prepared with various functional groups both on the anionic carbon center and on the sulfur . The substitution pattern can influence the ease of preparation for the reagents ( typically from the sulfonium halide , e.g. trimethylsulfonium iodide ) and overall reaction rate in various ways . The general format for the reagent is shown on the right . 
 Use of a sulfoxonium allows more facile preparation of the reagent using weaker bases as compared to sulfonium ylides . ( The difference being that a sulfoxonium contains a doubly bonded oxygen whereas the sulfonium does not . ) The former react slower due to their increased stability . In addition , the dialkylsulfoxide by @-@ products of sulfoxonium reagents are greatly preferred to the significantly more toxic , volatile , and odorous dialkylsulfide by @-@ products from sulfonium reagents . 
 The vast majority of reagents are monosubstituted at the ylide carbon ( either R1 or R2 as hydrogen ) . Disubstituted reagents are much rarer but have been described : 
 If the ylide carbon is substituted with an electron @-@ withdrawing group ( EWG ) , the reagent is referred to as a stabilized ylide . These , similarly to sulfoxonium reagents , react much slower and are typically easier to prepare . These are limited in their usefulness as the reaction can become prohibitively sluggish : examples involving amides are widespread , with many fewer involving esters and virtually no examples involving other EWG 's . For these , the related Darzens reaction is typically more appropriate . 
 If the ylide carbon is substituted with an aryl or allyl group , the reagent is referred to as a semi @-@ stabilized ylide . These have been developed extensively , second only to the classical methylene reagents ( R1 = R2 = H ) . The substitution pattern on aryl reagents can heavily influence the selectivity of the reaction as per the criteria above . 
 If the ylide carbon is substituted with an alkyl group the reagent is referred to as an unstabilized ylide . The size of the alkyl groups are the major factors in selectivity with these reagents . 
 The R @-@ groups on the sulfur , though typically methyls , have been used to synthesize reagents that can perform enantioselective variants of the reaction ( See Variations below ) . The size of the groups can also influence diastereoselectivity in alicyclic substrates . 
 
 = = = Synthesis of epoxides = = = 
 
 Reactions of sulfur ylides with ketones and aldehydes to form epoxides are by far the most common application of the Johnson – Corey – Chaykovsky reaction . Examples involving complex substrates and ' exotic ' ylides have been reported , as shown below . 
 The reaction has been used in a number of notable total syntheses including the Danishefsky Taxol total synthesis , which produces the chemotherapeutic drug taxol , and the Kuehne Strychnine total synthesis which produces the pesticide strychnine . 
 
 = = = Synthesis of aziridines = = = 
 
 The synthesis of aziridines from imines is another important application of the Johnson – Corey – Chaykovsky reaction and provides an alternative to amine transfer from oxaziridines . Though less widely applied , the reaction has a similar substrate scope and functional group tolerance to the carbonyl equivalent . The examples shown below are representative ; in the latter , an aziridine forms in situ and is opened via nucleophilic attack to form the corresponding amine . 
 
 = = = Synthesis of cyclopropanes = = = 
 
 For addition of sulfur ylides to enones , higher 1 @,@ 4 @-@ selectivity is typically obtained with sulfoxonium reagents than with sulfonium reagents . Many electron @-@ withdrawing groups have been shown compatible with the reaction including ketones , esters , and amides ( the example below involves a Weinreb amide ) . With further conjugated systems 1 @,@ 6 @-@ addition tends to predominate over 1 @,@ 4 @-@ addition . 
 
 = = = Other reactions = = = 
 
 In addition to the reactions originally reported by Johnson , Corey , and Chaykovsky , sulfur ylides have been used for a number of related homologation reactions that tend to be grouped under the same name . 
 With epoxides and aziridines the reaction serves as a ring @-@ expansion to produce the corresponding oxetane or azetidine . The long reaction times required for these reactions prevent them from occurring as significant side reactions when synthesizing epoxides and aziridines . 
 Several cycloadditions wherein the ylide serves as a " nucleophilic carbenoid equivalent " have been reported . 
 Living polymerizations using trialkylboranes as the catalyst and ( dimethyloxosulfaniumyl ) methanide as the monomer have been reported for the synthesis of various complex polymers . 
 
 = = Enantioselective variations = = 
 
 The development of an enantioselective ( i.e. yielding an enantiomeric excess , which is labelled as " ee " ) variant of the Johnson – Corey – Chaykovsky reaction remains an active area of academic research . The use of chiral sulfides in a stoichiometric fashion has proved more successful than the corresponding catalytic variants , but the substrate scope is still limited in all cases . The catalytic variants have been developed almost exclusively for enantioselective purposes ; typical organosulfide reagents are not prohibitively expensive and the racemic reactions can be carried out with equimolar amounts of ylide without raising costs significantly . Chiral sulfides , on the other hand , are more costly to prepare , spurring the advancement of catalytic enantioselective methods . 
 
 = = = Stoichiometric reagents = = = 
 
 The most successful reagents employed in a stoichiometric fashion are shown below . The first is a bicyclic oxathiane that has been employed in the synthesis of the β @-@ adrenergic compound dichloroisoproterenol ( DCI ) but is limited by the availability of only one enantiomer of the reagent . The synthesis of the axial diastereomer is rationalized via the 1 @,@ 3 @-@ anomeric effect which reduces the nucleophilicity of the equatorial lone pair . The conformation of the ylide is limited by transannular strain and approach of the aldehyde is limited to one face of the ylide by steric interactions with the methyl substituents . 
 The other major reagent is a camphor @-@ derived reagent developed by Varinder Aggarwal of the University of Bristol . Both enantiomers are easily synthesized , although the yields are lower than for the oxathiane reagent . The ylide conformation is determined by interaction with the bridgehead hydrogens and approach of the aldehyde is blocked by the camphor moiety . The reaction employs a phosphazene base to promote formation of the ylide . 
 
 = = = Catalytic reagents = = = 
 
 Catalytic reagents have been less successful , with most variations suffering from poor yield , poor enantioselectivity , or both . There are also issues with substrate scope , most having limitations with methylene transfer and aliphatic aldehydes . The trouble stems from the need for a nucleophilic sulfide that efficiently generates the ylide which can also act as a good leaving group to form the epoxide . Since the factors underlying these desiderata are at odds , tuning of the catalyst properties has proven difficult . Shown below are several of the most successful catalysts along with the yields and enantiomeric excess for their use in synthesis of ( E ) -stilbene oxide . 
 Aggarwal has developed an alternative method employing the same sulfide as above and a novel alkylation involving a rhodium carbenoid formed in situ . The method too has limited substrate scope , failing for any electrophiles possessing basic substituents due to competitive consumption of the carbenoid . 
 
 