Asymmetric routes towards polyfunctionalized pyrrolidines: Application to the synthesis of alkaloid analogues

Article abstract of DOI:10.1016/S0957-4166(03)00592-5

The Mukaiyama aldol type condensation of t-butyldimethylsilyloxypyrrole 1b with methyl 2-formylbenzoate furnished the aldol adduct 9 with high yield and complete stereoselectivity. An erythro (anti) configuration was established (X-ray) in sharp contrast

Full text of DOI:10.1016/S0957-4166(03)00592-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3365–3370
Asymmetric routes towards polyfunctionalized pyrrolidines:
application to the synthesis of alkaloid analogues
Martial Toffano,a Bruno Dudot,a Anne Zaparucha,a Jacques Royer,a,* Mireille Sevrin,b
Pascal Georgeb and Ange`le Chiaronic
aLaboratoire de Chimie The´rapeutique associe´ au CNRS et a` l’Universite´ Rene´ Descartes (UMR 8638). Faculte´ de Pharmacie,
4, Avenue de l’Observatoire, 75270 Paris cedex 06, France
bSanofi-Synthe´labo Recherche, 31 Avenue Paul Vaillant-Couturier, 92220 Bagneux cedex, France
cInstitut de Chimie des Substances Naturelles, CNRS, 91198 Gif Sur Yvette cedex, France
Received 16 July 2003; accepted 23 July 2003
Abstract—The Mukaiyama aldol type condensation of t-butyldimethylsilyloxypyrrole 1b with methyl 2-formylbenzoate furnished
the aldol adduct 9 with high yield and complete stereoselectivity. An erythro (anti) configuration was established (X-ray) in sharp
contrast with the reaction of 1b with aliphatic aldehydes. Simple chemical transformations were used to transform 9 into original
phthalidopyrrolidine compound analogous of bicuculline alkaloids.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
when aromatic or aliphatic aldehydes were condensed
with silyloxypyrrolooxazole 3 (Scheme 2).5–7 This dif-
ference of selectivity was rationalised by those authors
In previous papers, we reported on the Mukaiyama–
aldol type condensation1 between chiral non-racemic
silyloxypyrroles 1 and various aliphatic aldehydes
(Scheme 1).2–4 The reactions occurred in high yield and
good diastereoselectivity. Further studies showed
improved yields and selectivities by the use of benzoyl-
ated silyloxypyrrole 1b.4 In the latter case, only threo
(syn) derivatives 2b were observed. The diastereofacial
selectivity of the reaction was generally good (RR:SS
>75:25) allowing the synthesis of pyrrolidine
derivatives.3,4
In our previous studies, aromatic aldehydes were not
extensively examined since the only example we
reported on was the condensation of 1a with benzalde-
hyde which exhibited apparent good diastereoselectivity
but in rather low yield (only 25%).2 We were particu-
larly interested to investigate further the condensation
with aromatic aldehydes in order to improve the diver-
sity of R2 substituents. Moreover the possibility to
obtain erythro (anti) derivatives instead of threo could
be expected. In fact, it was reported by Baldwin and
Uno that a reverse relative configuration was observed
Scheme 1. Reaction conditions: (a) BF3·OEt2, CH2Cl2, −70°C.
* Corresponding
jacques.royer@pharmacie.univ-paris5.fr
author.
Fax:
+33-(0)1-4329-1403;
e-mail:
Scheme 2.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00592-5

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M. Toffano et al. / Tetrahedron: Asymmetry 14 (2003) 3365–3370
with transition states implying aromatic p–p
almost no stereoselectivity. Then, we decided to con-
sider the introduction of a chelating goup on the phenyl
ring. By constrast we were delighted to observe that
reaction of 1b with methyl-2-formylbenzoate gave aldol
adduct 9 with both excellent yield and selectivity
(Scheme 3). In this case, only one diastereoisomer was
isolated. Careful analysis of 1H NMR spectra of 9
showed a very small coupling constant (J ꢀ1 Hz)
between the two protons borne at the stereogenic car-
bons. This coupling constant value contrasts with previ-
ous observations made with aliphatic derivatives (J ꢀ6
Hz) and could suggest a stereochemical change as was
indicated above. Proof of the erythro (anti) configura-
tion was assigned by single crystal X-ray analysis on a
further derivative as shown below (Scheme 5, Fig. 3).
interactions.7
Herein we present recent results on the condensation of
silyloxypyrrole 1b with some aromatic aldehydes. We
show that good reverse diastereoselectvity can be
observed with one particular aromatic aldehyde. Appli-
cations of this reaction to the efficient asymmetric
synthesis of alkaloid analogues is described. These
molecules have potential activities on the nervous cen-
tral system by analogy to phthalidoisoquinoline such as
bicuculline (Fig. 1) and congeners (strong antagonists
of Gaba receptors).8–12
Figure 1.
Scheme 3. Reagents and conditions: (a) o-MeO2CC6H4CHO,
BF3·OEt2, CH2Cl2, −70°C, 95%.
2. Results and discussion
2.1. Aldol condensation
The difference of selectivity could be explained, because
of steric influences, by a [4+2] exo transition state TA
for aliphatic aldehydes where the Lewis acid is s-trans
relative to the R2 substituent (Fig. 2). In contrast, with
the methyl 2-formylbenzoate, a synclinal approach TB
can be suggested. In the latter case, the boron atom
adopts an s-cis conformation relative to the substituent
by linking the ester group and, therefore, p–p interac-
tions between the aromatic ring and the pyrrole moiety
become the controlling factor.
The condensation of 1b with some aromatic aldehydes
was conducted using standard conditions: CH2Cl2,
−70°C, BF3·OEt2 (Scheme 1). The results of this aldoli-
sation reaction are summarized in Table 1.
Table 1. Aldol condensation of silyloxypyrrole 1b with
various aromatic aldehydes
R2
Yield (%)a
Isomeric ratiob
C6H5
5
6
7
8
94
99
80
80
40/40/20
40/38/18/4
40/35/25
50/25/25
p-NO2C6H4
1-Naphthyl
2-Naphthyl
a Isolated yield after purification by flash chromatography on silica
gel.
b Determined by 1H and 13C NMR of the crude reaction mixture.
In every case, very good yields for aldol products 2b
were obtained, but most of them were isolated as a
mixture of stereoisomers without any selectivity. In
some instances, one epimer could be separated from the
mixture but not many attempts were made in order to
determine its relative configuration. At this point, we
thought to try heteroaromatic aldehydes. The presence
of a supplementary chelating center could help to rigid-
ify the transition state and then improve the
diastereoselectivity. Unfortunately, reaction with pyri-
dine-, furane-, N-methylpyrrole-, free and N-protected
indole-carboxaldehyde failed to give aldol adducts
under the above conditions. The thiophene-2-carbox-
aldehyde is the only heteroaromatic carboxaldehyde
which could be condensed but in poor yield and with
Figure 2.
2.2. Synthesis of alkaloid analogues
The presence of the ester group induces a new relative
configuration during the aldolisation reaction and also
allows access to the phthalidopyrrolidine moiety with a
relative erythro (anti) configuration in agreement with
the natural bicuculline to be considered. In fact, after
purification on silica gel, it appears that the major aldol
product 9 was contaminated by small amount of
cyclized product 10 (Scheme 4). Aldol adduct 9 was
then cleanly and completely cyclised to 10 in an excel-
lent yield (90–98%) in the presence of silica gel in

M. Toffano et al. / Tetrahedron: Asymmetry 14 (2003) 3365–3370
3367
Scheme 4. Reagents and conditions: (a) o-MeO2CC6H4CHO,
BF3·OEt2, CH2Cl2, −70°C, 95%. Path A: (b) SiO2, CH2Cl2,
90–98%; (c) H2, Pd/C, CH3OH, 90%. Path B: (a), (c), (b) 79%
overall.
Scheme 5. Reagents and conditions: (a) BH3·THF, 81%; (b)
H2, Pd(OH)2/C, AcONa, CH3OH, 54%; (c) H2, Pd/C, Boc2O,
proton sponge, CH3OH, 95%.
dichloromethane at room temperature, or with a cata-
lytic amount of titanium tetraisopropoxide in refluxing
chloroform (95%).13
Cleavage of the chiral auxiliary of pyrrolidine phthalide
12 occurred in the presence of Pd/C at atmospheric
pressure of hydrogen to give the pyrrolidine 13. Unfor-
tunately, the latter was not stable and upon purification
was transformed into the hydroxy-lactam 14 which
could be isolated in 54% yield. An N-Boc derivative 15
was eventually prepared and obtained in 95% yield
when the hydrogenolysis was performed in the presence
of Boc2O providing a stable N-protected derivative of
the target molecule (Scheme 5).
The reduction of the double bond of 10 was easily
achieved by simple palladium catalysed hydrogenation
to give 11 as a single stereomer after flash chromatogra-
phy. After optimisation, it was found more convenient
to first reduce the double bond of adduct 9 and then
perform the cyclization by simple stirring in CH2Cl2 in
the presence of some silica gel (Scheme 4, path B).
Compound 11 was then isolated in 79% overall yield
from silyloxypyrrole 1b with only one final silica gel
purification. The synthesis was followed by the selective
reduction of the lactam function of 11. This was
obtained by the use of BH3·THF which allowed the
preparation of the pyrrolidine phthalide 12 in 81% yield
after purification (Scheme 5). At this stage, it was
possible to determine the absolute configuration of the
two stereogenic centers generated through the aldol
condensation as discussed above. Pyrrolidine phthalide
12 furnished crystals which were found suitable for
single crystal X-ray analysis (the ORTEP representa-
tion is given in Fig. 3).
A totally reduced compound 16 was obtained from 11
in a quantitative yield by reaction with LiAlH4 in
refluxing THF. Deprotection of the chiral auxiliary by
hydrogenolysis led to the dihydroisobenzofuranpyrro-
lidine 17 (Scheme 6).
Scheme 6. Reagents and conditions: (a) LiAlH4, THF, reflux,
99%; (b) H2, Pd/C, CH3OH, 59%.
In conclusion, we have shown that condensation of 1b
with benzaldehyde ortho-substituted by an ester group
furnished the aldol product in high yield and com-
pletely stereoselectively. X-Ray crystallographic analy-
sis showed that this reaction occurred with an opposite
relative configuration as that usually observed with
Figure 3. ORTEP drawing of 12. Displacement ellipsoids are
shown at the 30% probability level.

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M. Toffano et al. / Tetrahedron: Asymmetry 14 (2003) 3365–3370
aliphatic aldehydes. This process allowed us to synthe-
sise enantiomerically pure pyrrolidines bearing lactone
or dihydrobenzofuran moieties in only five steps (from
1b) with excellent overall yields of 61 and 46%,
respectively.
in 100 mL of dichloromethane at −78°C under argon,
were added 11 g of methyl 2-formylbenzoate (71.3
mmol) and 8.8 mL of boron trifluoride diethyl etherate
(71.3 mmol). The reaction mixture was stirred at −78°C
for 2 h and the temperature was allowed to warm to
0°C. The reaction was quenched by addition of water
(50 mL) and the aqueous layer was extracted twice with
CH2Cl2. The organic layers were dried over Na2SO4
and concentrated to dryness. The resulted oil was dis-
solved in methanol (200 mL), 2 g of Pd/C were added
and the reaction mixture was stirred under hydrogen (1
atm) for 4 h. The catalyst was removed by filtration
and the filtrate was evaporated to dryness. The residue
was dissolved in 100 mL of CH2Cl2 and silica gel was
added in order to obtain a thick suspension. After
stirring for 2 h at room temperature, the silica gel was
filtered off and rinsed with a mixture of CH2Cl2–
CH3OH (95–5). The filtrate was evaporated and the
product was purified by flash chromatography on SiO2
using heptane–AcOEt (1–1) as eluent, to afford 16.6 g
(79%) of pure 11. Amorphous white solid. [h]2D0=+56 (c
3. Experimental
3.1. General
All solvents were purified by standard methods. Melt-
ing points were determinated on a Bu¨chi BS-540 melt-
ing point microscope and are uncorrected. IR spectra
were obtained using a Nicolet 205-FT infrared spec-
trophotometer. Only noteworthy IR absorptions are
listed (cm−1). 1H and 13C NMR spectra (l (ppm), J
(hertz), solvent CDCl3) were recorded with a Bruker
AC-300 (300 and 75.5 MHz) instrument. Elementary
analyses were performed at the Institut de Chimie des
Substances Naturelles, in Gif sur Yvette, France. Mass
spectra were recorded with a AEI MS-9 instrument.
Optical rotations were measured with a Perkin–Elmer
241 polarimeter. Analytical TLC were carried out using
aluminium-backed plates coated with 0.2 mm silica gel
60 F254 Merck. Preparative flash chromatography was
carried out using SDS silica gel 60 (35–70 mm).
1
0.7, CHCl3); H NMR l 1.25 (m, 1H), 1.7 (m, 1H), 2.3
(ddd, J=2.8, 10, 16.6, 1H), 2.65 (m, 1H), 3.9 (d, J=3.9,
1H), 5.05 (m, 2H), 5.6 (m, 2H), 7.05 (d, J=7.4, 1H),
7.4–7.7 (m, 10 H), 7.9 (d, J=7.0, 1H), 8.05 (d, J=7.4,
1H); 13C NMR l 17.9, 30.3, 56.1, 60.9, 63.1, 80.3,
121.1, 125.1, 127.3, 128, 128.7, 129.2, 129.5, 129.6,
132.8, 134, 135.3, 145.1, 165.9, 168.8, 172.2; IR (neat)
1769, 1719, 1688; Anal. calcd for C27H23NO5: C, 73.46;
H, 5.25; N, 3.17. Found: C, 73.14; H, 5.81; N, 3.16; m/z
(CI) 442 (M+H)+, 351 (M−OCOPh).
3.2. Benzoic acid 2-[2-oxo-(5R)-5-[(1S)-3-oxo-1,3-dihy-
droisobenzofuran-1-yl]-2,5-dihydropyrrolidin-1-yl]-(2R)-
2-phenylethyl ester 10
To a solution of 500 mg of silyloxypyrrole 1b4 (1.19
mmol) in 5 mL of dichloromethane at −78°C under
argon, were added 275 mg of methyl 2-formylbenzoate
(1.677 mmol) and 0.16 mL of boron trifluoride diethyl
etherate (1.73 mmol). The reaction mixture was stirred
at −78°C for 2 h and the temperature was allowed to
warm to 0°C. The reaction was quenched by addition
of water and the aqueous layer was extracted twice with
CH2Cl2. The organic layers were joined, dried over
Na2SO4. Drying agent was removed by filtration and
silica gel was added to the CH2Cl2 solution (about 20
mL) in order to obtain a thick. After stirring for 2 h at
room temperature, the silica gel was filtered off and
rinsed with a mixture of CH2Cl2–CH3OH (95–5). The
filtrate was evaporated and the product was purified by
flash chromatography on SiO2 using heptane–AcOEt
(1–1) as eluent, to afford 497 mg (95%) of pure 10.
3.4. Benzoic acid 2-[(2R)-2-[(1S)-3-oxo-1,3-dihydro-
isobenzofuran-1-yl]pyrrolidin-1-yl]-(2R)-2-phenylethyl
ester 12
To a THF solution of 11 (10 mL, 1.6 g, 36.2 mmol) at
0°C under argon, were added 10.8 mL of BH3·THF
(10.9 mmol). The reaction mixture was stirred at room
temperature for 4 h then the reaction was quenched
with methanol. The solvents were evaporated and the
residue was dissolved in a mixture of CH2Cl2–water (10
mL, 1–1) and the biphasic mixture was stirred at room
temperature for 2 h. The organic layer was then sepa-
rated, washed with water, dried over Na2SO4 and evap-
orated to dryness. After recrystallisation from
methanol, 1.55 g of pure 12 was obtained (81%).
Colourless crystals; mp 107°C (CH3OH), [h]2D0=+34 (c
1.6, CHCl3); 1H NMR l 1.15 (m, 1H), 1.5 (m, 1H), 1.65
(m, 1H), 1.9 (m, 1H), 2.8 (m, 1H), 3.25 (m, 1H), 3.5 (td,
J=2.8, 9.2, 1H), 4.15 (t, J=6.4, 1H), 4.65 (dd, J=6.8,
11.2, 1H), 4.85 (dd, J=6.0, 11.2, 1H), 5.1 (d, J=2.2,
1H), 7.0 (d, J=7.8, 1H), 7.2–7.5 (m, 10H), 7.8 (d,
J=2.6, 1H), 7.9 (d, J=6.0, 2H); 13C NMR l 25.0, 52.0,
65.5, 66.5, 66.6, 83.5, 122.0, 125.7, 126.7, 127.6, 128.1,
128.5, 128.6, 128.7, 129.1, 129.6, 133.4, 140.5, 166.4,
171.0; IR (neat) 1762, 1717, 1688; Anal. calcd for
C27H25NO4: C, 75.86; H, 5.89; N, 3.28. Found: C,
75.51; H, 6.21; N, 3.17; m/z (CI) 428 (M+H)+, 306
(M−OCOPh).
1
Amorphous white solid. [h]2D0=+175 (c 0.5, CHCl3); H
NMR l 4.75 (s, 1H), 4.85 (dd, J=6.4, 11, 1H), 5.10 (t,
J=11, 1H), 5.35 (t, J=6.4, 1H), 5.70 (s, 1H), 6.35 (d,
J=5.4, 1H), 6.75 (d, J=5.4, 2H), 7.20 (s, 5H), 7.4 (m,
4 H), 7.5 (m, 3H), 7.95 (d, J=7.2, 2H); 13C NMR l
58.3, 63.7, 67.0, 78.6, 121.4, 126.1, 126.3, 127.4, 127.8,
128.3, 128.6, 128.9, 129.5, 129.7, 129.8, 131.9, 133.1,
133.9, 135.8, 141.7, 144.4, 165.9, 168.8, 172.2.
3.3. Benzoic acid 2-[2-oxo-(5R)-5-[(1S)-3-oxo-1,3-dihy-
droisobenzofuran-1-yl]pyrrolidin-1-yl]-(2R)-2-phenylethyl
ester 11
To a solution of 20 g of silyloxypyrrole 1b4 (47.5 mmol)

M. Toffano et al. / Tetrahedron: Asymmetry 14 (2003) 3365–3370
3369
3.4.1. X-Ray structure analysis of compound 12. Data
were obtained from a colorless small crystal of 0.38×
0.45×0.62 mm. The compound: C27H25NO4, Mw=
427.48, crystallizes in the monoclinic system, space
group P21. There are two molecules (Z=2) in the
by flash chromatography on SiO2 using cyclohexane–
AcOEt (60–40) to afford 41 mg (95%) of pure 15.
Colourless oil; [h]D20=+51 (c 0.7, CHCl3); NMR of the
1
major conformer H NMR l 1.5 (s, 9H), 1.5–1.85 (m,
3H), 2.0 (m, 1H), 3.5 (m, 2H), 4.4 (m, 1H), 6.2 (bs, 1H),
7.55 (t, J=7.0, 2H), 7.7 (t, J=7.0, 1H), 7.95 (d, J=7.0,
1H); 13C NMR l 24.1, 24.6, 28.6, 47.0, 59.9, 81.2,
122.2, 125.8, 129.4, 134.3, 147.7; IR (neat) 1756, 1687;
Anal. calcd for C17H21NO4·0.5H2O: C, 65.35; H, 7.1; N,
4.49. Found: C, 65.22; H, 7.09; N, 4.62; HRMS calcd
for C17H22NO4 (MH+) 304.1549, found 304.1547.
unit-cell of parameters: a=9.318(9), b=10.476(12), c=
3
,
,
12.259(12) A, i=108.30(5)°, V=1136 A , Dcalcd=1.250
−3
,
g cm , F(000)=452, u (Mo Ka)=0.71073 A, v=0.20
mm−1; 6062 intensity data were measured in phi scans,
up to q=29.7°, with a Nonius Kappa-CCD area-detec-
tor diffractometer.
The structure was solved with program SHELXS-8622
and refined with SHELXL-9323.14,15 All the H atoms
were located on difference maps and fitted at theoreti-
cal positions. Refinement converged to R1(F)=0.0488
for the 2723 observed reflections having Fo ]4|(Fo)
and wR2(F2)=0.1145 for all the 3399 unique data,
3.7. (2R)-2-[2-[(1S)-1,3-Dihydroisobenzofuran-1-yl]-
pyrrolidin-1-yl]-(2R)-2-phenylethanol 16
To a THF solution of 15 (15 mL, 206 mg, 0.48 mmol)
at room temperature under argon, lithium aluminium
hydride (73 mg, 1.9 mmol) was added by small por-
tions. The reaction mixture was stirred under reflux for
3 h then allowed to cool to room temperature. Excess
LiAlH4 was destroyed by addition of ethyl acetate
followed by addition of saturated aqueous solution of
Na2SO4. The aqueous layer was extracted three times
with CH2Cl2 and the organic layers were washed with
water and dried over Na2SO4. The solvents were evapo-
rated to dryness to lead to 180 mg of crude 16 engaged
goodness-of-fit S=1.104. The residual electron density
−3
,
was found between −0.25 and 0.15 e A . In the crystal,
only van der Waals contacts are observed.
Crystallographic data for the structure in this paper
have been deposited at the Cambridge Crystallographic
Data Centre (CIF file), as supplementary publication
number CCDC 198 123. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
1
without further purification in the next step. H NMR
l 1.3 (m, 1H), 1.55 (m, 2H), 1.8 (m, 1H), 2.7 (m, 1H),
2.95 (m, 1H), 3.2 (m, 1H), 3.55 (m, 3H), 4.15 (d, J=4.3,
1H), 4.35 (d, J=12.9, 1H), 4.5 (d, J=5.9, 1H), 6.95 (m,
2H), 7.15 (m, 7H), 7.35 (m, 1H); 13C NMR 24.5, 26.5,
52.1, 62.7, 63.2, 66.5, 68.5, 70.4, 126.9, 127.5, 127.9,
128.3, 128.6, 128.7, 129.3, 129.7, 138.0, 139.3, 140.9;
m/z (CI) 310 (M+H)+, 328 (M+NH4)+.
3.5. 10-Hydroxy-(10S,10aR)-2,3,10,10a-tetrahydro-1H-
pyrrolo[1,2-b]isoquinolin-5-one 14
Compound 12 (500 mg, 1.18 mmol) was dissolved in
100 mL of methanol. 200 mg of Pd(OH)2 and 97 mg
(1.18 mmol) of sodium acetate were added and the
reaction mixture was stirred under hydrogen (1 atm) for
3 days. The reaction mixture was filtered through a
Celite pad, the filtrate was evaporated to dryness and
the product was purified by flash chromatography on
SiO2 using CH2Cl2–CH3OH (95–5), to afford 129 mg
(54%) of pure 14. Amorphous white solid; mp 168°C;
3.8. (2R)-2-[(1S)-1,3-Dihydroisobenzofuran-1-yl]-
pyrrolidine 17
Crude 16 (180 mg) was dissolved in 20 mL of methanol.
60 mg of Pd/C were added and the reaction mixture
was stirred overnight under hydrogen (1 atm). The
catalyst was removed by filtration and the filtrate was
evaporated to dryness. The compound was purified by
flash chromatography on SiO2 using CH2Cl2–CH3OH–
NEt3 (95–4.5–0.5) to afford 53 mg (59%) of pure 17.
White solid; mp 164°C; [h]2D0=+24 (c 0.45, CH3OH); 1H
NMR l 1.6–2.1 (m, 4H), 2.8 (m, 2H), 3.25 (m, 1H),
4.45 (d, J=11.8, 1H), 4.75 (m, 2H), 7.1–7.6 (m, 4H);
13C NMR l 25.5, 28.9, 45.8, 61.9, 63.8, 72.1, 126.3,
127.2, 128.2, 129.0; IR (neat) 3284; HRMS calcd for
C12H16NO (MH+) 190.1232, found 190.1229. Addition
of HCl/CH3OH solution followed by evaporation to
dryness, furnished the HCl salt as an amorphous solid.
Anal. calcd for C12H15NO·HCl·2H2O: C, 55.15; H,
7.72; N, 5.36. Found: C, 55.57; H, 7.27; N, 5.40.
1
[h]2D0=−172 (c 0.5, CHCl3); H NMR l 1.85 (m, 2H),
2.1 (m, 1H), 2.45 (m, 1H), 3.65 (m, 2H), 3.75 (ddd,
J=2.6, 8.2, 10.8, 1H), 4.75 (d, J=11.0, 1H), 7.35 (td,
J=1.6, 8.0, 1H), 7.6 (m, 10H), 8.0 (d, J=8.0, 1H), 8.05
(d, J=7.4, 2H); 13C NMR l 23.1, 32.1, 45.5, 62.9, 72.6,
123.5, 127.5, 127.8, 132.2, 135.3, 141.6, 163.2; IR (neat)
3290, 1630; Anal. calcd for C12H13NO2: C, 70.89; H,
6.42; N, 6.71. Found: C, 70.92; H, 6.45; N, 6.89;
HRMS calcd for C12H14NO2 (MH+) 204.1025, found
204.1026.
3.6. (2R)-2-[(1S)-3-Oxo-1,3-dihydroisobenzofuran-1-yl]-
pyrrolodone-1-carboxylic acid tert-butyl ester 15
Compound 12 (61 mg, 0.14 mmol) was dissolved in 3
mL of methanol. 30 mg of Pd/C, 156 ml of di-t-butyldi-
carbonate (0.68 mmol) and 36 mg of N,N,N%,N%-tetra-
methyl-1,8-naphtalenediamine (0.17 mmol) were added.
The reaction mixture was stirred under hydrogen (1
atm) for 3 days then filtered over Celite and the filtrate
was evaporated to dryness. The compound was purified
References
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see: Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.
Chem. Rev. 2000, 100, 1929.
2. Baussanne, I.; Royer, J. Tetrahedron Lett. 1996, 37, 1213.

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