Enantiospecific synthesis of 3,4-disubstituted glutamic acids via controlled stepwise ring-opening of 2,3-aziridino-γ-lactone

Article abstract of DOI:10.1016/S0040-4039(02)01762-8

The preparation of enantiomerically pure 3,4-disubstituted glutamic acids is described starting from D-ribose. This preparation involved the use of a 2,3-aziridino-γ-lactone whose reactivity towards nucleophiles could be efficiently controlled to allow selective functionalization at the β-position. A key step of the strategy was a titanate-mediated transesterification of a dimethyl ester into a dibenzyl analogue, allowing efficient deprotection to the free amino acid by hydrogenolysis.

Full text of DOI:10.1016/S0040-4039(02)01762-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7593–7595
Enantiospecific synthesis of 3,4-disubstituted glutamic acids via
controlled stepwise ring-opening of 2,3-aziridino-g-lactone
Zhaohua Yan, Robert Weaving, Philippe Dauban and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, C.N.R.S., 91198 Gif-sur-Yvette Cedex, France
Received 3 July 2002; accepted 18 August 2002
Abstract—The preparation of enantiomerically pure 3,4-disubstituted glutamic acids is described starting from
D-ribose. This
preparation involved the use of a 2,3-aziridino-g-lactone whose reactivity towards nucleophiles could be efficiently controlled to
allow selective functionalization at the b-position. A key step of the strategy was a titanate-mediated transesterification of a
dimethyl ester into a dibenzyl analogue, allowing efficient deprotection to the free amino acid by hydrogenolysis. © 2002 Elsevier
Science Ltd. All rights reserved.
The conformational flexibility of
L
-glutamic acid 1, the
C-3 and C-4 substituted derivatives.3 Recently, our
interest in 2,3-aziridino-g-lactone methodology2l,4 cul-
minated in the first stereoselective total synthesis of
major excitatory neurotransmitter of the central ner-
vous system, confers the ability to bind to several types
of glutamic acid receptors which are divided into two
main classes: the ionotropic receptors (iGluRs) which
are associated with cation-gated channels, and the
metabotropic receptors (mGluRs) coupled to second
messenger systems through GTP-binding proteins.1
Each receptor class is divided into three subclasses
which are in turn subdivided into several subtypes.
such a compound, namely (3S,4S)-3,4-dihydroxy-L-glu-
tamic acid [(3S,4S)-DHGA] 25 which was subsequently
shown to be selective mGluR1 agonist.6 For the pur-
pose of structure–activity studies, we decided to prepare
the methoxy and dimethoxy analogues of 2, i.e. the
amino acids 3, 4 and 5.
The synthesis of compound 2 involved the use of the
bicyclic intermediate 6. Simultaneous nucleophilic lac-
tone and aziridine ring-opening by benzyl alcohol
afforded, after removal of all the blocking groups by
hydrogenolysis, (3S,4S)-DHGA 2 (Scheme 1).5 How-
ever, although successful, the efficiency of this strategy
In order to gain insight into the physiological role of
each of these receptor subtypes, the development of
selective ligands is needed. To this end, several C-3 or
C-4 substituted glutamic acids have been prepared2 but
few syntheses have been dedicated to the obtention of
Scheme 1.
* Corresponding author. Tel.: 33-1-69-82-45-94; fax : 33-1-69 07 72 47; e-mail: robert.dodd@icsn.cnrs-gif.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01762-8

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Z. Yan et al. / Tetrahedron Letters 43 (2002) 7593–7595
diastereoisomers.9 These results prompted us to turn
our attention to the aziridine 2-carboxylate 15 for the
preparation of amino acids 4 and 5.
was hampered by the sensitivity of the benzyl ester
which made the preparation of the aziridino-g-lactone 6
tedious, the latter being synthesized in 13 steps from
D
-ribose in only 6% overall yield.
Thus, by working at a lower temperature, reaction of
compound 7 in methanol in the presence of boron
trifluoride etherate could efficiently be controlled to
give only the lactone ring-opened product 15 in 73%
yield (Scheme 3).10 Transesterification at this stage of
the synthesis was envisaged but it appeared to us that
the Lewis acidity of the titanium complex could acti-
vate the aziridine ring towards ring opening by the free
hydroxyl group. The latter was thus methylated to give
the protected derivative 16 in 76% yield. The reaction
of 16 with benzyl alcohol then occurred at the C-3
position as expected affording compound 17 in 83%
yield while aziridine ring-opening with methanol led to
the dimethoxy derivative 19 in 80% yield. Finally, the
key step, i.e. the titanate-mediated transesterification,
was investigated. After several experiments, it was
found that the reaction was best run with freshly pre-
We therefore decided to reconsider use of the methyl
ester analogue of 6, i.e. compound 7, that we previously
prepared for the same purpose.2l Due to the increased
stability of the methyl ester, its synthesis from
D-ribose
was performed in a more acceptable 17% overall yield
(Scheme 1). But we failed to complete the total synthe-
sis of substituted glutamic acids from 7 since acidic
hydrolysis or saponification of the methyl esters were
not compatible with the high functionality of these
molecules. In order to fully explore the synthetic oppor-
tunities provided by the 2,3-aziridino-g-lactone 7, we
turned our attention to a possible transesterification of
the methyl esters into benzyl esters based on the pio-
neering work of Seebach7 recently revisited by Shapiro8
related to the titanate-mediated transesterification of
functionalized substrates.
11
pared Ti(OBn)4 in toluene at reflux and was complete
Initial efforts were devoted to the preparation of amino
acid 3. Reaction of compound 7 in methanol in the
presence of boron trifluoride etherate led to the forma-
tion of the glutamate analogue 9 in 83% yield (Scheme
2). However, application of the titanate-mediated trans-
esterification did not afford the expected dibenzyl ester
10. Reaction of the silylated derivated 11 with Ti(OBn)4
also failed while the lactone 13, obtained after acidic
cyclization of compound 9, afforded the desired benzyl
ester 14 but as an inseparable 1:1 mixture of
within 10–15 minutes. The resulting dibenzyl esters 18
and 20 were isolated, in 83 and 85% yield, respectively,
after careful purification by flash chromatography. No
traces of monobenzyl esters could be detected under
these conditions. Hydrogenolysis of all the protecting
groups then afforded the desired amino acids 4 and 5 in
quantitative yield.12
In conclusion, use of the 2,3-aziridino-g-lactone methyl
ester 7 allowed preparation of (2S,3S,4S)-3-hydroxy-4-
Scheme 2.
Scheme 3.

Z. Yan et al. / Tetrahedron Letters 43 (2002) 7593–7595
7595
methoxy- and (2S,3S,4S)-3,4-dimethoxyglutamic acids
in 18 steps starting from -ribose with an overall yield
hedron Lett. 1998, 39, 2167–2170; (j) Wermuth, C. G.;
Mann, A.; Schoenfelder, A.; Wright, R. A.; Johnson, B.
G.; Burnett, J. P.; Mayne, N. G.; Schoepp, D. D. J. Med.
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Pelletier, J. C.; Maccechini, M. L.; Zhou, L. M.; Skol-
nick, P. J. Med. Chem. 1995, 38, 2518–2520; (l) For a
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D
of 6%. Key steps are, on one hand, the selective lactone
ring-opening of compound 7 to afford the useful
aziridine 2-carboxylate 15 and, on the other hand, the
titanate-mediated transesterification of the dimethyl
ester into the more easily deprotected dibenzyl ana-
logue. The pharmacological activity of these substituted
glutamic acids with respect to GluRs will be reported
elsewhere.
3. (a) Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron
Lett. 2001, 42, 5901–5902; (b) Langlois, N. Tetrahedron
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Acknowledgements
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910; (b) Dubois, L.; Mehta, A.; Tourette, E.; Dodd, R.
H. J. Org. Chem. 1994, 59, 434–441; (c) Dauban, P.;
Dubois, L.; Tran Huu Dau, E.; Dodd, R. H. J. Org.
Chem. 1995, 60, 2035–2043; (d) Dauban, P.; Dodd, R. H.
J. Org. Chem. 1997, 62, 4277–4284; (e) Dauban, P.;
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Dodd, R. H. Tetrahedron Lett. 2000, 41, 6393–6397.
5. Dauban, P.; De Saint-Fuscien, C.; Dodd, R. H. Tetra-
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6. Dauban, P.; De Saint-Fuscien, C.; Acher, F.; Pre´zeau, L.;
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9. The epimerization at the C-4 position could be related to
the Lewis acidity of the titanium complexes.
10. It should be mentioned that such a controlled lactone
ring-opening reaction was also performed with 2,3-
aziridino-g-lactone 6 in the presence of benzyl alcohol,
but in rather poor yield (<35%).
We thank the CNRS (Z.Y.) for a fellowship and the
EEC for a Marie Curie (R.W.) fellowship and financial
support.
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11. Ti(OBn)4 was prepared by refluxing a solution of Ti(Oi-
Pr)4 in toluene in the presence of 5 equiv. of benzyl
alcohol.
12. Selected data: compound 4: mp 192–193°C; [h]2D1 −19.1 (c
1
0.115, MeOH); H NMR (200 MHz, CD3OD) l 3.42 (s,
3H), 3.91 (m, 1H), 4.04 (m, 1H), 4.48 (m, 1H); 13C NMR
(50 MHz, CD3OD) l 53.0, 59.2, 70.0, 84.9, 163.8, 169.2.
Compound 5: mp 191–193°C; [h]2D1 −35.2 (c 0.125,
MeOH); 1H NMR (200 MHz, CD3OD) l 3.42 (s, 3H),
3.46 (s, 3H), 3.85 (m, 1H), 4.16 (m, 1H), 4.20 (m, 1H);
13C NMR (50 MHz, CD3OD) l 53.4, 58.0, 79.2, 82.9,
173.0, 178.2.