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An efficient enantioselective synthesisof the chiral polycycliccholesteryl ester transfer protein (CETP) inhibitor 1has been developed. The synthesis was rendered practical for largescale via the development of a modified Hantzsch-type reaction toprepare the sterically hindered pyridine ring, enantioselective hydrogenationof hindered ketone 6utilizing novel BIBOP-amino-pyridinederived Ru complex, efficient ICl promoted lactone formation, anda BF3mediated hydrogenation process for diastereoselectivelactol reduction. This efficient route was successfully scaled toproduce multikilogram quantities of challenging CETP drug candidate 1. [ABSTRACT FROM AUTHOR]

A general and efficient method for the synthesis of bulky and structurally diverse P-stereogenic chiral secondary phosphine oxides (SPOs) by using readily available chiral amino alcohol templates is described. These chiral SPOs could be used as chiral building blocks for the synthesis of difficult-to-access bulky P-stereogenic phosphine compounds or ligands for organic catalysis.

S-Alkyl, S-aryl, and S-vinyl thiosulfate sodium salts (Bunte salts) react with Grignard reagents to give sulfides in good yields. The S-alkyl Bunte salts are prepared from odorless sodium thiosulfate by an SN2 reaction with alkyl halides. A Cu-catalyzed coupling of sodium thiosulfate with aryl and vinyl halides was developed to access S-aryl and S-vinyl Bunte salts. The reaction is amenable to a broad structural array of Bunte salts and Grignard reagents. Importantly, this route to sulfides avoids the use of malodorous thiol starting materials or byproducts.

A three-stage process for the synthesis of LFA-1 inhibitor 1 from amine 4 with an overall yield of 65% is described. The key stage involves a Ph(3)PCl(2)-induced dehydration/cyclization of urea 6 followed by a regioselective bromination to give 1H-imidazo[1,2-a]imidazol-2-one 9. Br/Mg exchange of 9 followed by addition to SO(2) in THF and subsequent oxidation produces a sulfonyl chloride which is directly reacted with L-alaninamide using K(2)CO(3) as base in aqueous DMF/THF to give 1 in a one-pot operation. The process was implemented for the production of 1 on a metric ton scale.

[reaction: see text] Iodoaromatics bearing a reactive pyrimidine ring underwent a clean iodine-magnesium exchange with isopropylmagnesium chloride in the presence of bis[2-(N,N-dimethylamino)ethyl] ether to provide the corresponding Grignard reagents. The presence of bis[2-(N,N-dimethylamino)ethyl] ether prevented reduction of the pyrimidine ring and addition by isopropylmagnesium chloride. As a result, the newly formed reactive Grignard reagents were allowed to react with electrophiles in a highly selective manner to afford adducts in excellent yields.

[reaction: see text] Iodo- and bromoaromatics bearing sensitive carboxylic ester and cyano groups underwent a selective halide-magnesium exchange with isopropylmagnesium chloride at ambient temperature in the presence of bis[2-(N,N-dimethylamino)ethyl] ether to afford the corresponding Grignard reagents. The newly formed reactive Grignard reagents were allowed to react with electrophiles such as trimethylborate to afford arylboronic acids in good to excellent yields.

[chemical reaction: see text]. Direct addition of Grignard reagents to acid chlorides in the presence of bis[2-(N,N-dimethylamino)ethyl] ether proceeds selectively to provide aryl ketones in high yields. A possible tridentate interaction between Grignard reagents and bis[2-(N,N-dimethylamino)ethyl] ether moderates the reactivity of Grignard reagents, preventing the newly formed ketones from nucleophilic addition by Grignard reagents.