| Oregon State University | The Chemistry Department | The Organic Division |

Current Synthetic Targets

My research program blends studies of synthetic methods with the total synthesis of natural products and other complex molecules. The goal of our work is to develop new strategies in synthesis and then apply them to the elaboration of targets where particular structural features present a significant challenge. Some examples of the synthetic targets presently being studied are shown below.
The synthesis of complex, highly functionalized structures often requires new methodology, and a substantial part of my research is devoted to finding new reactions and improving old ones. I am particularly interested in devising better ways to secure stereochemistry in densely functionalized structural environments, such as that present in the perimeter of certain macrocycles, and for this purpose we are developing new chiral reagents which should facilitate asymmetric synthesis of subunits of these structures. In addition, we seek novel ways to exploit radical chemistry, photochemistry, and enzymes in the synthesis of specific structural motifs found in natural products.
In designing synthetic routes to complex molecules, the plan often incorporates a key step which plays a pivotal role in establishing the molecular framework. This central reaction may be one patterned after the presumed biogenesis of the compound, or it may be one intended to test the efficiency of a particular bond construction, ring forming process, skeletal rearrangement, etc. These exercises in synthesis usually have a specific target in mind, but the conciseness and novelty of the route to our objectives is always considered at least as important as reaching the goal.

In 1998, Fenical and co-workers reported the isolation and structure of three novel sesterterpenes, neomangicols A, B and C from a Fusarium marine fungus. Neomangicol A was found to possess significant in vitro cytotoxicity toward HCT-116 human colon tumor cell line, while neomangicol B showed antibiotic properties toward the Gram-positive bacterium Bacillus subtilus. The neomangicols all posses a unique fused 5,6,5,6 tetracyclic framework.
Elisabethin A was isolated from the West Indian sea whip Pseudopterogorgia elisabethae found in the Eastern Caribbean Sea. It is a terpenoid metabolite possessing a distinctive tricyclic skeleton different from other members of the elisabethane family. The functionality and arrangement of substituents in elisabethin A are suggestive of an origin via intramolecular Diels-Alder addition to a benzoquinone.
Phomactin A was isolated from the culture filtrate of a fungus (Phoma species) growing on the shells of snow crabs collected of the coast of Japan. Phomactin A and several other phomactins belong to a novel class of platelet activating factor (PAF) antagonists and are of interest as agents for treatment of inflammatory and respiratory diseases such as asthma. The unique bridged structure of phomactin A embedded in a bicyclo[9.3.1]pentadecane ring system has attracted much synthetic attention.

Kendomycin has been isolated from two different Streptomyces species and has been described in the patent literature as a potent endothelin receptor antagonist and an antiosteoporotic compound. It also exhibits antibacterial activity against both Gram-positive and Gram-negative bacteria and it is especialy effective against multi-resistant strains of Staphylococcus Aureus. Kendomycin features a unique ansa structure in which the macrocycle is attached to a quinone methide core.

Koumine is the principle alkaloid present in the Chinese medicinal plant Kou-wen. It is formally a member of the gelsemine class of alkaloids but its cage-like alicyclic structure fused to an indolenine is unique. Its structure and relative configuration have been determined, but only the non-natural enantiomer of koumine has been synthesized.
Ligulaverin A is the major metabolite among a family of related substances (Ligulaverins) found in Ligularia species used in traditional Chinese medicine. The unusual structure of Ligulaverin A and other Ligulaverins is believed to arise in Nature from an enzyme catalyzed intramolecular Diels-Alder addition of a highly functionalized eremophilenolide sesquiterpenoid system. A synthesis plan has been formulated to test this hypothesis.
Pillaromycinone is the aglycone of the anthracycline antibiotic Pillaromycin A, a substance isolated from the culture broth of Streptomyces flavovirens. Pillaromycin A displays potent anti-tumor activity and is less cardiotoxic than other members of the anthracycline family used medicinally. Pillaromycinone is obtained from Pillaromycin A along with the unusual sugar pillarose by acidic hydrolysis.

Providencin is a cytotoxin isolated in 2003 from the gorgonian octacoral Pseudopterogorgia kallos, an animal widely distributed in the shallower region of the southwestern Caribbean sea and the Nicaraguan shelf. The structure of Providencin contains a previously unknown bicyclo[12.2.0]hexadecane skeleton and is formally a member of the cembranoid class of diterpenes. The absolute configuration is unknown.
Vindoline is a major alkaloid of the plant Catharanthus roseus; when coupled to a second alkaloid, catharanthine, it forms the bisindole alkaloid vinblastine, an antineoplastic drug widely used in the treatment of cancer. Vindoline, with its pentacyclic framework and embedded cyclohexane bearing six contiguous stereogenic carbons, has presented a long-standing challenge to synthesis and an efficient solution is still an important objective.

Sanglifehrin A was isolated by scientists at Novartis and was found to possess immunosuppressant activity that resulted in inhibition of both T- and B-lymphocytes. Sanglifehrin, like the immunosuppressant cyclosporine, binds to cyclophilin A and promises to be a useful drug to suppress rejection after organ transplantation. The complex structure of sanglifehrin A can be envisioned as a combination of three major subunits, each of which can be synthesized and assembled in a rational fashion.