Marcus A. Tius, Professor
Department of Chemistry
University of Hawai’i at Manoa
2545 McCarthy Mall
Honolulu, HI 96822-2275
Phone: (808) 956-2779
Fax: (808) 956-5908
Email: Marcus Tius
Office: Bilger 321D
Marcus A. Tius received his B.A. degree in 1975 from Dartmouth College (mathematics and chemistry) and his Ph.D. degree in 1980 from Harvard University. He joined the faculty of the University of Hawaii in 1980 where his research interests are in the areas of total synthesis and the development of new synthetic methods.
Organic synthesis has marked impressive advances during the past few decades. Sensitive new analytical techniques have had a large role in bringing this about, particularly the developments in NMR. Problems that arise during the execution of a total synthesis very often suggest areas in which existing methodology is deficient. This, in turn, creates a challenge and an opportunity to address the deficiency by developing new methodology.
In the broader discussion of organic synthesis, a feature that often gets scant attention is the practicality of the work. While it may be true that extraordinarily complex structures are amenable to assembly through synthesis, success may require truly heroic effort, and vast material and human resources for the production of modest quantities of material. Whereas this approach to the science may have been adequate in the past, in the future the issue of practicality will have to be addressed. This is especially true for materials with useful pharmacological properties that are not available through fermentation, and are therefore scarce. While organic synthesis is capable of producing complex natural products, these may be produced in quantities sufficient only for spectroscopic characterization. If the problem is to produce gram quantities of a material of molecular weight ca. 1000, there are two approaches that can be followed. The first is to treat this as a logistical problem, and to organize the efforts of a large team; the second approach is to redefine the way one thinks about problem solving in organic synthesis and to devise an approach which can be implemented by a small team. In our research we have attempted to follow this second approach.
We have ongoing work in three areas: total synthesis, the development of new synhetic methods and the preparation of specific ligands for the CB1 and CB2 receptors. This last area is part of a long-term collaborative effort with the medicinal chemistry group of Professor Alexandros Makriyannis (Center for Drug Discovery, Northeastern University).
Our methods development has focused on catalytic asymmetric versions of the Nazarov cyclization. In the past we had developed a series of very effective pyranose-derived chiral auxiliaries for use in the allene ether version of the Nazarov cyclization. More recently we have directed our attention to the development of organocatalysts as well as transition metal based catalysts for the Nazarov cyclization. Our initial attempts to use alpha-ketoenones (see compound 1) led to the development of a highly enantioselective cyclization that used diamine salt 2 as a stoichiometric reagent to produce alpha-hydroxyenones 3. The key to developing a successful catalytic process was to design a more reactive class of acyclic substrates that could be activated by weaker, non-covalent catalysts. We hypothesized that diketoesters such as 4 would be excellent substrates for Nazarov cyclizations because of their complementary polarization: carbon atom 2 bears a partial negative charge whereas carbon atom 5 bears a partial positive charge. We predicted that dual activation of 4 by an organocatalyst such as 5 would lead to Nazarov products. This proved to be the case, as indicated by the conversion of diketoester 6 to Nazarov product 7. The cyclizations of a series of diketoesters all led to products in good yields and enantioselectivities, however, the reaction was slow, presumably due to product inhibition. Efforts are underway to explore new catalysts and to modify the substrates so as to minimize product inhibition.
As a part of our collaboration with Professor Makriyannis (Northeastern University) we have prepared a series of tricyclic hybrid adamantyl cannabinoids (see structures 8 – 11). Both stereochemistries at C9 were examined. The affinities for human CB2 and rat CB1 receptors is indicated. The goal of this work is to determine whether there are specific interactions between the ligand (the cannabinoid) and the receptor (CB1 or CB2) that might give us the ability to design specificity into our structures. The chemistry in this project is more challenging than the structures might suggest.
- Bow, W. F.; Basak, A. K.; Jolit, A.; Vicic, D. A.; Tius M. A. Enamine-Iminium Ion Nazarov Cyclization of alpha-Ketoenones Org. Lett. 2010, 12, 440–443.
- Basak, A. K.; Shimada, N.; Bow, W. F.; Vicic, D. A.; Tius, M. A. An Organocatalytic Asymmetric Nazarov Cyclization J. Am. Chem. Soc. 2010, 132, 8266–8267.
- Dixon, D.; Divakaramenon, S.; Benneche, T.; Banaag, A.; Tius, M. A.; Thakur, G.; Bowman, A.; Wood, J.; Makriyannis, A. J. Heteroadamantyl Cannabinoids J. Med. Chem. 2010, 53, 5656–5666.