Additions of organozinc reagents to carbonyl compounds: The development of new and efficient processes

A long standing problem in organic synthesis is the catalytic asymmetric addition of alkyl groups to ketones to establish chiral quaternary centers. Such compounds are valuable chiral building blocks that can be further elaborated. In chapter 1, the development of the first effective catalyst for the enantioselective addition of dialkylzinc reagents to ketones is described.; In chapter 2, the catalytic asymmetric addition of alkyl groups to ketones under solvent-free and highly concentrated conditions was investigated. In comparison with standard reaction conditions employing toluene and hexanes, the solvent-free and highly concentrated conditions permit reduction in catalyst loading by a factor of 2- to 40-fold. These new conditions were general and applicable to a variety of ketones and dialkylzinc reagents to provide diverse tertiary alcohols with high enantioselectivities. Using cyclic conjugated enones, we have performed a tandem asymmetric addition/diastereoselective epoxidation using the solvent-free addition conditions followed by introduction of tert-butyl hydroperoxide (TBHP) to generate epoxy alcohols. This one-pot procedure allowed access to syn epoxy alcohols containing three contiguous stereocenters with excellent enantio- and diastereoselectivities and high yields. The solvent-free and highly concentrated conditions were a significant improvement over previous solvent-based protocols. Furthermore, this chemistry represents a rare example of a catalytic asymmetric reaction that is highly enantioselective under more environmentally friendly solvent-free conditions.; In chapter 3, a new non-aldol approach to the enantioenriched beta-hydroxy aldehydes involving catalytic asymmetric addition of a vinyl ether to an aldehyde and hydrolysis of the newly formed enol ether is discussed. Thus, hydroboration of ethoxy acetylene, transmetallation to zinc, and addition to aldehydes in the presence of a chiral amino alcohol ligand (MIB) afforded hydroxyl enol ethers with high enantioselectivities. The resultant enantiomerically enriched hydroxyl enol ethers were converted to protected hydroxyl aldehydes, a useful synthetic building block for the construction of a variety of polyoxygenated natural products. In addition, diastereoselective formation of syn - and anti-1,3-diols was studied.; In chapter 4, the utility of (Z)-vinyl organometallic reagents is described, which are used in the highly enantioselective synthesis of (Z)-trisubstituted allylic alcohols and direct stereospecific generation of (Z)-disubstituted allylic alcohols. (Abstract shortened by UMI.)...