Our research program emphasizes modern synthetic and physical-organic chemistry to solve current problems inherent to the preparation of new organic materials and bioactive compounds. Interesting and synthetically challenging compounds are designed, prepared, and studied by various physical methods to verify our hypotheses. We are presently working on three different projects which have recently gained tremendous significance.
1. Fullerene Chemistry: Since the isolation of the highly symmetrical all-carbon molecule buckminsterfullerene C60 (1), this new field of research has led to several major discoveries. One is the finding that the alkali metal salts K3C60 and Rb3C60 are superconductors with the highest critical transition temperatures ever achieved for organic materials (Tc = 18 and 33 K). This result by itself is enough to justify the intense ongoing research on C60. One of our contributions to this field will take advantage of the powerful tools of organic synthesis to prepare endohedral metal derivatives of C60 (1áMn+), compounds in which a metal atom or ion is entrapped within C60Õs framework. It is expected that the availability of endohedral C60-complexes in isolable quantities will lead to new superconducting phases, redox systems, and other interesting materials. Also, water-soluble derivatives of endohedral fullerenes incorporating radioactive elements may be useful in cancer diagnostic and therapy or as NMR-imaging agents (e.g. with gadolinium) for magnetic resonance imaging (MRI), and may have important medical applications.
We are currently working on a short synthesis of C60 and its endohedral complexes involving the conversion of intermediate 2 to 1 (or 2áM+ to 1áM+ respectively). A large choice of endohedral complexes of C60 should become available by complexation of 2 prior to full closure to the C60-framework. This thermodynamically advantageous reaction may be easily adapted to larger precursors (e.g. for C72, C84, C96) by homologation of the diyne units in 2 with extra acetylene moieties. Another goal is to synthesize the interesting bowl-shaped hydrocarbon 3 (C30H10) that constitutes half of C60Õs framework. The bowl-to-bowl inversion in 3 which proceeds like the folding-over of an umbrella will be studied through variable temperature NMR of a prochiral derivative.
We are also actively exploring the biological activity of C60 derivatives. We have recently prepared several well-characterized Diels-Alder derivatives of C60, of which some are provided with water-solubilizing functional groups (e.g. amino acids 4). These compounds will be anchored to peptides or tumor-specific antibodies. In a collaborative effort with Prof. Foote, we have found that the photophysical properties of C60 are retained in these derivatives, i.e. efficient triplet excited state formation is obaserved and energy transfer to 3O2 results in high yields of singlet oxygen. This means that such compounds may become excellent agents for the photodynamic therapy of cancer. The biological aspect of C60 chemistry should gain increasing appeal, especially since it was recently found that some C60 derivatives inhibit HIV-1 protease, an enzyme that is vital to the function of the AIDS-inducing virus.
We have also begun to explore the preparation and chemistry of multiple-addition derivatives of C60. However, this study is strongly complicated by the fact that many regio- and stereoisomers are obtained from an uncontrolled multiple addition to C60. In the approach shown below, we use a templated tris-addition to effect a selective derivatization. The tris-diene is designed to add only at the 6,6-ring junctions of C60 directly linked to the benzene ring situated on one of C60Õs C3-axes. Once the tris-adduct is obtained, the template can be removed. The primary adducts will provide a ÒcapÓ to C60 permitting the selective oxidation (e.g. O3 or RuO4) of the unprotected C60 surface to take out part of its framework. The availability of these ÒopenÓ derivatives is extremely important, because they could be used to prepare endohedral metal complexes of C60 after complexing a metal, closing back the framework, and regenerating C60 through a retro-Diels-Alder reaction.
2. Organic Ferromagnets: Nature has imposed on us the very challenging task of understanding the rules that govern the alignement of unpaired spins in organic solids in our efforts to achieve bulk ferromagnetism. This problem remains unresolved and incites new approaches. Ours is based on the interaction of new stable organic radicals (e.g. 5, 6) with the high-spin manganese(II) chelate 7 in a designed effort to obtain two- and three-dimensional networks of interacting free spins. We will determine the ground spin states of radicals 5 and 6 by electron spin resonance (ESR) and the magnetic properties of complexes 5/7 or 6/7 by SQUID magnetometry. We will also use X-ray crystallography to obtain important structural information on these complexes.
3. Enediyne Antitumor Drugs: Our bio-organic project is aimed at preparing improved antitumor drugs with low cytotoxicity. Members of the enediyne class of antitumor antibiotics (e.g. calicheamicin, esperamicin, dynemicin, kedarcidin) have recently been under intense scrutiny since they are the most potent antitumor drugs discovered. Unfortunately, the high cytotoxicity of these natural enediynes prevents them from being used in clinical studies. The design of synthetic drugs incorporating the enediyne ÒwarheadÓ should obviate this problem by making them more specific in their interaction with DNA in vivo. In our approach, the ÒwarheadÓ is designed to have more than two radical centers generated in a double-Bergman cyclization reaction. Compound 8 should cyclize to tetraradical 9, likely to be much more potent in its DNA cleaving action. The enediyne ÒwarheadsÓ will be attached to molecules that are known to undergo sequence-specific DNA binding and their strand cleaving ability tested.
(2) Khan, S. I.; Oliver, A. M.; Paddon-Row, M. N.; Rubin, Y. ÒSynthesis of a Rigid ÒBall-and-ChainÓ Donor-Acceptor System through Diels-Alder Functionalization of Buckminsterfullerene (C60)Ó, J. Am. Chem. Soc. 1993, 115, 4919-4920.
(3) Rubin, Y.; Khan, S.; Freedberg, D. I.; Yeretzian, C. ÒSynthesis and X-Ray Structure of a Diels-Alder Adduct of C60Ó, J. Am. Chem. Soc. 1993, 115, 344-345.
(4) Diederich, F.; Rubin, Y. ÒSynthetic Approaches toward Molecular and Polymeric Carbon AllotropesÓ, Angew. Chem. 1992, 104, 1123-1146; Angew. Chem. Int. Ed. Engl. 1992, 31, 1101-1123 (Review).
(5) Rubin, Y.; Lin, S. S.; Knobler, C. B.; Anthony, J.; Boldi, A. M.; Diederich, F. ÒSolution-Spray Flash Vacuum Pyrolysis: A New Method for the Synthesis of Linear Poliynes with Odd Numbers of CºC Bonds from Substituted 3,4-Dialkynyl-3-cyclobutene-1,2-dionesÓ, J. Am. Chem. Soc. 1991, 113, 6943-6949.
(6) Rubin, Y.; Knobler, C. B.; Diederich, F. ÒTetraethynyletheneÓ, Angew. Chem. 1991, 103, 708-710; Angew. Chem. Int. Ed. Engl. 1991, 30, 698-700.
(7) Diederich, F.; Ettl, R.; Rubin, Y.; Whetten, R. L.; Beck, R. D.; Alvarez, M. M.; Anz, S. J.; Sensharma, D.; Wudl, F.; Khemani, K. C.; Koch, A. ÒThe Higher Fullerenes: Isolation and Characterization of C76, C84, C90, C94, and C70O, an Oxide of D5h-C70Ó, Science 1991, 252, 548-551.
(8) Ajie, H.; Alvarez, M. M.; Anz, S. J.; Beck, R. D.; Diederich, F.; Fostiropoulos, K.; Huffman, D. R.; KrŠtschmer, W.; Rubin, Y.; Schriver, K. E.; Sensharma, D.; Whetten, R. L. ÒCharacterization of the Soluble All-Carbon Molecules C60 and C70Ó, J. Phys. Chem. 1990, 94, 8630-8633.
(9) Rubin, Y., Kahr, M., Knobler, C. B.; Diederich, F.; Wilkins, C. L. ÒThe Higher Oxides of Carbon C8nO2n (n = 3-5): Synthesis, Characterization and X-Ray Crystal Structure; Formation of Cyclo[n]carbon Ions Cn+ (n = 18, 24) and CnÐ (n = 18, 24, 30), and Higher Carbon Ions Including C60+ in Laser Desorption Fourier Transform Mass Spectrometric ExperimentsÓ, J. Am. Chem. Soc. 1991, 113, 495-500.
(10) Rubin, Y.; Knobler, C. B.; Diederich, F. ÒSynthesis and Crystal Structure of a Stable Hexacobalt Complex of Cyclo[18]carbonÓ, J. Am. Chem. Soc. 1990, 112, 4966-4968.
(11) Rubin, Y.; Knobler, C. B.; Diederich, F. ÒPrecursors to the Cyclo[n]carbons: From 3,4-Dialkynyl-3-cyclobutenediones and 3,4-Dialkynyl-3-Cyclobutene-1,2-Diols to Cyclobuteno-dehydroannulenes and Higher Oxides of CarbonÓ, J. Am. Chem. Soc. 1990, 112, 1607-1617.
(12) Diederich, F.; Rubin, Y.; Knobler, C. B.; Whetten, R. L.; Schriver, K. E.; Houk, K. N.; Li, Y. ÒAll-Carbon Molecules: Evidence for the Generation of Cyclo[18]carbon from a Stable Organic PrecursorÓ, Science 1989, 245, 1088-1090.