General Procedure for the Workup of the Payne Rearrangement-Opening Reaction of a 2,3-Epoxy Alcohol with an Amine. The reaction mixture is brought to room temperature and concentrated. After all of the volatile amine and most of the water are removed, a semisolid mass remains in the flask. This material is dried under high vacuum and then peracetylated in the usual way. The product thus obtained is taken up in CH2C12 and a minimum amount of water. The aqueous phase is extracted with CH2C12, and the combined organic portions are washed with water (IX), dried (Na2S04), concentrated, and dried under high vacuum to constant weight.Payne Rearrangement-Opening Reaction of (2R*,3R*)-2,3-Epoxy-1 -decanol (4) with Me2NH/KOH. The epoxy alcohol 4 (0.0531 g, 0.309 mmol) in 8 mL of a solution prepared by dissolving KOH (0.6 g, 10.7 mmol) in 20 mL of 40% aqueous Me2NH was stirred at room temperature for 37 h and worked up according to the general procedure to afford 0.0875 g (94%) of a 10:2.8:1.0 mixture of (2R*,3S*)-l-(dimethylamino)-2,3-decanediol diacetate (41a), (2R*,3fi*)-3-(dimethylamino)-l,2-decanediol diacetate (41b), and (2R*,3S*)-2-(dimethylamino)-l,3-decanediol diacetate (41c) as an oil. Purification by flash chromatography (4:1 hexane-acetone) affords 0.0507 g

In connection with the continuing recent interest in the stereoselective synthesis of epoxy alcohols, a systematic investigation of the bimolecular nucleophilic ring-opening reactions of acyclic 2,3-epoxy alcohols was undertaken. Strategies for nucleophilic attack at C-l of a 2,3-epoxy alcohol, each of which depends upon the regioselective ring-opening of a 1,2-epoxy 3-ol, were explored. Under Payne rearrangement conditions, i-BuSNa was found to react with 2,3-epoxy alcohols to afford 1-tert-butylthio 2,3-diols. These diols can be readily converted to 1,2-epoxy 3-ols via S-alkylation followed by treatment with base. Alternatively, 1,2-epoxy 3-ols can be prepared from 2,3-epoxy alcohols by sulfonylation and acidic hydrolysis followed by ring-closure of the diol sulfonate intermediate. Dialkylamines were also found to react selectively with 2,3-epoxy alcohols under Payne rearrangement conditions to afford 1-amino 2,3-diols.

Abstract

A safe, practical and scalable process for manufacture of (−)-huperzine A has been developed and scaled up to manufacture several hundred grams of (−)-huperzine A with chemical and optical purity of >99%. The process consists of 11 chemical stages starting from commercially available materials with only nine isolation steps and no chromatography purification. This process provides a reliable and cost-effective source of synthetic (−)-huperzine A and its derivatives for pharmaceutical and nutraceutical markets.

A series of quinoxaline analogs of the herbicide Assure was found to have selective cytotoxicity for solid tumors of mice in a disk-diffusion-soft-agar-colony-formation-assay compared to L1210 leukemia. Four agents without selective cytotoxicity and 14 agents with selective cytotoxicity were evaluated in vivo for activity against a solid tumor. The four agents without selective cytotoxicity in the disk-assay were inactive in vivo (T/C > 42%). Thirteen of the fourteen agents with selectivity in the disk-assay were active in vivo (T/C < 42%). Five of the agents had curative activity. These five agents had a halogen (F, Cl, Br) in the 7-position (whereas Assure had a CI in the 6 position). All agents with curative activity were either a carboxylic acid, or a derivative thereof, whereas Assure is the ethyl ester of the carboxylic acid. All other structural features were identical between Assure and the curative agents. Assure had no selective cytotoxicity for solid tumors in the disk-assay, and was devoid of antitumor activity. The analog XK469 is in clinical development.