“…Structurally related compounds, mevinolin ( 1b ) and the 4a,5-dihydro derivatives of 1a and 1b , , were isolated thereafter, and numerous structural modifications have been done to improve their potency and pharmacological properties as a potential therapeutic for treating hypercholesterolemia. Consequently, a number of novel HMGR inhibitors have been discovered 6-8 and three inhibitors of natural origin, , mevinolin ( 1b ), pravastatin ( 1d ), and simvastatin ( 1c ), have been marketed. …”
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, (+)-6-epi-mevinolin (2a) and (+)-6-epi-4a,5-dihydromevinolin (2b), were prepared by combining two nonracemic units, phosphonate 3 and decalin 4, which were prepared from enantiopure 3-substituted pentanedioic acid monoesters 5a and 5b, respectively. Each acid was synthesized from cyclic anhydrides 7a and 7b by diastereoselective ring opening by means of (S)-benzyl mandelate as a common chiral auxiliary. The construction of decalin moiety 4 was accomplished by asymmetric intramolecular Diels-Alder (IMDA) reaction of nonracemic trienone 6 bearing a methyl group as a chiral controller. The IMDA diastereoselectivity of trienone 6 is discussed in terms of the configuration of (E)-and (Z)-dienophiles which are activated by an endogenous carbonyl group. The IMDA reaction of (R)-(Z)-6 under high pressure is highly selective and gives cis-decalins exclusively with preferential formation of 4 over 16. The inhibitory activity of (+)-6-epi-mevinolin (2a) and several analogs against HMG-CoA reductase was compared with mevinolin (1b). (+)-6-epi-Mevinolin (2a) was shown to be half as potent as mevinolin (1b) while (+)-6-epi-4a,5-dihydromevinolin (2b) was as potent as mevinolin.
“…Structurally related compounds, mevinolin ( 1b ) and the 4a,5-dihydro derivatives of 1a and 1b , , were isolated thereafter, and numerous structural modifications have been done to improve their potency and pharmacological properties as a potential therapeutic for treating hypercholesterolemia. Consequently, a number of novel HMGR inhibitors have been discovered 6-8 and three inhibitors of natural origin, , mevinolin ( 1b ), pravastatin ( 1d ), and simvastatin ( 1c ), have been marketed. …”
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, (+)-6-epi-mevinolin (2a) and (+)-6-epi-4a,5-dihydromevinolin (2b), were prepared by combining two nonracemic units, phosphonate 3 and decalin 4, which were prepared from enantiopure 3-substituted pentanedioic acid monoesters 5a and 5b, respectively. Each acid was synthesized from cyclic anhydrides 7a and 7b by diastereoselective ring opening by means of (S)-benzyl mandelate as a common chiral auxiliary. The construction of decalin moiety 4 was accomplished by asymmetric intramolecular Diels-Alder (IMDA) reaction of nonracemic trienone 6 bearing a methyl group as a chiral controller. The IMDA diastereoselectivity of trienone 6 is discussed in terms of the configuration of (E)-and (Z)-dienophiles which are activated by an endogenous carbonyl group. The IMDA reaction of (R)-(Z)-6 under high pressure is highly selective and gives cis-decalins exclusively with preferential formation of 4 over 16. The inhibitory activity of (+)-6-epi-mevinolin (2a) and several analogs against HMG-CoA reductase was compared with mevinolin (1b). (+)-6-epi-Mevinolin (2a) was shown to be half as potent as mevinolin (1b) while (+)-6-epi-4a,5-dihydromevinolin (2b) was as potent as mevinolin.
“…The relative stereochemistries of 22 and 23 were determined by evaluation of 1 H NMR coupling constants. In decalin ring systems, the trans protons generally have larger coupling constants than the corresponding cis protons . Interestingly, we found that by treatment with 1.0 equiv of anhydrous HCl, cis isomer 22 could be cleanly transformed to the thermodynamically favored trans isomer 23 in good yield .…”
Section: Resultsmentioning
confidence: 85%
“…In decalin ring systems, the trans protons generally have larger coupling constants than the corresponding cis protons. 22 Interestingly, we found that by treatment with 1.0 equiv of anhydrous HCl, cis isomer 22 could be cleanly transformed to the thermodynamically favored trans isomer 23 in good yield. 23 Further evaluation of acid catalysts led to the serendipitous finding that trans isomer 23 could be cleanly dehydrated to enone 24 using 0.2 equiv of a macroporous p-toluenesulfonic acid resin (MP-TsOH).…”
We have accomplished the synthesis of a complex chemical library via elaboration of angular epoxyquinol scaffolds with distinct skeletal frameworks. The key strategy involves highly stereocontrolled [4 + 2] Diels-Alder cycloadditions of chiral, nonracemic epoxyquinol dienes to generate the scaffolds. Further scaffold diversification involves hydrogenation, epimerization, dehydration, and condensation of the carbonyl group with alkoxyamine and carbazate building blocks. Further elaboration of the scaffolds also provided new skeletal frameworks using hydroxyl-directed Diels-Alder cycloaddition and reductive N-N bond cleavage. The overall process afforded 244 highly complex and functionalized compounds. Preliminary biological screening of the library uncovered six compounds which showed significant inhibition of Hsp 72 induction.
“… 57 This natural product, along with mevinolin, is historically significant in providing the original information for eventual development of the well-known statin drugs, lovastatin (Mevacor®) and simvastatin (Zocor®). In one approach to dihydrocompactin by Hagiwara, 58 the bicyclic ketodiol 15 was employed in racemic form. We recognized that the tricyclic lactone (–)- 14d could be fashioned into this precursor to dihydrocompactin with a few additional synthetic manipulations.…”
Section: Resultsmentioning
confidence: 99%
“…Under the basic conditions of the deprotection, thermodynamic equilibration occurred to provide the desired trans -decalin of the targeted ketodiol (+)- 15 which previously served as a precursor to dihydrocompactin. 58 …”
Chiral α,β-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels–Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic γ- and δ-lactones.
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