- Total synthesis of (+)-compactin by a double Michael protocol
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The total synthesis of (+)-compactin 1 has been achieved by employing a double Michael reaction of (R)-1-acetyl-3-(tert-butyldimethylsiloxy)cyclohexene 16 with methyl crotonate as the key reaction.
- Hagiwara, Hisahiro,Nakano, Takashi,Kon-no, Masakazu,Uda, Hisashi
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p. 777 - 784
(2007/10/02)
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- Total Synthesis and Biological Evaluation of Structural Analogues of Compactin and Dihydromevinolin
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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full carbon skeleton of compactin or dihydromevinolin, (2) functional analogues in which one carbon of the skeleton has been replaced by oxygen, and (3) analogues in which all of the 3,5-dihydroxyvaleric acid moiety has been omitted.Our most potent inhibitors belong to the first class of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.
- Heathcock, Clayton H.,Hadley, Cheri R.,Rosen, Terry,Theisen, Peter D.,Hecker, Scott J.
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p. 1858 - 1873
(2007/10/02)
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- A new route in the sequential total synthesis of compactin
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The synthesis and regioselective hydrogenation of 1,2,6,7,8,8aβ-hexahydro-8α-hydroxy-2-methylene-1β-naphthaleneacetic acid methyl ester 4a, has provided a novel synthetic pathway to the hypocholesterolemic agent, compactin 9.
- Girotra,Wendler
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p. 3687 - 3688
(2007/10/02)
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- Total synthesis of the hypocholesterolemic agent compactin
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A total synthesis of ( plus )-compactin (ML-236B), a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, is presented. The key chiral hexahydronaphthalene intermediate was efficiently synthesized in 70% overall yield from the optically active diol. In turn, the diol was obtained via microbiological reduction of the racemic dione. ( plus )-Compactin was prepared in 14 steps from the chiral hexahydronaphthalene intermediate in 0. 8% yield. Refs.
- Hsu,Wang,Latimer,Sih
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p. 593 - 601
(2007/10/02)
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