 = Johnson – Corey – Chaykovsky reaction = 
 
 The Johnson – Corey – Chaykovsky reaction ( sometimes referred to as the Corey – Chaykovsky reaction or <unk> ) is a chemical reaction used in organic chemistry for the synthesis of epoxides , aziridines , and <unk> . 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 <unk> , aldehyde , <unk> , or <unk> to produce the corresponding 3 @-@ membered ring . The reaction is <unk> favoring trans substitution in the product regardless of the initial <unk> . The synthesis of epoxides via this method serves as an important <unk> alternative to the traditional <unk> reactions of <unk> . 
 The reaction is most often employed for <unk> 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 @-@ <unk> <unk> with substituted <unk> derivatives . The attempted <unk> @-@ like reaction failed and a <unk> oxide was obtained instead , noting that " Reaction between the sulfur <unk> and <unk> did not afford <unk> as had the phosphorus and arsenic <unk> . " 
 The subsequent development of ( <unk> ) methanide , ( <unk> ) <unk> and ( <unk> ) methanide , ( <unk> ) <unk> ( known as Corey – Chaykovsky reagents ) by Corey and Chaykovsky as efficient methylene @-@ transfer reagents established the reaction as a part of the organic canon . 
 
 = = <unk> = = 
 
 The reaction mechanism for the Johnson – Corey – Chaykovsky reaction consists of nucleophilic addition of the ylide to the <unk> or <unk> group . A negative charge is transferred to the <unk> and because the sulfonium cation is a good leaving group it gets expelled forming the ring . In the related <unk> reaction , the formation of the much stronger phosphorus @-@ oxygen double bond prevents <unk> formation and instead , <unk> takes place through a 4 @-@ membered cyclic intermediate . 
 The trans diastereoselectivity observed results from the reversibility of the initial addition , allowing <unk> to the favored anti betaine over the <unk> 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 <unk> necessary for <unk> 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 : 
 <unk> of the substrate with higher stability leading to greater reversibility by favoring the starting material over the betaine . 
 <unk> of the ylide with higher stability similarly leading to greater reversibility . 
 <unk> hindrance in the betaine with greater hindrance leading to greater reversibility by <unk> formation of the intermediate and slowing the rate @-@ limiting rotation of the central bond . 
 <unk> of charges in the betaine by <unk> such as lithium with greater <unk> allowing more <unk> rotation in the betaine intermediate , lowering the amount of reversibility . 
 
 = = <unk> = = 
 
 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 <unk> 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 <unk> tool in the organic repertoire . 
 
 = = = Types of ylides = = = 
 
 Many types of ylides can be prepared with various functional groups both on the <unk> carbon center and on the sulfur . The substitution pattern can influence the ease of preparation for the reagents ( typically from the sulfonium <unk> , e.g. <unk> 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 <unk> preparation of the reagent using weaker bases as compared to sulfonium ylides . ( The difference being that a sulfoxonium contains a <unk> bonded oxygen whereas the sulfonium does not . ) The former react slower due to their increased stability . In addition , the <unk> by @-@ products of sulfoxonium reagents are greatly preferred to the significantly more toxic , volatile , and <unk> <unk> by @-@ products from sulfonium reagents . 
 The vast majority of reagents are <unk> at the ylide carbon ( either R1 or <unk> as hydrogen ) . <unk> reagents are much rarer but have been described : 
 If the ylide carbon is substituted with an electron @-@ withdrawing group ( <unk> ) , 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 <unk> sluggish : examples involving <unk> are widespread , with many fewer involving <unk> and virtually no examples involving other <unk> 's . For these , the related <unk> reaction is typically more appropriate . 
 If the ylide carbon is substituted with an <unk> or <unk> group , the reagent is referred to as a semi @-@ stabilized ylide . These have been developed extensively , second only to the classical methylene reagents ( R1 = <unk> = H ) . The substitution pattern on <unk> reagents can heavily influence the selectivity of the reaction as per the criteria above . 
 If the ylide carbon is substituted with an <unk> group the reagent is referred to as an <unk> ylide . The size of the <unk> groups are the major factors in selectivity with these reagents . 
 The R @-@ groups on the sulfur , though typically <unk> , 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 <unk> substrates . 
 
 = = = Synthesis of epoxides = = = 
 
 Reactions of sulfur ylides with <unk> and <unk> 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 <unk> <unk> total synthesis , which produces the <unk> drug <unk> , and the <unk> <unk> total synthesis which produces the <unk> <unk> . 
 
 = = = Synthesis of aziridines = = = 
 
 The synthesis of aziridines from <unk> is another important application of the Johnson – Corey – Chaykovsky reaction and provides an alternative to amine transfer from <unk> . Though less widely applied , the reaction has a similar substrate scope and functional group tolerance to the <unk> equivalent . The examples shown below are representative ; in the latter , an <unk> forms in situ and is opened via nucleophilic attack to form the corresponding amine . 
 
 = = = Synthesis of <unk> = = = 
 
 For addition of sulfur ylides to <unk> , 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 <unk> , <unk> , and <unk> ( the example below involves a <unk> <unk> ) . 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 <unk> 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 <unk> or <unk> . The long reaction times required for these reactions prevent them from occurring as significant side reactions when <unk> epoxides and aziridines . 
 Several <unk> wherein the ylide serves as a " nucleophilic carbenoid equivalent " have been reported . 
 Living <unk> using <unk> as the catalyst and ( <unk> ) methanide as the <unk> have been reported for the synthesis of various complex polymers . 
 
 = = <unk> 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 <unk> 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 <unk> reagents are not <unk> expensive and the <unk> reactions can be carried out with <unk> amounts of ylide without raising costs significantly . <unk> sulfides , on the other hand , are more costly to prepare , spurring the advancement of catalytic enantioselective methods . 
 
 = = = <unk> reagents = = = 
 
 The most successful reagents employed in a stoichiometric fashion are shown below . The first is a <unk> <unk> that has been employed in the synthesis of the β @-@ <unk> compound <unk> ( <unk> ) but is limited by the availability of only one <unk> of the reagent . The synthesis of the axial <unk> is <unk> via the 1 @,@ 3 @-@ <unk> effect which reduces the <unk> of the equatorial lone pair . The conformation of the ylide is limited by <unk> strain and approach of the aldehyde is limited to one face of the ylide by <unk> interactions with the methyl <unk> . 
 The other major reagent is a camphor @-@ derived reagent developed by <unk> Aggarwal of the University of Bristol . Both <unk> are easily synthesized , although the yields are lower than for the <unk> reagent . The ylide conformation is determined by interaction with the bridgehead <unk> and approach of the aldehyde is blocked by the camphor <unk> . The reaction employs a <unk> base to promote formation of the ylide . 
 
 = = = <unk> reagents = = = 
 
 <unk> reagents have been less successful , with most variations suffering from poor yield , poor <unk> , or both . There are also issues with substrate scope , most having limitations with methylene transfer and <unk> <unk> . 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 <unk> . Since the factors underlying these <unk> are at odds , tuning of the catalyst properties has proven difficult . <unk> below are several of the most successful <unk> along with the yields and enantiomeric excess for their use in synthesis of ( E ) <unk> oxide . 
 Aggarwal has developed an alternative method employing the same sulfide as above and a novel <unk> involving a <unk> carbenoid formed in situ . The method too has limited substrate scope , failing for any <unk> possessing basic <unk> due to competitive consumption of the carbenoid . 
 
 