J. Am. Chem. Soc. 2001, 123, 10131-10132
10131
Total Synthesis of Pamamycin-607
Eun Lee,* Eun Jeong Jeong, Eun Joo Kang,
Lee Taek Sung, and Sung Kil Hong
School of Chemistry and Molecular Engineering
Seoul National UniVersity, Seoul 151-747, Korea
ReceiVed May 24, 2001
Pamamycins are 16-membered macrodiolides isolated from
Streptomyces alboniger and S. aurantiacus.1 They display auto-
regulatory, antibiotic, and anionophoric activities2 (Figure 1).
Pamamycin-6071b-d is especially interesting for its potent activity2e
against gram-positive bacteria (including multiple antibiotic-
resistant strains of Mycobacterium tuberculosis) as well as against
phytopathogenic fungi.
Figure 1.
Scheme 1
Total synthesis of pamamycin-607 and other members of the
family have not yet been communicated in the literature despite
intense synthetic efforts,3,4 and we wish to report here the results
of our research which culminated in a total synthesis of pama-
mycin-607.
In retrosynthetic analysis (Scheme 1), the ester bond formation
between the carboxylic acid A and the alcohol E would set the
stage for the final macrodiolide cyclization required in the
preparation of pamamycin-607 (1). The acid A may be obtained
from the ester D, employing the key radical cyclization reaction5
converting the â-alkoxyvinyl ketone C into the tetrahydrofuranyl
ester B. The two tetrahydrofuran rings in E and F were also
envisaged to arise from radical cyclization reactions of the
intermediates such as G (in practice, two separate radical
cyclization reactions are deemed necessary), which may be
synthesized from the protected pentahydroxy intermediate H.
The PMB-protected 3-hydroxypropanal 2 was reacted with the
(Z)-boron enolate prepared from the chiral imide 3.6 The imide
Scheme 2
(1) (a) McCann, P. A.; Pogell, B. M. J. Antibiot. 1979, 32, 673-678. (b)
Kondo, S.; Yasui, K.; Katayama, M.; Marumo, S.; Kondo, T.; Hattori, H.
Tetrahedron Lett. 1987, 28, 5861-5864. (c) Kondo, S.; Yasui, K.; Natsume,
M.; Katayama, M.; Marumo, S. J. Antibiot. 1988, 41, 1196-1204. (d)
Natsume, M.; Kondo, S.; Marumo, S. J. Chem. Soc., Chem. Commun. 1989,
1911-1913. (e) Natsume, M.; Yasui, K.; Kondo, S.; Marumo, S. Tetrahedron
Lett. 1991, 32, 3087-3090. (f) Natsume, M.; Tazawa, J.; Yagi, K.; Abe, H.;
Kondo, S.; Marumo, S. J. Antibiot. 1995, 48, 1159-1164. (g) Ha¨rtl, A.;
Stelzner, A.; Schlegel, R.; Heinze, S.; Hu¨lsmann, H.; Fleck, W.; Gra¨fe, U. J.
Antibiot. 1998, 51, 1040-1046. (h) Kozone, I.; Chikamoto, N.; Abe, H.;
Natsume, M. J. Antibiot. 1999, 52, 329-331.
(2) (a) Stengel, C.; Reinhardt, G.; Gra¨fe, U. J. Basic Microbiol. 1992, 32,
339-345. (b) Gra¨fe, U.; Stengel, C.; Mo¨llmann, U.; Heinisch, L. Pharmazie
1994, 49, 343-346. (c) Natsume, M.; Honda, A.; Oshima, Y.; Abe, H.; Kondo,
S.; Tanaka, F.; Marumo, S. Biosci. Biotechnol. Biochem. 1995, 59, 1766-
1768. (d) Grigoriev, P. A.; Berg, A.; Schlegel, R.; Gra¨fe, U. Bioelectrochem.
Bioenerg. 1996, 39, 295-298. (e) Pogell, B. M. Cell. Mol. Biol. 1998, 44,
461-463.
(3) (a) Walkup, R. D.; Park, G. Tetrahedron Lett. 1988, 29, 5505-5508.
(b) Walkup, R. D.; Kim, S. W.; Wagy, S. D. J. Org. Chem. 1993, 58, 6486-
6490. (c) Walkup, R. D.; Kim, S. W. J. Org. Chem. 1994, 59, 3433-3441.
(d) Walkup, R. D.; Kim, Y. S. Tetrahedron Lett. 1995, 36, 3091-3094. (e)
Mavropoulos, I.; Perlmutter, P. Tetrahedron Lett. 1996, 37, 3751-3754. (f)
Arista, L.; Gruttadauria, M.; Thomas, E. J. Synlett 1997, 627-628. (g)
Mandville, G.; Girard, C.; Bloch, R. Tetrahedron: Asymmetry 1997, 8, 3665-
3673. (h) Mandville, G.; Bloch, R. Eur. J. Org. Chem. 1999, 2303-2307. (i)
Solladie´, G.; Salom-Roig, X. J.; Hanquet, G. Tetrahedron Lett. 2000, 41, 551-
554. (j) Bernsmann, H.; Hungerhoff, B.; Fechner, R.; Fro¨hlich, R.; Metz, P.
Tetrahedron Lett. 2000, 41, 1721-1724. (k) Calter, M. A.; Bi, F. C. Org.
Lett. 2000, 2, 1529-1531. (l) Solladie´, G.; Salom-Roig, X. J.; Hanquet, G.
Tetrahedron Lett. 2000, 41, 2737-2740. (m) Bernsmann, H.; Fro¨hlich, R.;
Metz, P. Tetrahedron Lett. 2000, 41, 4347-4351. (n) Bernsmann, H.; Gruner,
M.; Metz, P. Tetrahedron Lett. 2000, 41, 7629-7633.
aldol was converted into the corresponding methyl ester, and the
ester 4 was obtained via PMB-deprotection and tosylation. The
reaction of 4 with the acetal ketone 5 under acidic conditions
afforded the â-alkoxyvinyl ketone 67 after subsequent iodide
substitution. Radical cyclization of 6 in the presence of tributyl-
stannane and AIBN under the standard high-dilution conditions
proceeded efficiently to give the tetrahydrofuranyl ketone product
7 in high yield (Scheme 2). Samarium(II) iodide was the reagent
of choice8 for stereoselective reduction of the carbonyl group
(8.5:1) in 7, and the carboxylic acid 8 was prepared via TBS-
protection of the hydroxy group and basic hydrolysis of the methyl
ester moiety.
(4) A total synthesis was communicated by Professor Sung Ho Kang (Korea
Advanced Institute of Science and Technology) at the CMDS Symposium
2000, November 9, 2000, Daejon, Korea. A communication appeared in the
literature after submission of this manuscript: Germay, O.; Kumar, N.;
Thomas, E. J. Tetrahedron Lett. 2001, 42, 4969-4974.
(5) Lee, E. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Applications, Vol. 2; Wiley-VCH: Weinheim, 2001; pp 303-333.
(6) For an example of asymmetric aldol reactions, see: Evans, D. A.;
Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990,
112, 7001-7031.
(7) For an example of radical cyclizations of â-aminovinyl ketones, see:
Lee, E.; Kang, T. S.; Chung, C. K. Bull. Kor. Chem. Soc. 1996, 17, 212-
214.
(8) Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307-2309.
10.1021/ja016272z CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/20/2001