Journal of Molecular Graphics and Modelling 38 (2012) 290–297 Contents lists available at SciVerse ScienceDirect Journal of Molecular Graphics and Modelling j ourna l ho me page: www.elsevier.com/locate/JMGM Molecular modeling of the lipase-catalyzed hydrolysis of acetoxymethyl(i-propoxy)phenylphosphine oxide and its P-borane analogue Grzegorz Krasi ´ nski, Marek Cypryk ∗ , Małgorzata Kwiatkowska, Marian Mikołajczyk, Piotr Kiełbasi ´ nski Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lód´ z, Poland a r t i c l e i n f o Article history: Accepted 3 September 2012 Available online 17 September 2012 Keywords: Enzymatic catalysis CAL-B Hydrolysis, Enantioselectivity Molecular modeling a b s t r a c t The molecular modeling of the CAL-B-promoted hydrolysis reactions of acetoxymethyl (i-propoxy)phenylphosphine oxide and its P-borane analogue, acetoxymethyl(i-propoxy)- phenylphosphine P-borane, confirms that the reactions proceed with the same stereochemistry and in both cases the (S)-enantiomers are preferentially transformed by the enzyme. Molecular mechanics calculations show that the main reason for the particular stereoselectivity of the substrates is the steric effect of the phenyl group which causes a remarkable hindrance when placed inside the active site. The replacement of the oxygen by a borane group at the phosphorus stereogenic center does not nullify the stereorecognition by the enzyme, although for the P-borane a lower stereoselectivity is observed. The latter is explained in terms of a smaller energy difference between complexes of CAL-B and particular enantiomers of the P-borane in comparison with those of the phosphine oxide, resulting from the steric effect of the BH 3 group. The results helped to revise the previously published erroneous conclusions concerning absolute configuration of the phosphine–borane complex. © 2012 Elsevier Inc. All rights reserved. 1. Introduction Chiral, non-racemic organophosphorus compounds containing a stereogenic phosphorus atom play an important role in various areas of current research, such as asymmetric organic synthesis, biochemistry and catalysis. Among various methods of their syn- thesis, the one based on the enzyme-promoted stereoselective transformations has become a subject of growing interest [1]. In this way, a series of optically active hydroxymethylphosphine oxides 1, interesting as precursors of herbicides [2], were synthesized by us using either their lipase-promoted acetylation (Scheme 1) or lipase-promoted hydrolysis of the O-acetyl derivatives 2, both performed under kinetic resolution conditions. Their absolute con- figurations were determined [3,4]. Concerning the applicability of P-chiral phosphorus compounds it must be stressed that trivalent phosphorus compounds, espe- cially tertiary phosphines, are much more interesting since they are used as chiral ligands in transition metal catalysts. Unfortu- nately, trivalent phosphorus compounds are generally prone to oxidation and usually difficult to handle. Therefore, there is only one example reported in the literature on the enzymatic transfor- mation of hydroxy phosphines [5]. In this context there has recently been a growing interest in the synthesis and transformations of ∗ Corresponding author. E-mail address: mcypryk@cbmm.lodz.pl (M. Cypryk). borane complexes of trivalent phosphorus compounds [6–8], since, in contrast to phosphines and other derivatives of trivalent phos- phorus, they are stable compounds and can easily be converted into the corresponding P III compounds without racemization. Fol- lowing this tendency we applied some time ago the biocatalytic methodology for the synthesis of optically active borane analogues of compounds 1, namely P-chiral hydroxymethylphosphine P- boranes 3. Our investigations involved kinetic resolution of racemic P-chiral alkoxy(hydroxymethyl)phenylphosphine P-boranes 3 via their enzymatic acetylation (Scheme 2) or enzymatic hydrolysis of their O-acetyl derivatives 4 [9]. It turned out that the P-boranes 3 were poorer substrates for lipase-catalyzed transformations in comparison with the P-chiral alkoxy(hydroxymethyl)phenylphosphine oxides 1 described pre- viously, and underwent similar reaction much more slowly and with low stereoselectivity. Thus, for the enzymatic acetylation of 1c the enantiomer ratio E = 32 [4], while for 3c E is only about 3 [9]. Moreover, the P-borane derivatives, in contrast to the analo- gous phosphine oxides are not crystalline, which made their X-ray analysis impossible. Therefore, the absolute configuration of enan- tiomers was ascribed by chemical correlation assuming, by analogy to the borane reduction of bicyclic phosphine oxides [10], that the reaction proceeded with retention of configuration at phosphorus (Scheme 3). On this basis, the stereochemistry of the lipase-catalyzed acety- lation of 3 was considered to be as shown in Scheme 2. Interestingly, comparison of the stereochemical course of the two analogous 1093-3263/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jmgm.2012.09.001