Polar 1,4-cycloadditions of isoquinolinium salts are highly regio- and stereospecific. The overall process disrupts the aza aromatic ring creating a polycyclic system with two new carbon-carbon bonds and up to 5 new stereocenters. Significantly, however, the potential of this reaction is essentially unexplored. The long-range objectives of this proposal are to delineate the scope and limitations of polar 1,4-cycloadditions using isoquinolinium salts and related aza aromatics and to highlight their versatility for the stereorational preparation of chemotherapeutic natural products. These goals will be illustrated in conceptually novel total syntheses of representative examples from four classes of natural products. First, control of stereochemistry and functionality will be demonstrated by total syntheses of the anthracyclinones Alpha1-rhodomycinone, 11-deoxycarminomycinone, and the recently isolated 10-carbomethoxy congeners auramycinone and sulfurmycinone. Second, a highly efficient preparation of the vindoline-type Aspidosperma alkaloid vincadifformine will extend the useful range of polar 1,4-cycloadditions to other aza aromatics. Third, methodology for the regioselective construction of aromatic systems with complex appendages will be exploited in the total synthesis of (+)-vineomycin B2 aglycone. And fourth, a new annulation procedure will be utilized to prepare the protoberberine alkaloid berberine.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM036465-04
Application #
3290482
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1986-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Overall Medical
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390