Enantioselective total synthesis of cineromycin B

Article abstract of DOI:10.1016/j.tetlet.2003.10.021

The enantioselective total synthesis of cineomycin B, a 14-membered unsaturated macrolide with two doubly allylic alcohols, was completed using a Julia coupling, an oxidative [2,3]-sigmatropic rearrangement of selenide, and a Yamaguchi macrolactonization as key reactions.

Full text of DOI:10.1016/j.tetlet.2003.10.021

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9219–9222
Enantioselective total synthesis of cineromycin B
Tatsuhisa Takahashi, Hidenori Watanabe and Takeshi Kitahara*
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo,
1-1-1 Yayoi Bunkyo-ku, Tokyo 113-8657, Japan
Received 15 August 2003; revised 29 September 2003; accepted 3 October 2003
Abstract—The enantioselective total synthesis of cineromycin B, a 14-membered unsaturated macrolide with two doubly allylic
alcohols, was completed using a Julia coupling, an oxidative [2,3]-sigmatropic rearrangement of selenide, and a Yamaguchi
macrolactonization as key reactions.
© 2003 Elsevier Ltd. All rights reserved.
The fourteen-membered unsaturated macrolide,
cineromycin B (1), was isolated from various strains of
Streptomyces sp.,1–3 and the close relation albocycline
(2) was obtained from other strains of Streptomyces
sp.4,5 (Fig. 1). In addition to the antibiotic activity
against B. subtilis and S. aureus,1,4,6 these macrolides
were reported to inhibit prolyl endopeptidases.7
Although 2 exhibits notable antibacterial and inhibitory
activities, those of 1 were moderate and no other
remarkable activity was revealed. As a result of these
biological properties, albocycline (2) has been synthe-
sized previously by Tanner et al. in 1987,8 but a synthe-
sis of 1 has not yet been reported. Very recently,
however, it was found that cineromycin (1) induces
apoptosis of tumor cells9 and this inspired us to embark
upon a total synthesis. The structure contains two
doubly allylic alcohols (C4, C7) in 1 and as a result is
very acid sensitive. For this reason, in a synthesis of 1,
it is important to introduce chiral alcohols under mild
and non-acidic conditions. Herein, we wish to describe
a
convergent and enantioselective synthesis of
cineromycin B (1) making use of an oxidative [2,3]-sig-
matropic rearrangement of selenide10,11 for construction
of ene-1,4-diol system.
Our plan for the synthesis of cineromycin B is shown in
Scheme 1. Yamaguchi macrolactonization12 of trihy-
Figure 1.
Scheme 1.
Keywords: cineromycin B; doubly allylic alcohol; Julia coupling; oxidative [2,3]-sigmatropic rearrangement; Yamaguchi macrolactonization.
* Corresponding author. Fax: 81-3-5841-8019; e-mail: atkita@mail.ecc.u-tokyo.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.021

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T. Takahashi et al. / Tetrahedron Letters 44 (2003) 9219–9222
Scheme 2. Reagents and conditions: (a) DIBAL-H, CH2Cl2, −78°C; (b) Ph3PꢀC(CH3)CO2Et, CHCl3, 40°C (96%, two steps); (c)
TBSCl, imidazole, DMF (96%); (d) DIBAL-H, CH2Cl2, −78°C (94%); (e) 2-mercaptobenzothiazole, PPh, DEAD, THF (98%); (f)
H2O2, (NH4)6Mo7O24·4H2O, EtOH, 0°C to rt (87%); (g) Ph3PꢀCHCO2Me, PhH, reflux (92%); (h) TBAF, THF, −78°C to 0°C
,
(95%); (i) L-(+)-DET, TBHP, Ti(O-i-Pr)4, MS 4A, CH2Cl2, −25°C to 15°C (96%, 93% ee); (j) Dess–Martin oxidn., pyr., CH2Cl2,
then recryst. (80%).
droxycarboxylic acid A was thought to form 14-mem-
bered macrolide predominantly due to the steric restric-
tion of the trans-double bonds. Epoxide opening of B
with selenide, followed by oxidative [2,3]-sigmatropic
rearrangement10,11 should provide a method for the
stereoselective introduction of two doubly allylic alco-
hols. Epoxy triene B would be accessible by Julia
coupling13–15 of sulfone C with epoxy aldehyde D.
(after subsequent two steps) was disappointingly poor.
On the other hand, when the reaction was carried out
at −98°C, the yield was remarkably improved, while the
undesired Z selectivity was observed (entry 2). We
thought that this uncommon inverse selectivity was
caused by some chelation effect of the epoxide oxygen
,
and found that using HMPA and MS 4A as additives
restored the E selectivity to 70:30 (entry 3). Without
separating the E/Z isomers, 10 was subjected to regio-
and stereoselective epoxide opening with selenium
reagent and the resulting selenide was oxidized to
selenoxide with hydrogen peroxide, which caused [2,3]-
sigmatropic rearrangement10,11 at 0°C to afford 11.
The synthesis commenced with the preparation of sul-
fone 6 for Julia coupling (Scheme 2). Reduction of
known lactone 316 with DIBAL-H to a corresponding
lactol,
followed
by
Wittig
reaction
with
Ph3PꢀC(Me)CO2Et afforded hydroxy ester 4. Protec-
tion of the alcohol in 4 as a TBS ether and subsequent
reduction of the ester moiety with DIBAL-H gave
allylic alcohol 5 in satisfactory yield. Alcohol 5 was
then transformed into corresponding sulfone 6 in two
steps via Mitsunobu reaction with 2-mercaptobenzothi-
azole,17,18 and ammonium heptamolybdate catalyzed
oxidation.18,19 The overall yield was 74% over six steps
from 3. We then moved to a synthesis of epoxy alde-
hyde 9, a coupling partner in the Julia reaction. Known
aldehyde 720 was treated with Ph3PꢀCHCO2Me to
afford the corresponding conjugated ester, whose pro-
tected alcohol was then liberated by TBAF treatment to
give allylic alcohol 8. Katsuki–Sharpless asymmetric
epoxidation21,22 of 8 (0.5 equiv. of Ti(Oi-Pr)4, 0.6 equiv.
Cleavage of TBS ether in 11 with TBAF in HMPA
followed by hydrolysis of the ester with NaOH gave
trihydroxycarboxylic acid 12 (Scheme 4). However,
Yamaguchi macrolactonization12 of 12 did not afford
cineromycin B (1), and g-lactone 13 was obtained in
68% yield. Modified Keck’s method (DCC, DMAP,
DMAP·TFA),23,24 which was used in the synthesis of
2,8 also gave the same result.
Since this isomerization of the double bond was
thought to be caused by the presence of g-tertiary
alcohol, it was protected as the TES ether. Successive
treatment with TESCl and TESOTf produced a com-
pound whose all alcohols were protected. This sequence
was necessary; using only TESCl led to the protection
of the secondary alcohols, while using only TESOTf led
to decomposition. Treatment of 15 with 2.0 equiv. of
of L-diethyl tartrate, 3.0 equiv. of TBHP) proceeded in
excellent yield and acceptable enantioselectivity (96%
yield, 93% ee). When a lesser amount of catalysts was
used, a longer reaction time was required and enan-
tioselectivity of the product has decreased. Dess–Martin
oxidation and recrystallization afforded enantiomeri-
cally pure 9 (mp 76.5–76.8°C) in 67% overall yield (four
steps) from 7.
Thus, with both segments in hand, the Julia coupling13–15
of 6 with 9 was investigated (Scheme 3). In this reac-
tion, geometry of the newly introduced double bond is
important since it is reflected in the stereochemistry of
the secondary alcohol of 11. Firstly, the coupling was
performed under the standard condition (LHMDS,
THF at −78°C) and the unstable product (10) was
subjected immediately to the next reaction. As shown in
Table 1 (entry 1), E/Z selectivity as well as the yield
Scheme 3. Reagents and conditions: (a) LHMDS, THF, Table
1; (b) (PhSe)2, NaBH4, MeOH, 0°C to rt; (c) H2O2, THF,
0°C.

T. Takahashi et al. / Tetrahedron Letters 44 (2003) 9219–9222
9221
Table 1.
Entry
Additive (equiv.)
Temp. (°C)
E/Z*
Yield of 11 over three steps (%)
1
2
3
None
None
HMPA (2.0), MS 4A
−78
−98
−98
50:50
38:62
70:30
14
62
52
,
* Determined by 1H NMR of the crude product.
,
Scheme 4. Reagents and conditions: (a) TBAF·xH2O, MS 4A, HMPA (86%); (b) NaOH, H2O/THF (1:1), 0°C (78%); (c)
2,4,6-trichlorobenzoyl chloride, Et3N, THF; DMAP, PhH, reflux (68%); (d) TESCl, pyr., 60°C; (e) TESOTf, pyr., 60°C (80%, two
steps); (f) TBAF (2 equiv.), THF, rt (70%); (g) 2,4,6-trichlorobenzoyl chloride, Et3N, THF; DMAP, PhMe, reflux (17: 42%,
7-epi-17: 22%); (h) TBAF, THF (quant.).
TBAF at room temperature cleaved the secondary TES
ethers to give 16. Yamaguchi macrocyclization12
afforded the desired lactone 17 (42%) along with its C-7
epimer (22%) which originated from Z isomer of 10,
and the ratio of diastereomers was in accord with E/Z
ratio of 10. Finally, cleavage of TES group with TBAF
led 17 to cineromycin B (1) in quantitative yield. Our
synthetic 1 was identical in all respects with the natural
sample; mp 147.8–148.5°C (lit.1 149–150°C); [h]D26=
−127° (c 0.48, methanol) [lit.1 [h]D24=−110° (c 1,
methanol)].
2. Burkhardt, K.; Fiedler, H.-P.; Grabley, S.; Thiericke, R.;
Zeeck, A. J. Antibiot. 1996, 49, 432–437.
3. Schiewe, H.-J.; Zeeck, A. J. Antibiot. 1999, 52, 635–642.
4. Nagahama, N.; Suzuki, M.; Awataguchi, S.; Okuda, T. J.
Antibiot., Ser. A 1967, 20, 261–266.
5. Furumai, T.; Nagahama, N.; Okuda, T. J. Antibiot. 1968,
21, 85–90.
6. Reusser, F. J. Bacteriol. 1969, 100, 11–13.
7. Christner, C.; Ku¨llertz, G.; Fischer, G.; Zerlin, M.; Grab-
ley, S.; Thiericke, R.; Taddei, A.; Zeeck, A. J. Antibiot.
1998, 51, 368–371.
8. Tanner, D.; Somfai, P. Tetrahedron 1987, 43, 4395–4406.
9. Yoshida, M. Personal communication to Kitahara, T.
10. Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1972,
94, 7154–7155.
In conclusion, the first total synthesis of cineromycin B
(1) has been accomplished by employing epoxide open-
ing with selenide and subsequent oxidative rearrange-
ment as key steps. The overall yield in the longest linear
sequence (16 steps from lactone 3) was 6.1%.
11. Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetra-
hedron Lett. 1973, 22, 1979–1982.
12. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 53, 1989–
1993.
Acknowledgements
13. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetra-
hedron Lett. 1991, 32, 1175–1178.
We are grateful to Professor S. Horinouchi of the
University of Tokyo and Dr. M. Yoshida of RIKEN
for generous gift of spectral data of natural
cineromycin B (1).
14. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 336–357.
15. Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel,
O. Bull. Soc. Chim. Fr. 1993, 130, 856–878.
16. Pinyarat, W.; Mori, K. Biosci. Biotech. Biochem. 1993,
57, 419–421.
References
17. Loibner, H.; Zbiral, E. Helv. Chim. Acta 1976, 59, 2100–
2113.
1. Miyairi, N.; Takashima, M.; Shimizu, K.; Sakai, H. J.
Antibiot., Ser. A 1966, 19, 56–62.
18. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K.
J. Chem. Soc., Perkin Trans. 1 1999, 955–968.

9222
T. Takahashi et al. / Tetrahedron Letters 44 (2003) 9219–9222
19. Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org.
Chem. 1963, 28, 1140–1142.
22. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780.
23. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50,
2394–2395.
20. Keck, G. E.; Wager, C. A.; Wager, T. T.; Savin, K. A.;
Covel, J. A.; McLaws, M. D.; Krishnamurthy, D.; Cee,
V. J. Angew. Chem., Int. Ed. 2001, 40, 231–234.
21. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5974–5976.
24. Stork, G.; Rychnovsky, S. D. J. Am. Chem. Soc. 1987,
109, 1565–1567.