ZARAGOZIC ACID A, A POTENT INHIBITOR OF SQUALENE SYNTHASE - INITIAL CHEMISTRY AND ABSOLUTE STEREOCHEMISTRY

Chemical studies on the highly potent squalene synthase inhibitor zaragozic acid A (1) have led to the determination of the total absolute stereochemistry of the molecule as shown in Figure 3 and to the feasibility of selectively manipulating the carboxyl and ester groups of the molecule. The absolute stereochemistry of the central core of 1 was established based on CD measurements on the bis(4-bromobenzoate) 8. The configuration of the methyl group in the C1 alkyl side chain was deduced by degrading 1 to (R)-(-)-2-methyl-3-phenylpropanoic acid, while the configuration of the adjacent acetoxy group was established from H-1 NMR considerations of the (R)- and (S)-O-methyl mandelates 14 and 15. Single-crystal X-ray diffraction data on two crystalline derivatives (16 and 17) not only led to clarification of the asymmetric centers in the 4,6-dimethyl-2-octenoyl side chain but also afforded independent structural confirmation of the nature of the chemical and biological heart of zaragozic acid A.