Total synthesis of reveromycin B

Article abstract of DOI:10.1021/ol990884v

(equation presented) The stereoselective total synthesis of reveromycin B (2), a novel polyketide-type antibiotic, has been accomplished.

Full text of DOI:10.1021/ol990884v

ORGANIC
LETTERS
1999
Vol. 1, No. 6
941-944
Total Synthesis of Reveromycin B
,†
Tsutomu Masuda, Katsuhisa Osako, Takeshi Shimizu,* and Tadashi Nakata*
The Institute of Physical and Chemical Research (RIKEN), Wako-shi,
Saitama 351-0198, Japan
nakata@postman.riken.go.jp
Received July 28, 1999
ABSTRACT
The stereoselective total synthesis of reveromycin B (2), a novel polyketide-type antibiotic, has been accomplished.
Reveromycins A-D are novel polyketide-type antibiotics
produced by Streptomyces sp. and inhibit mitogenic activity
induced by the epidermal growth factor (EGF) in a mouse
epidermal keratinocyte.1 An inhibitor of mitogenic activity
of EGF or TGF-R, which shares the same receptor with EGF,
may be the focal point for the development of a novel range
of antitumor drugs. Therefore, the reveromycins due to their
pertinent bioactivity and low toxicity may be ideal drug
candidates. Furthermore, reveromycins A, C, and D induced
the morphological reversion of srcts-NRK cells from spherical
transformed cells to flat normal cells. In addition to the
inhibition of mitogenic activity, the reveromycins showed
antifungal activity and inhibition of protein synthesis and in
the latter were selective toward eukaryotic cells only.
The characteristic structural features of the reveromycins
Figure 1. Structures of reveromycins A (1) and B (2).
include a 6,6- or a 5,6-spiroketal system, containing a
hemisuccinate, two alkenyl carboxylic acids, and two alkyl
groups.2 The absolute configuration of reveromycin A (1;
Figure 1) was determined on the basis of its chemical
degradation and spectroscopic analysis,3 while only the two-
dimensional structure of reveromycin B (2) was reported.
Their potent biological activity as potential drugs and their
synthetically challenging, unique structure have attracted the
attention of synthetic organic chemists.4-6
Quite recently, Theodorakis et al.6 reported the first total
synthesis of 2, which confirmed the absolute configuration
of 2 as shown in Figure 1. We have also been investigating
the total synthesis of reveromycins A (1) and B (2) and have
already reported the stereoselective construction of the 6,6-
† E-mail: tshimizu@postman.riken.go.jp.
(1) (a) Takahashi, H.; Osada, H.; Koshino, H.; Kudo, T.; Amano, S.;
Shimizu, S.; Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1409-1413.
(b) Takahashi, H.; Osada, H.; Koshino, H.; Sasaki, M.; Onose, R.;
Nakakoshi, M.; Yoshihama, M.; Isono, K. J. Antibiot. 1992, 45, 1414-
1419.
(2) Koshino, H.; Takahashi, H.; Osada, H.; Isono, K. J. Antibiot. 1992,
45, 1420-1427.
(3) Ubukata, M.; Koshino, H.; Osada, H.; Isono, K. J. Chem. Soc., Chem.
Commun. 1994, 1877-1878.
(4) Shimizu, T.; Kobayashi, R.; Osako, K.; Nakata, T. Tetrahedron Lett.
1996, 37, 6755-6758.
(5) McRae, K. J.; Rizzacasa, M. A. J. Org. Chem. 1997, 62, 1196-
1197.
(6) Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc. 1999, 121, 456-
457.
10.1021/ol990884v CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/03/1999

spiroketal part of 1, confirming the absolute configuration.4
We now report the stereoselective total synthesis of revero-
mycin B (2).
Scheme 2a
Our synthetic strategy for reveromycin B (2) is outlined
in Scheme 1. It is postulated that a one-pot Julia olefination
Scheme 1
a Reagents and conditions: (a) AcOH, THF, H2O, room tem-
perature, then TsOH, MeOH, room temperature (88%); (b) TBSCl,
Et3N, DMAP, DMF, 0 °C to room temperature (96%); (c)
TBDPSOTf, lutidine, CH2Cl2, 0 °C to room temperature (95%);
(d) RuCl3, NaIO4, CH3CN, CCl4, phosphate buffer (pH 8), room
temperature (92%); (e) Me2AlCl, MeNHOMe‚HCl, CH2Cl2, 0 °C
to room temperature; (f) TBSCl, imidazole, DMAP, DMF, 0 °C to
room temperature (65%, 2 steps; 11% of 14 was recovered); (g)
DMSO, Ac2O, room temperature (94%).
11 with aqueous AcOH produced a simultaneous cyclization
to give the tetrahydrofuran 12 in 88% yield.9 After successive
silylation of 12 with TBSCl and TBDPSOTf, oxidation with
RuCl3-NaIO410 selectively afforded the γ-butyrolactone 14
in 84% yield over three steps. The aminolysis of 14 with
Me2AlCl-MeNHOMe‚HCl,11 an effective reagent for con-
struction of Weinreb amides from sterically hindered lac-
tones, cleanly proceeded to give the dihydroxy amide 15,
which was treated with TBSCl to produce the TBS ether 16
in 65% yield along with 14 (11%).12 Protection of the tertiary
alcohol in 16 with DMSO-Ac2O gave the desired Weinreb
amide 9 in 94% yield.
The alkyne 10 was prepared from the known alcohol 174
(Scheme 3). After protection of 17 with TESCl, successive
Scheme 3a
employing sulfone 3 and aldehyde 4, followed by a Wittig
reaction, would lead to the stepwise elaboration of the labile
polyunsaturated right chain.7 Conversely, the left chain may
be constructed via the Horner-Wadsworth-Emmons reac-
tion using phosphonate 5, following esterification with the
mono(allyl succinate) 6.8 The 5,6-spiroketal core 7 would
be synthesized via the coupling reaction of the Weinreb
amide 9 and alkyne 10.
a Reagents and conditions: (a) TESCl, imidazole, DMAP, DMF,
0 °C to room temperature (96%); (b) OsO4, NMO, acetone, H2O,
room temperature (87%); (c) Pb(OAc)4, toluene, room temperature
(97%); (d) TMSCHN2, nBuLi, THF, -78 to 0 °C (70%).
treatment with OsO4-NMO and Pb(OAc)4 afforded the
aldehyde 19 (81%), which was converted into the alkyne 10
(70%) by the Colvin rearrangement.13
The Weinreb amide 9 was prepared from the known
epoxide 114 (Scheme 2). Hydrolysis of the THP group in
(9) During evaporation of the solvents, the resulting diol 12 was converted
into the THP derivative, which was then treated with TsOH in MeOH to
give 12.
(10) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936-3938.
(7) â-Elimination of the silylated C-5 hydroxy group occurred under
various basic conditions.
(8) The mono(allyl succinate) 6 was prepared by alcoholysis of succinic
anhydride with allyl alcohol in 94% yield.
942
Org. Lett., Vol. 1, No. 6, 1999

With the desired Weinreb amide 9 and alkyne 10 in hand,
we then investigated the union of these fragments leading
to the spirocyclic core and incorporation of the dienyl
carboxylic side chain (Scheme 4). The coupling reaction of
Scheme 5a
Scheme 4a
a Reagents and conditions: (a) nBu2BOTf, iPr2NEt, crotonalde-
hyde, CH2Cl2, -78 °C to room temperature (86%); (b) TBSOTf,
lutidine, CH2Cl2, 0 °C (100%); (c) NaBH4, THF, H2, room
temperature (87%); (d) TESCl, imidazole, DMF, 0 °C to room
temperature (100%); (e) OsO4, NMO, acetone, H2O, room tem-
perature (82%); (f) Pb(OAc)4, toluene, room temperature (97%).
Scheme 6a
a Reagents and conditions: (a) nBuLi, THF, 0 °C; (b) Pd/C, H2,
AcOEt, room temperature (94%, 2 steps); (c) TsOH, CHCl3, EtOH,
0 °C to room temperature (83%); (d) TBAF, THF, room temperature
(86%); (e) TESCl, Et3N, CH2Cl2, 0 °C; (f) 6, DIC, DMAP, CH2Cl2,
room temperature (98%, 2 steps); (g) PPTS, CHCl3, MeOH, 0 °C
(92%); (h) TPAP, NMO, CH2Cl2, room temperature (93%); (i) 5,
LiHMDS, THF, HMPA, -78 to 0 °C; (j) 6, DIC, DMAP, CH2Cl2,
room temperature (77%, 2 steps).
the lithio derivative of 10 and amide 9 followed by
hydrogenation furnished the saturated ketone 8 in 94% yield.
Treatment of 8 with TsOH in EtOH-CHCl3 effected
deprotection of the TES, TBS, and MTM groups and
simultaneous 5,6-spiroketalization to give the thermodynami-
cally stable isomer 20 in 83% yield. After deprotection of
the TBDPS group with TBAF and silylation with TESCl,
the resulting alcohol 21 was subjected to esterification with
the mono(allyl succinate) 6 to give the succinate 22 in 84%
yield. Desilylation of 22 with PPTS followed by TPAP
oxidation gave the aldehyde 23 in 86% yield. The Horner-
Wadsworth-Emmons reaction of 23 with phosphonate 514
in the presence of HMPA at -78 to 0 °C15 gave a ca. 7:3
inseparable mixture of dienoic esters and their des-succinate
derivatives. This mixture was resubjected to esterification
with 6 to give the desired (20E,22E)-24 along with the 20E,-
22Z isomer (77% yield; the ratio of 24 to its isomer is 14:
1).
a Reagents and conditions: (a) DDQ, CH2Cl2, H2O, room
temperature (91%); (b) SO3‚Py, Et3N, CH2Cl2, DMSO, 0 °C to room
temperature (99%); (c) Ph3PdC(Me)CHO, toluene, 110 °C (93%);
(d) Zn(BH4)2, Et2O, 0 °C; (e) 2-mercaptobenzothiazole, Ph3P,
DEAD, THF, room temperature; (f) Mo7O24(NH4)6‚4H2O, H2O2,
EtOH, 0 °C to room temperature, (79% from 33); (g) LiHMDS, 4,
THF, -78 to 0 °C (56%: 76% yield based on consumed 3); (h)
PPTS, CHCl3, MeOH, 0 °C (95%); (i) Dess-Martin periodinane,
CH2Cl2, room temperature (90%); (j) Ph3PdCHCO2(allyl), toluene,
80 °C (98%); (k) HF‚Py, THF, 0 °C to room temperature (78%);
(l) Pd2(dba)3‚CHCl3, nBu3P, HCO2H, Et3N, 1,4-dioxane, 50 °C
(62%).
(11) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38,
2685-2688.
(12) Treatment of 15 with TBSOTf exclusively gave the lactone 14.
(13) (a) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun.
1973, 151-152. (b) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin
Trans. 1 1977, 869-874. (c) Miwa, K.; Aoyama, T.; Shioiri, T. Synlett
1994, 107-108.
Two asymmetric centers in the right chain were set by
Evans asymmetric aldol methodology16 (Scheme 5). The
Org. Lett., Vol. 1, No. 6, 1999
943

aldol reaction of the boron enolate of the oxazolidinone 25
with crotonaldehyde exclusively furnished the syn-alcohol
26 in 86% yield. Treatment of 26 with TBSOTf followed
by NaBH4 reduction in aqueous THF17 produced the alcohol
27 in 87% yield. After protection of 27 with TESCl, the
oxidative cleavage of the olefin by successive treatment with
OsO4-NMO and Pb(OAc)4 afforded the desired aldehyde
4 in 80% yield.
The final elaboration of the dienyl alcohol side chain began
with deprotection of the MPM group in 24 (Scheme 6).
Treatment of 24 with DDQ followed by oxidation with SO3‚
Py gave the aldehyde 29 (90%), which was subjected to the
Wittig reaction to give the R,â-unsaturated aldehyde 30 in
93% yield. Reduction of 30 with Zn(BH4)2 afforded the allyl
alcohol 31, which was converted into the sulfone 3 in 79%
yield by the Mitsunobu reaction with 2-mercaptobenzothia-
zole followed by Mo(VI)-mediated oxidation.18 The one-pot
Julia olefination of the sulfone 3 and the aldehyde 4
stereoselectively produced the (6E,8E)-diene 32 in 56% yield
(76% yield based on the consumed 3). After selective
desilylation of 32 with PPTS followed by oxidation with the
Dess-Martin periodinane, the resulting aldehyde 33 was
subjected to a Wittig reaction employing the neutral phos-
phorane to afford the R,â-unsaturated ester 34 in 84% yield.
Deprotection of the TBS group in 34 was achieved by HF‚
Py in THF; the use of TBAF caused decomposition of the
substrate. Finally, removal of the three allyl groups in 35 by
the Pd catalyst19 cleanly proceeded to give reveromycin B
(2). The spectral data (1H NMR, 13C NMR, [R]D, IR, HRMS)
of the synthetic 2 were identical with those of natural
reveromycin B (2).
Acknowledgment. This work was supported in part by
Special Project Funding for Basic Science (Multibioprobes)
from RIKEN. We thank Dr. H. Koshino and Dr. H. Osada
for supplying the spectra of the natural product and Ms. K.
Harata for the mass spectral measurements.
(14) The phosphonate 5 was prepared as follows:
Supporting Information Available: IR, [R]D, 1H NMR,
13C NMR, and mass spectroscopy data for compounds 3-5,
7, 9, 10, 22, 24, 32, 34, and 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
Reagents and conditions: (a) Ph3PdCHCO2Me, benzene, 70 °C (81%);
(b) allyl alcohol, ClBu2SnOSnBu2OH,14a,b toluene, 110 °C (85%); (c) CBr4,
Ph3P, lutidine, CH3CN, 0 °C (94%); (d) P(OEt)3, 90 °C (90%). (a) Otera,
J.; Yano, T.; Kawabata, A.; Nozaki, H. Tetrahedron Lett. 1986, 27, 2383-
2386. (b) Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307-
5311.
OL990884V
(18) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim.
Fr. 1993, 130, 336-357. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne,
R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856-878. Application to total
synthesis: (c) Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V.
Synthesis 1996, 285-296. (d) Smith, N. D.; Kocienski, P.; Street, D. A.
Synthesis 1996, 652-666.
(15) Corey, E. J.; Katzenellenbogen, J. A.; Roman, S. A.; Gilman, N.
W. Tetrahedron Lett. 1971, 21, 1821-1824.
(16) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127-2129.
(17) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067-7070.
(19) Tsuji, J.; Minami, I.; Shimizu, I. Synthesis 1986, 623-627.
944
Org. Lett., Vol. 1, No. 6, 1999