Chemoenzymatic Synthesis Of Key Chiral Intermediates Of Statins

Statin is one of new and best-selling medicines which is used as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase(HMG-CoA),the rate limiting enzyme in cholesterol biosynthesis.This medicine can reduce the forming of dissociated cholesterol in cells and thus lower plasma an low density lipoprotein cholesterol in blood.In this dissertation,some new synthetic methods and technologies to its key structures are emphatically described.The main contents of this work are as follows:(1)The synthetic technology for the construction of tert-butyl(S)-6-chloro-5-hydroxyl-3-oxohexanoatewas optimized.Through analysis of reaction mechanism and operation of different experiments,the optimum reaction condition was obtained. Meanwhile,synthetic technology for the synthesis of ethyl(R)-4-cyano-3-hydroxybutanaote was improved,and the good reaction condition was that EtOH/H₂O,35℃and tetrabutylammonium bromide were selected as the reaction solvent,temperature and catalyzer,respectively.The synthetic technology were suitable for industrial production for its low manufacturing cost,mild reaction conditions,high purities and good yields.(2)A chemoenzymatie synthesis of tert-butyl(S)-6-benzyloxy-5-hydroxy-3-oxo-hexanoate was described.The kinetic resolution of 4-arylmethoxy-3-hydroxybutane-nitriles was investigated by lipase-catalyzed transesterification in organic solvent.High enantioselectivity was obtained by reaction with vinyl acetate in mixed solvent(n-heptane/acetonitrile 1:1),which was catalyzed by the lipase from Artgribacter sp.Better selectivity was demonstrated with the number of substituents on the aryl ring increasing.(3)A new synthetic method of(4R,6S)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid,1,1-dimethylethyl ester was accomplished.The target compound was successfully prepared via several mild reaction processes by using R-epichlorohydrin,which is an easily available starting material.Through comparing with three different synthetic methods,the best route was obtained.Dihydroxy ester was synthesized by a syn-selective triethylborane reduction with de value of 97%. After acid-catalyzed protection of dihydroxy ester and hydrogenolysis of the benzyl protecting group,the objective was obtained with high enantiomeric and diastereomeric purity.(4)A facile route to synthesis tert-butyl(3R,5S)-6-hydroxy-3,5-O-isopropylidene-3,5-dihydroxyhexanoate by a chemoenzymatic approach was described.To get the hydroxyl stereocenter at C5,the kinetic resolution of 1-arylmethoxy -3-chloro-2-propanols was investigated by lipase-catalyzed esterification in organic solvents.High enantioselectivity was obtained by reaction with vinyl acetate in mixed solvent(n-hexane/acetonitrile 3:1),which was catalyzed by the lipase from Alcaligenes sp.1-(4-methylbenzyloxy)-3-chloro-2-propanol was enantioselectively resolved by lipase from Alcaligenes sp.with excellent enantioselectivity(E≥200)and chosen as the optimum subtrate.Another hydroxyl stereocenter at C3 was built by a three-step method,first sodium borohydride reduction of tert-butyl(S)-6-(4-methybenzyloxy)-5-hydroxy-3-oxohexanoate in aqueous isopropyl alcohol with a high disastereomeric ratio(dr_s:a= 4.0:1),then acetonide protection,followed by hydrolysis of tert-butyl (5S)-6-(4-methybenzyloxy)-3,5-O-isopropylidene-3,5-dihydroxyhexanoate with acid solutions.The compound tert-butyl(3R,5S)-6-(4-methybenzyloxy)-3,5-O-isopropylidene-3, 5-dihydroxyhexanoate was obtained in 65%yield and 98.0%de.(5)A new synthesis method of tert-butyl(4R-cis)-6-cyanoxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate was achieved,which started from(S)-epichiorohydrin, followed by addition with sodium cyanide,hydroxyl-group protection, condensation,substitution,syn-selective reduction and dihydroxyl-group protection. This route was suitable for large-scale preparation for its high yields,mild reaction conditions,easily available materials and facile purification of products.