The total synthesis of a variety of compounds with demonstrated cardiac activity is proposed. Our general aim is to develop new efficient synthetic procedures such that the target compounds will be available, via total synthesis, in sufficient quantities for detailed pharmacological evaluations. The general target areas are the pumiliotoxin A and gelsemium alkaloids, and the forskolin family of labdane diterpenes. Specifically we propose total syntheses for the natural products pumiliotoxins A and B; allopumiliotoxins 267A, B1, and B2; gelsemine, 1, 9-dideoxyforskolin, forskolin, and coleonol. In most cases the target compounds are to be prepared in enantiomerically pure form. The pumiliotoxin A alkaloids represent a model for developing a new class of cardiotonic and myotonic agents which act via selective calcium channel effects.
We aim to exploit synthetic technology developed during the past grant period to prepare complex members of this class, which are available in only minute quantities in nature. We moreover propose a rational program of analog synthesis and testing which should yield basic structure-activity information, and hopefully yield compounds of greater activity than natural materials. Forskolin and coleonol display positive ionotropic and antihypertensive effects in cardiac muscle, which appear to be related to their ability to activate cardiac adenylate cyclase. To date, only analogs of the natural diterpenes have been biologically evaluated.
Our aim i s to see if these complex diterpenes (and analogs thereof) can be prepared by total synthesis. Gelsemine is a hexacyclic oxindole alkaloid for which antihypertensive activity has been reported.
Our aim i s to see if this complex alkaloid (and analogs thereof) can be prepared efficiently by total synthesis. Our proposed synthetic approaches are largely founded on new cyclization and rearrangement methodology recently developed in our laboratory.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025854-09
Application #
3338308
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1980-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
9
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Canham, Stephen M; Hafensteiner, Benjamin D; Lebsack, Alec D et al. (2015) Stereocontrolled enantioselective total synthesis of the [2+2] quadrigemine alkaloids. Tetrahedron 71:6424-6436
Quasdorf, Kyle W; Overman, Larry E (2014) Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516:181-91
Overman, Larry E; Roberts, Scott W; Sneddon, Helen F (2008) Catalytic asymmetric synthesis of allylic thiol derivatives. Org Lett 10:1485-8
Lanman, Brian A; Overman, Larry E; Paulini, Ralph et al. (2007) On the structure of palau'amine: evidence for the revised relative configuration from chemical synthesis. J Am Chem Soc 129:12896-900
Becker, Michael H; Chua, Peter; Downham, Robert et al. (2007) Total synthesis of (-)-sarain A. J Am Chem Soc 129:11987-2002
Gergely, Joshua; Morgan, Jeremy B; Overman, Larry E (2006) Stereocontrolled synthesis of functionalized cis-cyclopentapyrazolidines by 1,3-dipolar cycloaddition reactions of azomethine imines. J Org Chem 71:9144-52
Nilsson, Bradley L; Overman, Larry E (2006) Concise synthesis of guanidine-containing heterocycles using the Biginelli reaction. J Org Chem 71:7706-14
Garg, Neil K; Hiebert, Sheldon; Overman, Larry E (2006) Total synthesis of (-)-sarain A. Angew Chem Int Ed Engl 45:2912-5
Cohen, Frederick; Overman, Larry E (2006) Evolution of a strategy for the synthesis of structurally complex batzelladine alkaloids. Enantioselective total synthesis of the proposed structure of batzelladine F and structural revision. J Am Chem Soc 128:2594-603
Cohen, Frederick; Overman, Larry E (2006) Enantioselective total synthesis of batzelladine F and definition of its structure. J Am Chem Soc 128:2604-8

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