UVM Theses and Dissertations
Format:
Print
Author:
McCormack, Michael Patrick
Dept./Program:
Chemistry
Year:
2013
Degree:
PhD
Abstract:
Functionalized pyrrolidine rings are prevalent scaffolds in compounds of pharmaceutical interest as well as alkaloid natural products. A mild, one-pot multicomponent procedure for the synthesis of highly functionalized pyrrolidine rings through a domino 2-aza-Cope-[3+2] dipolar cycloaddition sequence was developed as a new route to 2-allylpyrrolidines. This work also led to a new method for the preparation of azomethine ylides from a-ketoallylimines through discovery of a dipolar cycloaddition of an unrearranged a-arylhomoallylamine. By coupling a thermally driven 2-aza-Cope rearrangement and a silver mediated dipolar cycloaddition, a library of 2-allylpyrrolidines was prepared in both a high-yielding and stereoselective fashion. The ability to rapidly access 2-allylpyrrolidine rings allowed us the opportunity to investigate their utility in further cyclization events.
This methodology was successfully extended to the synthesis of indolizidine and pyrrolizidine scaffolds. Realizing the potential for further ring closing events utilizing the 2-allyl handle and the rigidity of the cycloadducts, the 2-allylpyrrolidines underwent additional cyclization events through one and two-step synthetic sequences. Two different modes of one-step cyclizations were applied to the pyrrolidine cycloadducts, an aza-Prins cyclization and a phenyl selenyl chloride mediated cyclization to afford substituted indolizidine and pyrrolizidines, respectively. A two-step procedure' was adopted to generate an additional ring through an alkylation and subsequent cobalt mediated Pauson-Khand reaction affording substituted indolizidines as single diastereomers in high yield.
VM55599 contains a highly substituted pyrrolidine ring, three quaternary stereogenic centers and an indole ring, making it an appropriate and challenging synthetic target for applying a 2-allylpyrrolidine generated through a dipolar cycloaddition. The use of 2-allylpyrrolidines in the total synthesis of indole alkaloid VM55599 was investigated by coupling a Pauson-Khand cyclization and a ketocyclopropane ring expansion as a key synthetic step.
During the course of the investigation of the total synthesis of luciduline, the cis decalin ring system resulting from a Diels-Alder cyclization of the Sakurai diene was determined to be an optimal route to the natural product. In our investigation of this potential route, we realized that access to the Sakurai diene was limited. While chloroprene can be readily converted to a Grignard, its limited commercial availability at prohibitive costs makes it a poor synthetic precursor. The Sakurai diene has been used in the total synthesis of multiple natural products, and therefore a more convenient preparation is of significant interest. This led to an investigation of a new synthesis of the Sakurai diene using a Kumada coupling of a dienol phosphate and Grignard reagent in the presence of a Ni(II) catalyst. This material was next applied towards the total synthesis of an indole alkaloid natural product, luciduline.
This methodology was successfully extended to the synthesis of indolizidine and pyrrolizidine scaffolds. Realizing the potential for further ring closing events utilizing the 2-allyl handle and the rigidity of the cycloadducts, the 2-allylpyrrolidines underwent additional cyclization events through one and two-step synthetic sequences. Two different modes of one-step cyclizations were applied to the pyrrolidine cycloadducts, an aza-Prins cyclization and a phenyl selenyl chloride mediated cyclization to afford substituted indolizidine and pyrrolizidines, respectively. A two-step procedure' was adopted to generate an additional ring through an alkylation and subsequent cobalt mediated Pauson-Khand reaction affording substituted indolizidines as single diastereomers in high yield.
VM55599 contains a highly substituted pyrrolidine ring, three quaternary stereogenic centers and an indole ring, making it an appropriate and challenging synthetic target for applying a 2-allylpyrrolidine generated through a dipolar cycloaddition. The use of 2-allylpyrrolidines in the total synthesis of indole alkaloid VM55599 was investigated by coupling a Pauson-Khand cyclization and a ketocyclopropane ring expansion as a key synthetic step.
During the course of the investigation of the total synthesis of luciduline, the cis decalin ring system resulting from a Diels-Alder cyclization of the Sakurai diene was determined to be an optimal route to the natural product. In our investigation of this potential route, we realized that access to the Sakurai diene was limited. While chloroprene can be readily converted to a Grignard, its limited commercial availability at prohibitive costs makes it a poor synthetic precursor. The Sakurai diene has been used in the total synthesis of multiple natural products, and therefore a more convenient preparation is of significant interest. This led to an investigation of a new synthesis of the Sakurai diene using a Kumada coupling of a dienol phosphate and Grignard reagent in the presence of a Ni(II) catalyst. This material was next applied towards the total synthesis of an indole alkaloid natural product, luciduline.