Iridium(I)-catalyzed olefin isomerization in bis(allyl) ethers is integrated into a generally applicable strategy for affecting highly stereoselective Claisen rearrangements. Catalyzed alkene isomerization affords allyl vinyl ethers from easily prepared di(allyl) ethers; direct thermolysis of these reaction mixtures leads to highly diastereoselective [3,3] sigmatropic rearrangements affording syn-2,3-dialkyl-4-pentenal derivatives. An easily executed strategy for realizing asymmetric variants of the isomerization-Claisen rearrangement (ICR) reactions is also described.

Using the HIV-1 protease binding mode of and as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to .

A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.

Boron-substituted di(allyl) ethers provide an efficient conduit for expanding the structural diversity available from olefin isomerization-Claisen rearrangement (ICR) reactions. Easily prepared allyl propargyl ethers undergo chemoselective Zr(IV)-catalyzed hydroboration to afford the boron-substituted ICR substrates. The boron-substituted allyl residue undergoes chemoselective Ir(I)-catalyzed olefin isomerization and in situ Claisen rearrangement to afford stereodefined beta-boryl aldehyde products. Functionalization of the C-B linkage by oxidation or Suzuki cross-coupling provides a route to Claisen adducts previously inaccessible from the ICR methodology.

Chemo- and stereoselective Ir(I)-catalyzed isomerization of 1,1-disubstituted and trisubstituted allylic ethers and in situ [3,3] sigmatropic rearrangement of the resulting allyl vinyl ethers provide for the highly stereoselective construction of quaternary carbon stereocenters. The olefin isomerization-Claisen rearrangement (ICR) sequence allows adjacent quaternary-tertiary stereocenter relationships to be established with excellent diastereoselection. Several complementary strategies for enantioselective quaternary carbon synthesis derive directly from the ICR reaction design.