Rationalizing the stereoselectivity of paroline-catalyzed asymmetric aldol reactions in water

Over the last decade, organocatalysis has witnessed tremendous growth and has become a thriving area of general concepts and widely applicable asymmetric reactions [1]. The proline-catalyzed aldol condensations are both origin and prototype of such reactions [2-4]. In this contribution we will present an ab initio molecular dynamics study [5] of the proline amide-catalyzed self aldol reaction of propanaldehyde (PAD) in water, which is the first organocatalytic aldol reaction carried out in water featuring a good enantioselectivity [6]. We will focus on the stereogenic step of the whole catalytic cycle, which consists of a C-C bond formation by means of a nucleophilic addition of an enamine intermediate to the carbonyl group of PAD. Based on extensive CPMD simulations [5] in the condensed phase we have computed the activation free energies of the four different attacks leading to the corresponding four different stereoisomers. These activation free energies have been obtained from ”blue moon” constrained molecular dynamics [7] by thermodynamic integration [8]. Not only the computed enantiomeric excesses are in good agreement with the experimental ones but our simulations also provide a hitherto elusive rationale for the observed stereoinduction. Specifically, we have unveiled the key role played by the number of hydrogen bonds (coming either from the solvent water molecules or the amido group of proline amide) stabilizing the developing alkoxide as the C-C bond is formed. [1] D. W. C. MacMillan, Nature 455, 304 (2008). [2] B. List et al. J. Am. Chem. Soc. 122, 2395 (2000). [3] B. M. Trost, C. S. Brindle. Chem. Soc. Rev. 39, 1600 (2010). [4] M. Raj, V. K. Singh, Chem. Commun. 6687 (2009), [5] R. Car, M. Parrinello, Phys. Rev. Lett. 55, 2471 (1985), [6] S. Aratake et al. Chem. Commun. 2524 (2007). [7] E. Carter et al. Chem. Phys. Lett. 156, 472 (1989). [8] M. Sprik, G. Ciccotti, J. Chem. Phys. 109, 7737 (1998).