My graduate research in the Dr. Trevor McMorris group, described in detail in my doctoral dissertation, can be divided into two parts:
1.   The total asymmetric synthesis of antitumor compound irofulven
2.   The synthesis of new irofulven derivatives, including peptide conjugate prodrugs

(a) cat Rh₂(OAc)₄, CH₂Cl₂, reflux, 1 h (54% 4, 20% diastereomer of 4); (b) K₂CO₃, 90% i-PrOH/H₂O, rt, 6 h (70%); (c) Ac₂O, Py, rt, 2 h (90%); (d) MeMgCl, THF, -78^oC, 2 h, then 0^oC, 2 h (87%); (e) 2,2-dimethoxypropane, cat p-TsOH, DMF, rt, 24 h (83%); (f) DBU, benzene, rt, 1.5 h; (g) cat RhCl₃^.3H₂O, EtOH, reflux, 20 min (62%, 2 steps); (h) 80% AcOH/H₂O, 90^oC, 2 h (78%); (i) DIBALH, CH₂Cl₂, -78^oC, 30 min (49%); (j) IBX, EtOAc, 90^oC, 2 h (73%); (k) (CH₂O)_n, 1 M H₂SO₄, acetone, rt, 6h (84%).

Total Asymmetric Synthesis of Irofulven:
MGI Pharma's proprietary anticancer drug, irofulven (1, scheme 1 above) has demonstrated effectiveness against a variety of cancers and is currently in phase 2 clinical trials against refractory or recurrent advanced epithelial ovarian cancer, hormone-refractory prostate cancer, recurrent malignant glioma, and inoperable liver cancer. Irofulven has been obtained in a two-step reaction from illudin S, which is itself obtained as a natural product from the fermentation of the fungus Omphalotus illudens. Problems in the scale up of production of irofulven led our group to explore whether total synthesis might be a better option. Also, the synthesis of irofulven's enantiomer would allow us to better understand the biological mechanism of irofulven's antitumor activity and what role the tertiary hydroxyl stereocenter plays. I developed new 11-step synthesis to obtain enantiopure (-)-irofulven in 3.6% overall yield starting with a 1,3-dipolar cycloaddition reaction of 1-acetyl-1-diazoacetylcyclopropane (2) with (S)-5-chloro-5-methyl-2-cyclopentenone (3). (+)-Irofulven was similarly obtained beginning with the (R)-cyclopentenone. Each of the starting cyclopentenone enantiomers was obtained from the racemic material via a resolution method I developed.  In vitro and in vivo biological studies performed by our collaborator, Dr. Michael Kelner, found that the unnatural (+)-enantiomer of irofulven had about 5 to 6 times less antitumor activity in vitro than "natural" (-)-irofulven to MV522 lung adenocarcinoma cells, though both had nearly identical in vivo toxicity. Publications: "Synthesis and Biological Activity of Enantiomers of Antitumor Irofulven"; Journal of Organic Chemistry, 2004; 69(3); 619-623. "Resolution of Both Enantiomers of 5-Chloro-5-methyl-2-cyclopentenone"; Journal of Organic Chemistry, 2002; 67(22); 7902-7903.

The animated graphic below depicts the biological mechanism of action of irofulven. The a,ß-unsaturated ketone is first attacked by thiol or hydride from NADPH. The resulting cyclohexadiene is unstable and is attacked by a number of nucleophiles, including DNA. Alkylation of DNA leads to apoptosis of the tumor cell.

Irofulven Derivatives:
The Trevor McMorris group is also involved in synthesizing derivatives of irofulven with the goal of producing more effective and more selective antitumor compounds. One approach that has been used in our group is to form "prodrugs" by covalently linking peptides cleavable by prostate-specific antigen (PSA) to an irofulven derivative (8, Scheme 2). PSA is an enzyme produced in large quantities by prostate tumor cells. Our peptide prodrugs were expected to be relatively inactive until they reach the tumor site, whereupon PSA would cleave the peptide and release an active irofulven derivative into the tumor cell to destroy it. I prepared two peptide-irofulven derivatives (10, 13) which were found to be >30 times more potent against PSA-secreting prostate cancer cells than PSA-nonsecreting cells in vitro.
Our group also continues to prepare a number of non-peptide irofulven derivatives to be screened for antitumor activity. I personally have prepared over a dozen of such compounds. One particular derivative containing hydroxyurea was found to have even greater antitumor activity than irofulven and has the potential to be a future drug candidate.