Synthesis of New Tetracycline Antibiotics
A R T I C L E S
cycline) in 1962,16 one of particular note, and of relevance to
the results described herein, is Stork and Hagedorn’s strategy
for protection of the vinylogous carbamic acid group of the A
ring of the tetracyclines as a 3-benzyloxyisoxazole group;
subsequent deprotection occurs under mild (hydrogenolytic)
conditions.17
research groups first reported that simple o-toluate ester anions
(unsubstituted at the benzylic position) undergo Michael-Claisen
cyclization reactions with ꢀ-methoxycyclohexenones and γ-py-
rones to form naphthyl ketones (see eq 4 for one example), a
sequence sometimes referred to as the Staunton-Weinreb
annulation.25
Strategically, the original route developed by Woodward and
collaborators for the synthesis of sancycline employed a “left-
to-right” or DfA mode of construction. The Shemyakin and
Muxfeldt research groups adopted a similar directionality in their
remarkable syntheses of tetracycline (5; 1967) and terramycin
(4; 1968), respectively, using a bicyclic CD-ring precursor as
starting material.18,19 With the benefit of more than 50 years of
structure-activity relationship data, as well as X-ray crystal
structures of tetracycline bound to the bacterial ribosome (its
putative target),20 the left-to-right mode of construction used
in these pioneering synthetic efforts can be seen to present a
practical disadvantage to the discovery of new tetracycline
antibiotics, for the D ring has emerged as one of the most
promising sites for structural variation. This was a primary
consideration guiding our initial retrosynthetic analysis of the
tetracycline class, leading us to focus upon disconnection of
the C ring. Thus, we envisioned assembling tetracyclines by a
convergent coupling of D- and AB-ring precursors. Although
model studies suggested that both Diels-Alder and Michael-
Claisen cyclization reactions might be used to form the C ring,21
only the latter proved successful with the AB precursors that
we later targeted and synthesized (1 and 2).
Michael-Claisen and Michael-Dieckmann reaction se-
quences have been widely employed to construct naphthalene
derivatives since 1978, when three different cyclization protocols
were introduced by independent research groups. Hauser and
Rhee used a sulfoxide-stabilized o-toluate ester anion as the
nucleophilic component in a Michael-Dieckmann cyclization
reaction with methyl crotonate (eq 1). In this case, aromatization
occurred upon thermal elimination of phenylsulfenic acid.22 The
use of phthalide and cyanophthalide anions as nucleophilic
components was described by Broom and Sammes (eq 2)23 and
Kraus and Sugimoto (eq 3),24 respectively. Formal loss of water
and hydrogen cyanide, respectively, led to naphthoate ester
products in these procedures. In 1979, the Weinreb and Staunton
There is also precedent for the formation of non-aromatic
six-membered rings by Michael-Claisen and Michael-
Dieckmann reaction sequences.23,26,27 With few exceptions,27
stereochemical features of these cyclization reactions have not
been discussed, frequently because they were of little conse-
quence (aromatization followed cyclization). The Michael-Claisen
cyclizations detailed below are unusual in their stereochemical
complexity, stereocontrol, and efficiency. In 2000, while our
studies were in progress, Tatsuta and co-workers reported a
synthesis of (-)-tetracycline (34 steps, 0.002% yield) that
employed an early stage Michael-Claisen cyclization reaction
to form an aromatic C-ring precursor, which was dearomatized
later in the sequence.28 Since 2005, our laboratory has reported
two different routes to synthesize the AB precursor 1 in optically
active form; the more recent of these was scaled to prepare >40
g of crystalline product in one batch.29 Here we provide details
of the different protocols that can be used to construct the C
(16) (a) Conover, L. H.; Butler, K.; Johnston, J. D.; Korst, J. J.; Woodward,
R. B. J. Am. Chem. Soc. 1962, 84, 3222–3224. (b) Woodward, R. B.
Pure Appl. Chem. 1963, 6, 561–573. (c) 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.
(17) Stork, G.; Hagedorn, A. A., III. J. Am. Chem. Soc. 1978, 100, 3609–
3611.
(18) (a) Gurevich, A. I.; Karapetyan, M. G.; Kolosov, M. N.; Korobko,
V. G.; Onoprienko, V. V.; Popravko, S. A.; Shemyakin, M. M.
Tetrahedron Lett. 1967, 8, 131–134. (b) Kolosov, M. N.; Popravko,
S. A.; Shemyakin, M. M. Liebigs Ann. 1963, 668, 86–91.
(19) (a) Muxfeldt, H.; Hardtmann, G.; Kathawala, F.; Vedejs, E.; Mooberry,
J. B. J. Am. Chem. Soc. 1968, 90, 6534–6536. (b) Muxfeldt, H.; Haas,
G.; Hardtmann, G.; Kathawala, F.; Mooberry, J. B.; Vedejs, E. J. Am.
Chem. Soc. 1979, 101, 689–701.
(25) (a) Dodd, J. H.; Weinreb, S. M. Tetrahedron Lett. 1979, 38, 3593–
3596. (b) Dodd, J. H.; Starrett, J. E.; Weinreb, S. M. J. Am. Chem.
Soc. 1984, 106, 1811–1812. (c) Leeper, F. J.; Staunton, J. J. Chem.
Soc., Chem. Commun. 1979, 5, 206–207. (d) Leeper, F. J.; Staunton,
J. J. Chem. Soc., Perkin Trans. 1 1984, 1053–1059.
(26) (a) Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Synthesis
1986, 9, 785–786. (b) Boger, D. L.; Zhang, M. J. Org. Chem. 1992,
57, 3974–3977. (c) Nishizuka, T.; Hirosawa, S.; Kondo, S.; Ikeda,
D.; Takeuchi, T. J. Antibiot. 1997, 50, 755–764. (d) Hill, B.; Rodrigo,
R. Org. Lett. 2005, 7, 5223–5225.
(20) (a) Brodersen, D. E.; Clemons, W. M., Jr.; Carter, A. P.; Morgan-
Warren, R. J.; Wimberly, B. T.; Ramakrishnan, V. Cell 2000, 103,
1143–1154. (b) Pioletti, M.; Schlu¨nzen, F.; Harms, J.; Zarivach, R.;
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Jacobi, C.; Hartsch, T.; Yonath, A.; Franceschi, F EMBO J. 2001, 20,
1829–1839.
(27) For examples of stereocontrol in Michael-Claisen and Michael-
Dieckmann cyclization reactions, see: (a) Franck, R. W.; Bhat, V.;
Subramaniam, C. S. J. Am. Chem. Soc. 1986, 108, 2455–2457. (b)
Tatsuta, K.; Yamazaki, T.; Mase, T.; Yoshimoto, T. Tetrahedron Lett.
1998, 39, 1771–1772. (c) White, J. D.; Demnitz, F. W. J.; Qing, X.;
Martin, W. H. C. Org. Lett. 2008, 10, 2833–2836.
(21) Parrish, C. A. Ph.D. Thesis, California Institute of Technology,
Pasadena, CA, 1999.
(22) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178–180.
(23) Broom, N. J. P.; Sammes, P. G. J. Chem. Soc., Chem. Commun. 1978,
162–164.
(28) Tatsuta, K.; Yoshimoto, T.; Gunji, H.; Okado, Y.; Takahashi, M. Chem.
Lett. 2000, 646–647.
(24) Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 26, 2263–2266.
(29) Brubaker, J. D.; Myers, A. G. Org. Lett. 2007, 9, 3523–3525.
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