Chelates as intermediates in nucleophilic additions to alkoxy ketones according to Cram's rule (cyclic model)

Article abstract of DOI:10.1021/ja00031a036

Chelates have been considered intermediates in the often highly stereoselective reactions of α-alkoxy and similarly substituted ketones for over 30 years,¹⁰ but without mechanistic evidence. It is now shown, by stop-flow ("rapid injection") NMR kinetics,¹⁵ that the specific rates of reaction of ketones C₆H₅COCH(OR)CH₃ with Me₂Mg, where R = (i-Pr)₃ ("TIPS"), t-BuPh₂Si, t-BuMe₂Si, Et₃Si, Me₃Si, and Me, parallel the diastereoselectivity of the reaction; i.e., the fastest reacting compound (R = Me) is the one which gives the highest proportion of the product predicted by Cram's chelate rule. The major product of the slowest reacting compound (R = TIPS) is not in accord with Cram's chelate rule, and this compound reacts at the same specific rate as the parent, C₆H₅COCH₂CH₃. This is in accord with earlier work indicating that TIPSO does not chelate. Compounds intermediate in the series react at intermediate rates and give the two diastereomeric products in proportions which can be calculated by assuming two competing reactions (cf. Figure 2): one proceeding via the chelated transition states giving the product predicted by the chelate rule and one not involving chelation which gives the same product composition as the R = TIPS compound. Direct steric effects on carbonyl reactivity due to the remote bulky silyloxy substituents have been excluded by the study of carbon analogues bearing similar bulky groups. Thus, the kinetic effect in the above series appears to be due to steric hindrance to chelation; hence, the parallel of specific rate and stereoselectivity demonstrates that high stereoselectivity is associated with strong chelation, as postulated by Cram and Kopecky in 1959.¹⁰.