Synthesis of Novel HMG‐CoA Reductase Inhibitors, I. Naphthalene Analogs of Mevinolin

Abstract

~~~~~~~The title compounds 2 and their corresponding (6 S ) epimers 18 are prepared in several steps by starting with chiral formyl ester 5, and a-tetralones 10: (1) coupling reaction with the ylide generated from 11 to yield unsaturated ester 13, (2) reduction to the corresponding alcohol 14, (3) addition of the Grignard reagent derived from 14 to formyl ester 5 to afford the hydroxy esters 16 and 17, and (4) lactonization. This procedure is also used to synthesize the p-naphthyl analogs 29 and 30. Some results obtained from HMG-CoA reductase inhibitor screening are also reported.

Novel Class of Potent 4-Arylalkyl Substituted 3-Isoxazolol GABAA Antagonists: Synthesis, Pharmacology, and Molecular Modeling

“…Ethyl 3-(1-Methoxycarbonyl-4-piperidyl)-2-[2-(2-naphthyl)ethyl]-3-oxopropionate (16n). 16n was synthesized as described above for 16a using 15 (3.0 g, 12 mmol), NaOEt (12 mmol) in EtOH (20 mL), and 2-(2-bromoethyl)naphthalene , (3.0 g, 13 mmol). The crude product was purified by CC (toluene/EtOAc (5:1)) to give the title compund as an oil (2.3 g, 48%).…”

Structure−Activity Relationship Studies on the 5-HT1A Receptor Affinity of 1-Phenyl-4-[ω-(α- or β-tetralinyl)alkyl]piperazines. 4

“…Condensation of triethyl phosphonoacetate with 5-methoxy-1-tetralone ( 7a ) according to the Wittig−Horner reaction yielded a mixture of the unsaturated isomeric esters 8 . The subsequent steps to obtain the bromo derivative 11 were carried out as described in the literature for 7-methoxy isomers. The catalytic hydrogenation of 8 afforded the saturated ester 9 which was reduced with LiAlH 4 to the alcohol 10 ; the latter was treated with PBr 3 to give the alkyl bromide 11 .…”

Diastereoselective and enantioselective preparation of nor-mevaldic acid surrogates through desymmetrisation methodology. Enantioselective synthesis of (+) and (−) nor-mevalonic lactones

“…Treatment of lactone (+)-14a with MeONa and MeOH at -35ºC yielded (-)-(R)-8 in 52% yield and 99% ee. 23 Reduction of (-)-(R)-8 with NaBH 4 at -35ºC to yield (-)-(R)-16 24 and subsequent lactonization with PTSA 25 produced the corresponding lactone (-)-(R)-17, that was subsequentially treated with TBAF/AcOH, 26 affording (R)-nor-mevalonic acid lactone ((-)-(R)-4) in 70% yield and 79% ee. 23,27 Desymmetrisation of the dialdehyde 3 with (-)-(S)-1-(naphthalen-2-yl)ethanol afforded the corresponding lactone (-)-15a in 14.7% overall yield and 96% de (scheme 3); methanolysis of which, reduction with NaBH 4 , lactonization 25 to yield (+)-(S)-19 and deprotection with TBAF/AcOH, 25 …”