Research Projects


Disclaimer: The description below is out-of-date. An update is coming. Our recent publications paint a better picture of what we are up to these days.

The Vanderwal research group focuses its attention on the synthesis of bioactive and structurally interesting natural products. Our current work can be roughly grouped into three different areas: the synthesis and study of polychlorinated natural products, the synthesis of alkaloids using chemistry inspired by the Zincke ring opening of pyridines, and the synthesis of polycyclic terpenes.

POLYCHLORINATED COMPOUNDS

In the area of polychlorinated natural products, our efforts have mostly been directed towards the chlorosulfolipids, an intriguing class of polychlorinated alkanes that bear up to eleven chlorine atoms. To date, we have contributed some methodology for diastereoselective alkene dichlorination and in collaboration with the Gerwick group at the Scripps Institution of Oceanography (UCSD), we have determined the stereochemistry and completed the synthesis of danicalipin A. In two subsequent papers, we have revised the structure and determined the stereochemistry of malhamensilipin A, and completed a short enantioselective synthesis of this chlorosulfolipid. We also wrote a short review describing research to date on the chlorosulfolipids. This work is supported by a grant from the NIGMS of the NIH.

Research 1

ALKALOIDS FROM PYRIDINES

We also enjoy contemplating the many potential applications of the century-old Zincke reaction, which involves the reaction of pyridinium salts with amines. The Zincke ring opening of pyridinium salts provides the versatile donor-acceptor diene known as a Zincke aldehyde. Our work in this area is supported by an NSF-CAREER grant.

Research 2

We have, and continue to uncover new and useful reactivity of both the ring opening reaction, and the Zincke aldehyde products. For instance, we have developed a new heterocycle synthesisbased on the intramolecular aminolysis of pyridinium salts. We have recently applied this reaction to short formal syntheses of the antitumor antibiotics porothramycins A and B.

Research 3
We have also uncovered a new thermal cascade rearrangement of Zincke aldehydes that stereoselectively generates Z-dienamides.
Research 4
When this thermal rearrangement reaction is performed on Zincke aldehydes derived from allylic or homoallylic amines, polycyclic lactams result from a terminal intramolecular Diels–Alder reaction of the Z-dienamide intermediate. In a collaborative effort with the Houk group at UCLA, we have studied the mechanism of these thermal pericyclic cascade rearrangements by computation and experiment.
Research 5
Applications of each of these new methods in concise syntheses of alkaloid natural products is ongoing.

We have recently developed formal intramolecular cycloaddition reactions of Zincke aldehydes, and used this reaction as the key architecture forming step in a short synthesis of the Strychnos alkaloid norfluorocurarine, and most recently in a synthesis of strychnine that proceeds in only six steps from commercially available starting materials. Application of this reaction, and related processes using donor-acceptor dienes, to the syntheses of other indole monoterpene alkaloids is ongoing.

Research 6

POLYCYCLIC TERPENES

Complex polycyclic terpenes demonstrate many opportunities for the development of new chemistry. In one recent contribution from our research group, we have found an effective strategy for the synthesis of exo-methylidenecycloalkanes, which are present in many terpenes. We applied this ring-closing-metathesis-based strategy to short syntheses of teucladiol and poitediol. A followup study further demonstrated the versatility of this strategy.

Research 7