Total synthesis and biological evaluation of structural analogues of compactin and dihydromevinolin.
The full experimental details for the total synthesis of (+)-compactin and 19 structural analogues are reported. We have evaluated three classes of analogues as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase: (1) functional and stereoisomeric analogues that possess the full carbon skeleton of compactin or dihydromevinolin, (2) functional analogues in which one carbon of the skeleton has been replaced by oxygen, and (3) analogues in which all of the 3,5-dihydroxyvaleric acid moiety has been omitted. Our most potent inhibitors belong to the first class of analogues. Compounds 42 (5-ketocompactin) and 69 (5-ketodihydromevinolin) are as active as the natural products compactin and dihydromevinolin, respectively (I50 = 1-20 nM). The corresponding enones 37 and 68 are less active, having I50 values 20-30 times larger. Inverting the stereochemistry at C-3 or C-5 or about the hexahydronaphthalene ring of compactin results in the elevation of the I50 to values in the micromolar range, comparable to the KM of the natural substrate 3-hydroxy-3-methylglutaryl coenzyme A. Class 2 analogues are active in this concentration range also. The synthetic sequence developed for compactin and its analogues includes a new method that permits the selective preparation of either the R or the S epimer at C-3 of the 3,5-dihydroxyvaleric acid moiety. This entails the reaction of anhydride 9 with either (R)- or (S)-1-phenylethanol in the presence of 4-(N,N-dimethylamino)pyridine and triethylamine. The prochiral recognition is surprisingly high; under optimum conditions, the reaction of 9 with (R)-1-phenylethanol leads to a 15:1 ratio of diesters 17 and 18.
Heathcock
C H
CH
Department of Chemistry, University of California, Berkeley 94720.
Hadley
C R
CR
Rosen
T
T
Theisen
P D
PD
Hecker
S J
SJ
D000818:Animals; D005977:Glutarates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship
D005977:Glutarates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C012258:mevastatin; C031351:dihydromevinolin; D008148:Lovastatin