Nucleophilic ring opening of epoxycyclohexane with a variety of pyrazoles afforded racemic 2-pyrazolylcyclohexan-1-ols in high yields. The kinetic resolution of these 1,3-diamino alcohols was achieved by enantioselective acylation with isopropenyl acetate in the presence of lipase B from Candida antarctica and separation of the enantiomerically pure alcohol and the ester by either MPLC or crystallization.For some time, we have been interested in the coordination chemistry of chiral 1,3-diamino alcohols bearing rigid cycloaliphatic backbones in combination with N -heterocycles like pyrazole or imidazole as amino functionality. 1-5 Beside their chelating features, these species are also versatile starting materials for the synthesis of chiral azides, amines and Schiff bases. 4 Starting with the nucleophilic ring opening of epoxicycloalkanes the trans -configurated products are obtained in high yields with both substituents in equatorial positions to avoid sterically unfavourable axial -axial interactions. Obviously, the products are obtained as racemic mixtures, which will make both enantiomers accessible after a separation procedure. Recently we were able to show for the most simple derivative trans -2-(pyrazolyl)cyclohexanol ( 1a ) that lipase B from Candida antarctica allows the selective acylation of the (1 R ,2 R )-enantiomer with isopropenyl acetate as the acylating agent. 2 In the present paper we describe the extension of this method to a series of derivatives with substituted pyrazoles and discuss its stereochemical and electronic scopes and limitations.The pyrazolyl cyclohexanols 1a-j are obtained as racemates in 65-90% yield by heating equimolar mixtures of the corresponding pyrazole and epoxycyclohexane at 160°C for 5 hours (Scheme 1). Dedicated to Professor Boche on the occasion of his 60th birthday Owing to the two tautomeric forms of the corresponding pyrazoles, the pyrazolyl cyclohexanols 1b , 1d-i could formally be obtained in two isomeric forms, resulting from an attack of either N-1 or N-2. However, only in the case of the cycloannullated derivatives 1g-i , bearing small methylene units in the 3-position of the pyrazole, could the N-2 isomer (not shown in Scheme 1) be found in traces by GC/MS. Under the given reaction conditions, the ring opening of epoxycyclohexane with enantiomerically pure (4 S ,7 R )-4,5,6,7-tetrahydro-7,8,8-trimethyl-4,7-methano-2-indazole generates the diastereomeric pyrazolyl cyclohexanols 1kA and 1kB in an almost 1:1 ratio (Scheme 2). All attempts to separate these diastereomers by crystallization or chromatography failed.Nucleophilic attack of excess of pyrazole on trans -1,2:4,5-diepoxycyclohexane, accessible by epoxidation of cyclohexa-1,4-diene with H 2 O 2 in the presence of CH 3 ReO 3 , 6 exclusively gives rac -(1 r ,3 t ,4 c ,6 t )-4,6-bis[2-(pyrazol-1-yl)]cyclohexane-1,3-diol ( 1l ) (Scheme 3).
Scheme 1 Scheme 2
Scheme 3The regio-and stereoselectivity of this reaction agree with results of other groups, 7,8 and is confirmed by molecular mechanics calculations (MM2...