Professor Marcus A. Tius

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 work in two areas: total synthesis and the development of new synthetic methods. We have completed syntheses of cryptophycin 1 and roseophilin and we are currently working on the synthesis of Nakadomarin A, guanacastepeneand terpestacin. Roseophilin is a Streptomyces-derived product with some selective cytotoxicity in vitro. Nakadomarin was isolated from a marine sponge with in vitro anti cancer activity. Guanacastepene is derived from an endophytic fungus from a Central American tree, and has antibacterial activity. Terpastacin inhibits syncytium formation, a key step in viral maturation, and may therefore be useful against HIV.

A second problem in this area of total synthesis involves a series of functional analogs of tetrahydrocannabinol. This work is part of a long-term collaborative effort with the medicinal chemistry group of Professor Alexandros Makriyannis (Northeastern University). The synthesis and pharmacological evaluation of a series of hetero-substituted adamantyl cannabinoids, typified by the aza compound shown above on the left has been completed. Incorporation of steric bulk at the benzylic position of the cannabinoids is known to potentiate some of the pharmacological properties of these compounds. The goal of this work is to determine whether there are specific interactions between the ligand (the cannabinoid) and the receptor that might give us the ability to design specificity into our structures.

We have also prepared a series of functional analogs of tetrahydrocannabinol that incorporate multiple sites for covalent interaction with the receptor protein (see the structure above and to the right) in order to probe the requirements for binding to the cannabinoid receptor. The chemistry in these projects is more challenging than the structures might suggest.

In parallel with our work in the area of total synthesis, we are also involved in developing new methods for the asymmetric construction of five membered rings by means of a modified Nazarov cyclization. Our early work (above) involved the use of allenyl lithium reagents bearing a sugar-derived chiral auxiliary. Very useful levels of asymmetric induction were obtained in these systems. Our focus on five membered ring synthesis is reflected in our choice of natural product target compounds. Nakadomarin A, guanacastepene and terpestacin were all chosen because of the embedded cyclopentanone, highlighted in red in the structures shown above.

In our search for improved auxiliaries, the tri-tert-butyldimethylsilyl derivative of 2-deoxy-D-glucose was chosen as the chiral auxiliary (see structure above; TBS = tert-butyldimethylsilyl). This chiral auxiliary appears to be close to optimal. Enantiomeric excesses of cyclopentenone products with this auxiliary range between 84% and 93% (enantiomer ratios between 92/8 and 96.5/3.5).

It now appears that this same auxiliary can also be used for the synthesis of cyclopentenones bearing a quaternary carbon atom in the ring (see above). In general, the asymmetric construction of quaternary carbon atoms (especially those in which all substituents are carbon atoms) is still a difficult problem in synthesis. Although the enantiomeric excesses of products are not as high in these cases, they are still synthetically useful

The example shown above reveals another aspect of the reactivity. γ-Butyrolactones are excellent substrates for the asymmetric Nazarov cyclization. The spirocyclic product shown above would be extremely difficult to prepare in any other way.

The reaction shown above summarizes a related cyclization process. Deprotonation of the propargyl ether with n-butyllithium takes place regioselectively adjacent to the methoxy methyl ether. The carbanion so formed undergoes fragmentation to a butatriene with loss of trimethylsilyl oxide. In the presence of more base, the butatriene is converted to its conjugate base, which is also a competent nucleophile. Addition of the morpholino enamide derived from α-methylcinnamic acid leads to a tetrahedral intermediate that undergoes very efficient cyclization upon workup with aqueous phosphate.

There are doubtless many more such variations on the general theme of the Nazarov cyclization. Our group hopes to continue our explorations in this area, and to apply our findings to natural product total synthesis.


	Marcus A. Tius Professor University of Hawaii at Manoa Department of Chemistry 2545 The Mall, Honolulu, HI 96822-2275 Phone: (808) 956-2779 Fax: (808) 956-5908 Email: tius@gold.chem.hawaii.edu
	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. Synthesis We work in two areas: total synthesis and the development of new synthetic methods. We have completed syntheses of cryptophycin 1 and roseophilin and we are currently working on the synthesis of Nakadomarin A, guanacastepeneand terpestacin. Roseophilin is a Streptomyces-derived product with some selective cytotoxicity in vitro. Nakadomarin was isolated from a marine sponge with in vitro anti cancer activity. Guanacastepene is derived from an endophytic fungus from a Central American tree, and has antibacterial activity. Terpastacin inhibits syncytium formation, a key step in viral maturation, and may therefore be useful against HIV. A second problem in this area of total synthesis involves a series of functional analogs of tetrahydrocannabinol. This work is part of a long-term collaborative effort with the medicinal chemistry group of Professor Alexandros Makriyannis (Northeastern University). The synthesis and pharmacological evaluation of a series of hetero-substituted adamantyl cannabinoids, typified by the aza compound shown above on the left has been completed. Incorporation of steric bulk at the benzylic position of the cannabinoids is known to potentiate some of the pharmacological properties of these compounds. The goal of this work is to determine whether there are specific interactions between the ligand (the cannabinoid) and the receptor that might give us the ability to design specificity into our structures. We have also prepared a series of functional analogs of tetrahydrocannabinol that incorporate multiple sites for covalent interaction with the receptor protein (see the structure above and to the right) in order to probe the requirements for binding to the cannabinoid receptor. The chemistry in these projects is more challenging than the structures might suggest. Methods Development In parallel with our work in the area of total synthesis, we are also involved in developing new methods for the asymmetric construction of five membered rings by means of a modified Nazarov cyclization. Our early work (above) involved the use of allenyl lithium reagents bearing a sugar-derived chiral auxiliary. Very useful levels of asymmetric induction were obtained in these systems. Our focus on five membered ring synthesis is reflected in our choice of natural product target compounds. Nakadomarin A, guanacastepene and terpestacin were all chosen because of the embedded cyclopentanone, highlighted in red in the structures shown above. In our search for improved auxiliaries, the tri-tert-butyldimethylsilyl derivative of 2-deoxy-D-glucose was chosen as the chiral auxiliary (see structure above; TBS = tert-butyldimethylsilyl). This chiral auxiliary appears to be close to optimal. Enantiomeric excesses of cyclopentenone products with this auxiliary range between 84% and 93% (enantiomer ratios between 92/8 and 96.5/3.5). It now appears that this same auxiliary can also be used for the synthesis of cyclopentenones bearing a quaternary carbon atom in the ring (see above). In general, the asymmetric construction of quaternary carbon atoms (especially those in which all substituents are carbon atoms) is still a difficult problem in synthesis. Although the enantiomeric excesses of products are not as high in these cases, they are still synthetically useful The example shown above reveals another aspect of the reactivity. γ-Butyrolactones are excellent substrates for the asymmetric Nazarov cyclization. The spirocyclic product shown above would be extremely difficult to prepare in any other way. The reaction shown above summarizes a related cyclization process. Deprotonation of the propargyl ether with n-butyllithium takes place regioselectively adjacent to the methoxy methyl ether. The carbanion so formed undergoes fragmentation to a butatriene with loss of trimethylsilyl oxide. In the presence of more base, the butatriene is converted to its conjugate base, which is also a competent nucleophile. Addition of the morpholino enamide derived from α-methylcinnamic acid leads to a tetrahedral intermediate that undergoes very efficient cyclization upon workup with aqueous phosphate. There are doubtless many more such variations on the general theme of the Nazarov cyclization. Our group hopes to continue our explorations in this area, and to apply our findings to natural product total synthesis.

	Representative Publications “Stereospecific Synthesis of Cryptophycin 1.” Li, L.-H.; Tius, M. A. Org. Lett. 2002, 4, 1637-1640. “Synthesis of Enantioenriched 5-Alkylidene-2-cyclopentenones from Chiral Allenyl Carbamates: Generation of a Chiral Lithium Allenolate and Allylic Activation for a Conrotatory 4-Electrocyclization” Schultz-Fademrecht, C.; Tius, M. A.; Grimme, S.; Wibbeling, B.; Hoppe, D. Ang. Chem. Int. Ed. 2002, 41, 1532-1535. “Synthesis of the Cryptophycins” Tius, M. A. Tetrahedron 2002, 58, 4343-4367. “Asymmetric Cyclopentannelation. Camphor-Derived Auxiliary.” Harrington, P. E.; Murai, T.; Chu, C., Tius, M. A. J. Am. Chem Soc. 2002, 124, 10091-10100. “Synthesis of the Hydroazulene Portion of Guanacastepene A from the Cyclopentannelation Reaction.” Nakazaki, A.; Sharma, U.; Tius, M. A. Org. Lett. 2002, 4, 3363-3366. "Cationic Cyclopentannelation of Allene Ethers." Tius, M. A. Accounts Chem. Res., 2003, 36, 284-290. “Enantiomeric resolution of a novel chiral cannabinoid receptor ligand.” Thakur, G. A.; Palmer, S. L.; Harrington, P. E.; Stergiades, I. A.; Tius, M. A.; Makriyannis, A. J. Biochem. Biophys. Methods 2002, 54, 415-422. “Synthesis of Covalent Probes for the Radiolabeling of the Cannabinoid Receptor.” Chu, C.; Ramamurthy, A.; Makriyannis, A.; Tius, M. A. J. Org. Chem. 2003, 68, 55-61. “The First Example of Nazarov Reactions of Vinyl Cumulenyl Ketones.” Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171-1174. “Convergent Cyclopentannelation Process.” Bee, C.; Tius, M. A. Org. Lett. 2003, 5, 1681-1684. “Isomerization-Cyclization Approach to the Synthesis of 2-Hydroxy-5-alkylidene-cyclopent-2-enones.” Forest, J.; Bee, C.; Cordaro, F.; Tius, M. A. Org. Lett. 2003, 5, 4069-4072. “The Palladium(II) Catalyzed Nazarov Reaction” Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927-4930. “Tetrasubstituted Allene Ethers; Synthesis and Use in Nazarov Reactions.” Tokeshi, B. K.; Tius, M. A. Synthesis 2004, 786-790. “A Tandem Alkylation-Cyclization Process via an O,C-Dianion.” Banaag, A. R.; Berger, G. O.; Dhoro, F.; delos Santos D. B.; Dixon, D. P.; Mitchell, J. P.; Tokeshi, B. K.; Tius, M. A. Tetrahedron 2005, 61, 3419-3428.
		Last updated 05/05/05