In situ formation of N-trifluoroacetoxy succinimide (TFA-NHS): one-pot formation of succinimidyl esters, N-trifluoroacetyl amino acid succinimidyl esters, and N-maleoyl amino acid succinimidyl esters.

A method for the in situ formation of N-trifluoroacetoxy succinimide (TFA-NHS) and its application in the formation of succinimidyl esters is presented. The developed method provides N-trifluoroacetyl and N-maleoyl amino acid succinimidyl esters from a variety of amino acids using a one-pot, high-yielding protocol. Investigations into the formation of an N-maleoyl amino acid succinimidyl ester supported the proposal of a revised reaction mechanism, and contributed to the optimization of the reaction conditions.

Formation of medium-sized nitrogen heterocycles from gamma-silyloxy-gamma-lactams.

Nitrogen heterocycles can be prepared by performing ring-expansion reactions of gamma-silyloxy-gamma-lactams, which are available by the annulation reactions of allylic silanes. Nucleophilic substitution of the annulation products and subsequent translactamization of nitrogen-tethered gamma-lactams provide six-, seven-, and eight-membered ring lactams. An enantiomerically enriched delta-lactam formed from this method was elaborated to form the hydroxypiperidine core structure of the pseudodistomin alkaloids.

Design, synthesis, and biological activity of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase inhibitors.

A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to explain the improved selectivity for this new series of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent cellular activity (EC(50) = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t(1/2), and 0.19 L/(h x kg) plasma clearance).

Synthesis of homoallyl ethers via allylation of acetals in ionic liquids catalyzed by trimethylsilyl trifluoromethanesulfonate.

The chemoselective allylation of acetals using allyltrimethylsilane in ionic liquids is catalyzed by TMS triflate (5.0-20.0 mol %). The reaction proceeds smoothly at room temperature to afford the corresponding homoallyl ether in good yield. Since the ionic liquids are easily recovered and recycled, they are a useful alternative to dichloromethane, which is the commonly used solvent for allylations. [reaction--see text]

A simple and versatile method for the synthesis of acetals from aldehydes and ketones using bismuth triflate.

Acetals are obtained in good yields by treatment of aldehydes and ketones with trialkyl orthoformate and the corresponding alcohol in the presence of 0.1 mol % Bi(OTf)3.4H2O. A simple procedure for the formation of acetals of diaryl ketones has also been developed. The conversion of carbonyl compounds to the corresponding 1,3-dioxolane using ethylene glycol is also catalyzed by Bi(OTf)3.4H2O (1 mol %). Two methods, both of which avoid the use of benzene, have been developed.