Candida antarctica Lipase B (CALB) catalyzed the highly enantioselective acetylation of 1,3-anti-diol monoesters which have been obtained through a zirconium-catalyzed aldol-Tishchenko reaction. The product 1,3-anti-diol diesters were formed in yields close to 50 % and Ͼ98 % ee. Separation from the unreactive enantiomers and subsequent hydrolysis furnished both enantiomers of unsymmetrically substi-

Several enantiomerically pure N(2)-substituted octahydroindazoles were prepared as bicyclic pyrazolidine derivatives of (+)-pulegone. Condensation of pulegone with hydrazine delivered a hexahydroindazole intermediate, which underwent N(2)-substitution with various electrophiles (alkyl halides, acyl chlorides, phenyl isocyanate). The resulting N(2)-substituted hexahydroindazoles could be reduced with LiBEt(3)H in THF to the target compounds. In addition, a N(2)-thiobenzoyl and some N(2)-carbamoyl derivatives as well as a N(1)-substituted octahydroindazole were synthesized. The compounds showed medium activity as iminium ion catalysts promoting quantitatively the Michael addition of nitroethane to cinnamaldehyde in up to 82% ee for the resulting syn-diastereoisomer and 78% ee for the anti-diastereoisomer. Unexpectedly, the N(2)-acyloctahydroindazoles were readily oxidized under aerobic conditions. Moreover, it was shown that an oxidation of methyl phenyl sulfide to the corresponding sulfoxide is promoted by an N(2)-acyloctahydroindazole in deuterochloroform as solvent. It is proposed that the oxidation of N(2)-acyloctahydroindazoles proceeds by in situ generation of hydrogen peroxide, which in turn can act as an oxidant.

Spirocyclic indazoles were designed as potential ligands for the glucocorticoid receptors (GRs). A short and efficient synthetic sequence was developed allowing the preparation of pure diastereomeric spirocyclic analogs of fluorocortivazol. Our studies also revealed a new application of Burgess reagent leading to a ring expansion. The structures and conformations of several key intermediates and products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. As a proof of concept we tested the affinity of diastereomeric compounds 13b and 14b for the GRs. Rewardingly, it was found that 14b showed a promising IC50 of 27 nM.

Pure diastereomeric spirocyclic analogs of fluorocortivazol were conveniently prepared by a short and efficient synthetic sequence recently developed in our laboratory. The structures and conformations of several key products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. Preliminary biological testing led to the identification of a highly potent hGR ligand with an excellent activity in the subnanomolar range. All tested compounds from this series were also selective versus the progesterone receptors.

Biochemical syntheses O 0035Enzyme-Catalyzed Kinetic Resolution of 1,3-anti-Diol Monoesters -Efficient Preparation of Enantiomerically Highly Enriched and Unsymmetrically Substituted 1,3-anti-Diols. -Esterification of title anti-diol monoesters (I) with vinyl acetate is smoothly catalyzed by immobilized Candida antarctica lipase B (Novozym 435) to furnish the mixed esters (III) as well as enantioenriched monoesters (I) in yields of about 50% and optical purity of 91 -99% e.e. Alkaline hydrolysis then provides the enantioenriched diols. Alternatively, the Novozym-catalyzed esterification of racemic diols (IV) with vinyl acetate proceeds efficiently to give enantioenriched monoesters (V) as well as enantiopure diols (IV). -(JAKOB, F.; SCHNEIDER*, C.; Eur.