1. Syntheses of alpha- and gamma-substituted amides, peptides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism
J R Piper, J A Montgomery, F M Sirotnak, P L Chello J Med Chem. 1982 Feb;25(2):182-7. doi: 10.1021/jm00344a018.
N-[4-[[(Benzyloxy)carbonyl]methylamino]benzoyl]-L-glutamic acid alpha-benzyl ester (2) and gamma-benzyl ester (6) served as key intermediates in syntheses of precursors to amides and peptides of methotrexate (MTX) involving both the alpha- and gamma-carboxyl groupings of the glutamate moiety. Coupling of 2 and 6 at the open carboxyl grouping with amino compounds was affected by the mixed anhydride method (using isobutyl chloroformate); carboxyl groupings of amino acids coupled with 2 and 6 were protected as benzyl esters. N-[4-[[(Benzyloxy)carbonyl]methylamino]benzoyl]-L-glutamic acid gamma-methyl ester (5), a precursor to MTX gamma-methyl ester, was prepared from L-glutamic acid gamma-methyl ester and 4-[[(benzyloxy)carbonyl]methylamino]benzoyl chloride (1) in a manner similar to that used to prepare 2 and 6. The precursor to MTX alpha-methyl ester was prepared from gamma-benzyl ester 6 by treatment with MeI in DMF containing (i-Pr)2NEt. Benzyl and (benzyloxy)carbonyl protective groupings were removed by hydrogenolysis, and the deprotected side-chain precursors were converted to alpha- and gamma-substituted amides, peptides, and esters of MTX by alkylation with 6-(bromomethyl)-2,4-pteridinediamine hydrobromide (12). Biochemical-pharmacological studies on the prepared compounds aided in establishing that the alpha-carboxyl grouping of the glutamate moiety contributes to the binding of MTX to dihydrofolate reductase while the gamma-carboxyl does not. Other studies on the peptide MTX-gamma-Glu (13h) are concerned with the contribution toward antifolate activity of this metabolite of MTX. The compounds prepared were also evaluated and compared with MTX with respect to cytotoxicity toward H.Ep.-2 cells and effect on L1210 murine leukemia.
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. 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.
