Chirospecific Syntheses of Conformationally Constrained 7-Azabicycloheptane Amino Acids by Transannular Alkylation

Abstract

A new method is reported for the chirospecific preparation of optically pure 1-carboxy-7-azabicycloheptane amino acids for the generation of peptidomimetics as conformational probes. The method allows for the multigram preparation of these amino acid analogues through use of a thiolactam sulfide contraction and a transannular alkylation sequence as the key C-C bond-forming steps, starting from L-glutamic acid. The route provides access to two common intermediates, 7-(benzyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptane and (1S,4R)-7-(benzyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptanone tert-butyl ester, for elaboration to symmetrical and chiral amino acid homologues, respectively. Decarboxylation of the C-1 carboxy unit of the latter intermediate also demonstrated the applicability of the method for a short, chirospecific preparation of a (+)-epibatidine intermediate, (1S,4R)-7-(tert-butyloxycarbonyl)-1-carboxy-7-azabicyclo[2.2.1]-3-heptanone.

Copper-catalyzed chemoselective cross-coupling reaction of thioamides and α-diazocarbonyl compounds: Synthesis of enaminones

“…The ESC also requires a long time for completion. [27][28][29][30] Furthermore, the ESC method is unsuccessful in coupling sterically hindered thioamides with α-halocarbonyl compounds. 14,31 Modified versions of the ESC reaction have emerged to overcome these shortcomings.…”

Scale-up of microdroplet reactions by heated ultrasonic nebulization

“…61,62 However, the coupling reaction oen requires a long reaction time. [63][64][65] Fig . 5a shows the reaction schematic of the Eschenmoser coupling reaction between 1-methylpyrrolidine-2-thione 9 and diethyl bromomalonate 10 to form the enaminone product 11.…”

A Versatile and Stereoselective Synthesis of (±)-Epibatidine

“…Sequential formation of the activated ester of carboxylic acid 14 was achieved by the action of 2-chloro-N -methylpyridinium iodide in triethylamine, followed by coupling with N -hydroxy-2thiopyridone to afford the corresponding O -acyl thiohydroxamate. This compound was then photolyzed with tributyltin hydride, using a 200 W tungsten lamp, 13,21 to give the epibatidine precursor 15 . After purification of compound 15 by column chromatography, the benzamido group was hydrolyzed in aqueous 6 N HCl under reflux and further neutralization of the reaction mixture gave (±)-epibatidine 22 as an oil in 11% yield from 5(4 H )-oxazolone 6 .…”

“…11 In particular, we have recently reported the Diels-Alder reaction of oxazolone 2 with Danishefsky's diene [1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene] as the key step in the preparation of the cycloadduct 3 , which is subsequently reduced and cyclized to give a new type of constrained proline analogue 4 . 12 This is an interesting amino acid in that when it is exchanged for a natural amino acid into the backbone of a parent peptide, it could possibly play a dual role as a conformational probe and a bioactive peptidomimetic 13 (Scheme 1).…”