The complete mechanistic course of the atroposelective ring opening of a lactone-bridged biaryl, dinaphth[2,1-c:1',2'-e]oxepin-3-(5H)-one (3), with a chiral oxazaborolidine-BH3 complex was calculated using the semiempirical AM1 method. The first hydride transfer to the activated carbonyl function of the adduct complexes was elaborated to be the selectivity-determining step in the postulated five-step mechanism. The calculated enantioselectivity is in good accordance with the experimental results, so that related calculations were performed on the atroposelective ring opening of a sterically strongly hindered and therefore also configurationally stable six-membered biaryl lactone, 1,3-di-tert-butyl-6H-benzo[b]naphtho[1,2-d]pyran-6-one (6f). These calculations predicted a highly (M)-selective reduction of 6f (kM/kP = 358 at -78 degrees C), which, after the smooth preparation of 6f by intramolecular biaryl coupling in high yields, was fully confirmed experimentally (kM/kP > 200 at -78 degrees C). Isolation of the intermediate hydroxy aldehyde (M)-14 at the beginning of the reaction with the same enantiomeric excess as found for the corresponding alcohol (M)-7f conclusively showed the first hydride transfer step to determine the selectivity of this process. The good agreement of computationally predicted and experimentally confirmed values proves the suitability of the AM1 method for mechanistic studies on even such complex reactions and opens a most efficient overall synthesis of sterically highly hindered biaryls, in excellent chemical (for the ring closure) and optical (for the ring cleavage) yields and for any desired axial configuration.
The lipase from Pseudomonas cepacia represents a widely applied catalyst for highly enantioselective resolution of chiral secondary alcohols. While its stereopreference is determined predominantly by the substrate structure, stereoselectivity depends on atomic details of interactions between substrate and lipase. Thirty secondary alcohols with published E values using P. cepacia lipase in hydrolysis or esterification reactions were selected, and models of their octanoic acid esters were docked to the open conformation of P. cepacia lipase. The two enantiomers of 27 substrates bound preferentially in either of two binding modes: the fast-reacting enantiomer in a productive mode and the slow-reacting enantiomer in a nonproductive mode. Nonproductive mode of fast-reacting enantiomers was prohibited by repulsive interactions. For the slow-reacting enantiomers in the productive binding mode, the substrate pushes the active site histidine away from its proper orientation, and the distance d~H NE Ϫ O alc ! between the histidine side chain and the alcohol oxygen increases. d~H NE Ϫ O alc ! was correlated to experimentally observed enantioselectivity: in substrates for which P. cepacia lipase has high enantioselectivity~E Ͼ 100!, d~H NE Ϫ O alc ! is Ͼ2.2 Å for slow-reacting enantiomers, thus preventing efficient catalysis of this enantiomer. In substrates of low enantioselectivity~E Ͻ 20!, the distance d~H NE Ϫ O alc ! is less than 2.0 Å, and slow-and fast-reacting enantiomers are catalyzed at similar rates. For substrates of medium enantioselectivity~20 Ͻ E Ͻ 100!, d~H NE Ϫ O alc ! is around 2.1 Å. This simple model can be applied to predict enantioselectivity of P. cepacia lipase toward a broad range of secondary alcohols.Keywords: enantioselectivity; lipase; model; molecular dynamics; Pseudomonas cepacia; secondary alcohol; stereopreference Lipase from Pseudomonas cepacia~EC 3.1.1.3! is a popular catalyst in organic synthesis~Kazlauskas & Bornscheuer, 1998! for the kinetic resolution of racemic mixtures of secondary alcohols in hydrolysis~Laumen & Schneider, 1988;Liang & Paquette, 1990;Caron & Kazlauskas, 1991;Schneider & Georgens, 1992; Bän-ziger et al., 1993;Itoh et al., 1993;Partali et al., 1993;Takano et al., 1993;Waldinger et al., 1996!, esterification~Burgess & Jennings, 1991Uejima et al., 1993;Chadha & Manohar, 1995;Gaspar & Guerrero, 1995;Hamada et al., 1996;Petschen et al., 1996!, and transesterification~Kaminska et al., 1996;Takagi et al., 1996!. The mechanistic details of the catalytic reaction of serine hydrolases~Chapus et al., 1976;! have been well investigated by quantum-chemical methods like the ab initio and density functional theory~Hu et al., 1998!, and by semiempirical methods~Monecke et al., 1998!. The reaction mechanism of ester hydrolysis~Fig. 1! starts with the formation of a Michaelis complex followed by a first transition state~19! to the first tetrahedral intermediate~2!, where the substrate is covalently linked to side-chain oxygen Og of catalytic serine. The crucial hydrogen bonds...
Lipases are widely applied catalysts for highly enantioselective resolution of chiral secondary alcohols. While stereopreference is determined predominantly by the substrate structure, stereoselectivity (enantioselectivity and diastereoselectivity) depends on atomic details of interactions between substrate and lipase. Experimentally (≤ 1.8 Å) for RR stereo isomers, which were also experimentally found to be hydrolyzed most rapidly; distances d(H Nε -O alc ) were about 2 Å for SS and SR stereo isomers, which were converted at similar rates but at lower rate than RR stereo isomers; finally, distances d(H Nε -O alc ) for SR stereo isomers were greater than 4 Å, in accordance with very slow conversion of SR stereo isomers.
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