| SCH 351448 is a 28-membered C2-symmetric macrocyclic metabolite isolated from the fermentation broth of a Micromonospora microorganism. This diolide selectively activates transcription of the low-density lipoprotein promoter which is important for clearing the blood serum of cholesterol. Several strategies for the synthesis of SCH 351448 are discussed. The initial approach involves a tandem ring closing metathesis/cross metathesis dimerization strategy where four carbon-carbon bonds are formed in a single reaction vessel. An alternative approach, a tandem ring closing metathesis/cross metathesis followed by a lactonization dimerization, is also discussed. A more conservative approach involves a tandem ring closing metathesis/cross metathesis in conjunction with a sequential esterification/macrolactonization strategy to construct the macrodiolide. Lastly, the synthesis of SCH 351448, featuring two asymmetric glycolate alkylations and three asymmetric aldol additions to establish the key stereocenters in the natural product, is presented. |
