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A CONVERGENT AND BIO-INSPIRED TOTAL SYNTHESIS OF PHORBOL

Award Number: F32GM080868
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2007
PERIOD OF PERFORMANCE END DATE: 02/28/2009

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A CONVERGENT AND BIO-INSPIRED TOTAL SYNTHESIS OF PHORBOL - DESCRIPTION (provided by applicant): The total synthesis of phorbol represents a formidable challenge in organic chemistry. Isolated from the Euphorbiaceae plant family, phorbol is a tetracyclic tigliane diterpene that possesses a fused 5-7-6-3 ring system adorned with an array of stereogenic centers. Phorbol and derivatives containing lipophilic ester side chains are known to be potent tumor promoting agents and have also been found to induce other biological responses including HIV expression. The most notable physiological property of phorbol is its ability to bind the regulatory domain of protein kinase C (PKC) which plays a central role in cellular signal transduction. As a consequence of its structural complexity however, only two total syntheses have been reported. A practical and efficient route would be highly desirable to access both natural and unnatural phorbol derivatives. Moreover, despite the similarity of phorbol to other macrocyclic diterpenes (e.g., the daphnanes and ingenanes), a unifying synthetic strategy has not been forthcoming. Based on inspiration from Nature, a convergent total synthesis of phorbol is proposed. It has been known since 1977 that Nature constructs phorbol from a macrocyclic precursor using two transannular carbon-carbon bond forming reactions. Similarly herein, a functionalized macrocycle will provide the template for a chelation-controlled transannular allylation reaction and a conformation-controlled transannular aldol reaction. This strategy will not only serve as a viable means to access phorbol, but will shed light on the biosynthesis of these complex targets. The long-term objective of this research proposal is the efficient preparation and utilization of biologically active phorbol derivatives and other macrocyclic diterpenes for the improvement of public health. ** The development of strategies and techniques for the creation of complex molecules found in Nature is fundamentally important. Phorbol and related compounds have been shown to exhibit a range of biological responses toward the treatment of disease. This research provides an efficient and practical route to these compounds. **


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2008 ( Subtotal = $46,826 )
2008	2008	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	2/20/2008	NON-COMPETING CONTINUATION	$46,826
														Subtotal = $46,826

Issue Date FY: 2007 ( Subtotal = $44,846 )
2007	2007	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	2/23/2007	NEW	$44,846
														Subtotal = $44,846

Grand Total All Awards = $91,672

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A CONVERGENT AND BIO-INSPIRED TOTAL SYNTHESIS OF PHORBOL

Award Number: F32GM080868

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2007

PERIOD OF PERFORMANCE END DATE: 02/28/2009

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