Lewis acid (BF 3 ‚OEt 2 ) catalyzed condensation of dimethoxy acetal 2 with r-hydroxy acids produces chiral 1,3-dioxolanones I. The enolates derived from these compounds undergo reactions with alkyl halides with a high level of diastereoselectivity. Subsequent hydrolysis of these alkylated products II gives mono-and disubstituted r-hydroxy acids III with high enantiomeric excesses.Optically active R-hydroxy acids are structural subunits of many natural products, such as motuporin, 1a integerrimine, 1b monocrotaline, 1c and eremantholide A. 1d In addition, R-hydroxy acid derivatives are important intermediates for asymmetric synthesis. 2 A number of useful synthetic methods for the preparation of enantiomertically pure R-branched R-hydroxy acids have been developed. 3 However, the need for development of a more efficient method still exists. Herein we report an enantioselective synthetic method for mono-and disubstituted R-hydroxy acids from glycolic acid, lactic acid, and mandelic acid, employing (1S)-(+)-N,Ndiisopropyl-10-camphorsulfonamide 1 as a chiral auxiliary. 4 Under the conditions of Farines 5 or Pearson, 6 condensation of 1 with glycolic acid either did not give the expected chiral 1,3-dioxolanone or gave it in low yield. However, Lewis acid (BF 3 ‚OEt 2 ) catalyzed condensation of dimethoxy acetal
Synthesis of camphor derived chiral allenes and their hydroboration-oxidation reactions are described. Reaction of (1R)-(+)-camphor with alkynyllithium followed by the reduction of the resulted propargyl alcohol derivatives using AlH3 furnished chiral allenes 2a-g in excellent yields with high diastereoselectivity. Reduction of the propargyl alcohols with aluminum hydride proceeded through selective intermolecular anti-addition of hydride ion. The stereochemistry of the chiral allenes 2 was assigned based on lanthanide shift studies and chemical correlations. Diastereoselectivity was observed in the hydroboration-oxidation of 2 which produced a mixture of (E,R) and (E,S) stereoisomers in a ratio of 6:1 to 18:1.
A systematic series of methyl (2 and 3) and dimethyl (4) analogues of trimetoquinol (1) were synthesized and evaluated for their beta 1 (atria) and beta 2 (trachea) and adrenoceptor activities. Structural assignments for the erythro (2) and the threo (3) diastereoisomers of 1-(3,4,5-trimethoxy-alpha-methylbenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline were based on NMR spectra of the 6,7-dibenzyl precursors 15 and 16, respectively, and on the synthetic derivatives of cis- and trans-13-methyl-2,3-bis(benzyloxy)-9,10,11-trimethoxytetrahydroprotoberberine (18 and 17). The rank order of beta 2-agonist activity for these compounds was 3 greater than 1 greater than 2 greater than 4. The rank order of activity as beta 1 agonists on the guinea pig atria is 1 greater than 3 greater than 2, and 4 was inactive. The methylated analogues show selectivity for beta 2 receptors in our preliminary pharmacological studies. The threo isomer 3 is the most potent and selective beta 2 stimulant reported to date in the tetrahydroisoquinoline class.
Michael addition of enolates of 2a and 2b to r,β-unsaturated esters took place selectively on different faces (Si and Re, respectively) of the double bond to give the corresponding products 4 and 5, respectively, with >98% de. Subsequent hydrolysis of these Micheal adducts gives 3,4-disubstituted γ-lactones with high enantiomeric excesses.The Michael addition reaction is one of the most important processes for C-C bond formation in organic synthesis. 1 A number of methods for asymmetric Michael addition were developed in the 1980s. 2 In previous reports, diastereoselective Michael addition reactions using R-amino acid derivatives as Michael donors have been examined as a method for introducing an R-substituent. 3 Stereoselective synthesis of an R-substituted R-hydroxy acid has been explored. 4 However, application of the Michael addition reaction with respect to the newly formed bond on the R-hydroxy acid derivative is quite rare 5 and has not been probed thoroughly. Recently, we have shown that chiral dioxolanones 2a and 2b, derived from 1, could be used for the preparation of enantiopure R-substituted R-hydroxy acids. 6 As a result, we decided to explore the diastereo-
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