Asymmetric sulfonium ylide mediated cyclopropanation: stereocontrolled synthesis of (+)-LY354740.
The reaction of ester-stabilized sulfonium ylides with cyclopentenone to give (+)-5 ((1S,5R,6S)-ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate), an important precursor to the pharmacologically important compound (+)-LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)2, ethyl diazoacetate, 60 degrees C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo- and enantioselectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base-mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide-mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95 % ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.
Aggarwal
Varinder K
VK
School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK. v.aggarwal@bristol.ac.uk
Grange
Emma
E
D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis*; D003517:Cyclopentanes / Q000737:chemistry; D003521:Cyclopropanes / Q000737:chemistry*; D008956:Models, Chemical; D013237:Stereoisomerism; D013452:Sulfonium Compounds / Q000737:chemistry*
D001643:Bridged Bicyclo Compounds; D003517:Cyclopentanes; D003521:Cyclopropanes; D013452:Sulfonium Compounds; C030797:cyclopropane; C104753:eglumetad; C013905:cyclopentenone