Toward Diels-Alder reactions on a solid support using polymer bound N-substituted 3-hydroxy-4,4-dimethyl-2-pyrrolidinone acrylate derivatives

Article abstract of DOI:10.1002/ejoc.200400019

Several N-substituted 3-hydroxy-4,4-dimethyl-2-pyrrolidinone acrylate derivatives, selected to allow their attachment to a polymer, have been prepared and tested as dienophiles in the Diels-Alder reaction. The experiments, performed under TiCl₄ catalysis in solution or the solid phase with isoprene and cyclopentadiene as dienes, pointed out the difficulties associated with some of these compounds that failed to give the corresponding cycloadduct. ¹³C NMR studies provided some evidence regarding the nature of the interactions between the acrylate compounds and TiCl₄. It appears that the outcome of the reaction is dependent on the acrylate structure and that the 4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoic acid acrylate derivatives are highly efficient to give the cycloadduct in good yield and with high regio- or endoselectivity in both solution and solid-phase reaction conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400019

FULL PAPER
Toward Diels؊Alder Reactions on a Solid Support Using Polymer Bound
N-Substituted 3-Hydroxy-4,4-dimethyl-2-pyrrolidinone Acrylate Derivatives
[a]
[a]
[a]
`
Rhalid Akkari, Monique Calmes,* and Jean Martinez
Keywords: DielsϪAlder reaction / Solid-phase synthesis / Pyrrolidinone acrylate derivatives
Several N-substituted 3-hydroxy-4,4-dimethyl-2-pyrrolidi-
none acrylate derivatives, selected to allow their attachment
to a polymer, have been prepared and tested as dienophiles
in the Diels−Alder reaction. The experiments, performed un-
der TiCl4 catalysis in solution or the solid phase with isoprene
tween the acrylate compounds and TiCl4. It appears that the
outcome of the reaction is dependent on the acrylate struc-
ture and that the 4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-
1-yl)benzoic acid acrylate derivatives are highly efficient to
give the cycloadduct in good yield and with high regio- or
and cyclopentadiene as dienes, pointed out the difficulties endoselectivity in both solution and solid-phase reaction con-
associated with some of these compounds that failed to give
the corresponding cycloadduct. 13C NMR studies provided
some evidence regarding the nature of the interactions be-
ditions.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
cines.[13] As part of our program directed towards the devel-
opment of asymmetric solid-phase reactions, we planned to
examine the asymmetric solid-phase DielsϪAlder reaction
using the corresponding acrylate 2 of the polymer-sup-
ported chiral alcohol 1 as chiral dienophile.
In an initial approach we decided to investigate the
DielsϪAlder reaction on a solid support using the racemic
dienophile (Ϯ)-2.
The DielsϪAlder reaction can be considered as one of
the most powerful transformations in synthetic organic
chemistry.[1,2] The stereospecific creation of several stereog-
enic centers in a single step makes this reaction suitable for
the preparation of complex molecules.[3] The development
of asymmetric DielsϪAlder reactions involves the use of a
chiral auxiliary[1,4,5] or a chiral catalyst.[6] Actually, among
several possible combinations of chiral reactants, reactions
between achiral dienes and chiral dienophiles such as acry-
lates or methacrylates of enantiomerically pure alcohols or
amines have been extensively studied.[4,5,7]
In recent years a number of asymmetric organic reactions
have been carried out with polymer-supported chiral re-
agents or catalysts,[8] although stereoselective syntheses of
complex molecules using a polymer supported chiral auxili-
ary[9] are not always well developed. This is the case of
solid-phase DielsϪAlder reactions, whose syntheses mainly
concern racemic preparation.[10,11] Only a very few asym-
metric examples have been reported so far.[11,12] Neverthe-
less, the usual advantages of the solid-phase strategy — easy
workup, simple isolation of the desired compounds and
facile separation and recovery of the chiral material — are
now reliable.
Results and Discussion
The polymer-supported racemic alcohol (Ϯ)-1 was ob-
tained as described previously,[13] starting from a Rink am-
ide resin and the racemic (3-hydroxy-4,4-dimethyl-2-oxo-
pyrrolidin-1-yl)acetic acid (3). The corresponding supported
acrylic ester (Ϯ)-2 was prepared in an improved way by
reaction of the supported alcohol (Ϯ)-1 with an excess of
both acryloyl chloride and triethylamine in anhydrous
CH2Cl2 at room temperature.
We have recently described the preparation of a new in-
soluble polymer-supported chiral alcohol 1 and its use for
the asymmetric transformation, via ketene formation, of
both racemic aryl propionic acids and β2-homoarylgly-
[a]
´
Laboratoire des Amino acides, Peptides et Proteines, UMR
´
CNRS 5810, Universites Montpellier I et II,
We used a Rink amide resin[14] since the benzhydrylamine
bond created between the alcohol and the polymer is stable
`
Place Eugene Bataillon, 34095 Montpellier cedex 5, France
E-mail: monique@univ-montp2.fr
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DOI: 10.1002/ejoc.200400019
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`
R. Akkari, M. Calmes, J. Martinez
FULL PAPER
under the reaction conditions and during the basic final duced from HPLC analysis of compound 4, which was the
cleavage of the ester bond (Scheme 1, step d). The benzhyd- only detectable product isolated after acid cleavage.
rylamine bond could be selectively cleaved in acidic medium
(5% TFA in CH2Cl2) allowing an easier control of the dif-
ferent steps of the synthesis (Scheme 1, step c). The quanti-
tative formation of the supported acrylate (Ϯ)-2 was de-
Isoprene and cyclopentadiene were chosen as representa-
tive dienes. According to previous studies performed in
solution with both pantolactone acrylate 8[7aϪ7c,15] or with
4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl acrylate (9a),[16]
the supported DielsϪAlder reaction was carried out under
TiCl4 catalysis in anhydrous CH2Cl2.
From the reaction of the supported acrylate ester (Ϯ)-2
with isoprene (2.0 equiv.; Scheme 1) in the presence of 0.5
equivalents of TiCl4 in a temperature ranging from Ϫ20 °C
to 10 °C for 16 h, no cycloadduct 6 was isolated (Table 1,
Entry 1). Only the acrylate ester 4 was obtained after acid
cleavage of the benzhydrylamine bond.
No improvement was observed under more drastic con-
ditions: 1 to 10 equivalents of TiCl4, 5 to 10 equivalents of
diene, longer reaction time (24 to 92 h) and various tempera-
tures (Table 1, Entry 1). The supported acrylate ester (Ϯ)-2
also failed to react under similar experimental conditions
with the more reactive cyclopentadiene (Table 1, Entry 2).
However, the acrylate 8 or 9a reacted with isoprene in
solution under TiCl4 catalysis affording the corresponding
para-cycloadducts 11 and 12a in high yield.[15,16] Similarly,
we observed that reaction between the acrylate ester (Ϯ)-9b,
bearing an alkyl group on the lactam function, and isoprene
under the same experimental conditions yielded the cyclo-
adduct 12b in good yield (76%; Table 1, Entry 3).
Scheme 1. Reagents: (a) acryloyl chloride, NEt3, CH2Cl2; (b)
CH2Cl2, TiCl4, isoprene; (c) TFA, CH2Cl2; (d) LiOH, H2O, THF
Table 1. DielsϪAlder reaction using the N-substituted 3-hydroxy-4,4-dimethyl-2-pyrrolidinones as acrylate derivatives
[a]
[b]
Entry
Dienophiles
Dienes (equiv.)
Lewis acids (equiv.)
T1
T2 (reaction time)
Yields (%)
1
2
2
2
isoprene (2 to 10)
cyclopentadiene (2 to 10)
TiCl4 (0.5Ϫ10)
TiCl4 (1.5Ϫ5)
Ϫ20 °C
Ϫ10 °C or
room temp.
Ϫ20 °C
Ϫ20 °C
Ϫ
Ϫ20 °C Ǟ 10 °C (16 to 92 h)
Ϫ20 °C Ǟ 0 °C (12 to 20 h)
Ϫ
Ϫ
3
4
5
9b
13
13
isoprene (2)
isoprene (2)
isoprene (2)
TiCl4 (0.5)
TiCl4 (0.5 Ϫ1)
Ϫ
Ϫ20 °C Ǟ 0 °C (25 h)
Ϫ20 °C Ǟ 0 °C (25 h)
room temp., CH2Cl2 or reflux,
C6H5 (72 h)
76 (12b)
Ϫ
Ϫ
6
7
8
14
14
14
isoprene (2Ϫ4)
isoprene (2)
isoprene (2)
TiCl4 (0.5Ϫ2)
room temp. or
-20 °C
Ϫ20 °C
Ϫ20 °C Ǟ 10 °C (16 to 70 h)
Ϫ
Ϫ
Ϫ
Et2AlCl
Ϫ20 °C Ǟ 0 °C (5 h) and
0 °C (12 h) and 10 °C (24 h)
Ϫ20 °C Ǟ 0 °C (5 h) and
0 °C (12 h) and 10 °C (24 h)
Zn(CF3SO3)2 (1)
Sm(CF3SO3)2 (1)
Sc(CF3SO3)2 (1)
TiCl4 (1)
Ϫ20 °C
9
15a
isoprene (2)
Ϫ20 °C
Ϫ20 °C Ǟ 0 °C (5 h)
and 0 °C (12 h)
90 (26a)
10
11
12
15b
15b
16
isoprene (6)
cyclopentadiene (6)
isoprene (2)
TiCl4 (1.1)
TiCl4 (1.1)
TiCl4 (1)
0 °C
0 °C
Ϫ20 °C
0 °C (16h)
0 °C (16h)
Ϫ20 °C Ǟ 0 °C (5 h) and 0 °C (36 h)
80 (26b)
95 (29)
90 (27)
[a]
[b]
T1: Temperature of the formation of the acrylate/Lewis acid complexes. T2: Temperature of the cycloaddition reaction.
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Toward DielsϪAlder Reactions on a Solid Support
FULL PAPER
trum of the acrylates 9b and 13 alone or in the presence of
TiCl4 in CD2Cl2 at room temperature. Addition of increas-
ing amounts of TiCl4 (0.1Ϫ0.5 equiv.) to a CD2Cl2 solution
of the acrylate 9b resulted in progressive chemical-shift
variations of most of the 13C NMR resonance signals. For
instance, a large downfield shift of the 13C NMR resonance
of the two carbonyl carbon signals of the acryloyl and lac-
tam moieties was observed in the presence of 0.5 equiv. of
TiCl4 (Table 2), indicating the existence of complex D,
which promotes the DielsϪAlder reactions. Subsequently,
when 0.5Ϫ1.0 equiv. of TiCl4 were added, the variation in
the chemical shifts of the carbon signals remained un-
changed, suggesting that a 2:1 complex E was present in
which two molecules of the acrylate were coordinated to
one molecule of the Lewis acid.
It can be assumed that lack of reactivity of the supported
Lewis acid coordinated-dienophile (Ϯ)-2 might be due to
the steric hindrance induced by the backbone of the insol-
uble polymer. However, no cycloadduct was formed in solu-
tion under similar conditions from the reaction of isoprene
and the acrylate ester derivative 13 (which is the tert-butyl
ester equivalent of 2) (Table 1, Entry 4), suggesting that the
resin alone does not influence the outcome of the reaction.
Table 2. 13C NMR chemical shifts of free and TiCl4-complexed
substrates (0.5 equiv. TiCl4)
9b
9b-TiCl4
δ (ppm)
13
13-TiCl4
δ (ppm)
The formation of a doubly coordinated complex A (8- Carbon atoms
TiCl4) between TiCl4 and the dienophile derived from (R)-
δ (ppm)
δ (ppm)
pantolactone has been proposed by Helmchen.[7a,7b,17] This
ϪOϪCOϪC2H3
165.6
/
169.6
131.9
128.1
172.0
/
175.2
142.7
125.1
165.5
167.7
170.2
132.1
128.1
164.6-165.6
174.8-175.2
176.9-177.5
133.2-132.5
127.2-127.9
ϪCOϪOtBu
coordination increases the reactivity of the dienophile and
ϪCOϪN(R)-
also improves the regio- and stereoselectivity relative to un-
ϪCHϭCH2
catalyzed DielsϪAlder reactions. The results obtained re- ϪCHϭCH2
cently by Camps[16] and Cativiela[18] with the 4,4-dimethyl-
2-oxo-1-phenylpyrrolidin-3-yl acrylate 9a and the (R)-pan-
tolactone acrylate 8, respectively, are in good agreement
with this model.
We expected that a similar seven-membered chelate com-
plex B between TiCl4 and both the acrylate ester 13 and the
supported acrylate 2 could be formed to lead to an acti-
vated dienophile. However, besides complex B other species
could be present, like the doubly coordinated complex C
for compounds 2 and 13, for instance.
Addition of 0.5 equiv. of TiCl4 to the acrylate 13 resulted
in a splitting of most of the 13C NMR resonance signals
and in a large downfield shift of the 13C NMR resonance
signals associated with the two carbonyl carbons of the tert-
butyl ester and lactam moieties (Table 2). In contrast, a
lesser upfield shift was observed for the carbonyl carbon of
the acryloyl moiety suggesting the presence in this case of
the complex C. This latter complex leads to a poorly acti-
vated dienophile that is probably also sterically hindered,
thus restricting the approach of the diene.[5] This could ex-
plain why no reaction occurred when using compounds 13
even under drastic thermal reaction conditions (excess of
isoprene in refluxing benzene for 72 h; Table 1, Entry 5).
For the chemical shifts of the two vinyl carbons we ob-
served significant chemical-shift changes for the 9b-TiCl4
complex (131.9 Ǟ 142.7) and (128.1 Ǟ 125.0) and, in con-
trast, lower values for the 13-TiCl4 complex (132.1 Ǟ
132.2Ϫ132.5) and (128.1 Ǟ 127.2Ϫ127.9) (Table 2), in
agreement with the results obtained above.
According to these results, we decided to synthesize and
To investigate the question of the acrylate/Lewis acid test several new acrylate ester derivatives of the 3-hydroxy-
complexes, an NMR spectroscopic study (HMQC and 4,4-dimethyl-2-oxopyrrolidine type. Reactions were first
HMBC experiments) was performed. We recorded the spec- carried out in solution with the racemic dienophiles 14, 15a
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R. Akkari, M. Calmes, J. Martinez
FULL PAPER
and 16. The use of compounds 14 or 15a should make it
possible to eliminate or minimize the risks of competitive
complexation of the TiCl4 with the carbonyl group of the
nitrogen substituent. Indeed, the increase in the length of
the functionalised arm on the lactam nitrogen in com-
pounds 14 or its rigidification in compounds 15a should
mainly favour the complexation of the TiCl4 with the car-
bonyl function of the acrylate. Moreover, it can be assumed
that a similar result should be obtained by using the acry-
late 16, which does not contain a third carbonyl group.
Scheme 2. Reagents: (a) BnBr, Cs2CO3, DMF; (b) NH3 aq., 230
°C; (c) NaH, Br(CH2)5CO2Et, DMF; (d) NaH, Br(CH2)2OMe,
DMF; (e) H2, Pd(OH)2, EtOAc; (f) acryloyl chloride, NEt3, CH2Cl2
To prepare 14 and 16, the commercially available pantol-
actone 17 was transformed into the corresponding benzyl
ether as described recently (Scheme 2).[19] Then, the racemic
3-benzyloxy-4,4-dimethyl-yrrolidin-2-one (19) was formed
at 230 °C in a sealed tube by reaction with an excess of
aqueous ammonia solution. Alkylation of the lactam nitro-
gen with ethyl 6-bromohexanoate or with 2-bromoethyl
methyl ether gave racemic compounds 20 and 21, respec-
tively. The benzyl ether was easily cleaved by hydrogenolysis
affording the corresponding racemic alcohols 22 and 23.
The acrylate derivatives 14 and 16 were prepared by reac-
Scheme 3. Reagents: (a) 190 °C, 72 h; (b) BnOH, BOP/DIEA,
DMF; (c) polymer-NH2; BOP/DIEA, DMF; (d) acryloyl chloride,
NEt3, CH2Cl2
A second NMR spectroscopic study, at room tempera-
tion of 22 and 23 with acryloyl chloride and triethylamine ture in CD2Cl2, of the acrylates 14, 15a and 16 alone or
in anhydrous CH2Cl2 at Ϫ20 °C. in the presence of TiCl4 was realized. In each case a large
The racemic
1-(4-carboxyphenyl)-3-hydroxy-4,4-di- downfield shift of the 13C NMR resonance of the acryloyl
methyl-2-pyrrolidinone (24) was prepared in moderate and lactam carbonyl carbons was observed in the Lewis
yield, as described previously,[20] by fusion of a mixture of acid coordinated-acrylate, indicating a favourable com-
an excess of the lactone 17 with the sodium salt of 4-amino- plexation for the DielsϪAlder reaction (Table 3).
benzoic acid at 190 °C (Scheme 3). The corresponding ra-
No cycloadduct was isolated from the reaction of the
cemic benzyl ester 25a was obtained in high yield upon re- acrylate ester 14 with isoprene (2.0 equiv.) in the presence
action with (benzotriazolyloxy)tris(dimethylamino)phos- of 0.5 equivalents of TiCl4 in a temperature range from Ϫ20
phonium hexafluorophosphate (BOP) and diisopropylethyl- °C to 10 °C for 16 h, (Table 1, Entry 6). No improvement
amine (DIEA). Finally, the acrylic ester derivative 15a was was observed under more drastic conditions — 1Ϫ2 equiva-
prepared as described above from acryloyl chloride.
lents of TiCl4, 2Ϫ4 equivalents of diene, longer reaction
Table 3. 13C NMR chemical shifts of free and TiCl4-complexed substrates (0.5 equiv. TiCl4)
14
δ (ppm)
14-TiCl4
δ (ppm)
15a
δ (ppm)
15a-TiCl4
δ (ppm)
16
δ (ppm)
16-TiCl4
δ (ppm)
Carbon atoms
ϪOϪCOϪC2H3
ϪCOϪOR
ϪCOϪN(RЈ)Ϫ
ϪCHϭCH2
165.6
173.6
169.5
131.9
128.2
172.6
174.0
177.6
141.6
125.3
165.5
166.0
169.7
132.5
127.9
174.8
164.5
171.1
142.6
124.3
165.6
Ϫ
169.7
131.9
128.2
173.1
Ϫ
174.1
141.0
125.8
ϪCHϭCH2
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Toward DielsϪAlder Reactions on a Solid Support
FULL PAPER
time (24Ϫ70 h) and different temperatures (Table 1, Entry tion or solid-phase DielsϪAlder reaction. We have demon-
6). strated, by NMR spectroscopy, that the outcome of the
Reaction of acrylates 15a and 16 with isoprene (2.0 DielsϪAlder reaction is dependent on the pyrrolidinone
equiv.) in the presence of one equivalent of TiCl4 at a tem- structure. Good results, high yield and regio- or endoselec-
perature between Ϫ20 and 0 °C gave the desired compound, tivity were obtained using the 4-(3-hydroxy-4,4-dimethyl-2-
which consisted only of the corresponding para adducts 26a oxo-pyrrolidin-1-yl) benzoic acid derivatives in solution or
and 27 (Table 1, Entry 9 and 12), in 90% yield. The absence solid phase DielsϪAlder reaction. Studies are now in pro-
of the meta regioisomer was confirmed by 13C NMR analy- gress to convert this racemic compound into the corre-
sis of the methylcyclohex-3-enecarboxylic acid obtained sponding enantiopure compound and to evaluate its pos-
after LiOH hydrolysis of each cycloadduct.
sible use as a supported chiral auxiliary in the asymmetric
DielsϪAlder reaction.
Experimental Section
General Remarks: All reagents were used as purchased from com-
mercial suppliers without further purification, except triethylamine,
which was distilled from KOH and ninhydrin. Solvents were dried
and purified by conventional methods prior to use; THF was
freshly distilled under argon from sodium and benzophenone.
Melting points were determined with a Büchi apparatus and are
uncorrected. IR spectra were recorded with a FT-IR PerkinϪElmer
1000 spectrometer. 1H or 13C NMR spectra (DEPT, HMQC,
A possible explanation for the absence of reaction in the
case of 14 could be the significance of the steric hindrance
of the complexed molecule related to the nitrogen substitu- HMBC experiments) were recorded with a Bruker Advance 300
spectrometer or a Bruker A DRX 400 spectrometer using the sol-
vent as internal reference. Data are reported as follows: chemical
shifts (δ) in ppm, coupling constants (J) in Hz. The ESI mass spec-
tra were recorded with a platform II quadrupole mass spectrometer
(Micromass, Manchester, UK) fitted with an electrospray source.
HPLC analysis were performed with a Waters model 510 instru-
ment with variable detector at 214 nm using a reversed-phase Nu-
cleosil C18 column, 3.5 µm, (50 ϫ 4.6 mm), flow: 1 mL/min, H2O
(0.1% TFA)/CH3CN (0.1% TFA) gradient 0Ǟ100% (15 min) and
100% (4 min).
ent and the Lewis acid. To complete this study we decided
to test other Lewis acid catalysts [Et2AlCl, Zn(CF3SO3)2,
Sm(CF3SO3)2, Sc(CF3SO3)2] with 14 and isoprene, but
again no reaction occurred (Table 1, Entry 7 and 8).
Returning to the initial strategy, and considering the re-
sults obtained in solution with the acrylate 15a (i.e. import-
ant yield and favourable TiCl4 complexation), we decided
to perform the solid-phase experiments using the supported
acrylate 15b. The supported acrylate 15b, anchored on a
Rink amide resin, was easily obtained, as described pre-
viously in the case of the acrylic ester 2, by acryloyl chloride
treatment of the corresponding supported alcohol 25b
(Scheme 3). As expected, using the optimized reaction con-
ditions, the reaction of 15b with six equivalents of isoprene
or cyclopentadiene in the presence of 1.1 equivalents of
TiCl4 at 0 °C for 16 h yielded the para-compound 26b
(؎)-(3-Hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)acetic Acid (3):
Racemic tert-butyl (3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)a-
cetate (2 g, 8 mmol), obtained in 71% yield as described pre-
viously[13a], was treated with TFA (30 mL) in CH2Cl2 (140 mL).
After standing for 1 h at room temperature, the volatile products
were evaporated under reduced pressure and co-evaporated with
cyclohexane and diethyl ether to afford the expected racemic com-
(Table 1, Entry 10) and the endo-compound 28, respectively, pound 3 as a white solid (1.45 g, 100% yield). m.p. 168.5 °C; HPLC,
NMR and MS (ESI) physical data are identical to those of the
in good yield (Table 1, Entry 11) after removal from the
resin by acidic cleavage of the benzhydrylamine bond.
LiOH hydrolysis of these compounds afforded the expected
racemic 4-methylcyclohex-3-enecarboxylic acid (7) or the
racemic bicyclo[2,2,1]hept-5-ene-2-carboxylic acid (29).
optically pure compounds.[13a]
Preparation of the Supported (؎)-(3-Hydroxy-4,4-dimethyl-2-oxo-
pyrrolidin-1-yl)acetic Acid (؎)-1: After deprotection of the Fmoc
group of the Rink amide resin (2.0 g, 1.0 mmol) by the standard
procedure (20% piperidine in DMF, 40 min), a solution of the al-
cohol 3 (0.28 g, 1.5 mmol, 1.5 equiv.), BOP (0.73 g, 1.65 mmol, 1.65
equiv.) and DIEA (0.31 mL, 1.8 mmol, 1.8 equiv.) in DMF (15
mL) was added to the resin. The suspension was stirred at room
temperature for 12 h and the solution was removed from the resin
by filtration. The resin was washed with DMF (3 ϫ 15 mL),
CH2Cl2 (3 ϫ 15 mL), CH2Cl2/CH3OH (8:2) (3 ϫ 15 mL), CH2Cl2
(3 ϫ 15 mL) and diethyl ether (3 ϫ 15 mL), and then dried under
reduced pressure. Reaction was monitored by the ninhydrin test.
Conclusions
General Procedure for the Preparation of Compounds 20 and 21:
Racemic 3-benzyloxy-4,4-dimethylpyrrolidin-2-one (19) was ob-
tained in 75% yield (two steps) starting from the commercially
In conclusion, several new acrylate compounds have been
prepared starting from N-substituted 3-hydroxy-4,4-di-
methyl-2-pyrrolidinones and tested as dienophiles in solu- available pantolactone as described previously.[13a] Sodium hydride
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R. Akkari, M. Calmes, J. Martinez
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(614 mg, 15.3 mmol, 60% in paraffin, 1.7 equiv.) was slowly added tR (HPLC) ϭ 8.54 min. IR (CH2Cl2): ν˜ ϭ 3332 (br), 3055 (w), 2933
at 0 °C to a solution of racemic 3-benzyloxy-4,4-dimethylpyrroli-
(m), 2866 (m), 1727 (s), 1682 (s), cmϪ1. MS (ESI): m/z ϭ 272.1 [M
1
din-2-one (1.97 g, 9.0 mmol) in 100 mL of dry DMF under argon. ϩ H]ϩ, 543.4, 565.5. H NMR (CDCl3): δ ϭ 0.86 (s, 3 H, CH3),
After 15 min stirring at room temperature, ethyl 6-bromohexanoate
or 2-bromoethyl methyl ether (9.9 mmol, 1.10 equiv.) was added
dropwise and stirring was continued for 12 h at the same tempera-
ture until TLC indicated complete consumption of the starting ma-
terial. The reaction mixture was then neutralized with 1  HCl and
the DMF was concentrated in vacuo. The residue was diluted with
a 1  HCl solution (100 mL) and was extracted with ethyl acetate
(2 ϫ 100 mL). The combined organic layers were dried with anhy-
drous sodium sulfate and concentrated in vacuo.
1.03 (s, 3 H, CH3), 1.08 (t, J ϭ 7.1 Hz, 3 H, CH3CH2O), 1.15 (m,
2 H, CH2), 1.35 (m, 2 H, CH2), 1.47 (m, 2 H, CH2), 2.12 (t, J ϭ
7.4 Hz, 2 H, CH2CO), 2.82 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 2.90
(d, J ϭ 9.6 Hz, 1 H, NCHAHB), 3.09 (t, J ϭ 7.2 Hz, 2 H, CH2N),
3.82 (s, 1 H, CMe2CH), 3.94 (q, J ϭ 7.1 Hz, 2 H, CH3CH2O), 5.02
(br., 1 H, OH) ppm. 13C NMR (CDCl3): δ ϭ 12.7 (CH3CH2O),
18.8 (CH3), 23.0 (CH2), 23.4 (CH3), 24.7 (CH2), 25.2 (CH2), 32.6
(CH2CO), 36.9 (CMe2), 41.0 (CH2N), 55.6 (NCHAHB), 58.7
(CH3CH2O), 76.2 (CMe2CH), 172.0 (CO), 173.5 (CO) ppm.
HRMS (FAB) calcd. for C14H26NO4 (MHϩ) 272.1862, found
272.1857.
(؎)-Ethyl 6-(3-Benzyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)hexano-
ate (20): Synthesised following the general procedure from benzyl-
oxy-4,4-dimethylpyrrolidin-2-one (1.97 g, 9.0 mmol) and ethyl 6-
(؎)-3-Hydroxy-1-(2-methoxyethyl)-4,4-dimethylpyrrolidin-2-one
bromohexanoate (1.5 mL, 9.9 mmol, 1.10 equiv.). Pure 20 was ob- (23):
A solution of (Ϯ)-3-benzyloxy-1-(2-methoxyethyl)-4,4-di-
tained as a colourless oil (2.27 g, 6.3 mmol, 70%) after column
chromatography on silica gel, eluting with hexane/ethyl acetate
methylpyrrolidin-2-one 21 (1.53 g, 5.5 mmol) in ethyl acetate (25
mL) was added to a cooled solution (Ϫ20 °C) of 20% palladium
(6:4); tR (HPLC) ϭ 12.03 min. IR (CH2Cl2): ν˜ ϭ 3054 (m), 2934 hydroxide on charcoal in ethyl acetate (25 mL) under an argon
(m), 2866 (m), 1728 (s), 1693 (s), 1269 (s) cmϪ1. MS (ESI): m/z ϭ
atmosphere. The mixture was then stirred for 5 h at room tempera-
ture under H2 (the reaction was monitored by TLC). After fil-
362.2 [M ϩ H]ϩ, 723.8. 1H NMR (CDCl3): δ ϭ 1.09 (s, 3 H, CH3),
1.10 (s, 3 H, CH3), 1.25 (t, J ϭ 7.1 Hz, 3 H, CH3CH2O), 1.33 (m, tration through celite, concentration of the filtrate yielded the ex-
2 H, CH2), 1.51 (m, 2 H, CH2), 1.65 (m, 2 H, CH2), 2.29 (t, J ϭ pected compound 23 as a colourless oil (1.03 g, 5.5 mmol, 100%);
7.4 Hz, 2 H, CH2CO), 2.95 (d, J ϭ 9.5 Hz, 1 H, NCHAHB), 3.05 tR (HPLC) ϭ 5.46 min. IR (CH2Cl2): ν˜ ϭ 3349 (br), 2960 (s), 2871
(d, J ϭ 9.5 Hz, 1 H, NCHAHB), 3.25 (m, 2 H, CH2N), 3.60 (s, 1 (s), 1686 (s), 1458 (s), 1119 (m) cmϪ1. MS (ESI): m/z ϭ 188.0 [M
1
H, CMe2CH), 4.11 (q, J ϭ 7.1 Hz, 2 H, CH3CH2O), 4.78 (d, J ϭ ϩ H]ϩ, 375.2. H NMR (CDCl3): δ ϭ 0.97 (s, 3 H, CH3), 1.14 (s,
12.2 Hz,
1
H, OHCHC6H5), 5.05 (d,
J
ϭ
12.2 Hz,
1
H,
3 H, CH3), 3.04 (d, J ϭ 9.7 Hz, 1 H, NCHAHB), 3.13 (d, J ϭ 9.7
OHCHC6H5), 7.34 (m, 5 H, H-arom.) ppm. 13C NMR (CDCl3): Hz, 1 H, NCHAHB), 3.26 (s, 3 H, CH3O), 3.39 (m, 4 H, CH2N and
δ ϭ 14.6 (CH3CH2O), 21.2 (CH3), 25.0 (CH2), 25.8 (CH3), 26.7 CH2O), 3.94 (s, 1 H, CMe2CH), 4.74 (br., 1 H, OH) ppm. 13C
(CH2), 27.2 (CH2), 34.5 (CH2CO), 38.2 (CMe2), 42.6 (CH2N), 57.6
NMR (CDCl3): δ ϭ 18.3 (CH3), 22.9 (CH3), 37.1 (CMe2), 40.8
(NCHAHB), 60.6 (CH3CH2O), 72.8 (OCH2C6H5), 84.0 (CMe2CH), (CH2N), 56.6 (NCHAHB), 56.8 (CH3O), 68.7 (CH2O), 76.1
127.9 (CH-arom.), 128.2 (CH-arom.), 128.7 (CH-arom.), 138.8 (C- (CMe2CH), 173.3 (CON) ppm. HRMS (FAB) calcd. for C9H18NO3
arom.), 173.2 (CO), 173.9 (CO) ppm. HRMS (FAB) calcd. for [MHϩ] 188.1287, found 188.1290.
C21H32NO4 [MHϩ] 362.2331, found 362.2327.
(؎)-4-(3-Hydroxy-4,4-dimethyl-2-oxo-pyrrolidin-1-yl)benzoic Acid
(؎)-3-Benzyloxy-1-(2-methoxyethyl)-4,4-dimethylpyrrolidin-2-one
(21): Synthesised following the general procedure from benzyloxy-
4,4-dimethylpyrrolidin-2-one (1.97 g, 9.0 mmol) and 2-bromoethyl
24:[20] Commercially available pantolactone (25 g, 192.0 mmol, 2.9
equiv.) was melted at 190 °C and then sodium 4-aminobenzoate
(10.5 g, 65.9 mmol) was added in one go. The mixture was vigor-
methyl ether (0.93 mL, 9.9 mmol, 1.1 equiv.). Pure 21 was obtained ously stirred for 72 h at the same temperature. The temperature was
as a colourless oil (2.17 g, 7.8 mmol, 87%) after column chromatog-
raphy on silica gel, eluting with hexane/ethyl acetate (5:5); tR
(HPLC) ϭ 10.08 min. IR (CH2Cl2): ν˜ ϭ 2929 (m), 1695 (s), 1119
(m) cmϪ1. MS (ESI): m/z ϭ 278.1 [M ϩ H]ϩ, 555.2. 1H NMR
then reduced to 80 °C and the reaction mixture was dissolved by
addition of ethyl acetate (200 mL), water (200 mL) and saturated
NaHCO3 (100 mL). The combined aqueous phase was washed with
ethyl acetate (2 ϫ 200 mL), acidified to pH 1 with concentrated
(CDCl3): δ ϭ 1.09 (s, 3 H, CH3), 1.10 (s, 3 H, CH3), 3.10 (d, J ϭ HCl and then extracted with ethyl acetate (2 ϫ 500 mL). The com-
9.6 Hz, 1 H, NCHAHB), 3.16 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 3.33 bined organic layers were dried with anhydrous sodium sulfate and
(s, 3 H, CH3O), 3.46 (m, 4 H, CH2N and CH2O), 3.65 (s, 1 H, concentrated in vacuo. The expected compound 24 was precipitated
CMe2CH), 4.79 (d, J ϭ 12.2 Hz, 1 H, OHCHC6H5), 5.07 (d, J ϭ by addition of CH2Cl2, isolated by filtration and washed success-
12.2 Hz, 1 H, OHCHC6H5), 7.33 (m, 5 H, H-arom.). ppm. 13C ively with CH2Cl2 and diethyl ether (7.37 g; 29.6 mmol, 45%): m.p.
NMR (CDCl3): δ ϭ 20.7 (CH3), 25.2 (CH3), 38.1 (CMe2), 42.4
222Ϫ223 °C; tR (HPLC) ϭ 7.64 min. IR (KBr): ν˜ ϭ 3438 (m),
(CH2N), 58.5 (NCHAHB), 58.7 (CH3O), 70.7 (CH2O), 72.5 2964Ϫ2667 (br), 1680 (s), 1606 (m) cmϪ1. MS (ESI): m/z ϭ 250.2
1
(OCH2C6H5), 83.5 (CMe2CH), 127.6 (CH-arom.), 127.8 (CH-
[M ϩ H]ϩ, 499.1. H NMR ([D6]DMSO): δ ϭ 0.94 (s, 3 H, CH3),
arom.), 128.3 (CH-arom.), 138.3 (C-arom.), 173.1 (CON) ppm. 1.18 (s, 3 H, CH3), 3.49 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 3.55 (d,
HRMS (FAB) calcd. for C16H24NO3 [MHϩ] 278.1756, found J ϭ 9.6 Hz, 1 H, NCHAHB), 4.03 (s, 1 H, CMe2CH), 5.82 (br., 1
278.1768.
H, OH), 7.80 (d, J ϭ 8.9 Hz, 2 H, H-arom.), 7.95 (d, J ϭ 8.9 Hz,
2 H, H-arom.). ppm. 13C NMR ([D6]DMSO): δ ϭ 20.0 (CH3),
23.9 (CH3), 37.1 (CMe2), 56.0 (NCHAHB), 77.4 (CMe2CH), 118.0
(CH-arom.), 125.5 (C-arom.), 130.2 (CH-arom.), 143.4 (C-arom.),
166.8 (CO), 174.1 (CO) ppm. HRMS (FAB) calcd. for C13H16NO4
[MHϩ] 250.1079, found 250.1081.
(؎)-Ethyl 6-(3-Hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)hexano-
ate (22): A solution of (Ϯ)-ethyl 6-(3-benzyloxy-4,4-dimethyl-2-ox-
opyrrolidin-1-yl)hexanoate (20, 2.06 g, 5.7 mmol) in ethyl acetate
(35 mL) was added to a cooled solution (Ϫ20 °C) of 20% palladium
hydroxide on charcoal in ethyl acetate (35 mL) under an argon
atmosphere. The mixture was then stirred for 5 h at room tempera-
ture under H2 (the reaction was monitored by TLC). After fil-
tration through celite, concentration of the filtrate yielded the ex-
pected compound 22 as a colourless oil (1.54 g, 5.7 mmol, 100%);
(؎)-Benzyl 4-(3-Hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzo-
ate (25a): 2.2 Equivalents of diisopropylethylamine (2.51 mL, 14.4
mmol) and 2.0 equivalents of BOP (5.80g, 13.1 mmol) were added
to (Ϯ)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) benzoic
2446
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2441Ϫ2450

Toward DielsϪAlder Reactions on a Solid Support
acid 24 (1.63 g, 6.5 mmol) in dry DMF (20 mL). After 15 min (m), 1712 (s), 1456 (m) cmϪ1. MS (ESI): m/z ϭ 144.1 [M ϩ H]ϩ,
FULL PAPER
stirring at room temperature, benzyl alcohol (1.36 mL, 13.1 mmol,
2 equiv.) was added dropwise and stirring was continued for 5 h at
the same temperature. The DMF solution was concentrated in va-
cuo, the mixture diluted with ethyl acetate (200 mL) and then suc-
cessively washed with a saturated aqueous NaHCO3 solution (200
mL), a 1  KHSO4 solution (200 mL) and water (200 mL). The
organic layer was dried with anhydrous Na2SO4 and concentrated
in vacuo. Column chromatography on silica gel, eluting with hex-
ane/ethyl acetate/CH2Cl2 (5:4:1), yielded the pure compound 25a as
287.0. 1H NMR (CDCl3): δ ϭ 0.97 (s, 3 H, CH3), 1.13 (s, 3 H,
CH3), 2.78 (s, 3 H, NCH3), 2.91 (d, J ϭ 9.7 Hz, 1 H, NCHAHB),
3.03 (d, J ϭ 9.7 Hz, 1 H, NCHAHB), 4.08 (s, 1 H, CMe2CH), 4.89
(br. s, 1 H, OH) ppm. 13C NMR (CDCl3): δ ϭ 20.6 (CH3), 25.4
(CH3), 30.4 (NCH3), 38.8 (CMe2), 59.9 (NCHAHB), 78.1
(CMe2CH), 175.5 (CO) ppm. Following the general procedure,
compound 9b was obtained as a white solid from (Ϯ)-3-hydroxy-
1,4,4-trimethyl-2-pyrrolidinone (0.58 g, 4.1 mmol) after column
chromatography on silica gel, eluting with ethyl acetate/hexane
a white solid (1.98 g, 5.8 mmol, 90%); m.p. 108.4 °C; tR (HPLC) ϭ (8:2) (0.53 g, 2.66 mmol, 65%); m.p. 58.6 °C; tR (HPLC) ϭ
10.97 min. IR (KBr): ν˜ ϭ 2964 (s), 2879 (s), 1790 (s), 1719 (s) 1269 7.36 min. IR (CH2Cl2): ν˜ ϭ 2967 (w), 2873 (w), 1732 (s), 1707 (s),
(s) cmϪ1. MS (ESI): m/z ϭ 340.0 [M ϩ H]ϩ, 679.3. 1H NMR
cmϪ1. MS (ESI): m/z ϭ 197.9 [M ϩ H]ϩ, 395.1. 1H NMR
(CDCl3): δ ϭ 1.01 (s, 3 H, CH3), 1.24 (s, 3 H, CH3), 3.40 (d, J ϭ (CD2Cl2): δ ϭ 1.06 (s, 3 H, CH3), 1.22 (s, 3 H, CH3), 2.85 (s, 3 H,
9.6 Hz, 1 H, NCHAHB), 3.46 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 3.80 NCH3), 3.06 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 3.18 (d, J ϭ 9.6 Hz,
(br., 1 H, OH), 4.07 (s, 1 H, CMe2CH), 5.27 (s, 2 H, OCH2C6H5), 1 H, NCHAHB), 5.24 (s, 1 H, CMe2CH), 5.93 (dd, J ϭ 1.5 and J ϭ
7.3 (m, 5 H, H-arom.), 7.63 (d, J ϭ 11.2 Hz, 2 H, H-arom.), 7.99 10.4 Hz, 1 H, HCHϭ), 6.22 (dd, J ϭ 10.4 and J ϭ 17.3 Hz, 1 H,
(d, J ϭ 11.2 Hz, 2 H, H-arom.). ppm. 13C NMR (CDCl3): δ ϭ
CHϭ), 6.48 (dd, J ϭ 1.5 and J ϭ 17.3 Hz, 1 H, HCHϭ) ppm. 13C
20.1 (CH3), 24.6 (CH3), 38.3 (CMe2), 57.5 (NCHAHB), 66.8 NMR (CD2Cl2): δ ϭ 21.5 (CH3), 25.4 (CH3), 30.1 (NCH3), 37.8
(OCH2C6H5), 78.5 (CMe2CH), 118.5 (CH-arom.), 126.0 (C-arom.), (CMe2), 59.6 (NCHAHB), 78.2 (CMe2CH), 128.1 (CHϭ), 131.9
128.2 (CH-arom.), 128.3 (CH-arom.), 128.7 (CH-arom.), 130.8
(CH2ϭ), 165.6 (COCHϭCH2), 169.6 (CONCH3) ppm. HRMS
(CH-arom.), 136.1 (C-arom.), 143.2 (C-arom.), 165.9 (CO), 174.8 (FAB) calcd. for C10H16NO3 [MHϩ] 198.1130, found 198.1132.
(CO) ppm. HRMS (FAB) calcd. for C20H22NO4 [MHϩ] 340.1549,
(؎)-(1-tert-Butoxycarbonylmethyl-4,4-dimethyl-2-oxopyrrolidin-3-
yl) Acrylate (13): Racemic tert-butyl (3-hydroxy-4,4-dimethyl-2-ox-
opyrrolidin-1-yl)acetate was obtained in 71% yield as described
previously.[13a] Following the general procedure, compound 13 was
obtained as a colourless oil from racemic tert-butyl (3-hydroxy-4,4-
dimethyl-2-oxopyrrolidin-1-yl)acetate (0.99 g, 4.1 mmol) after col-
umn chromatography on silica gel, eluting with ethyl acetate/hex-
ane (8:2) (0.91 g, 3.1 mmol, 75%); tR (HPLC) ϭ 10.39 min. IR
found 340.1555.
Preparation of the Supported (؎)-4-(3-Hydroxy-4,4-dimethyl-2-oxo-
pyrrolidin-1-yl)benzoic Acid (25b): After deprotection of the Fmoc
group of the Rink amide resin (2.0 g, 1.0 mmol) by the standard
procedure (20% piperidine in DMF, 40 min), a solution of the al-
cohol 24 (0.37 g, 1.5 mmol, 1.5 equiv.), BOP (0.73 g, 1.65 mmol,
1.65 equiv.) and DIEA (0.32 mL, 1.80 mmol, 1.8 equiv.) in DMF
(15 mL) was added to the resin. The suspension was stirred for
12 h at room temperature and the solution was removed from the
resin by filtration. The resin was washed with DMF (3 ϫ 15 mL),
CH2Cl2 (3 ϫ 15 mL), CH2Cl2/CH3OH (8:2) (3 ϫ 15 mL), CH2Cl2
(3 ϫ 15 mL) and diethyl ether (3 ϫ 15 mL), and then dried under
reduced pressure. The reaction was monitored by the ninhydrin
test.
(CH2Cl2): ν˜ ϭ 3054 (m), 2984 (m), 1738 (s), 1713 (s), 1264 (s) cmϪ1
.
MS (ESI): m/z ϭ 242.0, 297.9 [M ϩ H]ϩ, 595.2. 1H NMR
(CD2Cl2): δ ϭ 1.12 (s, 3 H, CH3), 1.23 (s, 3 H, CH3), 1.48 [s, 9 H,
OC(CH3)3], 3.15 (d, J ϭ 9.3 Hz, 1 H, NCHAHB), 3.29 (d, J ϭ
9.3 Hz, 1 H, NCHAHB), 3.93 (s, 2 H, NϪCH2ϪCO), 5.30 (s, 1 H,
CMe2CH), 5.93 (dd, J ϭ 1.5 Hz and J ϭ 10.4 Hz, 1 H, HCHϭ),
6.22 (dd, J ϭ 10.4 and J ϭ 17.3 Hz, 1 H, CHϭ), 6.48 (dd, J ϭ 1.5
and J ϭ 17.3 Hz, 1 H, HCHϭ) ppm. 13C NMR (CD2Cl2): δ ϭ
21.3 (CH3), 25.2 (CH3), 28.3 [OC(CH3)3], 38.2 (CMe2), 45.2
(NϪCH2ϪCO), 57.9 (NCHAHB), 77.8 (CMe2CH), 82.4
[OC(CH3)3], 128.1 (CHϭ), 132.1 (CH2ϭ), 165.5 (COCHϭCH2),
167.7 (CO2tBu), 170.2 (CON) ppm. HRMS (FAB) calcd. for
C15H24NO5 [MHϩ] 298.1654, found 298.1650.
Polymer-Bound Acrylates (؎)-2 and 15b: Triethylamine (1.2 mL,
8.5 mmol, 8.5 equiv.) and then acryloyl chloride (0.4 mL, 5.0 mmol,
5 equiv.) were added dropwise to the stirred and swollen resin (Ϯ)-
1 or 25b (1.0 mmol) in anhydrous CH2Cl2 (15 mL) at room tem-
perature. The suspension was stirred for 4Ϫ5 h at the same tem-
perature and the solution was removed from the resin by filtration.
After washing with CH2Cl2 (3 ϫ 20 mL), CH2Cl2/ CH3OH (8:2)
(3 ϫ 20 mL), CH2Cl2 (3 ϫ 20 mL) and diethyl ether (3 ϫ 20 mL),
the expected resin (Ϯ)-2 or 15b was dried under reduced pressure.
(؎)-[1-(5-Ethoxycarbonylpentyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl]
Acrylate (14): Following the general procedure, compound 14 was
obtained as a colourless oil from (Ϯ)-ethyl 6-(3-hydroxy-4,4-di-
methyl-2-oxopyrrolidin-1-yl)hexanoate (22, 1.11 g, 4.1 mmol) after
column chromatography on silica gel, eluting with ethyl acetate/
hexane (6:4) (1.17 g, 3.6 mmol, 88%); tR (HPLC) ϭ 10.38 min. IR
General Procedure for the Preparation of the Acrylates 9b, 13, 14,
15a, 16: Acryloyl chloride (4.92 mmol, 1.2 equiv.) was added drop-
wise to
a mixture of the racemic pyrrolidinone derivative
(CH2Cl2): ν˜ ϭ 2934 (m), 2866 (m), 1729 (s), 1703 (s), 1184 (s) cmϪ1
.
(4.1 mmol) and triethylamine (8.2 mmol, 2 equiv.) in anhydrous
CH2Cl2 (10 mL) at Ϫ20 °C. After 2 h at this temperature the mix-
ture was washed with a 1  HCl solution (2 ϫ 10 mL) and saturated
aqueous NaHCO3 (2 ϫ 10 mL). The organic layer was dried with
anhydrous Na2SO4 and concentrated in vacuo. Column chromatog-
raphy of the residue on silica gel yielded the pure acrylate deriva-
tive.
MS (ESI): m/z ϭ 326.1 [M ϩ H]ϩ, 651.4. 1H NMR (CD2Cl2): δ ϭ
1.02 (s, 3 H, CH3), 1.19 (s, 3 H, CH3), 1.21 (t, J ϭ 7.1 Hz, 3 H,
CH3CH2O), 1.28 (m, 2 H, CH2), 1.48 (m, 2 H, CH2), 1.59 (m, 2
H, CH2), 2.25 (t, J ϭ 7.4 Hz, 2 H, CH2CO), 3.02 (d, J ϭ 9.6 Hz,
1 H, NCHAHB), 3.13 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 3.22 (t, J ϭ
7.1 Hz, 2 H, CH2N), 4.05 (q, J ϭ 7.1 Hz, 2 H, CH3CH2O), 5.21
(s, 1 H, CMe2CH), 5.88 (dd, J ϭ 1.5 and J ϭ 10.3 Hz, 1 H, HCHϭ
), 6.17 (dd, J ϭ 10.3 and J ϭ 17.6 Hz, 1 H, CHϭ), 6.42 (dd, J ϭ
1.5 and J ϭ 17.6 Hz, 1 H, HCHϭ) ppm. 13C NMR (CD2Cl2): δ ϭ
(؎)-1,4,4-Trimethyl-2-oxopyrrolin-3-yl Acrylate 9b: (Ϯ)-3-Hydroxy-
1,4,4-trimethyl-2-pyrrolidinone was obtained in 80% yield by reac-
tion of the commercially available pantolactone and methylamine 14.4 (CH3CH2O), 21.4 (CH3), 24.9 (CH2), 25.3 (CH3), 26.6 (CH2),
according to the method described by Ryan et al,[21] m.p. 70Ϫ72
°C; tR (HPLC) ϭ 3.30 min. IR (KBr): ν˜ ϭ 3300Ϫ2600 (br), 1966
27.1 (CH2), 34.4 (CH2CO), 38.0 (CMe2), 42.8 (CH2N), 57.2
(NCHAHB), 60.4 (CH3CH2O), 78.4 (CMe2CH), 128.2 (CHϭ),
Eur. J. Org. Chem. 2004, 2441Ϫ2450
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2447

`
R. Akkari, M. Calmes, J. Martinez
FULL PAPER
131.9 (CH2ϭ), 165.6 (COCHϭCH2), 169.5 (CON), 173.6 cmϪ1. MS (ESI): m/z ϭ 265.9 [M ϩ H]ϩ, 553.3. 1H NMR (CDCl3):
(CO2C2H5) ppm. HRMS (FAB) calcd. for C17H28NO5 [MHϩ]
326.1967, found 326.1964.
δ ϭ 0.96 (s, 3 H, CH3), 1.12 (s, 3 H, CH3), 1.57 (s, 3 H, CH3), 1.71
(m, 1 H, HCH), 1.96 (m, 3 H, CH2 and HCH), 2.20 (m, 2 H, CH2),
2.58 (m, 1 H, CHCO), 2.80 (s, 3 H, NCH3), 2.99 (d, J ϭ 9.7 Hz,
1 H, NCHAHB), 3.10 (d, J ϭ 9.7, 1 H, NCHAHB), 5.13 (s, 1 H,
CMe2CH), 5.30 (br. s, 1 H, CHϭ) ppm. 13C NMR (CDCl3): δ ϭ
21.3 (CH3), 23.4 (CH3), 25.2 (CH2), 25.4 (CH3), 27.8 (CH2), 28.9
(CH2), 30.0 (NCH3), 37.4 (CHCO), 39.0 (CMe2), 59.5 (NCHAHB),
77.3 (CMe2CH), 118.9 (CHϭ), 133.9 (CH3Cϭ), 169.9 (CO), 175.2
(CO) ppm. HRMS (FAB) calcd. for C15H24NO3 [MHϩ] 266.1756,
found 266.1753.
(؎)-Benzyl 4-(3-Acryloyloxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)ben-
zoate (15a): Following the general procedure, compound 15a was
obtained as a colourless oil from (Ϯ)-benzyl 4-(3-hydroxy-4,4-di-
methyl-2-oxopyrrolidin-1-yl)benzoate (25a, 1.39 g, 4.1 mmol) after
column chromatography on silica gel, eluting with acetone/hexane
(3:7) (1.32 g, 3.36 mmol, 82%); tR (HPLC) ϭ 13.01 min. IR
(CH2Cl2): ν˜ ϭ 2928 (w), 1716 (s), 1606 (m), 1181 (s) cmϪ1. MS
(ESI): m/z ϭ 394.3 [M ϩ H]ϩ, 787.3. 1H NMR (CD2Cl2): δ ϭ 1.22
(s, 3 H, CH3), 1.36 (s, 3 H, CH3), 3.61 (d, J ϭ 9.6 Hz, 1 H,
NCHAHB), 3.67 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 5.42 (s, 2 H,
CH2ϪC6H5), 5.56 (s, 1 H, CMe2CH), 6.02 (d, J ϭ 10.6 Hz, 1 H,
HCHϭ), 6.34 (dd, J ϭ 10.6 and J ϭ 17.3 Hz, 1 H, CHϭ), 6.60 (d,
J ϭ 17.3 Hz, 1 H, HCHϭ), 7.46 (m, 5 H, H-arom.), 7.83 (d, J ϭ
8.7 Hz, 2 H, H-arom.), 8.16 (d, J ϭ 8.7 Hz, 2 H, H-arom.) ppm.
13C NMR (CD2Cl2): δ ϭ 21.3 (CH3), 24.8 (CH3), 37.6 (CMe2),
57.6 (NCHAHB), 66.9 (OCH2C6H5), 78.5 (CMe2CH), 118.8 (CH-
arom.), 126.3 (C-arom.), 127.9 (CHϭ), 128.5 (CH-arom.), 129.0
(CH-arom.), 130.9 (CH-arom.), 132.5 (CH2ϭ), 136.8 (C-arom.),
143.7 (C-arom.), 165.5 (COCHϭCH2), 166.0 (COOCH2C6H5),
169.7 (CON) ppm. HRMS (FAB) calcd. for C23H24NO5 [MHϩ]
394.1654, found 394.1639.
Benzyl 4-[4,4-Dimethyl-3-(4-methylcyclohex-3-enylcarbonyloxy)-2-
oxopyrrolidin-1-yl]benzoate (26a): Synthesized following the general
procedure from the dienophile 15a (236 mg, 0.6 mmol) and iso-
prene. Compound 26a was obtained as a white solid after column
chromatography on silica gel, eluting with acetone/hexane (2:8)
(249 mg, 0.54 mmol, 90%); m.p. 72Ϫ73 °C; tR (HPLC)
ϭ
14.90 min. IR (CH2Cl2): ν˜ ϭ 3053 (m), 2933 (m), 1718 (s), 1268
(m) cmϪ1. MS (ESI): m/z ϭ 462.2 [M ϩ H]ϩ, 923.1. 1H NMR
([D6]DMSO): δ ϭ 1.03 (s, 3 H, CH3), 1.19 (s, 3 H, CH3), 1.64 (s,
3 H, CH3), 1.70 (m, 2 H, CH2), 1.97 (m, 2 H, CH2), 2.23 (m, 2 H,
CH2), 2.66 (m, 1 H, CHCO), 3.59 (d, J ϭ 9.6 Hz, 1 H, NCHAHB),
3.75 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 5.34 (s, 2 H, OCH2C6H5),
5.37 (br. s, 1 H, CHϭ), 5.52 (s, 1 H, CMe2CH), 7.40 (m, 5 H, H-
arom.), 7.81 (d, J ϭ 8.8 Hz, 2 H, H-arom.), 8.02 (d, J ϭ 8.8 Hz, 2
H, H-arom.) ppm. 13C NMR ([D6]DMSO): δ ϭ 21.6 (CH3), 24.2
(CH3), 24.5 (CH3), 25.8 (CH2), 28.1 (CH2), 29.2 (CH2), 37.6
(CMe2), 39.1 (CHCO), 57.1 (NCHAHB), 66.9 (OCH2C6H5), 78.2
(CMe2CH), 119.3 (CH-arom.), 119.8 (CHϭ), 125.7 (C-arom.),
128.8 (CH-arom.), 128.9 (CH-arom.), 129.4 (CH-arom.), 131.0
(CH-arom.), 134.2 (CH3Cϭ), 137.1 (C-arom.), 144.2 (C-arom.),
165.9 (CO), 170.3(CO), 175.0 (CO) ppm. HRMS (FAB) calcd. for
C28H32NO5 [MHϩ] 462.2280, found 462.2280.
(؎)-[1-(2-Methoxyethyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl] Acrylate
(16): Following the general procedure, compound 16 was obtained
as a colourless oil from (Ϯ)-3-hydroxy-1-(2-methoxyethyl)-4,4-di-
methylpyrrolidin-2-one (23, 0.76 g, 4.1 mmol) after column chro-
matography on silica gel, eluting with ethyl acetate (0.51 g,
2.1 mmol, 52%); tR (HPLC) ϭ 7.99 min. IR (CH2Cl2): ν˜ ϭ 3054
(w), 2984 (w), 2875 (w), 1731 (s), 1704 (s), 1266 (s) cmϪ1. MS (ESI):
1
m/z ϭ 242.0 [M ϩ H]ϩ, 483.3. H NMR (CD2Cl2): δ ϭ 1.08 (s, 3
H, CH3), 1.21 (s, 3 H, CH3), 3.17 (d, J ϭ 9.7 Hz, 1 H, NCHAHB),
3.28 (d, J ϭ 9.7 Hz, 1 H, NCHAHB), 3.34 (s, 3 H, CH3O), 3.46 (m,
4 H, CH2N and CH2O), 5.29 (s, 1 H, CMe2CH), 5.94 (dd, J ϭ 1.4
and J ϭ 10.4 Hz, 1 H, HCHϭ), 6.24 (dd, J ϭ 10.4 and J ϭ
17.3 Hz, 1 H, CHϭ), 6.48 (dd, J ϭ 1.4 and J ϭ 17.3 Hz, 1 H,
HCHϭ) ppm. 13C NMR (CD2Cl2): δ ϭ 21.2 (CH3), 25.1 (CH3),
38.3 (CMe2), 42.9 (CH2N), 58.3 (NCHAHB), 58.8 (CH3O), 70.6
(CH2O), 78.3 (CMe2CH), 128.2 (CHϭ), 131.9 (CH2ϭ), 165.6
(COCHϭCH2), 169.7 (CON) ppm. HRMS (FAB) calcd. for
C12H20NO4 [MHϩ] 242.1392, found 242.1387.
[1-(2-Methoxyethyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl] 4-Methyl-
cyclohex-3-ene-1-carboxylate (27): Synthesized following the gen-
eral procedure from the dienophile 16 (144 mg, 0.6 mmol) and iso-
prene. Compound 27 was obtained as a colourless oil after column
chromatography on silica gel, eluting with hexane/ethyl acetate
(4:6) (166 mg, 0.54 mmol, 90%); tR (HPLC) ϭ 11.00 min. IR
(CH2Cl2): ν˜ ϭ 3054 (w), 2930 (m), 1738 (s), 1705 (s), 1166 (s) cmϪ1
.
1
MS (ESI): m/z ϭ 310.2 [M ϩ H]ϩ, 619.2. H NMR (CDCl3): δ ϭ
0.97 (s, 3 H, CH3), 1.12 (s, 3 H, CH3), 1.58 (s, 3 H, CH3), 1.70 (m,
1 H, HCH), 1.97 (m, 3 H, CH2 and HCH), 2.21 (m, 2 H, CH2),
2.56 (m, 1 H, CHCO), 3.11 (d, J ϭ 9.8 Hz, 1 H, NCHAHB), 3.22
(d, J ϭ 9.8 Hz, 1 H, NCHAHB), 3.26 (s, 3 H, CH3O), 3.30Ϫ3.50
(m, 4 H, CH2N and CH2O), 5.20 (s, 1 H, CMe2CH), 5.30 (br. s, 1
H, CHϭ) ppm. 13C NMR (CDCl3): δ ϭ 18.7 (CH3), 21.0 (CH3),
22.6 (CH3), 22.8 (CH2), 25.5 (CH2), 26.6 (CH2), 35.8 (CHCO), 36.7
(CMe2), 40.4 (CH2N), 56.2 (NCHAHB), 56.2 (CH3O), 68.1
(CH2O), 75.0 (CMe2CH), 116.5 (CHϭ), 131.5 (CH3Cϭ), 168.1
(CO), 172.81 (CO) ppm. HRMS (FAB) calcd. for C17H28NO4
[MHϩ] 310.2018, found 310.2010.
General Procedure for Diels؊Alder Reactions of the Acrylate Esters
9b, 13, 14, 15a, 16 with Isoprene: A 1  solution of TiCl4 (0.5 to 1
equiv.) in dry CH2Cl2 was added to the ester 9b, 13, 14, 15a or 16
(0.6 mmol) in dry CH2Cl2 (10 mL) at the selected temperature (T1,
Table 1) under argon. The mixture was stirred at the same tempera-
ture for 20 min and then heated to the temperature T2 (Table 1). A
solution of isoprene (123 µL, 1.2 mmol, 2 equiv.) was added and
the mixture was stirred for the specified time at the indicated tem-
perature. Powdered Na2CO3·10H2O was added to hydrolyse the
TiCl4 complexes, the mixture was filtered and the filtrate was con-
centrated in vacuo. The residue was then submitted to column
chromatography on silica gel
General Procedure for Diels؊Alder Reaction of the Supported Acry-
late Esters with Isoprene or Cyclopentadiene and for Benzhydrylam-
ine-Bond Hydrolysis: A 1  solution of TiCl4 (0.5 to 10 equiv.) in
dry CH2Cl2 was added to the resin 15b (0.6 mmol) swollen in dry
CH2Cl2 (15 mL) at the selected temperature T1 (Table 1) under ar-
gon. The suspension was stirred at the same temperature for 30 min
and then cooled to the temperature T2 (Table 1). A solution of
isoprene (2Ϫ10 equiv.) was added and the suspension was stirred
for the specified time at the indicated temperature. The solution
(1,4,4-Trimethyl-2-oxopyrrolidin-3-yl)
4-Methylcyclohex-3-ene-1-
carboxylate (12b): Synthesized following the general procedure
from the dienophile 9b (118 mg, 0.6 mmol) and isoprene. Com-
pound 12b was obtained as a white solid after column chromatog-
raphy on silica gel, eluting with ethyl acetate/hexane (8:2) (119 mg,
0.45 mmol, 76%); m.p. 79.0 °C, tR (HPLC) ϭ 10.68 min. IR
(CH2Cl2): ν˜ ϭ 3049 (w), 2965 (w), 1735 (s), 1706 (s), 1164 (m) was removed from the resin by filtration, the resin was washed with
2448  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 2441Ϫ2450

Toward DielsϪAlder Reactions on a Solid Support
CH2Cl2 (3 ϫ 15 mL), CH3OH (2 ϫ 15 mL), CH2Cl2/CH3OH (8:2) mL). The aqueous phase was acidified to pH 1 and was then ex-
FULL PAPER
(3 ϫ 15 mL), CH2Cl2 (3 ϫ 15 mL) and diethyl ether (3 ϫ 15 mL),
and then dried under reduced pressure. A solution of 5% TFA in
dry CH2Cl2 (40 mL) was added to this resin swollen in dry CH2Cl2
and the suspension was stirred for 40 min. The solution was re-
moved from the resin by filtration and the resin was washed with
CH2Cl2 (3 ϫ 15 mL), CH2Cl2/CH3OH (8:2) (3 ϫ 15 mL) and
CH2Cl2 (3 ϫ 15 mL). Evaporation of the combined solvents in
vacuo afforded the expected compound.
tracted with a mixture of n-pentane and CH2Cl2 (98:2; 2 ϫ 25 mL).
The combined organic phases were dried with anhydrous Na2SO4
and concentrated in vacuo to give the expected acid.
(؎)-4-Methylcyclohex-3-ene-1-carboxylic Acid (7): Following the
general procedure the expected acid 7 (0.24Ϫ0.32 mmol, 60Ϫ80%)
was obtained from the compound 12b, 26a, 26b or 27 (0.4 mmol)
in THF; tR (HPLC) ϭ 9.23 min. 13C NMR (CDCl3): δ ϭ 23.73
(CH3), 25.56, 27.76, 29.51 (CH2), 39.46 (CHCO2H), 119.46
(CHϭ), 134.02 (CH3Cϭ), 183.26 (CO) ppm.
(1-Carbamoylphenyl-4,4-dimethyl-2-oxopyrrolidin-3-yl) 4-Methyl-
cyclohex-3-ene-1-carboxylate (26b): Synthesized following the gen-
eral procedure from the resin 15b (0.6 mmol) and isoprene (6
equiv.), T1 ϭ T2 ϭ 0 °C, reaction time: 16 h. The expected pure
compound 26b was obtained as a colourless solid after column
chromatography on silica gel, eluting with ethyl acetate (177 mg,
0.48 mmol, 80%); m.p. 105 °C; tR (HPLC) ϭ 11.42 min. IR (KBr):
ν˜ ϭ 3327Ϫ3219 (br), 2969 (s) 1742 (s), 1694 (s) cmϪ1. MS (ESI):
(؎)-endo-Bicyclo[2.2.1]hept-5-ene-2-carboxylic Acid (29): Following
the general procedure the expected acid 29 (0.23 mmol, 58%) was
obtained from compound 28 (0.4 mmol) in DMF; tR (HPLC) ϭ
7.92 min (95% endo) and 8.54 min (5% exo). 13C NMR (CDCl3)
(endo): δ ϭ 29.5 (CH2), 42.9 (CH), 43.6 (CH2), 46.1 (CH), 50.1
(CH2CH), 132.8 (CHϭCH), 138.3 (CHϭCH), 181.4 (CO) ppm.
1
m/z ϭ 371.1 [M ϩ H]ϩ, 741.5. H NMR (CDCl3): δ ϭ 1.05 and
(؎)-4-Methylcyclohex-3-ene-1-carboxylic Acid (7) and (؎)-3-
Methyl Isomer: A mixture of (Ϯ)-3- and (Ϯ)-4-methylcyclohex-3-
ene-1-carboxylic acids was obtained in 46% yield by reaction of
isoprene and acrylic acid at 120 °C following the method described
by Kuehne et al.[22] tR (HPLC) ϭ 9.23 min. 13C NMR [CDCl3
(Ϯ)-3-methylcyclohex-3-ene-1-carboxylic acid (minor product)]:
δ ϭ 23.8 (CH3), 24.8 (CH2), 25.0 (CH2), 32.2 (CH2), 40.1
(CHCO2H), 121.0 (CHϭ), 132.4 (CH3Cϭ), 183.1 (CO) ppm.
1.06 (s, 3 H, CH3), 1.20 and 1.21 (s, 3 H, CH3), 1.57 and 1.59 (s, 3
H, CH3), 1.71 (m, 1 H, HCH), 1.9Ϫ2.00 (m, 3 H, HCH and CH2),
2.22 (m, 2 H, CH2), 2.61 (m, 1 H, CHCO), 3.46 (d, J ϭ 9.6 Hz, 1
H, NCHAHB), 3.57 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 5.30 (CHϭ),
5.35 and 5.36 (s, 1 H, CMe2CH), 7.61 (d, J ϭ 8.5 Hz, 2 H, H-
arom.), 7.81 (d, J ϭ 8.5 Hz, 2 H, H-arom.) ppm. 13C NMR
(CDCl3): δ ϭ 21.4 and 21.5 (CH3), 23.8 and 23.9 (CH3), 24.9 and
24.9 (CH3), 25.7 and 26.0 (CH2), 27.9 and 28.2 (CH2), 29.3 and
29.5 (CH2), 37.8 (CMe2), 39.5 and 39.5 (CHCO), 57.9 (NCHAHB),
78.1 and 79.2 (CMe2CH), 119.3 (CH-arom.), 119.2 and 119.4
(CHϭ), 128.0 (C-arom.), 129.3 (CH-arom.), 134.1 and 134.5
(CH3Cϭ), 143.0 (C-arom.), 170.6 and 170.7 (CO), 171.5 (CO),
175.6 and 175.8 (CO) ppm. HRMS (FAB) calcd. for C21H27N2O4
[MHϩ] 371.1971, found 371.1981.
NMR Spectroscopy of the Acrylate/TiCl4 Complexes: A solution of
TiCl4 (100 µL, 0.2 mmol, 0.5 equiv.) in CD2Cl2 (1 mL) was added
dropwise at room temperature and under argon to a stirred solu-
tion of the acrylate (0.4 mmol) in CD2Cl2 (1 mmol in 0.5 mL of
CD2Cl2). After 5 min, the solution (0.6 mL) was transferred to a
1
dry NMR tube and analysed by H and 13C NMR spectroscopy.
[1-(4-Carbamoylphenyl)-4,4-dimethyl-2-oxopyrrolidin-3-yl] Bicyclo-
[2.2.1]hept-5-ene-2-carboxylate (28): Synthesized following the gen-
eral procedure from the resin 15b (0.6 mmol) and cyclopentadiene
(6 equiv.), T1 ϭ T2 ϭ 0 °C, reaction time: 16 h. The expected pure
compound 28 (209 mg, 0.57 mmol, 95%), was obtained as a colour-
less solid; m.p. 132Ϫ134 °C; tR (HPLC) ϭ 10.4 min (95% endo),
10.78 (5% exo). IR (KBr): ν˜ ϭ 3404Ϫ3320 (br), 2975 (s) 1775 (s),
[1]
F. Fringuelli, A. Tatichi, The DielsϪAlder Reaction: Selected
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K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. Vassilikogian-
[2]
1
1695 (s) cmϪ1. MS (ESI): m/z ϭ 369.4 [M ϩ H]ϩ, 737.5. H NMR
[3]
(CDCl3): δ ϭ 1.22 and 1.32 (s, 3 H, CH3), 1.37 (m, 1 H, HCH),
1.53 (m, 2 H, HCH and HCH), 1.99 (ddd, J ϭ 3.6, J ϭ 9.1 and
J ϭ 12.5 Hz, 1 H, HCH), 2.98 (br. s, 1 H, CH), 3.21 (td, J ϭ 9.1
and J ϭ 3.9 Hz, 1 H, CH-1Ј), 3.31 (br. s, 1 H, CH), 3.6 (d, J ϭ
9.6 Hz, 1 H, NCHAHB), 3.7 (d, J ϭ 9.6 Hz, 1 H, NCHAHB), 5.45
(s, 1 H, CMe2CH), 5.95 (dd, J ϭ 2.7 and J ϭ 5.6 Hz, 1 H, HCϭ),
6.3 (dd, J ϭ 3.1 and J ϭ 5.6 Hz, 1 H, HCϭ), 7.79 (d, J ϭ 8.9 Hz,
2 H, H-arom.), 7.91 (d, J ϭ 8.9 Hz, 2 H, H-arom.) ppm. 13C NMR:
(CDCl3): δ ϭ 21.3 and 24.6 (CH3), 28.9 (CH2), 37.6 (CMe2), 42.5
(CH2CH), 43.1 and 46.1 (CH) 49.9 (CH2), 57.6 (NCHAHB), 77.7
(CMe2CH), 119.2 (CH-arom.), 127.4 (C-arom.), 128.9 (CH-arom.),
131.5 and 138.7 (HCϭ), 142.8 (C-arom.), 170.8 (CO), 171.5 (CO),
174.2 (CO) ppm. HRMS (FAB) calcd. for C21H25N2O4 [MHϩ]
369.1814, found 369.1823.
nakis, Angew. Chem. Int. Ed. 2002, 41, 1669Ϫ1698.
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General Procedure for the Hydrolysis of Compounds 12b, 26a, 26b,
27 and 28: A solution of LiOH·H2O (0.8 mmol, 2 equiv.) in water
(1 mL) was added dropwise to a solution of the compound
(0.4 mmol) in THF (5 mL) or DMF (6 mL) and the mixture was
stirred at room temperature till completion of the hydrolysis (reac-
tion monitored by HPLC). The organic solvent was then removed
in vacuo, water (10 mL) and saturated aqueous NaHCO3 (5 mL)
were added and the mixture was extracted with CH2Cl2 (2 ϫ 15
[7g]
M. Kawamura, K.
[7h]
S. M. Lait, M. Parvez,
B. A. Keay, Tetrahedron: Asymmetry 2003, 14, 749Ϫ756.
For recent examples of synthetic solid-supported chiral re-
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2449

`
R. Akkari, M. Calmes, J. Martinez
FULL PAPER
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Received January 13, 2004
2450
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2441Ϫ2450