An Efficient, Modular Approach for the Synthesis of (+)-Strictifolione and a Related Natural Product

An efficient, library amenable, “pot economical” total synthesis of (+)-strictifolione and the related natural product, (6R)-6[(E,4R,6R)-4,6-dihydroxy-10-phenyl-1-decenyl]-5,6-dihydro-2H-2-pyrone are reported. This modular approach takes advantage of two consecutive phosphate tether-mediated, one-pot, sequential protocols, followed by a final cross metathesis to deliver both antifungal natural products in a three-pot process from the respective enantiomeric (R,R)- and (S,S)-trienes with minimal purification. A salient feature of this route is that additional protecting groups are not required as a result of the orthogonal protecting- and leaving-group properties innate to phosphate triesters

A Concise, Phosphate-Mediated Approach to the Total Synthesis of (−)-Tetrahydrolipstatin

An efficient synthesis of (−)-tetrahydrolipstatin (THL) is reported. This method takes advantage of a phosphate tether-mediated, one-pot, sequential RCM/CM/hydrogenation protocol to deliver THL in 8 total steps from a readily prepared (S,S)-triene. The strategy incorporates selective cross metathesis, regio-selective hydrogenation, regio- and diastereoselective cuprate addition and Mitsunobu inversion for installation of the C5 formamide ester subunit

A Phosphate Tether-Mediated, One-pot, Sequential RCM/CM/Chemo-selective Hydrogenation Protocol

A versatile three-step, one-pot, sequential reaction protocol involving RCM, CM, and chemoselective hydrogenation is reported. This phosphate tether-mediated process occurs without intermediate isolation, is chemoselective and is governed by stereoelectronic properties innate to phosphate tethers, which ultimately act to preserve the integrity of the bisallylic, bicyclic phosphate for subsequent nucleophilic additions. Overall, this process can be used to efficiently generate advanced polyol synthons

A Phosphate Tether-Mediated, One-Pot, Sequential Ring-Closing Metathesis/Cross-Metathesis/Chemoselective Hydrogenation Protocol

A versatile three-step, one-pot, sequential reaction protocol involving ring-closing metathesis, cross-metathesis, and chemoselective hydrogenation is reported. This phosphate tether-mediated process occurs without intermediate isolation, is chemoselective, and is governed by stereoelectronic properties innate to phosphate tethers, which ultimately act to preserve the integrity of the bisallylic, bicyclic phosphate for subsequent nucleophilic additions. Overall, this process can be used to efficiently generate advanced polyol synthons

Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation

In this letter we report first nonpeptide inhibitors of hepatocyte growth factor (HGF) activation. These compounds inhibit the three proteases (matriptase, hepsin, and HGF activator) required for HGF maturation. We show that <b>6</b>, <b>8a</b>, <b>8b</b>, and <b>8d</b> block activation of fibroblast-derived pro-HGF, thus preventing fibroblast-induced scattering of DU145 prostate cancer cells. Compound <b>6</b> (SRI 31215) is very soluble (91 μM) and has excellent microsome stability (human <i>t</i>_1/2 = 162 min; mouse <i>t</i>_1/2 = 296 min). In mouse <b>6</b> has an <i>in vivo</i> <i>t</i>_1/2 = 5.8 h following IV administration. The high solubility of <b>6</b> and IV <i>t</i>_1/2 make this compound a suitable prototype “triplex inhibitor” for the study of the inhibition of HGF activation <i>in vivo</i>