Eliezer Falb

Acetyl Chloride-Methanol as a Convenient Reagent for: A) Quantitative Formation of Amine Hydrochlorides B) Carboxylate Ester Formation C) Mild Removal of N-t-Boc-Protective Group.

Abstract Hydrogen chloride qualitatively generated in situ by the addition of acetyl chloride to alcoholic solutions is a useful reagent for carboxylic acid esterification, N-t-Boc deprotection and phosphoramide solvolysis reactions.

Utilization of L-serine in an oxime olefin cycloaddition route to a functionalized asymmetric pyrrolidine, a selective α-glucosidase inhibitor

Abstract A new route for asymmetric aza-sugar analogs starting with L-serine and utilizing an intramolecular oxime olefin cycloaddition has been successfully developed. A member of this family of branched chain sugar amino di(hydroxymethyl) pyrrolidines ( 1 and 2 ) exhibits selective inhibition of α-glucosidase, while no inhibition of β-glucosidase was detected.

A Convenient Synthesis of Chiral Oxazolidin-2-Ones and Thiazolidin-2-Ones and an Improved Preparation of Triphosgene

Abstract Oxazolidin-2-ones and thiazolidin-2-one are conveniently prepared by condensation of L-serine, L-threonine and L-cysteine, respectively with triphosgene. The corresponding methyl esters may be subsequently obtained by quenching the reaction mixture with methanol, without prior need for the isolation of the free acids. An improved procedure for preparation of triphosgene using an internal cooling system is described.

Cinnamic acid derived oxazolinium ions as novel cytotoxic agents.

Substituted cinnamoyl chlorides, 11, were converted into (2-hydroxyethyl)-oxazolinium chlorides 14, N,N-bis-(2-chloroethyl)amides 16 and (2-chloroethyl)-oxazolinium chlorides 17. Although derivatives 14 which possess electron-donating substituents (Me or MeO) were more potent than those substituted by electron-withdrawing groups (NO(2), Cl or CF(3)), the difference in cytotoxic actin was not significant. Modification of the lipophilic character in a series of alkoxy-substituted derivatives 14 led to more active compounds, where 14t that possesses a 4-octyloxy-phenyl-substituent was the most potent and displayed cytotoxic activity in the microM range. It is assumed that the oxazolinium salts act as alkylating agents, and undergo nucleophilic attack on the methylene adjacent to the ring oxygen where the oxazolinium ring parallels the aziridinium ring intermediate found in classical alkylating agents.

From Amino Acids to Fused Chiral Pyrrolidines and Piperidines via the INOC Route

Intramolecular nitrile oxide olefin cycloaddition (INOC) reactions of oximes 1–3 and of 24–27 derived from L-amino acids have been found to proceed stereoselectively, yielding tricyclic fused pyrrolidines and piperidines. Further manipulation led to chiral hydroxymethyl-substituted fused piperidines 33–35 and to 3-amino-4-(1-hydroxypropyl)-2-mercaptomethyl-N-methylpiperidine (36). The structures and stereochemistries of the fused systems, as well as those of the piperidines, have been established by NMR.

A highly efficient Suzuki–Miyaura methylation of pyridines leading to the drug pirfenidone and its CD3 version (SD-560)

Efficient introduction of methyl or methyl-d3 into aromatic and heteroaromatic systems still presents a synthetic challenge. In particular, we were in search of a non-cryogenic synthesis of the 5-CD3 version of pirfenidone (4d, also known as Pirespa®, Esbriet® or Pirfenex®), one of the two drugs approved to date for retarding idiopathic pulmonary fibrosis (IPF), a serious, rare and fatal lung disease, with a life expectancy of 3–5 years. The methyl-deuterated version of pirfenidone (4e, also known as SD-560) was designed with the objective of attenuating the rate of drug metabolism, and our goal was to find a green methylation route to avoid the environmental and economic impact of employing alkyllithium at cryogenic temperatures. The examination of several cross-coupling strategies for the introduction of methyl or methyl-d3 into methoxypyridine and pyridone systems culminated in two green and nearly quantitative Suzuki–Miyaura cross-coupling routes in the presence of RuPhos ligand: the first, using commercially available methyl boronic acid or its CD3 analog and the second, employing potassium methyl trifluoroborate or CD3BF3K, the latter obtained by a new route in 88% yield. This led, on a scale of tens of grams, to the synthesis of pirfenidone (4d) and its d3 analog, SD-560 (4e), at 99% isotopic purity.

An unusual rearrangement involving 5-bromo-1-phenylpyridone during its methyl cross coupling with turbo-Grignard reagent, leading to a 5-bromopyridone-fused seven-membered carbocyclic ring

The structure of a cyclohepta[c]pyridin-1-one, a product of an unusual transformation, isolated during a turbo-Grignard reagentpromoted methyl cross coupling to 5-bromo-1-phenyl-2-pyridone, was determined by 1H and 13C NMR, COSY and high-resolution MS, as well as computer modeling. Its formation suggests a remarkable nucleophilic attack at the α-position to the pyridone carbonyl group. A rational pathway is presented.