ABSTRACT
A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular NâC benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of ß3-AR agonists is synthesized in 38% overall yield.
Subject(s)
Adrenergic beta-3 Receptor Agonists/chemical synthesis , Pyrrolidines/chemical synthesis , Adrenergic beta-3 Receptor Agonists/chemistry , Adrenergic beta-3 Receptor Agonists/pharmacology , Amino Alcohols/chemistry , Catalysis , Hydrogenation , Imines/chemistry , Molecular Structure , Oxidation-Reduction , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , StereoisomerismABSTRACT
Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).
Subject(s)
Benzenesulfonates/chemical synthesis , Benzopyrans/chemical synthesis , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/chemical synthesis , Oxadiazoles/chemical synthesis , Arachidonate 5-Lipoxygenase/chemistry , Benzenesulfonates/chemistry , Benzopyrans/chemistry , Lipoxygenase Inhibitors/chemistry , Molecular Structure , Oxadiazoles/chemistry , StereoisomerismABSTRACT
A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-propan-2-ol (1), an oral GABA(A) alpha(2/3)-selective agonist, is described. The five-step process, which afforded 1 in 40% overall yield, included imidazopyrimidine 2 and pyridine boronic acid 4 as key fragments. The synthesis is highlighted by consecutive Pd-catalyzed coupling steps to assemble the final free base 1 in high yield and regioselectivity. A novel method for Pd removal in the final step is also described.
Subject(s)
GABA Agonists/chemical synthesis , Palladium/chemistry , Propanols/chemical synthesis , Pyrimidines/chemical synthesis , Allosteric Regulation , Boronic Acids/chemistry , Catalysis , Imidazoles/chemistry , Molecular Structure , Oxidation-Reduction , Pyridines/chemistry , Pyrimidines/chemistry , StereoisomerismABSTRACT
A general synthetic approach to the isoprostanes has been established, based on intermolecular aldol condensation of a diazo ketone with an unsaturated aldehyde, followed by cyclization of the resulting diazo ketone to the cyclopropane. Subsequent kinetic opening with thiophenol followed by further elaboration then leads to the isoprostane. The history of this approach and the details of its development are discussed.
Subject(s)
Isoprostanes/chemical synthesis , Ketones/chemistry , Isoprostanes/chemistryABSTRACT
Imidazo[1,2-a]pyrimidine can be arylated at the 3-position with aryl bromides in the presence of base and a catalytic amount of palladium. This provides an efficient one-step synthesis of 3-arylimidazo[1,2-a]pyrimidines from the unsubstituted heterocycle. [reaction: see text]
ABSTRACT
[reaction: see text] Chemoselective alcohol oxidations using catalytic TEMPO and stoichiometric iodine as the terminal oxidant were studied. Iodine was compared to other positive halogens as the terminal oxidant and shown to be superior in cases of electron-rich and heteroaromatic rings. The new conditions were successfully applied to an important intermediate (2) in the synthesis of Losartan.
Subject(s)
Alcohols/chemistry , Aldehydes/chemistry , Cyclic N-Oxides/chemistry , Iodine/chemistry , Ketones/chemistry , Oxidants/chemistry , Catalysis , Losartan/chemical synthesis , Losartan/chemistry , Molecular Structure , Oxidation-ReductionABSTRACT
3-Pyridylboronic acid was prepared in high yield and bulk quantity from 3-bromopyridine via a protocol of lithium-halogen exchange and "in situ quench". This technique was further studied and evaluated on other aryl halides in the preparation of arylboronic acids.