Synthesis of the ABC ring fragment of brevisin, a new dinoflagellate polycyclic ether

Article abstract of DOI:10.3987/COM-09-S(S)93

A polycyclic ether, brevisin was isolated from the red-tide dinoflagellate Karenia brevis. Its unique skeletal structure consists of two separate tricyclic ether assemblies connected by a methylene bridge. The ABC ring fragment of brevisin was synthesized

Full text of DOI:10.3987/COM-09-S(S)93

HETEROCYCLES, Vol. 80, No. 2, 2010
825
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 825 - 830. © The Japan Institute of Heterocyclic Chemistry
Received, 31st July, 2009, Accepted, 31st August, 2009, Published online, 3rd September, 2009
DOI: 10.3987/COM-09-S(S)93
SYNTHESIS OF THE ABC RING FRAGMENT OF BREVISIN, A NEW
DINOFLAGELLATE POLYCYCLIC ETHER
Naohito Ohtani,a Ryosuke Tsutsumi,a Takefumi Kuranaga,a Tomohiro
Shirai,a Jeffrey L. C. Wright,b Daniel G. Baden,b Masayuki Satake,a* and
Kazuo Tachibanaa*
aDepartment of Chemistry, School of Science, The University of Tokyo, 7-3-1
b
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Center for Marine Science,
University of North Carolina, Wilmington, 5600 Marvin K. Moss Lane,
Wilmington, NC 28409, USA
E-mail: msatake@chem.s.u-tokyo.ac.jp; ktachi@chem.s.u-tokyo.ac.jp
Abstract – A polycyclic ether, brevisin was isolated from the red-tide
dinoflagellate Karenia brevis. Its unique skeletal structure consists of two
separate tricyclic ether assemblies connected by a methylene bridge. The ABC
ring fragment of brevisin was synthesized via Suzuki–Miyaura cross coupling
toward a total synthesis of brevisin.
A polycyclic ether, brevisin (1)1 was isolated from the red tide dinoflagellate Karenia brevis which
simultaneously produces a range of ladder-frame polyethers, including brevetoxins,2-4 brevenal and its
acetal,5 and a cyclic ether amide, brevisamide.6 The structure of 1 is characterized by two tricyclic ether
ring assemblies linked by a methylene group. One of the assemblies contains a conjugated aldehyde side
chain which has been found in brevenal and brevisamide. The interrupted polycyclic ether skeleton of the
molecule is quite unique. Common structural features for representative marine polycyclic ethers such as
the brevetoxins, ciguatoxins7 and yessotoxins8 are contiguous fused ether ring assemblies containing
middle size (from 7 to 9-membered) ether rings at the center of their polycyclic ether skeletons.9
This paper is dedicated to Dr. Akira Suzuki on the occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 2, 2010
Interestingly, even though the skeletal structure of 1 is divided into two ether ring assemblies by the
methylene, 1 inhibited the binding of 42-dihydrobrevetoxin B (PbTx-3) to the VSSC.1 Stereochemical
information of 1 is essential in order to elucidate the relationship between its unique structure and
biological activity. However, the relative stereochemistry of the ABC and DEF ring assemblies could be
only determined separately due to the shortage of natural brevisin which hampered determination of the
stereochemical correlation between the ether ring assemblies and the absolute configuration by NMR
methods. Therefore we have begun synthesis of 1 to determine the complete stereostructure of this
unusual polyether. Including our group, numerous efforts have been directed toward the synthesis of
marine polycyclic ethers using various approaches.10 Our synthetic strategy based on Suzuki–Miyaura
cross coupling11 has led to convergent synthesis of ether ring skeletons of polycyclic ethers12 and the
recent successful synthesis of the related metabolite brevisamide.13 Herein we report synthesis of the
ABC-ring fragment 2 leading toward the total synthesis of 1 via Suzuki–Miyaura cross coupling.
OH
OH
Me
OH
Me
O
B
30
F
10
A
O
Me
15
Me
OH
C
8
33
1
E
H
D
O
25
O
O
Me
20
Me
O
O
Me
brevisin (1)
OH
OH
OH
Me
H
H
H
30
F
Me
O
O
E
10
A
15
Me
OH
B
C
8
33
D
O
25
O
O
Me
20
Me
O
H
H
H
H
H
Figure 1. Structure of brevisin (1) and its probable stereostructure of the ABC and DEF ring assemblies.
OAc
H
10
OTES
OTES
Me
Me
O
B
Me
H
O
P
15
O
O
OAc
OAc
PhO
PhO
A
C
A
C
8
+
Ph
O
BnO
O
H
O
Me
O
Me
BnO
O
20
H
H
H
2
3
4
BnO
OH
5
Scheme 1. Retrosynthetic analysis of 2.14

HETEROCYCLES, Vol. 80, No. 2, 2010
827
Based on the structural similarity of the dienal side chain and the 6-membered ether ring in 1, brevenal,
and brevisin, we synthesized the ABC-ring fragment with an 8S configuration. Our synthetic strategy is
summarized in Scheme 1. The A-ring exo-olefin 3 was prepared from 3-benzyloxypropan-1-ol (5) and the
C-ring ketene acetal phosphate 4 was prepared from 2-deoxy-D-ribose by reported procedures.15 The
A-ring exo-olefin 3 and the C-ring ketene acetal phosphate 4 could be linked by a Suzuki–Miyaura cross
coupling and subsequent B-ring construction by mixed thioacetalization/methylation to yield the
ABC-ring fragment 2.
The synthesis of the A-ring exo-olefin 3 began with 3-benzyloxypropan-1-ol (5), which was oxidized with
TEMPO and PhI(OAc)2 to generate aldehyde 6.16 Optically active homoallylic alcohol 7 was
streoselectively prepared from 6 by the following procedures. Reagent-controlled enantioselective
crotylation of aldehyde using (Z)-2-butene and (+)--methoxydiisopinocampheylborane17 gave the
desired alcohol 7 in 56% yield (90% ee). Determination of the absolute configuration of alcohol 7 was
confirmed by the modified Mosher method.18 The alcohol was esterified with acryloyl chloride and
i-Pr2NEt (DIPEA) to furnish acrylate 8 in 92% yield. Treatment of 8 with the second-generation Grubbs’
catalyst (Grubbs’ II)19 resulted in successful closure of ,-unsaturated six-membered lactone 9 in 94%
yield, and was subsequently oxidized to diol 10 with OsO and NMO in 88% yield. After protection of
the diol with TESOTf to give lactone 11, the stereostructure of this key intermediate was assigned by
3
NOE correlations and JH,H coupling constants. NOE correlations between the C-9 methyl and H-11, and
the C-9 methyl and H-10 suggested an axial orientation of the C-9 methyl and H-11, and an equatorial
orientation of H-10. An NOE correlation and small coupling constant (J =3 Hz) between H-9 and H-8
confirmed an axial direction of H-8. The A-ring exo-olefin 3 was generated by a Petasis–Tebbe reaction
with Cp2TiMe2 at 65 °C in 92% yield (Scheme 2).20
OH
Me
a
b
c
d
5
BnO
BnO
O
6
7
BnO
O
O
Me
H
g
8
OH
O
OTES
OTES
OTES
Me
Me
OH
Me
OTES
Me
10
e
f
A
8
BnO
O
O
BnO
O
BnO
O
O
BnO
O
H
H
H
H
9
10
11
3
Scheme 2. Reagents and conditions (a) TEMPO, PhI(OAc)2, CH2Cl2, 94%; (b) (+)-(Z)-crotyldiisopino-
campheylborane, Et2O, THF, –78 °C; then 3 M aq NaOH, H2O2, reflux, 56%, 90% ee; (c) acryloyl
chloride, DIPEA, CH2Cl2, 0 °C, 92%; (d) Grubbs’ II, CH2Cl2, 94%; (e) OsO4, NMO, tBuOH, H2O, 0 °C,
88%; (f) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 87%; (g) Cp2TiMe2, toluene, THF, 65 °C, 92%.

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HETEROCYCLES, Vol. 80, No. 2, 2010
The known lactone 12 was prepared from 2-deoxy-D-ribose in seven steps.15 Enolization of this lactone
with KHMDS in the presence of (PhO)2P(O)Cl generated the C-ring ketene acetal phosphate 4 in 96%
yield. Stereoselective hydroboration of the A-ring exo-olefin 3 with 9-BBN-H produced an alkylborane,
which was reacted in situ with the C-ring ketene acetal phosphate 4 in the presence of aqueous Cs2CO3
and a catalytic amount of PdCl2(dppf), to give rise to the cross coupling product 13 in 66% yield from 4.
A
diastereomer could not be detected because of its trace amount. Stereoselective
hydroboration-oxidation of the coupling product 13 furnished alcohol 14 in 77% yield. An NOE
correlation between H-14 and the C-19 methyl unambiguously indicated the stereochemistry of 14 as
shown in Scheme 3. Oxidation of the resultant hydroxy group with TPAP/NMO led to ketone 15 in 93%
yield. Treatment of 15 with EtSH and Zn(OTf)2 led to removal of the TES group and formation of mixed
thioacetal, and following acetylation yielded mixed thioacetals 16 (29%) and 17 (48%) for the two steps.
Introduction of the C-15 methyl group in the triacetylated thioacetal 16 was achieved in a one pot manner
with mCPBA and then AlMe3 giving rise to triether ring assembly 2 in 98% yield (Scheme 3).21,22 The
stereochemistry of 2 was confirmed by NOE correlations H-11/the C-15 methyl and H-12/H-8 and H-14.
H
H
O
P
a
O
O
O
O
PhO
PhO
C
Ph
Ph
O
O
O
Me
O
Me
12
4
OTES
OTES
OTES
OH
3
+
Me
OTES
Me
H
O
H
b
c
d
O
O
14
19
Ph
Ph
4
BnO
O
BnO
O
O
Me
O
Me
H
H
H
H
H
O
13
14
OTES
OAc
OAc
H
10
OTES
SEt
Me
Me
H
H
O
O
Me
O
Me
O
B
g
e, f
15
15
OAc
OAc
OAc
OAc
A
C
8
Ph
BnO
O
O
Me
BnO
BnO
O
H
H
H
BnO
O
H
O
Me
O
Me
O
20
H
H
H
H
H
15
16
2
OAc
H
SEt
Me
O
H
15
O
O
Ph
O
H
O
Me
H
H
17
Scheme 3.Reagents and conditions (a) KHMDS, (PhO) 2P(O)Cl, HMPA, THF, –78 °C, 96%; (b) 3,
9-BBN-H, THF, 50 °C; then 4, 3 M aq Cs2CO3, PdCl2 (dppf), DMF, 50 °C, 66%; (c) BH3•SMe2, 0 °C to
rt; then 3 M aq NaOH, H2O2, 0 °C to rt, 77%; (d) TPAP, NMO, MS4A, CH2Cl2, 93%; (e) Zn(OTf) 2,
EtSH, THF, rt; (f) Ac2O, pyridine, 29% for 16, 48% for 17 (two steps); (g) mCPBA, CH2Cl2, 0 °C; then
AlMe3, 0 °C, 98%.

HETEROCYCLES, Vol. 80, No. 2, 2010
829
1
Although the H NMR chemical shifts from H-8 to H-18 of the ABC-ring fragment 2 are slightly
different from those of the corresponding domain of tetraacetylated brevisin probably due to the absence
of a dienal structure and the DEF ring assembly, the coupling constants of 2 agreed well with those of 1.
In summary, the ABC-ring fragment 2 of brevisin was synthesized in a stereocontrolled manner from
commercially available materials, 3-benzyloxypropan-1-ol and 2-deoxy-D-ribose. Olefin metathesis was
highly effective for construction of the A-ring. The ,-unsaturated lactone 9 was constructed in only two
steps from homoallylic alcohol 7. Assembly of the A-ring exo-olefin 3 and the C-ring ketene acetal
phosphate 4 was accomplished by an effective Suzuki–Miyaura coupling reaction. Further study toward
the total synthesis of brevisin is now in progress.
ACKNOWLEDGEMENTS
This work was financially supported by KAKENHI (No. 2061102) and the Global COE Program for
Chemistry Innovation, the University of Tokyo. T.K. is grateful for a SUNBOR Scholarship. The natural
brevisin was isolated from the cultures maintained under grants P01 ES 10594 (NIEHS, DHHS) and
MARBIONC, Marine Biotechnology in North Carolina. J.L.C.W. acknowledges funding from
NOAA-ECOHAB (MML-106390A) and NCDHHS (01515-04).
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22. Physicochemical data of 2: []D29 –15 (c 0.13, CHCl3); 1H-NMR (500 MHz, CD3OD)  7.36 (5H, m,
Ph), 5.16 (1H, br dd, J=2.1, 5.4 Hz), 4.92 (1H, m), 4.53 (1H, d, J=12.2 Hz), 4.47 (1H, d, J=12.2 Hz),
3.95 (1H, m), 3.94 (1H, d, J=11.4 Hz), 3.89 (1H, d, J=11.4 Hz), 3.65 (1H, dd, J=5.1, 12.2 Hz), 3.57
(1H, m), 3.55 (1H, m), 3.46 (1H, dd, J=2.9, 11.5 Hz), 3.46 (1H, ddd, J=3.8, 13.5, 13.5 Hz), 2.16 (3H,
s), 2.08 (3H, s), 2.07 (3H, s), 1.89 (1H, m), 1.87 (1H, m), 1.85 (2H, m), 1.73 (1H, ddd, J=4.2, 9.2,
9.2 Hz), 1.69 (1H, dd, J=4.6, 10.9 Hz), 1.58 (1H, m), 1.51 (1H, m), 1.49 (1H, ddd, J=13, 13, 13 Hz),
13
1.22 (3H, s), 1.19 (3H, s), 1.01 (3H, d, J=7.6 Hz); C-NMR (100 MHz, CD3OD)  172.2, 172.1,
171.6, 139.9, 129.3, 129.0, 128.7, 80.3, 79.0, 75.9, 74.9, 73.9, 73.3, 73.1, 72.9, 69.5, 68.7, 67.7, 39.3,
36.4, 35.0, 33.2, 30.8, 24.4, 21.2, 20.8, 18.5, 15.7, 11.3, HRMS (FAB), calcd for C31H44O10Na
599.2827 (M+Na+), found 599.2823.