1. Two Scalable Syntheses of (S)-2-Methylazetidine
Matthew S Dowling, Dilinie P Fernando, Jie Hou, Bo Liu, Aaron C Smith J Org Chem. 2016 Apr 1;81(7):3031-6. doi: 10.1021/acs.joc.6b00149. Epub 2016 Mar 11.
Two orthogonal routes for preparing (S)-2-methylazetidine as a bench stable, crystalline (R)-(-)-CSA salt are presented. One route features the in situ generation and cyclization of a 1,3-bis-triflate to form the azetidine ring, while the second route involves chemoselective reduction of N-Boc azetidine-2-carboxylic acid. Both sequences afford the desired product in good overall yields (61% and 49%) and high enantiomeric excess (>99% ee), avoid column chromatography, and are suitable for the large-scale production of this material.
2. The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase
Jan Pícha, Václav Vaněk, Miloš Buděšínský, Jana Mládková, Timothy A Garrow, Jiří Jiráček Eur J Med Chem. 2013 Jul;65:256-75. doi: 10.1016/j.ejmech.2013.04.039. Epub 2013 Apr 30.
Betaine-homocysteine S-methyltransferase (BHMT) is an important zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. In the liver, BHMT performs to half of the homocysteine remethylation. In this study, we systematically investigated the tolerance of the enzyme for modifications at the "homocysteine" part of the previously reported potent inhibitor (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid (1). In the new compounds, which are S-alkylated homocysteine derivatives, we replaced the carboxylic group in the "homocysteine" part of inhibitor 1 with different isosteric moieties (tetrazole and oxadiazolone); we suppressed the carboxylic negative charge by amidations; we enhanced acidity by replacing the carboxylate with phosphonic or phosphinic acids; and we introduced pyrrolidine steric constraints. Some of these compounds display high affinity toward human BHMT and may be useful for further pharmacological studies of this enzyme. Although none of the new compounds were more potent inhibitors than the reference inhibitor 1, this study helped to completely define the structural requirements of the active site of BHMT and revealed the remarkable selectivity of the enzyme for homocysteine.
3. Synthesis of (S)- and (R)-5-oxo-piperazine-2-carboxylic acid and its application to peptidomimetics
Karine Guitot, Stefano Carboni, Oliver Reiser, Umberto Piarulli J Org Chem. 2009 Nov 6;74(21):8433-6. doi: 10.1021/jo901389q.
A straightforward synthesis of (S)- and (R)-N-Boc-5-oxo-piperazine-2-carboxylic acid is reported starting from L- or D-serine and ethyl glyoxylate. Those were evaluated as constituents in two tetrapeptides by studying their secondary structure by (1)H NMR spectroscopy. In the case of Boc-Val-(S)-PCA-Gly-Leu-OMe, two readily interconverting conformations (in a 40%:60% ratio) were observed, differing for the cis-trans isomerizaton of the tertiary amide bond, while Boc-Val-(R)-PCA-Gly-Leu-OMe displayed an equilibrium between a gamma-turn and a type II beta-turn conformation.
