Stereoselective Mukaiyama-Michael/Michael/Aldol Domino Cyclization as the Key Step in the Synthesis of Pentasubstituted Arenes: An Efficient Access to Highly Active Inhibitors of Cholesteryl Ester Transfer Protein (CETP).

In spite of a number of successes, the treatment of arteriosclerosis is still a challenge for medicine. In addition to a high LDL-C (low density lipoprotein cholesterol) level, a low HDL-C (high density lipoprotein cholesterol) level is a further, main independent risk factor for coronary heart disease. Whereas the regulation of the LDL-C level by blockade of cholesterol biosynthesis with HMG-CoA reductase (3-hydroxy-methylglutaryl coenzyme A) inhibitors[1] is established medical practice, the increase in HDL-C levels offers a new and promising therapeutic principle. HDL absorbs cholesterol from the periphery, including the coronary arteries, and carries it to the liver for metabolic degradation. The action of cholesteryl ester transfer protein (CETP) leads to a transfer of cholesteryl ester molecules from HDL to LDL in a triglyceride exchange. The disadvantageous net effect is a reduction in HDL-C level and an increase in LDL-C level.[2] Compounds of structure 1 have been identified as highly active CETP inhibitors (IC50 3 nmol Ly1).[3] The complexity of this class of structures and the substance requirements for further testing demanded an efficient synthesis in order to pave the way for applying this innovative principle. We have tried a number of different strategies and with the example of 1b we present here a multigram synthesis which features a new domino reaction as the key step.