A convergent, enantioselective total synthesis of streptogramin antibiotic (-)-madumycin II

Full text of DOI:10.1021/jo971616i

7908
J . Org. Chem. 1997, 62, 7908-7909
Sch em e 1a
A Con ver gen t, En a n tioselective Tota l
Syn th esis of Str ep togr a m in An tibiotic
(-)-Ma d u m ycin II†
Arun K. Ghosh* and Wenming Liu1
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607
Received September 2, 1997
With the increasing threat of resistant microbes, the
search for antibacterial agents effective against these
pathogens is of contemporary interest in medicine.2 The
emergence of methicillin-resistant S. aureus or MRSA is
particularly alarming since this strain of bacteria is
resistant to all current antibiotics except vancomycin,
which is burdened by its serious side effects.3 The
streptogramin antibiotics are comprised of two main
groups; the group A antibiotics exhibit synergism with
group B, and the possible mode of action includes the
inhibition of protein synthesis by interfering with the
bacterial ribosomal function.4 Molecular modification
and combination of both classes of streptogramins have
been shown to be effective against MRSA and erythro-
mycin-resistant S. aureus and S. epidermidis.5 The
significant therapeutic potential of streptogramins con-
tinues to foster immense synthetic interest.6 Represen-
tative of group A streptogramins are madumycin II7 and
virginiamycin,8 and their first enantioselective syntheses
have been recently reported by Meyers9 and Schlessing-
er,10 respectively. We herein report a convergent and
enantioselective total synthesis of (-)-madumycin II.
Our synthetic plan was to construct the oxazole-
containing 1,3-diol synthon 15 and R,â-unsaturated acid
unit 19 stereoselectively and assemble madumycin II by
a macrolactonization strategy. To set both stereogenic
centers of the 1,3-diol, an enzymatic asymmetrization of
meso-diacetate 2 provided the monoacetate 3 in 95%
enantiomeric excess (Scheme 1).11 The hydroxyl group
a
Key: (a) acetyl cholinesterase, pH ) 7 buffer, 12 h, 85%; (b)
MOMCl, i-Pr2NEt, DMAP, 95%; (c) O3, MeOH-CH2Cl2 (1:1), -78
°C, then Me2S, -78 to +23 °C; (d) NaBH4, EtOH, 0 °C, 2 h, 95%;
(e) aqueous MeOH, Et3N, 23 °C, 12 h; (f) Me2C(OMe)2, p-TsOH
(cat.), CH2Cl2, 23 °C, 1 h, 90%; (g) PCC, 4A-sieves, CH2Cl2, 6 h;
(h) Ph3PdC(Me)CHO, PhMe, 114 °C, 12 h; (i) NaH, (EtO)2P(O)-
CH2CO2Et, 82%; (j) DIBAL-H, CH2Cl2, -78 °C, 1 h, 95%; (k) MsCl,
Et3N, CH2Cl2; (l) NaN3, DMF, 23 °C, 8 h, 67%; (m) p-TsOH, MeOH,
23 °C, 12 h; (n) LiCN, THF-EtOH (1:1), 80 °C, 2 h, 75%; (o)
aqueous 4N NaOH, MeOH, 60 °C, 8 h then H3O+; (p) BOP,
i-Pr2NEt, O-TBS-L-serine methyl ester, MeCN, 23 °C, 5 h, 72%;
(q) TBAF, THF, 0 °C, 1 h; (r) Burgess salt, THF, 23 °C, 6 h; (s)
CuBr2, DBU, HMTA, CH2Cl2, 42 °C, 5 h, 45% from 12; (t) aqueous
LiOH, THF, 23 °C, 4 h then H3O+; (u) D-alanine-OMe, BOP,
i-Pr2NEt, MeCN, 99%; (v) HS(CH2)3SH, Et3N, MeOH, 65%.
† This manuscript is dedicated to Professor A. I. Meyers on the
occasion of his 65th birthday.
(1) (a) University Fellow. (b) Present address: Novartis Pharma-
ceuticals Corporation, Process R & D, East Hanover, NJ 07936.
(2) J aynes, B. H.; Dirlam, J . P.; Hecker, S. C. Annu. Rep. Med. Chem.
1996, 31, 121.
(3) (a) Service, R. F. Science 1995, 270, 724. (b) Neu, H. C. Science
1992, 257, 1064.
(4) (a) Purvis, M. B.; LeFevre, J . W.; J ones, V. L.; Kingston, D. G.
I.; Biot, A. M.; Gossele, F. J . Am. Chem. Soc. 1989, 111, 5931. (b)
Parfait, R.; Cocito, C. Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 5492.
(5) Brighty, K. E.; McGuirk, P. R. Annu. Rep. Med. Chem. 1991,
26, 123.
(6) (a) Meyers, A. I.; Walker, D. G. J . Org. Chem. 1982, 47, 2999.
(b) Nagao, Y.; Yamada, S.; Fujita, E. Tetrahedron Lett. 1983, 24, 2287.
(c) Wood, R. D.; Ganem, B. ibid. 1983, 24, 4391. (d) Fujita, E.
Hetereocycles 1984, 21, 41. (e) Meyers, A. I.; Spohn, R. F.; Linderman,
R. J . J . Org. Chem. 1985, 50, 3633. (f) Schlessinger, R. H.; Iwanowicz,
E. J .; Springer, J . P. Ibid. 1986, 51, 3070. (g) Liu, L.; Tanke, R. S.;
Miller, M. J . Org. Chem. 1986, 51, 5332. (h) Adje, N.; Breulles, P.;
Uguen, D. Tetrahedron Lett. 1992, 33, 2151. (i) Helquist, P.; Bergdahl,
M.; Hett, R.; Gangloff, A. R.; Demillequand, M.; Cottard, M.; Mader,
M. M.; Friebe, T. L.; Iqbal, J .; Wu, Y.; Akermark, B.; Rein, T.; Kann,
N. Pure Appl. Chem. 1994, 66, 2063 and references therein.
(7) (a) Brazhnikova, M. G.; Kudinova, M. K.; Potapova, N. P.;
Fillipova, T. M.; Borowski, E.; Zelinski, Y.; Golik, J . Bioorgan. Khim.
1976, 2, 149. (b) Chamberlin, J . W.; Chen, S. J . Antibiot. 1977, 30,
197.
(8) 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.
(9) Tavares, F.; Lawson, J . P.; Meyers, A. I. J . Am. Chem. Soc. 1996,
118, 3303.
(10) Schlessinger, R. H.; Li, Y.-J . J . Am. Chem. Soc. 1996, 118, 3301.
(11) Busato, S.; Tinembart, O.; Zhang, Z.; Scheffold, R. Tetrahedron
1990, 46, 3155.
in 3 was protected as methoxymethyl (MOM) ether 4 in
95% yield.12 Ozonolysis of 4 provided the corresponding
dialdehyde, which was reduced with sodium borohydride
to furnish the diol 5. The removal of the acetate group
in 5 afforded the triol, which was protected as the
isopropylidene derivative 6 in 90% yield. Oxidation of
the alcohol 6 with PCC followed by Wittig olefination
furnished the R,â-unsaturated aldehyde 7 (E:Z ratio 10:
1). Exposure of the aldehyde 7 to a Horner-Emmons
olefination with triethyl phosphonoacetate afforded the
E,E-diene ester 8 in 82% yield from 6. Dibal-H reduction,
followed by mesylation of the resulting alcohol, afforded
(12) Stork, G.; Takahashi, T. J . Am. Chem. Soc. 1977, 99, 1275.
S0022-3263(97)01616-2 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 23, 1997 7909
Sch em e 2a
the mesylate. Treatment of the mesylate with sodium
azide in DMF furnished the azide 9. Selective removal
of the isopropylidene group in 9 resulted in diol which
was converted to the cyanide 10.
To elaborate the oxazole functionality, the cyanide 10
was hydrolyzed, and the resulting acid was treated with
1.5 equiv of BOP reagent13 and 4 equiv of i-Pr2NEt in
acetonitrile in the presence of 2 equiv of silyl-protected
L-serine methyl ester to furnish the amide 11 in 72%
yield. Protection of the hydroxyl group of 11 afforded the
bis-MOM derivative 12 in 78% yield. The bis-MOM 12
was transformed into oxazole 13 by the following reaction
sequence: (1) deprotection of the silyl group by exposure
to n-Bu4N+F- in THF at 0 °C for 1 h; (2) conversion of
the resulting alcohol to oxazoline with Burgess salt14 in
THF at 23 °C for 6 h, and (3) oxidation15 of the corre-
sponding oxazoline to oxazole 13. Methyl ester hydroly-
sis of 13 followed by coupling of the resulting acid with
D-alanine methyl ester furnished the depsiptide 14.
Selective reduction16 of azide 14 with an excess of
propanedithiol and Et3N in methanol afforded amine 15
in 65% yield.
The synthesis of R,â-unsaturated acid 19 is outlined
in Scheme 2. Reaction of 16 with isobutyraldehyde
afforded syn-homoallyl alcohol 17 in 75% yield and high
optical purity (>95% ee).17 Olefin 17 was subjected to
ozonolytic cleavage, and the resulting aldehyde was
exposed to a Horner-Emmons olefination protocol to
provide the corresponding R,â-unsaturated ester. The
hydroxyl group was subsequently protected as THP ether
18 in 75% yield. Saponification of 18 with aqueous LiOH
provided the acid 19 in quantitative yield.
After construction of amine 15 and acid 19 with the
appropriate stereochemistry, our plan was to form an
amide bond between these fragments and then effect
macrolactonization between the C-2 hydroxyl group and
C-23 carboxylic acid. Thus, coupling of amine 15 and acid
19 was carried out in the presence of BOP reagent13 to
furnish the amide 20 in 78% yield. The removal of THP
ether was carried out by treatment of 20 with a catalytic
amount of p-TsOH in methanol. Saponification of 21
with aqueous LiOH at 0 °C for 3 h furnished the
corresponding hydroxy acid, which was subjected to
Yamaguchi macrolactonization18 conditions with 2,4,6-
trichlorobenzoyl chloride, Et3N, and DMAP at 23 °C for
a
Key: (a) Me2CHCHO, -78 °C, 3 h, then 3 N NaOH and H2O2,
75%; (b) O3, MeOH-CH2Cl2 (1:1), -78 °C, then Me2S, -78 °C to
23 °C; (c) NaH, (EtO)2P(O)CH2CO2Et, THF, 23 °C; (d) dihydropy-
ran, PPTS, CH2Cl2, 23 °C, 1 h, 75% from 17; (e) aqueous LiOH,
THF; (f) amine 15, BOP, i-Pr2NEt, MeCN, 23 °C, 6 h, 78%; (g)
p-TsOH (cat.), MeOH, 23 °C, 4 h, 95%; (h) Cl3C6H2COCl, Et3N,
PhMe, 23 °C, 4 h then DMAP, 23 °C, 12 h, 63% from 21; (i)
Me2SiCl2, n-Bu4N+Br-, 4A sieves, CH2Cl2, 0 °C, 6 h, 47%.
synthetic (-)-madumycin II (47% yield) and both mono-
MOM derivatives of madumycin II (10-12%).19 Spectral
data (IR and 400 MHz NMR) and TLC characteristics of
synthetic madumycin II (R23 -115, c 0.03, CHCl3) are
D
12 h to provide the macrolactone 22 (R23 -144, c 0.15,
identical with a sample of natural madumycin II (R23
D
D
CHCl3) in 63% yield. Removal of the bis-MOM by
exposure to n-Bu4N+Br- (2 equiv) and an excess of
dichlorodimethylsilane in CH2Cl2 at 0 °C for 6 h provided
-127, c 0.11, CHCl3) provided by Eli Lilly.20
In conclusion, an enantioselective, convergent synthe-
sis of (-)-madumycin II has been accomplished. The
current synthesis of madumycin II may find useful
application for the preparation of structural variants of
madumycin and other members in this family of antibiot-
ics.
(13) Castro, B.; Dormoy, J . R.; Evin, G.; Selve, C. Tetrahedron Lett.
1975, 1219.
(14) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J . Org. Chem. 1973,
38, 26.
(15) Barish, J . C.; Singh, J .; Spergel, S. H.; Han, W.-C.; Kissick, T.
P.; Kronenthal, D. R.; Mueller, R. H. J . Org. Chem. 1993, 58, 4494.
(16) Bayley, H.; Standring, D. N.; Knowles, J . R. Tetrahedron Lett.
1978, 19, 3633.
(17) Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986, 108, 5919.
(18) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
Ack n ow led gm en t. Financial support of this work
by the National Institutes of Health (GM 53386) is
gratefully acknowledged. We thank Eli Lilly Laborato-
ries for a sample of natural (-)-madumycin II.
(19) For another method for removal of MOM from 1,3-bis-MOM
derivative without formation of formal, see: Corey, E. J .; Hua, D. H.;
Seitz, S. P. Tetrahedron Lett. 1984, 25, 3.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for synthetic intermediates 2-22
and NMR spectra for natural and synthetic madumycin II (22
pages).
(20) The 1H NMR of synthetic madumycin showed the presence of
a small amount (5-6%) of double-bond-isomerized product. Meyers et
al.9 have also noted a similar observation and a comparable optical
rotation (R23 -118, c 0.1, CHCl3) for their synthetic madumycin II.
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