No abstract

Ginkgolides are structurally unique constituents of Ginkgo biloba extracts and are known antagonists of the platelet-activating factor (PAF) receptor. Ginkgolide C is 25-fold less potent than ginkgolide B as a PAF receptor antagonist, due to the presence of the 7beta-OH. Recently, we found that 7alpha-fluoro ginkgolide B was equipotent to ginkgolide B underlining the critical importance of the 7-position of ginkgolides for PAF receptor activity. Herein we describe the synthesis of a series of ginkgolide B derivatives with modifications at the 7-position and the pharmacological evaluation of these derivatives as assayed by cloned PAF receptors. In two cases nucleophilic attack on a 7beta-O-triflate ginkgolide B did not lead to the expected products, but gave rise to two unprecedented ginkgolide derivatives, one with a novel rearranged skeleton. Furthermore, standard reduction of 7alpha-azido ginkgolide B did not give the expected primary amine, but instead yielded alkylated amines depending on the solvent employed. Pharmacological testing with cloned PAF receptors showed that ginkgolides with 7alpha-substitutents had increased affinity compared to 7beta-substituents, in particular 7alpha-chloro ginkgolide B, the most potent nonaromatic ginkgolide derivative described to date with a K(i) value of 110 nM.

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High-yield reductive alkylation of (R)-(+)-1 and (R)-(+)-2 has been accomplished with a series of ketones (even as bulky as 2-adamantanone) and NaBH 4 /H 2 SO 4 in THF at room temperature to give the respective N-alkylated binaphthyls 6a-c, 9a-c, and 10a-c. Related N-phenyl derivatives 14, 16, and 17 were obtained via the Pd(0)-catalyzed coupling of (R)-(+)-1 and (R)-(+)-2, respectively, with PhBr; no racemization was observed. Subsequent reductive methylation with CH 2 O and NaBH 4 /H 2 SO 4 afforded the bidentate ligands 8a-c, 12a-c, 13a-c, 15, 18, and 19, which comprise a new class of binaphthyls. Their utility as chiral ligands has been demonstrated for the addition of Et 2 Zn to benzaldehyde and its congeners; the highest level of asymmetric induction was observed for N,N-dimethyl NOBIN (R)-(+)-3 (3 mol %) in conjunction with n-BuLi (5.4 mol %), which gave (R)-(+)-21a in 88% ee. Derivatives of the amino phenol 1 (NOBIN) proved more efficient than the corresponding diamines derived from 2. The stereochemical outcome and the enhancement of asymmetric induction by Li + are discussed in terms of the chelated transition state 26.