Lipase-mediated stereoselective transformations of chiral organophosphorus P-boranes revisited: revision of the absolute configuration of alkoxy(hydroxymethyl)phenylphosphine P-boranes

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Abstract

The lipase-promoted kinetic resolution of a series of alkoxy(hydroxymethyl)phenylphosphine P-boranes proceeded with moderate stereoselectivity to give both the unreacted substrates and their O-acetyl derivatives. The absolute configurations of the products, which were earlier ascribed on the basis of the stereoselective reduction of the corresponding phosphine oxides with borane and comparison with the literature data concerning bicyclic phosphine oxides, were disputed by theoretical calculation. Some additional studies were carried out, including theoretical calculations and more accurate chemical correlation, which proved that the borane reduction of acyclic phosphine oxides proceeded with inversion of configuration at the phosphorus center and, therefore, the former assignment of the absolute configurations was incorrect. On this basis, the stereochemistry of the enzymatic reaction was ultimately determined. A mechanism of the borane reduction of acyclic phosphine oxides explaining inversion of configuration at phosphorus is proposed.

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. For example, trivalent phosphorus compounds, especially tertiary phosphines, are used as chiral ligands in transition metal catalysts. Recently, there has been growing interest in the synthesis and transformation of borane complexes of trivalent phosphorus compounds.1, 2 In contrast to phosphines and other derivatives of trivalent phosphorus, which are prone to oxidation and are usually difficult to handle, they are stable compounds and can be easily converted into the corresponding PIII compounds without racemization. Following this tendency and taking into account the fact that many hydrolytic enzymes proved to be capable of recognizing and stereoselectively binding heteroatom stereogenic centers, among them those located on the phosphorus,3 we4 and others5, 6 applied biocatalytic methods in the synthesis of optically active borane complexes of chiral PIII compounds. Our investigations concerned the kinetic resolution of racemic P-stereogenic alkoxy(hydroxymethyl)phenylphosphine P-boranes 1 via their enzymatic acetylation (Eq. 1).

The results showed that the P-boranes, in contrast to the analogous P-stereogenic alkoxy(hydroxymethyl)phenylphosphine oxides 3 described previously (Eq. 2),7, 8 were relatively poor substrates for lipase-catalyzed transformations and underwent similar reaction that was much slower and with low stereoselectivity (e.g., for the CAL-B-catalyzed acetylation of 3c the enantiomer ratio E = 32, while for 1c E = 3).

In contrast to the phosphine oxides 3, whose absolute configurations were known,7, 8 the direct determination of the absolute configuration of 1 using X-ray analysis could not be performed since no crystals could be obtained. Therefore, a simple chemical correlation was performed, which was based on the reduction of enantiomerically enriched hydroxymethyl(i-propoxy)phenylphosphine oxide (−)-(R)-3c and acetoxymethyl(i-propoxy)phenylphosphine oxide (+)-(S)-4c with borane.4 As a conclusion, the absolute configurations (+)-(R) and (−)-(S) were ascribed to the resulting 1c, assuming, by analogy to the borane reduction of bicyclic phosphine oxides,9, 10 that the reaction proceeded with retention of configuration at the phosphorus center. On this basis, the stereochemistry of the lipase-catalyzed acetylation of 1 was considered to be as shown in Eq. 1.4 Moreover, comparison of the stereochemistry of the two analogous enzymatic reactions, the acetylation of 1 (Eq. 1)4 and the acetylation of 3 (Eq. 2),7, 8 indicated that the same enzymes recognized and preferentially transformed the enantiomers of 1 and 3 (and led to the corresponding acetates 2 and 4) which had opposite spatial arrangement around the phosphorus.

This would mean that a simple replacement of the oxygen atom with the borane moiety at the phosphorus atom would result in an inversion of stereochemistry of the enzymatic reaction. Such different behavior of enzymes seemed very interesting. Attempting to explain this phenomenon, we decided to perform molecular modeling for the enzymatic reaction. The theoretical calculations cast doubt on this result, predicting the same stereochemical course of both reactions shown in Eqs. (1), (2), which means that the replacement of oxygen by a borane group at the phosphorus stereogenic center does not influence the stereorecognition by the enzyme.11 Since there is no doubt about the absolute configuration of the phosphine oxides 3 and 4,7, 8 we have surmised that the absolute configuration of P-boranes 1 and 2 might have been wrongly ascribed4 and decided to reinvestigate it using both theoretical calculations and a more detailed chemical correlation.

Section snippets

Synthesis of (hydroxymethyl)phenylphosphine P-boranes

Enantiomerically pure alkoxy(hydroxymethyl)phenylphosphine boranes 1 were synthesized by reduction of the corresponding enantiomerically pure phosphine oxides 3 or 4, obtained via iterative enzymatic resolution (Eq. 2), with borane–THF complex (Eq. 3, Table 1, entries 1–4). The reaction proceeded smoothly, but unwanted by-products, a secondary phosphine borane 5 and hydroxyphosphine borane 6 were always formed. They were the products of a subsequent/simultaneous reduction of the alkoxy group

Conclusions

A reinvestigation of the sterical course of the borane reduction of acyclic phosphine oxides was performed using both theoretical calculations and a detailed chemical correlation. It allowed us to prove that the reduction proceeds with full inversion of configuration at the phosphorus and to correct the former wrongly ascribed absolute configurations of the resulting phosphine P-boranes. On this basis, the formerly established stereochemistry of the lipase-promoted kinetic resolution of a

General

NMR spectra were recorded on a Bruker instrument at 200 MHz for 1H and 81 MHz for 31P with CDCl3 as solvent. Optical rotations were measured on a Perkin–Elmer 241 MC polarimeter at 20 °C. Column chromatography was carried out using Merck 60 silica gel. TLC was performed on Merck 60 F254 silica gel plates. The enantiomeric excess (ee) values were determined by chiral HPLC (Varian Pro Star 210, Chiralpak OD). Enantiomerically pure 3a and 3c were obtained according to the literature,7, 8

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