The D-leucine amino acid residue necessary for the synthesis of BMS-561392, 1, was employed as a chiral directing group for a diastereoselective enolate amination to establish the quaternary chiral center. Enhanced diastereomeric ratios were observed while conducting the enolate amination with 1-chloro-1-nitrosocyclopentane 6 in the presence of LiCl. Analogies are drawn between known tertiary amide amino alcohol chiral auxiliaries which have been used to effect diastereoselective enolate alkylations and aminations. Once the stereochemical features of 1 were established, an efficient reaction sequence was devised to complete its synthesis. During the course of this research, accelerated reaction calorimetry (ARC) data substantiated that the aminating agent 1-chloro-1-nitrosocyclopentane 6 was not safe to use as a neat compound. Consequently, a preparation and use of 6 as a stock solution in methyl tert-butyl ether (MTBE) was developed that rendered it safe for use.

The decomposition of primary sodium alkoxide salts under ambient storage conditions and the effects of this phenomenon on commonly employed transition-metal-catalyzed cross-coupling reactions are described. By utilizing NMR, IR, and Raman spectroscopy, along with a modified Karl Fischer analysis, the main inorganic degradants were characterized, and CO2 in the air was found to be a critical reactant within the decomposition process. The effects of storage conditions on decomposition were evaluated, and the preliminary experiments to understand the kinetics of this process were performed. ASSOCIATED CONTENT Supporting InformationDetailed experimental procedures, spectroscopic data, and compound characterization. This material is available free of charge via the Internet at http://pubs.acs.org.

Two efficient large scale syntheses of (Z)-(1-bromobut-1-ene-1,2diyl)dibenzene are described. The first is a three-step synthetic sequence from trimethyl(phenylethynyl)silane in 63% overall yield. The key transformations involved the stereospecific carbometalation reaction of trimethyl(phenylethynyl)silane followed by a bromination. Subsequent Miyaura-Suzuki coupling with phenylboronic acid and transformation of the vinyltrimethylsilane to a vinyl bromide afforded the target. In an improved synthesis, a stereoselective nickel acetylacetonate catalyzed PhZnEt addition to but-1-ynylbenzene, generated an organozincate intermediate, which was brominated in 58-62% overall yield. A key feature of this work was the production of highly regiopure olefin. The optimization effort that resulted in the utilization of substoichiometric amounts of Ph 2 Zn and the safety precautions taken to facilitate process scale-up are discussed.

The decomposition of primary sodium alkoxide salts under ambient storage conditions and the effects of this phenomenon on commonly employed transition-metal-catalyzed cross-coupling reactions are described. By utilizing NMR, IR, and Raman spectroscopy, along with a modified Karl Fischer analysis, the main inorganic degradants were characterized, and CO₂ in the air was found to be a critical reactant within the decomposition process. The effects of storage conditions on decomposition were evaluated, and the preliminary experiments to understand the kinetics of this process were performed.

Having robust and reliable methods for monitoring catalyst activation processes is an important part of ensuring the reproducibility of a catalytic reaction. For asymmetric Diels−Alder reactions, chiral oxazaborolidine or oxazaborolidinium catalysts are powerful reagents that promote these reactions in high yield and selectivity. Supported by mechanistic findings, several modern analytical methods are compared for quantitating the oxazaborolidine catalyst formation from amino alcohol and boroxine to arrive at useful monitoring methods for this important transformation.