Regioselective domino metathesis of 7-oxanorbornenes and its application to the synthesis of biologically active glutamate analogues

Article abstract of DOI:10.1002/ejoc.200800704

A highly regioselective domino metathesis reaction of 7-oxanorbornene was developed that employed an intramolecular association of an amide carbonyl group to a ruthenium metal centre. By using this reaction, twelve glutamate analogues inspired by dysiherbaine were efficiently synthesized over 12-14 steps; one of the analogues exhibited bioactivity consistent with central nervous system depression. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800704

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800704
Regioselective Domino Metathesis of 7-Oxanorbornenes and Its Application to
the Synthesis of Biologically Active Glutamate Analogues
Minoru Ikoma,[a] Masato Oikawa,*[a] Martin B. Gill,[b] Geoffrey T. Swanson,[b]
Ryuichi Sakai,[c] Keiko Shimamoto,[d] and Makoto Sasaki[a]
Keywords: Nitrogen heterocycles / Oxygen heterocycles / Combinatorial chemistry / Domino reactions / Metathesis / Regio-
selectivity
A highly regioselective domino metathesis reaction of 7-oxa-
norbornene was developed that employed an intramolecu-
lar association of an amide carbonyl group to a ruthenium
over 12–14 steps; one of the analogues exhibited bioactivity
consistent with central nervous system depression.
metal centre. By using this reaction, twelve glutamate ana- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
logues inspired by dysiherbaine were efficiently synthesized
Germany, 2008)
Introduction
mation of the intermediary metallacyclobutane in the
The olefin metathesis reaction plays an important role in Chauvin mechanism.[6] In the present study, we investigated
modern synthetic organic chemistry.[1] Although it has been domino metathesis of various 7-oxanorbornenes to examine
shown to be useful for the synthesis of complex molecules, the origin of the regioselectivity we observed previously. We
including biologically active natural products, the chemo- eventually found that the substrates with an upper exocyclic
or regioselectivities are not always controlled well. For ex- amide carbonyl group generally provided products with a
ample, a series of domino ring-opening metathesis (ROM)/ high level of regioselectivity, whereas this was not the case
cross-metathesis (CM) reactions of unsymmetrical norbor- for substrates without the carbonyl associating group. Re-
nene derivatives has been shown to be poorly regioselec- gio- and chemoselectivity in the olefin metathesis directed
tive.[2] However, these studies suggested that a long-range by an internal functionality has been proposed by Cossy
electronic effect of a remote substituent might be useful for (CM),[7a] Fürstner (RCM),[5] Grubbs (CM)[7b] and Tayler
controlling the regioselectivity; indeed, Rainier et al. found (CM),[7c] but ours is the one to address the associating effect
that a p-tolylsulfonyl group is efficient for realization of the on the ROM reaction.[8] In addition, the present study dem-
regioselective domino ROM/CM sequence when it is intro- onstrates the utility of the reactions by preparing novel
duced into a norbornene skeleton as a substituent.[3] We bioactive glutamate analogues (Scheme 1, compound C).
found independently that compound 1 was transformed Twelve novel and structurally diverse analogues of the
into a seven-membered ring by ring-closing metathesis marine toxin dysiherbaine[9] and its synthetic analogue
(RCM) in a good yield, whereas 2 was shown to be a mis-
matched substrate (Figure 1).[4] Although the details of the
mechanism remain unclear, we speculated that the upper
exocyclic amide carbonyl group (arrow) defined the regi-
ochemistry by interacting with the ruthenium (Ru) metal
centre[5] and led to kinetically controlled regioselective for-
[a] Graduate School of Life Sciences, Tohoku University
Aoba-ku, Sendai 981-8555, Japan
Fax: +81-22-717-8827
E-mail: mao@bios.tohoku.ac.jp
[b] Department of Molecular Pharmacology and Biological Chem-
istry, Northwestern University Feinberg School of Medicine
303 E. Chicago Ave., Chicago, IL 60611, USA
[c] Graduate School of Fisheries Sciences, Hokkaido University
Minato-cho, Hakodate 041-8611, Japan
[d] Suntory Institute for Bioorganic Research
Figure 1. Our previous observation suggested a directing effect of
the exocyclic carbonyl group.[4] Pointing arrow indicates the pro-
posed coordinating site to the Ru metal centre in the matched case.
Mishima-gun, Osaka 618-8503, Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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M. Oikawa et al.
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MSVIII-19, which exhibited antagonist actions on iono- (76%). Ns-amide 4d was further converted into trifluoro-
tropic glutamate receptors (iGluRs)[10] (Figure 2), were con- acetamide (TFA-amide) 4e in two steps (65% yield), thereby
veniently prepared from oxanorbornene A by way of me- enabling us to examine the effects of these protecting
tathesis product B (Scheme 1). Interestingly, one of these groups on the metathesis reaction. Compounds 5 and 6,[4c]
unique cyclic analogues of glutamate exhibited marked cen- which do not bear the N-benzyl (Bn) amide group, were
tral depressant activity in vivo and in vitro assays, suggest- also used for comparison.[11]
ing that its molecular mechanism of action is fundamentally
distinct from that of the parent dysiherbaine molecule.
Scheme 1. Our strategy for the synthesis of the glutamate ana-
logues.
Scheme 2. Replacement of the iodide with four heteroalkenyl
groups leading to 4a–e, and the structure of simple 7-oxanorboron-
enes 5 and 6 used for control experiments.
The metathesis reaction of 7-oxanorbornenes 3–6 with
vinyl acetate in benzene was next examined by using Hov-
eyda–Grubbs second-generation catalyst 7,[13a] as other cat-
alysts, such as the Grubbs second-generation catalyst,[13b]
did not sustain the catalytic activity long enough for the
domino reaction of 7-oxanorbornenes.[4a] As shown in
Table 1 (run 1), iodide 3 was treated at room temperature
to generate 8 in 87% yield with exclusive regio- (Ͼ99%)
and good stereoselectivities (E/Z = 13:1). The structure of
8 was unambiguously determined as the desired dia-
stereomer by analysis of the 1H–1H connectivities in the
NMR spectra. The formation of 8 indicates that the inter-
mediary Ru carbene was generated regioselectively at the
C5 position despite severe steric repulsion with the fused
Figure 2. Dysiherbaine congeners[9] and its antagonistic analogue
MSVIII-19.[10]
Results and Discussion
The highly functionalized 7-oxanorbornene skeleton 3 pyrrolidone ring. Interestingly, in the absence of an N-ben-
was first constructed selectively in 68% yield by tandem zylaminocarbonyl side chain, the same reaction with 5 gen-
Ugi/Diels–Alder reactions by using furfural and (Z)-3- erated a mixture of four products (10, 30:28:6:1) in only
iodoacrylic acid for the aldehyde and carboxylic acid com- 31% combined yield (Table 1, run 2). The metathesis reac-
ponents, respectively (Scheme 2).[4c,12] Sterically demanding tion of 4a proceeded well at room temperature up to 4 h
iodine-substituted acrylate was used in the intramolecular to generate heterotricycle 9a in quantitative yield (Table 1,
Diels–Alder reaction in a series of our study[4c] and also run 3). In contrast, the reaction of 6 occurred slowly over
worked well in the present tandem reaction. Subsequently, 8.5 h and was not highly selective, yielding two products, 11
four olefin groups were introduced into 3 by replacement and 12, by a less-regioselective ROM reaction (Table 1,
of the iodo group. In order to introduce alkenyloxy groups, run 4). Arjona et al.[14a] and Tadano et al.[14b] also observed
sodium hydride was used at –40 °C to give 4a and 4b with this low selectivity in a closely related domino metathesis
yields of 73 and 49%, respectively. As an alternative ap- reaction. Thus, a directing effect of the amide carbonyl
proach, Cs2CO3 was used at 50 °C for the preparation of group (indicated by the arrow on 3) should reasonably ac-
2-nitrobenzenesulfonamides (Ns-amides) 4c (100%) and 4d count for these selectivities. Interestingly, only a very small
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Regioselective Domino Metathesis of 7-Oxanorbornenes
amount of the cis isomer was detected at the acetoxyalkenyl Table 1. Results for the domino metathesis reaction of 7-oxanor-
bornenes 3–6.[a]
moiety in the presence of the exocyclic carbonyl group. The
CM reaction is now speculated to be kinetically controlled,
and the selectivity in runs 1 and 3 indicates that the forma-
tion of a trans-metallacyclobutane intermediate is favoured,
because of the steric bulkiness of the upper exocyclic amide
group, whereas this is not the case for runs 2 and 4, where
the sterically demanding group is absent. This is also sup-
ported by semiempirical molecular orbital calculations
(PM3) for a model compound (see Supporting Infor-
mation). The same result was also obtained with Ns-amide
4c, which selectively produced 9c in 97% yield (Table 1,
run 6).
Seven-membered heterocycles were generated in runs 5,
7, and 8 (Table 1), suggesting that the course of the metath-
esis (ROM/CM) reactions had occurred, although the reac-
tions were slow and did not reach completion even after
heating at 69 °C. In fact, the intermediary ROM/CM bicy-
clic product with a 5/5 ring system was isolated as the sole
product by the first metathesis reaction of 4b (Table 1,
run 5; see the Supporting Information), suggesting again
that the directing effect of the upper exocyclic amide car-
bonyl group occurred in the ROM. In these runs, desired
seven-membered heterocycles 9b, 9d and 9e were eventually
obtained cleanly after a second metathesis reaction, which
was performed on the purified bicyclic product in the ab-
sence of vinyl acetate (see the Supporting Information).
These observations indicated that this metathesis sequence
takes place in the order of regioselective ROM, CM and
RCM.[15] Nitrogen protecting groups were found to have no
significant effect on these metathesis reactions (Table 1,
run 7 vs. run 8).
Our experiment thus demonstrated that a neighbouring
amide carbonyl group can direct regiochemistry in
the ROM reaction of norbornenes (Scheme 3,
DǞEǞF).[2b,2c,3a,16] This is a unique example of a directing
effect of the carbonyl group in olefin metathesis, because
stable chelation of the oxygen atom usually causes a drastic
loss of reactivity in the metal centre.[5,7] It is likely, however,
that the sterically hindered cis-fused pyrrolidone ring sys-
tem hampers the formation of a “too stable” chelate with
the amide oxygen atom when metallacyclobutane E is
formed, allowing the successive CM and RCM reactions to
proceed smoothly, leading to tricycles 9a–e by way of triene
G. Some of the intermediates were optimized at PM3 to
rationalize the reaction course (see the Supporting Infor-
mation). It should also be noted here that although we cur-
rently believe that the associating mechanism shown in Fig-
ure 1 and Scheme 3 is the most plausible from a series of
our studies,[4] a Fischer carbene mechanism[17] cannot be
completely ruled out with the present data. In the latter
case, steric interaction of the large ruthenium Fischer car-
bene complex would determine the regioselectivity. A more
detailed discussion will be described in a full account of this
work.
The metathesis products were further converted into glu-
tamate analogues by functional group transformation reac-
tions as follows. For seven-membered nitrogen heterocycles,
[a] PMB = 4-methoxybenzyl. [b] An arrow pointing to 3 indicates
the proposed coordinating site to the Ru metal centre. [c] Dia-
stereomeric ratio for 10 was determined by LC–MS analysis.
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M. Oikawa et al.
SHORT COMMUNICATION
a moderate yield of the ester aldehyde (13a–c, 13e;
Scheme 4). The aldehyde functionality was further trans-
formed into a methyl ester in two steps, and the p-meth-
oxybenzyl (PMB) group was removed by ceric ammonium
nitrate (CAN) at –10 °C to obtain 14a–c and 14e. For the
deoxygenation of the pyrrolidone carbonyl group, several
methods were attempted, including reduction with borane
or silyl hydride. We eventually found that the reduction of
the imidate with NaBH3CN, derived from 14a–c and 14e
by using the Meerwein reagent,[18] was the most efficient in
our case, giving the desired pyrrolidine in good yields (59–
85%). The amine functionality was temporarily protected
with a Boc group to yield 15a–c and 15e. At this stage, the
Ns group in 15c was replaced with a Boc group for the
simultaneous generation of the active functional groups
later. Finally, 15a, 15b, 15e and 15f were transformed into
dihydroxylated glutamate analogues by a sequence of dia-
stereoselective dihydroxylation from the convex β-face by
OsO4, followed by acidic hydrolysis to give 16–19 in fairly
good yields. Total yields were 9.5–16.0% over 13–15 steps
starting from (Z)-3-iodoacrylic acid. We also achieved the
synthesis of another eight analogues, which exhibit struc-
tural diversity in the lowest third ring as shown in
Scheme 5.
Scheme 3. Proposed reaction pathway for domino metathesis of
dienes 4a–e.
In our preliminary biological evaluations, both in vivo
and in vitro, these artificial glutamate analogues were found
to have bioactivities that contrasted those elicited by the
parent dysiherbaine or neodysiherbaine A,[19] which are po-
tent convulsants. Namely, intracranial injection of com-
pound 16 in mice induced profound hypoactivity (20 µg/
mouse, n = 3) consistent with a cataleptic state.[20] This hy-
poactivity likely arose from attenuation of central excitatory
TFA-protected 9e was employed, because of the low reac-
tivity of 9d that was often encountered in the subsequent
series of syntheses. First, the exocyclic Bn amide was treated
with Boc2O, followed by careful methanolysis of the gener-
ated Boc imide and the acetyl (Ac) group at –20 °C to give
Scheme 4. Functional groups transformation to set the glutamate moiety.
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Regioselective Domino Metathesis of 7-Oxanorbornenes
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details, spectroscopic data and calculation
data.
Acknowledgments
This research was financially supported by the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan (Priority Area
16073202). A research fellowship to M.I. from the Japan Society
for the Promotion of Science (JSPS) is gratefully acknowledged. We
thank one of the reviewers for valuable comments for the possible
involvement of a Fischer carbene mechanism in these studies.
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Scheme 5. Synthesis of eight glutamate analogues.
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In conclusion, we developed a highly regioselective dom-
ino metathesis (ROM/CM/RCM) reaction of 7-oxanor-
bornenes. The selectivity was proposed to be controlled by
association of a neighbouring amide carbonyl group to the
ruthenium metal centre. A nearly common sequence con-
sisting of 12–14 steps of reactions yielded cis-fused hetero-
cycles with a high level of efficiency (14.0–23.5% total
yields from 3). By using this pathway, we achieved the syn-
thesis of 12 unique glutamate analogues with structural re-
semblance to dysiherbaines. Preliminary biological evalu-
ation revealed unexpected neuronal inhibition and catalep-
tic mouse behavioural activity by 16. Thus, our present
work demonstrates that synthetic strategies toward skel-
etally and functionally diverse glutamate analogues may
generate bioactive compounds that modulate synaptic
transmission through distinct mechanisms. It should be
noted that small molecules that modulate the synaptic func-
tion of iGluRs are of significant biomedical interest, as glu-
tamatergic neurotransmission is essential for higher brain
functions such as memory formation, learning or neuropa-
thology of brain and nociception.[21] Further biological
evaluation and structure refinement may lead to the identi-
fication of both the pharmacophore and the molecular tar-
get(s) of these novel glutamate analogues. Our regioselective
domino metathesis approach will also play a key role in
further studies.
[8] In ref.[3b] the carbonyl groups are also reported to affect the
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[11] We recently reported a tandem ROM/RCM reaction of 6,[4c]
but the regiocontrol in the ROM/CM/RCM of 7-oxanorborn-
enes was not included in that paper. This paper is the report
that addresses the regioselective metathesis reaction of unsym-
metrical 7-oxanorbornenes controlled by an internal carbonyl
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Received: July 16, 2008
Published Online: September 22, 2008
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