The synthesis of α-amino-γ-substituted adipic acids: Stereoelectronic effects during the 1,4-addition of organocuprates to methyl N-tert-butoxy-6-oxo-1,2,3,6-tetrahydropyridine-2-carboxylate

Article abstract of DOI:10.1039/a809274e

The α,β-unsaturated lactam 3 was submitted to 1,4-addition of organocuprate reagents R₂CuLiI₂ (R = Me, Bu or Ph) to provide the 4-substituted compounds 5a-c, 6a-c as a mixture of diastereomers; these intermediates were then transform

Full text of DOI:10.1039/a809274e

The synthesis of a-amino-g-substituted adipic acids: stereoelectronic effects
during the 1,4-addition of organocuprates to methyl
N-tert-butoxy-6-oxo-1,2,3,6-tetrahydropyridine-2-carboxylate
Mireille Muller, Angèle Schoenfelder, Bruno Didier, André Mann* and Camille-Georges Wermuth
Laboratoire de Pharmacochimie de la Communication Cellulaire, ERS 655, Faculté de Pharmacie, 74, route du
Rhin, BP 24, F-67401 Illkirch Cedex, France. E-mail: andre.mann@pharma.u-strasbg.fr
Received (in Liverpool, UK) 26th November 1998, Accepted 4th March 1999
The a,b-unsaturated lactam 3 was submitted to 1,4-addition
of organocuprate reagents R2CuLiI2 (R = Me, Bu or Ph) to
provide the 4-substituted compounds 5a–c, 6a–c as a
mixture of diastereomers; these intermediates were then
transformed into the corresponding a-amino-g-substituted
adipic acids 7a–c, 8a–c.
has a well resolved signal (dd) between d 4.5–4.8 for the
hydrogen attached at C-2. Surprisingly, in analyzing these
signals for the 5a/6a, 5b/6b and 5c/6c mixtures, we observed
that the intensity for the upfield signal (trans diastereomer)
increases at the expense of the corresponding downfield one (cis
diastereomer). These results indicate a change in the cis:trans
ratio related to the structure of the transfered substituent. After
purification, the pattern of the H-5ax proton was identified in
each diastereomer as a doublet of doublets (B part of an ABX
spin sytem) in which largest J value (around 17 Hz),
corresponds to the geminal coupling H-5ax/H5eq. The smaller
J value (around 11 Hz) arises from to the coupling between H-
5ax and H-4, and these were of comparable value in all the
compounds (5a–c and 6a–c), consistent with an axial disposi-
tion of the proton at C-4. As a consequence the Me, Bu or Ph
substituents attached at C-4 have an equatorial disposition in
each diastereomer. For the protons attached at C-2 in 5a and 6a
two sets of coupling constants were measured: J = 10 and 6 Hz,
and J = 4 and 2 Hz, repectively. From these data it was clear
that in the analogues 5a–c the carboxylate adopts an equatorial
disposition (large J values = axial orientation of the proton at
C-2) whilst in contrast for derivatives 6a–c the carboxylate has
The synthesis of modified and unnatural amino acids is a source
of constant inspiration in organic chemistry.1–3 In recent years
glutamic acid, a major neurotransmitter in the mammalian
brain, has received considerable attention from chemists
involved in neurosciences.4,5 During earlier studies on modified
glutamates, we and others have found that the g-substituted
analogues of structure 1 are invaluable tools for the pharmaco-
NH2
R
NH2
R
CO2H
HO2C
CO2H HO2C
O
N
CO2Me
Boc
1
2
3
logical exploration of excitatory amino acid receptors.6,7
Interestingly it was found that the biological activity of such
derivatives was largely confined to the 2S,4S diastereomers. For
structure–activity studies devoted to this class of amino acids,
we decided to synthesize compounds of type 2 in which the
distal carboxylate is moved an additional methylene unit away
from the a-amino acid group compared with 1, generating g-
substituted a-amino adipic acids (Adi). As earlier observations
have already demonstrated that Adi itself possesses good
affinity for the glutamate receptors,8 the introduction of
different substituents on the Adi backbone may contribute to a
better knowledge of steric demands at the receptor level.9 Our
goal was to employ an enantiospecific and diastereoselective
synthesis which would provide analogues 2 in which the C-2
and C-4 substituents have the correct configuration for high
biological activity. Since we have previously prepared modified
glutamic acids using a conjugate addition of organocopper
reagents,10 we therefore proposed to submit compound 3 to a
similar sequence, in the expectation that the presence of the C-2
carboxylate would provide facial selectivity.11,12 We report
herein our observations on the diastereoselectivity obtained in
the 1,4-addition of organocuprate reagents to the a,b-un-
saturated lactam 3.
i, i i
i i i
3
O
N
CO2Me
Boc
4
R
NH2
R
i v
CO2H
HO2C
O
N
CO2Me
Boc
5a, 5b, 5c
7a, 7b, 7c
a = Me; b = Bu; c = Ph
+
R
NH2
R
i v
CO2H
HO2C
O
N
CO2Me
Boc
The starting compound 3 was obtained from (S)-lysine in
enantiomerically pure form via piperidone 4, following lit-
erature reports.13215 The unsaturation was introduced by a
sequence involving selenation and oxidative elimination, as
decribed for the preparation of the corresponding benzyl ester
(Scheme 1).15 Since lactam 3 is potentially prone to nucleo-
philic attack, we were pleased to find that the reaction of this
substrate in Et2O with different organocuprates gave the
expected adducts as mixtures of cis/trans diastereomers (5a–c
and 6a–c) in acceptable yields, and in moderate to good
6a, 6b, 6c
8a, 8b, 8c
5a : 6a = 5 : 1; 5b : 6b = 1 : 1
5c : 6c = 1 : 20
Scheme 1 Reagents and conditions: i, LiHMDS (1.1 equiv.), PhSeCl (1. 2
equiv.), THF 278 °C, 2 h (78%); ii, MCPBA (2 equiv.), CH2Cl2, 25 °C, 12
h (72%); iii, for 5a/6a: MeLi (2 equiv.), CuI (1 equiv.), Et2O, 278 °C, 2 h,
5a (68%) and 6a (9%); for 5b/6b: BuLi (2 equiv.), CuI (1 equiv.), 278 °C,
2 h , 5b (35%) and 6b (33%); for 5c/6c: PhLi (2 equiv.), CuI (1 equiv.),
Et2O, 278 °C, 2 h , 6c (48%); HCl in AcOH, reflux, 3 h (from 45 to
80%).
1
stereoselectivity.† Examination of the H NMR (200 MHz)
spectra of the crude mixtures revealed that each diastereomer
Chem. Commun., 1999, 683–684
683

an axial orientation (small J values = equatorial orientation of
the proton at C-2). These data are consistent with a chair
conformation for all of the isolated compounds, in which the
products 5a–c have the substituents in a 1,3-cis arrangement,
and 6a–c in a 1,3-trans arrangement. In order to explain these
findings, we performed calculations on lactam 3 (MOPAC out
of SYBYL 6.3) which demonstrated that the conformer having
the carboxylate at C-2 in an axial disposition is, by far, more
stable (5 kcal mol21) than the corresponding equatorial
conformer‡ (Scheme 1). This result is the obvious consequence
of a strong A1,3 strain between the carboxylate at C-2 and the
Boc group on the nitrogen atom.16 Based on these calculations
and several literature reports on the stereoelectronic effects
during conjugated addition in related a,b-unsaturated cyclohex-
anones or 2,3-dihydro-4-pyridones,17,18 a strong axial bias was
expected to operate during the addition of nucleophilic reagents
to lactam 3. Therefore one should observe the preferential
formation of the cis adducts (5a–c) at the expense of the
corresponding trans epimers (6a–c). Indeed for the smallest
substituent (R = Me) an appreciable diastereoselectivity in
favor of the cis adduct was observed (5a:6a = 5:1). However
when the steric demand of the organocuprate was increased (R
= Bu), the facial selectivity was lost (5b:6b = 1:1) or, for still
bulkier groups (R = Ph) the facial steroselectivity was reversed,
and the trans diastereomer was the only one detected (5c:6c =
1:30). Allinger has discussed a closely related example
involving the 1,4-addition of Grignard reagents to 5-methyl-
cyclohex-2-enone,19 in which the importance of the conforma-
tion of the conjugated enolate (chair or boat) produced by
parallel or anti-parallel attack was considered. As the carbox-
ylate function in 3 is assumed to be axial, the major pathway for
the reaction with Me2CuLi2I was via an anti-parallel attack to
give the transient enolate of 5a. This intermediate possesses a
low energy chair-like conformation (TS chair), in spite of the
1,3-diaxial interaction between the carboxylate and the incom-
ing methyl group. When the nucleophile is larger, such as in
Bu2CuLi2I (5b/6b) or Ph2CuLi2I (5c/6c), the reaction pathway
via parallel attack takes place preferentially due to a competing
strong 1,3-diaxial interaction between the carboxylate and the
bulky incoming nucleophile. This gives a transient, boat-like
(TS boat) enolate, which collapses to the trans chair conformer.
The final transformation of 5a–c and 6a–c into the desired
substituted adipic acids was realized under hydrolytic condi-
tions and the amino acids 7a,b and 8a–c were obtained as
crystalline hydrochlorides.§
In conclusion, the diastereoselectivity observed for the
conjugate addition of organocuprates to cyclic enamide 3 could
be controlled by an appropriate choice of the transferable
nucleophilic reagent. The significant A1,3 strain inherent to the
ring system and the size of the nucleophile are probably the key
factors responsible for the diastereoselectivity observed in this
conjugate addition reaction. Our findings demonstrate that a,b-
unsaturated species 3 is an excellent substrate for the prepara-
tion of enantiomerically pure (2S,4S)- or (2S,4R)-2-amino-
4-substituted adipic acids.
We thank Dr Jacques Royer (Gif sur Yvette, France) and
Professor Maurizio Taddei (Sassari, Italy) for valuable discus-
sions.
Notes and references
† Selected data for 5a: mp 60 °C; Rf 0.30 (hexanes–Et2O = 5:5); [a]D
266.2 (c 5, CHCl3); dH(200 MHz, 30 °C) 4.51 (dd, J 10.2 and 6.2, 1 H), 3.74
(s, 3 H), 2.62 (dt, J 17 and 2.4, 1 H), 2.30 (m, 1 H), 2.10 (dd, J 17 and 10,
1 H), 2.15 (m, 1 H), 1.53 (m, 1 H),1.48 (s, 9 H), 1.02 (d, J 6, 3 H); dC(50
MHz) 172.1, 170.1, 151.9, 83.6, 58.6, 52.3, 42.7, 34.1, 28.3, 27.7, 26.3,
20.7. (Calc. for C13H21NO5 : C, 57.54; H, 7.80; N, 5.16. Found: C, 57.3; H,
7.9; N, 5.2%). For 6a: oil; Rf 0.35 (hexanes–Et2O = 6:5); [a]D +20.1 (c 2,
CHCl3, 30 °C); dH(200 MHz) 4.71 (dd, J 4 and 1.8, 1 H), 3.80 (s, 3 H), 2.66
(ddd, J 16.3, 3.2 and 1.4, 1 H), 2.21 (dd, J 9.1, 4 and 1.4, 1 H), 2.09 (dd, J
16.3 and 9.6, 1 H), 1.96 (m, 1 H), 1.73 (m, 1 H), 1.51 (s, 9 H), 1.01 (d, J
4.2, 3 H); dC(50 MHz) 172.2, 169.9, 152.2, 83.6, 58.3, 52.6, 42.8, 33.5, 29.7,
27.9, 25.1, 21.1. (Calc. for C13H21NO5: C, 57.54; H, 7.80; N, 5.16. Found:
C, 57.6; H, 7.6; N, 5.1%).
‡ In compound 3, the recorded coupling constant (dd, J 4.5) is consistant
with an axial orientation of the carboxylate.
§ Preparation of 7a: Lactam 5a (96 mg, 0.35 mmol) was heated at reflux for
2 h in a mixture of concentrated HCl (2 ml) and AcOH (4 ml). The mixture
was concentrated in vacuo and triturated with Et2O, to provide a solid which
was filtered to yield 7a (60 mg, 81%) as a hygroscopic solid; mp 178 °C;
[a]D 279 (c 1, MeOH); m/z (FAB) 176 (M + H+). For 8a: mp 196 °C; [a]D
+26 (c = 1.8, MeOH); m/z (FAB) 176 (M + H+).
parallel attack
a
H
O
Boc
H
N
H
H
1 F. J. Sardina and H. Rapoport, Chem. Rev., 1996, 96, 1825.
2 R. O. Duthaler, Tetrahedron, 1994, 50, 1539.
3 J. Jurczak and A. Golebiowski, Chem. Rev., 1989, 89, 149.
4 M. G. Moloney, Nat. Prod. Rep., 1998, 205.
H
CO2Me
b
5 T. Knöpfel, R. Kuhn and A. Allgeier, J. Med. Chem., 1995, 38, 1417.
6 C. G. Wermuth, A. Mann, A. Schoenfelder, R. A. Wright, B. G.
Johnson, J. P. Burnett, N.G. Mayne and D. D. Schoepp, J. Med. Chem.,
1996, 39, 814.
anti-parallel attack
b
a
7 Z.-Q. Gu, X.-F.Lin and D. P. Hesson, Bioorg. Med. Chem. Lett., 1995,
5, 1973.
8 R. H. Evans, A. A. Francis and J. C. Watkins, Brain Res., 1978, 148,
536.
9 J. Ezquerra, C. Pedregal, A. Escribano, M. C. Carreno and J. L. G.
Ruano, Tetrahedron Lett., 1995, 36, 3247.
10 I. Jako, P. Uiber, A. Mann, C. G. Wermuth, T. Boulanger, B. Norberg,
G. Evrard and F. Durant, J. Org. Chem., 1991, 56, 5729.
11 N. Krause and A. Gerold, Angew. Chem., Int. Ed. Engl., 1997, 36,
186.
R
H
H
LiO
LiO
Boc
H
Boc
N
N
H
H
H
H
H
H
CO2Me
R
CO2Me
TS chair-like
TS boat-like
12 P. Perlmutter, in Conjugate Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992, pp. 137–197 and references cited therein.
13 S. A. Hermitage and M. G. Moloney, Tetrahedron: Asymmetry, 1994, 5,
1463.
14 C. E. Davies, T. D. Heightman, S. A. Hermitage and M. G. Moloney,
Synth. Commun., 1996, 26, 687.
15 P. J. Murray and I. D. Starkey, Tetrahedron Lett., 1996, 37, 1875.
16 R. W. Hoffmann, Chem. Rev., 1989, 89, 1841.
17 P. Deslongchamp, in Stereoelectronic Effects in Organic Chemistry,
Pergamon, Oxford, 1983, p. 209.
18 J. D. Brown, M. A. Foley and D. L. Comins, J. Am. Chem. Soc., 1988,
110, 7445.
H5
H4
H5
H3
O
H2
O
N
Boc
H2
H5
R
Boc
CO2Me
R
H3
N
H5
H3
H3
H4
CO2Me
5a–c (cis)
6a–c (trans)
4 Hz < J H-2 H-3ax < 5.6 Hz
7 Hz < J H-5ax H-4 < 12 Hz
10 Hz < J H-2 H-3ax <10.5 Hz
8 Hz < J H-5ax H-4 < 11 Hz
Scheme 2 Possible transition states and recorded values for coupling
19 N. L. Allinger and C. K. Riew, Tetrahedron Lett., 1966, 7, 1269.
constants.
Communication 8/09274F
684
Chem. Commun., 1999, 683–684