- Carbohydrate Phosphinites as Practical Ligands in Asymmetric Catalysis: Electronic Effects and Dependence of Backbone Chirality in Rh-Catalyzed Asymmetric Hydrogenations. Synthesis of R- or S-Amino Acids Using Natural Sugars as Ligand Precursors
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Vicinal diarylphosphinites derived from carbohydrates are excellent ligands for the Rh(I)-catalyzed enantioselective asymmetric hydrogenation of dehydroamino acid derivatives, producing the highest enantioselectivity of any ligands directly prepared from natural products. The enantioselectivity can be enhanced by the appropriate choice of substituents on the aromatic rings of the phosphinites. For example, the use of phosphinites with electron-donating bis(3,5-dimethylphenyl) groups on phosphorus provides ee's up to 99% for a wide range of amino acids including some with easily removable N-protecting groups. Electron-withdrawing aryl substituents, on the other hand, decrease the enantioselectivity. Sense of chiral induction in the amino acid product depends on the relative juxtaposition of the vicinal diphosphinites on a given sugar backbone. When readily available D-glucopyranosides are used as the starting sugars, 2,3-phosphinites give the S-amino acids and 3,4-phosphinites give the R-amino acids. In the case of aromatic and heteroaromatic amino acids, enantioselectivities > 95% are consistently obtained. Practical considerations such as the ease of ligand synthesis, rates of reactions, catalyst turnover, and scope and limitations in terms of substrates are discussed. A possible explanation for the enhancement of enantioselectivity by electron-rich phosphinites is offered.
- RajanBabu,Ayers, Timothy A.,Halliday, Gary A.,You, Kimberly K.,Calabrese, Joseph C.
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p. 6012 - 6025
(2007/10/03)
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- Enzymes in organic synthesis: Use of subtilisin and a highly stable mutant derived from multiple site-specific mutations
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A subtilisin mutant (subtilisin 8350) derived from subtilisin BPN' via six-specific mutations (Met50Phe, Gly169Ala, Asn76Asp, Gln206Cys, Tyr217Lys, and Asn218Ser) was found to be 100 times more stable than the wild-type enzyme in aqueous solution at room temperature and 50 times more stable than the wild type in anhydrous dimethylformamide. Kinetic studies using ester, thio ester, and amide substrates, and the transition-state analogue inhibitor Boc-Ala-Val-Phe-CF3, indicate the both the wild-type and the mutant enzymes have very similar specificities and catalytic properties. The inhibition constant (K(i)) = 5.0 μM) for the wild-type enzyme is approximately 5 times that of the mutant enzyme (K(i)) = 1.1 μM), suggesting that the mutant enzyme binds the reaction transition state more strongly than the wild-type enzyme. This result is consistent with the observed rate constants for the corresponding ester and amide substrates; i.e. the k(cat)/k(m) values for the mutant are larger than those for hhe wild-type enzyme. Application of the mutant enzyme and the wild-type enzyme to organic synthesis has been demonstrated in the regioselective acylation of nucleosides in anhydrous dimethylformamide (with 65-100% regioselectivity at the 5'-position), in the enantioselective hydrolysis of N-protected and unprotected common and uncommon amino acid esters in water (with 85-98% enantioselectivity for the L-isomer), and in the synthesis of di- and oligopeptides via aminolysis of N-protected amino acid and peptide esters. The enzymatic peptide synthesis was carried out under high concentrations of DMF (~50%) to improve substrate solubility and to minimize enzymatic peptide cleavage. Low enantioselectivity was observed in the enzymatic transformation of non-amino acid alcohols and acids.
- Wong,Chen,Hennen,Bibbs,Wang,L iu,Pantoliano,Whitlow,Bryan
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p. 945 - 953
(2007/10/02)
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