Alan Whitehead

A convenient approach to cyclic enol phosphates via ring-closing metathesis

A strategy employing the second generation Grubbs catalyst in order to facilitate the generation of a variety of cyclic enol phosphates, including 2H-chromen-4-yl, 1,2-dihydroquinolin-4-yl, 2H-thiochromen-4-yl, 2H-thiochromen-4-yl 1,1-dioxide, and benzofuran-2-yl enol phosphate scaffolds is described. This work represents the first case of an olefin metathesis reaction in which one of the groups participating in the metathesis event is an enol phosphate moiety.

Total Synthesis of Dolabelide C: A Phosphate-Mediated Approach

The first synthesis of dolabelide C (1), a cytotoxic marine macrolide, is reported utilizing a phosphate tether-mediated approach. Bicyclic phosphates (S,S,S(P))-5 and (R,R,R(P))-5 serve as the central building blocks for the construction of two major 1,3-anti-diol subunits in 1 through selective cleavage pathways, regioselective olefin reduction, and cross-metathesis. Overall, phosphate-mediated processes provided copious amounts of both major subunits allowing for a detailed RCM macrocyclization study to the 24-membered macrolactone 1.

A Multifaceted Phosphate Tether: Application to the C15-C30 Subunit of Dolabelides A-D

Construction of the C15-C30 subunit of dolabelide utilizing a temporary phosphate tether is described. Two routes are reported that make use of the orthogonal protecting- and leaving-group properties innate to phosphate esters. One route relies on a selective terminal oxidation, while a second utilizes a CM/selective hydrogenation sequence. Both routes depend on a highly regio- and diastereoselective cuprate addition to set the requisite stereochemistry at C22.

Selective Formation of Functionalized α-Quaternary Malononitriles toward 5,5-Disubstituted Pyrrolopyrimidinones

A modular, selective approach to complex α-tertiary substituted malononitriles is reported. The method takes advantage of β-ester-substituted α,α-dinitrile alkenes as highly reactive, chemoselective electrophiles for 1,4-additions with organometallic nucleophiles to produce functionally and sterically dense all-carbon quaternary centers. In the presence of a chiral ester auxiliary bearing an aromatic ring, the 1,4-addition occurs with good to excellent selectivity due to favorable cation-π interactions. The highly functionalized malononitriles represent versatile building blocks and can be applied toward efficient, highly selective syntheses of 5,5-disubstituted pyrrolopyrimidinones.