Target Oriented Synthesis (TOS) of Natural Products
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1. Indole Alkaloid Synthesis
One of the central themes of research in our laboratories is development of phosphine-catalyzed allenoate annulations and their applications in the chemical synthesis of natural products and their unnatural analogs of medicinal significance. Toward this goal we have developed eleven phosphine-catalyzed allenoate annulations. One specific reaction, a phosphine-catalyzed [4+2] annulation of 2-alkyl-2,3-butadienoates with aldimines to form tetrahydropyridines, presented a unique opportunity in the chemical synthesis of monoterpenoid indole alkaloids such as hirsuteine (1), hirsutine (2), alstonerine (3), macroline (4), alstomicine (5), and reserpine (6). The synthetic targets are highly relevant to human health, specifically the treatment of the common cold, hypertension, amoebic dysentery, malaria, arrhythmia, and cancer.
We recently completed formal total syntheses of macroline-type indole alkaloids Alstonerine and Macroline.
Org. Lett. 2005, 7, 4289-4291. [PDF]
For Hirsuteine/Hirsutine, a key tetracyclic intermediate was synthesized in eight steps from indole 2-carboxaldehyde at 22% overall yield. Three more steps remain to complete the first total synthesis of Hirsuteine, and one additional step will give us Hirsutine. The synthetic route we developed for the synthesis of Hirsuteine is essential to making key intermediates for the synthesis of other monoterpenoid indole alkaloids such as Reserpine, a potent antihypertensive and sedative natural product.
2. Total Synthesis of MDR Antibiotic Guanacastepene A and the Combinatorial Synthesis of its Analogs
Emergence of vancomycin-resistant Enterococcus (VRE) in conjunction with methicillin-resistant S. aureus (MRSA) has become a tremendous threat to human health since vancomycin has been the last resort for treating infections caused by MRSA. Isolation of guanacastepene A and its antibiotic activity against MRSA and VRE has attracted many interests in the synthetic community. Unfortunately, guanacastepene A demonstrates hemolytic activity as well as its activity against multi drug-resistant strains of pathogenic bacteria. Our plan is to apply the scheme developed in its total synthesis to the solid-phase split-pool synthesis of guanacastepene analogs. Combined with comparative assays against red blood cells and pathogenic bacteria, a library of guanacastepene A-like compounds presents a possibility of discovering a new multi drug-resistant antibiotic.
We have established a route to synthesize the [5-7-6] tricyclic core of guanacastepene A.
Org. Lett. 2003, 5, 1923–1926. [PDF]
An advanced tricyclic intermediate for the synthesis of MDR antibiotic Guanacastepene A is achieved in 16 steps from 3-butyn-1-ol. Six additional steps remain for a diastereoselective synthesis of the target natural product.
Tetrahedron Lett. 2004, 45, 8843-8846. [PDF]
3. Total Synthesis of Resiniferatoxin
In its practice, developing new organic transformations is multifaceted. As part of our endeavor to synthesize resiniferatoxin, a “vinylogous pinacol rearrangement” is proposed for the construction of hydroazulene system from trans-decalin framework. This new reaction is of critical use for the synthesis of resiniferatoxin.
I. Development of New Synthetic Methods