Three-component aza[4+2] cycloaddition/allylboration/retro-sufinyl-ene approach to alpha-hydroxyalkyl piperidines and palustrine alkaloids

Multicomponent reactions (MCR) that rapidly generate molecular complexity from readily available starting materials represent ideal tools in both diversity-oriented and target-oriented synthesis. This work describes the development of one such MCR based on a three-component aza[4+2]cycloaddition/allylboration involving boronodienes, dienophiles and aldehydes. The reaction affords alpha-hydroxyalkyl piperidine motifs, a feature that is encountered in a number of biological active natural products such as quinine, palustrine, cannabisativine and some azasugars. The process is highly stereoselective and creates up to four contiguous stereocenters, and four degrees of diversity in a densely substituted heterobicyclic scaffold.; Chapter 2 describes the development of a convenient procedure for the isolation of functionalized (E)-1-alkenylboronic acids, which greatly facilitated the synthesis of the required boronodiene components. With this tool in hand, we were able to initiate studies aimed at exploring the scope and limitations as well as expanding the scope of compatible dienophiles of our three-component aza-Diels-Alder reaction. This work is described in Chapter 3. It followed that the three-component reaction tolerates a wide variety of aldehydes and hydrazines, which makes it suitable for diversity-oriented synthesis applications. However, it was found that the scope is limited to diactivated dienophiles such as maleimides.; In order to apply this reaction to complex targets such as the palustrine alkaloids, we turned our attention to the isothiazolidinone dienophiles. The MCR adducts involving these dienophiles were efficiently carried through a retro-sulfinyi-ene reaction, which culminated in the efficient regioselective introduction of the C3--C4 unsaturation of the palustrine alkaloids. These successful efforts are summarized in Chapter 4. This double alkene migration strategy was applied to the asymmetric synthesis of (-)-methyl dihydropalustramate, a palustrine degradation product. The synthesis of the latter target was completed in only ten linear steps, which represents the shortest sequence to this target reported to this date.; Chapter 5 describes the synthesis of 1-(trimethylsilylmethyl)benzylhydrazines, which played a pivotal role in our completed synthesis of (-)-methyl palustramate. These tetraalkylhydrazines can be cleaved under mildly acidic conditions in the presence of double bonds. This work represents the first report of a non-reductive/oxidative cleavage of hydrazines.