T. Kuranaga et al. / Tetrahedron Letters 51 (2010) 4673–4676
4675
Coupling of the BC ring fragment 4 and the E ring fragment 5
and subsequent construction of the D ring were accomplished, as
shown in Scheme 4. Treatment of the lithium enolate derived from
4 with aldehyde 5 furnished a separable 1:1 mixture of C-23
diastereomers 3 and 22.23 The ketone 3 was reduced stereoselec-
tively16 with Et3SiH in the presence of TMSOTf to afford the ben-
zyl-protected BC/DE ring 23. The orientation of H-21 in 23 was
confirmed by a ROESY cross-peak H-21/H-25. Finally, removal of
the benzyl groups of 23 furnished the BC/DE ring model 2.24
The NMR chemical shifts from CH-14 to CH-25 of 2 were com-
pared with those of brevisin (1), as listed in Table 1. The observed
chemical shifts of 2 agreed well with those of 1, although there are
relatively large differences in the B ring and the E ring regions
(C-15, C-37, C-24, and C-25) which are to be expected due to the
absence of the A ring and the F ring. The maximum difference of
13C NMR chemical shifts around the methylene juncture (C-18, C-
19, C-38, C-20, C-21, and C-22) is 0.3 ppm. The NMR spectral data
of the synthetic BC/DE ring model bore a strong similarity to the
data for the same region of brevisin, supporting the unique struc-
ture of brevisin around the methylene juncture.
The BC/DE ring model of brevisin was synthesized based on a
convergent strategy by means of aldol coupling and the subse-
quent construction of the D ring. We already succeeded in the syn-
thesis of the ABC ring of
1 via the Suzuki–Miyaura cross-
coupling.25 Therefore, this result will accelerate the total synthesis
of this intriguing molecule.
+
4
5
Acknowledgments
a
This work was supported by KAKENHI (No. 20611002) and the
Global COE Program for Chemistry Innovation, the University of
Tokyo. T.K. is grateful for a SUNBOR Scholarship. The natural brev-
isin was isolated from cultures maintained under grants P01 ES
10594 (NIEHS, DHHS) and MARBIONC, Marine Biotechnology in
North Carolina.
OH
H
OBn
OBn
H
OBn
O
Me
O
H
O
O
Me
OTES
H
3
BnO
BnO
OH
H
OBn
OBn
H
OBn
O
Me
O
H
References and notes
O
O
b
Me
OTES
H
22
BnO
BnO
1. (a) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897; (b) Wright, J. L. C.;
Cembella, A. D. In Physiological Ecology of Harmful Algal Blooms; Anderson, D. M.,
Cembella, A. D., Hallegraeff, G. M., Eds.; Springer: Heidelberg, 1998; pp 427–
451; (c) Satake, M. In Gupta, R. R., Kiyota, H., Eds.; Topics in Heterocyclic
Chemistry; Springer: Heidelberg, 2006; Vol. 5, pp 21–51.
2. Recent reviews for polycyclic ethers (a) Nakata, T. Chem. Rev. 2005, 105, 4314;
(b) Inoue, M. Chem. Rev. 2005, 105, 4379; (c) Fuwa, H.; Sasaki, M. Nat. Prod. Rep.
2008, 25, 401; (d) Nicolaou, K. C.; Frederick, M. O.; Aversa, R. J. Angew. Chem.,
Int. Ed. 2008, 47, 7182.
OH
H
H
OBn
OBn
OBn
O
Me
O
H
21
c
O
O
Me
H
H
H
BnO
BnO
23
3. Satake, M.; Campbell, A.; Van Wagoner, R. M.; Bourdelais, A. J.; Jacocks, H.;
Baden, D. G.; Wright, J. L. C. J. Org. Chem. 2009, 74, 989.
OH
H
OH
OH
H
OH
O
Me
O
4. (a) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.; Golik, J.; James, J. C.;
Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773; (b) Shimizu, Y.; Chou, H. N.;
Bando, H.; Van Duyne, G.; Clardy, J. J. Am. Chem. Soc. 1986, 108, 514; (c) Baden,
D. G.; Bourdelais, A. J.; Jacocks, H.; Michelliza, S.; Naar, J. J. Environ. Health
Perspect. 2005, 113, 621.
H
O
O
Me
H
H
H
HO
HO
2
5. (a) Bourdelais, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M., Jr.; Baden, D.
G. J. Nat. Prod. 2005, 68, 2; (b) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.;
Sasaki, M. J. Am. Chem. Soc. 2006, 128, 16989; (c) Ebine, M.; Fuwa, H.; Sasaki, M.
Org. Lett. 2008, 10, 2275; (d) Takamura, H.; Kikuchi, S.; Nakamura, Y.;
Yamagami, Y.; Kishi, T.; Kadota, I.; Yamamoto, Y. Org. Lett. 2009, 11, 2531; (e)
Takamura, H.; Yamagami, Y.; Kishi, T.; Kikuchi, S.; Nakamura, Y.; Kadota, I.;
Yamamoto, Y. Tetrahedron 2010, 66, 5329.
Scheme 4. Reagents and conditions: (a) LDA, THF, ꢁ78 °C, 42% (82% br sm), 20% for
3, 21% for 22, 50% for recovered 4; (b) Et3SiH, TMSOTf, CH2Cl2, ꢁ78 °C, 62%; (c) Pd/C,
H2, THF, 99%.
6. Satake, M.; Bourdelais, A. J.; Van Wagoner, R. M.; Baden, D. G.; Wright, J. L. C.
Org. Lett. 2008, 10, 3465.
Table 1
NMR chemical shifts (d) from the CH-14 to CH-25 of brevisin (1), the BC/DE ring
model 2, and their differences (Dd) in pyridine-d5
7. (a) Kuranaga, T.; Shirai, T.; Baden, D. G.; Wright, J. L. C.; Satake, M.; Tachibana,
K. Org. Lett. 2009, 11, 217; (b) Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2009, 11,
3950; (c) Ghosh, A. K.; Li, J. Org. Lett. 2009, 11, 4164; (d) Lee, J.; Panek, J. S. Org.
Lett. 2009, 11, 4390.
Pos.
1H
13C
8. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092.
2
1
D
d
2
1
D
d
9. Van Wagoner, R. M.; Satake, M.; Bourdelais, A. J.; Baden, D. G.; Wright, J. L. C. J.
Nat. Prod. 2010, 73, 1177.
10. (a) Dechraoui, M.-Y.; Naar, J.; Pauillac, S.; Legrand, A.-M. Toxicon 1999, 37, 125;
(b) Inoue, M.; Hirama, M.; Satake, M.; Sugiyama, K.; Yasumoto, T. Toxicon 2003,
41, 469.
11. (a) Nicolaou, K. C.; Cole, K. P.; Frederick, M. O.; Aversa, R. J.; Denton, R. M.
Angew. Chem., Int. Ed. 2007, 46, 8875; (b) Nicolaou, K. C.; Frederick, M. O.;
Burtoloso, A. C. B.; Denton, R. M.; Rivas, F.; Cole, K. P.; Aversa, R. J.; Gibe, R.;
Umezawa, T.; Suzuki, T. J. Am. Chem. Soc. 2008, 130, 7466.
12. (a) Sasaki, M.; Matsumori, N.; Maruyama, T.; Nonomura, T.; Murata, M.;
Tachibana, K.; Yasumoto, T. Angew. Chem., Int. Ed. 1996, 35, 1672; (b) Sasaki,
M.; Takeda, N.; Fuwa, H.; Watanabe, R.; Satake, M.; Oshima, Y. Tetrahedron Lett.
2006, 47, 5687.
14
15
37
16a
16b
17a
17b
18
4.42
4.42
0.00
71.6
77.0
16.4
35.7
71.6
78.8
16.7
35.8
0.0
ꢁ1.8
ꢁ0.3
ꢁ0.1
1.49
2.70
1.75
2.06
2.06
4.47
1.54
2.70
1.75
2.05
2.04
4.45
ꢁ0.05
0.00
0.00
0.01
0.02
0.02
26.7
26.8
ꢁ0.1
73.2
80.9
21.9
48.0
73.5
81.1
21.8
48.0
ꢁ0.3
ꢁ0.2
0.1
19
38
1.68
1.97
1.75
4.46
2.01
1.67
4.48
3.62
4.10
1.66
1.96
1.72
4.40
2.03
1.69
4.37
3.33
4.03
0.02
0.01
0.03
20a
20b
21
22ax
22eq
23
0.0
0.06
68.9
41.1
68.9
40.8
0.0
0.3
13. (a) Zheng, W.; DeMattei, J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L. R.; Oinuma, H.;
Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946; (b) Cook, L. R.; Oinuma, H.; Semones,
M. A.; Kishi, Y. J. Am. Chem. Soc. 1997, 119, 7928.
14. Kadota, I.; Kadowaki, C.; Park, C.-H.; Takamura, H.; Sato, K.; Chan, P. W. H.;
Thorand, S.; Yamamoto, Y. Tetrahedron 2002, 58, 1799.
ꢁ0.02
ꢁ0.02
0.11
0.29
0.07
67.7
84.9
75.4
67.9
83.8
74.8
ꢁ0.2
1.1
0.6
24
25
15. Kadota, I.; Ohno, A.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron Lett. 1998, 39,
6373.