An alternative to the use of delta-lactam urethanes in the "ring switch" approach to higher homologues of AMPA-type glutamate antagonists.

Article abstract of DOI:10.1039/b304609p

In an alternative strategy to the use of delta-lactam urethanes for the preparation of homologues of AMPA-type glutamate antagonists, we have used 5-exomethylene derivatives of pyroglutamate esters. The homochiral pyrazole amino acid derivatives 18 and 19 have been prepared in this way. Although this synthesis yields products with a glycine residue separated from a heterocyclic ring by two carbon atoms, the substitution of the heterocyclic ring is different from that in compounds prepared from delta-lactam urethanes. The branched chain compounds 32 and 33 have also been prepared in this way but the second chiral centre is epimerised during the synthesis. An interesting reaction, giving the pyridone 27 from the imino ether 24 and tert-butyl acetoacetate, is also reported.

Full text of DOI:10.1039/b304609p

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An alternative to the use of ꢀ-lactam urethanes in the
“ring switch” approach to higher homologues of AMPA-type
glutamate antagonists
Peter B. Hitchcock, Shazia Rahman (née Masood) and Douglas W. Young*
Sussex Centre for Biomolecular Design and Drug Development, CPES, University of Sussex,
Falmer, Brighton, UK BN1 9QJ
Received 25th April 2003, Accepted 9th June 2003
First published as an Advance Article on the web 25th June 2003
In an alternative strategy to the use of δ-lactam urethanes for the preparation of homologues of AMPA-type
glutamate antagonists, we have used 5-exomethylene derivatives of pyroglutamate esters. The homochiral pyrazole
amino acid derivatives 18 and 19 have been prepared in this way. Although this synthesis yields products with a
glycine residue separated from a heterocyclic ring by two carbon atoms, the substitution of the heterocyclic ring is
different from that in compounds prepared from δ-lactam urethanes. The branched chain compounds 32 and 33 have
also been prepared in this way but the second chiral centre is epimerised during the synthesis. An interesting reaction,
giving the pyridone 27 from the imino ether 24 and tert-butyl acetoacetate, is also reported.
γ-lactams,7a–f β-lactams7g,h and δ-lactams8 are used as starting
materials and homochiral compounds with different numbers
of atoms in the chain between the heterocyclic and amino acid
Introduction
Glutamic acid is an excitatory neurotransmitter in the central
nervous system and its receptors have been shown to be divided
into a variety of sub-types which are addressed separately by
moieties are obtained. Use of β-lactam urethanes gives the
greatest variety of products in this approach.7g,h The approach
various analogues of the neurotransmitter. Thus, compounds
has also been applied to the synthesis of potential antibacterial
such as ibotenic acid 1, consisting of a heterocyclic ring system
compounds.9
fused to the α-carbon atom of a glycine moiety, and the
Reaction of δ-lactam urethane aldehydes 3 with bisnucleo-
homologous compounds such as AMPA 2 with a heterocyclic
philes yields a variety of homochiral compounds such as 4, 5, 6
ring fused to the β-carbon atom of an -alanine moiety are
and 7 where two carbon atoms separate the heterocyclic and
biologically active at specific and different ionotropic and
amino acid moieties,8 as shown in Scheme 1. It is known10 that
metabotropic glutamate receptor sub-types.1 This has led to
exocyclic enaminones of type 8 react with a variety of bisnucleo-
philes to yield substituted heterocyclic compounds such as 9.
This reaction involves 1,2-attack on the enaminone by the first
nucleophilic group, followed by Michael attack by the second
nucleophilic moiety as shown in Scheme 2. It therefore appeared
that if this reaction could be applied to pyroglutamate deriv-
great interest in the synthesis of such compounds. The glutam-
ate receptors have a variety of rôles in the central nervous sys-
tem2 and antagonists have been identified as potential drugs for
a variety of illnesses, including persistent pain,3 Alzheimer’s
disease,4 epilepsy5 and ischaemia.6
atives such as compound 10, then homochiral homologues of
AMPA type compounds might be obtained. The method would
not only be complementary to our “ring switching” reaction on
δ-lactam urethanes8 but it would give rise to compounds with
heterocyclic moieties which were differently substituted from
those prepared in our earlier synthesis.
Results and discussion
We have developed a versatile synthetic approach to homo-
chiral compounds of this type, which is ideally suited to library
Our first task was to prepare a series of exocyclic enaminones
of (2S)-pyroglutamate of type 10. We therefore converted
synthesis.7,8 In this method urethanes of aldehydes of activated
Scheme 1
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 2 – 2 6 8 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
2682

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Fig. 1 NOE studies on compound 13.
first instance, we prepared the imino ether ethyl ester 24 as
shown in Scheme 4. The urethane ester 2012 was converted into
the enaminone 21 in 88% yield using Bredereck’s reagent,
tert-butoxybis(dimethylamino)methane, and was hydrogenated
to yield compound 22 as a single diastereoisomer in 73%
yield. Compound 22 was assumed to be the (2S,4S)-isomer by
analogy to our work on the corresponding tert-butyl ester13 and
this was confirmed by using NOE experiments on the nitrile
ester 25 as discussed below. Removal of the urethane to give the
amide 23 in 93% yield was achieved using trifluoroacetic acid in
dichloromethane, and the imino ether 24 was prepared from
this in 86% yield using Meerwein’s reagent, triethoxonium
fluoroborate. The imino ether 24 could readily be converted to
the nitrile ester 25 in 47% yield by heating with tert-butyl
cyanoacetate and triethylamine. The (2S,4S)-stereochemistry
of this compound was confirmed by the NOE experiments
summarised in Fig. 2 where irradiation of the multiplet for H-2
at δ 4.44 ppm caused a 3.9% enhancement in the one proton
multiplet for H-3 at δ 2.61 indicating it to be H-3S. Irradiation
of the methyl doublet at δ 1.37 ppm caused an enhancement
of 3.4% in the other one proton multiplet for H-3 (H-3R) at
δ 2.0 ppm. The E-stereochemistry was proved by Secondary
Isotope Multiplet NMR spectroscopy of Partially Labelled
Entities (SIMPLE).14 Addition of 0.3 molar equivalents of
[2H4]-methanol to a weighed sample in C2HCl3 caused upfield
shifts to signals in the 13C-NMR spectrum. This was due to the
proximity of the relevant carbon atom in the molecule to
the N–2H function in the compound as noted in Fig. 2. The
carbonyl carbon of the tert-butyl ester showed a 64 ppb shift
and the C(CH3)3 carbon showed a 14 ppb shift. This can only
be due to the ester being on the same side of the double bond as
the NH group in compound 25.
Scheme 2
tert-butyl (2S)-pyroglutamate 1111 into the imino ether 12
using methyl trifluoromethanesulfonate as shown in Scheme 3.
This was reacted with tert-butyl acetoacetate and triethylamine
to yield the ketoester 13 in 36% yield. The ketoester 13 was
shown to have E-stereochemistry on the basis of the NOE stud-
ies described in Fig. 1. Enhancements were seen in both signals
for the protons, H-4, at δ 3.1 ppm and in the methyl proton
singlet at δ 2.37 ppm when the tert-butyl singlet at δ 1.50 ppm
was irradiated and enhancements were seen in the multiplet
for H-2 at δ 4.35 ppm and in one of the multiplets for H-3 at
δ 2.08 ppm when the tert-butyl signal at δ 1.45 ppm was irradi-
ated. The nitrile ester 14 was also prepared in 52% yield from
the imino ether 12 using tert-butyl cyanoacetate and triethyl-
amine. The product 14 was accompanied by a 6% yield of the
N-methyl derivative 15, presumably due to alkylation of the
product by the imino ether 12. The structure of the compound
15 was confirmed by alkylation of the ester 14 using NaHMDS
and methyl iodide when an identical compound was obtained.
The diketone 16 and the dinitrile 17 were also prepared from
the imino ether 12 in this way, and so a series of compounds
was available for application to the “ring switching” reaction. In
the event we were only able to obtain “ring switched” products
from the dinitrile 17. Reaction of this with hydrazine gave the
pyrazole 18 in 50% yield, and reaction with methylhydrazine
gave the N-methylpyrazole 19 in 87% yield.
Although the imino ether 12 had given the desired product 13
when reacted with tert-butyl acetoacetate and triethylamine,
reaction of the imino ether 24 with ethyl acetoacetate and
triethylamine in an attempt to prepare the corresponding
methylated product 26 gave no reaction. Further, reaction with
tert-butyl acetoacetate and Ni(acac)2 monohydrate gave no
product. Only when forcing conditions using Ni(acac)2 mono-
hydrate and triethylamine were used was any product obtained
and this proved to be the pyridone 27 in 22% yield. The
structure of this compound was confirmed by X-ray structure
The alternative “ring switching” reaction had therefore given
homochiral products in which a heterocyclic ring was separated
from a glycine moiety by a two carbon bridge.
We now investigated the possibility of using our synthesis to
prepare compounds with a branch in the side chain and, in the
t
t
Scheme 3 Reagents and conditions (i) CH3OSO2CF3–Et2O, Ϫ78 ЊC (71%); (ii) CH3COCH2CO2 Bu–Et3N (36%); (iii) NCCH2CO2 Bu–Et3N (52% 14
ϩ 6% 15); (iv) CH3COCH2COCH3–Et3N (40%); (v) NCCH2CN (76%); (vi) RNHNH2 (18 50%; 19 87%).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 2 – 2 6 8 8
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Scheme 4 Reagents and conditions (i) HC(NMe2)2OtBu (88%); (ii) H2/10% Pd–C (73%); (iii) F3CCO2H–CH2Cl2 (93%); (iv) (EtO)3ؒBF4–CH2Cl2
t
t
(86%); (v) NCCH2CO2 Bu–NEt3 (47%); (vi) H3CCOCH2CO2 Bu–NEt3–Ni(acac)2 (22%).
λmax 274 nm, due to the starting material had disappeared, the
“ring switched” product 32 was obtained as a mixture of
diastereoisomers in 28% yield. Thus we had obtained the
desired branched chain “ring switched” product but epimeris-
ation had occurred under the conditions of the reaction. Reac-
tion of the dinitrile 31 with methylhydrazine gave the “ring
switched” product 33 in 62% yield but again a mixture of
diastereoisomers was obtained (Scheme 5).
We have therefore succeeded in developing an alternative
“ring switching” reaction to prepare potential glutamate
antagonists with a two carbon chain between an amino acid
α-carbon atom and a heterocyclic moiety. Branched chain com-
pounds were also prepared by the method but epimerisation
was a problem and these compounds were prepared as mixtures
of epimers.
Fig. 2 NOE studies and upfield 13C isotope shifts for N–2H on
compound 25.
Experimental
Melting points were determined on a Kofler hot-stage and are
uncorrected. Optical rotation measurements were measured on
a PE 241 polarimeter using a 1 dm path length. Specific rotation
values are in 10Ϫ1 deg cm2 gϪ1 and concentrations, c, in g 100
mlϪ1. Infra-red spectra were recorded on a Perkin Elmer 1710
Fourier transform instrument and UV absorption spectra on an
ATI Unicam UV2-100 Fourier transform scanning spectro-
analysis (Fig. 3). Presumably this compound was formed
by hydrolytic ring opening of the imino ether 24 to the
corresponding ethyl ester, rather than the alternative hydrolysis
to the lactam 23. The amino ester would then react with two
molecules of tert-butyl acetoacetate to yield the pyridone 27.
The 4-methyl group had evidently had a profound effect on
preventing the “normal” reaction to give 26.
1
photometer. ε values are given in dm3 molϪ1 cmϪ1. H-NMR
spectra were recorded on Bruker WM 360 (360 MHz), DPX
300 (300 MHz) and AMX 500 (500 MHz) Fourier transform
instruments. J values are given in Hz. 13C-NMR spectra were
recorded on Bruker DPX 300 (75.5 MHz), AMX 500 (125.8)
and AC–P 250 (62.9 MHz) Fourier transform instruments.
INEPT and DEPT experiments were used to help assign
13C-NMR resonances where necessary. Residual solvent peaks
were used as internal references for all NMR spectra. Micro-
analyses were performed by Medac Ltd and also by Wellcome
Research Laboratories, Beckenham and GlaxoSmithKline,
Stevenage. Low resolution mass spectra and accurate mass
measurements were recorded on Kratos MS80RF and Fisons
Instruments VG Autospec double focusing spectrometers by
Dr A. Abdul-Sada. Flash column chromatography was per-
formed using Merck Kieselgel 60 (230–400 mesh–Art. 9385)
and Sorbsil C60 40/60 A. Unless otherwise stated all experi-
ments were conducted under an inert atmosphere of argon.
Petroleum ether refers to the fraction of hexanes of bp 60–80
ЊC.
Fig. 3 X-Ray structure of the pyridone 27 from the reaction of the
iminoether 24 with tert-butyl acetoacetate, triethylamine and Ni(acac)2.
We had already prepared the tert-butyl ester 2813,15 and,
using the method involving reduction of the corresponding
enaminone,13 we prepared a sample, mp 69–71 ЊC, [α]2D2 Ϫ44.8
(c 1.12, CHCl3).16 The urethane was selectively removed in the
presence of the tert-butyl ester using anhydrous 1 M HCl in
ethyl acetate to give the amide 29 in 64% yield. This was con-
verted to the imino ether 30 in 70% yield using methyl triflate in
ether. Reaction with malononitrile then gave the dinitrile 31 as a
single diastereoisomer in 90% yield. When the dinitrile 31 was
heated in aqueous hydrazine until the ultra violet absorption,
tert-Butyl (2S )-5-Methoxy-3,4-dihydro-2H-pyrrole-2-
carboxylate (12)
Methyl trifluoromethanesulfonate (0.90 ml, 8.1 mmol) was
added with care to a stirred solution of tert-butyl (2S)-pyro-
glutamate 1111 (1.0 g, 5.4 mmol) in anhydrous diethyl ether
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 2 – 2 6 8 8
2684

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Scheme 5 Reagents and conditions (i) 1 M HCl–EtOAc (64%); (ii) H3COSO2CF3–Et2O (70%); (iii) NCCH2CN (90%); (iv) RNHNH2 (32 28%,
33 62%).
(50 ml) at Ϫ78 ЊC. The reaction was stirred for 3 h at Ϫ78 ЊC
and at room temperature for 18 h. Aqueous ammonium
hydroxide (0.5M, 20 ml) was added and the mixture was stirred
for 1 h to ensure that excess reagent was destroyed. The mixture
was diluted with dichloromethane (20 ml) and the aqueous
phase was extracted with dichloromethane (5 × 30 ml). The
organic layers were combined and dried (MgSO4). The solvent
was removed in vacuo to yield tert-butyl (2S)-5-methoxy-3,4-
dihydro-2H-pyrrole-2-carboxylate 12 as a colourless oil (1.1 g,
ca. 100%), which was used without further purification; m/z
[ϩve FAB (3-NBA)] 222 [M ϩ Na]ϩ and 200 [M ϩ H]ϩ;
νmax (film)/cmϪ1 1737 (ester), 1681 (imine) and 1051 (ether);
δH (300 MHz, C2HCl3) 4.34 (1H, dd, J2,3A 7.9, J2,3B 5.3, H-2),
3.86 (3H, s, OCH3), 2.00–2.55 (4H, m, H-4 and H-3) and 1.44
(9H, s, OC(CH3)3); δC (75.5 MHz, C2HCl3) 174.7 (ester), 172.2
(C-5), 79.9 (OC(CH3)3), 67.7 (OCH3), 55.0 (C-2), 29.8 (C-4),
27.0 (OC(CH3)3) and 26.9 (C-3).
C16H24N2O4 requires C, 62.3; H, 7.8; N, 9.1%.); m/z [ϩve FAB
(3-NBA)] 331 [M ϩ Na]ϩ and 309 [M ϩ H]ϩ; νmax (film)/cmϪ1
3335 (NH), 2208 (CN) and 1739 (ester); λmax (MeOH)/nm
272 (ε 15100); δH (300 MHz, C2HCl3) 9.10 (1H, br s, NH,
2
slowly exchanges in H2O), 4.34 (1H, dd, J2,3A 8.5, J2,3B 5.8,
H-2), 2.87 (2H, m, H-4), 2.34 (1H, m, H-3A), 2.11 (1H, m,
H-3B), 1.43 (9H, s, OC(CH3)3) and 1.41 (9H, s, OC(CH3)3);
δC (75.5 MHz, C2HCl3) 173.3 (C-5), 170.1 (ester), 167.4 (ester),
119.9 (CN), 83.5 (OC(CH3)3), 81.6 (OC(CH3)3), 70.6 (C-6),
63.1 (C-2), 32.8 (C-4), 28.7 (OC(CH3)3), 28.3 (OC(CH3)3) and
25.8 (C-3).
tert-Butyl (2S )-5-(tert-butoxycarbonylcyanomethylene)-1-
methylpyrrolidine-2-carboxylate (15)
tert-Butyl (2S)-5-(tert-butoxycarbonylcyanomethylene)pyrrol-
idine-2-carboxylate 14 (100 mg, 0.33 mmol) was dissolved in
anhydrous tetrahydrofuran (1 ml), cooled to Ϫ78 ЊC and
stirred. Hexamethylphosphoramide (56 µl, 0.33 mmol) was
added, followed by a solution of NaHMDS (1.0 M in THF)
(0.32 ml, 0.33 mmol). The reaction was stirred at Ϫ78 ЊC for
1 h. Methyl iodide (44 µl, 0.72 mmol) was added and the mix-
ture was stirred at Ϫ78 ЊC for 9 h and at room temperature for a
further 16 h. Aqueous citric acid (5%, 1 ml) was added and the
tetrahydrofuran was removed in vacuo. The mixture was diluted
with water (2 ml) and extracted with ethyl acetate (5 × 1 ml).
The organic layers were combined and dried (MgSO4). The sol-
vent was removed in vacuo to yield a yellow oil, which was
purified by column chromatography on silica gel, using diethyl
ether–dichloromethane–petroleum ether (5 : 20 : 30) as eluent
to yield tert-butyl (2S)-5-(tert-butoxycarbonylcyanomethyl-
ene)-1-methylpyrrolidine-2-carboxylate 15 as a colourless oil (30
mg, 29%); [α]2D8 Ϫ74.5 (c 1.0, MeOH); (m/z (EI) Found
322.1894. C17H26N2O4 requires 322.1893); m/z [ϩve FAB (3-
NBA)] 345 [M ϩ Na]ϩ and 323 [M ϩ H]ϩ; νmax (film)/cmϪ1 2198
(CN) and 1723 (ester); λmax (MeOH)/nm 285 (ε 16800); δH (300
MHz, C2HCl3) 4.10 (1H, dd, J2,3A 9.1, J2,3B 4.2, H-2), 3.36 (3H,
s, NCH3), 3.14 (2H, m, H-4), 2.22 (1H, m, H-3A), 2.01 (1H, m,
H-3B) and 1.47 (18H, s, 2 × OC(CH3)3); δC (75.5 MHz, C2HCl3)
172.0 (C-5), 170.0 (ester), 166.1 (ester), 119.1 (CN), 83.6
(OC(CH3)3), 80.9 (OC(CH3)3), 70.9 (C-6), 70.3 (C-2), 36.5
(NCH3), 34.5 (C-4), 28.7 (OC(CH3)3), 28.4 (OC(CH3)3) and
25.3 (C-3).
tert-Butyl (2S )-5-(1-tert-butoxycarbonyl-2-oxopropylidene)-
pyrrolidine-2-carboxylate (13)
tert-Butyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxyl-
ate 12 (500 mg, 2.5 mmol), tert-butyl acetoacetate (0.72 ml,
5.0 mmol) and triethylamine (1.0 ml, 7.2 mmol) were heated at
100 ЊC for 120 h in a sealed tube. The solvent was removed in
vacuo to give a brown oil. Purification by column chromato-
graphy on silica gel, using ethyl acetate–petroleum ether (1 : 5)
as eluent gave a white solid, which was recrystallised from ethyl
acetate and petroleum ether to yield tert-butyl (2S)-5-(1-tert-
butoxycarbonyl-2-oxopropylidene)pyrrolidine-2-carboxylate 13
as a white solid (290 mg, 36%) mp 120–122 ЊC; [α]2D5 ϩ0.70
(c 1.0, MeOH) (Found: C, 63.0; H, 8.5; N, 4.3. C17H27NO5
requires C, 62.75; H, 8.4; N, 4.3%); m/z [ϩve FAB (3-NBA)] 326
[M ϩ H]ϩ; νmax (film)/cmϪ1 1736 (ester) and 1690 (ketone);
λmax (MeOH)/nm 293 (ε 20700); δH (300 MHz, C2HCl3) 11.53
(1H, br s, NH, slowly exchanges in 2H2O), 4.35 (1H, dd,
J2,3A 8.8, J2,3B 5.7, H-2), 3.10 (2H, m, H-4), 2.37 (3H, s, CH C᎐
᎐
3
O), 2.34 (1H, m, H-3A), 2.08 (1H, m, H-3B), 1.50 (9H, s,
OC(CH3)3) and 1.45 (9H, s, OC(CH3)3); δC (75.5 MHz, C2HCl3)
198.2 (ketone), 173.4 (ester), 170.5 (ester), 168.3 (C-6), 126.2
(C-5), 83.0 (OC(CH3)3), 80.4 (OC(CH3)3), 62.4 (C-2), 34.5
(C-4), 31.3 (CH C᎐O), 28.9 (OC(CH ) ), 28.3 (OC(CH ) ) and
᎐
3
3
3
3 3
25.8 (C-3).
tert-Butyl (2S )-5-(tert-Butoxycarbonylcyanomethylene)-
pyrrolidine-2-carboxylate (14)
tert-Butyl (2S )-5-(1-acetyl-2-oxopropylidene)pyrrolidine-2-
carboxylate (16)
tert-Butyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxyl-
ate 12 (8.50 g, 42.7 mmol), tert-butyl cyanoacetate (12.2 ml,
85.4 mmol) and triethylamine (1.0 ml, 7.17 mmol) were stirred
at 60 ЊC for 48 h. The solvent was removed in vacuo to give a
beige solid. Purification by column chromatography on silica
gel, using ethyl acetate–petroleum ether (1 : 4) as eluent gave
two products, tert-butyl (2S)-5-(tert-butoxycarbonylcyano-
methylene)-1-methylpyrrolidine-2-carboxylate 15 as a colourless
oil (0.83 g, 6%), identical in all respects with the compound
prepared independently below, and tert-butyl (2S)-5-(tert-
butoxycarbonylcyanomethylene)pyrrolidine-2-carboxylate 14 as
a white crystalline solid (6.80 g, 52%), mp 144–146 ЊC; [α]2D8
Ϫ2.8 (c 1.0, MeOH) (Found: C, 62.1; H, 8.05; N, 9.0.
tert-Butyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxyl-
ate 12 (300 mg, 1.5 mmol), acetylacetone (0.34 ml, 3.4 mmol)
and triethylamine (0.2 ml, 2.0 mmol) were heated at 100 ЊC for
120 h in a sealed tube. The solvent was removed in vacuo to give
a brown oil. Purification by column chromatography on silica
gel, using ethyl acetate–petroleum ether (1 : 5) as eluent gave
tert-butyl(2S)-5-(1-acetyl-2-oxopropylidene)pyrrolidine-2-carb-
oxylate 16 as a white crystalline solid (160 mg, 40%), mp 83–84
ЊC; [α]2D9 ϩ0.4 (c 1.0, MeOH) (Found: C, 62.95; H, 8.0; N, 5.2.
C14H21NO4 requires C, 62.9; H, 7.9; N, 5.2%); m/z [ϩve FAB
(3-NBA)] 290 [M ϩ Na]ϩ and 268 [M ϩ H]ϩ; νmax (film)/cmϪ1
3230 (NH), 1743 (ester) and 1697 (ketone); λmax (MeOH)/nm
293 (ε 14200); δH (300 MHz, C2HCl3) 11.53 (1H, br s, NH,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 2 – 2 6 8 8
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2
slowly exchanges in H2O), 4.40 (1H, dd, J2,3A 8.9, J2,3B 5.9,
Ethyl (2S )-N-tert-butoxycarbonyl-4-dimethylaminomethylene-
H-2), 3.08 (2H, m, H-4), 2.36 (6H, s, 2 × CH C᎐O), 2.31 (1H,
pyroglutamate (21)
᎐
3
m, H-3A), 2.12 (1H, m, H-3B) and 1.47 (9H, s, OC(CH3)3);
δC (75.5 MHz, C2HCl3) 198.2 (2 × ketone), 172.7 (C-5), 170.3
(ester), 112.2 (C-6), 83.1 (OC(CH3)3), 62.3 (C-2), 34.2 (C-4),
Ethyl (2S)-N-tert-butoxycarbonylpyroglutamate 2012 (6.0 g, 23.3
mmol) was dissolved in anhydrous dimethoxyethane (65 ml) and
the solution was stirred at room temperature under nitrogen.
tert-Butoxybis(dimethylamino)methane (Bredereck’s reagent)
(7.22 ml, 35.0 mmol) was added and the mixture was heated at 80
ЊC for 15 h. The solvent was removed in vacuo to give a solid,
which was recrystallised using ethyl acetate–petroleum ether to
yield ethyl (2S)-N-tert-butoxycarbonyl-4-dimethylaminomethyl-
enepyroglutamate 21 as an off-white crystalline solid (6.39 g,
88%), mp 79–81 ЊC, [α]1D8 Ϫ50.3 (c 1.31, CHCl3) (Found: C, 57.5;
H, 7.6; N, 9.0. C15H24N2O5 requires C, 57.7; H, 7.7; N, 9.0%); m/z
[ϩve FAB (3-NBA)] 313 [M ϩ H]ϩ; νmax (film)/cmϪ1 1745, (br,
imide / urethane / ester); λmax (MeOH)/nm 313 (ε 31700); δH (360
MHz, C2HCl3) 7.10 (1H, t, J6,3 1.6 Hz, H-6), 4.50 (1H, dd, J2,3A
10.8, J2,3B 3.2, H-2), 4.18 (2H, m, OCH2CH3), 3.21 (1H, m, J3A,2
10 8, J3A,3B 14.5, H-3A), 2.98 (6H, s, N(CH3)2), 2.85 (1H, m, J3B,2
3.2, J3B,3A 14.5, H-3B), 1.47 (9H, s, OC(CH3)3) and 1.25 (3H, t, J
7.12, CH2CH3); δC (62.9 MHz, C2HCl3) 172.1 (amide), 169.4
(ester), 150.5 (urethane), 146.3 (C-6), 90.9 (C-4), 82.1
(OC(CH3)3), 61.3 (OCH2CH3), 56.9 (C-2), 41.9 (N(CH3)2), 28.0
(OC(CH3)3), 26.2 (C-3), and 14.1 (OCH2CH3).
31.8 (2 × CH C᎐O), 28.3 (OC(CH ) ) and 26.0 (C-3).
᎐
3
3 3
tert-Butyl (2S )-5-dicyanomethylenepyrrolidine-2-carboxylate
(17)
tert-Butyl (2S)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxyl-
ate 12 (1.6 g, 8.0 mmol) and malononitrile (600 mg, 9.1 mmol)
were stirred together for 16 h at room temperature. The residual
solid was washed with diethyl ether and recrystallised from
absolute ethanol to yield tert-butyl (2S)-5-dicyanomethylene-
pyrrolidine-2-carboxylate 17 as a beige solid (1.4 g, 75%); mp
130–131 ЊC; [α]2D8 Ϫ52.3 (c 1.0, MeOH) (Found: C, 61.6; H, 6.5;
N, 18.0. C12H15N3O2 requires C, 61.8; H, 6.5; N, 18.0%); m/z
[ϩve FAB (3-NBA)] 256 [M ϩ Na]ϩ and 234 [M ϩ H]ϩ;
νmax (film)/cmϪ1 3227 (NH), 2212 (CN), 2195 (CN) and 1733
(ester); λmax (MeOH)/nm 270 (ε 26200); δH (300 MHz, C2HCl3)
7.74 (1H, br s, NH, exchanges in 2H2O), 4.37 (1H, dd, J2,3A 8.6,
J2,3B 5.9, H-2), 2.90 (2H, m, H-4), 2.42 (1H, m, H-3A), 2.21 (1H,
m, H-3B) and 1.42 (9H, s, OC(CH3)3); δC (75.5 MHz, C2HCl3)
177.7 (ester), 171.0 (C-5), 126.2 (C-6), 116.6 (CN), 116.9 (CN),
85.4 (OC(CH3)3), 64.6 (C-2), 33.7 (C-4), 29.5 (OC(CH3)3) and
27.7 (C-3).
Ethyl (2S,4S )-N-tert-butoxycarbonyl-4-methylpyroglutamate
(22)
Ethyl (2S)-N-tert-butoxycarbonyl-4-dimethylaminomethylene-
pyroglutamate 21 (4.1 g, 13 mmol) was dissolved in ethyl acet-
ate (80 ml) and the solution was stirred under nitrogen at room
temperature. 10% Palladium on activated carbon (4.1 g, 100%
w/w) was carefully added. The solution was vigorously stirred
for 115 h under an atmosphere of hydrogen at room temper-
ature. The mixture was filtered through Celite® and the solvent
was removed in vacuo to yield ethyl (2S,4S)-N-tert-butoxy-
carbonyl-4-methylpyroglutamate 22 as a colourless oil (2.6 g,
73%), [α]2D8 Ϫ46.9 (c 1.0, MeOH) (Found C, 57.6; H, 7.9; N, 5.4.
C13H21NO5 requires C, 57.55; H, 7.8; N, 5.2%); m/z [EI] 271
[M]ϩ; νmax (film)/cmϪ1 1792, 1749 and 1719 (imide/urethane/
ester), δH (360 MHz, C2HCl3) 4.46 (1H, t, J2,3 8.2, H-2), 4.20
(2H, q, J 7.2, OCH2CH3), 2.56 (2H, m, H-4 and H-3A), 1.58
(1H, m, H-3B), 1.47 (9H, s, OC(CH3)3) and 1.27 (6H, 2 × t,
OCH2CH3 and CH3); δC (62.9 MHz, C2HCl3) 178.3 (amide),
174.1 (ester), 152.1 (urethane), 86.2 (OC(CH3)3), 64.2 (OCH2-
CH3), 60.1 (C-2), 40.1 (C-4), 32.3 (C-3), 30.4 (OC(CH3)3), 18.8
(C–CH3) and 16.7 (OCH2CH3).
tert-Butyl (2S )-2-amino-4-(5-amino-4-cyano-1H-pyrazol-3-yl)-
butyrate (18)
A suspension of tert-butyl (2S)-5-dicyanomethylenepyrrol-
idine-2-carboxylate 17 (1.0 g, 4.3 mmol) in hydrazine mono-
hydrate (0.95 ml, 21.5 mmol) and distilled water (0.4 ml) was
heated at reflux for 15 min. After cooling, distilled water (8.6
ml) was added and the solution turned opaque. The solvent was
removed in vacuo to yield tert-butyl (2S)-2-amino-4-(5-amino-
4-cyano-1H-pyrazol-3-yl)butyrate 18 as a white solid (600 mg,
52%); mp 135–137 ЊC; [α]2D8 ϩ6.5 (c 1, DMSO) (Found: C, 54.3;
H, 7.25; N, 26.5. C12H19N5O2 requires C, 54.3; H, 7.2; N,
26.4%); m/z [ϩve FAB (3-NBA)], 288 [M ϩ Na]ϩ and 266
[M ϩ H]ϩ; νmax (film)/cmϪ1 3393 (NH, br), 2212 (CN) and 1727
(ester); δH (300 MHz, [2H6]-DMSO) 11.62 (1H, br s, NH,
2
exchanges in H2O), 5.89 (4H, br s, 2 × NH2, exchanges in
2H2O), 3.4 (1H, t, J2,3 6.0, H-2), 2.61 (2H, t, J4,3 7.7, H-4), 2.24
(1H, m, J3A,3B 13.6, J3A,4 7.7, J3A,2 6.0, H-3A), 1.91 (1H, m, J3B,3A
13.6, J3B,4 7.7, J3B,26.0, H-3B) and 1.30 (9H, s, OC(CH3)3);
δC (75.5 MHz, 2H2O) 176.0 (ester), 155.4 (Ar), 152.5 (Ar), 126.3
(CN), 83.5 (OC(CH3)3), 72.1 (Ar), 54.0 (C-2), 32.3 (C-4), 27.4
(OC(CH3)3) and 22.4 (C-3).
Ethyl (2S,4S )-4-methylpyroglutamate (23)
Trifluoroacetic acid (15 ml) was added to a stirred solution of
ethyl (2S,4S)-N-tert-butoxycarbonyl-4-methylpyroglutamate 22
(2.6 g, 9.59 mmol) in anhydrous dichloromethane (30 ml) at room
temperature. The reaction was stirred for 18 h at room temper-
ature. The solvent was azeotropically removed in vacuo with di-
ethyl ether to give a colourless oil. Purification by flash column
chromatography on silica gel using ethyl acetate as eluent gave
ethyl (2S,4S)-4-methylpyroglutamate 23 as a white crystalline
solid (1.52 g, 93%), mp 63–66 ЊC; [α]2D1 Ϫ27.2 (c 1.0, MeOH);
m/z [ϩve FAB (3-NBA)] 194 [M ϩ Na]ϩ and 172 [M ϩ H]ϩ;
νmax (film)/cmϪ1 3276 (br, NH) and 1739 (ester); δH (360 MHz,
tert-Butyl (2S )-2-amino-4-(5-amino-4-cyano-1-methyl-1H-
pyrazol-3-yl)butyrate (19)
A suspension of tert-butyl (2S)-5-dicyanomethylenepyrrol-
idine-2-carboxylate 17 (500 mg, 2.1 mmol) in methylhydrazine
(0.6 ml, 10.7 mmol) and distilled water (0.2 ml) was heated at
reflux for 20 min. After cooling, distilled water (0.2 ml) was
added and the solution turned opaque. The solvent was
removed in vacuo to yield tert-butyl (2S)-2-amino-4-(5-amino-
4-cyano-1-methyl-1H-pyrazol-3-yl)butyrate 19 as an orange oil
(500 mg, 87%); [α]2D5 ϩ5.0 (c 1.0, DMSO); (m/z (EI) Found:
279.1673. C13H21N5O2 requires 279.1695); m/z [ϩve FAB
(glycerol–water)] 280 [M ϩ H]ϩ; νmax (film)/cmϪ1 3343 (NH2,
2
C2HCl3) 6.12 (1H, br s, NH, exchanges in H2O), 4.17 (3H, m,
H-2 and OCH2CH3), 2.66 (1H, m, H-3A), 2.48 (1H, m, H-4), 1.75
(1H, m, H-3B), 1.26 (3H, t, J 7.1, OCH2CH3) and 1.18 (3H, d,
JMe,4 7.1, CH3); δC (62.9 MHz, C2HCl3) 180.3 (amide), 172.0
(ester), 61.5 (OCH2CH3), 53.7 (C-2), 35.9 (C-4), 33.3 (C-3), 15.8
(OCH2CH3) and 13.94 (C–CH3).
2
br), 2209 (CN) and 1726 (ester); δH (300 MHz, H6-DMSO)
2
6.55 (2H, br s, NH2, exchanges in H2O), 3.51 (3H, s, NCH3),
3.26 (1H, t, J2,3 5.8, H-2), 2.54 (2H, t, J4,3 7.7, H-4), 1.92 (1H, m,
H-3A), 1.78 (1H, m, H-3B) and 1.48 (9H, s, OC(CH3)3); δC (75.5
MHz, H2O) 176.0 (ester), 153.7 (Ar), 152.3 (Ar), 115.8 (CN),
Ethyl (2S,4S )-5-ethoxy-3,4-dihydro-4-methyl-2H-pyrrole-2-
carboxylate (24)
2
83.3 (Ar), 73.4 (OC(CH3)3), 54.1 (C-2), 34.2 (NCH3), 32.7
(C-4), 27.5 (OC(CH3)3) and 23.3 (C-3).
A solution of triethyloxonium tetrafluoroborate (1.67 g,
8.8 mmol) in dichloromethane (10 ml) was added to a solution
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 2 – 2 6 8 8
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of ethyl (2S,4S)-4-methylpyroglutamate 23 (1.5 g, 8.8 mmol) in
anhydrous dichloromethane (20 ml) with stirring at room tem-
perature. The reaction was stirred at room temperature for 48 h.
Saturated aqueous potassium hydrogen carbonate (30 ml) was
carefully added. When effervescence had ceased, the mixture
was filtered through Celite® and the organic layer was separ-
ated. The aqueous layer was extracted with dichloromethane
(5 × 30 ml). The organic layers were combined and dried
(MgSO4). The solvent was removed in vacuo to yield ethyl
(2S,4S)-5-ethoxy-3,4-dihydro-4-methyl-2H-pyrrole-2-carboxyl-
ate 24 as a colourless oil (1.50 g, 86%), which was used without
further purification, [α]2D8 ϩ4.1 (c 0.68, CHCl3); (m/z (EI)
Found: 199.1214. C10H17NO3 requires 199.1208); νmax (film)/
cmϪ1 1741 (ester); δH (300 MHz, C2HCl3) 4.36–4.15 (5H, m, H-2
and 2 × OCH2CH3), 2.70 (1H, m, H-3A), 2.56 (1H, m, H-4),
1.68 (1H, m, H-3B), 1.24 (6H, m, 2 × OCH2CH3) and 1.18 (3H,
d, JMe,4 7.1, CH3); δC (75.5 MHz, C2HCl3) 176.9 (ester), 174.1
(C-5), 66.0 (C-2), 64.4 (OCH2CH3), 60.9 (OCH2CH3), 38.7
(C-4), 35.3 (C-3), 17.1 (C–CH3), 14.28 (OCH2CH3) and 13.94
(OCH2CH3).
(C-3), 31.3 (CH C᎐O), 21.2 (Ar–CH ), 18.7 (OCH CH ) and
14.1 (OCH2CH3).
᎐
3
3
2
3
Crystal data– compound 27†
C18H25NO7, M = 367.4, hexagonal, space group P61 (No169),
a = 8.994(2), b = 8.994(2), c = 43.134(6) Å, α = 90Њ, β = 90Њ,
γ = 120Њ, V = 3021.7(10) Å3, Z = 6, Dcalc= 1.211 mg mϪ3, F(000) =
1170, µ(Mo-Kα) = 0.09 mmϪ1, T = 293(2) K, 2787 total reflec-
tions measured; 1259 independent reflections collected on
Enruf-Nonius CAD4 diffractometer (Rint= 0.0837) using
Mo-Kα radiation (λ = 0.71073 Å) for 2 < θ < 22Њ. Structure
solution by direct methods (SHELXS) and refinement on
F 2 using SHELXL-93 with non-H atoms anisotropic and H
atoms in riding mode. Final residuals were R1 = 0.045 and
wR2 = 0.108 (for 1031 reflections with I > 2σ(I )), R1 = 0.062,
wR2 = 0.120 for all reflections.
tert-Butyl (2S,4S )-4-methylpyroglutamate (29)
tert-Butyl (2S,4S)-N-tert-butoxycarbonyl-4-methylpyroglut-
amate 2813 (5.9 g, 19.7 mmol) was dissolved in anhydrous 1 M
HCl in ethyl acetate (850 ml) and stirred at room temperature
for 3 h. The solvent was removed in vacuo to give a pale yellow
solid, which was recrystallised from diethyl ether–petroleum
ether to yield tert-butyl (2S,4S)-4-methylpyroglutamate 29 as a
white solid (2.52 g, 64%); mp 54–60 ЊC; [α]2D2 Ϫ19.72 (c 1.0,
MeOH); m/z [ϩve FAB (3-NBA)] 222 [M ϩ Na]ϩ and 200
[M ϩ H]ϩ; νmax (film)/cmϪ1 3269 (br, NH), 1739 (ester) and 1708
(lactam); δH (360 MHz, C2HCl3) 6.55 (1H, br s, NH, exchanges
Ethyl (2S,4S )-5-(tert-butoxycarbonylcyanomethylene)-4-
methylpyrrolidine-2-carboxylate (25)
(2S,4S)-5-Ethoxy-2-ethoxycarbonyl-4-methyl-1-pyrroline 24
(310 mg, 1.6 mmol), tert-butyl cyanoacetate (0.45 ml, 3.2 mmol)
and triethylamine ( 0.22 ml, 1.6 mmol) were stirred at 70 ЊC for
48 h. The solvent was removed in vacuo to give a brown oil,
which was purified by column chromatography on silica gel,
using ethyl acetate–petroleum ether (1 : 3) as eluent to yield
ethyl (2S,4S)-5-(tert-butoxycarbonylcyanomethylene)-4-meth-
ylpyrrolidine-2-carboxylate 25 as a white crystalline solid (210
mg, 47%), mp 124–127 ЊC; [α]2D8 ϩ55.6 (c 0.9, MeOH) (Found:
C, 61.2; H, 7.6; N, 9.4. C15H22N2O4 requires C, 61.2; H, 7.5; N,
9.5%); m/z [ϩve FAB (3-NBA)] 317 [M ϩ Na]ϩand 295
[M ϩ H]ϩ; νmax (film) / cmϪ1 3337 (NH), 2203 (CN), 1747 (ester)
2
in H2O), 4.03 (1H, t, J2,3 7.9, H-2), 2.57 (1H, m, H-3A), 2.44
(1H, m, H-4), 1.67 (1H, m, H-3B), 1.42 (9H, s, OC(CH3)3) and
1.16 (3H, d, JMe,4 7, CH3); δC (62.9 MHz, C2HCl3) 182.8
(amide), 173.3 (ester), 83.1 (OC(CH3)3), 55.9 (C-2), 37.3 (C-4),
34.5 (C-3), 28.2 (OC(CH3)3) and 16.6 (C–CH3).
tert-Butyl (2S,4S )-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole-
2-carboxylate (30)
and 1672 (C᎐C); λmax (MeOH)/nm 280 (ε 16800); δH (500 MHz,
᎐
2
C2HCl3) 9.25 (1H, s br, NH, slowly exchanges in H2O), 4.44
Methyl trifluoromethanesulfonate (0.45 ml, 4.0 mmol) was
added with care to a stirred solution of tert-butyl (2S,4S)-4-
methylpyroglutamate 29 (400 mg, 2.0 mmol) in anhydrous
diethyl ether (40 ml) at Ϫ78 ЊC. The reaction was stirred at
Ϫ78 ЊC for 3 h and at room temperature for 18 h. 0.5 M Aque-
ous ammonium hydroxide (20 ml) was added, the mixture was
stirred for 1 h, dichloromethane (20 ml) was added and the
aqueous phase was extracted with dichloromethane (4 × 40 ml).
The organic layers were combined and dried (MgSO4). The
solvent was removed in vacuo to yield tert-butyl (2S,4S)-5-
methoxy-4-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate 30 as a
colourless oil (300 mg, 70%), which was used without further
purification, [α]2D5 Ϫ21.8 (c 1.0, MeOH); m/z [ϩve FAB
(3-NBA)] 236 [M ϩ Na]ϩ and 214 [M ϩ H]ϩ; νmax (film)/cmϪ1
1737 (ester); δH (300 MHz, C2HCl3) 4.36 (1H, t, J2,3 7.5, H-2),
3.86 (3H, s, OCH3), 2.76 (1H, m, H-3A), 2.58 (1H, m, H-4),
2.25 (1H, m, H-3B), 1.47 (9H, s, OC(CH3)3) and 1.18 (3H, d,
JMe,4 7.1, CH3); δC (75.5 MHz, C2HCl3) 177.7 (ester), 173.8
(C-5), 81.2 (OC(CH3)3), 66.7 (OCH3), 56.3 (C-2), 38.9 (C-4),
36.8 (C-3), 28.4 (OC(CH3)3) and 17.5 (C–CH3).
(1H, ddd, J2,3A 5.8, J2,3B 2.9, J2,NH 1.3, H-2), 4.25 (2H, ABX3,
OCH2CH3), 3.23 (1H, m, H-4), 2.61 (1H, m, H-3S), 2.01 (1H,
m, H-3R), 1.50 (9H, s, OC(CH3)3), 1.37 (3H, d, JMe,4 7.3, CH3),
1.33 (3H, t, J 7.1, OCH2CH3); δC (125.8 MHz, C2HCl3) 177.1
(C-5), 171.1 (ester), 167.5 (ester), 118.2 (CN), 81.2 (OC(CH3)3),
69.9 (C-6), 62.0 (OCH2CH3), 60.1 (C-2), 39.3 (C-4), 33.2 (C-3),
28.3 (OC(CH3)3), 19.1 (C–CH3), and 14.1 (OCH2CH3).
Diethyl (2S,4S )-2-(3-acetyl-4-hydroxy-6-methyl-2-oxo-2H-
pyridin-1-yl)-4-methylpentanedioate (27)
Ethyl
(2S,4S)-5-ethoxy-3,4-dihydro-4-methyl-2H-pyrrole-2-
carboxylate 24 (160 mg, 0.80 mmol), tert-butyl acetoacetate
(0.26 ml, 1.6 mmol), nickel acetylacetonate monohydrate (3 mg,
1 µmol) and triethylamine (1 ml, 7.2 mmol) were stirred at 80 ЊC
for 20 h, followed by further addition of nickel acetylacetonate
monohydrate (3 mg, 1 µmol). The reaction was stirred for a
further 24 h and the solvent was removed in vacuo to give a
brown oil. Purification by column chromatography on silica gel,
using ethyl acetate and petroleum ether (1 : 6) as eluent gave
diethyl
(2S,4S)-2-(3-acetyl-4-hydroxy-6-methyl-2-oxo-2H-
tert-Butyl (2S,4S )-5-dicyanomethylene-4-methylpyrrolidine-2-
carboxylate (31)
pyridin-1-yl)-4-methylpentanedioate 27 as a white crystalline
solid (60 mg, 22%), mp 124–127 ЊC, [α]2D8 Ϫ35.8 (c 0.6, MeOH);
m/z [ϩve FAB (3-NBA)] 390 [M ϩ Na]ϩand 368 [M ϩ H]ϩ; νmax
(film)/cmϪ1 2983 (br, OH) and 1744 (ester); λmax (MeOH)/nm
330 (ε 87100); δH (500 MHz, C2HCl3, Ϫ30 ЊC) 15.54 (1H, s, OH,
exchanges in 2H2O), 5.85 (1H, s, ArH), 4.32 (1H, m, H-2), 4.24
and 4.10 (4H, m, 2 × OCH2CH3), 2.97 (1H, m, H-4), 2.72 (4H,
tert-Butyl
(2S,4S)-5-methoxy-4-methyl-3,4-dihydro-2H-
pyrrole-2-carboxylate 30 (0.43 g, 2.0 mmol) and malononitrile
(0.13 g, 2.0 mmol) were stirred together for 16 h at room tem-
perature to give a red oil. Purification by column chromato-
graphy on silica gel using ethyl acetate–petroleum ether (1 : 3)
as eluent gave tert-butyl (2S,4S)-5-dicyanomethylene-4-methyl-
m, H-3A and CH C᎐O), 2.42 (3H, s, ArCH ), 2.05 (1H, m,
᎐
3
3
H-3B) and 1.24 (9H, m, CH3 and 2 × OCH2CH3); δC (75.5
MHz, C2HCl3) 205.6 (ketone), 176.5 (C-2Ј), 175.4 (C-4Ј), 169.4
(ester), 162.5 (ester), 153.4 (C-6Ј), 105.7 (C-3Ј), 101.7 (C-5Ј),
61.4 (OCH2CH3), 60.7 (OCH2CH3), 57.2 (C-2), 36.9 (C-4), 33.8
† CCDC reference numbers 209172. See http://www.rsc.org/suppdata/
ob/b3/b304609p/ for crystallographic data in .cif or other electronic
format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 2 – 2 6 8 8
2687

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pyrrolidine-2-carboxylate 31 as an off-white crystalline solid
(450 mg, 90%) mp 104–106 ЊC; [α]2D8 ϩ36.4 (c 1.0, CHCl3)
(Found: C, 62.8; H, 6.9; N, 16.9. C13H17N3O2 requires C, 63.1;
H, 6.9; N, 17.0%.); m/z [ϩve FAB (3-NBA)] 270 [M ϩ Na]ϩ and
248 [M ϩ H]ϩ; νmax (film)/cmϪ1 3255 (br, NH), 2217 (CN), 2199
(CN) and 1733 (ester); λmax (MeOH)/nm 274 (ε 2800); δH (300
δH (300 MHz, [2H6]-DMSO) 6.39 (2H, br s, NH2, exchanges in
2H2O), 3.70 (1H, m, H-2 both isomers), 3.32 (3H, 2 × s, NCH3,
both isomers), 2.83 (1H, m, H-4), 2.02 (2H, m, H-3), 1.79 (9H, 2
× s, OC(CH3)3, both isomers) and 1.08 (3H, 2 × d, JMe,4 7.0,
2
CH3, both isomers); δC (75.5 MHz, H2O) 179.1 (ester), 169.4
(Ar), 157.2 (Ar), 153.1 (CN), 116.4 (Ar), 86.4 (OC(CH3)3), 52.2
(C-2), 35.9 (C-3), 34.5 (NCH3), 30.1 (C-4), 27.7 and 22.2
((OC(CH3)3, both isomers) and 20.8 and 19.9 (C–CH3, both
isomers).
2
MHz, C2HCl3) 7.41 (1H, br s, NH, exchanges in H2O), 4.26
(1H, dd, J2,3A 9.8, J2,3B 6.9, H-2), 3.13 (1H, m, H-3A), 2.60 (1H,
m, H-4), 1.96 (1H, m, H-3B), 1.43 (9H, s, OC(CH3)3) and 1.29
(3H, d, JMe,4 7.3, CH3); δC (75.5 MHz, C2HCl3) 180.5 (C-5),
170.3 (ester), 115.5 (CN), 115.4 (CN), 84.1 (OC(CH3)3), 61.9
(C-2), 55.1 (C-6), 39.5 (C-4), 34.7 (C-3), 28.4 (OC(CH3)3) and
19.3 (C–CH3).
Acknowledgements
One of us (S. R.) thanks the University of Sussex for a bursary.
tert-Butyl (2S,4RS )-2-amino-4-(5-amino-4-cyano-1H-pyrazol-
3yl)pentanoate (32)
References
A
suspension of tert-butyl (2S,4S)-5-dicyanomethylene-4-
1 H. Bräuner-Osborne, J. Egebjerg, E. Ø. Nielson, U. Madsen and
P. Krogsgaard-Larsen, J. Med. Chem., 2000, 43, 2610.
2 E. K. Michaelis, Prog. Neurobiol., 1998, 54, 369.
methylpyrrolidine-2-carboxylate 31 (100 mg, 0.4 mmol) in
hydrazine monohydrate (98 µl, 2.0 mmol) and distilled water
(35 µl,) was heated at reflux for 15 min. After cooling, the sol-
vent was removed in vacuo to give a colourless oil. Purification
by column chromatography on silica gel using ammonia–
ethanol–dichloromethane (1 : 18 : 89) as eluent gave tert-butyl
(2S,4RS)-2-amino-4-(5-amino-4-cyano-1H-pyrazol-3yl)penta-
noate 32 as an inseparable mixture of two diastereoisomers in
the form of an oil (30 mg, 28%); m/z [ϩve FAB (3-NBA)] 280
[M ϩ H]ϩ; νmax (film)/cmϪ1 3393 (br, NH), 2212 (CN) and 1727
(ester); δH (300 MHz, H2O) 3.80 (1H, m, H-2), 2.90 (1H, m,
H-4), 2.10 (2H, m, H-3), 1.24 (9H, s, OC(CH3)3) and 1.12 (3H,
2 × d, JMe,4 7, CH3); δC (75.5 MHz, H2O) 178.2 (ester), 168.8
(Ar), 156.8 (Ar), 126.3 (CN), 116.0 (Ar), 86.1 (OC(CH3)3), 52.2
and 51.8 (C-2, both isomers), 35.4 (C-3), 29.3 (C-4), 27.2 and
21.4 (OC(CH3)3) and 20.0 and 19.2 (C–CH3, both isomers).
3 M. Zhuo, Drug Discovery Today, 2002, 7, 259.
4 R. J. Bridges, J. W. Geddes, D. T. Monaghan and C. W. Cotman,
in Excitatory Amino Acids in Health and Disease, Ed.D. Lodge,
John Wiley, New York, 1988, p. 321.
5 S. Patel, A. G. Chapman, M. H. Millan and B. S. Meldrum
in Excitatory Amino Acids in Health and Disease, Ed.D. Lodge,
John Wiley, New York, 1988, p. 353.
6 G. K. Steinberg, J. Saleh, D. Kunis, R. DeLaPaz and S. R. Zarnegar,
Stroke, 1989, 20, 1247.
7 (a) A. N. Bowler, P. M. Doyle and D. W. Young, J. Chem. Soc.,
Chem. Commun., 1991, 314; (b) A. Dinsmore, P. M. Doyle and
D. W. Young, Tetrahedron Lett., 1995, 36, 7503; (c) A. N. Bowler,
A. Dinsmore, P. M. Doyle and D. W. Young, J. Chem. Soc.,
Perkin Trans. 1, 1997, 1297; (d ) A. Dinsmore, P. M. Doyle,
P. B. Hitchcock and D. W. Young, Tetrahedron Lett., 2000, 41,
10153; (e) A. Dinsmore, P. M. Doyle and D. W. Young, J. Chem.
Soc., Perkin Trans. 1, 2002, 155; ( f ) A. Dinsmore, P. M. Doyle,
M. Steger and D. W. Young, J. Chem. Soc., Perkin Trans. 1, 2002,
613; (g) K. Papadopoulos and D. W. Young, Tetrahedron Lett., 2002,
43, 3951; (h) Preceding paper P. B. Hitchcock, K. Papadopoulos and
D. W. Young, Org. Biomol. Chem., 2003, DOI: 10.1039/b304607a.
8 D. Coe, M. Drysdale, O. Philps, R. West and D. W. Young, J. Chem.
Soc., Perkin Trans. 1, 2002, 2459.
9 M. Steger and D. W. Young, Tetrahedron, 1999, 55, 7935.
10 see M. Pätzel and J. Liebscher, Synthesis, 1995, 879 and references
cited therein.
11 T. Kosala and M. J. Miller, J. Org. Chem., 1990, 55, 1711.
12 M. Bergmann and L. Zervas, Chem. Ber., 1932, 65, 1192.
13 R. A. August, J. A. Khan, C. M. Moody and D. W. Young, J. Chem.
Soc., Perkin Trans. 1, 1996, 507.
2
2
tert-Butyl (2S,4RS )-2-amino-4-(5-amino-4-cyano-1-methyl-1H-
pyrazol-3yl)pentanoate (33)
A
suspension of tert-butyl (2S,4S)-5-dicyanomethylene-4-
methylpyrrolidine-2-carboxylate 31 (60 mg, 0.28 mmol) in
methylhydrazine (120 µl, 2.0 mmol) and distilled water (22 µl, 1
mmol) was heated at reflux for 20 min. After cooling, distilled
water (22 µl) was added and the solution turned opaque. The
solvent was removed in vacuo to give an orange oil, which was
purified by column chromatography using trifluoroacetic acid,
water, methanol and dichloromethane (3 : 6 : 30 : 70) as eluent
to yield tert-butyl (2S,4RS)-2-amino-4-(5-amino-4-cyano-1-
methyl-1H-pyrazol-3yl)pentanoate 33 as an inseparable mixture
of two diastereoisomers as an orange oil (51 mg, 62%); [α]2D5
Ϫ98.5 (c 1.0, H2O); (m/z (EI) Found 293.1851. C14H23N5O2
requires 293.1851.); m/z [ϩve FAB (glycerol)] 294 [M ϩ H]ϩ;
νmax (film)/cmϪ1 3343 (br, NH), 2212 (CN) and 1736 (ester);
14 J. C. Christofides and D. B. Davies, J. Am. Chem. Soc., 1983, 105,
5099.
15 J.-D. Charrier, J. E. S. Duffy, P. B. Hitchcock and D. W. Young,
J. Chem. Soc., Perkin Trans. 1, 2001, 2367.
16 This value for the specific rotation is in keeping with that reported in
reference 15, further suggesting that the value quoted in reference 13
was in error.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 2 – 2 6 8 8
2688