1. Catalytic Asymmetric Benzylation of Azomethine Ylides Enabled by Synergistic Lewis Acid/Palladium Catalysis
Xin Chang, Jing-Di Ran, Xue-Tao Liu, Chun-Jiang Wang Org Lett. 2022 Apr 8;24(13):2573-2578. doi: 10.1021/acs.orglett.2c00865. Epub 2022 Mar 29.
The synergistic chiral Lewis acid/achiral Pd catalyst system was successfully applied in the enantioselective benzylation of various imine esters, giving a range of α-benzyl-substituted α-amino acid derivatives in satisfactory yield with excellent enantioselectivity. It is worth noting that this strategy exhibits good tolerance for bicyclic and monocyclic benzylic electrophiles. Furthermore, the utility of this synthetic protocol was demonstrated by the expedient preparation of enantioenriched antihypertensive drug α-methyl-l-dopa.
2. Catalytic asymmetric Tsuji-Trost α-benzylation reaction of N-unprotected amino acids and benzyl alcohol derivatives
Jian-Hua Liu, Wei Wen, Jian Liao, Qi-Wen Shen, Yao Lin, Zhu-Lian Wu, Tian Cai, Qi-Xiang Guo Nat Commun. 2022 May 6;13(1):2509. doi: 10.1038/s41467-022-30277-9.
Catalytic asymmetric Tsuji-Trost benzylation is a promising strategy for the preparation of chiral benzylic compounds. However, only a few such transformations with both good yields and enantioselectivities have been achieved since this reaction was first reported in 1992, and its use in current organic synthesis is restricted. In this work, we use N-unprotected amino acid esters as nucleophiles in reactions with benzyl alcohol derivatives. A ternary catalyst comprising a chiral aldehyde, a palladium species, and a Lewis acid is used to promote the reaction. Both mono- and polycyclic benzyl alcohols are excellent benzylation reagents. Various unnatural optically active α-benzyl amino acids are produced in good-to-excellent yields and with good-to-excellent enantioselectivities. This catalytic asymmetric method is used for the formal synthesis of two somatostatin mimetics and the proposed structure of natural product hypoestestatin 1. A mechanism that plausibly explains the stereoselective control is proposed.
3. Modification of the vitamin K-dependent carboxylase assay
S Romiti, W K Kappel J Biochem Biophys Methods. 1985 May;11(1):59-68. doi: 10.1016/0165-022x(85)90041-7.
Methods are presented that describe alternative protocols for the isolation of rat liver microsomes containing the vitamin K-dependent carboxylase and the procedure in which the solubilized enzyme is assayed. The method for determining the rate of 14CO2 incorporation into low molecular weight, acid soluble substrates by the rat liver microsomal vitamin K-dependent carboxylase has been modified in order to optimize safety, accuracy and simplicity. For these studies the rat liver microsomes containing the vitamin K-dependent carboxylase were isolated by CaCl2 precipitation. These Triton X-100 solubilized microsomes were found to be equivalent to the microsomes obtained by high speed ultracentrifugation with regard to protein concentration, pentapeptide carboxylase activity, carboxylase activity, preprothrombin concentration and total carboxylatable endogenous protein substrate. This modified assay procedure requires fewer steps and pipetting transfers and is quantitatively equivalent to previously employed protocols. The described technique can be adapted for any assay where 14CO2 or H14CO3- is incorporated into non-volatile products. This newly developed assay procedure was employed to assess conditions necessary for optimal vitamin K-dependent carboxylation of the less expensive substrate, N-t-Boc-L-glutamic acid alpha-benzyl ester. The optimal conditions for the carboxylation of N-t-Boc-L-glutamic acid alpha-benzyl ester by the carboxylase were found to be 10 mM N-t-Boc-L-glutamic acid alpha-benzyl ester, 10 mM MgCl2 at 15-18 degrees C. The rate of N-t-Boc-L-glutamic acid alpha-benzyl ester carboxylation under these optimized conditions was found to be higher (1.5-fold) than the rate of carboxylation of 1 mM Phe-Leu-Glu-Glu-Ile in the presence of the cation activator, MgCl2.
