Regioselective domino metathesis of unsymmetrical 7-oxanorbornenes with electron-rich vinyl acetate toward biologically active glutamate analogues

FULL PAPER

DOI: 10.1002/ejoc.200900580

Regioselective Domino Metathesis of Unsymmetrical 7-Oxanorbornenes with

Electron-Rich Vinyl Acetate toward Biologically Active Glutamate Analogues

Masato Oikawa,*^[a,b]Minoru Ikoma,^[b]Makoto Sasaki,^[b]Martin B. Gill,^[c]

Geoffrey T. Swanson,^[c]Keiko Shimamoto,^[d]and Ryuichi Sakai^[e]

Dedicated to Emeritus Professor H. Shirahama

Keywords: Domino reactions / Regioselectivity / Carbenes / Combinatorial chemistry / Glutamate analogues / Metathesis

In this article a regioselective domino metathesis reaction of

unsymmetrical 7-oxanorbornenes, readily available by a tan-

dem Ugi/Diels–Alder reaction as a key step, promoted by the

Hoveyda–Grubbs second-generation catalyst in the presence

of electron-rich vinyl acetate as a cross metathesis (CM) sub-

glutamate analogues whose structures were inspired by nat-

urally derived excitatory glutamate analogues, dysiherbaine

and neodysiherbaine. Interestingly, one of the synthetic ana-

logues (28a) induced a cataleptic state in mice. Further elec-

trophysiological studies suggest that 28a might inhibit excit-

strate is reported. The mechanism for the unusually high re- atory synaptic transmission by a yet unknown indirect path-

gioselectivity observed in the CM reaction was investigated,

and a reaction course where a Fischer-type carbene [“Ru”=

CH(OAc)] generates a steric interaction is proposed. The

metathesis products were further converted to four artificial

way.

Germany, 2009)

We recently reported that domino metathesis of 7-oxa-

norbornene 1 was cleanly converted to heterotricycle 2 in

good yield (81%) with high regioselectivity (Scheme 1).^[2]

This observation is of particular interest, because metathe-

sis of unsymmetrical norbornenes is, in general, poorly re-

gioselective, as was reported by several groups.^[4,5]However,

Rainier recently demonstrated a highly regioselective dom-

ino metathesis reaction of norbornenes bearing a p-tolyl-

sulfinyl (Ts) group as a substituent,^[6–8]suggesting that a

long-range electronic effect of a remote substituent can con-

tribute to regiochemical control in metathesis reactions of

norbornenes. In light of the regioselective metathesis reac-

tion step, we envisaged that functionalized glutamate ana-

logues could be prepared efficiently in a diversity-oriented

manner.

Introduction

Olefin metathesis plays a crucial role in modern synthetic

organic chemistry.^[1]In a rough classification, three types

of reactions have been known for olefin metathesis: cross

metathesis (CM), ring-closing metathesis (RCM), and ring-

opening metathesis (ROM). A combination of these me-

tathesis reactions (domino reaction) is frequently used as a

key reaction in multi-step syntheses of, for example, biolo-

gically active compounds. We have been studying domino

metathesis reaction of 7-oxanorbornenes, because these

compounds are readily converted into structurally complex

heterocycles that are interesting in terms of molecular diver-

sity.^[2,3]

[a] Graduate School of Nanobioscience, Yokohama City Univer-

sity,

Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan

Fax: +81-45-787-2403

E-mail: moikawa@yokohama-cu.ac.jp

[b] Graduate School of Life Sciences, Tohoku University,

Aoba-ku, Sendai 981-8555, Japan

[c] Department of Molecular Pharmacology and Biological Chem-

istry, Northwestern University Feinberg School of Medicine,

303 E. Chicago Ave., Chicago, IL 60611, USA

[d] Suntory Institute for Bioorganic Research,

Mishima-gun, Osaka 618-8503, Japan

[e] Graduate School of Fisheries Sciences, Hokkaido University,

Minato-cho, Hakodate 041-8611, Japan

Scheme 1. Our previous demonstration for regioselective domino

metathesis of 7-oxanorbornene.^[2]

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.200900580.

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As shown in Scheme 2, regioselective domino metathesis

of suitably functionalized 7-oxanorbornene A would pro-

vide heterotricycle B. After functional group transforma-

tions, several glutamate analogues C would be furnished

with some structural diversity at the lowest third ring. Be-

cause the structure of C shares some structural units similar

to marine sponge-derived excitatory amino acids dysiher-

baine^[9]and neodysiherbaine A,^[10]it was anticipated to ex-

hibit unique neuronal activities.

Scheme 3. Tandem Ugi/Diels–Alder reaction followed by introduc-

tion of heteroalkenyl groups to synthesize 7-oxanorbornenes as me-

tathesis substrates.

Introduction of heteroalkenyl groups was next explored.

After several experiments, it was found that, for alkenyloxy

groups, the use of sodium alkoxide in DMF at –40 °C was

effective, giving rise to 5a and 5b in 73 and 49% yields,

respectively. On the other hand, N-Ns-N-alkenylamino

groups (Ns = 2-nitrobenzenesulfinyl)^[16]were introduced in

combination with Cs₂CO₃at elevated temperature (50 °C)

to provide 5c and 5d in 100 and 76% yields, respectively. It

should be noted that these reactions proceed via a sequence

of elimination of hydrogen iodide followed by 1,4-conjugate

addition, as we have mentioned recently,^[3]and in all cases,

the reactions were highly stereoselective.

Scheme 2. Our strategy for the synthesis of artificial glutamate ana-

logues by a key domino metathesis reaction in the presence of vinyl

acetate.

In this paper, we report a full account^[11,12]of the synthe-

sis of biologically interesting glutamate analogues em-

ploying regioselective domino metathesis of unsymmetrical

7-oxanorbornenes as a key reaction. Because this regiose-

lectivity is essential for efficient formation of glutamate-like

functionality at earlier steps, we assessed for the origin of

the selectivity. Evidence obtained in the present work sup-

ported that the mechanism that involves a directing effect

by the amide carbonyl group is not applicable in this par-

ticular reaction, but that the Fischer carbene pathway is

likely. Our recent progress in the biological evaluation for

compound 28a is also reported.

Protecting group manipulation was further carried out

on N-butenylamino product 5d to see the effect of the

groups on the metathesis reactions. Thus, the N-Ns group

[16]

was removed by PhSH and Cs₂CO₃

followed by acyl-

ation with trifluoroacetic anhydride (TFAA) to give TFA

amide 5e in 65% yield.

Other 7-oxanorbornenes 6 and 7 (Figure 1) were also

prepared according to our previous publication,^[3]and used

for control experiments in the metathesis study.

Results

Preparation of 7-Oxanorbornenes as Metathesis Substrates

7-Oxanorbornenes 5a–5e with five heteroalkenyl groups

were prepared in 2–3 steps as shown in Scheme 3. The mo-

lecular framework was readily constructed in a single tan-

dem Ugi/Diels–Alder reaction^[13]between 4-methoxyben-

zylamine (PMB-NH₂), benzyl isocyanide (Bn-NC), (Z)-3-

iodoacrylic acid,^[3]and 2-furfural. The reaction proceeded

smoothly in MeOH at 50 °C for 4.5 h to give 4 in 68% yield

Figure 1. Two 7-oxanorbornenes without amide side chains, used

for control metathesis experiments.

1

as a sole product. The structure was determined from H

NMR spectra by analogy with those of closely related com-

pounds reported earlier by us^[14]and others.^[13,15]It should

be noted here that the use of sterically demanding iodine-

substituted acrylate in the Diels–Alder reaction had not

Domino Metathesis of 7-Oxanorbornenes

In the metathesis study of norbornenes, Rainier et al.^[7]

been reported before our demonstration in 2008,^[3]and it used Grubbs’ second-generation catalyst 3.^[17]They re-

also worked well in the present tandem reaction.

ported that the catalyst was added twice to the mixture dur-

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Biologically Active Glutamate Analogues

ing the reaction to complete the transformation, presum- Table 1. Results for the domino metathesis reaction of 7-oxanor-

bornenes 4, 5a, 5c, 6, and 7.

ably due to the catalyst’s instability. Indeed, we also encoun-

tered problem of incomplete reaction with Grubbs’ second-

generation catalyst 3 in these studies. Therefore, the Ho-

veyda–Grubbs second-generation catalyst 8^[18](0.5–10 mol-

%) was used in the present study, because the catalyst cycle

is known to be initiated rapidly and to be stable. All reac-

tions were carried out with 5 equiv. of vinyl acetate in ben-

zene at room temp. The structures of the products were de-

1

termined by H NMR, including COSY spectra.

At first, 7-oxanorbornene 4 was subjected to the reaction

(Table 1, run 1). The reaction was found to be highly re-

gioselective to give heterobicycle 9 in 87% yield (E/Z =

13:1). Interestingly, with 7-oxanorbornene 6, which lacks

the N-Bn-amide side chain, the reaction was slow (24 h)

with low yield and regioselectivity to give 10 as a mixture

of all four possible isomers (31%, Table 1, run 2).

The reaction of 7-oxanorbornene 5a bearing an allyloxy

group was next examined, and found to provide heterotricy-

cle 11a rapidly at room temp. after 4 h in 100% yield

(Table 1, run 3). The vinylic acetate moiety was also com-

pletely controlled to be in the trans configuration, as judged

1

from the H NMR spectrum [³J(H,H) = 12.0 Hz]. In con-

trast, we have recently reported that 7-oxanorbornene 7,

without the N-Bn-amide side chain, was converted to heter-

otricycles 12 and 13 in 88% (E/Z = 5:4) and 10% yields,

respectively (Table 1, run 4).^[3]The ratio of the yields

(88%:10%) provides information on the regioselectivity of

the first ROM reaction, since it is generally accepted that

no CM reaction takes place between monosubstituted ole-

fins and vinyl acetate, and we also observed no reaction

between vinyl acetate and triene intermediates 11bЈ, 11dЈ,

and 11eЈ (vide infra, Table 2). It is therefore conclusive that

the first ROM reaction would be less regioselective for the

simple 7-oxanorbornene 7 than 5a.

N-Allyl-N-Ns-amine 5c also reacted as smoothly as 5a

in the metathesis sequence to give heterotricycle 11c in an

excellent yield (97%, run 5). The geometry for the vinylic

acetate moiety was again controlled exclusively to be trans,

as in run 3.

Table 2 summarizes the results for domino metathesis re-

actions of 7-oxanorbornenes 5b, 5d, and 5e, bearing butenyl

groups, to form seven-membered heterocycles. It was soon

realized that in all cases, the metathesis sequence stopped

before RCM took place. We therefore quenched the reac-

tion and the crude material was again subjected to the me-

tathesis reaction for ring closure just with the metathesis

catalyst 8. For example, when 7-oxanorbornene 5b was

[a] Diastereomeric ratio for 10 was determined by LC-MS analysis.

treated with vinyl acetate in the presence of metathesis cata- 84% yield (2 steps) after 21 h. Since it was found that even

lyst 8 at 69 °C, triene 11bЈ was cleanly obtained in 84% crude triene could be used for the second metathesis, the

yield after 46 h (run 1). It should be noted that the reaction intermediate trienes were conveniently used without purifi-

was completed cleanly even at room temp. The structure cation for the ring closure in runs 2 and 3. Thus, hetero-

was unambiguously clarified by spectroscopic analysis, in- tricycles 11d and 11e were readily obtained in 90 and 85%

1

cluding H and ¹³C NMR, and the vinylic acetate moiety yields, respectively, without isolation of the intermediary

was found to be completely controlled to be the trans iso- trienes 11dЈ and 11eЈ. These results also indicated that an

mer. Triene 11bЈ was then subjected to the second metathe- N-Ns-amine requires higher temperature (80 °C) for cycliza-

sis reaction with the metathesis catalyst 8 at 69 °C to pro- tion as compared to a TFA amide (69 °C), while the yields

mote the ring closure, giving rise to heterotricycle 11b in are nearly comparable.^[19]

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Table 2. Results for the domino metathesis reaction of 7-oxanorbornenes 5b, 5d, and 5e.

[a] Intermediates 11dЈ and 11eЈ were not isolated, but used directly for the second metathesis.

Synthesis of Artificial Glutamate Analogues

With metathesis products 11a and 11b in hand, we next

explored a method that converted them into artificial glut-

amate analogues. Initially, transformation of the vinylic ace-

tate moiety to a methyl ester was attempted, because we

previously found that vinylic acetate 12 reacts readily with

methanolic HCl at –10 °C to give methyl acetal 14 in 83%

yield. The methyl acetal was subsequently hydrolyzed by

hydrochloric acid (1 ) to provide aldehyde 15 in 90% yield

(Scheme 4).^[3]However, with the metathesis product 11a,

neither the acidic methanolysis nor alkaline hydrolysis fur-

nished the desired aldehyde. Instead, hemiaminal 16 was

provided in 91 and 86% yields, respectively. Although oxi-

dation of 16 was found to give imide 17 in 100% yield, the

route seemed to be inconvenient in terms of overall yield.

Therefore, we decided to modify the upper N-Bn-amide

of the metathesis products 11a and 11b to transform them

into artificial glutamate analogues. Synthesis of common

intermediates 19a and 19b are summarized in Scheme 5.

Scheme 4. Failed attempt to construct the glutamate structural unit

from 11a.

First, 11a and 11b were treated with Boc₂O, DMAP, and carefully, to provide 18a and 18b in 79% yield for both

triethylamine (TEA) to form N-Boc-imides, which, in turn, compounds. After oxidation (NaClO₂, 2-methyl-2-butene,

were subjected to methanolysis at –20 °C (K₂CO₃, MeOH) NaH₂PO₄),^[20]the resulting carboxylic acids were esterified

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Biologically Active Glutamate Analogues

with TMS-CHN₂to give diesters 19a and 19b in 94 and reactions, such as the decomposition of acid-sensitive

73% yields, respectively.

groups such as the acetonide groups in 25a and 25b (vide

infra). Fortunately, BH₃·SMe₂^[22]was found to promote the

selective reduction at 40 °C to give pyrrolidines 21a and 21b

in moderate yields (53 and 43%) with satisfactory reprodu-

cibility. From 21a and 21b, glutamate analogues 23a and

23b were synthesized by stepwise protective group manipu-

lations, including conversion of the PMB groups to Boc

groups under hydrogenolytic conditions (68 and 100%),

and acidic hydrolysis for global deprotection (79 and

100%).

Dihydroxylated glutamate analogues 28a and 28b were

also synthesized from the common intermediates 19a and

19b as shown in Scheme 7. These intermediates were stereo-

selectively dihydroxylated under standard conditions

(OsO₄, NMO, tBuOH, H₂O) to give diols 24a and 24b in

excellent yields (88 and 83%) with complete stereoselecti-

vity. The diols were subsequently protected as acetonides

(2,2-dimethoxypropane, CSA, CH₂Cl₂). The structures

were confirmed by NOESY analysis as shown in Figure 2,

which showed that dihydroxylation had taken place from

the convex faces of the molecules. Application of the same

sequence of reactions as those for the transformation of

20a(20b) into 23a(23b), to acetonides 25a and 25b success-

fully furnished dihydroxylated glutamate analogues 28a and

28b in 62 and 36% yields, respectively, for 3 steps each.

Scheme 5. Synthesis of common intermediates 19a and 19b.

From the common intermediates 19a and 19b, two artifi-

cial glutamate analogues 23a and 23b, wherein the olefinic

double bonds are hydrogenated, were synthesized as shown

in Scheme 6. The hydrogenation was performed by using

10% Pd/C as a catalyst under hydrogen atmosphere, giving

rise to 20a and 20b in 96 and 100% yields, respectively. Se-

lective reduction of the pyrrolidone was next attempted. It

was first found that a two-step transformation via a thio-

amide (Lawesson’s reagent,^[21]toluene, 80 °C; NaBH₄,

NiCl₂·6H₂O, THF, MeOH) successfully gave 21a from 20a

in 50% overall yield. However, this transformation was po-

orly reproducible and often accompanied by undesired side

Scheme 6. Synthesis of two glutamate analogues, 23a and 23b, with

saturated ether rings.

Scheme 7. Synthesis of two glutamate analogues, 28a and 28b, with

dihydroxylated ether rings.

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onic acid (AMPA), kainate (KA), or N-methyl--aspartate

(NMDA) receptors, subtypes of ionotropic GluRs, even at

1ϫ10^–5.

The biological activity of the dihydroxylated pyran ana-

logue 28a was next evaluated by current- and voltage-clamp

electrophysiological analyses from cultured hippocampal

neurons. Consistent with the hypoactivity observed in be-

havioral experiments, 28a markedly reduced excitatory neu-

rotransmission in these highly active neuronal cultures.

Voltage-clamp recordings of spontaneous bursts of excit-

atory synaptic currents revealed that the mean charge trans-

fer mediated by activation of pharmacologically isolated

AMPA/kainate-type ionotropic glutamate receptors de-

clined by 43.5Ϯ10.5% (n = 3, p Ͻ 0.05 in a Student’s paired

t-test) in the presence of 28a (20ϫ10^–6). Similarly, spon-

taneous action potential firing was reduced by 39.2Ϯ11.6%

(n = 3, p Ͻ 0.05 in a Student’s paired t-test) in highly active

neurons. These data demonstrate that 28a reduces neuronal

excitability in the CNS, presumably through an indirect ac-

tion on glutamatergic neurotransmission, which likely ac-

counts for the depressive neuroactivity in the mouse bioas-

say. The precise mechanism(s) of action of 28a and other

analogues are the subject of active investigation.

Figure 2. Key NOEs for stereochemical confirmation of com-

pounds 25a and 25b. Plain and dashed arrows indicate NOEs ob-

served at the β-side and the α-side of the molecules, respectively.

PMB and two methyl esters are omitted for clarity.

Discussion

Evaluation of Biological Activities

Mechanism for the Regioselective Domino Metathesis

The biological activities of the artificial glutamate ana-

In this paper, we report the domino metathesis of unsym-

logues 23a, 23b, 28a, and 28b, synthesized in the present metrical 7-oxanorbornenes with electron-rich vinyl acetate

study, were evaluated in vivo using a mouse behavioral as- as a CM substrate. Although electron-rich olefins are gen-

say, and in vitro by radioligand binding assays and by elec- erally a poor substrate for CM reactions, the domino me-

trophysiological analyses.

tathesis reaction of 7-oxanorbornenes proceeded smoothly

Biological evaluation of four artificial glutamate ana- by virtue of the structural strain of the skeleton. It is also

logues was first performed in mice behavioral assays,^[23]be- noteworthy that the regioselectivity was highly controlled,

cause ligands for glutamate receptors (GluR) generally in- affording glutamic acid analogs (Tables 1 and 2). In the

duce dose-dependent behavioral toxicity.^[24]An intracranial present study, we used the Hoveyda–Grubbs second-genera-

injection of each compound (0.02 mg/mouse) induced a tion catalyst 8,^[18,25]which is also of significance, since most

variety of behavioral changes that could be categorized into of the previous metathesis reactions with electron-rich ole-

hyper- and hypoactive groups. The hyperactive group dis- fins were studied with Grubbs’ second-generation cata-

played stereotyped behavior such as scratching or hypersen- lyst.^[6,7,26,27]

sitivity, while the hypoactive animals were in depression

For these regioselective metathesis reactions, either or

(loss of mobility) and some rigidity in the limbs was ob- both of two mechanisms could be operative. The first

served. Although the relationship between structure and ac- mechanism is an association mechanism, and the second

tivity type was not definitive, the saturated pyran 23a was one is a Fischer-type carbene mechanism. In the association

weakly hyperactive, while dihydroxylated pyran 28a induced mechanism, the reaction is guided by the interaction of the

hypoactivity. Oxepanes 23b and 28b induced hyperactivity ruthenium metal center and an electron-donating group

and caused a loss of balance, sudden running and jumping. such as hydroxy or carbonyl groups involved in the metath-

It is noteworthy that in all cases, the mice recovered fully esis substrate. Well-known examples are Cossy’s synthetic

and were apparently normal by several hours after treat- study on amphidinol 3,^[28]and Fürstner’s macrocycle syn-

ment. These in vivo activities, especially depression caused thesis.^[29]In connection with these studies, we initially

by 28a, are unique and are not observed with parental dy- thought that the association mechanism was primarily op-

siherbaines, which are potent convulsants.

erative also in our case,^[11]since the N-benzylamide car-

The glutamate analogues 23a, 23b, 28a, and 28b were bonyl group was conveniently located at a position spatially

further characterized in radioligand binding assays using close to the 7-oxanorbornene olefin in cases where the reac-

rat synaptic membranes.^[24]It was found out, however, that tions were regioselective (Table 1 and Table 2). We thus

none of these compounds replaced the radioactive ligands tested the former mechanism by an experiment shown in

for (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propi- Scheme 8. If the association mechanism were operable here,

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Biologically Active Glutamate Analogues

the regioselectivity would rely on the type of catalyst-sub- electron-rich olefins were successfully performed by Rainier

strate interaction but not type of the olefin added. When 7- et al.^[6,7]Because precatalyst formation was reported to be

oxanorbornene 3 was treated with but-3-enyl bromide essential for those reactions, it is plausible that a Fischer-

(5 equiv.) in the presence of metathesis catalyst 8 (5 mol-%), type carbene mechanism was operative in their reactions.

however, three products 29a–29c were found to be gener-

We therefore attempted to detect a Fischer-type carbene

1

ated (Scheme 8). The reaction proceeded quite smoothly complex by H NMR spectroscopy. It has been reported

and was completed in 3 h. This result was in clear contrast that some Fischer-type carbene complexes are readily gen-

to the regioselective reaction with vinyl acetate (Table 1, run erated upon simply mixing in appropriate solvents. For ex-

1). It is generally accepted that domino metathesis of nor- ample, Grubbs et al. reported that they detected the Fi-

bornenes starts with a ring-opening reaction with the me- scher-type carbene that formed from (PPh₃)₂(TFA)₂Ru=

tathesis catalyst (ROM),^[5,30,31]by which regioselectivity is CH–CH=CPh₂and vinyl acetate before it rapidly decom-

determined. If the reaction shares common or even similar posed.^[32]Similarly, in the present study; when metathesis

intermediates at the earlier stage, then the comparable re- catalyst 8 and vinyl acetate (10 equiv.) were mixed at room

gioselectivity is expected. In our case, shown in Table 1 (run temp. in C₆D₆, the carbene proton of 8 at 16.7 ppm disap-

1) and Scheme 8, however, the regioselectivity outcomes are peared in 1 min, and a new peak assignable to the Fischer

far different, and we hence concluded that, 1) these two carbene complex [“Ru”=CH(OAc)] was observed instead at

reactions do not share a common mechanism, but proceed 11.9 ppm, which was also observed in the Grubbs study.^[32]

via different mechanisms; and 2) the association mechanism The Fischer-type carbene complex was not stable, and de-

1

is not primarily operative in these metathesis reactions.

composed after 12 h as judged from H NMR spectra.

Since the Fischer-type carbene formation was much

faster than the domino metathesis shown in Tables 1 and 2,

we now believe a Fischer-type carbene was present during

propagation phase.

The domino metathesis reaction of a 7-oxanorbornene

substrate bearing a Bn group substituent instead of N-Bn-

amide side chain at the C8-position was examined next to

study whether association is involved in the domino metath-

esis reaction promoted by the Fischer-type carbene catalyst

[“Ru”=CH(OAc)]. The substrate 32 was synthesized in 3

steps as shown in Scheme 9. A three-component coupling

reaction between benzyl bromide, 2-furfural, and 4-meth-

oxyaniline in the presence of zinc dust in THF, gave amine

30 in 78% yield.^[38]Acylation with (Z)-3-iodoacryl chlo-

ride^[3]in the presence of Cs₂CO₃provided 31 (45%), which

was further heated (100 °C) to promote an intramolecular

Diels–Alder reaction to furnish 32 in 28% yield, ac-

companied by isomeric 8-epi-32 in 51% yield. The struc-

tures were determined by NOESY analysis as indicated.

Results for the metathesis reaction of 32 in the presence

Scheme 8. A control domino metathesis reaction of 4 in the pres-

ence of but-3-enyl bromide as a CM substrate.

We next turned our attention to the Fischer-type carbene of vinyl acetate are shown in Table 3. Under the same con-

mechanism. Fischer-type carbenes are complexes contain- ditions as for 4–7 (see Tables 1 and 2), the reaction pro-

ing an electron-donating group on the carbene carbon. ceeded quite smoothly in 3 h to give heterobicycles (E)-33

They are thermodynamically stable and hence poorly reac- and (Z)-33 in 26 and 33% isolated yields, respectively (run

tive.^[32,33]They are also generated when ROMP (ring-open- 1). NMR analyses (¹H NMR and COSY) indicated that the

ing metathesis polymerization) reactions are terminated by regioselectivity was identical with that for reactions of 4

electron-rich olefins such as ethyl vinyl ether.^[34]In contrast and 5 (see Tables 1 and 2). Neither regioisomer correspond-

to these common examples, remarkable catalytic activities ing to 29a nor divinyl product corresponding to 29c was

of Fischer-type carbenes have often been reported. For ex- detected. Instead, ROMP product 34 was found to be gen-

ample, Grubbs et al. reported that some Fischer-type carb- erated. Although 34 was obtained as a complex mixture,

enes initiate ROMP of strained cyclic olefins and RCM of dimer 35 (Figure 3) was successfully isolated and charac-

diethyl diallylmalonate.^[26]Fischer-type carbenes can be in- terized as, 1) a mixture of two olefin geometrical isomers,

volved also in enyne ring-closing metathesis (RCM)^[35]and and 2) monoacetates that were introduced regioselectively.

intermolecular reaction (CM).^[36]Ozawa et al. reported that We then carried out the reaction under diluted conditions

Fischer-type selenocarbene complexes smoothly reacts with (3.8 m, run 2). As expected, formation of the undesired

norbornene at room temp. to provide monomeric ring- ROMP product 34 was completely suppressed in run 2, and

opening cross metathesis (ROCM) products without forma- heterobicycle 33 was formed in 60% yield (E/Z = 50:50),

tion of ROMP products.^[37]More recently, highly regioselec- accompanied by unreacted 7-oxanobornene 32 (28% yield).

tive ROCM reactions of unsymmetrical norbornenes with The high level of regioselectivity observed in the reaction

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M. Oikawa et al.

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Figure 3. A dimer, 35, isolated as one of the ROMP products in

the domino metathesis of 32 (Table 3, run 1).

ents in the catalyst and substrate, but not by association

between 7-oxanorbornene substrates and the active carbene

species.^[39,40]

Novelty in Biological Properties of Artificial Glutamate

Analogues

Scheme 9. Preparation of 7-oxanorbornene 32 for control experi-

ments. Arrows on 32 and 8-epi-32 indicate key NOEs for stereo-

chemical assignments.

Starting from the domino metathesis products 11a and

11b, we successfully synthesized four artificial glutamate an-

alogues in 8 steps (for 23a and 23b) and in 9 steps (for

28a and 28b) via advanced intermediates 19a and 19b. Total

yields were 10.1% (for 23a), 6.9% (for 23b), 18.5% (for

28a), and 4.7% (for 28b). The key reaction is the chemose-

lective reduction of pyrrolidines by BH₃·SMe₂into pyrrol-

idones. Although the reaction proceeded only in moderate

yields (40–62%), it was satisfactorily reproducible for all

compounds.

with the substrate lacking the N-Bn-amide side chain could

be provided by steric interaction between 7-oxanorbornene

32 and the Fischer-type carbene catalyst [“Ru”=CH(OAc)].

The incomplete reaction in run 2 is probably due to decom-

position of the metathesis catalyst 8 or the Fischer-type car-

bene, as observed in our NMR study (vide supra).

Table 3. Domino metathesis of 7-oxanorbornene 32 bearing a Bn

substituent instead of an N-Bn-amide side chain at C8.

Biological evaluation of the artificial glutamate ana-

logues, 23a, 23b, 28a, and 28b, by intracranial injection in

mice revealed that the dihydroxylated pyran 28a was hy-

poactive, whereas other three analogues were hyperactive.

The structures for the four analogues were inspired by dy-

siherbaine^[9]and neodysiherbaine A,^[10]which are naturally

derived, excitatory amino acids, and the antagonist ana-

logue MSVIII-19^[41](Figure 4). The discovery of hypoactive

28a is particularly noteworthy, since dysiherbaines are le-

thally convulsant.

[a] 0.01 equiv. of metathesis catalyst 8 was used. [b] 0.03 equiv. of

metathesis catalyst 8 was used. [c] We assumed that the average

MW was 559.4 (same as 33).

Taken together, the above experimental results support

that, 1) the mechanism based on Fischer-type carbene

[“Ru”=CH(OAc)] is probably operative in our regioselective

domino metathesis of 7-oxanorbornenes (designated as “A”

Figure 4. Dysiherbaine congeners^[9,10]and the antagonistic ana-

logue MSVIII-19.^[41]

Although the electrophysiological assays suggested that

in Scheme 2), and 2) the [2+2] cycloaddition may be con- 28a inhibited the primary mediators of excitatory neuro-

trolled by some steric interactions between bulky substitu- transmitter currents, AMPA receptors, our radioligand

5538

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Eur. J. Org. Chem. 2009, 5531–5548

Biologically Active Glutamate Analogues

binding assays did not find evidence for direct binding of

28a to any subtype of ionotropic glutamate receptor

(AMPA, kainate or NMDA receptors). Therefore, it is pos-

sible that 28a reduces spontaneous glutamatergic synaptic

currents and action potential initiation through actions on

other receptors or channels that dampen neuronal excitabil-

ity. Alternatively, 28a might bind to AMPA receptors with

a very weak affinity that went undetected in the binding

assays. Interestingly, our research group previously found

that one of the dysiherbaine analogues MSVIII-19 (Fig-

ure 4) caused mice to fall into a coma-like sleep upon intra-

cranial injection; physiological studies have indicated that it

binds to GluR5 kainate receptors and acts as a functional

antagonist.^[41,42]It also reduced currents mediated by re-

combinant AMPA receptors (GluR1, 2 or 4) and excitatory

postsynaptic currents (EPSCs) in mouse brain slices.^[41,42]

Generally, small molecules that modulate the synaptic func-

tion of ionotropic GluRs are of significant biomedical

interest, because glutamatergic neurotransmission is essen-

tial for both basic operation of the CNS as well as higher

brain functions such as memory formation, learning, or

neuropathology of brain and nociception.^[43]Starting from

28a, further structural refinement and biological evaluation

will be necessary to determine the precise mode of bio-

logical action of these novel glutamate analogues.

Experimental Section

7-Oxanorbornene 4 (Tandem Ugi/Diels–Alder Reaction): To a

stirred solution of furfural (0.500 mL, 5.31 mmol) in methanol

(25 mL) at room temp. were added 4-methoxybenzylamine

(0.459 mL, 3.54 mmol), (Z)-iodoacrylic acid (750 mg, 3.54 mmol),

and benzyl isocyanide (0.647 mL, 5.31 mmol). After stirring at

50 °C for 4.5 h, the mixture was concentrated under reduced pres-

sure and the residue was diluted with chloroform (200 mL). The

solution was washed with saturated aqueous NaHCO₃(100 mL),

saturated aqueous NH₄Cl (100 mL), and brine (100 mL), dried

with Na₂SO₄, and concentrated under reduced pressure. The resi-

due was purified by column chromatography on silica gel (20 g,

hexane/EtOAc = 6:4) to give 7-oxanorbornene 4 (1.29 g, 68%) as

a white solid. IR (film): ν = 2921, 1684, 1512, 1384, 1247, 1029,

˜

701 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.36–7.30 (m, 3 H),

7.22 (d, J = 7.0 Hz, 2 H), 7.09 (d, J = 8.0 Hz, 2 H), 6.81 (d, J =

8.0 Hz, 2 H), 6.35 (d, J = 6.0 Hz, 1 H), 5.96 (br. s, 1 H), 5.25 (d, J

= 1.5 Hz, 1 H), 5.04 (d, J = 15.5 Hz, 1 H), 5.96 (br. s, 1 H), 5.25

(d, J = 1.5 Hz, 1 H), 5.04 (d, J = 15.5 Hz, 1 H), 4.45 (dd, J = 14.5,

5.5 Hz, 1 H), 4.36 (dd, J = 14.5, 5.5 Hz, 1 H), 3.94 (s, 1 H), 3.89

(d, J = 15.5 Hz, 1 H), 3.86 (d, J = 15.5 Hz, 1 H), 3.76 (s, 3 H),

2.62 (d, J = 7.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ =

170.9, 166.8, 159.3, 137.3, 135.2, 135.0, 129.4, 128.9, 128.0, 128.0,

126.8, 114.3, 92.0, 88.8, 61.6, 55.3, 49.2, 45.4, 43.9, 18.2 ppm.

HRMS (ESI, positive): calcd. for C₂₄H₂₄IN₂O₄[M + H]⁺531.0775;

found 531.0782.

7-Oxanorbornene Allyl Ether 5a: To a stirred solution of allyl

alcohol (7.80 mL, 11.3 mmol) in DMF (22 mL) at room temp. was

added NaH (60% in mineral oil, 452 mg, 11.3 mmol). After 30 min,

a solution of iodide 4 (1.011 g, 1.89 mmol) in DMF (44 mL) was

added via a cannula, and the mixture was stirred at –40 °C for

1.5 h. The mixture was poured into saturated aqueous NH₄Cl

(100 mL) and extracted with EtOAc (100 mL). The extract was

washed with water (3ϫ30 mL) and brine (50 mL), dried with

Conclusions

In summary, this paper describes our demonstration of

regioselective domino metathesis of unsymmetrical 7-oxa-

norbornenes in the presence of electron-rich vinyl acetate

as a CM substrate. In this study, it was concluded that the Na₂SO₄, and concentrated under reduced pressure. The residue was

purified by column chromatography on silica gel (20 g, hexane/

reaction was driven by a Fischer-type carbene [“Ru”=

CH(OAc)], and the regioselectivity was controlled by steric

interactions, but not by association. The metathesis prod-

ucts were further transformed into four biologically active,

artificial glutamate analogues, one of which (compound

28a) exhibited a novel hypoactivity on mice. It is thus pro-

posed that natural-product-inspired diversity-oriented syn-

thesis is a useful approach to develop novel biologically

active compounds that modulate synaptic transmission

through diverse mechanisms.

Unfortunately, the synthetic pathway shown in

Schemes 6 and 7 was not applied to a synthesis of glut-

amate analogues from metathesis products 11c, 11d, and

11e, which contain a nitrogen functionality at the lowest

EtOAc = 7:3) to give allyl ether 5a (633 mg, 73%) as a yellow solid.

IR (film): ν = 3298, 2921, 1669, 1513, 1247, 1055, 701 cm^–1. ¹H

˜

NMR (500 MHz, CDCl₃): δ = 7.35–7.28 (m, 3 H), 7.18 (d, J =

6.5 Hz, 2 H), 7.06 (d, J = 8.5 Hz, 2 H), 6.39 (s, 2 H), 6.03 (br. t, J

= 5.0 Hz, 1 H), 5.87 (m, 1 H), 5.30 (dd, J = 17.5, 1.5 Hz, 1 H),

5.19 (d, J = 10.0 Hz, 1 H), 4.98 (d, J = 4.0 Hz, 1 H), 4.80 (d, J =

15.0 Hz, 1 H), 4.40 (dd, J = 14.8, 6.0 Hz, 1 H), 4.33 (s, 1 H), 4.32

(dd, J = 14.8, 6.0 Hz, 1 H), 4.10 (dd, J = 12.8, 5.0 Hz, 1 H), 4.03

(d, J = 14.5 Hz, 1 H), 4.02 (dd, J = 12.8, 5.0 Hz, 1 H), 3.97 (s, 1

H), 3.75 (s, 3 H), 2.45 (d, J = 2.0 Hz) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 173.4, 166.8, 159.1, 137.5, 134.6, 133.7, 133.5, 129.3,

128.7, 127.8, 127.7, 126.9, 117.6, 91.7, 79.4, 78.5, 71.3, 63.4, 55.1,

54.3, 45.3, 43.7 ppm. HRMS (ESI, positive): calcd. for C₂₇H₂₉N₂O₅

[M + H]⁺461.2074; found 461.2071.

third ring. These reactions were inefficient in terms of syn- 7-Oxanorbornene Butenyl Ether 5b: With the same procedure as for

the synthesis of 5a, 5b (407 mg, 49%) was obtained as a yellow

solid starting from (900 mg, 1.75 mmol), NaH (430 mg,

thetic steps and yields. The diminished reactivities, probably

due to a presence of an N-protecting group which might

sterically shield the heterotricycle skeleton, was also an ob-

stacle. Instead, we have recently developed an improved

synthetic pathway to twelve glutamate analogues including

piperidine and azepane rings as the lowest third ring.^[11]Ef-

forts are in progress in our laboratories to develop artificial

glutamate analogues with improved biological functions.

Our highly regiocontrolled domino metathesis reaction will

play a key role in the further studies.

4

10.4 mmol), and 3-buten-1-ol (903 mL, 10.41 mmol). IR (film): ν

˜

= 3074, 2912, 1667, 1513, 1247, 1031, 820, 713 cm^–1. ¹H NMR

(500 MHz, CDCl₃): δ = 7.35–7.27 (m, 3 H), 7.18 (d, J = 10.0 Hz,

2 H), 7.06 (d, J = 9.0 Hz, 2 H), 6.78 (d, J = 9.0 Hz, 2 H), 6.37 (dd,

J = 8.5, 6.5 Hz, 2 H), 6.11 (br. t, J = 5.5 Hz, 1 H), 5.74 (m, 1 H),

5.05 (dd, J = 17.0, 2.0 Hz, 1 H), 5.00 (d, J = 10.5 Hz, 1 H), 4.96

(dd, J = 4.5, 1.5 Hz, 1 H), 4.80 (d, J = 15.0 Hz, 1 H), 4.39 (dd, J

= 14.1, 6.0 Hz, 1 H), 4.33 (dd, J = 14.1, 6.0 Hz, 1 H), 4.27 (dd, J

= 4.5, 2.0 Hz, 1 H), 4.02 (d, J = 15.0 Hz, 1 H), 3.97 (s, 1 H), 3.74

Eur. J. Org. Chem. 2009, 5531–5548

www.eurjoc.org

5539

M. Oikawa et al.

FULL PAPER

(s, 3 H), 3.60–3.53 (m, 2 H), 2.42 (d, J = 2.0 Hz, 1 H), 2.29 (dd, J (10 mL) at 0 °C were added TEA (0.138 mL, 0.992 mmol) and

= 7.0, 6.8 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 173.5, TFAA (0.138 mL, 0.992 mmol). After stirring at room temp. for

166.8, 159.2, 137.5 (ϫ2), 134.6, 133.5, 129.4, 128.7, 127.9, 127.8,

127.0, 116.6, 114.1, 91.7, 79.5, 79.0, 69.9, 63.5, 55.2, 54.2, 45.4,

43.7, 33.9 ppm. HRMS (ESI, positive): calcd. for C₂₈H₃₁N₂O₅[M

+ H]⁺475.2223; found 475.2215.

30 min, the mixture was then poured into saturated aqueous

NaHCO₃(50 mL) and extracted with EtOAc (2ϫ100 mL). The

combined extracts were washed with brine (30 mL), dried with

Na₂SO₄, and concentrated under reduced pressure. The residue was

purified by column chromatography on silica gel (8 g, hexane/

EtOAc = 3:1) to give TFA amide 5e (379.6 mg, 74%) as a pale

7-Oxanorbornene N-Allyl-N-Ns-Amide 5c: To a stirred solution of

iodide 4 (201.1 mg, 0.38 mmol) in DMF (5.0 mL) at room temp.

yellow oil. IR (film): ν = 2934, 1697, 1540, 1513, 1417, 1246, 1204,

˜

were

added

N-allyl-2-nitrobenzenesulfonamide

(138 mg,

1

1146, 700 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.35–7.29 (m, 3

0.57 mmol) and Cs₂CO₃(1.14 mmol). After stirring at 50 °C for

10 h, the mixture was cooled to room temp., poured into saturated

aqueous NH₄Cl (20 mL), and extracted with EtOAc (50 mL). The

extract was washed with water (3ϫ10 mL) and brine (30 mL),

dried with Na₂SO₄, and concentrated under reduced pressure. The

residue was purified by column chromatography on silica gel (4 g,

hexane/EtOAc = 5:5) to give Ns-amide 5c (244.5 mg, 100%) as a

H), 7.20 (d, J = 7.5 Hz, 2 H), 7.05 (d, J = 8.5 Hz, 2 H), 6.79 (d, J

= 8.5 Hz, 2 H), 6.34 (d, J = 5.5 Hz, 1 H), 6.21 (d, J = 6.0 Hz, 1

H), 6.11 (br. t, J = 5.0 Hz, 1 H), 5.68 (m, 1 H), 5.68 (s, 1 H), 5.16

(d, J = 17.0 Hz, 1 H), 5.08 (d, J = 10.5 Hz, 1 H), 4.88 (d, J =

14.5 Hz, 1 H), 4.43–4.34 (m, 3 H), 3.97 (d, J = 17.0 Hz, 1 H), 3.95

(s, 1 H), 3.74 (s, 3 H), 3.60 (m, 1 H), 3.15 (m, 1 H), 2.88 (d, J =

3.5 Hz, 1 H), 2.65 (m, 1 H), 2.35 (m, 1 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 172.4, 166.9, 159.3, 157.7, 137.1, 135.3,

134.2, 132.8, 129.5, 128.8, 128.0, 127.8, 126.6, 118.3, 117.3, 114.2,

90.8, 80.7, 62.6, 58.9, 55.2, 51.7, 46.7, 45.4, 43.8, 32.6 ppm. HRMS

(ESI, positive): calcd. for C₃₀H₃₁N₃O₅[M + H]⁺570.2210; found

570.2198.

yellow solid. IR (film): ν = 3087, 2933, 1695, 1541, 1513, 1359,

˜

1

1247, 1173, 1031, 737, 589 cm^–1. H NMR (500 MHz, CDCl₃): δ =

8.15 (dd, J = 7.3, 2.0 Hz, 1 H), 7.76–7.70 (m, 2 H), 7.64 (dd, J =

7.3, 2.0 Hz, 1 H), 7.35–7.29 (m, 3 H), 7.19 (d, J = 7.0 Hz, 1 H),

7.03 (d, J = 9.0 Hz, 2 H), 6.79 (d, J = 9.0 Hz, 2 H), 6.50 (dd, J =

6.0, 1.5 Hz, 1 H), 6.35 (d, J = 6.0 Hz, 1 H), 5.98 (br. t, J = 5.5 Hz,

1 H), 5.68 (m, 1 H), 5.18 (d, J = 11.5 Hz, 1 H), 5.16 (s, 1 H), 5.07

Heterobicycle 9: To a stirred solution of 4 (200 mg, 0.38 mmol) in

(d, J = 11.5 Hz, 1 H), 4.83 (d, J = 15.0 Hz, 1 H), 4.46 (t, J = benzene (5.0 mL) at room temp. were added vinyl acetate

3.5 Hz, 1 H), 4.43 (dd, J = 15.0, 6.5 Hz, 1 H), 4.31 (dd, J = 15.0,

6.5 Hz, 1 H), 3.94 (d, J = 15.0 Hz, 1 H), 3.92 (s, 1 H), 3.88 (br. s,

(0.173 mL, 1.87 mmol) and catalyst 8 (2.3 mg, 0.0038 mmol) under

argon atmosphere. After 14 h, the mixture was concentrated under

2 H), 3.75 (s, 3 H), 2.93 (d, J = 3.5 Hz, 1 H) ppm. ¹³C NMR reduced pressure. The residue was purified by column chromatog-

(125 MHz, CDCl₃): δ = 172.7, 166.7, 159.3, 138.5, 137.2, 135.7, raphy on silica gel (4 g, hexane/EtOAc = 7:3) to give heterobicycle

134.0, 133.9, 133.5, 132.1, 132.0, 130.8, 129.5, 128.9, 128.0, 127.8,

126.6, 124.3, 117.9, 114.2, 91.2, 81.9, 62.9, 59.8, 55.2, 50.4, 49.8,

45.4, 43.8 ppm. HRMS (ESI, positive): calcd. for C₃₃H₃₃N₄O₈[M

+ H]⁺645.2014; found 645.2018.

9 (205.7 mg, 87%, E/Z = 13:1) as a colorless oil. IR (film): ν =

˜

3042, 1759, 1683, 1557, 1540, 1513, 1212, 1028, 699 cm^–1. ¹H NMR

(500 MHz, CDCl₃): δ = 7.42 (d, J = 12.0 Hz, 1 H), 7.33–7.28 (m,

3 H), 7.20 (d, J = 7.5 Hz, 2 H), 7.02 (d, J = 8.5 Hz, 2 H), 6.78 (d,

J = 8.5 Hz, 2 H), 5.78–5.71 (m, 2 H), 5.43 (d, J = 12.0 Hz, 1 H),

5.42 (d, J = 14.5 Hz, 1 H), 5.36 (d, J = 10.0 Hz, 1 H), 5.05 (d, J =

14.5 Hz, 1 H), 4.41 (dd, J = 10.5, 7.0 Hz, 1 H), 4.34 (dd, J = 14.8,

6.0 Hz, 1 H), 4.29 (dd, J = 10.1, 7.0 Hz, 1 H), 3.92 (dd, J = 10.1,

7.0 Hz, 1 H), 3.78 (d, J = 14.5 Hz, 1 H), 3.76 (s, 3 H), 3.52 (s, 1

H), 3.09 (d, J = 7.0 Hz, 1 H), 2.10 (s, 3 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 169.8, 167.5, 167.3, 159.2, 139.3, 137.3,

133.0, 129.7, 128.7, 128.0, 127.7, 127.0, 121.1, 114.1, 112.6, 87.2,

84.7, 69.9, 55.2, 53.6, 45.3, 43.7, 20.6, 20.0 ppm. HRMS (ESI, posi-

tive): calcd. for C₂₈H₃₀N₂O₆I [M + H]⁺617.1143; found 617.1151.

7-Oxanorbornene N-Butenyl-N-Ns-Amide 5d: With the same pro-

cedure as for the synthesis of 5c, 5d (1.04 g, 85%) was obtained as

a yellow solid starting from 4 (1.00 g, 1.87 mmol), Cs₂CO₃(1.22 g,

3.74 mmol),

and

N-(3-butenyl)

2-nitrobenzenesulfonamide

(719 mg, 2.81 mmol). IR (film): ν = 3088, 2933, 1695, 1542, 1512,

˜

1355, 1246, 1173, 1032, 681, 589 cm^–1. ¹H NMR (500 MHz,

CDCl₃): δ = 8.17 (d, J = 8.0 Hz, 1 H), 7.77–7.65 (m, 3 H), 7.36–

7.30 (m, 3 H), 7.21 (d, J = 7.0 Hz, 2 H), 7.03 (d, J = 8.5 Hz, 2 H),

6.79 (d, J = 8.5 Hz, 2 H), 6.47 (d, J = 6.0 Hz, 1 H), 6.37 (d, J =

6.0 Hz, 1 H), 6.03 (br. s, 1 H), 5.61 (m, 1 H), 5.21 (d, J = 4.0 Hz,

1 H), 5.01 (d, J = 5.5 Hz, 1 H), 4.99 (s, 1 H), 4.86 (d, J = 15.0 Hz,

1 H), 4.43 (dd, J = 14.5, 5.5 Hz, 1 H), 4.36 (dd, J = 14.5, 5.5 Hz,

1 H), 3.95 (d, J = 15.0 Hz, 1 H), 3.93 (s, 1 H), 3.75 (s, 3 H), 3.21

Heterobicycle 10: To a stirred solution of 7-oxanorbornene 6

(50.0 mg, 0.122 mmol) in benzene (3.0 mL) at room temp. were

added vinyl acetate (0.0567 mL, 0.611 mmol) and catalyst 8

(m, 2 H), 2.81 (d, J = 4.0 Hz, 1 H), 2.43 (m, 1 H), 2.08 (m, 1 H) (3.80 mg, 0.00611 mmol) under argon atmosphere. After stirring

ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 172.7, 166.8, 159.4, 137.0,

for 24 h, the mixture was concentrated under reduced pressure. The

136.0, 133.9, 133.8, 133.6, 132.2, 132.1, 130.3, 129.6, 129.0 (ϫ2), residue was purified by column chromatography on silica gel (4 g,

128.1, 127.9, 126.5, 124.4, 121.2, 117.7, 114.3, 91.1, 82.2, 62.9, 60.0,

55.3, 50.9, 47.4, 45.5, 44.0, 33.9 ppm. HRMS (ESI, positive): calcd.

for C₃₄H₃₅N₄O₈S [M + H]⁺659.2170; found 659.2179.

hexane/EtOAc = 7:3) to give heterobicycle 10 (18.5 mg, 31%) as a

brown oil. The oil was an inseparable mixture of four diastereomers

1

as judged from LC-MS and H NMR spectra. HRMS (ESI, posi-

tive, for the major isomer): calcd. for C₂₀H₂₃INO₅[M + H]⁺

484.0621; found 484.0620.

TFA Amide 5e: To a stirred solution of 5d (1.00 g, 1.50 mmol) in

acetonitrile (20 mL) at 0 °C were added thiophenol (0.308 mL,

3.00 mmol) and Cs₂CO₃(733 mg, 2.3 mmol). After stirring at room Heterotricycle 11a: To a stirred solution of 5a (310 mg, 0.64 mmol)

temp. for 2.5 h, the mixture was then poured into saturated aque- in benzene (5.0 mL) at room temp. were added vinyl acetate

ous NaHCO₃(100 mL) and extracted with CH₂Cl₂(2ϫ100 mL). (0.312 mL, 3.37 mmol) and catalyst 8 (2.1 mg, 0.0032 mmol) under

The combined extracts were dried with Na₂SO₄and concentrated

under reduced pressure. The residue was purified by column

chromatography on silica gel (20 g, methanol/chloroform = 1:9) to

give the free amine (628 mg, 88%) as a pale yellow oil, which was

used in the next reaction without characterization. To a stirred

solution of the resulting amine (426.8 mg, 0.099 mmol) in CH₂Cl₂

argon atmosphere. After 4 h, the mixture was concentrated under

reduced pressure. The residue was purified by column chromatog-

raphy on silica gel (4 g, hexane/EtOAc = 6:4) to give heterotricycle

11a (345.9 mg, 100%) as a brown liquid. IR (film): ν = 2835, 1758,

˜

1682, 1541, 1513, 1455, 1246, 1219, 1090, 1031, 700 cm^–1. ¹H NMR

(500 MHz, CDCl₃): δ = 7.34 (d, J = 12.0 Hz, 1 H), 7.33–7.27 (m,

5540

www.eurjoc.org

Eur. J. Org. Chem. 2009, 5531–5548

Biologically Active Glutamate Analogues

3 H), 7.21 (d, J = 6.5 Hz, 2 H), 7.00 (d, J = 8.5 Hz, 2 H), 6.79 (d, H), 7.34–7.30 (m, 3 H), 7.20 (d, J = 7.5 Hz, 2 H), 7.05 (d, J =

J = 8.5 Hz, 2 H), 6.04 (dd, J = 10.0, 3.5 Hz, 1 H), 5.94 (d, J =

10.0, 2.5 Hz, 1 H), 5.78 (br. t, J = 5.5 Hz, 1 H), 5.41 (d, J = 12.0 Hz,

1 H), 5.03 (d, J = 14.5 Hz, 1 H), 4.43 (dd, J = 14.5, 6.0 Hz, 1 H),

8.5 Hz, 2 H), 6.83 (d, J = 8.5 Hz, 2 H), 5.91 (dd, J = 10.5, 5.0 Hz,

1 H), 5.80–5.77 (m, 2 H), 5.46 (d, J = 12.5 Hz, 1 H), 5.04 (d, J =

14.5 Hz, 1 H), 4.95 (t, J = 6.5 Hz, 1 H), 4.75 (d, J = 6.5 Hz, 1 H),

4.38 (d, J = 3.5 Hz, 1 H), 4.34 (dd, J = 14.5, 6.0 Hz, 1 H), 4.10 4.38 (dd, J = 14.5, 5.5 Hz, 1 H), 4.32 (dd, J = 14.5, 5.5 Hz, 1 H),

(dd, J = 17.0, 3.5 Hz, 1 H), 4.10 (br. s, 1 H), 3.98 (d, J = 17.0 Hz, 4.19 (dd, J = 18.5, 5.0 Hz, 1 H), 3.81 (s, 3 H), 3.77 (d, J = 14.5 Hz,

1 H), 3.76 (s, 3 H), 3.71 (d, J = 14.5 Hz, 1 H), 3.66 (s, 1 H), 3.33

(s, 1 H), 2.05 (s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ =

171.6, 167.9 (ϫ2), 159.5, 139.2, 137.6, 131.4, 130.0, 129.9, 129.0,

128.3, 128.0, 127.4, 122.0, 114.5, 113.2, 85.6, 78.5, 74.0, 71.6, 64.2,

1 H), 3.16 (d, J = 4.0 Hz, 1 H), 2.11 (s, 3 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 172.2, 167.6, 166.9, 159.3, 128.0, 138.1,

137.4, 133.9, 132.3, 132.1, 129.7, 128.6 (ϫ2), 128.2, 128.0, 127.6,

127.4, 126.8, 126.1, 124.2, 114.2, 112.6, 84.5, 72.8, 70.6, 57.9, 55.2,

59.0, 55.5, 45.4, 44.1, 21.0 ppm. HRMS (ESI, positive): calcd. for 54.6, 45.0, 43.6, 40.3, 20.6 ppm. HRMS (ESI, positive): calcd. for

C₂₉H₃₁N₂O₇[M + H]⁺519.2126; found 519.2119.

C₃₅H₃₅N₄O₁₀S [M + H]⁺703.2068; found 703.2076.

Heterotricycle 11b: To stirred solution of 5b (298.1 mg,

0.63 mmol) in benzene (7.0 mL) at 69 °C were added vinyl acetate

a

Heterotricycle 11d: Using the same procedure as for the synthesis

of 11b, 11d (220.1 mg, 90%) was obtained as a brown solid starting

(0.291 mL, 3.15 mmol) and catalyst 8 (3.9 mg, 0.0063 mmol) under from 5d (225.9 mg, 0.343 mmol), catalyst 8 (21.5 mg, 0.034 mmol),

argon atmosphere. After 46 h, the mixture was concentrated under

reduced pressure. The Ru catalyst was removed by passing through

a short pad of silica gel (6 g, hexane/EtOAc = 4:6). The filtrate was

concentrated under reduced pressure to give a residue which was

and vinyl acetate (0.159 mL, 1.720 mmol). IR (film): ν = 3033,

˜

2975, 1757, 1697, 1542, 1246, 1165, 681 cm^–1. ¹H NMR (500 MHz,

CDCl₃): δ = 8.43 (d, J = 8.0 Hz, 1 H), 7.81 (t, J = 7.5 Hz, 1 H),

7.72 (t, J = 7.5 Hz, 2 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.31 (d, J =

mainly composed of triene ROM/CM product 11bЈ (84% yield on 13.0 Hz, 1 H), 7.31–7.27 (m, 3 H), 7.18 (d, J = 5.5 Hz, 2 H), 6.97

isolation, E/Z = Ͼ20:1). The resulting residue was, without purifi-

cation, dissolved in benzene (7.0 mL). To the stirred mixture at

69 °C was added catalyst 8 (3.9 mg, 0.0063 mmol). After 21 h, the

mixture was cooled to room temp. and concentrated under reduced

pressure. The residue was purified by column chromatography on

silica gel (6 g, hexane/EtOAc = 6:4) to give heterotricycle 11b

(d, J = 8.5 Hz, 2 H), 6.78 (d, J = 8.5 Hz, 2 H), 5.96 (dt, J = 11.5,

3.5 Hz, 1 H), 5.69 (br. t, J = 5.5 Hz, 1 H), 5.60 (m, 1 H), 5.51 (d,

J = 13.0 Hz, 1 H), 5.09 (d, J = 14.5 Hz, 1 H), 4.81 (d, J = 5.5 Hz,

1 H), 4.35 (d, J = 5.5 Hz, 2 H), 3.83 (s, 3 H), 3.77 (d, J = 9.5 Hz,

1 H), 3.77 (s, 3 H), 3.59 (d, J = 15.0 Hz, 1 H), 3.54 (s, 1 H), 3.45

(m, 1 H), 2.69 (s, 1 H), 2.67 (m, 1 H), 2.37 (d, J = 17.5 Hz, 1 H),

(281.9 mg, 84%, E/Z Ͼ 20:1) as a brown liquid. IR (film): ν = 2.10 (s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 170.8, 167.6,

˜

2932, 1757, 1674, 1513, 1455, 1246, 1217, 1111, 1031, 699 cm^–1. ¹H 166.8, 159.4, 147.6, 138.0, 137.1, 133.8, 132.9, 132.7, 132.1, 129.9,

NMR (500 MHz, CDCl₃): δ = 7.42 (d, J = 12.0 Hz, 1 H), 7.32– 128.7, 128.2, 128.0, 127.8, 126.7, 123.7, 120.6, 114.3, 112.1, 84.2,

7.26 (m, 3 H), 7.16 (d, J = 7.0 Hz, 1 H), 7.00 (d, J = 8.5 Hz, 2 H),

6.79 (d, J = 8.5 Hz, 2 H), 5.79 (m, 1 H), 5.74 (br. s, 1 H), 5.60 (dd,

J = 11.8, 4.0 Hz, 1 H), 5.40 (d, J = 12.0 Hz, 1 H), 5.01 (d, J =

14.5 Hz, 1 H), 4.48–4.45 (m, 2 H), 4.42 (dd, J = 14.5, 6.0 Hz, 1 H),

4.34 (dd, J = 14.5, 6.0 Hz, 1 H), 3.94 (m, 1 H), 3.76 (s, 3 H), 3.72

(d, J = 14.5 Hz, 1 H), 3.65 (d, J = 1.5 Hz, 1 H), 3.57 (m, 1 H), 3.30

(s, 1 H), 2.34–2.28 (m, 2 H), 2.06 (s, 3 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 171.8, 167.6 (ϫ2) 159.1, 138.8, 137.4,

129.8, 129.5, 128.5, 127.8, 127.5, 127.1, 125.7, 114.0, 112.3, 83.9,

83.0, 82.5, 71.0, 69.0, 59.9, 55.1, 44.9, 43.6, 30.6, 20.6 ppm. HRMS

(ESI, positive): calcd. for C₃₀H₃₃N₂O₇[M + H]⁺533.2282; found

533.2281.

82.4, 70.8, 65.6, 59.8, 55.2, 45.0, 43.7, 42.8, 33.3, 20.6 ppm. HRMS

(ESI, positive): calcd. for C₃₆H₃₇N₄O₁₀S [M + H]⁺717.2225; found

714.2218.

Heterotricycle 11e: Using the same procedure as for the synthesis of

11b, 11e (363.0 mg, 94%) was obtained starting from 5e (354.0 mg,

0.620 mmol), catalyst 8 (38.8 mg, 0.062 mmol), and vinyl acetate

(0.288 mL, 3.11 mmol). IR (film): ν = 2934, 1760, 1696, 1514, 1210,

˜

1035, 700 cm^–1. ¹H NMR (500 MHz, CDCl₃, ca 7:3 mixture of

rotamers): δ = 7.41 (d, J = 12.5 Hz, 0.3 H), 7.35 (d, J = 12.5 Hz,

0.7 H), 7.31–7.18 (m, 5 H), 7.02 (d, J = 8.0 Hz, 0.6 H), 7.00 (d, J

= 8.0 Hz, 1.4 H), 6.80 (d, J = 12.5 Hz, 0.7 H), 6.78 (d, J = 8.0 Hz,

0.6 H), 6.11 (br. s, 1 H), 5.94 (dt, J = 11.5, 4.0 Hz, 0.7 H), 5.88 (dt,

Data for Intermediate Triene 11bЈ: IR (film): ν = 2931, 1758, 1675, J = 11.5, 4.0 Hz, 0.3 H), 5.65 (d, J = 12.5 Hz, 0.7 H), 5.64 (d, J =

˜

1551, 1513, 1453, 1370, 1247, 1216, 1108, 1035, 930, 700, 649,

12.5 Hz, 0.3 H), 5.57 (m, 1 H), 5.19–5.02 (m, 2 H), 4.76 (d, J =

1

596 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.40 (d, J = 12.0 Hz, 5.0 Hz, 1.4 H), 4.46 (dd, J = 14.5, 6.0 Hz, 1 H), 4.39–4.35 (m, 2

1 H), 7.32–7.26 (m, 3 H), 7.21–7.20 (m, 2 H), 7.00 (d, J = 8.5 Hz, H), 4.15 (t, J = 6.5 Hz, 0.7 H), 4.04–3.85 (m, 3.3 H), 3.85–3.77 (m,

2 H), 6.78 (d, J = 8.5 Hz, 2 H), 5.94 (m, 1 H), 5.85 (br. s, 1 H),

5.72 (m, 1 H), 5.41 (d, J = 12.0 Hz, 1 H), 5.26 (d, J = 17.0 Hz, 1

6 H), 3.74–3.65 (m, 3 H), 3.55 (m, 1 H), 3.23 (d, J = 11.5 Hz, 1.4

H), 2.72 (m, 0.3 H), 2.50–2.22 (m, 1.7 H), 2.10 (s, 0.9 H), 2.08 (s,

H), 5.23 (d, J = 10.0 Hz, 1 H), 5.02–4.94 (m, 3 H), 4.43 (dd, J = 2.1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.2, 170.8, 167.7,

14.5, 6.0 Hz, 1 H), 4.31 (dd, J = 14.5, 6.0 Hz, 1 H), 4.28 (dd, J =

8.0, 3.5 Hz, 1 H), 4.21 (d, J = 3.5 Hz, 1 H), 3.75 (s, 3 H), 3.71 (d,

167.6, 166.9, 166.8, 166.5, 166.3, 159.4, 159.3, 138.3, 137.9, 137.8,

137.7, 137.5, 137.3, 130.0 (ϫ2), 128.5, 128.4, 128.2, 128.1, 127.5,

J = 15.0 Hz, 1 H), 3.69 (s, 1 H), 3.54–3.43 (m, 1 H), 2.24 (m, 2 H), 127.2, 126.9, 126.7, 121.2, 120.4, 114.2 (ϫ2), 113.0, 112.6 ppm.

2.08 (s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.9, 167.7, HRMS (ESI, positive): calcd. for C₃₆H₃₇N₄O₁₀S [M + H]⁺

167.6, 159.3, 138.7, 137.3, 135.0, 133.1, 129.7, 128.7, 128.0, 127.8,

127.1, 119.2, 116.4, 114.2, 112.7, 85.2, 84.8, 83.6, 71.5, 69.2, 57.3,

55.3, 45.1, 43.8, 34.0, 20.7 ppm. HRMS (ESI, positive): calcd. for

C₃₂H₃₇N₂O₇[M + H]⁺561.2595; found 561.2600.

717.2225; found 717.2217.

Aminal 16: To a stirred solution of vinylic acetate 11a (1.3 mg,

0.0025 mmol) in MeOH (0.5 mL) and CH₂Cl₂(0.5 mL) at –10 °C

was added AcCl (0.38 mL, 0.0051 mmol). After 12 h, the mixture

was quenched with TEA (0.5 mL) and concentrated under reduced

pressure. The residue was purified by column chromatography on

silica gel (0.1 g, hexane/EtOAc = 5:5) to give aminal 16 (1.1 mg,

Heterotricycle 11c: Using the same procedure as for the synthesis

of 11a, 11c (1.07 g, 97%) was obtained as a brown solid starting

from 5c (1.00 g, 1.42 mmol), catalyst 8 (19.6 mg, 0.032 mmol), and

vinyl acetate (0.727 mL, 7.85 mmol). IR (film): ν = 2940, 1758,

91%) as a colorless solid. IR (film): ν = 2917, 2247, 1658, 1513,

˜

1

1696, 1542, 1513, 1370, 1245, 1172, 1031, 682, 583 cm^–1. H NMR 1453, 1247, 1091, 911, 730, 697 cm^–1. ¹H NMR (500 MHz, CDCl₃):

(500 MHz, CDCl₃): δ = 8.42 (d, J = 8.0 Hz, 1 H), 7.81–7.68 (m, 3 δ = 7.34–7.19 (m, 7 H), 6.85 (d, J = 8.5 Hz, 2 H), 6.04 (dd, J =

Eur. J. Org. Chem. 2009, 5531–5548

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5541

M. Oikawa et al.

FULL PAPER

9.8, 3.0 Hz, 1 H), 5.88 (ddd, J = 9.8, 4.5, 4.5 Hz, 1 H), 5.14 (d, J

14.5 Hz, 1 H), 3.60 (dd, J = 17.0, 4.0 Hz, 1 H), 3.42 (d, J = 17.0 Hz,

= 14.0 Hz, 1 H), 5.05 (d, J = 2.5 Hz, 1 H), 4.67 (d, J = 14.5 Hz, 1 1 H), 3.30 (s, 1 H), 3.22 (s, 3 H), 3.09 (s, 3 H), 2.87 (d, J = 16.5 Hz,

H), 4.62 (d, J = 14.5 Hz, 1 H), 4.38 (d, J = 14.0 Hz, 1 H), 4.29 (d,

J = 2.5 Hz, 1 H), 4.17 (dd, J = 16.8, 4.5 Hz, 1 H), 4.07 (d, J =

16.8 Hz, 1 H), 3.91 (s, 1 H), 3.78 (s, 3 H), 3.71 (dd, J = 2.5, 2.5 Hz,

1 H), 2.46 (dd, J = 14.3, 2.5 Hz, 1 H), 2.34 (d, J = 2.5 Hz, 1 H),

1 H), 2.45 (d, J = 16.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, C₆D₆):

δ = 198.4, 170.5, 169.8, 159.8, 130.9, 130.1, 128.3, 122.0, 114.4,

85.1, 78.8, 74.1, 69.4, 63.9, 58.2, 54.7, 51.8, 49.1, 45.5 ppm. HRMS

(ESI, positive): calcd. for C₂₁H₂₃NO₇Na [M + Na]⁺424.1367;

2.05 (dd, J = 14.3, 2.5 Hz, 1 H) ppm. HRMS (ESI, positive): calcd. found 424.1366.

for C₂₇H₂₉N₂O₆[M + H]⁺477.2026; found 477.2029.

Ester Aldehyde 18b: Using the same procedure as for the synthesis

of 18a, intermediate N-Boc-imide for 18b (311.7 mg, 95%) was ob-

and molecular sieves (4 Å, 1.0 mg) in CH₂Cl₂(0.5 mL) at 0 °C were tained as a white solid starting from 11b (275.0 g, 0.52 mmol),

Imide 17: To a stirred solution of aminal 16 (1.0 mg, 0.0021 mmol)

added NMO (0.74 mg, 0.0063 mmol) and TPAP (0.15 mg,

0.0004 mmol). After 30 min, the mixture was filtered, and the fitr-

ate was concentrated under reduced pressure. The residue was puri-

fied by column chromatography on silica gel (0.2 g, hexane/EtOAc

Boc₂O (0.364 mL, 1.55 mmol), DMAP (19.1 mg, 0.15 mmol), and

TEA (0.215 mL, 1.55 mmol). IR (film): ν = 2834, 1692, 1513, 1249,

˜

1

1147, 847, 630 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.42 (d, J

= 12.5 Hz, 1 H), 7.28–7.21 (m, 5 H), 6.96 (d, J = 8.5 Hz, 2 H), 6.78

(d, J = 8.5 Hz, 2 H), 5.75 (dt, J = 12.0, 5.5 Hz, 1 H), 5.66 (dd, J

= 12.0, 4.0 Hz, 1 H), 5.37 (s, 1 H), 5.22 (d, J = 12.5 Hz, 1 H), 4.83

= 7:3) to give imide 17 (1.0 mg, 100%) as a colorless solid. IR

1

(film): ν = 2918, 1680, 1514, 1384, 1248, 1059, 850, 698 cm^–1. H

˜

NMR (500 MHz, CDCl₃): δ = 7.27–7.24 (m, 5 H), 7.21 (d, J = (d, J = 12.5 Hz, 1 H), 4.77 (d, J = 14.5 Hz, 1 H), 4.69 (d, J =

9.0 Hz, 1 H), 6.85 (d, J = 9.0 Hz, 1 H), 6.06 (dd, J = 10.5, 4.0 Hz,

1 H), 5.89 (ddd, J = 10.5, 2.0, 2.0 Hz, 1 H), 5.15 (d, J = 14.5 Hz,

1 H), 4.24 (d, J = 14.5 Hz, 1 H), 4.18 (dd, J = 16.5, 2.0 Hz, 1 H),

15.0 Hz, 1 H), 4.58 (br. s, 1 H), 4.47 (d, J = 3.0 Hz, 1 H), 3.91 (m,

1 H), 3.77–3.74 (m, 4 H), 3.58 (m, 1 H), 3.27 (s, 1 H), 2.30 (m, 2

H), 2.04 (s, 3 H), 1.30 (s, 9 H) ppm. ¹³C NMR (125 MHz, CDCl₃):

4.04 (d, J = 16.5 Hz, 1 H), 3.69–3.95 (m, 2 H), 3.79 (s, 3 H), 3.34 δ = 172.2, 172.0, 167.3, 159.2, 151.8, 139.2, 137.1, 130.0, 129.1,

(d, J = 16.5 Hz, 1 H), 3.08 (s, 1 H), 2.80 (d, J = 16.5 Hz, 1 H) ppm. 128.2, 128.1, 127.4, 127.0, 126.4, 114.1, 111.9, 84.7, 84.5, 83.4, 82.3,

¹³C NMR (CDCl₃, 125 MHz): δ = 169.6, 169.3, 168.5, 159.4, 131.4, 69.5, 69.0, 60.1, 55.2, 47.8, 45.3, 30.4, 27.6, 20.6 ppm. HRMS (ESI,

130.2, 128.6, 128.5, 127.9, 126.9, 126.0, 121.7, 114.2, 80.4, 78.3,

73.6, 64.2, 63.0, 56.7, 55.3, 45.0, 43.8, 41.1 ppm. HRMS (FAB,

positive): calcd. for C₂₇H₂₇N₆O₂[M + H]⁺475.1869; found

475.1875.

positive): calcd. for C₃₅H₄₁N₂O₉[M + H]⁺633.2807; found

633.2803.

Using the same procedure as for the synthesis of 18a, 18b

(147.1 mg, 83%) was obtained as a white solid starting from inter-

mediate N-Boc-imide for 18b (270.0 mg, 0.43 mmol) and K₂CO₃

Ester Aldehyde 18a: To a stirred solution of N-Bn-amide 11a

(290.0 mg, 0.56 mmol) in CH₂Cl₂(5.0 mL) at 0 °C were added (29.5 mg, 0.21 mmol). IR (film): ν = 2953, 1743, 1698, 1514, 1436,

˜

1

Boc₂O (0.396 mL, 1.69 mmol), TEA (0.310 mL, 2.24 mmol) and 1249, 1177, 1027, 683 cm^–1. H NMR (500 MHz, C₆D₆): δ = 9.86

DMAP (34 mg, 0.28 mmol). After 2.5 h, the mixture was diluted

with EtOAc (20 mL), washed with saturated aqueous NH₄Cl

(20 mL) and brine (20 mL), dried with Na₂SO₄, and concentrated

under reduced pressure. The residue was purified by column

chromatography on silica gel (6 g, hexane/EtOAc = 7:3) to give the

intermediate N-Boc-imide (329 mg, 95%) as a white solid. IR

(s, 1 H), 7.16 (d, J = 8.5 Hz, 2 H), 6.80 (d, J = 8.5 Hz, 2 H), 5.60

(dd, J = 11.8, 3.5 Hz, 1 H), 5.45 (m, 1 H), 5.06 (d, J = 15.0 Hz, 1

H), 4.67 (s, 1 H), 4.66 (d, J = 14.5 Hz, 1 H), 4.48 (s, 1 H), 4.11 (d,

J = 14.5 Hz, 1 H), 3.65 (m, 1 H), 3.44 (s, 1 H), 3.36 (s, 3 H), 3.22

(s, 3 H), 3.21 (m, 1 H), 3.08 (d, J = 17.3 Hz, 1 H), 2.62 (d, J =

17.3 Hz, 1 H), 1.85 (m, 2 H) ppm. ¹³C NMR (125 MHz, C₆D₆): δ

(film): ν = 2892, 2836, 1697, 1513, 1250, 1147, 1032, 848, 700 cm^–1. = 198.6, 171.0, 169.8, 159.8, 130.1, 128.9, 128.5, 126.7, 114.4, 83.8,

˜

¹H NMR (500 MHz, CDCl₃): δ = 7.36 (d, J = 12.0 Hz, 1 H), 7.29–

7.21 (m, 5 H), 6.96 (d, J = 8.0 Hz, 2 H), 6.78 (d, J = 8.0 Hz, 1 H),

83.7, 82.5, 69.2, 68.8, 59.5, 54.7, 51.8, 48.7, 45.6, 30.0 ppm. HRMS

(ESI, positive): calcd. for C₂₂H₂₅NO₇Na [M + H]⁺438.1523; found

6.02–5.96 (m, 2 H), 5.41 (s, 1 H), 5.22 (d, J = 12.0 Hz, 2 H), 4.84 438.1518.

(d, J = 15.0 Hz, 1 H), 4.80 (d, J = 14.5 Hz, 1 H), 4.70 (d, J =

Diester 19a: To a stirred solution of aldehyde 18a (222.7 mg,

0.55 mmol) in tBuOH (15.0 mL) and water (5.0 mL) at room temp.

were added 2-methyl-2-butene (0.291 mL, 2.75 mmol),

15.0 Hz, 1 H), 4.39 (d, J = 2.5 Hz, 1 H), 4.15 (d, J = 2.0 Hz, 1 H),

4.08 (dd, J = 13.5, 3.0 Hz, 1 H), 3.97 (d, J = 13.5 Hz, 1 H), 3.75

(s, 3 H), 3.74 (d, J = 14.5 Hz, 1 H), 3.29 (s, 1 H), 2.02 (s, 3 H),

1.30 (s, 9 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 172.1, 171.6,

167.3, 159.2, 151.9, 139.1, 137.2, 130.8, 130.0, 128.3, 127.4, 127.1,

122.1, 114.1, 112.5, 85.9, 84.8, 78.1, 73.9, 69.7, 63.9, 58.7, 55.2,

47.8, 45.3, 27.6, 20.6 ppm. HRMS (ESI, positive): calcd. for

C₃₄H₃₉N₂O₉[M + H]⁺619.2650; found 619.2660.

NaH₂PO₄·2H₂O (94.2 mg, 0.60 mmol), and NaClO₂(148.3 mg,

1.65 mmol). After 5 h, the mixture was diluted with CH₂Cl₂

(50 mL), and the mixture was washed with hydrochloric acid (1 ,

20 mL) and brine (20 mL). The organic layer was dried with

Na₂SO₄and concentrated under reduced pressure. The residue was

dissolved in methanol (15.0 mL) and cooled to 0 °C. TMS-CHN₂

(2  in Et₂O, 0.84 mL, 1.68 mmol) was added, and the mixture was

allowed to warm to room temp. After stirring for 30 min, the mix-

ture was concentrated under reduced pressure. The residue was

purified by column chromatography on silica gel (6 g, hexane/

To a stirred solution of intermediate N-Boc-imide (290.0 mg,

0.56 mmol) in methanol (15 mL) at –20 °C was added K₂CO₃

(36.6 mg, 0.27 mmol). After 5 h, the mixture was poured into satu-

rated aqueous NH₄Cl (30 mL), and the mixture was extracted with

EtOAc (50 mL). The extract was washed with brine (50 mL), dried EtOAc = 4:6) to give diester 19a (235.4 mg, 94%) as a white solid.

with Na₂SO₄, and concentrated under reduced pressure. The resi-

due was purified by column chromatography on silica gel (6 g, hex-

ane/EtOAc = 7:3) to give ester aldehyde 18a (178 mg, 84%) as a

IR (film): ν = 2953, 1744, 1698, 1513, 1437, 1248, 1178, 1049, 822,

˜

1

684 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.10 (d, J = 8.5 Hz, 2

H), 6.82 (d, J = 8.5 Hz, 2 H), 6.02 (dd, J = 10.5, 3.5 Hz, 1 H), 5.93

(m, 1 H), 4.81 (d, J = 14.5 Hz, 1 H), 4.39 (d, J = 3.0 Hz, 1 H), 4.34

white solid. IR (film): ν = 2954, 1745, 1696, 1513, 1441, 1248, 1030,

˜

1

684 cm^–1. H NMR (500 MHz, C₆D₆): δ = 9.67 (s, 1 H), 703 (d, J (s, 1 H), 4.15 (dd, J = 17.3, 3.5 Hz, 1 H), 4.03 (d, J = 17.3 Hz, 1

= 8.5 Hz, 2 H), 6.67 (d, J = 8.5 Hz, 2 H), 5.53 (dd, J = 5.5, 2.0 Hz,

1 H), 5.32 (dd, J = 10.0, 3.5 Hz, 1 H), 4.97 (d, J = 14.5 Hz, 1 H),

H), 4.01 (s, 1 H), 4.00 (d, J = 14.5 Hz, 1 H), 3.77 (s, 3 H), 3.61 (s,

3 H), 3.58 (s, 3 H), 3.37 (s, 1 H), 3.11 (d, J = 16.5 Hz, 1 H), 2.75

4.39 (d, J = 2.0 Hz, 1 H), 4.34 (s, 1 H), 3.94 (s, 1 H), 3.92 (d, J = (d, J = 16.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ =

5542

www.eurjoc.org

Eur. J. Org. Chem. 2009, 5531–5548

Biologically Active Glutamate Analogues

1

170.8, 170.3, 170.1, 159.2, 130.6, 129.7, 127.1, 122.5, 114.1, 85.1,

78.3, 73.6, 68.2, 64.1, 57.7, 55.2, 52.4, 51.7, 45.4, 40.1 ppm. HRMS

1746, 1612, 1513, 1438, 1253, 1171, 1038, 647, 732 cm^–1. H NMR

(500 MHz, CDCl₃): δ = 7.15 (d, J = 9.0 Hz, 2 H), 6.81 (d, J =

(ESI, positive): calcd. for C₂₂H₂₅NO₈Na [M + Na]⁺454.1472; 9.0 Hz, 2 H), 4.13 (br. s, 1 H), 3.89 (s, 1 H), 3.81 (br. d, J = 11.0 Hz,

found 454.1477.

1 H), 3.78 (s, 3 H), 3.71 (s, 3 H), 3.64 (s, 3 H), 3.63 (d, J = 13.0 Hz,

1 H), 3.60 (br. s, 1 H), 3.43 (d, J = 13.0 Hz, 1 H), 3.24 (dd, J =

11.5, 11.5 Hz, 1 H), 3.07 (dd, J = 9.5, 9.5 Hz, 1 H), 3.02 (d, J =

15.0 Hz, 1 H), 2.76 (d, J = 15.0 Hz, 1 H), 2.70 (dd, J = 15.0, 4.5 Hz,

1 H), 2.32 (dd, J = 15.0, 4.5 Hz, 1 H), 2.14 (br. d, J = 15.0 Hz, 1

H), 1.86 (m, 1 H), 1.62 (m, 1 H), 1.27 (br. d, J = 15.0 Hz, 1 H)

ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.3, 171.0, 158.7, 130.1,

129.7, 113.6, 91.4, 81.5, 76.6, 74.2, 66.6, 55.2, 55.1, 53.6, 53.0, 51.5,

51.2, 40.9, 25.0, 20.0 ppm. HRMS (FAB, positive): calcd. for

C₂₂H₃₀NO₇[M + H]⁺420.2022; found 420.2027.

Diester 19b: Using the same procedure as for the synthesis of 19a,

19b (139.3 mg, 73%) was obtained as a colorless oil starting from

18b (147.1 mg, 0.35 mmol), 2-methyl-2-butene (0.226 mL,

2.14 mmol), NaH₂PO₄·2H₂O (73.3 mg, 0.47 mmol), NaClO₂

(115.3 mg, 1.28 mmol), and TMS-CHN₂(2  in Et₂O, 0.35 mL,

0.70 mmol). IR (film): ν = 2953, 1744, 1698, 1513, 1437, 1248,

˜

1047, 820 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.08 (d, J =

8.5 Hz, 2 H), 6.81 (d, J = 8.5 Hz, 2 H), 5.73 (dt, J = 11.5, 5.5 Hz,

1 H), 5.58 (dd, J = 11.5, 3.5 Hz, 1 H), 4.77 (d, J = 14.5 Hz, 1 H),

4.49–4.47 (m, 2 H), 4.30 (s, 1 H), 4.02 (d, J = 14.5 Hz, 1 H), 3.93 Pyrrolidine 21b: Using the same procedure as for the synthesis of

(m, 1 H), 3.77 (s, 3 H), 3.66 (m, 1 H), 3.62 (s, 3 H), 3.56 (s, 3 H),

21a, 21b (11.3 mg, 43%) was obtained as a colorless oil starting

from 20b (27.4 mg, 0.061 mmol). IR (film): ν = 2934, 1746, 1697,

3.34 (s, 1 H), 3.11 (d, J = 17.0 Hz, 1 H), 2.72 (d, J = 17.0 Hz, 1

˜

H), 2.38–2.26 (m, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 1612, 1513, 1439, 1250, 1176, 1110, 822, 736 cm^–1. ¹H NMR

171.4, 170.3, 170.0, 159.2, 129.7, 128.3, 127.2, 127.1, 114.1, 83.7,

83.3, 81.8, 68.7, 68.0, 58.9, 55.2, 52.3, 51.6, 45.3, 39.4, 29.9 ppm.

HRMS (ESI, positive): calcd. for C₂₃H₂₇NO₈Na [M + Na]⁺

468.1629; found 468.1634.

(500 MHz, CDCl₃): δ = 7.16 (d, J = 9.0 Hz, 2 H), 6.82 (d, J =

9.0 Hz, 2 H), 4.26 (m, 1 H), 4.04 (dd, J = 12.3, 5.0 Hz, 1 H), 3.80

(s, 1 H), 3.77 (s, 3 H), 3.69 (s, 3 H), 3.64–3.60 (m, 5 H), 3.48 (d, J

= 13.5 Hz, 1 H), 3.19 (m, 1 H), 3.16 (dd, J = 9.5, 9.5 Hz, 1 H),

2.89 (d, J = 15.5 Hz, 1 H), 2.78 (d, J = 15.5 Hz, 1 H), 2.76 (dd, J

= 9.5, 4.5 Hz, 1 H), 2.38 (dd, J = 9.5, 4.5 Hz, 1 H), 2.03 (m, 1 H),

1.85–1.66 (m, 3 H), 1.66 (m, 1 H), 1.26 (m, 1 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 171.4, 171.0, 158.7, 130.1, 129.7, 113.6,

91.5, 91.0, 84.1, 74.1, 72.7, 55.2, 54.8, 54.6, 51.5, 51.3, 41.0, 31.9,

30.6, 20.7 ppm. HRMS (FAB, positive): calcd. for C₂₃H₃₂NO₇[M

+ H]⁺434.2179; found 434.2170.

Tetrahydropyran 20a: To a stirred solution of 19a (12.2 mg,

0.028 mmol) in MeOH (0.5 mL) at room temp. was added Pd/C (10

wt.-%, 0.6 mg). The mixture was stirred vigorously under hydrogen

atmosphere for 1 h. The catalyst was then removed by filtration,

and the filtrate was concentrated under reduced pressure. The resi-

due was purified by column chromatography on silica gel (1 g, hex-

ane/EtOAc = 2:8) to give 20a (11.8 mg, 96%) as a colorless oil. IR

(film): ν = 2849, 1746, 1695, 1513, 1433, 1250, 1166, 1105, 1030,

N-Boc-Pyrrolidine 22a: To a stirred solution of PMB amine 21a

˜

821, 658 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.09 (d, J = (18.0 mg, 0.043 mmol) in EtOH (0.5 mL) at room temp. were added

8.5 Hz, 2 H), 6.81 (d, J = 8.5 Hz, 2 H), 4.78 (d, J = 15.0 Hz, 1 H), palladium hydroxide (10 wt.-% on carbon, 2.0 mg) and Boc₂O

4.31 (s, 1 H), 4.24 (br. s, 1 H), 3.96 (d, J = 15.0 Hz, 1 H), 3.86 (dd,

J = 9.5, 2.0 Hz, 1 H), 3.77 (m, 4 H), 3.63 (s, 3 H), 3.58 (s, 3 H),

3.34 (dd, J = 9.5, 9.5 Hz, 1 H), 3.21 (br. s, 1 H), 3.18 (d, J =

17.0 Hz, 1 H), 2.77 (d, J = 17.0 Hz, 1 H), 2.00 (br. d, J = 14.5 Hz,

1 H), 1.75 (m, 1 H), 1.62 (m, 1 H), 1.31 (ddd, J = 14.5, 3.0, 3.0 Hz,

1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.1, 170.3, 170.2,

159.2, 129.9, 127.2, 114.1, 84.4, 78.6, 76.6, 69.0, 66.4, 58.0, 55.2,

52.4, 51.7, 45.3, 39.9, 24.8, 19.8 ppm. HRMS (FAB, positive):

calcd. for C₂₂H₂₈NO₈[M + H]⁺434.1815; found 434.1817.

(0.0500 mL, 0.215 mmol). The mixture was stirred vigorously un-

der hydrogen atmosphere for 24 h. The catalyst was then removed

by filtration, and the filtrate was concentrated under reduced pres-

sure. The residue was purified by column chromatography on silica

gel (1 g, hexane/EtOAc = 15:85) to give 22a (12.0 mg, 68%) as a

white solid. IR (film): ν = 1742, 1701, 1391, 1250, 1169, 1105, 1041,

˜

1

897 cm^–1. H NMR (500 MHz, CDCl₃, mixture of rotamers): δ =

4.72 (br. s, 1 H), 4.05 (br. s, 1 H), 3.84 (m, 2 H), 3.78 (br. s, 1 H),

3.67 (m, 6 H), 3.34–3.14 (m, 3 H), 2.92–2.82 (m, 1 H), 2.76–2.66

(m, 1 H), 2.10 (m, 1 H), 1.80 (m, 1 H), 1.64 (m, 1 H), 1.42–1.38 (m,

9 H), 1.32 (m, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃, selected): δ

= 171.1, 170.5, 154.1, 91.7, 81.8, 80.5, 75.8, 69.5, 66.4, 52.0, 51.6,

48.6, 40.3, 28.3, 28.2, 24.9, 19.8 ppm. HRMS (ESI, positive): calcd.

for C₁₉H₂₉NO₈Na [M + Na]⁺422.1785; found 422.1791.

Oxepane 20b: Using the same procedure as for the synthesis of 20a,

20b (30.0 mg, 100%) was obtained as a white solid starting from

19b (30.0 mg, 0.067 mmol) and Pd/C (10 wt.-%, 3 mg). IR (film):

ν = 2949, 1746, 1698, 1514, 1437, 1249, 1176, 1078, 1051, 823,

˜

1

737 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.07 (d, J = 9.0 Hz, 2

H), 6.80 (d, J = 9.0 Hz, 2 H), 4.72 (d, J = 14.5 Hz, 1 H), 4.35 (d, N-Boc-Pyrrolidine 22b: Using the same procedure as for the synthe-

J = 4.5 Hz, 1 H), 4.25 (s, 1 H), 4.14 (dd, J = 12.3, 4.5 Hz, 1 H), sis of 22a, 22b (11.3 mg, 92%) was obtained as a white solid start-

4.05 (m, 1 H), 4.03 (d, J = 14.5 Hz, 1 H), 3.75 (s, 1 H), 3.06 (d, J ing from 21b (11.3 mg, 0.026 mmol). IR (film): ν = 1701, 1384,

˜

1

= 16.0 Hz, 1 H), 2.73 (d, J = 16.0 Hz, 1 H), 2.07 (m, 1 H), 1.77– 1070 cm^–1. H NMR (500 MHz, CDCl₃, mixture of rotamers): δ =

1.56 (m, 2 H), 1.22 (m, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): 4.67 (br. s, 1 H), 3.30 (m, 1 H), 4.10 (m, 1 H), 3.91–3.86 (m, 2 H),

δ = 171.6, 170.3, 170.2, 159.2, 129.6, 127.1, 114.1, 87.0, 84.9, 84.7,

74.4, 67.8, 59.1, 55.2, 52.3, 51.7, 45.4, 39.5, 32.2 (ϫ2), 21.4 ppm.

3.67 (m, 6 H), 3.31–3.19 (m, 2 H), 3.14–3.04 (m, 1 H), 2.99–2.89

(m, 1 H), 2.61–2.53 (m, 1 H), 2.09 (m, 1 H), 1.77–1.65 (m, 4 H),

HRMS (FAB, positive): calcd. for C₂₃H₃₀NO₈[M + H]⁺448.1971; 1.42–1.37 (m, 9 H), 1.27–1.20 (m, 1 H) ppm. ¹³C NMR (125 MHz,

found 448.1965.

CDCl₃, selected): δ = 171.3, 170.3, 154.0, 91.2, 90.0, 83.9, 80.4,

74.0, 68.7, 52.9, 52.0, 51.6, 49.4, 39.6, 32.1, 31.8, 28.2, 21.4 ppm.

HRMS (ESI, positive): calcd. for C₂₀H₃₁NO₈Na [M + Na]⁺

436.1941; found 436.1946.

Pyrrolidine 21a: To a stirred solution of pyrrolidone 20a (9.2 mg,

0.021 mmol) in THF (0.5 mL) at 0 °C was added BH₃·SMe₂(1.0 

solution in THF, 0.11 mL, 0.110 mmol). The mixture was stirred

vigorously under Ar atmosphere at 40 °C for 48 h. The mixture was

then quenched by the addition of MeOH (1 mL) and concentrated

under reduced pressure. The residue was purified by column

chromatography on silica gel (1 g, hexane/EtOAc = 85:15) to give

Glutamate Analogue 23a: A suspension of fully protected glutamate

analogue 22a (5.4 mg, 0.014 mmol) in hydrochloric acid (6 ,

0.5 mL) was heated at 65 °C for 10 h. The reaction mixture was

then cooled to room temp. and concentrated under reduced pres-

sure. The residue was purified by column chromatography on re-

pyrrolidine 21a (4.7 mg, 53%) as a colorless oil. IR (film): ν = 2847,

˜

Eur. J. Org. Chem. 2009, 5531–5548

www.eurjoc.org

5543

M. Oikawa et al.

FULL PAPER

versed-phase silica gel (500 mg, water). The active fractions were

oxypropane (0.0158 mL, 0.129 mmol) and CSA (2.0 mg,

0.0086 mmol). The mixture was stirred vigorously at room temp.

for 1 h. The reaction mixture was then quenched by the addition

of triethylamine (1 mL) and concentrated under reduced pressure.

The residue was purified by column chromatography on silica gel

(1 g, hexane/EtOAc = 7:3) to give 25a (20.0 mg, 92%) as a colorless

lyophilized to afford glutamate analogue 23a (2.6 mg, 63%) as a

white solid. IR (film): ν = 1717, 1704, 1419, 1199, 1104, 1050 cm^–1.

˜

¹H NMR (500 MHz, D₂O): δ = 4.22 (s, 1 H), 4.18 (s, 1 H), 3.90 (s,

1 H), 3.83 (dd, J = 12.8, 10.0 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H),

3.32 (t, J = 12.0 Hz, 1 H), 3.17 (d, J = 16.5 Hz, 1 H), 3.06 (dd, J

= 12.8, 9.0 Hz, 1 H), 2.95 (t, J = 9.0 Hz, 1 H), 2.92 (d, J = 16.5 Hz, oil. IR (film): ν = 2917, 1746, 1700, 1513, 1438, 1249, 1176, 1065,

˜

1 H), 1.97 (br. d, J = 14.0 Hz, 1 H), 1.81–1.65 (m, 2 H), 1.34 (d, J

= 16.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, D₂O/CD₃OD = 15:1):

δ = 174.2, 168.7, 89.9, 78.9, 75.4, 67.5, 66.5, 52.7, 45.2, 40.4, 23.5,

854, 734 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.09 (d, J =

8.0 Hz, 2 H), 6.83 (d, J = 8.0 Hz, 2 H), 4.81 (d, J = 14.5 Hz, 1 H),

4.39 (br. d, J = 2.0 Hz, 1 H), 4.31 (br. d, J = 2.0 Hz, 1 H), 4.30 (s,

19.2 ppm. HRMS (ESI, positive): calcd. for C₁₂H₁₈NO₆[M + H]⁺1 H), 4.16 (m, 1 H), 4.03 (br. s, 1 H), 3.93 (d, J = 14.5 Hz, 1 H),

272.1129; found 272.1133.

3.78–3.76 (m, 4 H), 3.62 (s, 3 H), 3.60 (s, 3 H), 3.33 (s, 1 H), 3.10

(dd, J = 11.0 Hz, 1 H), 3.00 (d, J = 16.5 Hz, 1 H), 2.72 (d, J =

16.5 Hz, 1 H), 1.42 (s, 3 H), 1.31 (s, 3 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 170.3, 170.0 (ϫ2), 159.3, 130.0, 126.9,

114.2, 108.9, 84.0, 77.9, 74.4, 72.3, 68.5, 68.3, 65.8, 57.3, 55.3, 52.5,

51.8, 45.4, 40.0, 28.1, 26.0 ppm. HRMS (FAB, positive): calcd. for

C₂₅H₃₂NO₁₀[M + H]⁺506.2026; found 506.2032.

Glutamate Analogue 23b: Using the same deprotection procedure

as for the synthesis of 23a, 22b (2.4 mg, 0.014 mmol) was depro-

tected to give glutamate analogue 23b (1.4 mg, 77%) as a white

solid. IR (film): ν = 1716, 1635, 1397, 1085, 1062, 979 cm^–1. ¹H

˜

NMR (500 MHz, D₂O): δ = 4.39 (ddd, J = 7.0, 6.0, 3.5 Hz, 1 H),

4.22 (s, 1 H), 4.10 (d, J = 3.5 Hz, 1 H), 4.03 (d, J = 12.0 Hz, 1 H),

3.91 (t, J = 11.0 Hz, 1 H), 3.29 (m, 1 H), 3.11 (d, J = 16.5 Hz, 1

H), 3.09 (d, J = 7.5 Hz, 1 H), 2.93 (dd, J = 11.0, 7.5 Hz, 1 H), 2.82

(d, J = 16.5 Hz, 1 H), 2.06 (m, 1 H), 1.71 (m, 1 H), 1.64–1.60 (m,

3 H), 1.25 (m, 1 H) ppm. ¹³C NMR (125 MHz, D₂O/CD₃OD =

15:1): δ = 174.6, 170.2, 90.2, 88.9, 83.6, 74.2, 68.2, 53.4, 46.9, 41.0,

31.5, 31.0, 20.9 ppm. HRMS (ESI, positive): calcd. for C₁₃H₁₉NO₆

[M + H]⁺286.1293; found 286.1285.

Acetonide 25b: Using the same procedure as for the synthesis of

25a, 25b (84.2 mg, 99%) was obtained as a colorless oil starting

from 24b (78.5 mg, 0.164 mmol). IR (film): ν = 2952, 1745, 1700,

˜

1

1612, 1513, 1438, 1249, 1210, 1174, 1065, 843, 684 cm^–1. H NMR

(500 MHz, CDCl₃): δ = 7.06 (d, J = 8.5 Hz, 2 H), 6.78 (d, J =

8.5 Hz, 2 H), 4.58 (d, J = 15.0 Hz, 1 H), 4.52 (d, J = 6.0 Hz, 1 H),

4.35 (dd, J = 7.5, 6.0 Hz, 1 H), 4.32 (m, 1 H), 4.28 (s, 1 H), 4.18

(d, J = 15.0 Hz, 1 H), 4.17 (dd, J = 7.5, 6.0 Hz, 1 H), 3.86 (dd, J

= 11.5, 5.0 Hz, 1 H), 3.79 (dd, J = 11.5, 5.0 Hz, 1 H), 3.75 (s, 3

H), 3.64 (s, 3 H), 3.51 (s, 3 H), 3.35 (s, 1 H), 3.04 (d, J = 16.0 Hz,

1 H), 2.82 (d, J = 16.0 Hz, 1 H), 2.09–1.99 (m, 2 H), 1.45 (s, 3 H),

1.31 (s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.3, 170.0,

169.6, 159.2, 129.7, 126.9, 114.0, 108.2, 86.7, 85.2, 81.1, 78.9, 73.9,

67.3, 65.7, 58.3, 55.2, 52.4, 51.9, 45.7, 39.2, 29.9, 27.5, 24.4 ppm.

HRMS (FAB, positive): calcd. for C₂₆H₃₄NO₁₀[M + H]⁺520.2183;

found 520.2181.

Diol 24a: To a stirred solution of olefin 19a (39.1 mg, 0.091 mmol)

in tBuOH (0.6 mL) at room temp. was added a solution of NMO

(50% in water, 0.3 mL) and OsO4 (1% in tBuOH, 0.300 mL,

0.003 mmol). After 10 h, saturated aqueous Na₂S₂O₄(5 mL) was

added, and the mixture was extracted with EtOAc (3ϫ5 mL). The

combined extracts were washed with brine (2 mL), dried with

Na₂SO₄, and concentrated under reduced pressure. The residue was

purified by column chromatography on silica gel (1 g, hexane/

EtOAc = 3:7) to give diol 24a (37.1 mg, 88%) as a colorless

amorphous solid. IR (film): ν = 3389, 2917, 1745, 1680, 1513, 1439,

˜

1250, 1177, 1082, 842, 742, 658 cm^–1. ¹H NMR (500 MHz, CDCl₃):

δ = 7.12 (d, J = 9.0 Hz, 2 H), 6.85 (d, J = 9.0 Hz, 2 H), 4.78 (d, J

= 14.5 Hz, 1 H), 4.50 (br. s, 1 H), 4.33 (s, 1 H), 4.09 (br. s, 1 H),

3.99 (d, J = 14.5 Hz, 1 H), 3.90 (m, 1 H), 3.87 (dd, J = 2.5, 2.5 Hz,

1 H), 3.80 (s, 3 H), 3.67–3.65 (m, 4 H), 3.61 (s, 3 H), 3.54 (dd, J =

10.5, 10.5 Hz, 1 H), 3.28 (s, 1 H), 3.10 (d, J = 16.5 Hz, 1 H), 2.91

(br. s, 1 H), 2.77 (d, J = 16.5 Hz, 1 H), 2.54 (br. d, J = 7.0 Hz, 1

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 170.6, 170.1, 169.9,

159.3, 130.0, 126.8, 114.2, 84.6, 82.1, 76.4, 68.8, 66.5, 64.5, 64.1,

57.0, 55.3, 52.5, 51.8, 45.4, 39.9 ppm. HRMS (FAB, positive):

calcd. for C₂₂H₂₈NO₁₀[M + H]⁺466.1713; found 466.1720.

Pyrrolidine 26a: Using the same procedure as for the synthesis of

21a, 26a (13.2 mg, 33%) was obtained as a colorless oil starting

from pyrrolidone 25a (40.0 mg, 0.079 mmol). IR (film): ν = 2951,

˜

1

1743, 1613, 1512, 1436, 1248, 1150, 1063, 855, 735 cm^–1. H NMR

(500 MHz, CDCl₃): δ = 7.15 (d, J = 8.5 Hz, 2 H), 6.82 (d, J =

8.5 Hz, 2 H), 4.43 (br. d, J = 4.5 Hz, 1 H), 4.36 (br. s, 1 H), 4.18

(m, 1 H), 3.92 (s, 1 H), 3.78–3.76 (m, 4 H), 3.73–3.70 (m, 4 H),

3.63–3.61 (m, 4 H), 3.43 (d, J = 13.5 Hz, 1 H), 3.14 (dd, J = 9.5,

9.5 Hz, 1 H), 3.03 (dd, J = 10.5, 10.5 Hz, 1 H), 2.87 (d, J = 15.0 Hz,

1 H), 2.80 (dd, J = 9.5, 4.0 Hz, 1 H), 2.75 (dd, J = 10.5, 10.5 Hz,

1 H), 2.44 (dd, J = 9.5, 4.0 Hz, 1 H), 1.43 (s, 3 H), 1.34 (s, 3 H)

ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 170.9, 170.7, 158.8, 129.8,

129.7, 113.7, 108.7, 90.9, 80.7, 78.6, 73.7, 72.0, 68.6, 65.7, 55.2,

54.9, 53.2, 53.0, 51.6, 51.2, 40.9, 28.1, 26.0 ppm. HRMS (FAB,

positive): calcd. for C₂₅H₃₄NO₉[M + H]⁺492.2234; found

492.2229.

Diol 24b: Using the same procedure as for the synthesis of 24a, 24b

(89.6 mg, 83%) was obtained as a colorless oil starting from 19b

(80.4 mg, 0.172 mmol). IR (film): ν = 3401, 2918, 1744, 1691e,

˜

1612, 1514, 1439, 1249, 1177, 1065, 919, 734, 642 cm^–1. H NMR

1

(500 MHz, CDCl₃): δ = 7.07 (d, J = 9.0 Hz, 2 H), 6.82 (d, J =

9.0 Hz, 2 H), 4.66 (d, J = 15.5 Hz, 1 H), 4.59 (d, J = 4.5 Hz, 1 H),

4.22 (s, 1 H), 4.19 (br. s, 1 H), 4.13 (dd, J = 7.5, 4.5 Hz, 1 H), 4.11

(d, J = 15.5 Hz, 1 H), 3.94 (m, 1 H), 3.91 (br. d, J = 7.5 Hz, 1 H),

3.78–3.74 (m, 4 H), 3.64 (s, 3 H), 3.55 (s, 3 H), 3.55 (s, 3 H), 3.29

(s, 1 H), 3.02 (d, J = 16.0 Hz, 1 H), 2.75 (d, J = 16.0 Hz, 1 H),

2.56 (br. s, 1 H, OH), 2.32 (br. s, 1 H, OH), 1.91 (m, 1 H), 1.79 (m,

1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.1, 170.1, 170.0,

159.2, 129.7, 127.0, 114.0, 87.2, 84.9, 84.2, 77.5, 71.8, 68.0, 67.4,

59.3, 55.2, 52.4, 51.9, 45.5, 39.3, 34.7 ppm. HRMS (FAB, positive):

calcd. for C₂₃H₃₀NO₁₀[M + H]⁺480.1870; found 480.1872.

Pyrrolidine 26b: Using the same procedure as for the synthesis of

21a, 26b (15.3 mg, 36%) was obtained as a colorless oil starting

from 25b (43.4 mg, 0.084 mmol). IR (film): ν = 2916, 1743, 1613,

˜

1

1512, 1436, 1248, 1168, 1039, 821, 683 cm^–1. H NMR (500 MHz,

CDCl₃): δ = 7.16 (d, J = 8.5 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H),

4.39–4.30 (m, 3 H), 3.90 (dd, J = 5.0, 2.5 Hz, 1 H), 3.78 (s, 3 H),

3.78–3.73 (m, 2 H), 3.67 (s, 3 H), 3.64 (s, 3 H), 3.64–3.56 (m, 3 H),

3.25 (dd, J = 9.0, 9.0 Hz, 1 H), 2.95 (dd, J = 4.0, 2.5 Hz, 1 H), 2.88

(d, J = 15.0 Hz, 1 H), 2.84 (d, J = 15.0 Hz, 1 H), 2.52 (dd, J = 9.0,

3.5 Hz, 1 H), 2.02–1.90 (m, 2 H), 1.48 (s, 3 H), 1.32 (s, 3 H) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 171.1, 170.4, 158.5, 129.8, 129.5,

113.4, 107.3, 91.6, 85.5, 84.3, 79.2, 73.6, 73.5, 65.1, 55.2, 55.0, 54.8,

Acetonide 25a: To

a stirred solution of diol 24a (20.0 mg,

0.043 mmol) in CH₂Cl₂(1.0 mL) at 0 °C were added 2,2-dimeth-

5544

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Eur. J. Org. Chem. 2009, 5531–5548

Biologically Active Glutamate Analogues

53.5, 51.3, 51.1, 39.8, 30.5, 27.1, 24.0 ppm. HRMS (FAB, positive):

calcd. for C₂₆H₃₆NO₉[M + H]⁺506.2390; found 506.2387.

Data for (E)-Isomer of 29a: IR (film): ν = 2918, 1693, 1660, 1513,

˜

1416, 1246, 1031, 750, 632 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ =

7.34–7.19 (m, 5 H), 7.03 (d, J = 8.5 Hz, 2 H), 6.78 (d, J = 8.5 Hz,

2 H), 5.84 (ddd, J = 15.5, 6.5, 6.5 Hz, 1 H), 5.79 (dd, J = 16.8,

11.0 Hz, 1 H), 5.66 (br. s, 1 H), 5.47 (d, J = 16.8 Hz, 1 H), 5.44

(dd, J = 15.5, 10.5 Hz, 1 H), 5.20 (d, J = 11.0 Hz, 1 H), 5.06 (d, J

= 14.5 Hz, 1 H), 4.39 (dd, J = 14.3, 5.5 Hz, 1 H), 4.31 (dd, J =

14.3, 5.5 Hz, 1 H), 4.29 (dd, J = 10.5, 8.0 Hz, 1 H), 3.85 (dd, J =

8.0, 7.5 Hz, 1 H), 3.78 (d, J = 14.5 Hz, 1 H), 3.76 (s, 3 H), 3.50 (s,

1 H), 3.40 (m, 2 H), 3.08 (d, J = 7.5 Hz, 1 H), 2.64 (dd, J = 14.0,

6.5 Hz, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 169.9, 167.2,

159.2, 137.2, 135.1, 134.1, 129.8, 128.8, 128.1 (ϫ2), 128.0, 127.1,

117.8, 114.2, 86.7, 86.5, 69.8, 55.3, 53.1, 45.3, 43.8, 35.4, 31.4,

20.7 ppm. HRMS (FAB, positive): calcd. for C₂₈H₃₁O₄N₂BrI [M +

H]⁺665.0512; found 665.0513.

N-Boc-Pyrrolidine 27a: Using the same procedure as for the synthe-

sis of 22a, 27a (11.5 mg, 100%) was obtained as a white solid start-

ing from 26a (12.0 mg, 0.024 mmol). IR (film): ν = 2980, 1744,

˜

1

1703, 1392, 1249, 1170, 1063, 858, 764 cm^–1. H NMR (500 MHz,

CDCl₃): δ = 4.68 (br. s, 1 H), 4.40 (br. d, J = 4.5 Hz, 1 H), 4.28

(br. s, 1 H), 4.18 (m, 1 H), 3.91 (br. s, 1 H), 3.87 (d, J = 11.5 Hz,

1 H), 3.74 (dd, J = 11.3, 6.0 Hz, 1 H), 3.67–3.62 (m, 5 H), 3.40

(dd, J = 11.3, 3.5 Hz, 1 H), 3.07–2.94 (m, 3 H), 2.63 (d, J = 16.0 Hz,

1 H), 1.44–1.32 (m, 15 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ

= 170.8, 170.2, 153.8, 108.9, 91.3, 81.0, 80.7, 77.8, 72.0, 69.2, 68.4,

65.7, 52.1, 51.7, 51.4, 48.7, 40.2, 28.3, 28.2, 26.0 ppm. HRMS

(FAB, positive): calcd. for C₂₂H₃₄NO₁₀Na [M + Na]⁺472.2183;

found 472.2180.

Data for (Z)-Isomer of 29a: IR (film): ν = 2918, 1692, 1660, 1514,

˜

N-Boc-Pyrrolidine 27b: Using the same procedure as for the synthe-

sis of 22a, 27b (6.0 mg, 97%) was obtained as a white solid starting

1417, 1031, 732, 645 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.33–

7.20 (m, 5 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.80 (d, J = 8.5 Hz, 2 H),

6.02 (br. s, 1 H), 5.80–5.72 (m, 2 H), 5.45 (d, J = 16.5 Hz, 1 H),

5.35 (dd, J = 9.0, 9.0 Hz, 1 H), 5.18 (d, J = 10.5 Hz, 1 H), 5.10 (d,

J = 10.8, 7.0 Hz, 1 H), 3.75 (s, 3 H), 3.68 (d, J = 14.5 Hz, 1 H),

3.56 (s, 1 H), 3.45–3.32 (m, 2 H), 3.07 (d, J = 7.0 Hz, 1 H), 2.71–

2.66 (m, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 169.9, 167.2,

159.3, 137.2, 135.0, 134.4, 129.6, 128.7, 128.0, 127.9, 127.4, 127.2,

117.9, 114.2, 86.5, 81.3, 69.8, 55.3, 53.0, 45.2, 43.8, 31.5, 31.4,

20.4 ppm. HRMS (FAB, positive): calcd. for C₂₈H₃₁O₄N₂BrI [M +

H]⁺665.0512; found 665.0513.

from 26b (6.5 mg, 0.0129 mmol). IR (film): ν = 2979, 1747, 1702,

˜

1

1395, 1247, 1212, 1169, 1065, 919, 732 cm^–1. H NMR (500 MHz,

CDCl₃): δ = 4.74 (s, 1 H), 4.02 (br. s, 1 H), 3.83–3.64 (m, 10 H),

3.58 (dd, J = 11.5, 3.0 Hz, 1 H), 3.18 (m, 1 H), 2.84 (d, J = 16.5 Hz,

1 H), 2.79 (d, J = 16.5 Hz, 1 H), 2.03 (m, 1 H), 1.92 (m, 1 H), 1.48

(s, 3 H), 1.38 (s, 9 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ =

170.9, 169.8, 153.8, 108.1, 91.1, 84.6, 82.8, 80.7, 79.3, 73.6, 68.7,

65.5, 52.0, 51.8, 49.3, 38.4, 30.2, 28.3, 28.2, 27.3, 24.2 ppm. HRMS

(FAB, positive): calcd. for C₂₃H₃₆NO₁₀[M + H]⁺486.2339; found

486.2340.

Data for (E)-Isomer of 29b: IR (film): ν = 2920, 1693, 1660, 1555,

˜

1513, 1417, 1247, 1030, 732, 699, 647 cm^–1. ¹H NMR (500 MHz,

CDCl₃): δ = 7.34–7.20 (m, 5 H), 7.03 (d, J = 9.0 Hz, 1 H), 6.78 (d,

J = 9.0 Hz, 1 H), 5.86 (m, 1 H), 5.78 (m, 1 H), 5.48 (d, J = 17.0 Hz,

1 H), 5.43 (d, J = 17.0 Hz, 1 H), 5.19 (d, J = 11.0 Hz, 1 H), 5.06

(d, J = 14.5 Hz, 1 H), 4.39 (dd, J = 15.5, 6.0 Hz, 1 H), 4.34 (dd, J

= 15.5, 6.0 Hz, 1 H), 4.30 (dd, J = 9.5, 9.5 Hz, 1 H), 3.85 (dd, J =

9.5, 7.0 Hz, 1 H), 3.78 (d, J = 14.5 Hz, 1 H), 3.77 (s, 3 H), 3.52 (s,

1 H), 3.25 (m, 2 H), 3.09 (d, J = 7.0 Hz, 1 H), 2.43 (m, 2 H) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 170.0, 167.2, 159.2, 137.2, 133.2,

130.8, 130.1, 129.8, 129.6, 127.9, 120.9, 117.8, 114.2, 87.2, 81.3,

69.8, 53.1, 45.3, 43.8 (ϫ2), 34.8, 31.5, 20.2 ppm. HRMS (FAB,

positive): calcd. for C₂₈H₃₁O₄N₂BrI [M + H]⁺665.0512; found

665.0520.

Glutamate Analogue 28a: Using the same deprotection procedure

as for the synthesis of 23a, 27a (11.6 mg, 0.025 mmol) was depro-

tected to give glutamate analogue 28a (7.2 mg, 100%) as a white

1

solid. IR (film): ν = 3419, 1716, 1634, 1403, 1240, 1088 cm^–1. H

˜

NMR (500 MHz, D₂O): δ = 4.39 (s, 1 H), 4.18 (s, 1 H), 4.07 (s, 2

H), 3.86–3.82 (m, 2 H), 3.55 (dd, J = 11.0, 5.0 Hz, 1 H), 3.42 (t, J

= 11.0 Hz, 1 H), 3.13 (d, J = 17.0 Hz, 1 H), 3.09–3.00 (m, 2 H), 2.90

(d, J = 17.0 Hz, 1 H) ppm. ¹³C NMR (125 MHz, D₂O/CD₃OD =

15:1): δ = 175.7, 170.3, 92.0, 82.4, 78.6, 78.5, 67.3, 65.8, 65.3, 53.2,

46.9, 42.0 ppm. HRMS (ESI, positive): calcd. for C₁₂H₁₈NO₈[M

+ H]⁺304.1027; found 304.1032.

Glutamate Analogue 28b: Using the same deprotection procedure

as for the synthesis of 23a, 27b (7.7 mg, 0.016 mmol) was depro-

tected to give glutamate analogue 28b (5.0 mg, 100%) as a white

Data for 29c: IR (film): ν = 2917, 1692, 1660, 1514, 1416, 1246,

˜

1

solid. IR (film): ν = 3420, 1748, 1623, 1375, 1223, 1036 cm^–1. H

1

1030, 753, 700 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.34–7.20

˜

NMR (500 MHz, D₂O): δ = 4.34 (s, 1 H), 4.28 (dd, J = 7.5, 4.5 Hz,

1 H), 4.19 (d, J = 4.5 Hz, 1 H), 4.10 (d, J = 4.0 Hz, 1 H), 3.96–

3.87 (m, 3 H), 3.55 (t, J = 13.0 Hz, 1 H), 3.12 (d, J = 16.5 Hz, 1

H), 3.11 (dd, J = 12.5, 7.0 Hz, 1 H), 2.96 (dd, J = 10.8, 7.0 Hz, 1

H), 2.86 (d, J = 16.5 Hz, 1 H), 1.89 (ddd, J = 18.8, 13.0, 4.5 Hz, 1

H), 1.69 (dd, J = 13.3, 4.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz,

D₂O/CD₃OD = 15:1): δ = 174.3, 170.2, 90.7, 86.7, 86.0, 77.0, 72.8,

68.4, 68.3, 53.2, 47.0, 40.4, 34.4 ppm. HRMS (ESI, positive): calcd.

for C₁₃H₂₀NO₈[M + H]⁺318.1183; found 318.1193.

(m, 5 H), 7.03 (d, J = 8.5 Hz, 2 H), 6.78 (d, J = 8.5 Hz, 2 H), 5.77

(m, 1 H), 5.72 (dd, J = 10.5, 7.0 Hz, 1 H), 5.95 (br. s, 1 H), 5.49

(dd, J = 16.8, 1.5 Hz, 1 H), 5.44 (d, J = 17.0 Hz, 1 H), 5.35 (d, J

= 10.0 Hz, 1 H), 5.19 (d, J = 10.5, 1.5 Hz, 1 H), 5.08 (d, J =

15.0 Hz, 1 H), 4.40 (dd, J = 14.5, 6.0 Hz, 1 H), 4.37 (dd, J = 14.5,

6.0 Hz, 1 H), 4.31 (dd, J = 11.0, 7.0 Hz, 1 H), 3.86 (dd, J = 11.0,

7.5 Hz, 1 H), 3.78 (d, J = 15.0 Hz, 1 H), 3.76 (s, 3 H), 3.51 (s, 1

H), 3.09 (d, J = 7.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 169.9, 167.2, 159.2, 137.1, 135.1, 133.2, 129.8, 128.8, 128.1,

127.9, 127.1, 121.0, 117.9, 114.2, 87.2, 86.5, 69.8, 55.3, 53.2, 45.3,

43.9, 20.2 ppm. HRMS (FAB, positive): calcd. for C₂₆H₂₈O₄N₂I

[M + H]⁺559.1094; found 559.1100.

Heterobicycles 29a–29c: To a stirred solution of 4 (51.0 mg,

0.096 mmol) and 4-bromobutene (0.0485 mL, 0.478 mmol) in ben-

zene (1.1 mL) at room temp. was added catalyst 8 (3.0 mg,

0.0048 mmol). After 1 h, the mixture was concentrated under re-

duced pressure. The residue was purified by column chromatog-

raphy on silica gel (0.5 g, hexane/EtOAc = 4:6) to give an insepa-

rable mixture of heterobicycles 29a (62%), 29b (36%), and 29c

(2%) as colorless oils. Analytical samples were prepared by recycl-

ing gel-permeation liquid chromatography (GPC-LC) using CHCl₃

as an eluent.

Amine 30: A solution of 2-furfural (0.254 mL, 3.0 mmol) and 4-

methoxyaniline (739 mg, 6.0 mmol) in THF (9.0 mL) was stirred at

room temp. under Ar for 30 min, and then benzyl bromide

(1.07 mL, 9.0 mmol) and Zn dust (589 mg, 9.0 mmol) were added.

The resultant mixture was stirred for 24 h, quenched with 1% hy-

drochloric acid, and extracted with CH₂Cl₂(3ϫ50 mL). The com-

bined extracts were dried with Na₂SO₄and concentrated under re-

Eur. J. Org. Chem. 2009, 5531–5548

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5545

M. Oikawa et al.

FULL PAPER

duced pressure. The residue was purified by column chromatog-

raphy on silica gel (20 g, hexane/EtOAc = 9:1) to give amine 30

tate 33 (E/Z = 1:1, 25.8 mg, 60%) as a colorless oil, together with

unreacted 32 (10.0 mg, 28%).

(685.3 mg, 78%) as a yellow oil. IR (film): ν = 3389, 3027, 2931,

˜

Data for (E)-Isomer of 33: IR (film): ν = 2916, 1762, 1699, 1512,

˜

1603, 1511, 1239, 1037, 819, 736 cm^–1. ¹H NMR (500 MHz,

CDCl₃): δ = 7.35 (br. s, 1 H), 7.23–7.17 (m, 3 H), 7.03 (d, J =

7.0 Hz, 2 H), 6.71 (d, J = 8.5 Hz, 2 H), 6.23 (br. s, 1 H), 6.00 (br.

s, 1 H), 4.64 (dd, J = 6.0, 6.0 Hz, 1 H), 3.70 (s, 3 H), 3.18 (dd, J =

12.5, 6.0 Hz, 1 H), 3.14 (dd, J = 12.5, 6.0 Hz, 1 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 155.3, 152.4, 141.4, 140.9, 137.4, 129.2,

128.3, 126.6, 115.3, 114.7, 110.2, 106.7, 55.6, 54.1, 40.9 ppm.

HRMS (FAB, positive): calcd. for C₁₉H₁₉O₂N [M + H]⁺293.1416;

found 293.1421.

1395, 1249, 1205, 1035, 831, 751, 679 cm^–1. ¹H NMR (500 MHz,

CDCl₃): δ = 7.41 (d, J = 9.0 Hz, 2 H), 7.18–7.11 (m, 4 H), 7.01 (d,

J = 6.5 Hz, 2 H), 6.83 (d, J = 9.0 Hz, 2 H), 5.73 (m, 1 H), 5.54 (d,

J = 10.0 Hz, 1 H), 5.41 (d, J = 17.0 Hz, 1 H), 5.35 (d, J = 7.5 Hz,

1 H), 4.46–4.40 (m, 2 H), 4.00 (dd, J = 8.8, 8.5 Hz, 1 H), 3.77 (s,

3 H), 2.02–2.80 (m, 3 H), 2.12 (s, 3 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 167.8, 167.5, 157.5, 138.8, 136.1, 133.5, 130.0, 129.3,

128.4, 126.7, 125.0, 121.2, 114.3, 113.4, 87.3, 85.6, 69.2, 55.5, 53.3,

36.5, 20.6, 20.3 ppm. HRMS (FAB, positive): calcd. for

C₂₆H₂₇O₅NI [M + H]⁺560.0934; found 560.0939.

Amide 31: To a stirred solution of amine 30 (500.0 mg, 1.704 mmol)

in THF (5.0 mL) at room temp. were added (Z)-3-iodoacryl chlo-

ride (737.9 mg, 3.408 mmol) and Cs₂CO₃(1.100 g, 3.408 mmol).

After 1 h, saturated aqueous NH₄Cl (50 mL) was added, and the

mixture was extracted with EtOAc (50 mL). The extract was dried

with Na₂SO₄and concentrated under reduced pressure. The residue

was purified by column chromatography on silica gel (20 g, hexane/

EtOAc = 9:1) to give amide 31 (361.6 mg, 45%) as a yellow solid.

Data for (Z)-Isomer of 33: IR (film): ν = 2916, 1762, 1699, 1512,

˜

1395, 1249, 1205, 1035, 831, 751, 679 cm^–1. ¹H NMR (500 MHz,

CDCl₃): δ = 7.41 (d, J = 9.0 Hz, 2 H), 7.18–7.11 (m, 3 H), 7.13 (d,

J = 7.5 Hz, 1 H), 7.00 (d, J = 6.5 Hz, 2 H), 6.89 (d, J = 9.0 Hz, 2

H), 5.71 (m, 1 H), 5.37 (d, J = 17.0 Hz, 1 H), 5.28 (d, J = 10.0 Hz,

1 H), 4.95 (d, J = 7.5 Hz, 1 H), 4.56 (dd, J = 6.8, 4.5 Hz, 1 H),

4.48 (dd, J = 8.5, 8.5 Hz, 1 H), 4.11 (dd, J = 8.8, 8.5 Hz, 1 H), 3.79

(s, 3 H), 3.27 (d, J = 8.0 Hz, 1 H), 2.86 (dd, J = 14.8, 6.8 Hz, 1 H),

2.80 (dd, J = 14.8, 4.5 Hz, 1 H), 2.16 (s, 3 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 169.0, 166.7, 157.7, 136.2, 134.4, 134.2,

129.9, 129.5, 128.3, 126.6, 125.4, 119.9, 114.4, 112.0, 87.2, 86.3,

68.4, 55.5, 54.0, 35.6, 22.5, 20.7 ppm. HRMS (FAB, positive):

calcd. for C₂₆H₂₇O₅NI [M + H]⁺560.0934; found 560.0942.

IR (film): ν = 3372, 2917, 1650, 1509, 1385, 1250, 1025, 740 cm^–1.

˜

¹H NMR (500 MHz, CDCl₃): δ = 7.31 (br. s, 1 H), 7.25–7.16 (m,

4 H), 7.17 (m, 1 H), 6.86–6.69 (m, 5 H), 6.50 (d, J = 8.5 Hz, 1 H),

6.34 (dd, J = 8.0, 8.0 Hz, 1 H), 6.23 (dd, J = 3.0, 1.5 Hz, 1 H), 3.77

(s, 3 H), 3.19 (dd, J = 8.0, 4.5 Hz, 1 H), 3.15 (dd, J = 8.0, 4.5 Hz,

1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 165.3, 159.4, 152.3,

141.7, 137.2, 132.9, 130.5, 129.1, 128.4, 126.5, 114.1, 110.3, 109.8,

109.3, 88.8, 55.4, 53.1, 36.4 ppm. HRMS (FAB, positive): calcd. for

C₂₂H₂₁IO₃N [M + H]⁺474.0566; found 474.0573.

Data for Dimer 35: IR (film): ν = 2917, 1762, 1700, 1511, 1386,

˜

1248, 1034, 831, 681 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.45–

6.80 (m, 19 H), 6.02 (d, J = 15.0 Hz, 1 H), 5.93 (dd, J = 15.3,

6.0 Hz, 2 H), 5.73 (dddd, J = 17.0, 17.0, 10.3, 7.5 Hz, 1 H), 5.52

(d, J = 12.0 Hz, 1 H), 5.41 (d, J = 17.0 Hz, 1 H), 5.35 (d, J =

10.0 Hz, 1 H), 4.50–4.38 (m, 4 H), 4.01–3.98 (m, 2 H), 3.77 (s, 3

H), 3.76 (s, 3 H), 3.00–2.78 (m, 6 H), 2.10 (s, 3 H) ppm. HRMS

(FAB, positive): calcd. for C₄₈H₄₇O₈N₂I₂[M + H]⁺1033.1422;

found 1033.1421.

7-Oxanorbornene 32:

A solution of amide 31 (360.0 mg,

0.761 mmol) in toluene (30 mL) was heated to 100 °C for 24 h. The

mixture was then concentrated under reduced pressure and the resi-

due was purified by column chromatography on silica gel (10 g,

hexane/EtOAc = 7:3) to give 7-oxanenorbornene 32 (100.0 mg,

28%) and 7-epi-32 (184.6 mg, 51%) as colorless oils.

Data for 32: IR (film): ν = 2916, 1697, 1512, 1248, 1034, 833,

˜

Neuronal Culture and Electrophysiology: Rat hippocampal neurons

were isolated from E18 embryos and cultured as described pre-

viously.^[24]Electrophysiological recordings were performed at 17–

28 d in vitro with a Multiclamp 700A amplifier and pClamp 10

software (MDS Analytical Technologies, Sunnyvale, CA). Sponta-

neous action potentials were recorded using the current-clamp con-

figuration in HEPES-buffered saline external solution and K-meth-

anesulfonate-based internal solution. Neurons examined in this

study had spontaneous frequencies of action potential firing of

Ͼ0.5 Hz. AMPA/kainate-mediated excitatory postsynaptic currents

(EPSCs) were recorded in voltage-clamp in extracellular solution

1

680 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.49 (d, J = 9.0 Hz, 1

H), 7.28–7.15 (m, 5 H), 6.92 (d, J = 9.0 Hz, 1 H), 6.53 (d, J =

6.0 Hz, 1 H), 6.31 (dd, J = 6.0, 2.0 Hz, 1 H), 5.23 (d, J = 2.0 Hz,

1 H), 4.72 (dd, J = 8.3, 3.5 Hz, 1 H), 3.81 (d, J = 8.0 Hz, 1 H),

3.79 (s, 3 H), 3.17 (dd, J = 15.3, 3.5 Hz, 1 H), 3.07 (dd, J = 15.3,

8.3 Hz, 1 H), 2.26 (d, J = 8.0 Hz, 1 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 169.1, 157.5, 153.6, 153.5, 134.5, 130.2, 128.9, 128.8,

128.3, 125.2, 114.4, 93.1, 88.3, 60.9, 55.4, 48.9, 35.5, 18.7 ppm.

HRMS (FAB, positive): calcd. for C₂₂H₂₁IO₃N [M + H]⁺474.0566;

found 474.0566.

Data for 7-epi-32: IR (film): ν = 2954, 1701, 1511, 1248, 1035, containing bicuculline methiodide and picrotoxin (10 µ and

˜

842 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.28–7.16 (m, 7 H), 50 µ, respectively) to block GABA_Areceptors and D-APV

6.96 (d, J = 8.5 Hz, 2 H), 6.13 (dd, J = 5.5, 2.0 Hz, 1 H), 5.95 (d,

J = 5.5 Hz, 1 H), 5.36 (d, J = 2.0 Hz, 1 H), 4.62 (dd, J = 11.0,

4.5 Hz, 1 H), 3.88 (d, J = 7.5 Hz, 1 H), 3.82 (s, 3 H), 2.98 (dd, J =

13.3, 11.0 Hz, 1 H), 2.92 (dd, J = 13.3, 4.5 Hz, 1 H), 2.45 (d, J =

7.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 169.9, 158.1,

136.8, 136.2, 133.0, 129.7, 128.2, 127.0, 126.5, 125.1, 114.3, 91.8,

88.3, 60.6, 55.4, 49.8, 33.5, 19.4 ppm. HRMS (FAB, positive):

calcd. for C₂₂H₂₁IO₃N [M + H]⁺474.0566; found 474.0565.

(50 µ) to inhibit NMDA receptors. CsF/CsCl-based internal solu-

tion was used for voltage-clamp recordings. All recordings were

made at room temperature, and drugs were bath-applied. Analyses

of EPSCs were carried out in Clampfit (MDS Analytical Technol-

ogies) and consisted of charge transfer analysis (current area) dur-

ing 1–2 min recording segments in the absence and presence of 28a.

Action potential frequencies were analyzed using MiniAnal soft-

ware (Synaptosoft, Decatur, GA). Statistical analysis was per-

formed using GraphPad Prism 4 (La Jolla, CA).

Heterobicycle 33: To a stirred solution of 7-oxanorbornene 32

(36.4 mg, 0.077 mmol) and vinyl acetate (0.454 mL, 0.385 mmol)

in benzene (20 mL) at room temp. was added catalyst 8 (1.5 mg,

0.0023 mmol). After 5 h, the mixture was concentrated under re-

duced pressure. The residue was purified by column chromatog-

raphy on silica gel (0.5 g, hexane/EtOAc = 8:2) to give vinylic ace-

Supporting Information (see also the footnote on the first page of

this article): General experimental methods, LC-MS spectrum for

10, and ¹H and ¹³C NMR spectra for all compounds. NOESY

1

spectra for 25a, 25b, 32, and 8-epi-32. H NMR spectra for moni-

toring Fischer-type carbene formation.

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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.

G. T. S. was supported by a grant from the National Institutes of

Health (NIH, 2R01 NS44322) and thanks Dr. William Marszalec

for preparation of neuronal cultures. We thank one of the reviewers

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FULL PAPER

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Received: May 26, 2009

Published Online: September 23, 2009

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Article Doi

Regioselective domino metathesis of unsymmetrical 7-oxanorbornenes with electron-rich vinyl acetate toward biologically active glutamate analogues

DOI: 10.1002/ejoc.200900580

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Article abstract of DOI:10.1002/ejoc.200900580

Full text of DOI:10.1002/ejoc.200900580

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