Lewis base-catalyzed reactions of allenic esters with electrophilic coupling partners were developed. These transformations expand the versatility and complexity-generating potential of allenoates. In selected cases the methodology was elaborated into an asymmetric variant by employing peptide catalysts. A pyridine-catalyzed reaction of allenoates with N-acyl imines was optimized to provide α-allenic amides via a conjugate addition pathway. This reaction was rendered asymmetric through the use of a pyridylalanine-containing peptide to provide products in excellent yields (up to 88%) and good enantiomeric ratios (up to 94.5:5.5, up to 98.5:1.5 following recrystallization). Kinetics and hydrogen/deuterium kinetic isotope effect experiments revealed an "atypical" rate-determining step for the conjugate addition of allenoates to imines as compared to related aza-Morita–Baylis–Hillman reactions. Possible explanations for the mechanistic discrepancy and implications on allenoate reactivity are presented. The conjugate addition of allenoates to imines was extended to include racemic γ-substituted allenoate substrates. The effect of various reaction parameters on the reactivity, diastereoselectivity, and enantioselectivity is explored in depth. Products were obtained in good yields (up to 86%), modest diastereomeric ratios (up to 1.9:1.0) and moderate enantiomeric ratios (up to 76.5:23.5). Two distinct Lewis base-catalyzed reactions of allenoates with trifluoroacetophenones were developed. 1,4-Diazabicyclo[2.2.2]octane promoted a formal [2+2]-cycloaddition to provide oxetane products in good yields (up to 86%). Methyldiphenylphosphine catalyzed a [3+2]-cycloaddition to provide dihydrofuran products in moderate yields (up to 53%). The optimization of these reactions and a hypothesis for the Lewis-base dependent divergent reactivity is presented in the context of the reaction mechanisms.
|Advisor:||Miller, Scott J.|
|Commitee:||Miller, Scott J.|
|School Location:||United States -- Connecticut|
|Source:||DAI-B 74/05(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Organic chemistry|
|Keywords:||Allenic esters, Allenoates, Electrophilic coupling, Lewis base-catalyzed reactions, Peptide catalysts|
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