Origin of Syn/Anti Diastereoselectivity in Aldehyde and Ketone Crotylation Reactions:  A Combined Theoretical and Experimental Study

Abstract

We report on experimentally determined and computationally predicted diastereoselectivities of (a) multicomponent crotylation (MCC) reactions of simple aliphatic aldehydes and ketones and (b) of acetal substitution (AS) reactions of aldehyde dimethyl acetals with E- and Z-configurated crotyl trimethylsilane to give homoallylic methyl ethers bearing two newly formed stereogenic centers. We found that corresponding MCC and AS reactions give nearly equal syn/anti ratios. While the crotylations of acetaldehyde and propionaldehyde mainly result in the syn product for E-configurated silane and in the anti product for Z-configurated silane, the syn product is found as main product for the crotylation of pivaldehyde regardless of substrate double bond geometry. Using butanone as substrate, the anti product is found as main product in both cases. By computational investigation employing the B3LYP/6-31+G(d) level of theory in dichloromethane solution (PCM/UAKS), we found that the attack of O-methyl-substituted carboxenium ions by crotyl silane explains the experimentally observed selectivities, indicating that these crotylations in fact proceed in an S(N)1-type reaction via this ionic intermediate. Comparison of relevant open transition-state structures leads to a rationalization of the observed selectivities. For all systems studied, three transition-state conformations are necessary and sufficient to determine the selectivity. This has been confirmed by studying the MCC reactions of isobutyraldehyde. Activation energies for the stereogenic step have been determined by calculation of the transition state and substrate structures in dichloromethane solution at the B3LYP/6-311+G(2d,p)//B3LYP/6-31+G(d) level of theory in dichloromethane solution. The possibility to predict simple diastereoselectivity in general Lewis acid-mediated crotylations of aldehydes and ketones is discussed.

Effect of conformational rigidity on the stereoselectivity of nucleophilic additions to five-membered ring bicyclic oxocarbenium ion intermediates

“…The difference in energies for the oxepane-fused oxocarbenium ion is lower than for the cycloheptane-fused system, which is in accord with the experimental results. Although caution should be taken regarding the quantitative differences in energies because of the error bars associated with these calculations, 47 the lower selectivity for the oxepane system was reproduced by the calculations. The agreement between experiment and theory suggest that calculations may be used to predict outcomes in reactions that involve five-membered ring oxocarbenium ions.…”

“…All transition states were characterized by the presence of a single imaginary frequency corresponding to the newly formed carbon-carbon bond. Two different types of transition structures were identified, corresponding to synclinal and anti additions of the π-nucleophile to the cation 47 . The synclinal transition states had lower free energies than the anti ones by 0.5 to 1.3 kcal/mol at 195 K, likely because they minimize gauche interactions with the ring.…”

Diastereoselective Allylation of Carbonyl Compounds and Imines: Application to the Synthesis of Natural Products

“…To explain this difference, it was postulated that aldehydes reacts through the corresponding oxazolidines that are intercepted by the allyltrimethylsilane, 55 while oxocarbenium ions are the electrophilic species in the stereogenic step of ketone allylation. 56 A clear limitation of the former methodology resides on the fact that only one enantiomer of norpseudoephedrine is commercially available. In this context, a modified auxiliary that can be conveniently prepared from both enantiomeric forms of mandelic acid was also evaluated.…”

Reactions of Aldehydes and Ketones and their Derivatives

“…175 The stereochemical outcome is nearly identical in de the two reactions, and the computational results suggest that this is due to near identical mechanisms: an S N 1 process involving attack of O-methyl-substituted carboxenium ions by crotylsilane.…”