Total Synthesis of Herbimycin A

Article abstract of DOI:10.1021/ol036092p

(Equation presented) Herbimycin A (HA) belongs to a class of antibiotics known as the benzoquinoid ansamycins. Members of this class have shown promising biological activity as Hsp90 inhibitors. An enantioselective synthesis of HA is described, employing

Full text of DOI:10.1021/ol036092p

ORGANIC
LETTERS
2004
Vol. 6, No. 1
55-57
Total Synthesis of Herbimycin A
Kendra D. Carter and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
panek@chem.bu.edu
Received October 27, 2003
ABSTRACT
Herbimycin A (HA) belongs to a class of antibiotics known as the benzoquinoid ansamycins. Members of this class have shown promising
biological activity as Hsp90 inhibitors. An enantioselective synthesis of HA is described, employing asymmetric syn-crotylation methodology
to introduce the C10, C11, C14, and C15 stereocenters. The C6−C7 stereocenters were introduced using Brown’s r-pinene-derived γ-methoxy
allylborane reagent. The C12 stereocenter was established by diastereoselective hydroboration.
In 1979, herbimycin A (HA) was isolated from the fermenta-
tion broth of Streptomyces hygroscopicus strain AM-3672.1a
The structure and absolute configuration of herbimycin A
Our synthetic plan for HA, illustrated in Scheme 1,
involved bond disconnection at C1 of the lactam to give the
seco acid 2. Further simplification led to a disconnection of
the C4-C5 (Z)-olefin and the C5-C21 aromatic fragment,
from which the (E,Z)-dienoate would be established by a
1
was based on H and 13C NMR spectroscopic analysis and
single-crystal X-ray analysis.1 The natural product possesses
seven stereocenters, a carbamate, an (E,Z)-diene, and a 19-
membered macrocyclic lactam. Herbimycin A is a member
of the ansamycin benzoquinone class of natural products,
which possesses an aliphatic ansa bridge connecting two
nonadjacent positions of a benzoquinone or naphthoquinone
ring system.2 The biological activity3 of herbimycin A has
been shown to reduce radial tumor, bacterial, herbicidal, and
fungal cell growth.
Herbimycin A (1) was first synthesized by Tatsuta in 1991,
by a strategy that established three of the seven stereocenters
(C11, C12, and C14) from a derivative of D-mannose.4 Other
members of the ansamycin benzoquinone family that have
been synthesized include macbecin I and geldanamycin.5
(3) (a) Omura, S.; Iwai, Y.; Takahashi, Y.; Sadakane, N.; Nakagawa,
A.; Oiwa, H.; Hasegawa, Y.; Ikai, T. J. Antibiot. 1979, 32, 255. (b) Shibata,
K.; Satsumabaashi, S.; Sano, H.; Komiyama, K.; Nakagawa, A.; Omura,
S. J. Antibiot. 1986, 39, 415. (c) Yamashita, T.; Sakai, M.; Kawai, Y.; Aono,
M.; Takahashi, K. J. Antibiot. 1989, 42, 1015. (d) Suzukake-Tsuchiya, K.;
Moriya, Y.; Hori, M.; Uehara, Y.; Takeuchi, T. J. Antibiot. 1989, 42, 1831.
(e) Honma, Y.; Okabe-Kado, J.; Hozumi, M.; Uehara, Y.; Mizuno, S. Cancer
Res. 1989, 49, 331. (f) June, C. H.; Fletcher, M. C.; Ledbetter, J. A.;
Schieven, G. L.; Siegel, J. N.; Andrew, F.; Samelson, L. E. Proc. Natl.
Acad. Sci. U.S.A. 1990, 87, 7722. (g) Taniguchi, M.; Uehara, Y.; Matsuyama,
M.; Takahashi, M. Biochem. Biophys. Res. Commun. 1993, 195, 208. (h)
Svoboda, K.; Orlow, D.; Chu, C.; Reenstra, W. Anat. Rec. 1999, 254, 348.
(i) Sheski, R. D.; Natarajan, V.; Pottratz, S. T. J. Lab. Clin. Med. 1999,
133, 265. (j) Oikawa, T.; Ogasawara, H.; Sano, H.; Shibata, K.; Omura, S.
Biol. Pharm. Bull. 1994 17, 1430. (k) Iwai, Y.; Akira, N.; Sadakane, N.;
Omra, S.; Oiwa, H.; Matsumoto, S.; Takahashi, M.; Ikai, T.; Ochiai, Y. J.
Antibiot. 1980, 33, 1114.
(4) (a) Nakata, M.; Osumi, T.; Ueno, A.; Kimura, T.; Tamai, T.; Tatsuta,
K. Bull. Chem. Soc. Jpn. 1992, 65, 2974. (b) Nakata, M.; Osumi, T.; Ueno,
A.; Kimura, T.; Tamai, T.; Tatsuta, K. Tetrahedron Lett. 1991, 32, 6015.
Synthesis of advanced fragments: (c) Eshelman, J. E.; Epps, J. L.;
Kallmerten, J. Tetrahedron Lett. 1993, 34, 749. (d) Martin, S. F.; Dodge,
J. A.; Burgess, L. E.; Limberakis, C.; Hartmann, M. Tetrahedron 1996, 52,
3229. (e) Martin, S. F.; Limberakis, C.; Burgess, L. E.; Hartmann, M.
Tetrahedron 1999, 55, 3561.
(1) (a) Furusaki, A.; Matsumoto, T.; Nakagawa, A.; Omura, S. J. Antibiot.
1980, 33, 781. (b) Ishihara, Y.; Shirahata, K.; Sano, H. J. Antibiot. 1989,
42, 49. (c) Omura, S.; Nakagawa, A.; Sadakane, N. Tetrahedron Lett. 1979,
20, 4323.
(2) (a) Luttringhaus, A.; Gralheer, H. Justus Liebigs Ann. Chem. 1942,
67, 550. (b) Prelog, V.; Oppolzer, W. HelV. Chim. Acta 1973, 56, 2279. (c)
Rinehart, K. L. Acc. Chem. Res. 1972, 5, 57.
10.1021/ol036092p CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/10/2003

Scheme 1
Scheme 2
series of Wittig reactions. We anticipated that the C6-C7
syn-diol would be introduced by Brown’s asymmetric
allylboration methodology. In accordance with our previous
synthesis of macbecin, the C12 stereocenter would be created
by a diastereoselective hydroboration reaction,6 with the pair
of syn-methoxy-methyl stereocenters at C10-C11 and C14-
C15 being introduced by our organosilane methodology.7
Our synthesis began with protection of the known primary
alcohol in 7,5f which was followed by methylation of the
secondary alcohol using Meerwein’s reagent (Me3OBF4) to
give 8 in 80% yield (Scheme 2).5f,g Removal of the silicon
protecting group at C10 was followed by debenzylation of
the C11 hydroxy group with BCl3‚SMe2 complex in CH2Cl2
at -78 to 0 °C, which gave the diol in 87% yield. The 1,2-
diol was subjected to an oxidative cleavage reaction with
NaIO4 and NaHCO3 in a 1:1 mixture of acetone and water
to yield aldehyde 9, which was subjected to a second
crotylation with silane 10 to afford the syn-homoallylic ether
11 in 59% yield (dr ) 12:1). This reaction was carried out
as a multicomponent process that utilized the in situ
generation and trapping of an oxonium ion created by the
action of TMSOMe on aldehyde 9 in the presence of catalytic
amounts of TMSOTf. This material was subjected to a
dihydroxylation reaction with catalytic OsO4 (35 mol %,
NMO 1.08 equiv), and this was followed by cleavage of the
intermediate diol with Pb(OAc)4 (1.08 equiv) in buffered
(K2CO3) benzene to afford the aldehyde 12 in 61% yield
for the two steps (Scheme 3). A Wittig reaction with the
stabilized ylide Ph3PdC(Me)CO2Et in toluene gave the (E)-
olefin in 78% yield (Scheme 3).8 The ester was reduced with
DIBAL-H in THF to the alcohol, which underwent a Swern
oxidation to give the aldehyde 4 in 91% yield. Using Brown’s
allylboration technology, we constructed the C6-C7 syn-
stereocenters by asymmetric allylboration of 4 with the
γ-methoxyallyl organoborane reagent derived from (-)-R-
pinene.9 The corresponding allylation product was obtained
in good yield as a single diastereoisomer.
(5) Macbecin I: (a) Baker, R.; Castro, J. J. Chem. Soc., Chem. Commun.
1989, 378-381. (b) Baker, R.; Castro, J. J. Chem. Soc., Perkin Trans. 1
1990, 47. (c) Evans, D. A.; Miller, S. J.; Ennis, M. D.; Ornstein, P. L. J.
Org. Chem. 1992, 57, 1067. (d) Evans, D. A.; Miller, S. J.; Ennis, M. D.;
Ornstein, P. L. J. Org. Chem. 1993, 58, 471. (e) Panek, J. Xu, F. J. Am.
Chem. Soc. 1995, 117, 10587. (f) Panek, J. Xu, F.; Rondon, A. C. J. Am.
Chem. Soc. 1998, 120, 4113. (g) Kallmerten, J.; Eshelman, J. E.; Epps, J.
L. Tetrahedron Lett. 1993, 34, 749. (h) Martin, S. F.; Dodge, J. A.; Burgess,
L. E.; Harmann, M. J. Org. Chem. 1992, 57, 1070. Geldanamycin: (i)
Andrus, M. B.; Meredith, E. L.; Simmons, B. L.; Soma Sekhar, B. B. V.;
Hicken, E. J. Org. Lett. 2002, 4, 3549. (j) Andrus, M. B.; Meredith, E. L.;
Somo Sekhar, B. B. V. Org. Lett. 2001, 3, 259. (k) Andrus, M. B.; Somo
Sekhar, B. B. V.; Meredith, E. L.; Dalley, N. K. Org. Lett. 2000, 2, 3035.
(l) Andrus, M. B.; Meredith, E. L.; Hicken, E. J.; Simmons, B. L.; Glancey,
R. R.; Ma, W. J. Org. Chem. 2003, 68, 8162.
Protection of the C7 hydroxyl group as a TBS ether
allowed incorporation of the carbamate toward the end of
the synthesis. Using this reaction sequence, we were able to
(8) Kishi, Y.; Johnson, M. R. Tetrahedron Lett. 1979, 20, 4347.
(9) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988,
110, 1535.
(6) Xu, F.; Panek, J. J. Org. Chem. 1992, 57, 5288-5290.
(7) Masse, C.; Panek, J. Chem. ReV. 1995, 95, 1293.
56
Org. Lett., Vol. 6, No. 1, 2004

Scheme 3
Scheme 4
for 52 h gave the secondary alcohol in 73% yield. Formation
of the carbamate with trichloroacetylisocyanate13 and K2CO3/
MeOH gave the desired urethane product in 97% yield; this
was followed by oxidation of the dimethoxy aromatic core
to the quinone with CAN, which gave synthetic herbimycin
A in 63% yield. The spectroscopic and physical properties
were identical in all respects with those of natural herbimycin
A.
The present synthesis of herbimycin A uses chiral organo-
silanes to establish four (C10, C11, C14, and C15) of the
seven stereocenters, a diastereoselective hydroboration to
establish the C12 stereocenter, and Brown’s allylboration
methodology to install the C6-C7 stereocenters. Our syn-
thesis documents the reliability and high levels of stereo-
selectivity that can be obtained using our chiral organosilane
technology. The synthesis was accomplished in 27 steps
beginning with the crotylation reaction between the acetal 5
and the (E)-crotylsilane 6 with an overall yield of 1.09%.
Further studies on the chemistry and biology of this and other
members of this class of natural products are underway in
our laboratory and will be reported at a later time.
establish the C6,C7 stereochemical relationship and complete
the synthesis of the C5-C21 fragment 13 in 97% yield. The
installation of the C2-C5 (E,Z)-dienoate began with trans-
formation of the terminal olefin in 13 to the aldehyde 3. In
a two-step reaction sequence, the aldehyde 3 was obtained
after an oxidative cleavage of the terminal olefin with a
catalytic amount of OsO4 followed by treatment of the
intermediate diol with Pb(OAc)4 in benzene buffered with
K2CO3. The C4-C5 (Z)-olefin was then established by a
Horner-Emmons olefination reaction using the Still-
Gennari phosphonate to afford the (Z)-R,â-unsaturated ethyl
ester in 83% yield as a single isomer.10 Reduction of the
ester with DIBAL-H followed by Swern oxidation provided
the R,â-unsaturated aldehyde 14 with an 89% overall yield.
The synthesis of the (E,Z)-dienoate was completed by
installation of the C2-C3 trisubstituted (E)-olefin employing
similar conditions used earlier to install the C8-C9 trisub-
stituted (E)-olefin (Scheme 4). Accordingly, the (E,Z)-
dienoate was synthesized in quantitative yield as a single
isomer. The aryl nitro group was reduced under the mild
conditions developed by Lalancette,11 and this was followed
by saponification of the ester to give the advanced intermedi-
ate 2. As initially reported by Baker and Castro,5a,b treatment
of the unpurified seco acid with BOPCl and DIPEA gave
the macrocycle in 81% yield.12
Acknowledgment. We are grateful to the NIH-NCI, NIH-
GMS (CA56304), and UNCF-Merck Dissertation Fellowship
for funding and Pfizer for a sample of authentic herbimycin
A.
Supporting Information Available: Experimental pro-
cedures and characterization for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL036092P
(10) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(11) (a) Lalancette, J. M., Jr.; Freche, A.; Birndle, J. R.; Laliberte, M.
Synthesis 1972, 527-532. (b) Lalancette, J. M., Jr.; Freche, A.; Monteux,
R. Can. J. Chem. 1968, 46, 2754-2757.
(12) (a) Diago-eseguer, J.; Palomo-Col, A. L.; Fernandez-Lizarbe, J. R.
Synthesis 1980, 547. (b) Van Der Auwera, C.; Anteunis, M. J. O. Int. J.
Peptide Protein Res. 1987, 29, 574.
Completion of the synthesis of 1 was accomplished by a
few well-documented transformations. Deprotection of the
C7-silyl ether with TBAF in THF at ambient temperature
(13) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
Org. Lett., Vol. 6, No. 1, 2004
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