Stereocontrolled synthesis of a potent agonist of group II metabotropic glutamate receptors, (+)-LY354740, and its related derivatives

Article abstract of DOI:10.1016/S0040-4039(03)01316-9

Efficient synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740: 1) and its structurally related analogs (-)-2 and (-)-3 has been accomplished starting with (1S,2R)-1-amino-2-hydroxycyclopentane- or cyclohexanecarboxylic acid (4 or 17 ) via an intramolecular cyclopropanation of α-diazo acetamide.

Full text of DOI:10.1016/S0040-4039(03)01316-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5431–5434
Stereocontrolled synthesis of a potent agonist of group II
metabotropic glutamate receptors, (+)-LY354740, and its
related derivatives
Yasufumi Ohfune,a,* Takashi Demura,a Seiji Iwama,a Hiromi Matsuda,a Kosuke Namba,a
Keiko Shimamotob and Tetsuro Shinadaa
aDepartment of Material Science, Graduate School of Science, Osaka City University, Sugimoto, Osaka 558-8585, Japan
bSuntory Institute for Bioorganic Research, Shimamoto-cho, Osaka 618-8503, Japan
Received 21 April 2003; revised 23 May 2003; accepted 23 May 2003
Abstract—Efficient synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740: 1) and its structurally related
analogs (−)-2 and (−)-3 has been accomplished starting with (1S,2R)-1-amino-2-hydroxycyclopentane- or cyclohexanecarboxylic
acid (4 or 17 ) via an intramolecular cyclopropanation of a-diazo acetamide. © 2003 Elsevier Science Ltd. All rights reserved.
Metabotropic glutamate receptors (mGluRs) are impli-
cated in the regulation of many physiological and
pathological processes in the mammalian central ner-
vous system (CNS), including synaptic plasticity, learn-
ing and memory, motor coordination, pain
transmission, and neurodegeneration.1 These receptors
form a family of three groups (groups I–III) in which
presynaptic group II receptors (mGluR2 and 3) nega-
tively regulate glutamate release. An agonist of these
receptors markedly suppresses postsynaptic excitation.2
DCG-IV3 is a potent and selective agonist of mGluR2
and exhibits anesthetic action in rat, inhibition of AOB
memory of rat, and protection of kainate-induced neu-
ronal death both in vivo and in vitro.2 The structure of
DCG-IV fixes its glutamate sub-structure to an
extended conformation (anti–anti form), which has
been proposed as a crucial factor for the conforma-
tional requirement of mGluRs.4,5 These results
prompted the design and synthesis of an effective neu-
roprotecting agent based on the structure of DCG-IV.
have been used as important tools to investigate neuro-
biological functions of mGluRs.7,8 Since the synthesis
of 1 was performed in racemic form,6 the absolute
configuration of the active enantiomer was confirmed
by the synthesis of (+)-1 started with
D
-ribonic g-lac-
tone by Dominguez et al.9 Relevant to the development
of neuroactive glutamate analogs, our current interest
was to exploit an alternative route to (+)-1, and its
g-epimer 2 whose structure closely mimics that of a
potent glutamate transport inhibitor, L
-CCG-III.4,10 In
this report, we wish to describe an efficient route to the
synthesis of (+)-1 and the novel g-epimers 2 and 3.
Our synthetic plan toward 1 and 2 was the use of
(1S,2R)-1-amino-2-hydroxycyclopentanecarboxylic acid
4 as the starting material, readily available in multi-
gram quantities from racemic 2-hydoxycyclopentanone
using an asymmetric version of the Strecker synthesis.11
Intramolecular cyclopropanation of an a-diazo acet-
amide would produce a cycloadduct which possesses
the requisite consecutive chiral centers corresponding to
the g-epimer 2. Opening of the g-lactam followed by
epimerization of the resulting g-ester group would give
rise to (+)-1 (Scheme 1).
Thus, (+)-LY354740 (1) having
a
fused bicy-
clo[3.1.0]hexane skeleton has been developed by
Schoepp et al., which is a potent and selective mGluR2
agonist and exhibits anticonvulsant and anxiolytic
properties in mice.6 Therefore, both DCG-IV and 1
The synthesis began with protection of the amino and
carboxyl groups of 4 followed by dehydration of the
resulting alcohol 5. Initial attempts for the dehydration
using standard conditions (MsCl or TsCl using DBU or
2,6-lutidine in toluene at reflux, or Burgess reagent) did
not give any dehydrated product due probably to steric
Keywords: glutamate analog; mGluRs agonist; DCG-IV; LY354740;
L
-CCG-III; transport inhibitor; dehydration; a-diazo acetamide; [2+3]
dipolar cycloaddition:cyclopropanation:epimerization.
* Corresponding author. Fax: 81-6-6605-3153; e-mail: ohfune@
sci.osaka-cu.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01316-9

5432
Y. Ohfune et al. / Tetrahedron Letters 44 (2003) 5431–5434
Scheme 1.
protecting groups furnished (−)-2, a cyclic analog of
-CCG-III.23 The conversion leading to 1 is an inversion
reasons. The use of iodine (imidazole, Ph3P in CHCl3 in
a sealed tube at 90–110°C) gave 6 in poor yield (24%).
Finally, we found that the use of the Honda method
(Tf2O in pyridine)12 was quite effective for this transfor-
mation to give the desired olefin 6 in 40% yield.13 This
method is advantageous in terms of reproducibility,
multi-gram preparation, and purification avoiding haz-
ardous isolation processes, albeit the yield was moderate.
With the desired olefin in hand, we next attempted the
key cyclopropanation reaction. The use of a protection-
free a-diazo acetamide 9a, prepared in two steps from 6,
was found to be unstable to moisture resulting in the
formation of unwanted a-hydroxy amide B as the major
product (24%). N-Benzyl protected 9b, prepared in three
steps from 6, was stable under the preparation and
work-up conditions. Although the cyclopropyl group of
the expected cycloadduct would be intolerable under the
reductive removal of the N-benzyl group,14 we employed
9b as a model compound for the key cyclopropanation
reaction. Palladium- or rhodium-catalyzed reaction of 9b
did not give any cycloadduct, but afforded insertion
product C (Pd(OAc)2, 42% and Rh2(OAc)4, 57%).15 On
the other hand, 1,3-dipolar cycloaddition occurred to
give 10a when 9b in CHCl3 was stood at room temper-
ature for overnight.16 Based on these results, we turned
our attention to use of a p-methoxybenzyl (PMB) group
for the amide protecting group because this group can
be removed under oxidative conditions at the final stage
of the synthesis.17 After removal of the Boc group of the
olefin 5, the PMB group was introduced using reductive
amination18 to give 7. Condensation of the resulting
N-PMB derivative with Boc-Gly (HOAt, HATU, Et3N)
gave glycyl amide 8 (60% yield in three steps).19 This was
converted to a-diazo acetamide 9c using standard diazo-
tization conditions.20 The a-diazo acetamide 9c under-
went [3+2] cycloaddition to give desired cycloadduct 10b.
Photo-irradiation (450W high-pressure mercury lamp,
Pyrex tube) of 10b afforded cyclopropyl lactam 11.16,21
The PMB group was removed at this stage by oxidation
with CAN17 to give a mixture of deprotected g-lactam
12 (54%) and benzoyl derivative 13 (26%). The by-pro-
duced 13 was converted into 12 by means of LiOOH
(59%).22 Introduction of a Boc group followed by
methanolysis gave protected g-epimer 15. Removal of the
L
of the configuration at the g-ester group of 15.3,4 This was
successfully effected by KN(TMS)2 to give a mono ester
16 with unexpected concomitant hydrolysis of the a-ester
group.24 Since the reaction was performed under aprotic
reaction conditions, this would be attributed to an
internal attack of the carbamate oxygen to the neighbor-
ing ester group to form an oxazolone intermediate D.
Finally, removal of the Boc group followed by hydrolysis
gave (+)-1: [h]1D7 +19.5 (c 1.05, 1N HCl). The sign of the
optical rotation and 1H and 13C NMR data of synthetic
1 were identical with those of the reported data [lit. [h]D
+23 (c 1.0, 1 N HCl)] (Scheme 2).6,9
We considered that the present process is applicable to
the synthesis of six-membered ring analogs correspond-
ing to 1 and 2. A mixture of (1S,2R)- and (1S,2S)-1-
amino-2-hydroxycyclohexanecarboxylic acid (17) was
used as the starting material.11c Contrary to the dehydra-
tion of 5, the treatment of a protected form of 17 with
iodine gave the desired olefin 18 in excellent yield. Its
conversion to Boc-lactam 21 was performed in the same
manner as for the synthesis of 1. However, subsequent
lactam-opening under methanolysis (LiOH, MeOH)
afforded an inseparable mixture of the desired diester 23
and starting 21 (21/23=1:1). Therefore, this conversion
was carried out using a hydrolytic condition (1N NaOH)
to give dicarboxylate 22. Removal of the Boc group using
TFA gave (−)-3, a six-membered ring analog of L-CCG-
III.25 Our next effort was epimerization of the g-ester
group of the diester 23 leading to a 6-membered ring
analog of 1. The diester 23 was obtained in pure form
by treatment of 22 with diazomethane. In spite of our
numerous attempts, the desired epimerization did not
occur, e.g. the treatment of 23 with KN(TMS)2 gave
re-cyclized g-lactam 21 (−78°C for 1 h, then −15°C for
3 h) or a mono ester 24 (0°C for 5 h), exclusively. The
use of LiN(TMS)2 (0°C, 5 h) gave a complex mixture of
products. The diethyl ester 25 gave a monoester. These
results suggested that the desired epimerization requires
further modification of the amino or carboxyl group such
as introduction of an additional amino protecting group
or reduction of the g-ester group to an aldehyde (Scheme
3).26

Y. Ohfune et al. / Tetrahedron Letters 44 (2003) 5431–5434
5433
Scheme 2. Reagents and conditions: (a) i. (Boc)2O, [(CH3)4NOH]5H2O, CH3CN, rt, 6 days, ii. CH2N2, 73%; (b) triflic anhydride
(Tf2O), pyridine, −30°C, then rt, 21 h, 40%; (c) i. TFA, CH2Cl2; (ii) p-anisaldehyde, NaBH3CN, MeOH, rt, 22 h; (d) Boc-Gly,
HATU, HOAt, Et3N, DMF, rt, 7 h, 60% from 6; (e) i. TFA, CH2Cl2, ii. NaNO2, 5% citric acid, Et2O–H2O, pH 3, rt, 30 min;
(f) CHCl3, rt, 46 h; (g) 450 W high-pressure mercury lamp, benzene/CH2Cl2 (10:1), rt, 3 h, 100% from 8; (h) ceric ammonium
nitrate (CAN), CH3CN/H2O (2:1), 0°C, then rt, 50 min, 54% for 12 and 26% for 13; (i) LiOOH, THF/H2O (3:1), 15 h, then
Na2S2O3, 59%; (j) (Boc)2O, Et3N, cat. DMAP, THF, rt, 26 h; (k) cat. LiOH, MeOH, rt, 45 h, 82% from 12; (l) i. 1N NaOH, THF,
ii. TFA, CH2Cl2, 84% from 15; (m) KN(SiMe3)2, THF, −78°C, 1 h, then −15°C, 2 h, then AcOH, THF, −78°C; (n) i. TFA,
CH2Cl2, ii. 1N NaOH, THF, 63% from 15.
Scheme 3. Reagents and conditions: (a) i. (Boc)2O, [(CH3)4NOH]5H2O, CH3CN, rt, 6 days, ii. CH2N2, 73%, iii. I2, imidazole, Ph3P,
CHCl3, sealed tube, 80°C, 3 h, 83%; (b) i. TFA, CH2Cl2, ii. p-anisaldehyde, NaBH3CN, MeOH, rt, 22 h, iii. Boc-Gly, HATU,
HOAt, Et3N, DMF, rt, 7 h, 64% from 18; (c) i. TFA, CH2Cl2, ii. NaNO2, 5% citric acid, Et2O–H2O, pH 3, rt, 2 h; (d) CHCl3,
rt, 46 h, 85% for three steps; (e) 450 W high-pressure mercury lamp, benzene–CH2Cl2 (10:1), rt, 3 h, 92%; (f) i. CAN, CH3CN/H2O
(2:1), 0°C, 30 min, 71%, ii. (Boc)2O, Et3N, cat. DMAP, THF, 100%; (g) 1N NaOH, THF, 35°C, 2 days; (h) TFA, CH2Cl2, 100%;
(i) CH2N2; (j) 2.2 equiv. KN(SiMe3)2, THF, −78°C, 1 h, then −15°C, 3 h, then AcOH, THF, −78°C, 100%; (k) 2.2 equiv.
KN(SiMe3)2, THF, 0°C, 3 h, then AcOH, THF, −78°C, 100% (crude yield).

5434
Y. Ohfune et al. / Tetrahedron Letters 44 (2003) 5431–5434
In summary, optically active LY354740 (1) and its
g-epimers 2 and 3 have been synthesized in a highly
diastereoselective manner via 1,3-dipolar cycloaddition
of the a-diazo acetamide 9c or 19. During the epimer-
ization of the g-ester group of the diester 15 or 23,
unusual hydrolysis of the a-ester group was observed.
Neurobiological studies on glutamate transport systems
using the synthetic 2 and 3 are in progress in our
laboratories.
Ohfune, Y. Synlett 2000, 1631–1633; (g) Kawasaki, M.;
Namba, K.; Tsujishima, H.; Shinada, T.; Ohfune, Y.
Tetrahedron Lett. 2003, 44, 1234–1238; (h) Ohfune, Y.;
Shinada, T. Bull. Chem. Soc. Jpn., in press.
12. Honda, T.; Koizumi, T.; Komatsuzaki, Y.; Yamashita, R.;
Kanai, K.; Nagase, H. Tetrahedron: Asymmetry 1999, 10,
2703–2712.
13. Contrary to the dehydration of 5, its 2S-diastereomer did
not give the olefin 6 but afforded cyclic carbamate A
(Scheme 2) as the major product (25%) where an SC% N
reaction of the initially formed b-TfO group with the
internal carbamate group occurred.
14. In fact, hydrogenation of N-benzyl lactam corresponding
to 11 gave an N-benzyl bicyclic lactam where the cyclo-
propyl group was cleaved.
15. Doyle, M. P.; Shanklin, M. S.; Pho, H. Q. Tetrahedron
Lett. 1988, 29, 2619–2642.
16. (a) Padwa, A.; Ku, H. J. Org. Chem. 1980, 45, 3756–3766;
(b) Rife, J.; Ortuno, R. M. J. Org. Chem. 1999, 64,
8959–8961.
17. (a) Yoshimura, J.; Yamaura, M.; Suzuki, T.; Hashimoto,
H. Chem. Lett. 1983, 1001–1002; (b) Smith, A. B., III;
Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Daun, J.
J.-W.; Hull, K. G.; Iwashima, M.; Qiu, Y.; Spoors, G.;
Salvatore, B. A. J. Am. Chem. Soc. 1999, 121, 10478–
10486.
18. (a) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am.
Chem. Soc. 1971, 93, 2897–2904; (b) Ohfune, Y.; Tomita,
M.; Nomoto, K. J. Am. Chem. Soc. 1981, 103, 2409–2410.
19. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397–4398.
20. (a) Doyle, M. P.; Mckervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Com-
pounds: From Cyclopropanes to Ylides; John Wiley & Sons,
1998; p. 41; (b) Ouihia, A.; Rene, L.; Guilhem, J.; Pascard,
C.; Badet, B. J. Org. Chem. 1993, 58, 1641–1642.
21. Treatment of 10a or 10b in benzene at reflux for 4 h resulted
in complete recovery of the starting material, respectively.
22. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron
Lett. 1987, 28, 6141–6144.
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and the
Research for the Future Program (JSPS 99L01204).
References
1. (a) Collingridge, G. L.; Lester, R. A. Pharmacol. Rev. 1989,
40, 143–210; (b) Parthasarathy, H. S., Ed.; Neurological
disorders. Nature 1999, 399 (Suppl.), A1–A47.
2. (a) Nakanishi, S. Science 1992, 258, 597–603; (b) Ishida,
M.; Saitoh, T.; Shimamoto, K.; Ohfune, Y.; Shinozaki, H.
Br. J. Pharmacol. 1993, 109, 1169–1177; (c) Hayashi, Y.;
Moriyama, A.; Takahashi, T.; Ohishi, H.; Ogawa-Meguro,
R.; Shigemoto, R.; Mizuno, N.; Nakanishi, S. Nature 1993,
366, 687–688; (d) Conn, P. J.; Pin, J.-P. Annu. Rev.
Pharmacol. Toxicol. 1997, 37, 205–237 and references cited
therein.
3. Ohfune, Y.; Shimamoto, K.; Ishida, M.; Shinozaki, H.
Bioorg. Med. Chem. Lett. 1993, 3, 15–18.
4. Shimamoto, K.; Ohfune, Y. J. Med. Chem. 1996, 39,
407–423.
5. Bertrand, H.-O.; Bessis, A.-S.; Pin, J.-P.; Acher, F. C. J.
Med. Chem. 2002, 45, 3171–3183.
6. Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.;
Salhoff, C. R.; Johnson, B. G.; Howe, T.; Alt, C. A.;
Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J.
P.; Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528–537.
7. Both DCG-IV and LY354740 and their radio active
derivatives are commercially available from Tocris Co.
Ltd., UK.
8. Recently, a potent and selective agonist of mGluR2 has
been developed, see: Collado, I.; Pedregal, C.; Mazon, A.;
Espinosa, J. F.; Blanco-Urgoiti, J.; Schoepp, D. D.;
Wright, R. A.; Johnson, B. G.; Kingston, A. J. Med. Chem.
2002, 45, 3619–3629.
9. Dominguez, C.; Ezquerra, J.; Prieto, L.; Espada, M.;
Pedregal, C. Tetrahedron: Asymmetry 1997, 8, 511–514.
10. Bridges, R. J.; Kavanaugh, M. P.; Chamberlin, A. R. Curr.
Pharm. Des. 1999, 5, 363.
11. (a) Moon, S.-H.; Ohfune, Y. J. Am. Chem. Soc. 1994, 116,
7405–7406; (b) Horikawa, M.; Nakajima, T.; Ohfune, Y.
Synlett 1997, 253–254; (c) Ohfune, Y.; Nanba, K.; Takada,
I.; Kan, T.; Horikawa, M.; Nakajima, T. Chirality 1997,
9, 459–462; (d) Ohfune, Y.; Horikawa, M. J. Syn. Org.
Chem. Jpn. 1997, 55, 982–993; (e) Namba, K.; Shinada, T.;
Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122,
10708–10709; (f) Iwama, S.; Gao, W.-G.; Shinada, T.;
23. 2: Amorphous solid; [h]1D4 −14.6 (c 0.91, 1N HCl); 1H NMR
(400 MHz, D2O) l 2.13 (dtd, J=15.1, 10.0. 5.2 Hz, 1H),
2.01 (dd, J=14.0, 10.0 Hz, 1H), 1.84–1.89 (m, 2H), 1.77
(dt, J=9.3, 5.9 Hz, 1H), 1.77 (dt, J=9.3 Hz, 5.9 Hz, 1H),
1.69 (t, J=7.0 Hz, 1H), 1.39–1.47 (m, 1H); 13C NMR (100
MHz, D2O, MeOH as the internal standard: l 49.0) l
176.5, 174.0, 66.1, 32.4, 29.1, 27.2, 25.4, 25.1; HRMS
(FAB) m/z (M−H)+ calcd for [C8H11O4N-H]+ 184.0610,
found, 184.0591.
24. The same treatment using an N-Boc a-amino acid ester
(Boc-L-Phe methyl ester) did not give any ester-hydrolyzed
product at all.
25. 3: Amorphous solid; [h]1D8 −89.9 (c 0.94, 1N HCl); 1H NMR
(300 MHz, D2O) l 1.90 (ddd, J=14.3, 9.0, 4.6 Hz, 1H),
1.78 (dd, J=10.4, 9.0 Hz, 1H), 1.72–1.78 (m, 1H), 1.47 (dq,
J=9.0, 4.0 Hz, 1H), 1.15–1.40 (m, 4H), 0.95 (m, 1H); 13C
NMR (100 MHz, D2O, MeOH as the internal standard:
l 49.0) l 178.9, 178.2, 59.0, 30.5, 27.5, 18.9, 18.8, 18.2, 15.9;
HRMS (FAB) m/z (M+H)+ calcd for [C9H13O4N]+
200.0923, found 200.0899.
26. Calculations (MOPAC: AM1) suggested that the g-ester
group of the bicyclo[4.1.0] system 22 locates at a more
proximal position to the amino group (distance between
,
the carboxyl carbon and the nitrogen is 2.64 A[O1]) than
,
that of the bicyclo[3.1.0] system 15 (2.88 A).