Search

N-Heterocyclic carbenes were found to be highly effective organocatalysts in activating TMSCN for facile cyanosilylation of carbonyl compounds. Cyano transfer from TMSCN to aldehydes and ketones proceeds at room temperature in the presence of only 0.01-0.5 mol % of N-heterocyclic carbene (1), leading to a range of trimethylsilylated cyanohydrins in very good to excellent yields. These conditions are extremely mild and simple and tolerate various functional groups.

Dilithiation of 3-amino-4-picoline (1) was achieved with sec-BuLi at room temperature. Condensation of the resulting dianion (2) with carboxylic esters afforded a wide range of 2-substituted 6-azaindoles in good yields.

[reaction: see text]. A novel N-heterocyclic carbene (NHC) catalyzed trifluoromethylation reaction of carbonyl compounds was discovered. Both enolizable and nonenolizable aldehydes and alpha-keto esters undergo facile trifluoromethylation with TMSCF3 at room temperature in the presence of only 0.5-1 mol % of the commercially available NHC (1), providing CF3-substituted alcohols in good yields. Selective trifluoromethylation of aldehydes over ketones can be achieved under NHC catalysis. These conditions are mild and simple and tolerate a variety of functional groups.

[reaction: see text] The 5-bromopyridyl-2-magnesium chloride (2), which was not accessible previously, was efficiently synthesized for the first time via an iodo-magnesium exchange reaction with 5-bromo-2-iodopyridine (1). This reactive intermediate was allowed to react with a variety of electrophiles to afford a range of useful functionalized pyridine derivatives. Application of this methodology to 5-bromo-2-iodo-3-picoline provided a simple and economical synthesis of a key intermediate for the preparation of Lonafarnib, a potent anticancer agent.

A practical and improved synthesis of (3S,5S)-3-[(tert-butyloxycarbonyl)methyl]-5-[(methanesulfonyloxy)methyl]-2-pyrrolidinone (1) is described. The key transformations involve a highly efficient reaction sequence consisting of ethoxycarbonylation, alkylation, hydrolysis, and decarboxylation to produce compound 10. The process described herein is practical, robust, and cost-effective, and it has been successfully implemented in a pilot plant to produce a multikilogram quantity of mesylate 1.

[reaction: see text] An efficient enantiospecific synthesis of the LFA-1 antagonist BIRT-377 has been achieved in 43% overall yield in eight steps. The key transformations involve the stereospecific formation of the trans imidazolidinone 7, subsequent alkylation, and the efficient hydrolysis of disubstituted imidazolidinone 9. The process is practical, robust, and cost-effective; it has been successfully implemented in the pilot plant to produce multikilogram quantities of the drug BIRT-377.

[reaction: see text] A variety of 2-aryl-2H-indazoles were synthesized by the palladium-catalyzed intramolecular amination of the corresponding N-aryl-N(o-bromobenzyl)hydrazines. Of several sets of reaction conditions surveyed, the combination of Pd(OAc)2/dppf/tBuONa gave the best results. This method applies to a wide scope of substrates containing electron-donating and electron-withdrawing substituents.

The biosynthesis of diterpene hydrocarbons with enzyme extracts from rice cell suspension cultures was investigated to verify proposed pathways and intermediates in the production of the momilactone and oryzalexin phytoalexins. Diterpene synthase activity in cells treated with chitin to elicit the phytoalexin response was compared with the activity in untreated cells using the acyclic substrates [1-3H](E,E,E)- and [1-3H] (E,Z,E)-geranylgeranyl diphosphates (GGPPs 4-OPP and 11-OPP) as well as the bicyclic substrates [15-3H]ent-copalyl and [15-3H] syn-copalyl diphosphates (CPPs, 5-OPP, and 6-OPP). ent-kaurene (7), ent-sanda, racopimaradiene (8), 9 beta H-pimara-7,15-diene (9), and stemar-13-ene (10) were identified as major products by comparisons with authentic standards. Marked increases in diterpene synthase activities were observed with enzyme from chitin-treated cells: (E,E,E)-GGPP (approximately 100 fold), ent-CPP (approximately 3 fold), and syn-CPP (approximately 60 fold). The very low conversions of (E,Z,E)-GGPP to hydrocarbon products excludes its role in the biosynthesis of 9,10-syn-diterpenes in rice cells. ent-Kaurene was the major diterpene formed from ent-CPP with enzyme from unelicited cells. In contrast the enzyme from chitin-treated cells converted ent-CPP to a mixture of ent-kaurene, ent-sandaracopimaradiene, and a third unidentified diterpene. With syn-CPP as substrate the induced syntheses afforded a mixture of 9 beta-pimaradiene, stemarene, and a third, unidentified syn-diterpene. Overall the results are consistent with the hypothesis that rice cells respond to treatment with chitin fragments by producing new diterpene synthases not present in the untreated cells. These induced cyclases initiate phytoalexin biosynthesis by diverting (E,E,E)-GGPP into new cyclization modes that produce ent-sandaracopimaradiene, stemarene, and 9 beta-pimaradiene, the presumed precursors to oryzalexins A-F, oryzalexin S, and momilactones A-C, respectively. The intermediate role of 9,10-syn-CPP in syn diterpene biosynthesis is verified.