A novel and versatile approach to the asymmetric total synthesis of pravastatin, related mevinic acids, and analogs.

Pravastatin, lovastatin, and compactin are fungal metabolites, known collectively as mevinic acids, which are potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase. As a result of this activity, these compounds have found use as drugs to lower serum cholesterol in man. While a number of total syntheses of mevinic acids have recently appeared in the literature, there is still a need for efficient and versatile methods of obtaining these compounds. Such methods could assist researchers in the development of new analogs for therapeutic use, or provide tools to study the enzyme itself. A novel approach to the synthesis of the mevinic acids was developed based on the annulation of chiral cyclohexenones. While not all of the chiral cyclohexenones studied led successfully to useful products, it was demonstrated that both 5-(trimethylsilyl)cyclohex-2-en-1-one and 5-(dimethylphenylsilyl)cyclohex-2-en-1-one could be stereospecifically annulated. 5-(Dimethylphenylsilyl)cyclohex-2-en-1-one is a new cyclohexenone synthon which was specifically developed for these studies. The four step annulation method, consisting of a conjugate addition of a (tributylstannyl)vinyl cuprate, side chain extension via a Stille coupling, cyclopropanation, and cyclization, led to the production of bicyclo (4.4.0) decene systems which were ideally set up for further elaboration into mevinic acids. The one chiral center of the cyclohexenone directed the formation of four additional chiral centers with essentially complete diastereoselectivity. The cyclization step of the annulation sequence was studied in order to gain a better understanding of this important reaction and the factors which control its outcome. Variations in the structure of the cyclization precursor and in the amount of fluoride used to induce cyclization were shown to cause wide, yet reproducible, variation in the types and amounts of products formed. Efforts were also directed towards the further functionalization and elaboration of the annulation products. One annulation product was transformed in a single step into an extremely versatile enone synthon, which could potentially be used to synthesize a wide variety of mevinic acid analogs. As a demonstration of the usefulness of the new methodology, the enone synthon was transformed into a known precursor of a dihydropravastatin analog.Ph.D.Organic chemistryPharmacy sciencesPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/129186/2/9409682.pd