J. Am. Chem. Soc. 1996, 118, 3303-3304
3303
Scheme 1a
Total Synthesis of Streptogramin Antibiotics.
(-)-Madumycin II
Francis Tavares, Jon P. Lawson, and A. I. Meyers*
Department of Chemistry, Colorado State UniVersity
Fort Collins, Colorado 80523
ReceiVed December 28, 1995
The presence of oxazoles and thiazoles as masked dehydro-
peptides in a number of important natural substances continues
to attract considerable attention among organic chemists.1 The
streptogramin family of antibiotics, which arises from a number
of microorganisms,2 occurs as a mixture of two groups, A and
B. Group A contains the oxazole moiety, whereas group B is
mainly composed of peptide linkages. Their main mode of
action involves inhibition of peptide biosynthesis in the bacterial
ribosome.3,4 Typical members of the structurally interesting
group A are madumycin II (1) and virginiamycin M2 (2). The
former was isolated by Brazhnikova5 and also by Chamberlin,6
designating the same substance as A-2315A, whereas the latter
was isolated by Lord Todd7 and its structure confirmed by X-ray
analysis.8
Synthetic efforts toward these and other members of the
streptogramin group A compounds have been reported over the
past 15 years and to date none have succeeded in reaching any
of the targets.9 We now report the first enantioselective total
synthesis of madumycin II (A-2315A), (1) whereas the preced-
ing paper by Schlessinger10 reports the first enantioselective
synthesis of virginiamycin M2 (2).
a
Key: (a) -78 °C, 2.0 h, THF; (b) -100 °C, 45 min, 92%, Et2O;
workup; dry; TBDMSCI, imidazole, DMF; (c) O3, DMS; (d) NaClO2,
NaH2PO4, H2O2 CH3CN‚H2O; (e) isobutylchloroformate, N-methyl-
morpholine, serine methylester‚HCl; (f) MeCO2NS(O)2NEt3 (ref 16);
(g) tert-butylperbenzoate, CuBr, Cu(OAc)2, benzene, reflux 7.5 h; (h)
TBAF/THF, rt, 4 h; (i) camphorsulfonic acid, CH2Cl2, 0 °C, 48 h, 74%;
(j) SO3‚pyridine, DMSO, Et3N; (k) PhPdC(CH3)CHO, benzene, reflux,
23 h; (l) CH2dCHPBu3Br, potassium phthalimide, THF, 65 °C, 48 h;
(m) pyridine reflux, 11 h.
reconnected at these junctures with fragment B, representing
the northern and eastern quadrants of madumycin.11
The route to fragment A began by treatment of the Weinreb
amide 312 with allylmagnesium bromide to furnish the â,γ-
unsaturated ketone, which was reduced with high stereoselec-
tivity (>99%) to the single diastereomeric alcohol, under
chelation control (LiI, LiAlH4), possessing the syn 1,3-config-
uration13 (Scheme 1). The allylic alcohol was masked as the
tert-butyldimethylsilyl ether (TBS) 4 and was then subjected
to ozonolysis, affording the aldehyde 5. Oxidation14 of the
aldehyde 5 with sodium chlorite-H2O2 gave the carboxylic acid
6 which was immediately transformed with (S)-serine ethyl ester
into the hydroxyamide 7 Via the mixed anhydride. Cyclization15
(9) (a) Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Linderman, R. J. J.
Org. Chem. 1986, 51, 5111. (b) Helquist, P.; Bergdahl, M.; Hett, R.;
Gangloff, A. R.; Demillequand, M.; Cottard, M.; Mader, M. M.; Friebe,
T.; Iqbal, J.; Wu, Y.; Akermark, B.; Rein, T.; Kann, N. Pure Appl. Chem.
1994, 66, 2063. (c) Schlessinger, R. H.; Iwanowicz, E. J.; Springer, J. P.
Tetrahedron Lett. 1988, 29, 1489. (d) Wood, R. D.; Ganem, B. Tetrahedron
Lett. 1983, 24, 4391. (e) Liu, L.; Tanke, R. S.; Miller, M. J. J. Org. Chem.
1986, 51, 5332. (f) Adje, N.; Breuilles, P.; Uguen, D. Tetrahedron Lett.
1993, 34, 4631 and refs 9a-f.
Our route to 1 required two major components, A and B,
obtained by disconnecting 1 at C-6 and C-20. Fragment A,
representing the southern and western quadrants, was to be
(10) Schlessinger, R. H.; Li, Y-J. J. Am. Chem. Soc. 1996, 118, 0000.
We thank Professor Schlessinger for providing this information prior to
publication.
(1) (a) Michael, J. P.; Pattenden, G. Angew. Chem., Int. Ed. Engl. 1993,
32, 1. (b) Fusetani, N.; Matsunaga, S. Chem. ReV. 1993, 93, 1753. (c)
Davidson, B. S. Chem. ReV. 1993, 93, 1771. (d) Kobayashi, J.; Ishibashi,
M. Chem. ReV. 1993, 93, 1753. (e) Lewis, J. R. Nat. Prod. Rep. 1993, 10,
29. (f) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992,
114, 9434. (g) Smith, A. B.; Salvatore, B. A. Tetrahedron Lett. 1994, 35,
1329. (h) Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2477.
(2) (a) Cocito, C. Microbiol. ReV. 1979, 43, 145. (b) Vazquez, D. The
Streptogramin Family of Antibiotics. In Antibiotics III; Corcoran, J. W.,
Hahn, F. H., Eds.; Springer-Verlag: New York, 1975.
(3) (a) Cocito, C.; Kaji, A. Biochimie 1971, 53, 763. (b) Cocito, C.;
Giambattista, M. Mol. Gen. Genet. 1978, 166, 53. (c) Ennis, H. L.
Biochemistry 1971, 10, 1265.
(4) (a) Purvis, M. B.; Kingston, D. G. I.; Fujii, N.; Floss, H. G. J. Chem.
Soc., Chem. Commun. 1987, 302. (b) Purvis, M. B.; LeFevre, J. W.; Jones,
V. L.; Kingston, D. G. I.; Biot, A. M.; Gossele J. Am. Chem. Soc. 1989,
111, 5931. (c) Parfait, R.; Cocito, C. Proc. Natl. Acad. Sci. U.S.A. 1980,
77, 5496.
(11) There existed some doubt regarding the stereochemistry at C-13,
C-15 by the original workers5,6 who established the structure of 1. However,
this was resolved during our synthesis of 4 by independent means and shown
to be correct as previously proposed (syn C-13, C-15); see text and ref 26
below.
(12) (a) Piscopio, A. D.; Minowa, N.; Chakraborty, T. K.; Koide, K.;
Bertinato, P.; Nicolaou, K. C. J. Chem. Soc., Chem. Commun. 1993, 617.
(b) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. The amide
3 was prepared from (S)-malic acid in 44% overall yield as shown. The
chelation-controlled borane reduction of the R-carboxyl (i) was performed
according to: Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T.
Tetrahedron 1992, 48, 4067. Further details of this sequence are presented
in the Supporting Information. The entire synthesis of 1 is also detailed in:
Tavares, F. Ph.D. Dissertation, Colorado State University, 1996.
(5) Brazhnikova, M. G.; Kudinova, M. K.; Potapova, N. P.; Filippova,
T. M.; Borowski, E.; Zelinski, Y.; Golik, J. Bioorgan. Khim. 1976, 2, 149.
(6) Chamberlin, J. W.; Chen, S. J. Antibiot. 1977, 30, 197.
(7) Delpierre, G. R.; Eastwood, F. W.; Gream, G. E.; Kingston, D. G.
I.; Lord Todd, A. R.; Williams, D. H. J. Chem. Soc. C 1966, 1653.
(8) Durant, F.; Evard, G.; Declerq, J. P.; Germain, G. Cryst. Struct.
Commun. 1974, 3, 503.
(13) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett.
1988, 29, 5419.
(14) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
0002-7863/96/1518-3303$12.00/0 © 1996 American Chemical Society