Conformationally restricted glutamic acid derivatives: Asymmetric synthesis of 4-substituted 4,5-dihydro-3(2H)-pyridazinones

Article abstract of DOI:10.1016/S0040-4039(01)00147-2

The synthesis of optically pure 4,5-dihydro-3(2H)-pyridazinones substituted at C-4, which can be considered conformationally restricted cyclic Glu derivatives, has been accomplished by the asymmetric γ-alkylation of α,β-unsaturated glutamyl sultams under PTC conditions followed by reaction with hydrazines.

Full text of DOI:10.1016/S0040-4039(01)00147-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2129–2131
Conformationally restricted glutamic acid derivatives: asymmetric
synthesis of 4-substituted 4,5-dihydro-3(2H)-pyridazinones
Carlos Alvarez-Ibarra,* Aurelio G. Csa´ky¨, Cristina Go´mez de la Oliva and Eliazar Rodr´ıguez
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, Universidad Complutense, 28040 Madrid, Spain
Received 5 December 2000; accepted 23 January 2001
Abstract—The synthesis of optically pure 4,5-dihydro-3(2H)-pyridazinones substituted at C-4, which can be considered conforma-
tionally restricted cyclic Glu derivatives, has been accomplished by the asymmetric g-alkylation of a,b-unsaturated glutamyl
sultams under PTC conditions followed by reaction with hydrazines. © 2001 Elsevier Science Ltd. All rights reserved.
Conformationally constricted a-amino acids have
attracted a great deal of attention in recent times in the
design of peptide surrogates with improved metabolical
properties over the natural peptides.1 In particular, cyclic
compounds have been much used to induce turns in
peptide chains,2 and those which include a N–N linkage
in their cyclic structure are well known for their biological
activities.3 Dihydropyridazinones can be considered as
rigid analogues of hydrazinolactams.4 In view of the
ability of certain cyclic glutamic acid derivatives to induce
conformational restrictions to peptide chains,5 we consid-
ered that rigid cyclic Glu-derived dihydropyridazinones
which bear asymmetric carbon atoms on the heterocyclic
core could be particularly attractive in this area.
Scheme 1.
Keywords: alkylation; amino acids and derivatives; cyclization; pyridazinones; sultams.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00147-2

2130
C. Al6arez-Ibarra et al. / Tetrahedron Letters 42 (2001) 2129–2131
Table 1. g-Alkylation of substrates 3 under PTC conditions
No.
3
R1X
R1
t (min)
4 (2R:2Sa, %b)
(2R)-4, %c
1
2
3
4
5
6
7
3a
3a
3a
3a
3a
3a
3b
MeI
MeI
Me
Me
PhCH2
EtO2CCH2
pNO2-C6H4-CH2
CH2ꢀCHCH2
Me
10
60
60
60
60
60
60
4a (92:08, 30)
4a (92:08, 85)
4b (100:0, 90)
4c (100:0, 85)
4d (91:09, 85)
4e (93:07, 90)
4f (70:30, 50)
–
70
80
75
70
70
–
PhCH2Br
EtO2CCH2Br
pNO2-C6H4-CH2Br
CH2ꢀCHCH2Br
MeI
a Determined by integration of the 1H NMR (300 MHz, CDCl3) spectra of the crude reaction products.
b Isolated yields after filtration of the reaction crude, rinsing with Et2O, evaporation of the solvent and silica-gel chromatography (hexane:ethyl
acetate, 80:20).
c Isolated yields after crystallization (hexane:ethyl acetate).
Table 2. Synthesis of the 4-substituted 3,4-dihydro-
3(2H)pyridazinones 6
The results are given in Table 1. It is worth mentioning
that no racemization was observed upon increasing the
reaction time under the same reaction conditions (Table
1, entries 1 and 2). Furthermore, the diastereomeric
excesses observed in the asymmetric g-alkylation of
sultam 3a under PTC conditions were higher than those
previously reported for the corresponding 8-phenylmen-
thyl ester 3b in homogeneous solution (LDA or KOtBu,
THF).11 As a matter of fact, the g-alkylation of 3b
under the aforementioned PTC conditions (Table 1,
entry 7) took place with low diastereoselectivity and
low overall yield.
Entry
4
R1
5
R2
6 (%a)
1
2
3
4
5
6
4a
4a
4a
4b
4c
4d
CH3
CH3
CH3
PhCH2
EtO2CCH2
pNO2-C6H4-CH2Br
5a
5b
5c
5a
5a
5a
H
6a (95)
6b (95)
6c (90)
6d (90)
6e (90)
6f (90)
PhCH2
CH3
H
H
H
a Isolated yields after extraction with Et2O and silica-gel chromato-
graphy (hexane:ethyl acetate, 80:20).
An additional benefit in the use of Oppolzer’s camphor-
sultam arises in both the ease of cleave and the recovery
of the chiral auxiliary.8 Thus, the reaction of com-
pounds 4a–d with hydrazines 5 (2 equiv., EtOH, D, 24
h) allowed for the synthesis of the 4-substituted 3(2H)-
pyridazinones 6 in a one-pot N-deprotection12/cycliza-
tion sequence (Scheme 1), with recovery of the chiral
inducer after chromatography of the reaction mixture.
The results are given in Table 2.
Scheme 2.
No epimerization at C4 occurred in the cyclization
process, as evidenced by the transformation of com-
pound 6a into 7 (LiHMDS, ClCH2CO2R*, R*=(−)-
menthyl), which gave rise to a single diastereomer as
evidenced by 1H NMR (CDCl3, 300 MHz) of the
reaction crude (Scheme 2).
Therefore, we report herein the asymmetric g-alkylation
of a,b-unsaturated glutamic acid derivatives under
solid–liquid PTC conditions and their cyclization to
optically pure 4,5-dihydro-3(2H)-pyridazinones as a
new entry to this class of compounds.
t
Enolization of the butyl glycinate 1 with KOtBu (1.1
In conclusion, the procedure described herein consti-
tutes a novel entry to optically pure cyclic glutamic acid
derivatives, which may be of use in the preparation of
new conformationally restricted azapeptides. Further
research in this area is in progress, and will be reported
in due course.
equiv., THF, −78°C, 30 min) followed by reaction with
methyl propiolate (1.1 equiv.) afforded the a,b-didehy-
droglutamic acid derivative 2 via a Michael addition/
1,3-prototropic shift pathway.6 Selective Me3Al-
mediated acylation7 of the terminal methyl ester of 2
with Oppolzer’s (2R)-(−)-bornane-10,2-sultam8 (1.2
equiv. Me3Al, toluene, 50°C, 48 h) gave rise to the
a,b-didehydroglutamylsultam 3a (80% isolated yield).
This was regioselectively alkylated under solid–liquid
PTC conditions exclusively at the g-position (1.1 equiv.
RX, acetonitrile, 1.0 equiv. NaOH, 10% mol TEBA–Cl,
1 h, rt)9 with very good overall yields and high
diastereomeric excesses in favor of the 2R isomers10 of
compounds 4a–e (Scheme 1).
Acknowledgements
DGCYT (project PB96-0009) is gratefully thanked for
financial support and the predoctoral grant of one of
the authors (C.G.). We also thank UCM (MS, NMR
and elemental analysis services).

C. Al6arez-Ibarra et al. / Tetrahedron Letters 42 (2001) 2129–2131
2131
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