Chiral glutarates

Previous work has been extended to a route to chiral glutarates (e.g. (137)] by Michael additions of various chiral propionamides to... 

Chiral 3-substituted glutaric acid monoester (23) can be obtained via Pseuehmonasfiuoreseens hpase-catalyzed nucleophihc ting opening of anhydride (22) by butanol (38). 

Chiral butyrolactones of type 27 and 28 have substantial value in asymmetric synthesis because they contain readily differentiable difunctional group relationships e.g. 1,5-di-carboxylic acid, 1,4-hydroxy carboxylic acid, 1,6-hydroxy-carboxylic acid, 1,6-diol etc.) that would be difficult to assemble by existing asymmetric condensation and pericyclic processes. Applications of these chiral derivatives of glutaric acid to syntheses of indole, indoline and quinolinone alkaloids are illustrated in Schemes 16-18. 

Soluble polymer-bound catalysts for epoxidation reactions have also been explored, with a complete study into the nature of the polymeric backbone performed by Janda [70]. Chiral (salen)-Mn complexes were appended to MeO-PEG, NCPS, Jan-daJeF and Merrifield resin via a glutarate spacer. It was found that for the Jacobsen epoxidation of ds-/ -mefhylstyrene, the enantioselectivities for each polymer-supported catalyst were comparable (86-90%) to commercially available Jacobsen catalyst (88%). Both soluble polymer-supported catalysts could be used twice before a decline in yield and enantioselectivity was observed. However, neither soluble polymer support proved as suitable as the insoluble JandaJel-supported (salen)-Mn complex for the epoxidation because residual impurities during precipitation and leaching of Mn from the complex, resulted in lowered yields. 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

Pig Liver Esterase (PLE). This is the more used car-boxylesterase (carboxylic-ester hydrolase, EC 3.1.1.1, CAS 9016-18-6) which physiologically catalyzes the hydrolysis of carboxylic acid esters to the free acid anion and alcohol. PLE is a serine hydrolase which has been widely used for the preparation of chiral synthons and these applications have been fully reviewed. An active-site model for interpreting and predicting the specificity of the enzyme has been published. In the pioneering studies of the enzyme applications field, PLE was used for the chiral synthesis of mevalonolactone. Prochiral 3-substituted glutaric acid diesters... 

In the synthesis of (S)-zearalenone and of a chiral spiroac-etal, (2S,6/ )-2-methyl-l,7-dioxaspiro[5.6]dodecane, the starting product was a functionalized 3-keto sulfoxide resulting from the reaction of glutaric anhydride with lithiated (+)-(7 )-methyl p-tolyl sulfoxide (eq 6). 

By using chiral Ru complexes such as BINAP-Ru(II) or DIOP-Ru(II), 3-substituted glutaric anhydrides are enantioselectively hydrogenated to give 3-substituted d-valerolactone in up to 60% e.e. [201]. 

The highly enantioselective transformation of dimethyl meso-2,4-dimethyl-glutarate into its half ester had been performed only by a microorganism, Gliocraudiumroseum (81JA3580), and no report of a chemical chiral induction had been published before our success. 

Brooks and Palmer [15] synthesized two chiral precursors, representing the two halves of the aglycone of natamycin. Both fragments were prepared from dimethyl-3-hydroxy-glutarate. 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

Some chiral salen (N,N-ethyl( n(i)is(salicylirnine) ligands were attached as the end group of PEG. The soluble polymer-supported catalyst 18, with a glutarate spacer between the ligand and PEG, performed well in toluene and provided 82% ee in the asymmetric ethylation of benzaldehyde (Scheme 3.4) [14]. 

Complications arise when two esters of different acids are present or when acylation occurs on the aglycone. One must then rely on partial hydrolysis. The tactics are examplified hy the Entada saponins which contain C2 and Cjq acids (89). The acetate was selectively removed hy 0.025 % K2CO3 while both adds were removed by 1 % KOH. Comparison of C NMR spectra of the parent compound and of derivatives allowed determination of the points of acylation. The dicrotalic (3-hydroxy 3-methyl glutaric add) esters of the tubeistemosides and related compoimds (29-32) provide more complicated examples where the double anchoring of the diadd transforms a prochiral carbon atom into a center of chirality. 

DMAP is an efficient desynmetrisation catalyst. [Wilhs J Chem Soc, Perkin 1 1765 7999.] Thus it allows the use of an achiral or meso molecule, e.g. 3-substituted gjutaric anhydride to react with chiral alcohols e.g. 7 -l-(l -naphthyl)ethanol to produce (l 7 ,37 )-l(r-naphthyl)ethyl methyl 3-substituted-pentanoate di-esters (after treatment with diazomethane), which are now chiral at C-3. The achiral carbon atom at C-3 in the glutaric anhydride becomes chiral in the pentanoate (mono-ester of glutarate). [Theisen Heathcock J Org Chem 53 2374 1988, Theisen Heathcock J Org Chem 58 142 7995.]... 

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