The asymmetric total synthesis of 3-hydroxyleukotriene B4 (3-OH-LTB4), an ethanol-inducible proinflammatory autacoid, was achieved using a triply convergent strategy for the sequential union of propargylic arsonium salt 3 with pyranosides 2a,b and furanose 4. Both saccharide subunits were derived from commercial 2-deoxy-D-ribose. The key transformation involved palladium-mediated coupling of bromoacetylenide 9 with stannylglycal 6a,b. Subsequent Rieke zinc hydrogenation of acetylene 10a,b and controlled ionic reduction of the cross-conjugated cyclic enol ether using NaBH3CN at pH ~4-4.5 established the cis-Δ6-7-olefin and C(5)-hydroxyl stereochemistry, respectively, and led to 11a,b. Methyllactol hydrolysis, PCC oxidation, methanolysis, and desilylation afforded 3(R)- and 3(S)-OH-LTB4 methyl esters, respectively. On the basis of chromatographic and mass spectral comparisons, enzymatically derived 3-OH-LTB4 is composed principally of the 3(S)-isomer (>95%).
ASJC Scopus subject areas
- Colloid and Surface Chemistry