Total synthesis of (+)-SCH 351448 and rhodium catalyzed stereoselective nitrene/alkyne cycloaddition cascade

Thesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.SCH-351448 is a 28-membered C2-symmetric macrocyclic metabolite isolated from the fermentation broth of a Micromonospora microorganism. This macrodiolide selectively activates transcription of the low-density lipoprotein receptor (LDL-R) promoter, which is important in the treatment of people with high cholesterol levels. The biological potential as well as the intriguing structure of this natural product prompted us to initiate synthetic studies towards its preparation. A convergent, enantioselective total synthesis of (+)-SCH 351448 was achieved. The tetrahydropyran ring systems in both fragments were constructed through our organosilane-based [4+2]-annulation methodology. Olefin cross metathesis was utilized in the union of two advanced fragments to generate the monomeric subunit. A metal-template directed macrodimerization strategy was examined but proved unsuccessful. Thus, the macrodiolide was assembled through a two-step sequence involving dioxinone ring-opening with concomitant esterification followed by DMC/DMAP mediated macrolactonization. Due to the prevalence of nitrogen-containing heterocycles in many natural products and pharmaceutical agents, the development of efficient methods for N-incorporation has remained at the forefront of synthetic research. Transition metal-catalyzed nitrene chemistry, an effective method to incorporate N-containing functionality into simple organic substrates, has become an attractive field for direct carbon-nitrogen bond formation. Of particular interest in this area is the metallonitrene/alkyne cycloaddition cascade reaction, a process in which nitrenes formed from sulfamate esters undergo addition to alkynes. In light of this, homopropargylic ethers, derived from chiral allenylsilanes in high yields and levels of diastereoselectivity , were converted into sulfamate esters bearing an internal alkyne. The generated sulfamate esters then underwent a metallonitrene cycloaddition and a subsequent highly stereoselective dearomative cyclopropanation, which resulted in unique tetracyclic norcaradiene-like products with two contiguous quaternary stereocenters. After subsequent opening of the sulfamate ester ring, the norcaradiene scaffold rearranged via a 6π electrocyclic ring opening process to form a fused tricyclic cycloheptatriene