Search

Protection of the amino acid moiety using 9-BBN is an effective method to enable side chain manipulations in synthesis of complex amino acids. We investigated the standard, mild method for deprotection of the 9-BBN group in methanolic chloroform, and found that it relies on a slow oxidation mediated by molecular oxygen. Building on this insight, we have developed a method that allows for a fast and selective deprotection using simple peroxy acid reagents. After Fmoc protection, products were isolated in >90% yield for a series of amino acid derivatives, including a galactosylated derivative of hydroxylysine.

A procedure for Ni-catalyzed cross-coupling of ketone enolates with alkenyl halides has been developed. Intermolecular coupling of aromatic and aliphatic ketone lithium enolates with a variety of alkenyl halides is achieved in the presence of Ni(cod)(2) catalyst (5 mol %), an N-heterocyclic carbene (NHC) ligand, and LiI (10 mol %) at 6-22 degrees C for 0.5-12 h with yields of up to 90%. During the initial development of this reaction, a misleading result with respect to the actual active catalyst was obtained using commercially available Q:Phos ligand, which was found to contain a trace of Pd metal contaminant sufficient to catalyze the reaction. However, under the final conditions optimized for Ni(cod)(2) in the presence of an NHC ligand, Pd was incompetent as a catalyst.

A protocol for a mild, catalytic, intermolecular alkenylation of ketone enolates has been developed using a Pd/Q-Phos catalyst. Efficient intermolecular coupling of a variety of ketones with alkenyl bromides was achieved with a slight excess of LiHMDS and temperatures down to 0 degrees C.

Transition-metal-catalyzed alkenylation of enolates provides a direct method to synthesize broadly useful ,-unsaturated carbonyl compounds from the corresponding carbonyl compound and alkenyl halides. Despite being reported in the early seventies, this reaction class saw little development for many years. In the past decade, however, efforts to develop this reaction further have increased considerably, and many research groups have reported efficient coupling protocols, including enantioselective versions. These reactions most commonly employ palladium catalysts, but there are also some important reports using nickel. There are many examples of this powerful transformation being used in the synthesis of complex natural products., AuthorCount:3

(R)-(+)-Trichostatic acid and (R)-(+)-trichostatin A (TSA) are natural products that have attracted considerable attention in the field of epigenetic therapies. TSA in particular is a naturally occurring hydroxamic acid having potent activity as a histone deacetylase inhibitor (HDACi) and having significant potential for treatment of a myriad of genetically based diseases. Development of TSA and other trichostatic acid derivatives into useful small-molecule therapies has been hindered by the low natural abundance and high cost associated with these compounds. We report herein our collective efforts towards the development of concise and scalable routes for the synthesis of trichostatic acid and TSA in both racemic and enantioenriched forms. Three independent synthetic pathways were developed with varying degrees of efficiency and convergency. In the first synthesis, the key step was a vinylogous Horner-Wadsworth-Emmons condensation. A Marshall propargylation reaction was used as the key step in the second synthesis, and Pd-catalyzed a-alkenylation of a ketone zinc enolate by using various functionalized alkenyl or dienyl halides was developed for the third synthesis. The second pathway proved to be readily amenable to an enantioselective modification, and both the second and third pathways were straightforwardly adapted for the facile preparation of new analogues of trichostatic acid and TSA., AuthorCount:12