ORGANIC LETTERS
DFT Study of Pericyclic Reaction Cascades in the Synthesis of Antibiotic TAN-1085
2004 Vol. 6, No. 23 4273-4275
Zeve R. Akerling, Joseph E. Norton, and K. N. Houk* Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, Los Angeles, California 90095-1569
[email protected] Received August 27, 2004
ABSTRACT
DFT calculations show that aromatic and bis-methoxy substituent effects in a synthetic precursor of TAN-1085 strongly favor a [1,7] sigmatropic hydrogen shift over the 6π electrocyclic pathway, rendering the latter unfavorable in synthesis.
TAN-1085 (1) (Figure 1) is an antibiotic of the Angucycline family, first isolated by M. Muroi et al. from Streptomyces
Figure 1. Angucycline antibiotic TAN-1085 (1) and the synthetic precursor of Suzuki et al. (2).2
sp. S-11106,1 and first successfully synthesized by Suzuki and co-workers.2 A key step in their synthetic plan was ring (1) Kanamaru, T.; Nozaki, Y.; Muroi, M. (Kokai Tokyo Koho). JP 02289-532/1990, 1991; Chem. Abstr. 1991, 115, 47759n. 10.1021/ol048277h CCC: $27.50 Published on Web 10/21/2004
© 2004 American Chemical Society
enlargement of benzocyclobutene derivative 2 through a 4π ring-opening of the benzocyclobutene followed by 6π electrocyclization. This scheme proved to be unworkable due to the unexpected preference for another pericyclic process, a [1,7] sigmatropic hydrogen shift, over the 6π electrocyclization. Thus, thermolysis of 2 (3C) gave 6C rather than the desired 5C, shown in Scheme 1. None of the ring-closed product, 5C, was observed. While this reaction pathway was ultimately suppressed by derivatization of 2, the origin of the strong preference of the original system for the [1,7] shift remains of interest. As calculated by Hoffmann and Tantillo,3 the 6π electrocyclic reaction of hexatriene has a larger activation barrier than the [1,7] shift of heptatriene. In addition, it has been shown that the activation barriers for [1,7] hydrogen shifts in alkylsubstituted trienes are relatively low at around 15-20 kcal/ mol.4,5 Similarly, [1,7] hydrogen shifts with difluoro, meth(2) Ohmori, K.; Mori, K.; Ishikawa, Y.; Tsuruta, H.; Kuwahara, S.; Harada, N.; Suzuki, K. Angew. Chem., Int. Ed. 2004, 43, 3167-3171. (3) Hoffmann, R.; Tantillo, D. Angew. Chem., Int. Ed. 2003, 42, 58775882. (4) Tantillo, D. J.; Hoffmann, R. HelV. Chim. Acta 2003, 86, 35253532.
Scheme 1.
a
Synthetic Scheme of Suzuki et al. (C)2,a
Calculated model systems are A and B.
oxy, and fluoro substituents have been shown to be slightly higher, ranging roughly from 20 to 25 kcal/mol.6 However, the electrocyclic reaction is also found to be significantly exothermic, while the hydrogen migration is not since the [1,7] hydrogen shift of heptatriene itself is a degenerate rearrangement. Using these energies as a guide, some electrocyclic product might have been expected. A series of DFT calculations were performed on two model systems (Scheme 1, A and B) in order to examine substituent effects on the pericyclic reaction pathways. All calculations were performed at the B3LYP/6-31G* level of theory, with Gaussian 03.7 Transition structures were found through constrained optimizations along the desired reaction path, followed by unconstrained optimizations. The lowest energy methoxy rotamers for each model system were chosen. All transition states and local minima were validated through frequency analysis. All energies given in Figure 2 are electronic energies plus unscaled zero-point corrections.8 In model system A, energies for 6π electrocyclic transition state TS-5A and [1,7] sigmatropic shift TS-6A (Figure 2) were significantly lower than previously reported for the unsubstituted systems.3 Energies were reduced by 6.8 and (5) Hess, B. A., Jr. J. Org. Chem. 2001, 66, 5897-5900. (6) Dmitrenko, O.; Bach, R. D.; Sicinski, R. R.; Reischl, W. Thoer. Chem. Acc. 2003, 109, 170-175. (7) Gaussian 03, revision C.02; Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.; Gaussian, Inc.: Wallingford CT, 2004. (8) A scale factor of 0.98 has been recommended for zero-point energy corrections by Radom et al.5b (Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-16513.) However, unscaled values were used here. 4274
Figure 2. Energy diagram for reaction pathways of model systems. Values not in parentheses are for model A; values in parentheses are for model B.
10.6 kcal/mol, respectively, as measured against ortho-xylene intermediate 4A. This lowering is due to the developing
Figure 3. Transition state structures for 4π and 6π electrocyclic reactions and [1,7] sigmatropic shifts of models A and B. Org. Lett., Vol. 6, No. 23, 2004
aromaticity of the attached ring in the transition states upon conversion of 4A to 5A or 6A. The benzocyclobutene ringopening displayed an outward torquoselectivity of the methoxy group rather than the propenyl group, in agreement with previous work9 showing that the electron-donating methoxy group should rotate outward due to secondary orbital interactions. The sigmatropic shift was found to be the preferred pathway, 8.7 kcal/mol lower in activation energy than the electrocyclic path. While the formation of an aromatic system renders the sigmatropic shift exothermic, the electrocyclic product is still much lower in energy, by about 22.5 kcal/ mol. This is, at least in part, due to differences in developing aromaticity for the electrocyclic and sigmatropic reactions. More specifically, the transition structures TS-6A and TS6B for the sigmatropic shift are more planar than those for the electrocyclic reactions. The preference for the [1,7] shift is an inherent property of the system. The dimethoxy substituents in system B raise the [1,7] shift and electrocyclic reaction activation barriers by 5.2 and 7.9 kcal/mol, respectively, due to the repulsion caused by the inward methoxy group.10 The [1,7] shift is even more favorable in this case, despite the thermodynamic preference for electrocyclization. Examination of the forming and breaking transition-state bond lengths in models A and B (Figure 3) reveals that (9) Nakamura, K.; Houk, K. N. J. Org. Chem. 1995, 60, 686-691. (10) Dolbier, W.; Koroniak, H.; Houk, K.; Sheu, C. Acc. Chem. Res. 1996, 29, 471-477.
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dimethoxylation has little effect on the sigmatropic shift geometries. However, dimethoxylation does have a substantial effect on the geometry of the electrocyclic reactions. The bond lengths of the predicted transition states TS-3B and TS-5B are lengthened to 2.4 and 2.8 Å, respectively, evidence for the significant repulsion arising from the inward methoxy group. In conclusion, an experimentally observed preference for a [1,7] hydrogen shift over a 6π electrocyclic ring-closure in a synthetic precursor of TAN-1085 is explained. While the electrocyclic product is thermodynamically favored, the activation barrier for the sigmatropic reaction is significantly lower and, thus, is predicted to lead to the observed product. Even in the presence of dimethoxy substituents that effectively raise the activation barrier, the sigmatropic reaction is expected to prevail. Acknowledgment. We are grateful to the National Institute of General Medical Sciences, National Institutes of Health for financial support, and the California NanoSystems Institute for a CNSI Summer Undergraduate Research Fellowship Award to Z.R.A. Supporting Information Available: Cartesian coordinates and Gaussian output files for transition and ground states. This material is available free of charge via the Internet at http://pubs.acs.org. OL048277H
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