Total synthesis of dysiherbaine

Article abstract of DOI:10.1016/j.tetlet.2007.05.180

An efficient total synthesis of dysiherbaine, a potent and subtype-selective agonist for ionotropic glutamate receptors, has been achieved. An advanced key intermediate in the previous synthesis of neodysiherbaine A and its analogues was selected as the s

Full text of DOI:10.1016/j.tetlet.2007.05.180

Tetrahedron Letters 48 (2007) 5697–5700
Total synthesis of dysiherbaine
a,
a
a
a
*
Makoto Sasaki, Nobuyuki Akiyama, Koichi Tsubone, Muneo Shoji,
a
b
Masato Oikawa and Ryuichi Sakai
a
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, Sendai 981-8555, Japan
b
School of Fisheries Sciences, Kitasato University, Sanriku-cho, Iwate 022-0101, Japan
Received 9 May 2007; revised 28 May 2007; accepted 31 May 2007
Available online 8 June 2007
Abstract—An efficient total synthesis of dysiherbaine, a potent and subtype-selective agonist for ionotropic glutamate receptors, has
been achieved. An advanced key intermediate in the previous synthesis of neodysiherbaine A and its analogues was selected as the
starting point, and cis-oriented amino alcohol functionality on the tetrahydropyran ring was installed by using an intramolecular
S 2 cyclization of N-Boc-protected amino alcohol. The amino acid appendage was constructed by catalytic asymmetric hydro-
N
genation of enamide ester.
Ó 2007 Elsevier Ltd. All rights reserved.
Ionotropic glutamate receptors (iGluRs) form a family
of ligand-gated ion channels that mediate fast synaptic
transmission in the mammalian central nervous system.
The iGluRs can be divided, based on their affinities for
the selective agonists, into three subclasses: N-methyl-D-
aspartate (NMDA), (S)-2-amino-3-(3-hydroxy-5-methyl-
NHMe
OH
O
NH2
NH2
1
H
H
H
8
OH
OH
HO
2
C 2
O
HO
2
C
O
1
4
9
6
HO C
HO C
2
O
2
H
dysiherbaine (1)
neodysiherbaine A (2)
4
-isoxazolyl)propionic acid (AMPA), and kainate
Figure 1. Structures of dysiherbaine and neodysiherbaine A.
receptors. These receptors play important roles in many
processes, including learning and memory, and are also
implicated in a number of neuronal disorders. There are
seven NMDA receptor genes (NR1, NR2A-2D, NR3A,
and NR3B), four AMPA receptor genes (GluR1-4), and
five kainate receptor genes (GluR5-7 and KA1-2). This
diversity makes the functional analysis of native gluta-
mate receptors a formidable task. Therefore, the devel-
opment of selective ligands that can discriminate
between different glutamate receptors has been the focus
of extensive research.
affinity for the latter, but shows no detectable affinity
for NMDA receptors. Furthermore, it has been
5
revealed that dysiherbaine had extremely high affinity
for recombinant GluR5 or GluR6 kainate receptors
but very low affinity for KA2 receptors, and this differ-
ence of affinities produced unusual biophysical behavior
6
from heteromeric kainate receptors. Neodysiherbaine
A is also a selective agonist for AMPA and kainate
receptors, with slightly different binding affinities for
7
kainate receptor subunits. The high affinity and selec-
2
Dysiherbaine (1) and its congener, neodysiherbaine A
tivity of dysiherbaines for certain kainate receptor sub-
types made these natural products useful tools for
exploring the complex biophysical functions of gluta-
mate receptor ion channels; however, the exact mode
3
(
2), isolated by Sakai et al. from the Micronesian
sponge Dysidea herbacea, are remarkable excitatory
4
amino acids with potent convulsant activity (Fig. 1).
8
Structurally, these amino acids consist of a cis-fused
hexahydrofuro[3,2-b]pyran ring system containing a glu-
tamic acid substructure. Dysiherbaine activates the
AMPA and kainate classes of receptors, with a higher
of interaction is still elusive.
In addition to their unique biological profiles, the
unprecedented molecular structures of dysiherbaines
have attracted considerable attention from synthetic
chemists. Thus, several total syntheses and synthetic ap-
proaches have been reported, including structure–activ-
ity relationship studies of neodysiherbaine A from this
*
Corresponding author. Tel.: +81 22 717 8828; fax: +81 22 717
897; e-mail: masasaki@bios.tohoku.ac.jp
8
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.180

5698
M. Sasaki et al. / Tetrahedron Letters 48 (2007) 5697–5700
laboratory.3,9–12 Here, we describe an efficient synthetic
route to dysiherbaine that would allow for the prepara-
tion of analogues to elucidate the detailed structure–
activity relationships.
O
OH
8
H
H
H
H
O
HS(CH2)3SH
BF ·OEt
TBSO
MeO2C
O
TBSO
MeO2C
O
OH
3
2
9
O
O
6
9%
6
8
We previously reported the total synthesis of dysiherba-
ine (1), which featured the palladium(0)-catalyzed cross-
coupling reaction of organozinc compound 3 with vinyl
PivCl, Et3N
DMAP, 96%
9
b
iodide 4. This first-generation synthesis, however,
required a multi-step sequence of reactions (32 steps
from commercially available 1,6-anhydro-D-glucose)
N3
O
OH
H
H
H
2
1. Tf O, pyr
TBSO
MeO C
O
OPiv
TBSO
MeO C
O
OPiv
2
. TMGN3
(
Scheme 1).
2
2
O
7
1% (2 steps)
H
1
0
9
Recently, we developed an efficient synthetic route to
H2, Pd(OH)2/C
2
neodysiherbaine A (2) and its analogues starting from
Boc O, 100%
1
0d,11b
a common intermediate 7 (Scheme 2).
The synthe-
NHBoc
OPiv
NHBoc
sis of 7 featured (i) a concise synthesis of bicyclic ether 6
and (ii) a catalytic asymmetric hydrogenation to con-
struct the amino acid appendage.
H
H
H
H
TBSO
MeO2C
O
TBSO
MeO2C
O
OH
NaOMe
1%
O
9
O
1
1
12
We envisioned constructing dysiherbaine (1) from ester
1
0d
6
,
which would have required the introduction of an
Scheme 3. Introduction of C8 amino group.
amino functionality at the C8 position. For this pur-
pose, the acetonide from ester 6 was selectively deprotec-
ted by exposure to 1,3-propanedithiol in the presence of
boron trifluoride etherate (CH Cl , ꢀ30 °C) to afford
CH Cl , ꢀ20 °C), which was subsequently treated with
2
2
tetramethylguanidium azide (DMF, 35 °C). Smooth dis-
placement took place to provide the desired azide 10 in
2
2
diol 8 in 69% yield (Scheme 3). Treatment of diol 8 with
pivaloyl chloride and triethylamine (CH Cl , ꢀ78 °C)
7
1% yield over the two steps. Hydrogenation of 10 in the
2
2
presence of di-tert-butyl dicarbonate proceeded cleanly
to afford N-tert-butoxycarbonyl (Boc) derivative 11 in
quantitative yield. Subsequently, removal of the pivaloyl
group (NaOMe, MeOH) led to alcohol 12 in 91% yield.
afforded monopivaloate ester 9 selectively (96%) due to
the equatorial disposition of the C9 alcohol and the ste-
ric congestion of the axial-oriented C8 alcohol. The
remaining alcohol was converted to the corresponding
triflate (trifluoromethanesulfonic anhydride, pyridine,
Having successfully introduced an amino group at C8,
we were now in a position to invert the C9 hydroxy
group. We first attempted to perform this transforma-
tion by an oxidation–reduction sequence or Mitsunobu
reaction, but all of these attempts were unsuccessful.
We then opted for the inversion by an intramolecular
cyclization according to the procedure of Benedetti
TBS
O
NMeBoc
OBn
NHBoc
ZnI
Pd(0)
+
MeO2C
cross-coupling
I
O
H
3
4
1
3
and Norbedo. Thus, treatment of 12 with methane-
sulfonyl chloride and triethylamine (CH Cl , 0 °C)
2
2
TBS
O
NHMe
O
NHMe
NH2
H
H
afforded the corresponding mesylate 13, which, without
purification, was immediately treated with dimethylami-
nopyridine in DMF at 120 °C (Scheme 4). The expected
OBn
HO2C
OH
O
steps
BocHN
MeO2C
HO2C
O
H
5
1
t-BuO
Scheme 1. First-generation total synthesis of dysiherbaine.
NHBoc
HN
O
H
H
H
TBSO
MeO2C
O
OH MsCl, Et N
TBSO
MeO2C
OMs
O
3
9
OAc
O
O
O
O
H
H
H
O
OAc 11 steps TBSO
MeO2C
6 steps
12
13
O
DMAP, DMF
120 °C
O
O
9
9% (2 steps)
di-
O
-acetyl-L-arabinal
6
O
O
Me
H
N
HN
OH
OH
O
H
O
NHBoc
O
NH2
1. NaH, MeI
88%
H
H
H
H
HO
O
TBSO
O
MeO2C
OH steps HO2C
O
OH
MeO2C
O
2. TBAF, 84%
MeO2C
O
H
MeO2C
O
HO2C
H
1
5
14
7
2
and analogues
Scheme 4. Introduction of cis-oriented amino alcohol functionality on
Scheme 2. Synthesis of neodysiherbaine A and analogues.
the tetrahydropyran ring.

M. Sasaki et al. / Tetrahedron Letters 48 (2007) 5697–5700
5699
oxazolidinone 14 was obtained in excellent yield over the
two steps. Following N-methylation (NaH, MeI, DMF,
In summary, an efficient synthesis of dysiherbaine (1)
was achieved in 24 steps and 4.3% overall yield from
di-O-acetyl-L-arabinal. The present synthesis would
allow for the synthesis of various dysiherbaine
analogues to clarify the structure–activity relationship
profiles. Further studies along this line are under way
in our laboratory and will be reported in due course.
8
8%), the tert-butyldimethylsilyl (TBS) group was
removed (TBAF, THF, 84%) to afford primary alcohol
5. At this stage, the stereochemistry of the C8 and C9
positions was established by NOEs as shown in Figure
1
2
.
Oxidation of 15 under Parikh–Doering conditions
1
4
(
SO Æpyridine, Et N, DMSO, CH Cl ) followed by
3 3 2 2
Acknowledgment
Horner–Wadsworth–Emmons olefination using phos-
1
5
phonate 16 and tetramethylguanidine generated ena-
mide ester 17 in 73% yield over the two steps (E:Z =
ca. 1:14) (Scheme 5). Hydrogenation of 17 in the
presence of 5 mol % of [Rh(I)(COD)-(S,S)-Et-
This work was financially supported by a Grant-in-Aid
for Scientific Research on Priority Area ‘Creation of
Biologically Functional Molecules’ (No. 16073202) from
the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
+
ꢀ
16,17
DuPHOS] OTf catalyst
in THF under pressurized
hydrogen (0.9 MPa) at room temperature proceeded
smoothly to give the desired amino acid derivative 18
in 83% yield. The corresponding diastereomer could
1
not be detected in the 500 MHz H NMR spectra. The
References and notes
stereochemistry at C2 was tentatively assigned based
1
6
10d
on Burk’s empirical rule and our previous results.
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8
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(
ine was identical to the natural material as judged by the
1
13
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O
O
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N
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1
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+
—
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MeO2C
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6
O
O
Me
H
NHMe
N
O
NH2
NaOH, MeOH
OH 45 ºC
MeO2C
NHCbz
O
H
H
HO2C
O
1
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HO2C
O
MeO2C
8
4%
H
dysiherbaine (1)
1
8
Scheme 5. Completion of total synthesis of dysiherbaine.

5700
M. Sasaki et al. / Tetrahedron Letters 48 (2007) 5697–5700
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1
2
19
2
7
303.1174.