William G. Whittingham

A General Approach to the Asymmetric Synthesis of Vancomycin-Related Arylglycines by Enolate Azidation

The asymmetric synthesis of vancomycin-related 0t-azido arylglycines by direct azide transfer methodology is reported. Procedures for the conversion of the azides to N-protected arylglycines are provided. Vancomycin, ristocetin, and related glycopeptide antibiotics 2 contain three to five racemization-prone aryl- glycines 3 within the heptapeptide aglycones. Accordingly, any attempt to synthesize any member of this family of natural products must incorporate methodology for the construction of these nonproteinogenic arylglycines. 4 In conjunction with our studies directed toward the synthesis of these antibiotics, we have prepared a number of functionalized arylglycines by the asymmetric azidation methodology (eq 1) developed in this laboratory. 4b,c A recent publication by Williams and co-workers 5 which also described the application of our methodology to the asymmetric synthesis of vancomycin-related arylglycines noted that, in certain instances, the N-sulfonyltriazene intermediate 2 could not be decomposed to the azido imide 3. The purpose of this Letter is to describe our investigations in this area, and to discuss successful procedures for the decomposition of the intermediate triazenes to the azide products.

Stereoselective synthesis of the bicyclic core structure of the highly oxidised sesquiterpene neoliacinic acid

Abstract The bicyclic core ( 3 ) of the sesquiterpene neoliacinic acid ( 1 ) has been constructed in a stereoselective manner by [2,3]-sigmatropic ring-expansion of an oxonium ylide generated catalytically from the α-diazo ketone 4 .

Oxidative cyclization reactions of trienes and dienynes: total synthesis of membrarollin.

Trienes and dienynes containing one electron-deficient double bond were shown to undergo regio- and stereoselective oxidative cyclization in the presence of permanganate ion to afford 2,5-bis-hydroxyalkyltetrahydrofurans (THF diols). The THF diols produced retained either alkene or alkyne functionalities, which provided convenient handles for the metal oxo-mediated introduction of an adjacent THF ring with overall control of relative and absolute stereochemistry. Adjacent bis-THFs possessing threo-cis-threo-trans-erythro, threo-cis-threo-trans-threo, threo-cis-threo-cis-erythro, threo-cis-erythro-cis-threo, or threo-cis-erythro-trans-threo relationships were synthesized by appropriate selection of alkene geometry and methodology for the closure of the second ring. The threo-cis-threo-cis-erythro stereochemical arrangement is embodied within the bis-THF core units of a number of Annonaceous acetogenins including membrarollin, while trilobacin has a threo-cis-erythro-trans-threo configured core. As an application of the selective oxidative cyclization approach, a total synthesis of membrarollin was completed in 17 linear steps from dodecyne. The C21,C22 double epimer of membrarollin was also synthesized in 15 linear steps and without recourse to the use of hydroxyl group protection.

Stereoselective Construction of the Tricyclic Core of Neoliacinic Acid

The tricyclic core of the plant-derived sesquiterpene natural product neoliacinic acid was synthesized using a novel synthetic strategy. The pivotal synthetic transformations are construction of the key bicyclic ether-bridged intermediate by sequential deployment of metal carbenoid C-H insertion and ylide-forming reactions and installation of the lactone portion of neoliacinic acid by an acid-catalyzed intramolecular ring-opening reaction of an epoxide with a carboxylic acid.

A new synthesis of phosphoramidates: inhibitors of the key bacterial enzyme aspartate semi-aldehyde dehydrogenaseElectronic supplementary information (ESI) available: [??]D20 measurements for compounds 4, 5 and 11; analytical data for 11. See http://www.rsc.org/suppdata/cc/b2/b206199f/

A new, mild and high yielding synthesis of phosphoramidates is described: potassium salts of carboxylic acids are treated with ethylchloroformate and the resulting activated anhydride-carbonates are then treated with LiNH-P(O)(OEt)2 in situ--the methodology is especially suited to acid sensitive systems featuring BOC, tBu or acetal protecting groups.

Stereoselective dimerisation at the end of a radical cascade sequence

Abstract A novel cascade sequence, that begins with the samarium(II) iodide mediated formation of a ketyl radical, leads to a primary alkyl radical, which appears to be partially ‘protected’ from the anticipated further reduction to an organosamarium, and instead undergoes a highly stereoselective dimerisation.

Diastereoselective SmI2-mediated cascade radical cyclisations of methylenecyclopropane derivatives—a synthesis of paeonilactone B

The SmI2-mediated cascade reaction of methylenecyclopropyl ketone 9 proceeds with high diastereoselectivity, which is critically dependent on the presence of HMPA, and provides a short route to paeonilactone B.

Synthesis of the functionalised core of neoliacinic acid

An advanced intermediate in the synthesis of neoliacinic acid has been prepared, and the structure and relative stereochemistry have been confirmed by X-ray crystallography.