C O M M U N I C A T I O N S
but was subjected to hydrogenation in the presence of palladium
black, affording (-)-tetracycline (1) in 42% yield (from 7) after
purification by preparative HPLC. The synthetic product was shown
to be identical to an authentic sample of natural tetracycline in all
respects.
Richard Staples for crystallographic analysis of compound 5 and
Dr. Christian D. Lerner for assistance in determining conditions
for the HPLC purification of (-)-tetracycline.
Supporting Information Available: Experimental procedures,
listings of spectral data, and X-ray crystal structure data for the
cycloadduct 5 (CIF, PDF). This material is available free of charge
The transformation of the naphthol 8 to the hydroperoxide 9 is
functionally equivalent to the transformation of 7-chloroanhydrotet-
racycline to 7-chlorotetracycline (aureomycin) by photooxygen-
ation-reduction, first demonstrated by Scott and Bedford.12 Later,
the same transformation was successfully applied to anhydrotetra-
cycline (10) by the use of a dye-sensitized photooxygenation
procedure.13 Both transformations were reported to be highly
stereoselective. In the case of photooxygenation of anhydrotetra-
cycline (10), the stereoselectivity of the transformation observed
was attributed to selective ene reaction of singlet oxygen with the
(pseudoaxial) 5-â-hydrogen atom.13 Two observations in the present
work are noteworthy with respect to these precedents. First, is the
References
(1) (a) Cunha, B. A. Clinical Uses of the Tetracyclines. In Handbook of
Experimental Pharmacology; Hlavka, J. J., Boothe, J. H., Eds.; Springer-
Verlag: New York, 1985; Vol. 78, pp 393-404. (b) Tetracyclines in
Biology, Chemistry, and Medicine; Nelson, M., Hillen, W., Greenwald,
R. A., Eds.; Birkha¨user Verlag: Boston, MA, 2001; pp 237-265.
(2) Synthesis of (()-6-deoxy-6-demethyltetracycline (25 steps, ∼0.002%
yield): (a) Korst, J. J.; Johnston, J. D.; Butler, K.; Bianco, E. J.; Conover,
L. H.; Woodward, R. B. J. Am. Chem. Soc. 1968, 90, 439-457. Synthesis
of (()-12a-deoxy-5a,6-anhydrotetracycline: (b) Gurevich, A. I.; Kara-
petyan, M. G.; Kolosov, M. N.; Korobko, V. G.; Onoprienko, S. A.;
Shemyakin, M. M. Tetrahedron Lett. 1967, 2, 131-134. Synthesis of (()-
5-oxytetracycline (22 steps, 0.06% yield): (c) Muxfeldt, H.; Haas, G.;
Hardtmann, G.; Kathawala, F.; Mooberry, J. B.; Vedejs, E. J. J. Am. Chem.
Soc. 1979, 101, 689-701. Synthesis of (()-12a-deoxytetracycline (16
steps, 18-25% yield): (d) Stork, G.; La Clair, J.; Spargo, P.; Nargund,
R.; Totah, N. J. Am. Chem. Soc. 1996, 118, 5304-5305.
1
fact that H NMR analysis of the oxygenation reaction (8 f 9,
CDCl3) showed that the keto form of 9 (keto-9) was formed
exclusively as the direct product of the reaction. After standing for
several hours, solutions of keto-9 in CDCl3 were observed to
undergo equilibration with the enol form (enol-9, K ≈ 1). This
observation rules out the possibility that enol-9 is the direct product
of the oxygenation of 8 and thus discounts the possible involvement
of an ene mechanism involving C5.14 The second observation
concerns the extraordinary facility of the oxygenation of substrate
8, which far exceeds that of anhydrotetracycline (10).13,15 Reaction
of 8 to form 9 at 23 °C is evident within minutes of exposure to
the air in daylight; only with the rigorous exclusion of light is the
oxidation prevented. These observations are reminiscent of the
autoxidation of 2-naphthols bearing bulky 1-alkyl groups reported
several years ago, also producing hydroperoxide products.16 Al-
though we cannot rule out a mechanism involving singlet oxygen
in the transformation of 8 to 9 (by Diels-Alder reaction, then 1,4-
endoperoxide hemiketal opening), a simple photoinitiated free-
radical autoxidation mechanism may be operative instead.17 The
data thus far do not allow us to distinguish these possibilities. In
either case, stereoelectronic factors seem most plausible to account
for the stereochemistry of oxygen addition to 8 (generating a
pseudoaxial hydroperoxy group), but whether the basis for the
greater reactivity of 8 relative to anhydrotetracycline is related to
the modification of the A-ring by the incorporation of the Stork-
Hagedorn 3-benzyloxyisoxazole protective group18 or to benzylation
of the D-ring phenol is not known.
(3) Tatsuta, K.; Yoshimoto, T.; Gunji, H.; Okado, Y.; Takahashi, M. Chem.
Lett. 2000, 646-647.
(4) Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D. R.; Myers, A.
G. Science 2005, 308, 395-398.
(5) Knapp, S.; Lis, R.; Michna, P. J. Org. Chem. 1981, 46, 624-629.
(6) (a) Akgu¨n, E.; Glinski, M. B.; Dhawan, K. L.; Durst, T. J. Org. Chem.
1981, 46, 2730-2734. (b) Dhawan, K. L.; Gowland, B. D.; Durst, T. J.
Org. Chem. 1980, 45, 922-924.
(7) Extended heating of 5 at 85 °C was shown to produce 6.
(8) It is interesting to note that Curphey and Woodward had pursued an
isobenzofuran Diels-Alder strategy for the assembly of the CD rings of
the tetracyclines, at a time when isobenzofuran intermediates were
unknown: Curphey, T. J. Ph.D. Thesis, Harvard University, Cambridge,
MA, 1960.
(9) Attempted Diels-Alder additions of 2 and 4 also did not proceed,
supporting the idea that the R-phenylthio group of 3 is activating.5
(10) (a) Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351-
352. (b) Hentemann, M. F.; Allen, J. G.; Danishefsky, S. J. Angew. Chem.,
Int Ed. 2000, 39, 1937-1940. (c) Allen, J. G.; Hentemann, M. F.;
Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 571-575.
(11) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-8022.
(12) Scott, A. I.; Bedford, C. T. J. Am. Chem. Soc. 1962, 84, 2271-2272.
(13) Wasserman, H. H.; Lu, T.-J.; Scott, A. I. J. Am. Chem. Soc. 1986, 108,
4237-4238. See also ref 3.
(14) Schach von Wittenau had shown that photooxygenation of 7-chloroan-
hydrotetracycline in a deuterated medium does not lead to incorporation
of deuterium at C5 and therefore concluded that C5-bound hydrogens do
not participate in that transformation. Schach von Wittenau, M. J. Org.
Chem. 1964, 29, 2746-2749.
(15) Solutions of anhydrotetracycline (10) showed no evidence of reaction with
dioxygen in daylight at 23 °C after 24 h.
(16) Carnduff, J.; Leppard, D. G. Chem. Comm. 1967, 829-830.
(17) For a discussion, see: Saito, I.; Matsuura, T. Mechanisms for Photosen-
sitized Oxygenation of Phenols. In Singlet Oxygen; Wasserman, H. H.,
Murray, R. W., Eds.; Academic Press: New York, 1979; Vol. 40, pp
552-563.
Acknowledgment. Financial support from the National Institutes
of Health is gratefully acknowledged. M.G.C. acknowledges a
National Science Foundation predoctoral fellowship. We thank Dr.
(18) Stork, G.; Hagedorn, A. A., III. J. Am. Chem. Soc. 1978, 100, 3609-3611.
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