Concise synthesis of 4-acylamino analogues of 2-aminobicyclo[3.1.0]hexane- 2,6-dicarboxylic acids (LY354740) from an acylnitroso Diels-Alder cycloadduct

Article abstract of DOI:10.1021/jo0495034

Concise total syntheses of 4-acylamino analogues of LY354740 were accomplished employing an N-Boc acylnitroso Diels-Alder cycloadduct as the starting material. The syntheses involved N-O bond cleavage, oxidation, intermolecular cyclopropanation, Bucherer-

Full text of DOI:10.1021/jo0495034

Con cise Syn th esis of 4-Acyla m in o An a logu es of
-Am in obicyclo[3.1.0]h exa n e-2,6-d ica r boxylic Acid s (LY354740)
fr om a n Acyln itr oso Diels-Ald er Cycloa d d u ct
2
Wenlin Lee and Marvin J . Miller*
Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall,
Notre Dame, Indiana 46556-5670
mmiller1@nd.edu
Received March 26, 2004
Concise total syntheses of 4-acylamino analogues of LY354740 were accomplished employing an
N-Boc acylnitroso Diels-Alder cycloadduct as the starting material. The syntheses involved N-O
bond cleavage, oxidation, intermolecular cyclopropanation, Bucherer-Bergs reaction, hydrolysis,
and regioselective acylation with a temporary copper chelate. The synthesis of an optically active
compound was also achieved.
In tr od u ction
L-Glutamic acid (L-Glu) is the primary excitatory
neurotransmitter in the mammalian central nervous
system. It participates in a variety of brain functions such
as learning and memory, control of movements, and pain
sensitivity. Therefore, dysfunctional glutamate neu-
rotransmission has been implicated in brain disorders
1
2
The previously reported synthesis of compound 1
involved a 14-step sequence starting with cyclopropana-
tion of cyclopentenone, installation of a â-hydroxyl group
through a Saegusa oxidation, followed by epoxidation and
epoxide opening. The resultant intermediate was then
subjected to Bucherer-Bergs reaction followed by hy-
drolysis and reprotection to construct the amino acid
moiety, conversion of the hydroxyl group to an azide, and
finally reduction of the azide and derivatization of the
resulting amine (Scheme 1).13
such as Alzheimer’s disease, anxiety, and schizophre-
nia.3 The neuronal effects of L-Glu are mediated by
two heterogeneous families of cell membrane-assoc-
iated receptors, the ionotropic (ion-channel-linked) gluta-
mate receptors and the metabotropic (G-protein-coup-
1
4
led) glutamate receptors.4,5 There are currently eight
known subtypes of metabotropic glutamate receptors
(
mGluR1-8) which can be classified into three sub-
groups (groups I-III) on the basis of their sequence
similarities.4
,6-9
A number of conformationally con-
strained analogues of L-Glu have been designed and
synthesized to elucidate the conformational requirement
for the activation of different receptor types.10 These
efforts have resulted in the discovery of several potent
(
11) (a) Monn, J . A.; Valli, M. J .; J ohnson, B. G.; Salhoff, C. R.;
Wright, R. A.; Howe, T.; Bond, A.; Lodge, D.; Griffey, K.; Tiaazno, J .
P.; Schoepp, D. D. J . Med. Chem. 1996, 39, 2990. (b) Monn, J . A.; Valli,
M. J .; Massey, S. M.; Wright, R. A.; Salhoff, C. R.; J ohnson, B. G.;
Howe, T.; Alt, C. A.; Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tiaazno,
J . P.; Kallman, M. J .; Helton, D. R.; Schoepp, D. D. J . Med. Chem.
1997, 40, 528. (c) Dominguez, C.; Ezquerra, J .; Baker, S. R.; Borrelly,
S.; Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron Lett. 1998, 39,
and selective agonists for group II metabotropic glutamate
receptors,8
,11
including acylamino derivatives (1) of
LY354740.1
1a,b,12,13
9
305. (d) Tsujishima, H.; Nakatani, K.; Shimamoto, K.; Shigeri, Y.;
Yumoto, N.; Ohfune, Y. Tetrahedron Lett. 1998, 39, 1193. (e) Monn, J .
A.; Valli, M. J .; Massey, S. M.; Hansen, M. M.; Kress, T. J .; Wepsiec,
J . P.; Harkness, A. R.; Grutsch, J . L., J r.; Wright, R. A.; J ohnson, B.
G.; Andis, S. L.; Kingston, A.; Tomlinson, R.; Lewis, R.; Griffey, K. R.;
Tiaazno, J . P.; Schoepp, D. D. J . Med. Chem. 1999, 42, 1027. (f)
Nakazato, A.; Kumagai, T.; Sakagami, K.; Yoshikawa, R.; Suzuki, Y.;
Chaki, S.; Ito, H.; Taguchi, T.; Nakanishi, S.; Okuyama, S. J . Med.
Chem. 2000, 43, 4893. (g) Pedregal, C.; Prowse, W. Bioorg. Med. Chem.
2002, 10, 433. (h) Conti, P.; De Amici, M.; Roda, G.; Vistoli, G.;
Stensbol, T. B.; Br a¨ uner-Osborne, H.; Madsen, U.; Toma, L.; De
Micheli, C. Tetrahedron 2003, 59, 1443. (i) Pajouhesh, H.; Curry, K.;
Pajouhesh, H.; Meresht, M. H.; Patrick, B. Tetrahedron: Asymmetry
2003, 14, 593.
(12) Schoepp, D. D.; J ohnson, B. G.; Wright, R. A.; Salhoff, C. R.;
Mayne, N. G.; Wu, S.; Cockerham, S. L.; Burnett, J . P.; Belagaje, R.;
Bleakman, D.; Monn, J . A. Neuropharmacology 1997, 36, 1.
(13) (a) Massey, S. M.; Monn, J . A.; Prieto, L.; Valli, M. J . PCT Int.
Appl. WO 02068380, 2002. (b) Massey, S. M.; Monn, J . A.; Valli, M. J .
U.S. Patent 5,958,960, 1999.
(
1) Meldrum, B.; Garthwaite, J . Trends Pharmacol. Sci. 1990, 11,
79.
2) Helton, D. R.; Tizzano, J . P.; Monn, J . A.; Schoepp, D. D.;
Kallman, M. J . J . Pharmacol. Exp. Ther. 1998, 284, 651.
3
(
(3) Moghaddam, B.; Adams, B. W. Science 1998, 281, 1349.
(4) Hollman, M.; Heinemann, S. Annu. Rev. Neurosci. 1994, 17, 31.
(5) Nakanishi, S.; Masu, M. Annu. Rev. Biophys. Biomol. Struct.
1
1
7
994, 23, 319.
(6) Schoepp, D. D.; Conn, P. J . Trends Pharmacol. Sci. 1993, 14,
3.
(
, 473.
(
7) Bochaert, J .; Pin, J .; Fagni, L. Fundam. Clin. Pharmacol. 1993,
8) Pin, J .-P.; Duvoisin, R. Neuropharmacology 1995, 34, 1.
9) Conn, P. J .; Pin, J .-P. Annu. Rev. Pharmacol. Toxicol. 1997, 37,
(
2
05.
10) Shimamoto, K.; Ohfune, Y. J . Med. Chem. 1996, 39, 407.
J ullian, N.; Brabet, I.; Pin, J .-P.; Acher, F. C. J . Med. Chem. 1999, 42,
546.
(
1
1
0.1021/jo0495034 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/28/2004
4
516
J . Org. Chem. 2004, 69, 4516-4519

Synthesis of 4-Acylamino Analogues of LY354740
SCHEME 1
ated ketone 3, was accessed through an N-O bond
cleavage of N-Boc cycloadduct 4, using the procedure
developed in our laboratories,2
1,22
followed by a Swern
oxidation of the resultant alcohol 5 (Scheme 3). Subse-
quent intermolecular cyclopropanation of 3 was effected
by employing sulfonium ylide ethyl (dimethylsulfura-
nylidene)acetate 6, generated in situ from the corre-
sponding sulfonium bromide and DBU in CH
2
Cl
room temperature,1 to provide the bicyclic ketone 7 in
0-70% yield. Compound 7 was then subjected to a
Bucherer-Bergs reaction by using ammonium carbonate
and potassium cyanide in EtOH/H O at 45 °C to generate
2
at
1b
6
2
the spiro-hydantoin 2 in 59% isolated yield. The relative
stereochemistry of 2 was confirmed by its X-ray crystal
structure (see the Supporting Information). Basic hy-
drolysis of 2 at 100 °C removed all the protecting groups
and exposed two amines in the intermediate 8. At this
time, a method to selectively acylate the C4 amine was
required and the well-known procedure to differentiate
the two amino groups in lysine by using a temporary
cupric complex with the R-amino acid moiety appeared
to be an attractive option.23 The constrained conformation
of 8 guaranteed the R-amino acid group being the only
copper chelation site, and therefore elaboration at the
nonchelated C4 amine could be achieved. Indeed, when
the crude 8 was treated sequentially with copper(II)
carbonate, benzoyl chloride, or benzyloxy chloroformate
under Schotten-Baumann type conditions, and finally
Chelex resin, compound 1 was obtained with a total yield
of ∼30% from spiro-hydantoin 2. No purification of any
of the intermediates was required during this process.
The synthetic sequence delineated in Scheme 3 was
subsequently applied to the synthesis of optically active
compound 1 by using the highly enantioenriched starting
material (-)-5, obtained from the lipase-catalyzed enzy-
SCHEME 2
N-Acylnitroso Diels-Alder cycloadducts are a group of
compounds that can generate remarkable molecular
diversity despite their deceivingly simple structure. They
have been the starting materials for the syntheses of
numerous biologically significant compounds in our
laboratories and others,15 including benzodiazepines,16
1
7
human 5-lypoxygenase inhibitors, and carbocyclic nu-
cleosides.1
8,19
As part of our efforts to extend the synthetic
utility of N-acylnitroso Diels-Alder cycloadducts, we
envisioned a concise synthesis of compound 1 through
intermediates such as the spiro-hydantoin 2 and â-ami-
nocyclopentenone 3 using N-Boc cycloadduct 4 as the
starting material (Scheme 2). Some of the chemistry,
including the cyclopropanation and Bucherer-Bergs
reaction, delineated in Scheme 1 would be applied to our
synthesis; however, in contrast to the reported synthesis,
the 4-amino group would be installed at the beginning.
This synthetic scheme is even more attractive from the
standpoint that the optically active version of compound
matic resolution of (()-5 developed in these laboratories
9,24
(
Scheme 4).1
In conclusion, a highly concise total synthesis of
4
-acylamino analogues of LY354740 has been accom-
plished by using N-Boc acylnitroso Diels-Alder cycload-
duct as the starting material. The synthesis provides a
fast access to a variety of analogues for SAR studies in
order to search for new potent and selective agonists for
group II metabotropic glutamate receptors. The cupric
chelate methodology, well cited in the literature for
regioselective derivatization of lysine, proved to be fea-
sible in our molecule and enabled us to selectively acylate
the C4 amino group. The synthesis has been applied to
the assembly of optically active compound 1 by using one
of the enantiomers obtained from the enzymatic resolu-
tion of (()-5.
1
could be obtained by using an enzymatic resolution
2
0
developed in our laboratories (vide infra).
Resu lts a n d Discu ssion
The exploratory synthesis was carried out on racemic
materials. The first key intermediate, the R,â-unsatur-
(14) (a) Bergs, H. German Patent 566,094, 1929. (b) Bucherer, H.
T.; Fischbeck, H. T. J . Prakt. Chem. 1934, 140, 69. (c) Bucherer, H.
T.; Steiner, W. J . Prakt. Chem. 1934, 140, 219. (d) Chubb, F. L.;
Edward, J . T.; Wong, S. C. J . Org. Chem. 1980, 45, 2315. (e) Herdeis,
C.; Gebhard, R. Heterocycles 1986, 24, 1019. (f) Haroutounian, S. A.;
Georgiadis, M. P.; Polissiou, M. G. J . Heterocycl. Chem. 1989, 26, 1283.
Exp er im en ta l Section
(
()-4-(N-ter t-Bu toxycar bon yl)am in ocyclopen ten on e (3)
a n d (-)-3. To the stirred solution of oxalyl chloride (262 µL,
.00 mmol) in dry CH Cl (7 mL) at -78 °C was added dry
3
2
2
(
g) Tanaka, K.-I.; Iwabuchi, H.; Sawanishi, H. Tetrahedron: Asymmetry
995, 6, 2271.
15) King, S. B.; Ganem, B. J . Am. Chem. Soc. 1994, 116, 562. King,
S. B.; Ganem, B. J . Am. Chem. Soc. 1991, 113, 5089.
16) Surman, M. D.; Mulvihill, M. J .; Miller, M. J . Org. Lett. 2002,
, 139.
1
(
(21) Zhang, D. Y.; Ghosh, A.; Suling, C.; Miller, M. J . Tetrahedron
Lett. 1996, 37, 3799.
(22) Zhang, D. Y.; S u¨ ling, C.; Miller, M. J . J . Org. Chem. 1998, 63,
885.
(
4
(
17) Surman, M. D.; Mulvihill, M. J .; Miller, M. J . J . Org. Chem.
(23) Scott, J . W.; Parker, D.; Parrish, D. R. Synth. Commun. 1981,
11, 303.
2
002, 67, 4115.
(
(
(
18) Vogt, P. F.; Miller, M. J . Tetrahehron 1998, 54, 1317.
19) Zhang, D. Y.; Miller, M. J . J . Org. Chem. 1998, 63, 755.
20) Mulvihill, M. J .; Gage, J . L.; Miller, M. J . J . Org. Chem. 1998,
(24) Li, F.-Z.; Brogan, J . B.; Gage, J . L.; Miller, M. J . J . Org. Chem.
Submitted for publication.
(25) Vasanits, A.; Kutl a´ n, D.; Sass, P.; Moln a´ r-Perl, I. J . Chromatogr.
2000, 870, 271.
6
3, 3357.
J . Org. Chem, Vol. 69, No. 13, 2004 4517

Lee and Miller
SCHEME 3
SCHEME 4
DMSO (426 µL, 6.00 mmol) dropwise via syringe. The resultant
solution was stirred at -78 °C for 15 min, after which time
tioned between ethyl acetate and water. The layers were
separated and the aqueous solution was extracted with
another portion of ethyl acetate. The combined ethyl acetate
2
1,22
the solution of (()-5
2 2
(399 mg, 2.00 mmol) in dry CH Cl (6
mL + 2 mL wash) was added via cannula. The mixture was
stirred at -78 °C for 30 min. To this mixture was then added
triethylamine (1.4 mL, 10.00 mmol) and the resultant mixture
was stirred at -78 °C for 10 min and at -78 °C to room
2 4
portions were washed with brine and dried over Na SO . After
filtration, the solvent was removed under reduced pressure
and the product was purified by column chromatography (silica
gel, 6:1 to 4:1 hexanes/ethyl acetate) to give a white solid (404
mg, 71%), which contained a minor amount of inseparable
temperature for 20 min. CH
solution and the organic solution was washed with water and
brine and was dried over Na SO . After filtration, the filtrate
2 2
Cl was added to dilute the
diastereomer. Recrystallization from ether gave the major
1
2
4
product as white crystals. Mp 120-121 °C; H NMR (CDCl
3
)
was concentrated under reduced pressure and the product was
purified by column chromatography (silica gel, 3:1 hexanes/
ethyl acetate) to give a white solid (348 mg, 88%). Mp 124-
δ 1.27 (t, 3H, J ) 7.0 Hz), 1.44 (s, 9H), 2.01 (m, 2H), 2.37 (dd,
1H, J ) 2.5 and 5.0 Hz), 2.42 (dd, 1H, J ) 7.0 and 19.0 Hz),
2.62 (m, 1H), 4.16 (q, 2H, J ) 7.0 Hz), 4.36 (m, 1H), 4.91 (bd,
1
13
1
1
6
5
1
1
25 °C; H NMR (CDCl
3
) δ 1.42 (s, 9H), 2.15 (dapp, 1H, J )
1H, J ) 7.5 Hz); C NMR (CDCl ) δ 14.3, 26.0, 28.5, 34.7,
3
9.0 Hz), 2.81 (dd, 1H, J ) 6.3 and 19.0 Hz), 4.96 (m, 2H),
34.8, 40.8, 48.1, 61.8, 80.4, 155.1, 169.5, 209.0; FAB HRMS
+
.20 (dd, 1H, J ) 1.5 and 5.7 Hz), 7.51 (dd, 1H, J ) 1.8 and
284.1505 (MH , calcd for C14
tioenriched (-)-7 was obtained from (-)-3 with [R] 25 -16.6 (c
0.85, CHCl ) and spectral data were in accordance with the
5
H22NO 284.1498). The enan-
1
3
D
.4 Hz); C NMR (CDCl
62.6, 206.8; FAB HRMS 198.1108 (MH , calcd for C10
98.1130). The enantioenriched (-)-3 was obtained from (-)-5
3
) δ 28.5, 42.5, 51.2, 80.3, 135.3, 155.2,
+
H
16NO
3
3
racemic compound.
D
), 98% ee) with [R]D25 -73 (c 1.0,
3
) and spectral data were in accordance with the racemic
(
[R] 25 -73 (c 1.0, CHCl
3
(()-Eth yl 4-(N-ter t-Bu toxycar bon yl)am in obicyclo[3.1.0]-
CHCl
h exa n e-6-ca r boxyla te-2-sp ir o-5′-h yd a n toin (2) a n d (-)-
compound.
2
2. To the solution of 7 (99 mg, 0.35 mmol) in 3:2 EtOH/H O (2
(
()-Eth yl 2-(N-ter t-Bu toxycar bon yl)am in o-4-oxobicyclo-
mL) was added ammonium carbonate (196 mg, 2.04 mmol)
followed by KCN (46 mg, 0.70 mmol). The resultant mixture
was stirred at 45 °C for 24 h, after which time a white
precipitate was observed in the mixture. Water (1 mL) was
added and the mixture was cooled to 0 °C and stirred for 2 h.
The white precipitate was collected by filtration, washed with
cold water, and dried under reduced pressure to give 73 mg
[
3.1.0]h exa n e-6-ca r boxyla te (7) a n d (-)-7. To the solution
of (ethoxycarbonylmethyl)dimethylsulfonium bromide (1.15 g,
.00 mmol) in anhydrous CH Cl (20 mL) at room temperature
2 2
was added DBU (900 µL, 6.00 mmol) via syringe. The resultant
solution was stirred at room temperature for 1 h, after which
time the solid (()-3 (493 mg, 2.00 mmol) was added in one
portion. The stirring was continued overnight. The solvent was
removed on a rotary evaporator and the residue was parti-
5
(59%) of the major diastereomer as a white solid. Mp 239-
1
242 °C dec; H NMR (DMSO-d
6
) δ 1.19 (t, 3H, J ) 7.2 Hz),
4
518 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of 4-Acylamino Analogues of LY354740
1
1
3
1
.39 (s, 9H), 1.78 (m, 2H), 1.83 (dd, 1H, J ) 3.0 and 6.0 Hz),
.85 (overlapping dd, J ) 3.0 and 3.0 Hz), 2.12 (dd, 1H, J )
.0 and 6.0 Hz), 4.06 (dq, 2H, J ) 7.2 and 10.8 Hz), 4.15 (m,
time it was filtered and the filtrate was concentrated under
reduced pressure to give the crude product as a brownish solid.
The crude solid was dissolved in 2 mL of water and 1 N HCl
was added dropwise until the solution was at pH 3. The
mixture was stirred at room temperature for 1 h and at 0 °C
for another hour. The precipitate was collected by filtration
to give the desired product as an off-white powder (26 mg, 31%
H), 6.42 (d, 1H, J ) 9.6 Hz), 8.09 (s, 1H), 10.94 (s, 1H); 13
C
NMR (DMSO-d
6
6
) δ 14.1, 19.8, 28.1, 32.4, 32.9, 36.5, 51.1, 60.5,
8.7, 78.4, 154.4, 155.8, 170.9, 178.6; FAB HRMS 354.1688
+
(MH , calcd for C16
24 3 6
H N O 354.1665). The enantioenriched
D
from 2). Mp 260 °C dec; 1H NMR (KOD in D
O) δ 1.63
(-)-2 was obtained from (-)-7 with [R] 25 -70.0 (c 1.0, MeOH)
2
and spectral data were in accordance with the racemic
compound. The ee of (-)-2 was determined to be 96% judging
from the NMR of the Mosher amide prepared from Boc removal
of (-)-2 followed by N-acylation with a Mosher acid chloride.
(overlapping dd, 1H, J ) 3.0, 3.0 Hz), 1.68 (dd, 1H, J ) 7.2,
15.0 Hz), 1.90 (dd, 1H, J ) 3.0, 6.0 Hz), 2.04 (d, 1H, J ) 15.0
Hz), 2.08 (dd, 1H, J ) 3.0, 6.0 Hz), 4.53 (d, 1H, J ) 7.2 Hz),
7.58-7.80 (m, 5H); 13C NMR (KOD in D
O) δ 26.1, 34.6, 39.4,
42.7, 54.5, 68.3, 129.2, 131.3, 134.6, 135.7, 170.1, 182.9, 185.4;
2
(
()-2-Am in o-4-ben zoyla m in obicyclo[3.1.0]h exa n e-2,6-
+
d ica r boxylic Acid (1a ) a n d (-)-1a . The mixture of hydan-
toin (()-2 (100 mg, 0.28 mmol) and 2 N NaOH (1 mL) was
stirred at reflux for 27 h. The resultant light brown solution
was cooled to room temperature and 1 N HCl was added until
pH 7 was reached. The precipitate was filtered out and the
filtrate was concentrated in vacuo to give the crude product
17 2 5
FAB HRMS 305.1137 (MH , calcd for C15H N O 305.1117).
D
The (-)-1a was obtained from (-)-2 with [R] 25 -33.0 (c 0.8,
DMSO) and spectral data were in accordance with the racemic
compound. The ee of (-)-1a was determined to be >98% by
converting it to its o-phthaldialdehyde-N-acetyl-L-cysteine
(OPA/NAC) derivative and determined the ratio of two dia-
stereomers on HPLC.25
8
. This crude compound was redissolved in water (2 mL) and
warmed to 85-90 °C. To this stirred solution was added basic
copper(II) carbonate (46 mg, 0.21 mmol). The resultant mixture
was brought to reflux and stirred at that temperature for 20
min. The blue solution was hot filtered through a Pasteur pipet
equipped with a cotton plug (washed with 0.5-1.0 mL of
Ack n ow led gm en t. The authors gratefully acknowl-
edge Eli Lilly and Company and NIH for financial
support of this research as well as Drs. David Mendel,
Eric Moher, and Tony Zhang at Eli Lilly and Company
for their interest and suggestions. Dr. Greg Stephenson
at Eli Lilly and Company obtained the X-ray crystal
structure of (()-2. We appreciate the Lizzadro Magnetic
Resonance Research Center at Notre Dame for NMR
facilities, Dr. W. Boggess and Ms. N. Sevova for mass
spectrometry, and Ms. Maureen Metcalf for assistance
with the manuscript.
water). To the filtrate was added NaHCO
3
(70 mg, 0.84 mmol),
1
,4-dioxane (2 mL), and benzoyl chloride (42 µL, 0.36 mmol).
The mixture was stirred at room temperature overnight. The
blue precipitate was collected by filtration (washed with small
2
portions of 50% MeOH/H O). The filtrate was concentrated
under reduced pressure and a small amount of water was
added. The undissolved blue solid was collected by filtration
(washed with small portions of 50% MeOH/H
2
O). The two crops
of blue solid were pooled together and suspended in 50%
+
MeOH/H
2
O (∼20 mL). Chelex 100 resin (Na form, 1.4 g) was
Su p p or tin g In for m a tion Ava ila ble: General methods,
added to the suspension and the blue solid dissolved at this
time to give a blue solution. HCl (3 N) was added dropwise
until apparent pH ∼5 was reached. Within a short time, the
blue solution became colorless and the resin turned blue. The
mixture was stirred at room temperature for 1.5 h, after which
1
13
the X-ray crystal structure of (()-2, and H and C NMR of
compounds 3, 7, 2, and 1a . This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0495034
J . Org. Chem, Vol. 69, No. 13, 2004 4519