Glycosyl Exchange of Unactivated Glycosidic Bonds: Suppressing or Embracing Side Reactivity in Catalytic Glycosylations

While developing boron-catalyzed glycosylations using glycosyl fluoride donors and trialkylsilyl ether acceptors, competing pathways involving productive glycosylation or glycosyl exchange were observed. Experimental and computational mechanistic studies suggest a novel mode of reactivity where a dioxolenium ion is a key intermediate that promotes both pathways through addition to either a silyl ether or to the acetal of an existing glycosidic linkage. Modifications in catalyst structure enable either pathway to be favored, and with this understanding, improved multicomponent iterative couplings and glycosyl exchange processes were demonstrated.

Studies Towards the Synthesis of Peloruside A

<p>In the search for new treatments for cancer, advances in biology have provided targets for the destruction of cancer cells. One such structure the microtubule, a protein required for cell division, has been the target of many successful anticancer agents including the multi-million dollar earning Taxol [trademark] (paclitaxel) and the epothilones, currently in late-stage clinical trials. More recently it has been shown that peloruside A 1, a secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli, prevents cell division by stabilising microtubules, and thus offers promise as a novel anticancer agent. However, due to its limited natural abundance, significant quantities of peloruside A can only be obtained through chemical synthesis. A retrosynthetic analysis of peloruside A divided the molecule into four key fragments: a) the commercially available C-l to C-2 benzyloxy acetic acid fragment; b) the C-3 to C-7 fragment; c) the C-8 to C-11 fragment and d) the remaining C-12 to C-24 portion of the macrocycle and side chain. The C-3 to C-7 and C-8 to C-11 fragments combine to form a key intermediate pyranose ring. This thesis however, addresses the synthesis of two of these key fragments, namely the C-8 to C-11 and C-12 to C-24 fragments. An efficient synthesis of the C-8 to C-11 fragment of peloruside A, starting from commercially available pantolactone, has been developed. This synthesis proceeds in good overall yield, and has been successfully reproduced on the multigram scale. The significant portion of this thesis, however, is dedicated to the synthesis of the C-12 to C-24 fragment. After our initial strategy proved unviable, a short, facile method for the synthesis of the C-12 to C-24 fragment, involving the formation of a bis-silyl ether, was developed. The protocol for its desired coupling, via a boron_mediated, remote 1,5-anti-induction aldol reaction has also been established. These and subsequent studies provided valuable insight into the origin of 1,5-anti induction in boron-mediated aldol reactions.</p>

Studies Towards the Synthesis of Peloruside A

<p>In the search for new treatments for cancer, advances in biology have provided targets for the destruction of cancer cells. One such structure the microtubule, a protein required for cell division, has been the target of many successful anticancer agents including the multi-million dollar earning Taxol [trademark] (paclitaxel) and the epothilones, currently in late-stage clinical trials. More recently it has been shown that peloruside A 1, a secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli, prevents cell division by stabilising microtubules, and thus offers promise as a novel anticancer agent. However, due to its limited natural abundance, significant quantities of peloruside A can only be obtained through chemical synthesis. A retrosynthetic analysis of peloruside A divided the molecule into four key fragments: a) the commercially available C-l to C-2 benzyloxy acetic acid fragment; b) the C-3 to C-7 fragment; c) the C-8 to C-11 fragment and d) the remaining C-12 to C-24 portion of the macrocycle and side chain. The C-3 to C-7 and C-8 to C-11 fragments combine to form a key intermediate pyranose ring. This thesis however, addresses the synthesis of two of these key fragments, namely the C-8 to C-11 and C-12 to C-24 fragments. An efficient synthesis of the C-8 to C-11 fragment of peloruside A, starting from commercially available pantolactone, has been developed. This synthesis proceeds in good overall yield, and has been successfully reproduced on the multigram scale. The significant portion of this thesis, however, is dedicated to the synthesis of the C-12 to C-24 fragment. After our initial strategy proved unviable, a short, facile method for the synthesis of the C-12 to C-24 fragment, involving the formation of a bis-silyl ether, was developed. The protocol for its desired coupling, via a boron_mediated, remote 1,5-anti-induction aldol reaction has also been established. These and subsequent studies provided valuable insight into the origin of 1,5-anti induction in boron-mediated aldol reactions.</p>