Journal of Medicinal Chemistry p. 1858 - 1873 (1987)
Update date:2022-09-26
Topics:
Heathcock, Clayton H.
Hadley, Cheri R.
Rosen, Terry
Theisen, Peter D.
Hecker, Scott J.
The full experimetal 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 posses 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full carbon skeleton of compactin or dihydromevinolin, (2) functional analogues in which one carbon of the skeleton has been replaced by oxygen, and (3) analogues in which all of the 3,5-dihydroxyvaleric acid moiety has been omitted.Our most potent inhibitors belong to the first class of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.
View MoreDongguan Albiya Energy Science and Technology Co.,Ltd
Contact:+86-769-22181286
Address:Huanan Industial Park, Dongguan,China
Jinan Kaypharm Chemical Co.,Ltd
Contact:86-0531-86986780
Address:Room101,No189-2,Huayuan Road,Jinan City,Shandong Province
Contact:USA:563-513-3839
Address:No.121TANGU EAST STREET,SHIJIAZHAUNG,CHINA
website:http://www.sagechem.com
Contact:+86-571-86818502
Address:Room C1301, New Youth Plaza, 8 Jia Shan Road, Hangzhou, China
Contact:+86-021-58123769
Address:No.780 of Cailun Road,Zhangjiang Hi-tech Park,Pudong,Shanghai
Doi:10.1002/cssc.201901813
(2020)Doi:10.1134/S1068162018010132
(2018)Doi:10.1016/S0040-4039(98)01657-8
(1998)Doi:10.1002/(SICI)1522-2675(19980909)81:9<1585::AID-HLCA1585>3.0.CO;2-N
(1998)Doi:10.1021/jo981183z
(1998)Doi:10.1002/anie.201104216
(2011)