Total synthesis of streptogramin antibiotics. (-)-Madumycin II

Article abstract of DOI:10.1021/ja954312r

Synthetic efforts toward 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. We now report the first enantioselective total synthesis of Madumycin II (A-2

Full text of DOI:10.1021/ja954312r

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

3304 J. Am. Chem. Soc., Vol. 118, No. 13, 1996
Communications to the Editor
to the oxazoline 8 was accomplished in 65-70% overall yield
from the acid 6 using the Burgess reagent.16 Oxidation, using
our previously described Cu(I)-Cu(II) peroxide reagent,17
transformed the oxazoline 8 to the oxazole 9 in 81% yield.
Scheme 2a
It was now necessary to release the hydroxy group in 9 to
the hydroxydioxolane 10 in order to transform it to the isomeric
1,3-dioxane 11. This was accomplished by initially treating the
silyl ether 9 with fluoride ion and then subjecting the resulting
alcohol 10 to equilibrating exchange conditions9a using the
dimethylacetal of 1,3,5-mesitylformaldehyde (Mes). In this
fashion 10 was transformed, in good yield, with catalytic
camphorsulfonic acid, to the stereochemically pure18 1,3-dioxane
11. Oxidation gave the aldehyde 12 and Wittig olefination,
using R-formylethylidinetriphenylphosphorane,19 smoothly pro-
duced the pure (E)-R,â-unsaturated aldehyde 13. Chain exten-
sion of the aldehyde was implemented by treating 13 with vinyl
triphenylphosphonium bromide in the presence of potassium
phthalimide9a to afford the (E,E)-diene imide 14. Removal of
the methyl from the methyl ester with LiI in pyridine20 then
furnished the key fragment A as the free carboxylic acid 15.
The northeastern portion (B) was accessed by initially
preparing the syn adduct 16, Via an Evans’ chiral enolate as
earlier described,21 in 76% yield with greater than 99:1
diastereoselectivity. Removal of the chiral auxiliary Via the
Weinreb amide12b followed by DiBAH reduction22 produced the
unstable aldehyde 17, which was immediately subjected to
Horner-Emmons-Wadsworth olefination23 (Scheme 2). The
resulting unsaturated silyl ester (pure (E)-isomer, 72% yield)
was esterified with N-Boc-D-alanine to afford the depsipeptide
18a in quantitative yield. Removal of the Boc group with
toluenesulfonic acid gave the primary amino ester 18b, which
was now set to undergo amide coupling to fragment A (15).
a
Key: (a) (i) 0 °C, 3 h, CH2Cl2, (ii) 68%, toluene -78 °C, 30 min;
(b) (EtO)2 P(O)CH2CO2CH2CH2SiMe3, LiCl, CH3CN, i-PrEt2N; (c)
DCC, D-Boc-alanine, CH2Cl2, 0 °C f rt, 11 h; (d) TsOH‚H2O, 23 °C,
16 h; (e) DMAP, CH2Cl2, 0 f 25 °C, 9 h; (f) CH3NH2, ethanol‚benzene
50 °C, 48 h; (g) Bu4NF, THF, 0 f 25 °C, 4 h; (h) i-Pr2EtN, BopCl,
CH2Cl2, -10 to 23 °C, 18 h.
86% yield, which contained 8-10% of a double bond isomer
(NMR). This impurity was unexpected, and it was important
to determine whether it was carried forward from 15 or had
arisen during the hydrolysis of the dioxane 22. An authentic
sample of 1 (Eli Lilly) was, therefore, transformed into the
mesityldioxane 22 which was identical in every respect (NMR,
M/e) with 22 obtained in the current synthetic route. When
22, derived from authentic 1, was subjected to hydrolysis (TFA,
-5 °C) under conditions described above, the same quantity of
olefinic impurity (8-10%) in 1 appeared. Thus, the olefinic
isomer was simply a consequence of the hydrolysis conditions
to remove the mesitylene acetal (i.e. 22 to 1).
The amide connection of 15 to 18b was performed using DCC
and produced 19 in 63% yield. Treatment of the latter with
methylamine in ethanol-benzene24 gave the free primary amine
20 in 78% yield. After cooling in THF, the â-silylethyl ester
20 was smoothly fragmented using Bu4NF. The resulting crude
amino acid 21 was dried by azeotropic water removal using
benzene and cyclized (1.5 mM in CH2Cl2) with Bop-Cl25 in
the presence of Hu¨nig’s base to afford 22 (32% from 20).
Hydrolysis of the dioxane moiety in 22 gave madumycin II in
Finally, the earlier question11 of stereochemistry at C-13, C-15
can now be confirmed as syn, since complete identity between
synthetic and natural madumycin was observed. The C-13, C-15
syn stereochemistry in the synthetic sample was supported by
synthesis of 4 and further by an independent analysis26 as
described by Fenical and Rychnovsky.27
In summary, we have performed the first synthesis of
madumycin II (A-2315A) in 29 steps with an overall yield of
1.8% from malic acid. Furthermore, the stereochemistry appears
to be on firm ground on the basis of the synthetic intermediates
utilized.
(15) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907.
(16) Burgess, E. M.; Penton, H. R.; Taylor, E. A.; Williams, W. M
Organic Syntheses; Wiley: New York, 1988; Collect. Vol. VI, p 788.
(17) Tavares, F.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 6803.
(18) The driving force to provide the all-equatorial 1,3-dioxane in 11
has already been discussed (cf. ref 9a).
(19) Schlessinger, R. H.; Poss, M. A.; Richardson, S.; Lin, P. Tetrahedron
Lett. 1985, 26, 2391.
Acknowledgment. The authors are grateful to the National Institutes
of Health for financial support. We are also grateful for the technical
assistance of Dr. Chris Rithner and to Drs. Ronald Spohn, Russell
Linderman, and Donald Walker for their earlier contributions (1980-
1984) to this effort. We thank Eli Lilly for their cooperation in
providing an authentic sample of 1. We are further indebted to
Professor Paul Helquist for providing a copy of the 600 MHz spectrum
of 1.
(20) Kamiya, T.; Hashimoto, M.; Nakaguchi, O.; OKu, T. Tetrahedron
1979, 35, 323.
(21) Meyers, A. I.; Spohn, R. F.; Linderman, R. J. J. Org. Chem. 1985,
50, 3633.
(22) Evans, D. A.; Miller, S. J.; Ennis, M. D. J. Org. Chem. 1993, 58,
471.
(23) Blanchette, M. A.; Choy, W.; Davis, J. T.; Eisenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(24) Milgrom, L. R.; O’Neill, F. Tetrahedron 1995, 51, 2137.
(25) Diago-Meseguer, J.; Palomo-Call, A. L. Synthesis 1980, 547.
(26) To exclude the possibility that the dioxane aldehyde 12 may have
epimerized during the process, we sought further support for the C-13, C-15
syn stereochemistry. Utilizing the Fenical-Rychnovsky empirical rule27
concerning stereochemistry of 1,3-diols, we examined the NMR spectrum
of the acetonide of both synthetic and natural 1. The 13C chemical shifts of
the geminal methyl groups were seen at 19.6, 29.9 ppm in complete accord
with a syn diol configuration in 1.
Supporting Information Available: Experimental procedures for
3-9, 19-22, and 1; NMR spectra for all key intermediates (87 pages).
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follows this article in the microfilm version of the journal, can be
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instructions.
(27) Rychnovsky, S. D.; Skalitsky, D. J.; Pathirama, C.; Jensen, P. R.;
Fenical, W. J. Am. Chem. Soc. 1992, 114, 671; Tetrahedron Lett. 1990,
31, 945.
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