instead. It may well be that this is a general trend for the ortho-
fused ring systems, at least with the use of organisms described
in this manuscript, and this may explain why there is no dihy-
droxylation for 1,2,3,4-tetrahydro-1-naphthol and 1,4-dihydro-
1,4-epoxynaphthalene.12 It is however known that P. putida
UV4 oxidizes a number of ortho-fused ring systems.13
Acknowledgements
Financial support from the National Science Foundation
(NSF) (CHE-9615112 and CHE-9910412), the U.S. Environ-
mental Protection Agency (EPA) (R826113) and TDC
Research, Inc., as well as from the Agricultural University of
Norway (T. V. H. and Y. S.) and The Norwegian Research
Council (T. V. H.) is gratefully appreciated.
The substrate of most interest to us is trans-2-phenylcyclo-
hexanol (10) which has two neighboring stereogenic centers and
which most closely resembles the intended morphine models 18
or 19. However, racemic 10 was converted to the corresponding
dienediol as a 1:1 mixture of diastereomers indicating no
preference of the enzyme for either enantiomer. Three other
substrates, 1-phenylcyclohexanone (12), 1-phenylcyclohexene
(14) and phenylcyclohexane (16) were converted to the corre-
sponding dienediols for the purpose of correlation of absolute
stereochemistry in 11a/11b. Even though the kinetic resolution
in 10 did not occur, the utility of this type of substrate in
approaches to morphine is still viable and compounds of this
structural type with additional chiral centers, such as 18 and 19,
will be investigated, if for no other reason, because of the facile
introduction of the catechol unit to the morphine nucleus.
The absolute stereochemistry of the vic-diols in 11a, 11b, and
13a, 13b, 15 and 17 were proven according to the reactions in
Scheme 3. The mixture of triols 11a and 11b was reduced to the
alkenes 23a,b with potassium azodicarboxylate (PAD). Protec-
tion of the vic-diol as the ketals, bromination with CBr4–Ph3P
and reduction of the bromides with Bu3SnH yielded one com-
pound which was identical to 24 as prepared from 17. Since 17
was obtained from the biooxidation of phenylcyclohexane
followed by PAD reduction and protection with 2,2-dimethoxy-
propane (DMP), the absolute stereochemistry of the diol in
both 17 and 11 is identical. It is also of the same absolute
configuration as the diol derived from bromobenzene. Coupling
of bromide 25 of known14 stereochemistry with cyclohexyl
triflate 26 was achieved via the transformation of the bromide
to the Grignard compound in the presence of Li2CuCl4.15 The
product was identical by all means, including optical rotation,
with the material prepared from 11a and 11b, the products of
the biotransformation of 10. The absolute stereochemistry of
15 was proven by a similar sequence using the bromide 25, but
coupling with cyclohexenyl triflate 28 according to the work of
Stille et al.16 giving diene 27, identical in all respects to the one
derived from 15, the biotransformation product of 14. Finally,
the absolute stereochemistry of 13 was proven by conversion
to 24.
References
1 (a) T. Hudlicky, D. Gonzalez and D. T. Gibson, Aldrichimica Acta,
1999, 31, 35; (b) D. R. Boyd and G. N. Sheldrake, Nat. Prod. Rep.,
1998, 15, 309; (c) T. Hudlicky and J. W. Reed, in Advances in
Asymmetric Synthesis, ed. A. Hassner, JAI Press, Greenwich, CT,
1995, vol. 1, p. 271.
2 (a) For listing of the metabolites see refs. 1a and 1b; for recent
reports of new metabolites see (b) T. Hudlicky and B. Novak,
Tetrahedron: Asymmetry, 1999, 10, 2067.
3 D. T. Gibson, B. Gschwendt, W. K. Yeh and V. M. Kobal,
Biochemistry, 1973, 8, 1520.
4 R. E. Cripps, P. W. Trudgill and G. Whateley, Eur. J. Biochem., 1978,
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5 D. R. Boyd, N. D. Sharma, N. I. Bowers, J. Duffy, J. S. Harrison and
H. Dalton, J. Chem Soc., Perkin Trans. 1, 2000, 1345.
6 S. Ahmed, PhD Thesis, Imperial College of Science, Technology
and Medicine, London, 1991 (D. W. Ribbons, thesis supervisor).
7 The organisms in this study were supplied by David Gibson:
Pseudomonas putida F39/D see: (a) D. T. Gibson, J. R. Koch and
R. E. Kallio, Biochemistry, 1968, 7, 2653; (b) E. coli JM109 (pDTG
601) see G. J. Zylstra and D. T. Gibson, J. Biol. Chem., 1989, 264,
14940; (c) E. coli JM109 (pDTG 141) see M. J. Simon, T. D.
Osslund, R. Saunders, B. D. Ensley, S. Suggs, A. Harcourt, W. C.
Suen, D. L. Cruden and D. T. Gibson, Gene, 1993, 127, 31.
8 D. A. Frey, C. Duan and T. Hudlicky, Org. Lett., 1999, 1,
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9 (a) D. Gonzalez, V. Schapiro, G. Seoane and T. Hudlicky,
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G. Seoane, T. Hudlicky and K. Abboud, J. Org. Chem., 1997, 62,
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10 (a) For P. putidae F39/D see, T. Hudlicky, M. R. Stabile, D. T.
Gibson and G. M. Whited, Org. Synth., 1999, 76, 77; (b) For E. coli
see, T. Hudlicky, M. A. Endoma and G. Butora, J. Chem. Soc.,
Perkin Trans. 1, 1996, 2187.
11 (a) J. M. Brand, D. L. Cruden, G. J. Zylstra and D. T. Gibson, Appl.
Environ. Microbiol., 1992, 58, 3407; (b) S. M. Resnick, D. S. Torok,
K. Lee, J. M. Brand and D. T. Gibson, Appl. Environ. Microbiol.,
1994, 60, 3323.
It appears that the substrates chosen for this study were not
processed by the enzymes as separate enantiomeric entities.
While no significant kinetic resolution was observed the investi-
gation of compounds of type 18 and 19 remains of interest in
the production of synthons containing the ring A of morphine.
Because compounds of type 19 will be enantiomerically pure
it appears that the merit of their oxidation will be in the bio-
catalytic conversion of the phenyl ring directly to catechol when
the clone containing catechol diol dehydrogenase is used. We
will report on these studies as well as further details connected
to the work presented here in the near future.
12 A good model to test this assumption would be o-methylphenyl-
ethan-1-ol.
13 (a) D. R. Boyd, N. D. Sharma, T. A. Evans, M. Groocock, J. F.
Malone, P. J. Stevenson and H. Dalton, J. Chem. Soc., Perkin Trans.
1, 1997, 1879; (b) N. I. Bowers, D. R. Boyd, N. D. Sharma, P. A.
Goodrich, M. R. Groocock, A. J. Blacker, P. Goode and H. Dalton,
J. Chem. Soc., Perkin Trans. 1, 1999, 1453.
14 D. R. Boyd, M. R. Hand, N. D. Sharma, J. Chima, H. Dalton and
G. N. Sheldrake, J. Chem. Soc., Chem. Commun., 1991, 1630.
15 M. Tamura and J. Kochi, Synthesis, 1971, 303.
16 W. J. Scott, G. T. Crisp and J. K. Stille, Org. Synth., 1990, 68,
116.
1672
J. Chem. Soc., Perkin Trans. 1, 2000, 1669–1672