BIOCONVERSION OF INDENE TO TRANS-2S,1S-BROMOINDANOL AND 1S,2R-INDENE OXIDE BY A BROMOPEROXIDASE DEHYDROGENASE PREPARATION FROM CURVULARIA-PROTUBERATA MF5400/

1S,2R-Indene oxide is the precursor of cis-1S,2R-aminoindanol, a key i ntermediate for the Merck HN-I protease inhibitor, Crixivan(R). As an alternative to the challenging chemical synthesis of this chiral epoxi de from indene, the biotransformation route using an enzyme catalyst w as examined. Approximately 3% of the 400 fungal cultures isolated from high salt environments were found to possess neutral haloperoxidase a ctivities. Subsequent studies revealed that indene conversion by these positive cultures could only be obtained when both hydrogen peroxide and bromide ions were present. The products were generally racemic tra ns-bromoindanols which upon basification yielded racemic epoxides. Fin ally it was found that a crude enzyme preparation from the fungal cult ure Curvularia protuberata MF5400 converted indene To the chiral 2S,1S -bromoindanol which can be chemically converted to the desired 1S,2R-e poxide through basification or used directly in the asymmetric synthes is of cis-1S,2R-aminoindanol. The bioconversion rate and the enantiome ric excess (ee) achieved with this cell-free system were heavily pH de pendent. Art initial 1.5-h reaction at pH 7.0 gave similar to 10% yiel d of the chiral bromoindanol or epoxide from indene, and the yield was rapidly improved to >30% for trans-2S,1S-bromoindanol with an ee of 8 0%. Reaction mechanistic studies revealed that the stereoselectivity o bserved was apparently due to a specific dehydrogenase activity presen t in MF5400 which was also found to resolve chemically synthesized rac emic trans-2-bromoiadanols. (C) 1998 Elsevier Science Inc.