| NSF Org: |
CHE Division Of Chemistry |
| Recipient: |
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| Initial Amendment Date: | December 20, 2012 |
| Latest Amendment Date: | December 20, 2012 |
| Award Number: | 1305821 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Tingyu Li
tli@nsf.gov (703)292-4949 CHE Division Of Chemistry MPS Directorate for Mathematical and Physical Sciences |
| Start Date: | October 1, 2012 |
| End Date: | August 31, 2014 (Estimated) |
| Total Intended Award Amount: | $104,931.00 |
| Total Awarded Amount to Date: | $104,931.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
4300 MARTIN LUTHER KING BLVD HOUSTON TX US 77204-3067 (713)743-5773 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
4800 Calhoun Boulevard Houston TX US 77204-2015 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): | Chemical Synthesis |
| Primary Program Source: |
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| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.049 |
ABSTRACT
In this project funded by the Chemical Synthesis program of the Chemistry Division, Professor Don M. Coltart of the Department of Chemistry at Duke University will explore the development of new methods for the regiocontrolled asymmetric alpha-alkylation of ketones. The central hypothesis of the planned research is that activated hydrazones - those having at least one electron withdrawing group on the distal nitrogen - and oximes will provide the basis for a variety of new approaches to the asymmetric alpha-alkylation of ketones. From this work, fundamentally new regiochemical substitution patterns that cannot be generated using existing technology will be accessible in an asymmetric manner. Moreover, it will be possible to conduct asymmetric alpha-alkylation in an umpolung sense, thus enabling the incorporation of functionality that cannot be introduced using enolate-based methods.
This work could lead to facile methods for the asymmetric alpha-alkylation of ketones. The ability to easily and effectively prepare single enantiomer forms of alpha-alkylated ketones will contribute greatly to our ability to synthesize optically pure natural products, drugs and related compounds, thus impacting science and society in important ways. In addition, this project will provide excellent training of undergraduate and graduate students, including those from groups historically underrepresented in the sciences.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
The first asymmetric total synthesis of the marine natural product apratoxin D, a highly potent inhibitor of H-460 human lung cancer cell growth (IC50 value of 2.6 nM), was achieved under this award. Asymmetric N-amino cyclic carbamate (ACC) a,a-bisalkylation was developed and utilized to establish the isolated C-37 methyl group with excellent selectivity. Other key asymmetric transformations employed were an Evans syn-aldol and a Paterson anti-aldol, both of which also proceeded with excellent stereoselectivity. The synthetic material was evaluated in collaboration with the NCI using its 60 cell line screen, which reveled that it is highly active across a range of cancer cell lines.
The first asymmetric anti-aldol addition of a ketone-derived donor that is not limited by the structure of the ketone has been achieved through the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. Not only does this transformation exhibit essentially perfect anti-diastereoselectivity and enantioselectivity but, remarkably, it also proceeds via thermodynamic, rather than kinetic control. To our knowledge this is the first report of a thermodynamically controlled ketone-based aldol addition involving a chiral auxiliary. Significantly, by merging the known procedure of asymmetric a,a-bisalkylation of ACC hydrazones with this new aldol transformation, it is now possible to gain access to ketone-based aldol addition products that have previously been inaccessible via direct aldol methods.
Last Modified: 05/06/2015
Modified by: Don M Coltart
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