Synthesis of the BC/DE ring model of brevisin for confirmation of the structure around the acyclic junction

Article abstract of DOI:10.1016/j.tetlet.2010.07.001

Synthesis of the BC/DE ring model of brevisin, a polycyclic ether isolated from the red tide dinoflagellate Karenia brevis, is reported. Comparison of the NMR data of the BC/DE ring model with those corresponding to the same region of brevisin led to the

Full text of DOI:10.1016/j.tetlet.2010.07.001

Tetrahedron Letters 51 (2010) 4673–4676
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Synthesis of the BC/DE ring model of brevisin for confirmation
of the structure around the acyclic junction
b
b
a,
*
Takefumi Kuranaga a, Masayuki Satake a, , Daniel G. Baden , Jeffrey L. C. Wright , Kazuo Tachibana
*
a Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
b Center for Marine Science, University of North Carolina, Wilmington, Marvin K. Moss Lane, Wilmington, NC 28409, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of the BC/DE ring model of brevisin, a polycyclic ether isolated from the red tide dinoflagellate
Karenia brevis, is reported. Comparison of the NMR data of the BC/DE ring model with those correspond-
ing to the same region of brevisin led to the confirmation of its structure around the acyclic juncture.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 June 2010
Revised 29 June 2010
Accepted 1 July 2010
Available online 19 July 2010
Keywords:
Polycyclic ether
Aldol reaction
Dinoflagellate
Natural product
Polycyclic ethers, such as brevetoxins and ciguatoxins, are a
group of the most representative secondary metabolites produced
by dinoflagelates.1 These compounds have been of great interest
to many scientific groups because of their biological activity, their
unusual structures, unique aspects of their biosynthesis, and be-
cause of the synthetic challenges that they present.2 A new polycy-
clic ether, brevisin3 (1, Fig. 1), was isolated from the red tide
dinoflagellate, Karenia brevis that produces cyclic ether compounds,
the brevetoxins,2,4 brevenal,5 and brevisamide.6,7 Its unique struc-
ture consists of two tricyclic ether ring assemblies bridged by a
methylene group. One of the ring assemblies contains a conjugated
aldehyde side chain, which is similar to brevenal and brevisamide.
The separated polycyclic ether skeleton in the center of 1 is unusual
among marine polycyclic ethers.1 Although the stereochemistry of
each tricyclic ether moiety could be elucidated separately by
NMR experiments, the stereochemical correlation between the
ABC ring and the DEF ring portions in 1 could not be elucidated.
The absolute configuration of 1 was determined as shown in Figure
1 by esterification of the hydroxy groups at C10 and C31 in 1 with
the MTPA reagents.8,9 Interestingly, even though 1 does not have
flexible nine- or eight-membered ether rings in the middle of the
molecule, 1 inhibited the binding of [3H]-PbTx-3 to the voltage-sen-
sitive sodium channels (VSSCs) analogous with other marine poly-
cyclic ethers.10 The methylene-linked structure is presumed to
generate molecular flexibility which plays an important role in an
interaction with VSSC. In order to elucidate the interaction of 1 with
VSSC, structural and stereochemical confirmation of the linked
methylene portion in 1 is essential. Comparison of NMR chemical
shifts of a synthetic model with those of a corresponding domain
of a naturally occurring compound is a well-recognized approach
in the structural confirmation and stereochemical assignment of
complex molecules.11–13 Herein we report the chemical synthesis
of the BC/DE ring model 2 (Fig. 1) and comparison of its NMR chem-
ical shifts with those corresponding to the same region of natural
brevisin for confirmation of the structure around the acyclic junc-
tion in 1.
The synthetic plan employed was to build up the BC ring frag-
ment 4 from the lactone 614 and the E ring fragment 5 from the oxe-
pane 7,15 couple these fragments by means of an aldol reaction, and
then construct the D ring by a reductive etherification (Scheme 1).16
37
Me
OH
H
Me
O
B
10
A
15
Me
OH
H
OH
C
8
O
H
30
O
O
O
E
1
OH
H
H
H
D
Me
Me
20 H
38
25
F
O
H
O
Me
Brevisin (1)
Me
33
H
Me
15
O
B
HO
11
OH
H
OH
C
H
HO
O
O
E
H
D
Me
OH
20
29
25
O
H
2
H
OH
* Corresponding authors. Tel.: +81 3 5841 4357; fax: +81 3 5841 8380.
E-mail address: msatake@chem.s.u-tokyo.ac.jp (M. Satake).
Figure 1. Structures of 1 and 2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.001

4674
T. Kuranaga et al. / Tetrahedron Letters 51 (2010) 4673–4676
OH
H
H
H
H
H
H
OH
OH
H
O
a
O
OH
O
Me
O
B
O
O
HO
TESO
TESO
H
C
D
O
E
O
Ph
O
Ph
O
H
H
8
Me
H
H
7
H
2
HO
b
HO
H
H
O
H
OH
O
O
H
c,d
OBn
OBn
H
OBn
OBn
OBn
OH
OBn
O
Me
O
TESO
H
O
5
O
9
Me
OTES
H
3
BnO
H
BnO
Scheme 2. Reagents and conditions: (a) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 94%; (b)
DIBALH, CH2Cl2, 0 °C to rt, 67%; (c) BnBr, tBuOK, TBAI, THF; (d) O3, CH2Cl2, ꢁ78 °C;
then PPh3, 81% (two steps).
OBn
H
O
H
Me
O
O
O
C
+
OBn
OBn
E
TESO
HO
B
Me
O
Me
H
5
4
BnO
BnO
ꢁ78 °C20 followed by the removal of TBDPS group with TBAF affor-
ded the diol in 77% yield. The 1,5-diol was directly oxidized to lac-
tone 14 by TEMPO/PhI(OAc)2.21 Treatment of the lactone 14 with
KHMDS, Tf2NPh, and DMPU gave the corresponding ketene acetal
triflate 15. Hydroboration of the allyl benzyl ether 16 gave the
alkylborane which was reacted in situ with 15 under the Suzuki–
Miyaura coupling condition to generate the enol ether 17. Hydrob-
oration of 17 with BH3ꢀSMe2 gave the unwanted stereoisomer as
the sole product, and oxidation of the resulting alcohol with
TPAP–NMO afforded the ketone 18 in 62% yield for two steps. It
is likely that the undesired stereoselectivity following hydrobora-
tion of 17 was caused by the presence of an axial methyl group
on C-15, as observed with 12.22 The ketone 18 was treated with
DBU, reduced with NaBH4, and the resulting alcohol was protected
with the benzyl group to furnish the BC ring 19 as a single stereo-
isomer in 77% yield for three steps. The relative configurations of
19 were confirmed by the observed NOE correlations H-11/H3-
37, H-18/ H3-37, H-12/H-14, and H-14/ H3-38, and by the large
proton coupling constant of 8.8 Hz between H-11 and H-12. After
the regioselective DIBALH reduction of 19, oxidation in CH2Cl2–
DMSO with SO3ꢀpyridine and subsequent Wittig reaction of the
resulting aldehyde generated the olefin 20. Hydroboration of 20
with 9-BBN-H followed by oxidation with SO3ꢀpyridine/Et3N/
DMSO afforded the aldehyde 21, which was treated with MeMgBr
followed by oxidation of the resulting alcohol with TPAP/NMO to
furnish the BC ring-methyl ketone fragment 4.
H
H
H
O
Ph
O
O
O
O
O
Ph
Me
H
7
O
6
Scheme 1. Retrosynthetic analysis of 2.
The synthesis of the E ring fragment 5 started from the TES pro-
tection of oxepane 7 with TESOTf to provide the TES ether 8, and
regioselective DIBALH reduction17 of 8 gave alcohol 9. Benzylation
of 9 and subsequent ozonolysis gave the E ring aldehyde 5 in 51%
yield for the four steps (Scheme 2).
The synthesis of the BC ring fragment 4 is summarized in
Scheme 3. Treatment of lactone 6 with KHMDS and (PhO)2P(O)Cl
gave the corresponding ketene acetal phosphate 10. Hydroboration
of the allyl TBDPS ether 11 gave an alkylborane which was reacted
in situ with 10 under the Suzuki–Miyaura coupling condition2c,18
to generate the enol ether 12. Hydroboration of the enol ether 12
with BH3ꢀSMe2 gave a mixture of the stereoisomers, and subse-
quent oxidation of the mixture using TPAP–NMO19 followed by
treatment with DBU led to the ketone 13 as a single stereoisomer
in 69% yield for three steps. Steric hinderance arising from the axial
methyl group caused the low stereoselectivity in the hydrobora-
tion of 12. The methylation of 13 with MeMgBr in toluene at
H
H
O
Ph
H
O
Ph
Ph
H
TBDPSO
O
P
O
11
O
PhO
PhO
O
c,d,e
a
O
O
Ph
Ph
O
O
b
O
O
O
O
Me
12
Me
O
O
Me
H
Me
10
13
TBDPSO
TBDPSO
6
f,g,h
H
H
H
H
O
Ph
O
Ph
BnO
Me
O
Me
15
O
Ph
O
Me
O
Me
O
H
16
k,l
O
O
O
O
O
TfO
O
j
O
O
i
O
Me
O
Me
H
18
Me
H
Me
14
H
H
BnO
BnO
BnO
17
O
15
m,n,o
OBn
O
NOEs
OBn
H
Me
O
OBn
Me
O
Me37
O
Me
O
O
Ph
H
O
H
18
s,t
BnO
u,v
H
p,q,r
BnO
H
O
O
O
11
14
Me
Me
O
Me
O
H
H
Me
Me38
H
H
BnO
BnO
BnO
BnO
BnO
H
21
20
4
19
Scheme 3. Reagents and conditions: (a) KHMDS, (PhO)2P(O)Cl, HMPA, THF, ꢁ78 °C, 97%; (b) 11, 9-BBN-H, THF; then 10, 3 M Cs2CO3 aq, Pd(PPh3)4, DMF, 50 °C, 87%; (c)
BH3ꢀSMe2, THF, 45 °C; then satd NaHCO3 aq, H2O2; (d) TPAP, NMO, MS4A, CH2Cl2; (e) DBU, toluene, 110 °C, 69% (three steps); (f) MeMgBr, toluene, ꢁ78 °C; (g) TBAF, THF; (h)
TEMPO, PhI(OAc)2, CH2Cl2, 61% (three steps); (i) KHMDS, Tf2NPh, DMPU, THF, ꢁ78 to 0 °C; (j) 16, 9-BBN-H, THF; then 15, 3 M Cs2CO3 aq, Pd(PPh3)4, DMF, 88% (two steps); (k)
BH3ꢀSMe2, THF; then satd NaHCO3 aq, H2O2; (l) TPAP, NMO, MS4A, CH2Cl2, 62% (two steps); (m) DBU, CH2Cl2; (n) NaBH4, MeOH, CH2Cl2, ꢁ78 °C; (o) tBuOK, BnBr, TBAI, THF,
77% (three steps); (p) DIBALH, CH2Cl2, 0 °C to rt; (q) SO3ꢀpyridine, Et3N, DMSO, CH2Cl2; (r) Ph3P+CH3Brꢁ, NaHMDS, THF, 0 °C, 76% (three steps); (s) 9-BBN-H; then satd NaHCO3
aq, H2O2; (t) SO3ꢀpyridine, Et3N, DMSO, CH2Cl2, 85% (two steps); (u) MeMgBr, THF, 0 °C; (v) TPAP, NMO, MS4A, CH2Cl2, 99% (two steps).

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.;
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OH
H
H
OBn
OBn
OBn
O
Me
O
H
21
c
O
O
Me
H
H
H
BnO
BnO
23
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OH
H
OH
OH
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OH
O
Me
O
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H
O
O
Me
H
H
H
HO
HO
2
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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.
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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
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Pos.
1H
13C
8. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
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2
1
D
d
2
1
D
d
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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
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ꢁ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
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T. Kuranaga et al. / Tetrahedron Letters 51 (2010) 4673–4676
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constant (3 Hz) between H-23 and H-24 in 23 indicated the axial orientation of
the hydroxy group at C-23.
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22. The carbon numbering corresponds to that of brevisin 1 (Fig. 1).
23. The stereochemistry of the newly generated hydroxy group at the C-23 of 3
and 22 was assigned after the construction of the D ring. The proton coupling
24. Data for 2: ½a D18
ꢂ
ꢁ 3:1 (c 0.091, MeOH); 1H NMR (500 MHz, pyridine-d5) d 4.54–
4.45 (m, 3H), 4.42 (dd, J = 12.2, 4.6 Hz, 1H), 4.34–4.28 (m, 1H), 4.21 (dd, J = 10.5,
2.9 Hz, 1H), 4.15–4.03 (m, 3H), 3.96 (t, J = 6.3 Hz, 2H), 3.77–3.60 (m, 3H), 2.70
(dd, J = 13.5, 10.1 Hz, 1H), 2.62–2.51 (m, 1H), 2.49–2.32 (m, 2H), 2.27–1.95 (m,
10H), 1.92–1.64 (m, 7H), 1.49 (s, 3H), 1.42–1.16 (m, 6H); 13C NMR (100 MHz,
pyridine-d5) d 88.7, 84.9, 80.9, 77.0, 75.4, 74.9, 73.2, 71.6, 70.6, 70.4, 68.9, 67.7,
64.9, 62.5, 48.0, 41.1, 39.1, 35.7, 30.4, 30.1, 29.5, 27.6, 26.7, 21.9, 16.4; HRMS
(FAB) calcd for C25H44O10Na [M+Na]+ 527.2827, found 527.2823.
25. Ohtani, N.; Tsutsumi, R.; Kuranaga, T.; Shirai, T.; Baden, D. G.; Wright, J. L. C.;
Satake, M.; Tachibana, K. Heterocycles 2010, 80, 825.