PART ONE: TOTAL SYNTHESES OF AGELADINE A; PART TWO: STUDIES DIRECTED TOWARDS A TOTAL SYNTHESIS OF ACTINOPHYLLIC ACID
Open Access
- Author:
- Meketa, Matthew Lee
- Graduate Program:
- Chemistry
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 15, 2008
- Committee Members:
- Steven M Weinreb, Committee Chair/Co-Chair
Raymond L. Funk, Committee Member
Scott T Phillips, Committee Member
Caroline Elaine Clifford, Committee Member - Keywords:
- organic chemistry
ageladine A
actinophyllic acid
synthesis
electrocyclization
natural products - Abstract:
- Abstract Part One We have completed two unique total syntheses of the marine natural product ageladine A (1). Our first generation total synthesis of this angiogenesis-inhibitory metabolite featured a 6π-1-azatriene electrocyclization of triene 63 to form the pyridine ring of intermediate 66. A subsequent Suzuki-Miyaura coupling of N-Boc-pyrrole-2-boronic acid 67 with a chloroimidazopyridine 82 furnished tricycle 88. After some experimentation, the optimal conditions found for the dibromination of pyrrole 88 was to treat with Br2 in an acetic acid/methanol solvent mixture at 0 ºC to give ageladine A in 17% yield. We have recently completed a more efficient biogenetically-inspired, second generation total synthesis of ageladine A. Key transformations in this second synthesis included an effective 6π-2-azatriene electrocyclization of triene 128 to provide the desired imidazopyridine 129, which contained the imidazopyridine core of the marine metabolite. Ageladine A was synthesized in seven steps from (Z)-vinyl iodide 115 and dibromopyrrole amide 125 and in 13% overall yield. Part Two In work directed towards the total synthesis of the alkaloid actinophyllic acid (158), our proposed synthesis will incorporate several methods developed in the Weinreb lab including a vinyl chloride ring-closing metathesis (RCM) and an intramolecular vinyl nitroso cyclization. Thus, cyclic vinyl chloride 376 was prepared via RCM of vinyl chloride olefin 375. Unfortunately, treatment of vinyl chloride 380 with sodium hypochlorite in acetic acid/acetone did not give the desired α-chloroketone 381, but afforded 3-chloroindole product 383 via a retro-Mannich fragmentation process. In a revised strategy, ethylenol ether diene 404 successfully underwent RCM to yield the desired cyclic enol ether 405, which was then converted to the corresponding α-chloroketone 410 in high yield. Future studies will focus on completion of the synthesis of racemic actinophyllic acid (158) as well as an enantioselective total synthesis of the alkaloid.