Synthesis of 7-azabicyclo[2.2.1]heptane-1,4-dicarboxylic acid, a rigid non-chiral analogue of 2-aminoadipic acid

Article abstract of DOI:10.1016/j.tetlet.2007.04.019

A non-chiral, rigid 7-azabicyclo[2.2.1]heptane-1,4-dicarboxylic acid, an analogue of 2-aminoadipic acid, has been synthesized in six steps from dimethyl-meso-2,5-dibromohexanedioate in 28% total yield. A key step in the synthesis is double alkylation of a

Full text of DOI:10.1016/j.tetlet.2007.04.019

Tetrahedron Letters 48 (2007) 4061–4063
Synthesis of 7-azabicyclo[2.2.1]heptane-1,4-dicarboxylic acid,
a rigid non-chiral analogue of 2-aminoadipic acid
Vladimir S. Kubyshkin, Pavel K. Mikhailiuk and Igor V. Komarov*
Department of Chemistry, Kyiv Taras Shevchenko University, Volodymyrska Street, 64, Kyiv 01033, Ukraine
Received 24 February 2007; revised 27 March 2007; accepted 4 April 2007
Available online 11 April 2007
Abstract—A non-chiral, rigid 7-azabicyclo[2.2.1]heptane-1,4-dicarboxylic acid, an analogue of 2-aminoadipic acid, has been synthe-
sized in six steps from dimethyl-meso-2,5-dibromohexanedioate in 28% total yield. A key step in the synthesis is double alkylation of
a dimethyl pyrrolidine-2,5-dicarboxylate by 1-bromo-2-chloroethane.
Ó 2007 Elsevier Ltd. All rights reserved.
In recent years, conformationally restricted molecules
have received much attention. One of the reasons for
this is the fact that they have been successfully used in
medicinal chemistry as building blocks for drug design.1
As part of our program aimed at the synthesis and
application of conformationally restricted amino acids2
we synthesized and characterized compound 1, a rigid
analogue of (2R)-aminoadipic acid 2, a selective competi-
tive NMDA glutamate receptor antagonist.3 Compound
1 is also a rigid analogue of naturally occurring trans-5-
carboxy-L-proline (3) isolated from Schizymenia dubyi.4
This fact strengthened our interest in the synthesis,
which we report in this Letter.
proceeded smoothly affording a mixture of correspond-
ing cis- and trans-pyrrolidines (3/1). The diastereoiso-
mers were separated by flash chromatography; the
pure cis-isomer 5 being isolated in 71% yield.6 It was
planned to construct the bicyclic skeleton through an
alkylation of the corresponding bis-enolate with 1-bro-
mo-2-chloroethane, as has been described for the syn-
thesis of an analogous carbocyclic skeleton.7 However,
despite much effort, we failed to obtain azabicyclic com-
pound 6 directly from 5 via bis-alkylation. Moreover, all
our attempts at the monoalkylation of 5 were only
partly successful. A best yield of only 6% of the desired
a-(2-chloroethyl)pyrrolidine 7 was achieved. While try-
ing to improve the yield of 7, it became evident that
an N-protecting group other than benzyl had to be used.
We thus shifted our attention to the Cbz-protected
derivative 8, which was described recently.8
COOH
HOOC
COOH
HOOC
N
H
H2N
1
2
Hydrogenation of the disubstituted pyrrolidine 5 using
10% palladium on charcoal as the catalyst followed by
reaction with Cbz-Cl furnished the corresponding ure-
thane 8 in 96% overall yield. In contrast to 5, treating
8 with 1.15 equiv of LDA at ꢀ78 °C for 2 h and subse-
quent addition of 1.5 equiv of 1-bromo-2-chloroethane
generated 9 as a single stereoisomer in 64% yield. The
presence of HMPA (5 equiv) in the reaction mixture
was found to be crucial, otherwise the yield was only
5–10%. The relative configuration of the stereogenic
centers in 9 was not determined as these were lost in
the next step of the synthesis.
COOH
HOOC
N
H
3
As illustrated in Scheme 1, the synthesis started from
easily available dimethyl-meso-2,5-dibromohexanedio-
ate 4.5 Reaction of 4 with benzylamine in refluxing tol-
uene/water mixture using K2CO3 as a base for 30 h
Keywords: Non-natural amino acids; Conformational restriction; Ester
enolate alkylation.
*
Intramolecular alkylation of 9 to produce the key inter-
mediate 10 was next explored. Although the construction
Corresponding author. Tel.: +380 67 500 11 51; fax: +380 44 225 12
73; e-mail: ik214@yahoo.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.019

4062
V. S. Kubyshkin et al. / Tetrahedron Letters 48 (2007) 4061–4063
Cl
MeOOC
COOMe
CH2Ph
N
7
b
6%
Br
a
COOMe
COOMe
MeOOC
96%
COOMe
COOMe
MeOOC
N
N
71%
CH2Ph
CH2Ph
Br
c
4
6
5
Cl
d
MeOOC
COOMe
MeOOC
COOMe
N
64%
N
Cbz
Cbz
8
9
e
68%
f
COOH
Cl
HOOC
COOMe
N+
H
MeOOC
93%
N
H
Cbz
10
1.HCl
Scheme 1. Reagents and conditions: (a) PhCH2NH2, K2CO3, toluene/water, reflux, 30 h; (b) (i) 1.15 equiv LDA, 5 equiv HMPA, THF, ꢀ78 °C, 2 h;
(ii) 1.5 equiv BrCH2CH2Cl, ꢀ78 °C!rt, overnight; (c) (i) H2, Pd/C, 40 °C, 48 h; (ii) 1.1 Cbz-Cl, K2CO3, water, rt, overnight; (d) (i) 1.15 equiv LDA,
5 equiv HMPA, THF, ꢀ78 °C, 2 h; (ii) 1.5 equiv BrCH2CH2Cl, ꢀ78 °C!rt, overnight; (e) 1.3 equiv LDA, 5 equiv HMPA, THF (i) ꢀ78 °C, 2 h; (ii)
ꢀ78 °C!rt, overnight; (f) 3 N HCl, reflux, 12 h.
541; (c) Lodge, D.; Headley, P. M.; Hall, J. G. Brain Res.
1978, 152, 603.
of a 7-azabicyclo[2.2.1]heptane skeleton by an analogous
reaction has been documented in the literature,9 careful
experimentation was required to find the optimal condi-
tions in our particular case. The best result was obtained
while treating 9 with 1.3 equiv LDA/5 equiv of HMPA
at ꢀ78 °C for 2 h. Under the above conditions, com-
pound 10 was obtained in 68% yield as a colorless liquid.
It should be noted, that although procedures for the
synthesis of both 9 and 10 are almost identical, in our
hands, all attempts to carry out the direct conversion
of 8 to 10 were not productive. Finally, hydrolysis of
10 afforded the amino acid 1ÆHCl in 93% yield.10
4. Mauger, A. B. J. Nat. Prod. 1996, 59, 1205–1211.
5. Dimethyl-meso-2,5-dibromohexanedioate 4 was prepared
following the original procedure for diethyl-meso-2,5-
dibromohexanedioate (Guha, P. C.; Sankaran, D. K.
Org. Synth. Coll. 1955, 3, 623).
6. The synthesis of 5 has been described in the literature ((a)
Kemp, D. S.; Curran, T. P. J. Org. Chem. 1988, 53, 5729–
5731; (b) Cignarella, G.; Nathansohn, G. J. Org.
Chem. 1961, 26, 1500–1504); however we utilized the
modified procedure (water/toluene; K2CO3 as a base) as
was originally used for the preparation of N-phenylethyl
pyrrolidine-2,5-dicarboxylates (Yamamoto, Y.; Hoshino,
J.; Fujimoto, Y.; Ohmoto, J.; Sawada, S. Synthesis 1993, 3,
298–302).
7. Della, E. W.; Tsanaktsidis, J. Aust. J. Chem. 1985, 38,
1705–1718.
References and notes
8. (a) Kemp, D. S.; Curran, T. P. J. Org. Chem. 1986, 51,
2377–2378; (b) Chan, M. F.; Raju, B. G.; Kois, A.;
Varughese, J. I.; Varughese, K. I.; Balaji, V. N. Hetero-
cycles 1999, 51, 5–8.
1. Komarov, I. V.; Grygorenko, A. O.; Turov, A. V.; Khilya,
V. P. Russ. Chem. Rev. 2004, 73, 785–810.
2. (a) Gorichko, M. V.; Grygorenko, O. O.; Komarov, I. V.
Tetrahedron Lett. 2002, 43, 9411–9412; (b) Mikhailiuk, P.
K.; Afonin, S.; Chernega, A. N.; Rusanov, E. B.;
Platonov, M. O.; Dubinina, G. G.; Berditsch, M.; Ulrich,
A. S.; Komarov, I. V. Angew. Chem., Int. Ed. 2006, 45,
5659–5661; (c) Grygorenko, O. O.; Artamonov, O. S.;
Palamarchuk, G. V.; Zubatyuk, R. I.; Shishkin, O. V.;
Komarov, I. V. Tetrahedron: Asymmetry 2006, 17, 252–
258.
9. (a) Campbell, J. A.; Rapoport, H. J. Org. Chem. 1996, 61,
6313–6325; (b) Hart, B. P.; Rapoport, H. J. Org. Chem.
1999, 64, 2050–2056; (c) Xu, Y.; Choi, J.; Calaza, I.; Turnert,
S.; Rapoport, H. J. Org. Chem. 1999, 64, 4069–4078.
10. Spectral data of key compounds:
1
Compound 9: H NMR (500 MHz, CDCl3, rotamers), d:
7.32 (m, 5H), 5.23 and 5.02 (AB system, J = 12 Hz, 0.8H;
O–CH2–Ph), 5.14 and 5.08 (AB system, J = 12.5 Hz, 1.2H;
O–CH2–Ph), 4.65 (dd, J = 3.5; 9 Hz, 0.4H; CH–CH2),
4.58 (dd, J = 4; 8.5 Hz, 0.6H; CH–CH2), 3.77 (s, 1.2H,
OCH3), 3.72 (s, 1.8H, OCH3), 3.63 (s, 1.8H, OCH3), 3.44
3. (a) Biscoe, T. J.; Evans, R. H.; Francis, A. A.; Martin, M.
R.; Watkins, J. C.; Davies, J.; Dray, A. Nature 1977, 270,
743; (b) McLennan, H.; Hall, J. G. Brain Res. 1978, 149,

V. S. Kubyshkin et al. / Tetrahedron Letters 48 (2007) 4061–4063
4063
(s, 1.2H, OCH3), 3.7 (m, 2H, CH2Cl), 2.83 (m, 0.6H; CH2–
CH2Cl), 2.65 (m, 0.4H; CH2–CH2Cl), 2.55 (m, 1H; CH2–
CH2Cl), 2.29 (m, 2H), 2.13 (m, 1H), 2.00 (m, 1H); 13C
NMR (101 MHz, CDCl3, rotamers), d: 173.52 (CO2Me),
173.26 (CO2Me), 173.07 (CO2Me), 172.93 (CO2Me),
154.68 (NAC(@O)AO), 154.27 (NAC(@O)AO), 136.36
(C, Ph), 135.86 (C, Ph), 128.81 (CH, Ph), 128.73 (CH, Ph),
128.67 (CH, Ph), 128.64 (CH, Ph), 128.28 (CH, Ph),
127.77 (CH, Ph), 69.48 (O–CH2–Ph), 68.63 (O–CH2–Ph),
68.09 (N–C–CO2Me), 67.59 (N–C–CO2Me), 61.95
(NCH–CO2Me), 61.08 (N–CH–CO2Me), 53.00 (CO2Me),
52.74 (CO2Me), 52.68 (CO2Me), 52.51 (CO2Me), 40.43
(CH2Cl), 40.14 (CH2Cl), 38.50 (CH2), 37.99 (CH2), 36.16
(CH2), 35.06 (CH2), 27.76 (CH2CH2Cl), 27.03
Compound 10: 1H NMR (400 MHz, CDCl3), d: 7.20
(m, 5H; Ph), 4.90 (s, 2H; O–CH2–Ph), 3.45 (s, 6H; OCH3),
2.16 (d, J = 6.5 Hz, 4H), 1.66 (d, J = 6.5 Hz, 4H);
13C NMR (101 MHz, CDCl3), d: 168.99 (CO2Me),
155.63 (NAC(@O)AO), 135.33 (C, Ph), 128.49 (CH, Ph),
128.12 (CH, Ph), 127.98 (CH, Ph), 70.48 (O–CH2–Ph),
67.70 (N–C–COOMe), 51.45 (COOMe), 32.64 (CH2); IR
(KBr), cmꢀ1: 1745 (C@O), 1714 (C@O, NAC(@O)AO);
MS (m/z): 348 (M+1)+. Anal. Calcd for C18H21NO6: C,
62.24; H, 6.09; N, 4.03. Found: C, 61.92; H, 5.86; N,
4.00.
1
Compound 1ÆHCl: H NMR (400 MHz, CD3OD), d: 2.30
(s, 4H); 13C NMR (101 MHz, CD3OD), d: 170.52 (CO2H),
72.49 (N–C–CO2H), 32.28 (CH2); MS (m/z): 186
(MꢀCl)+. Anal. Calcd for C8H12ClNO4: C, 43.35; H,
5.46; N, 6.32. Found: C, 43.10; H, 5.14; N, 5.95. mp
>300 °C (decomp.). IR (KBr), cmꢀ1: 3030, 1741 (C@O),
1405, 1228.
(CH2CH2Cl); IR (KBr), cmꢀ1
:
1745 (C@O)+, 1710
(C@O, NAC(@O)AO); MS (m/z): 386 (37Cl M+1), 384
(35Cl M+1)+. Anal. Calcd for C18H22ClNO6: C, 56.33;
H, 5.78; N, 3.65. Found: C, 55.90; H, 5.35; N, 3.51.