Chemistry Letters 2000
647
2
3
4
L. H. Conover, K. Butler, J. D. Johnston, J. J. Korst, and R. B.
Woodward, J. Am. Chem. Soc., 84, 3222 (1962).
tures of 10 and 13 were reasonably confirmed by NMR studies.
After selective de-O-benzylation of 13 with BBr3 (Scheme
3), the alcohol was converted into 14 by exchange of the N-pro-
tecting group followed by O-methylation of the enol. The
direct oxidation of 14 gave no desired products 17 and 17’.
Treatment of 14 with Br2 gave stereoselectively the bromide
15.10 The opening of the pyran ring was examined under a
variety of conditions, but in vain. Dess-Martin oxidation of 15
was followed by treatment with Zn in AcOH14 to provide the
keto-alcohol 1610 with migration of the resulting double bond.
This was oxidized to a mixture of the enols 17 and 17’. Though
the process suffered from the loss of the valuable asymmetry at
C12a, it was expected that the mixture would be a useful inter-
mediate provided that epoxidation could be achieved at the α-
face. The mixture was submitted to epoxidation using
dimethyldioxirane with the chiral cyclic borane,15 where the
reaction occurred from the α-face as expected, affording pre-
dominantly the C12a alcohol 18.10 This was transformed to the
nitrile 1910 by our newly developed method. Hydrolysis of 19
to give the amide with concomitant removal of the N-Boc group
was followed by N-dimethylation to produce 20. De-O-methy-
lation gave anhydrotetracycline (21),10 which was identical with
a naturally derived sample in all respects.6
The final stage was to introduce stereoselectively the
hydroxy group into the C6 position according to the reported
procedures.6 By photooxidation of 21, the peroxide 22 was
obtained. The hydrogenolysis of 22 on Pd-C gave no signifi-
cant product,4 while the desired reduction proceeded smoothly
on Pt black to give (−)-tetracycline (23) in a fairly good yield,
which was neutralized with HCl in MeOH to give the
hydrochloride.10 This was identical with the hydrochloride of
natural (−)-tetracycline in all respects,16 completing the first
total synthesis.
H. Muxfeldt, G. Hardtmann, F. Kathawala, E. Vedejs, and J. B.
Mooberry, J. Am. Chem. Soc., 90, 6534 (1968).
G. Stork, J. J. La Clair, P. Spargo, R. P. Nargund, and N. Totah, J.
Am. Chem. Soc., 118, 5304 (1996), and references cited therein.
R. Gleiter and M. C. Böhm, Pure Appl. Chem., 55, 237 (1983).
H. H. Wasserman, T.-J. Lu, and A. I. Scott, J. Am. Chem. Soc., 108,
4237 (1986).
A. I. Gurevich, M. G. Karapetyan, M. N. Kolosov, V. G. Korobko,
V. V. Onoprienko, S. A. Popravko, and M. M. Shemyakin,
Tetrahedron Lett., 1967, 131 (1967).
5
6
7
8
9
J.-C. Jacquinet, M. Petitou, P. Duchaussoy, I. Lederman, J. Choay,
G. Torri, and P. Sinay, Carbohydr. Res., 130, 221 (1984).
P. A. Grieco, S. Gilman, and M. Nishizawa, J. Org. Chem., 41,1485
(1976), and references cited therein.
1
10 Selected data for key compounds: Optical rotations (22 °C) and H-
NMR spectra (J in Hz; 400, 500 and 600 MHz) were measured in
CHCl3 and CDCl3, respectively, unless otherwise noted. 5: [α]D
1
+61°(c 1.0); H-NMR δ 3.03 (1H, ddd, J = 5, 5 and 8, H-4), 4.48
(1H, s, H-6), 4.66 (1H, s, H’-6), 8: mp 75 °C; [α]D +50°(c 1.0); 1H-
NMR δ 2.57 (1H, d, J = 9, H-2), 4.02 (1H, dd, J = 8 and 9, H-3),
6.10 (1H, dd, J = 2 and 10, H-6), 6.76 (1H, br d, J = 10, H-5), 10:
1
mp 173 °C; [α]D -16°(c 1.0); H-NMR δ 2.15 (1H, br d, J = 12 and
18, Hβ-5), 2.56 (1H, ddd, J = 6, 6 and 18, Hα-5), 3.78 (1H, ddd, J =
10, 10 and 10, H-4), 3.87 (1H, dd, J = 10 and 10, H-3), 13: mp 204
1
°C(dec.); [α]D +397°(c 0.33); H-NMR (C5D5N) δ 2.24 (3H, s, Me-
6), 3.04 (1H, ddd, J = 4, 10 and 14, H-4a), 4.40 (1H, ddd, J = 10, 10
and 10, H-4), 4.46 (1H, dd, J = 10 and 10, H-3), 15: [α]D -99°(c
1
0.46); H-NMR δ 2.74 (1H, ddd, J = 4, 10 and 10, H-4a), 3.57 (1H,
dd, J = 7 and 9, CH-2), 4.08 (1H, dd, J = 7 and 7, CH’-2), 16: [α]D
1
-93°(c 0.27); H-NMR δ 2.92 (1H, dddd, J = 2, 4, 5 and 11, H-4a),
4.20 (1H, d, J = 4, H-12a), 4.46 (1H, dd, J = 6 and 12, CH-2), 4.54
1
(1H, dd, J = 8 and 12, CH’-2), 18: [α]D -106°(c 0.35, MeOH); H-
NMR (CD3OD) δ 2.66 (1H, ddd, J = 3, 4 and 11, H-4a), 4.04 (1H, d,
J = 12, H-4), 9.75 (1H, s, CHO), 19: [α]D -360°(c 0.12); 1H-NMR δ
2.79 (1H, dd, J = 5 and 13, H-4a), 4.54 (1H, d, J = 6, H-4); IR (neat)
1
2204 cm-1, 21: [α]D -86°(c 0.40, 0.1 M HCl); H-NMR δ 2.47 (9H,
s, N-Me and Me-6), 3.33 (1H, d, J = 11, H-4), 23·HCl: [α]D -261°(c
1
0.50, 0.1 M HCl); H-NMR (CD3OD-DCl/D2O) δ 1.65 (3H, s, Me-
6), 1.93 (1H, ddd, J = 11, 13 and 13, Hβ-5), 2.25 (1H, ddd, J = 3, 5
and 13, Hα-5), 3.04 (6H, s, N-Me).
11 R. J. Ferrier, J. Chem. Soc., Perkin Trans. 1, 1979, 1455 (1979).
12 K. Tatsuta, T. Yamazaki, T. Mase, and T. Yoshimoto, Tetrahedron
Lett., 39, 1771 (1998), and references cited therein.
13 S. Kushner, J. Morton, II, J. H. Boothe, and J. H. Williams, J. Am.
Chem. Soc., 74, 3710 (1952).
14 L. F. Fieser and R. Ettorre, J. Am. Chem. Soc., 75, 1700 (1953).
15 E. J. Corey, R. Imwinkelried, S. Pikul, and Y. B. Xiang, J. Am.
Chem. Soc., 111, 5493 (1989).
16 The authentic sample was prepared by purification of commercially
available sample.
This work was financially supported by Grant-in-Aid for
Specially Promoted Research from the Ministry of Education,
Science, Sports and Culture.
References and Notes
1
R. B. Woodward, Pure Appl. Chem., 6, 561 (1963).