Total synthesis of reveromycin A

Article abstract of DOI:10.1021/ol0060634

matrix presented The stereoselective total synthesis of reveromycin A (1), a potent inhibitor of eukaryotic cell growth, has been accomplished on the basis of the stereocontrolled construction of the 6,6-spiroketal system, efficient succinylation of the t

Full text of DOI:10.1021/ol0060634

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2153-2156
Total Synthesis of Reveromycin A
Takeshi Shimizu,* Tsutomu Masuda, Katsuya Hiramoto, and Tadashi Nakata*
,†
RIKEN (The Institute of Physical and Chemical Research),
Wako, Saitama 351-0198, Japan
tshimizu@postman.riken.go.jp
Received May 15, 2000
ABSTRACT
The stereoselective total synthesis of reveromycin A (1), a potent inhibitor of eukaryotic cell growth, has been accomplished on the basis of
the stereocontrolled construction of the 6,6-spiroketal system, efficient succinylation of the tert-alcohol under high pressure, and the introduction
of the unsaturated side chains.
Reveromycins A-D (1-4, Figure 1) are novel polyketide-
type antibiotics isolated from the genus Streptomyces as
inhibitors of mitogenic activity induced by the epidermal
growth factor (EGF) in a mouse epidermal keratinocyte.1
Reveromycins A, C, and D exhibit the morphological
reversion of srcts-NRK cells, the antiproliferative activity
against human tumor cell lines and antifungal activity.
Furthermore, reveromycin A is a selective inhibitor of protein
synthesis in eukaryotic cells.
The characteristic structural features of reveromycins
include a 6,6- or a 5,6-spiroketal system bearing a hemisuc-
cinate, two unsaturated side chains, and two alkyl groups.2,3
Their strong biological activity as potential drugs and their
synthetically challenging, unique structure have attracted the
attention of synthetic organic chemists, and the total synthesis
of reveromycin B (2) has been independently accomplished
Figure 1. Structures of reveromycins.
by three groups.4-6 Despite some synthetic efforts, however,
no synthesis of reveromycin A (1), which is the major and
most bioactive compound of the reveromycins, has been
accomplished to date.7-9 We now report the first asymmetric
total synthesis of 1.
† E-mail: nakata@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.
(5) Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1,
941-944.
(2) Koshino, H.; Takahashi, H.; Osada, H.; Isono, K. J. Antibiot. 1992,
45, 1420-1427.
(6) Cuzuppe, A. N.; Hutton, C. A.; Lilly, M. J.; Mann, R. K.; Rizzacasa,
M. A.; Zammit, S. C. Org. Lett. 2000, 2, 191-194.
(7) Shimizu, T.; Kobayashi, R.; Osako, K.; Nakata, T. Tetrahedron Lett.
1996, 37, 6755-6758.
(3) Ubukata, M.; Koshino, H.; Osada, H.; Isono, K. J. Chem. Soc., Chem.
Commun. 1994, 1877-1878.
(4) Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc. 1999, 121, 456-
457.
(8) Rizzacasa, M. A.; McRae, K. J. J. Org. Chem. 1997, 62, 1196-
1197.
10.1021/ol0060634 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/23/2000

Our retrosynthetic analysis of reveromycin A (1) is shown
in Figure 2. The unsaturated left and right side chains should
achieved by the intramolecular ketalization of the ketone 8,
in which the C18 hydroxyl group is protected as the MTM
ether. The ketone 8 would be synthesized via the coupling
reaction of the Weinreb amide 9 and alkyne 10.5
We first investigated the union of the Weinreb amide 912
and alkyne 1012 leading to the spiroketal core (Scheme 1).
Scheme 1. Synthesis of Spiroketals 12 and 13a
a Reagents and conditions: (a) n-BuLi, THF, 0 °C to room
temperature (93%); (b) H2, Pd/C, AcOEt, room temperature (99%);
(c) CSA, CHCl3, MeOH, 0 °C to room temperature (12, 54%; 13,
27%); (d) TBAF, THF, room temperature; (e) Ac2O, Py, CH2Cl2,
room temperature (98%, two steps).
Figure 2. Retrosynthetic analysis of reveromycin A (1).
The coupling reaction of 9 and the lithio derivative of 10
followed by hydrogenation furnished the saturated ketone
11 in 92% yield. The stage is now set for the construction
of the 6,6-spiroketal. The MM2 calculation of the spiroketals
5 and 6 (R ) R′ ) CH2OMe, X ) Me), corresponding to
12 and 13, revealed an energy difference of only 0.44 kcal/
mol, which means a 2.3:1 ratio of 5 and 6.13 The deprotection
of the two TES groups in 11 with CSA in CHCl3-MeOH
effected, as expected, the simultaneous intramolecular ket-
alization to give the 6,6-spiroketals 12 and 13 in 54% and
27% yields, respectively. The stereochemistry of 12 and 13
was determined by extensive NMR analysis of the corre-
sponding acetates 14 and 15; the NOEs between H11 and
H20 in 14 and NOEs between H11 and H16eq in 15 were
observed (Figure 4).
be produced by the Horner-Wadsworth-Emmons reaction,
Julia coupling, and Wittig reaction during the later stage as
a result of their instabilities. The construction of the
hemisuccinate of the C18 tert-hydroxyl group, which is one
of the difficult tasks in the synthesis of 1, might be achieved
by acylation under high pressure.10 The main problem should
be the construction of the 6,6-spiroketal core 5 in which the
C18 tert-hydroxyl group and C19 side chain are axially
oriented. The inherent instability of the 6,6-spiroketal system
in 5 may cause some difficulties during the synthetic studies,
e.g., easy transketalization of 5 (X ) H) into the stable 5,6-
spiroketal 7,7-9 transformation of 5 into the undesired 6,6-
spiroketals 6 in the unnatural form via an equilibration
(Figure 3),11 and so on. The construction of 5 could be
Figure 3. Conformations of 6,6-spiroketals 5 and 6.
Figure 4. NOE observed in spiroketals 14 and 15.
Org. Lett., Vol. 2, No. 14, 2000
2154

The 6,6-spiroketal 12 in the natural form was first
subjected to the introduction of succinate and dienoic ester
(Scheme 2). Deprotection of the MTM group in 12 with MeI
several attempts, we found that the succinylation of 16 with
mono-allyl succinate and DCC at 1.5 GPa efficiently
proceeded to give the succinate 17 in 83% yield. Desilylation
of 17 with HF‚Py (92%)15 followed by the Dess-Martin
oxidation gave the aldehyde, which was subjected to the
Horner-Wadsworth-Emmons reaction with (EtO)2P(O)-
CH2C(Me)dCHCO2Allyl5 and LHMDS in the presence of
HMPA16 to give the desired (20E,22E)-dienoic esters 18
along with the (20E,22Z)-isomer (18:22Z-isomer ) 14:1;
82% yield, two steps). Deprotection of the MPM group in
18 with DDQ afforded the alcohol 19 in 89% yield.
Scheme 2. Synthesis of Spiroketal 19a
Next, the conversion of the 6,6-spiroketal 13 in the
unnatural form into the desired 19 was examined (Scheme
3). We anticipated that this problem should be overcome by
an equilibration after the introduction of the unsaturated ester,
because the MM2 calculation of the spiroketals 5 and 6
having the C19 dienoic ester (R ) CHdCHsC(Me)d
CHCO2Me, R′ ) CH2OMe, X ) Me) suggested a large
energy difference (4.68 kcal/mol) in favor of 5.13 Being
encouraged by these studies, the isomer 13 was thus
a Reagents and conditions: (a) MeI, NaHCO3, acetone, H2O, 60
°C (96%); (b) mono-allyl succinate, DCC, DMAP, CH2Cl2, 1.5 GPa,
room temperature, 24 h (83%); (c) HF‚Py-Py (1:4), THF, room
temperature (92%); (d) Dess-Martin periodinane, MS4A, CH2Cl2,
room temperature (e) diethyl (2E)-3-(allyloxycarbonyl)-2-methyl-
prop-2-enylphosphonate, LHMDS, HMPA, THF, -78 to 0 °C
(82%, two steps; 22E:22Z ) 14:1); (f) DDQ, CH2Cl2, H2O, room
temperature (89%).
Scheme 4. Completion of the Total Synthesisa
in the presence of NaHCO3 proceeded without transketal-
ization leading to the undesired 5,6-spiroketal to afford the
alcohol 16 in 91% yield.14 The next crucial step is the
introduction of the hemisuccinate of the tert-hydroxyl group
in 16. The initial attempt using our reported procedure under
high pressure (succinic anhydride in pyridine in the presence
of DMAP at 1.5 GPa)10 resulted in the recovery of 16. After
Scheme 3. Conversion of Spiroketal 13 into 19a
a Reagents and conditions: (a) Dess-Martin periodinane, MS4A,
CH2Cl2, room temperature; (b) Ph3PdC(Me)CHO, toluene, 110 °C
(88%, two steps); (c) Zn(BH4)2, Et2O, 0 °C (99%); (d) 2-mercap-
tobenzothiazole, n-Bu3P, TMAD, benzene, 5 °C to room temper-
ature (87%); (e) Mo7O24(NH4)6‚4H2O, H2O2, EtOH, 0 °C to room
temperature (79%); (f) LHMDS, 28, THF, -78 °C to room
temperature (90%); (g) PPTS, CHCl3, MeOH, 0 °C; (h) Dess-
Martin periodinane, MS4A, CH2Cl2, room temperature (91%, two
steps); (i) Ph3PdCHCO2Allyl, toluene, 80 °C (98%); (j) Pd(Ph3P)4,
Ph3P, pyrrolidine, CH2Cl2, 0 °C to room temperature; (k)
TBAF‚3H2O, DMF, room temperature (71%, two steps).
a Reagents and conditions: (a) MeI, NaHCO3, acetone, H2O, 60
°C (91%); (b) mono-allyl succinate, DCC, DMAP, CH2Cl2, 1.5 GPa,
room temperature, 24 h (76%); (c) HF‚Py-Py (1:4), THF, room
temperature (95%); (d) Dess-Martin periodinane, MS4A, CH2Cl2,
room temperature; (e) diethyl (2E)-3-(allyloxycarbonyl)-2-methyl-
prop-2-enylphosphonate, LHMDS, HMPA, THF, -78 to 0 °C
(88%, two steps; 22E:22Z f 50:1); (f) DDQ, CH2Cl2, H2O, room
temperature (88%); (g) 0.1 equiv CSA, CHCl3, MeOH, room
temperature, 24 h; 2 times repeated (19, 82%; 21, 8%).
Org. Lett., Vol. 2, No. 14, 2000
2155

converted into 21 having the C19 dienoic ester via 20 in
54% overall yield, under the same procedure for the
preparation of 19 from 12. During these steps, no equilibra-
tion was observed. Upon treatment with 0.1 equiv of CSA
in CHCl3-MeOH, the spiroketal 21 was, as expected,
epimerized into the desired spiroketal 19 in the natural form
(82% of 19 and 8% of 21 after twice repeated treatments).
The final elaboration of the labile unsaturated right side
chain was accomplished in a stepwise procedure (Scheme
4). The Dess-Martin oxidation of 19 followed by the Wittig
reaction gave the R,â-unsaturated aldehyde 22 (88%), which
was reduced with Zn(BH4)2 to give the allyl alcohol 23 in
99% yield. The treatment of 23 with 2-mercaptobenzothia-
zole under the modified Mitsunobu conditions with TMAD
and n-Bu3P17 gave the sulfide (87%),18 which was subjected
to the Mo(VI)-mediated oxidation to give the sulfone 24 in
79% yield. The one-pot Julia olefination19 of 24 and the
aldehyde 28 stereoselectively produced the (6E,8E)-diene 25
in 90% yield. After selective deprotection of the TES group
in 25 with PPTS followed by the Dess-Martin oxidation
(91% yield, two steps), the resulting aldehyde 26 was treated
with Ph3PdCHCO2Allyl5 to afford the R,â-unsaturated ester
27 in 98% yield. Deprotection of the three allyl groups in
27 was cleanly achieved by treatment with Pd(Ph3P)4-Ph3P
in the presence of pyrrolidine.20 Finally, the removal of the
TBS group with TBAF in DMF gave reveromycin A (1) in
71% yield over two steps. The spectral data (1H NMR, 13C
NMR, [R]D, IR, HRMS) of the synthetic 1 were identical
with those of the natural reveromycin A (1).
(9) Drouet, K. E.; Ling, T.; Tran, H. V.; Theodorakis, E. A. Org. Lett.
2000, 2, 207-210.
(10) Shimizu, T.; Kobayashi, R.; Ohmori, H.; Nakata, T. Synlett 1995,
650-652.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, Japan, and by the
Special Project Funding for Basic Science (Multibioprobes)
from RIKEN. We thank Dr. H. Koshino for the NMR
measurements, Dr. H. Osada for supplying the natural
reveromycin A, and Ms. K. Harata for the mass spectral
measurements.
(11) The acid-catalyzed equilibration of spiroketal 5 (R ) acetyleneTMS,
R′ ) CH2OH, X ) TBS) was reported to provide a mixture of 5 and 6 in
a 1.5:1 ratio.9
(12) The synthetic schemes of 9 and 10 are included in Supporting
Information.
(13) The computational calculations were performed using MM2*/
MacroModel 6.0.
(14) The other conditions (HgCl2, CdCO3 or AgNO3, 2,6-lutidine)
induced transacetalization to give the corresponding 5,6-spiroketal.
(15) Deprotection of the TBDPS group in 17 or 20 with TBAF in THF
at room temperature afforded the C20-succinate via the migration.
(16) Corey, E. J.; Katzenellenbogen, J. A.; Roman, S. A.; Gilman N.
W. Tetrahedron Lett. 1971, 21, 1821-1824.
(17) Tsunoda, T.; Yamamiya, Y.; Kawamura, Y.; Ito, S. Tetrahedron
Lett. 1995, 36, 2529-2530.
(18) Treatment of 23 with 2-mercaptobenzothiazole-PPh3-DEAD,
which was effective for the synthesis of reveromycin B,5 resulted in the
recovery of 23. This result would be due to the steric hindrance of the C19
dienoic ester.
Supporting Information Available: Synthetic schemes
of 9 and 10 and 1H and 13C NMR data for compounds 9, 10,
12, 13, 19, 21, 27, and the synthetic 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0060634
(19) (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.
(20) Treatment of 27 with HF‚Py in THF or TBAF in DMF resulted in
the recovery or decomposition, respectively.
2156
Org. Lett., Vol. 2, No. 14, 2000