New arene cis-dihydrodiol metabolites from β-bromostyrenes

Article abstract of DOI:10.1016/S0957-4166(99)00237-2

Both (E)- and (Z)-β-bromostyrenes are substrates for toluene dioxygenase from Escherichia coli (JM109, pDTG601) and yield the corresponding diol metabolites in yields of 1 g/L, respectively.

Full text of DOI:10.1016/S0957-4166(99)00237-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2067–2069
New arene cis-dihydrodiol metabolites from β-bromostyrenes
Bennett H. Novak and Tomas Hudlicky∗
University of Florida, Department of Chemistry, Gainesville, FL 32611-7200, USA
Received 10 May 1999; accepted 3 June 1999
Abstract
Both (E)- and (Z)-β-bromostyrenes are substrates for toluene dioxygenase from Escherichia coli (JM109,
pDTG601) and yield the corresponding diol metabolites in yields of 1 g/L, respectively. © 1999 Elsevier Science
Ltd. All rights reserved.
The reports of new cis-diol metabolites1 of aromatics continue to be published with increasing
frequency as such compounds find an expanding utility in enantioselective synthesis.2 Several years
ago we published a report on the oxidation of o-, m-, and p-chlorostyrenes3 by the recombinant organism
designed and provided by David Gibson.4 Several other bromoaromatics have also been found to be
substrates for the enzyme5 and some of these have been and are of interest as potential starting materials
for the synthesis of morphine alkaloids.6 Consequently, it is now possible to design a synthesis based on
an anticipated rather than a known structure. In this manuscript we report the preparation and absolute
stereochemistry of compounds 2a and 2b,7 which were targeted as ideal synthons for intramolecular
Diels–Alder cycloadditions.
The whole cell fermentation was carried out as previously reported.8 Following isolation of the diols
2a and 2b, the absolute stereochemistry was determined as shown in Scheme 1. Diimide reduction
(potassium azodicarboxylate (PAD), methanol and acetic acid, 50% yield) of the diols furnished diols
3a and 3b, the protection of which was followed by removal of the halogen via metal/halogen exchange
(t-butyl lithium, 72%) to provide 4. Further diimide reduction (PAD) of the vinyl group and deprotection
afforded compound 5 (20%), which was shown to be identical (1H NMR, melting point and [α]D)9 to
the material derived from styrene diol 610 whose absolute configuration is known.11 The two compounds
are excellent intermediates for an approach to morphine6 and progress in this area will be reported in due
course.
∗
Corresponding author. E-mail: hudlicky@chem.ufl.edu
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00237-2

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B. H. Novak, T. Hudlicky / Tetrahedron: Asymmetry 10 (1999) 2067–2069
Scheme 1.
Acknowledgements
The authors would like to acknowledge the National Science Foundation (CHE-9615112), the Environ-
mental Protection Agency (R82613), and TDC Research, Inc. for funding of their research.
References
1. (a) Bowers, N. I.; Boyd, D. R.; Sharma, H. D.; Kennedy, M. A.; Sheldrake, G. N.; Dalton, H. Tetrahedron: Asymmetry
1998, 9, 1; (b) Hudlicky, T.; Gonzalez, D.; Stabile, M.; Endoma, M. A.; Deluca, M.; Parker, D.; Gibson, D. T.; Resnick,
S. M.; Whited, G. M. J. Fluorine Chem. 1998, 89, 23; (c) Boyd, D. R.; Sharma, N. D.; Carroll, J. G.; Malone, J. F.;
Mackerracker, D. G.; Allen, C. C. R. J. Chem. Soc., Chem. Commun. 1998, 683; for other metabolites see Ref. 2a.
2. (a) Hudlicky, T.; Gonzalez, D.; Gibson, D. T. Aldrichimica Acta 1999, in press; (b) Brown, S. M.; Hudlicky, T. Organic
Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, p. 113; (c) Widdowson, D.
A.; Ribbons, D. W.; Thomas, S. D. Janssen Chimica Acta 1990, 8, 3; (d) Carless, H. A. J. Tetrahedron: Asymmetry 1992, 3,
795; (e) Sheldrake, G. N. In Chirality and Industry; Collins, A. N.; Sheldrake, G. N.; Crosby, J., Eds.; John Wiley & Sons:
1992, p. 127; (f) Hudlicky, T.; Reed, J. R. In Advances in Asymmetric Synthesis; Hassner, A., Ed.; JAI Press: Greenwich,
CT, 1995; p. 271; (g) Hudlicky, T. In Green Chemistry: Designing Chemistry for the Environment, ACS Symposium Series,
Anastas, P. T.; Williamson, T., Eds.; Washington, DC, 1996; Vol. 626, p. 180; (h) Hudlicky, T.; Thorpe, A. J. J. Chem.
Soc., Chem. Commun. 1996, 1993; (i) Hudlicky, T. Chem. Rev. 1996, 96, 3; (j) Hudlicky, T.; Entwistle, D. A.; Pitzer, K.
K.; Thorpe, A. J. Chem. Rev. 1996, 96, 1195; (k) Grund, A. D. SIM News 1995, 45, 59; (l) Boyd, D. R. Nat. Prod. Rep.
1998, 309.
3. (a) Hudlicky, T.; Boros, E. E.; Boros, C. H. Tetrahedron: Asymmetry 1993, 4, 1365; (b) Hudlicky, T.; Boros, E. E.; Boros,
C. H. Synlett 1992, 391.
4. (a) Gibson, D. T.; Koch, J. R.; Kallio, R. E. Biochemistry 1968, 7, 2653; (b) Gibson, D. T.; Koch, J. R.; Schuld, C. L.;
Kallio, R. E. Biochemistry 1968, 7, 3795; (c) Zylstra, G. J.; Gibson, D. T. J. Biol. Chem. 1989, 264.
5. The following styrene-related metabolites have been identified: o-bromostyrene: Konigsberger, K.; Hudlicky, T.
Tetrahedron: Asymmetry 1993, 4, 2469; Ref. 3a,b; bromoethylbenzene: Stabile, M. R.; Hudlicky, T.; Meisels, M. L.
Tetrahedron: Asymmetry 1995, 6, 537; o-bromo bromoethylbenzene: Stabile, M. R.; Hudlicky, T.; Meisels, M. L.; Butora,
G.; Gum, A. G.; Fernley, S. P.; Thorpe, A. J.; Ellis, M. R. Chirality 1995, 7, 556.

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6. (a) Hudlicky, T.; Boros, C. H.; Boros, E. E. Synthesis 1992, 174; (b) Butora, G.; Hudlicky, T.; Fernley, S. P.; Stabile, M.
R.; Gum, A. G.; Gonzalez, D. Synthesis 1998, 665; (c) Hudlicky, T.; Butora, G.; Gum, A. G.; Abboud, K. A. Synthesis
1998, 275.
7. Experimental data for the metabolites: 2a: (Z)-β-bromostyrene diol was isolated as a brown oil; [α]2D5=40.3 (c 1.0, CHCl3);
1H NMR (CDCl3, J/Hz) δ 6.70 (d, J=8.3, 1H), 6.49 (d, J=5.6, 1H), 6.26 (d, J=8.3, 1H), 6.03 (ddd, J=9.6, 5.5, 2.0, 1H), 5.95
(dd, J=9.4, 2.8, 1H), 4.57 (d, J=6.1, 1H), 4.44–4.37 (m, 1H), 2.61 (br s, 1H), 2.31 (br s, 1H); 13C NMR (CDCl3) δ 134.3,
132.2, 130.7, 127.2, 124.0, 106.0, 69.3, 67.0. 2b: (E)-β-bromostyrene diol was isolated as a white solid, mp=48–51°C;
[α]2D3=83.1 (c 0.75, CHCl3); 1H NMR (CDCl3, J/Hz) δ 6.76 (d, J=14.0, 1H), 6.66 (d, J=14.2, 1H), 6.01–5.88 (m, 3H),
4.41 (td, J=5.9, 2.2, 1H), 4.25 (d, J=5.9, 1H), 2.29 (br s, 1H), 1.61 (br s, 1H); 13C NMR (CDCl3) δ 136.4, 135.8, 132.2,
124.8, 124.0, 108.1, 70.0, 66.6.
8. The fermentations were carried out as described previously (Refs. 3a, 6a) in a 12 L fermentor using IPTG as the inducer.
Hudlicky, T.; Stabile, M. R.; Gibson, D. T.; Whited, G. M. Org. Synth. 1999, 76, 77.
9. Experimental data for 5 synthesized from β-bromostyrene diols 2a and 2b: mp=78–79°C; [α]2D5=−156.9 (c 1.0, CHCl3).
10. Experimental data for 5 prepared from 6: isolated as a white solid, mp=79–80°C; [α]2D7=−150.2 (c 1.0, CHCl3); 1H NMR
(CDCl3, J/Hz) δ 5.54 (br s, 1H), 3.98 (d, J=3.8 Hz, 1H), 3.75–3.69 (m, 1H), 2.77 (br s, 2H), 2.21–2.05 (m, 4H), 1.73–1.65
(m, 2H), 1.03 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3) δ 139.1, 123.7, 69.8, 68.8, 27.1, 25.3, 24.0, 12.4; IR (KBr/cm−1) ν
3275, 1459. HRMS (EI): calcd for C8H15O2: m/z 143.1776; found: 143.1072. Anal. calcd for C8H14O2+1/3H2O: C, 65.10;
H, 9.97; found: C, 65.21; H, 9.56.
11. Hudlicky, T.; Boros, C. H. Tetrahedron Lett. 1993, 34, 2557.