Synthesis of dysiherbaine analogue

Article abstract of DOI:10.1016/j.tetlet.2005.06.093

Synthesis of dysiherbaine analogue 4, which corresponds to 8,9-epi-neodysiherbaine A, is described. The synthesis features a concise route to the bicyclic ether skeleton through stereoselective C-glycosylation to set the C₆ stereocenter and 5-e

Full text of DOI:10.1016/j.tetlet.2005.06.093

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5559–5562
Synthesis of dysiherbaine analogue
Muneo Shoji,a Kaoru Shiohara,a Masato Oikawa,a Ryuichi Sakaib and Makoto Sasakia,*
aGraduate School of Life Sciences, Tohoku University, Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan
bSchool of Fisheries Science, Kitasato University, Sanriku-cho, Iwate 022-0100, Japan
Received 4 April 2005; revised 6 June 2005; accepted 8 June 2005
Available online 5July 2005
Abstract—Synthesis of dysiherbaine analogue 4, which corresponds to 8,9-epi-neodysiherbaine A, is described. The synthesis
features a concise route to the bicyclic ether skeleton through stereoselective C-glycosylation to set the C6 stereocenter and 5-exo
ring-closure to form the tetrahydrofuran ring. The results of preliminary biological studies of 4 are also provided.
Ó 2005 Elsevier Ltd. All rights reserved.
+NH2Me
OH
O
Dysiherbaine (1), isolated from the Micronesian sponge,
Dysidea herbacea, is a novel excitatory amino acid with
potent convulsant activity.1,2 Dysiherbaine activates
neuronal non-NMDA type glutamate receptors,
namely, AMPA and kainic acid (KA) receptors, with
considerable preference over KA receptors (Ki values
of 26 and 153 nM for KA and AMPA receptors, respec-
tively).2 Moreover, it has been shown that dysiherbaine
could differentially activate one of the activation sites
within the subunit of a heteromeric GluR5/KA2 recep-
tor complex.3 This discrete affinity of dysiherbaine has
enabled characterization of the unexpectedly complex
behavior of the heteromeric KA receptors. Neodysiher-
baine A (2),4 isolated as a minor congener from the same
sponge, differs from dysiherbaine in the functional
group at the C8 position and is also a selective agonist
for non-NMDA type glutamate receptors (Fig. 1).
+NH3
+NH3
1
H
H
H
H
8
-OOC
-OOC
-OOC
OH
OH
OH
O
O
2
4
7
9
-OOC
HOOC
O
5
1: dysiherbaine
2: neodysiherbaine A
OH
+NH3
+NH3
H
H
H
-OOC
O
O
HOOC
HOOC
O
O
H
3
4
Figure 1. Structures of dysiherbaine and its analogues.
tors.8 These studies revealed that neodysiherbaine A is
similar to dysiherbaine in its pharmacological activity
on KA receptors, albeit with slightly different binding
affinities for individual receptor subunits, whereas
analogue 3, lacking the hydroxyl and N-methyl groups
on the tetrahydropyran ring, is a selective antagonist
for GluR5KA receptors. These results strongly suggest
that the C8 and C9 functional groups are critical struc-
tural elements for specificity and selectivity for KA
receptors. In order to reveal further the detailed struc-
ture–activity relationship profiles of dysiherbaine, we
undertook a diverted synthesis of structural analogues
of dysiherbaine. In this letter, we describe a synthesis
of dysiherbaine analogue 4, corresponding to 8,9-epi-
neodysiherbaine A, for the biological evaluation.
Due to these unusual pharmacological properties of
dysiherbaine to KA receptors and its potent epilepto-
genic activity, dysiherbaine and its designed analogues
are anticipated to serve as useful tools for understanding
the structure and functions of glutamate receptors in the
central nervous system. Thus, the total synthesis of dysi-
herbaine has been reported by several research
groups.5,6
Recently, Swanson and co-workers have characterized
the pharmacological action of neodysiherbaine A and
simplified synthetic analogue 37 on glutamate recep-
*
The synthesis started with C-glycosylation of allylsilane
69 with diacetyl-L-arabinal (5).10 Thus, reaction of 5
Corresponding author. Tel.: +81 22 717 8828; fax: +81 22 717
8897; e-mail: masasaki@bios.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.093

5560
M. Shoji et al. / Tetrahedron Letters 46 (2005) 5559–5562
OAc
BnO
TMS
6
OAc
O
O
H
H
H
H
OAc
O
O
O
HO
MeO2C
TBSO
O
O
BnO
a,b
O
a
H
O
TBSO
O
O
5
7
11a
12
b
ca. 1.6:1
RO
OH
O
c,d
O
H
OH
OAc
BnO
O
d,e
O
OH
O
HO
O
NBn
H
H
H
H
O
TBSO
O
O
O
e,f
4
H
H
O
TBSO
BnO
10
8: R = H
9: R = TBS
X
O
O
c
f,g
O
TBSO
14: X = OH
15: X = H
13
g,h
O
H
H
H
O
O
HO
TBSO
HO
O
O
Scheme 2. Reagents and conditions: (a) SO3Æpyr, DMSO, Et3N,
CH2Cl2, 0 °C; (b) Ph3P@CHCO2Me, CH2Cl2, rt, 88% (two steps); (c)
DIBALH, CH2Cl2, À78 °C, 98%; (d) t-BuOOH, Ti(Oi-Pr)4, (+)-DIPT,
4
+
TBSO
O
O
H
11b
˚
4 A MS, CH2Cl2, À20 °C, 95%; (e) BnNCO, i-Pr2NEt, benzene, 50 °C,
11a
80%; (f) KOt-Bu, THF, À20 ! 0 °C, 61%; (g) NaH, CS2, MeI, THF,
0 °C ! rt, 80%; (h) Bu3SnH, AIBN, toluene, 110 °C, 82%.
Scheme 1. Reagents and conditions: (a) compound 6, Yb(OTf)3
(10 mol%), CH2Cl2, rt, 85%; (b) AD mix-b, MeSO2NH2, t-BuOH/
H2O, 0 °C ! rt, quant.; (c) TBSOTf, Et3N, DMAP, CH2Cl2, 0 °C,
87%; (d) K2CO3, MeOH, rt, 92%; (e) m-CPBA, CH2Cl2/pH 7
phosphate buffer, 0 °C ! rt, then SiO2, 89%; (f) Me2C(OMe)2, CSA,
CH2Cl2, 0 °C, 85%; (g) H2, Pd/C, hexane, rt, 11a, 60%; 11b, 38%.
ylcarbamate with KOt-Bu afforded cyclic carbamate 14
(61%). Subsequent deoxygenation was carried out
according to the method of Barton and MaCombie14
to provide 15 in 66% yield for the two steps.
Diastereomeric alcohol 11b was also converted to 15 as
depicted in Scheme 3. Oxidation to the acid and subse-
quent esterification provided methyl ester 16 in 60%
overall yield. Desilylation followed by oxidation with
SO3Æpyr/DMSO afforded an aldehyde, which was
subjected to Wittig reaction to give 17 in 51% yield for
the three steps. Selective reduction of the enoate moiety
of diester 17 was achieved by exposure to DIBALH in
THF to yield an allylic alcohol (90%), which upon asym-
with 6 in the presence of Yb(OTf)3 (CH2Cl2, room tem-
perature)11 led to C-glycoside 7 as the sole product in
85% yield (Scheme 1). Subsequent treatment of 7 with
AD mix-bÒ (MeSO2NH2, t-BuOH/H2O, 0 °C ! rt)
effected regioselective dihydroxylation of the exocyclic
double bond to afford diol 8 in quantitative yield as an
approximately 1.6:1 mixture of diastereomers, which
was carried forward without separation through the
subsequent transformations. The primary hydroxy
group of 8 was selectively protected as the tert-butyldi-
methylsilyl (TBS) ether to give 9 in 87% yield. After
removal of the acetyl group (92%), treatment of the
resultant allylic alcohol with m-CPBA led exclusively
to the corresponding b-epoxide. When the crude epoxide
was subjected to purification by column chromato-
graphy on silica gel, epoxide ring-opening by an intra-
molecular attack of the tertiary alcohol occurred to
generate diol 10 in 89% yield. Protection of the diol as
the acetonide (85%) followed by removal of the benzyl
group under hydrogenolysis afforded alcohols 11a
(60%) and 11b (38%), which were readily separable by
flash column chromatography.12 Thus, the synthesis of
the bicyclic ether skeleton was realized in only seven
steps from 5.
O
O
H
H
H
H
O
O
TBSO
MeO2C
O
O
c-e
R
MeO2C
O
O
17
11b: R = CH2OH
16: R = CO2Me
a,b
f,g
H
O
O
O
HO
O
NBn
R
H
O
O
O
O
h-k
O
MeO2C
O
O
H
H
19: R = CO2Me
15: R = CH2OTBS
18
l,m
Oxidation of the major alcohol 11a with SO3Æpyr/DMSO
followed by Wittig reaction, gave enoate 12 in 88% over-
all yield (Scheme 2). DIBALH reduction and Sharpless
asymmetric epoxidation using (+)-diisopropyl tartrate
(DIPT) delivered epoxy alcohol 13 in 93% yield for the
two steps. Stereoselective introduction of the amino
group at the C2 position was carried out following the
procedure of Kishi and co-workers.13 Thus, treatment
of 13 with benzyl isocyanate (i-Pr2NEt, benzene,
50 °C, 80%) followed by reaction of the resultant benz-
Scheme 3. Reagents and conditions: (a) TEMPO, NaClO2, cat.
NaClO, MeCN/pH 7.0 phosphate buffer, 75%; (b) K2CO3, MeI,
DMF, rt, 80%; (c) TBAF, THF, rt, 85%; (d) SO3Æpyr, DMSO, Et3N,
CH2Cl2, 0 °C; (e) Ph3P@CHCO2Me, CH2Cl2, rt, 60% (two steps); (f)
DIBALH, THF, À78 °C, 90%; (g) t-BuOOH, Ti(i-PrO)4, (+)-DIPT,
˚
CH2Cl2, 4 A MS, À20 °C, 83%; (h) BnNCO, i-Pr2NEt, benzene, 50 °C,
95%; (i) KOt-Bu, THF, À20 °C, 78%; (j) NaH, CS2, MeI, THF,
0 °C ! rt, 80%; (k) Bu3SnH, AIBN, toluene, 110 °C, 75%; (l) LiBH4,
THF, 0 ! 60 °C, 74%; (m) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 87%.

M. Shoji et al. / Tetrahedron Letters 46 (2005) 5559–5562
5561
metric epoxidation delivered epoxy alcohol 18 in 83%
yield. Elaboration of 18 to cyclic carbamate 19 was
readily accomplished as described above. The resultant
ester 19 was then converted to 15 by ester reduction
and protection.15
the C8 and C9 hydroxy groups of 24 should lead to var-
ious dysiherbaine analogues.
The toxicity of dysiherbaine analogue 4 was preliminar-
ily tested on mice. Intracerebral injection of 4 against
mice did not induce any behavioral effects such as vio-
lent scratching and head bobbing even at higher dose
(20 lg/mouse).
Cyclic carbamate 15 was subsequently transformed to
diol 20 by a four-step sequence of protective group
manipulations, including reductive debenzylation with
lithium tert-butylbiphenylide (LDBB),16 reprotection
as the Boc group, ethanolysis of the cyclic carbamate
and desilylation with TBAF (Scheme 4). Oxidation of
20 with KMnO4 (1 M NaOH, H2O) gave a mixture of
diacid 21 and aminal 22, which without separation was
further oxidized with catalytic amounts of tetra-n-prop-
ylammonium perruthenate (TPAP) and N-methyl-
morpholine N-oxide (NMO)17 and subsequently treated
with excess trimethylsilyldiazomethane to deliver di-
methyl ester 23 in 61% yield over the three steps. Finally,
global deprotection by acid hydrolysis (6 M HCl, 65 °C)
furnished the target compound 4 in 90% yield.18 Thus,
the synthesis of analogue 4 was completed in 23 steps
and 3.4% overall yield from diacetyl-L-arabinal via
11a. In addition, selective deprotection of the acetonide
of 23 was realized by using DDQ (CH3CN/H2O, 50 °C)
to give diol 24 in 85% yield.19 Further modification of
In conclusion, we have developed a synthetic route to
dysiherbaine analogue 4, which features a concise synthe-
sis of the bicyclic ether skeleton through stereoselective
C-glycosylation to set the C6 stereocenter and 5-exo cycli-
zation for constructing the tetrahydrofuran ring. Further
neurophysiological studies of compound 4 and synthesis
of other analogues from a key intermediate 23 to probe
the structure–activity relationship of dysiherbaine are
in progress and will be reported in due course.
Acknowledgments
This work was financially supported by Yamada Science
Foundation and a Grant-in-Aid for Scientific Research
on Priority Area ꢀCreation of Biologically Functional
Moleculesꢁ from the Ministry of Education, Science,
Sports, Culture and Technology, Japan.
O
References and notes
O
O
O
NBn
HO
NHBoc
O
H
H
H
H
O
O
1. Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J.
Am. Chem. Soc. 1997, 119, 4112–4116.
2. Sakai, R.; Swanson, G. T.; Shimamoto, K.; Contractor,
A.; Ghetti, A.; Tamura-Horikawa, Y.; Oiwa, C.; Kamiya,
H. J. Pharm. Exp. Ther. 2001, 296, 655–663.
O
a-d
TBSO
HO
O
O
15
20
e
3. Swanson, G. T.; Green, T.; Sakai, R.; Contractor, A.;
Che, W.; Kamiya, H.; Heinemann, S. F. Neuron 2002, 34,
589–598.
4. Sakai, R.; Koike, T.; Sasaki, M.; Shimamoto, K.; Oiwa,
C.; Yano, A.; Suzuki, K.; Tachibana, K.; Kamiya, H. Org.
Lett. 2001, 3, 1479–1482.
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Maeyama, J.; Kamada, K.; Esumi, T.; Iwabuchi, Y.;
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(d) Phillips, D.; Chamberlin, A. R. J. Org. Chem. 2002, 67,
3194–3201.
6. (a) For synthetic studies on dysiherbaine, see: Naito, T.;
Nair, J. S.; Nishiki, A.; Yamashita, K.; Kiguchi, T.
Heterocycles 2000, 53, 2611–2615; (b) Huang, J.-M.; Xu,
K.-C.; Loh, T.-P. Synthesis 2003, 755–764; (c) Miyata, O.;
Iba, R.; Hashimoto, J.; Naito, T. Org. Biomol. Chem.
2003, 1, 772–774; (d) Kang, S. H.; Lee, Y. M. Synlett 2003,
993–994.
O
O
NHBoc
O
H
H
H
H
HO2C
BocN
O
O
HO2C
O
+
HO2C
O
O
OH
22
21
f,g
O
OH
O
NHBoc
O
+NH3
H
H
H
O
OH
MeO2C
-OOC
O
h
MeO2C
HOOC
O
H
23
4
OH
NHBoc
H
H
i
OH
MeO2C
O
7. Sasaki, M.; Maruyama, T.; Sakai, R.; Tachibana, K.
Tetrahedron Lett. 1999, 40, 3195–3198.
MeO2C
O
8. Sanders, J. M.; Ito, K.; Settimo, L.; Pentika¨inen, O. T.;
Shoji, M.; Sasaki, M.; Johnson, M. S.; Sakai, R.;
Swanson, G. T. J. Pharm. Exp. Ther. 2005, in press.
9. Konosu, T.; Furukawa, Y.; Hata, T.; Oida, S. Chem.
Pharm. Bull. 1991, 39, 2813–2818.
10. Diacetyl-L-arabinal (5) is readily available in two steps
from L-arabinose Hullomer, F. L. In Methods in Carbo-
hydrate Chemistry; Academic Press: New York, 1962; Vol.
I, pp 83–88.
24
Scheme 4. Reagents and conditions: (a) LDBB, THF, À78 °C, 76%;
(b) Boc2O, Et3N, DMAP, CH2Cl2, 85%; (c) Cs2CO3, EtOH, rt, 95%;
˚
(d) TBAF, THF, 4 A MS, rt, 94%; (e) KMnO4, aq NaOH, rt; (f)
˚
TPAP, NMO, 4 A MS, CH2Cl2, rt; (g) TMSCHN2, MeOH, rt, 61%
(three steps); (h) 6 M HCl, 65 °C, 90%; (i) DDQ, CH3CN/H2O, 50 °C,
85%.

5562
M. Shoji et al. / Tetrahedron Letters 46 (2005) 5559–5562
11. Takhi, M.; Rahman, A. A.-H. A.; Schmidt, R. R.
Tetrahedron Lett. 2001, 42, 4053–4056.
12. The stereochemistry at C4 position of each compound was
determined by NOE experiments of the corresponding
aldehydes (A and B).
16. (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980,
45, 1924–1930; (b) Ireland, R. E.; Smith, M. G. J. Am.
Chem. Soc. 1988, 110, 854–860.
17. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639–666.
25
18. Selected data for compound 4: ½aꢀD À40.0 (c 0.05, H2O);
1H NMR (600 MHz, D2O) d 2.00 (dd, J = 15.6, 10.6 Hz,
1H, 3-H), 2.09 (dd, J = 14.1, 3.8 Hz, 1H, 5-H), 2.53 (dd,
J = 15.6, 2.3 Hz, 1H, 3-H); 2.54 (d, J = 14.1 Hz, 1H, 5-H),
3.39 (dd, J = 10.6, 10.6 Hz, 1H, 10-H), 3.47 (dd, J = 10.6,
5.0 Hz, 1H, 10-H), 3.61 (dd, J = 10.6, 2.3 Hz, 1H, 2-H),
3.93 (ddd, J = 10.6, 5.0, 3.2 Hz, 1H, 9-H), 4.05 (m, 1H, 7-
H), 4.09 (m, 1H, 8-H), 4.13 (m, 1H, 6-H); 13C NMR
(125MHz, D 2O) d 178.57, 174.12, 86.89, 83.97, 74.24,
67.42, 65.11, 64.43, 53.79, 44.31, 39.70; HRMS (FAB)
calcd for C11H16NO8 [(MÀH)À]: 290.0876. Found:
290.0881.
O
O
H
H
H
O
O
O
H
O
H
OHC
TBSO
TBSO
OHC
O
O
H
H
H
NOE
NOE
A
B
13. Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982,
104, 1109–1111.
14. Barton, D. H. R.; MaCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585.
15. Attempts to remove the benzyl group of compound 19
were unsuccessful.
19. Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem.
2002, 67, 2435–2446.