A highly diastereoselective synthesis of isoindolinone-centered Meyers' tetracyclic lactams. Application to the asymmetric synthesis of 3-alkylisoindolinones

Article abstract of DOI:10.1016/j.tetasy.2011.07.020

A new methodology for the asymmetric synthesis of C-3 alkylated isoindolinones has been developed through a novel extension of Meyers' lactamisation. The key polycyclic lactam precursor was prepared in high yield and high diastereoselectivity by a two step sequence involving phthalic anhydride and aminoprolinol. Metallation/alkylation followed by hydride reduction of the transient N-acylhydrazonium species and ultimate removal of the chiral auxiliary without a loss of stereochemical integrity completed the synthesis of the target compounds.

Full text of DOI:10.1016/j.tetasy.2011.07.020

Tetrahedron: Asymmetry 22 (2011) 1441–1447
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Tetrahedron: Asymmetry
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A highly diastereoselective synthesis of isoindolinone-centered Meyers’
tetracyclic lactams. Application to the asymmetric synthesis
of 3-alkylisoindolinones
Vangelis Agouridas a,b, Frédéric Capet a,c, Axel Couture a,c, , Eric Deniau a,b, Pierre Grandclaudon a,b
⇑
a Université Lille Nord de France, F-59000 Lille, France
b USTL, Laboratoire de Chimie Organique Physique, EA CMF 4478, Bâtiment C3(2), F-59655 Villeneuve d’Ascq, France
c CNRS, UMR 8181 ‘UCCS’, F-59655 Villeneuve d’Ascq, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new methodology for the asymmetric synthesis of C-3 alkylated isoindolinones has been developed
through a novel extension of Meyers’ lactamisation. The key polycyclic lactam precursor was prepared
in high yield and high diastereoselectivity by a two step sequence involving phthalic anhydride and
aminoprolinol. Metallation/alkylation followed by hydride reduction of the transient N-acylhydrazonium
species and ultimate removal of the chiral auxiliary without a loss of stereochemical integrity completed
the synthesis of the target compounds.
Received 4 July 2011
Accepted 25 July 2011
Available online 22 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
O
O
1. Introduction
NH
N
Chiral non-racemic 3-substituted-2,3-dihydro-1H-isoindol-1-
ones (isoindolinones) 1 are the key structural feature of many
pharmaceutically interesting molecules and of naturally occurring
bioactive compounds.1 Typical examples include the PD-172938
enantiomers 22 that display an affinity for the dopamine D4 recep-
tor, pazinaclone 3, an anxiolytic drug candidate3 and (S)-pagoclone
4 which is under development for the treatment of anxiety disor-
ders4 (Fig. 1). Additionally, (R)- and (S)-3-methylisoindolinones
have been shown to be valuable chiral auxiliaries.5 Consequently
the chemistry and reactivity of 3-alkylisoindolinones are currently
an area of interest for many research groups and a number of syn-
thetic methods to such lactam compounds have been developed.2,6
Paradoxically, despite the fact that great progress has been made in
asymmetric synthesis within the last decade, methodologies for
the stereoselective synthesis of enantioenriched models alkylated
at C-3 have rarely been explored,7 even though it has been well
established that the absolute configuration at this stereogenic cen-
ter plays a crucial role with regard to the biological activity.1a,2 Sev-
eral synthetic approaches are based upon lactam ring construction
with concomitant creation of the stereogenic center at the C-3 po-
sition. This has been achieved by condensation of o-lithiated N,N-
dialkylbenzamides with chiral hydrazones8 or by diverse intramo-
lecular diastereoselective imine addition–cyclization sequences.9
N
H
N
H
N
N
Me
Me
Cl
O
N
N
O
3
O
2
O
N
N
H
Cl
O
4
Figure 1. Bioactive isoindolinone-centered compounds.
Several methods have been also developed,10 but the most
straightforward route to such compounds is based upon the diaste-
reoselective interception of cyclic N-acyliminium precursors with
carbon or hydride nucleophiles.6c,7a,b,d–g,11
Synthetic approaches to these key transient species and subse-
quent nucleophilic addition can be classified into two main catego-
ries as depicted in Scheme 1. The first one (Method A) relies
upon the diastereoselective reductive dehydroxylation of hemia-
minals 5 equipped with chiral auxiliaries on the nitrogen lactam.
The hydroxylactams 5 are readily accessible by the reaction of
⇑
Corresponding author. Tel.: +33 (0)3 20 33 44 32; fax: +33 (0)3 20 43 63 09.
E-mail address: axel.couture@univ-lille1.fr (A. Couture).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.020

1442
V. Agouridas et al. / Tetrahedron: Asymmetry 22 (2011) 1441–1447
O
A*
X
N
RM
O
O
Method A : Lewis acid , hydride reduction
6
A*
X
N
A*
O
OH
O
X
R
Method A
N
5
R
O
O
chiral auxiliary
release
A*
X
N
NH
I
path a
7
X = OH
R
R
COOH
O
1
O
Method B
N
A*
R(H)
9
O
(H)R
+
Method B :
8
A*
X
H2N
- path b (R = H) : Lewis acid , nucleophilic addition
- path c (R = H) : Lewis acid, hydride reduction
10
Scheme 1. Retrosynthetic scheme for the asymmetric synthesis of 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones.
appropriate organometallic reagents with suitably N-substituted
phthalimides 6.7b Alternatively they could be accessed by a Par-
ham-type anionic cyclization process applied to prochiral N-acyl-
o-iodobenzamides 7.7i The second synthetic approach (Method B)
comes within the scope of Meyers’ polycyclic lactam methodol-
ogy,12 which has been widely used in the stereoselective construc-
tion of enantiomerically pure nitrogen heterocycles.7b,d,e,g,13 These
lactams provide a variety of highly functionalized chiral building
blocks which may be further used in a wide range of stereoselec-
tive transformations, making these intermediates powerful tools
in asymmetric synthesis. The classical procedure used for accessing
the chiral polycyclic templates 8 consists of a cyclodehydration of
aromatic keto or formyl acids 9 with chiral aminoalcohols 10. They
could also be obtained by Lewis acid mediated cyclization of
hydroxylactams 5 tethered with a stereodefined hydroxyalkyl
appendage on the lactam nitrogen (path a). Until now all tricyclic
lactams 8 have been assembled by employing a chiral aminoalky-
lated alcohol 10 such as valinol, (R) or (S)-phenylglycinol and (R) or
(S)-phenylanilinol.7d,e The chemical treatment of the polycyclic lac-
tam 8, namely the reductive aminal ring opening reaction is condi-
tioned by the presence or absence of appropriate substituent
(paths b or c).
with a slight excess of NaBH4 to provide the N,O-hemiacetal 13
in almost quantitative yields. At this stage stereochemical consid-
erations on the newly created asymmetric benzylic center were
not crucial for the outcome of the synthetic process because con-
version of the benzylic hydroxy functionality into the mandatory
transient hydrazonium species 14 was planned in the sequel. This
operation was readily secured by acid-catalyzed treatment of the
transient diastereoisomeric mixture of crude azacarbinol 13 and
under refluxing conditions in toluene, the dehydroxylation reac-
tion was accompanied with a concomitant new ring forming reac-
tion to afford the target tetracyclic lactam 11.
Compound 11 was obtained with an excellent yield as a single
diastereoisomer detectable by NMR. On the basis of the high
degree of diastereoselectivity observed by several groups in related
systems7b,14 and due to configuration of the (S)-aminoprolinol used
herein we expected the single diastereoisomer thus obtained to be
the thermodynamically more stable diastereoisomer and to have
the trans-stereochemistry with respect to the hydrogen atoms at
the C-3a and C-5a positions. The configuration of the newly gener-
ated stereogenic center at C-5a and the nature of the A/B ring junc-
tion could not be unambiguously assigned by 1H NMR NOESY
experiments. The stereochemical prediction was finally confirmed
by X-ray crystal analysis of the (S)-prolinol derived product 11
(Fig. 2) which also verified the stereochemistry of the N-10b
center.
At this stage, the planned incorporation of the substituent at the
final C-3 position on the lactam nucleus could be a priori envisaged
by adopting two different protocols. Since isoindolinones have the
advantage of being easily deprotonated at the benzylic position of
the lactam unit7a,c,15 a sequence of metallation/Lewis acid treat-
ment/hydride reduction could be proposed. Alternatively a classi-
cal Lewis acid treatment/nucleophilic addition would hopefully
lead to the same targeted models. Due to the sensitivity of the
N,O-acetals to the organometallic reagents,14 the tetracyclic lactam
11 was initially smoothly deprotonated with KHMDS at low tem-
perature and the intermediate carbanionic species 15 was exposed
to a variety of electrophiles 17a–e to afford excellent yields of the
Herein we report a synthetic method based upon Meyers’ cyclic
lactam methodology with the development of an unusual tetracy-
clic model 11 incorporating a pyrrolidine chiral auxiliary embed-
ded in the molecular framework. We wish also to report our
preliminary studies on the synthetic potential of these highly fused
polycyclic hydrazides.
2. Results and discussion
The first facet of the synthesis which is depicted in Scheme 2
was the elaboration of the diazacarbinol 12. This was readily
achieved by heating a mixture of phthalic anhydride with the
enantiomerically pure hydrazine (S)-(ꢀ)-1-amino-2-(hydroxy-
methyl)pyrrolidine. This operation gave the requisite phthalimide
derivative 12 in excellent yield, which was subsequently treated

V. Agouridas et al. / Tetrahedron: Asymmetry 22 (2011) 1441–1447
1443
OH
N
NH2
PTSA , toluene
Dean-Stark ,
overnight
O
O
O
NaBH4 , MeOH
PTSA , toluene
reflux , 5 h
30 min
N
N
N N
O
94%
O
OH
O
OH
OH
13
12
O
O
KHMDS
O
O
THF , -78 °C
30 min
A
N
3a
N
O
N
N
N
N
N
O
N
5a
82%
B
H
H
O
OH
14
11
15
16
O
O
O
RX 17a-e
TFA , CH2Cl2
Et3SiH
r.t. , 48 h
-78 °C to r.t. , 2 h
72-98%
for 18b
N
N
N
N
N
N
H
R
O
Pr
Pr
19
OH
OH
18a-e
(R,S)-20b major
O
MMPP
MeOH , r.t. , 12 h
NH
Pr
(R)-1b
Scheme 2. Asymmetric synthetic approach to 3-akylated isoindolinones.
H
C-substituted models 18a–e (Scheme 2, Table 1). Despite the fact
that the carbanionic species 15 can also adopt the quinonic struc-
ture 16 due to electronic delocalization these novel lactams now
bearing a newly generated quaternary carbon center were ob-
tained as a single diastereoisomer.
Retention of configuration at the benzylic carbon center was
ascertained from the X-ray analysis of the propyl derivative 18b
(Fig. 3). These results have a marked difference on the diastereose-
lectivities observed upon the diastereoselective metallation/
electrophilic attack sequence applied to isoindolinones with
diverse stereocontrolling agents appended to the lactam nitrogen
such as (R)-phenylglycinol7h or SAMP.16 The same level of
Figure 2. ORTEP view of the cystal structure of (3aS,5aR)-2,3,3a,4-tetrahydro-1H-
5aH-5-oxa-10a,10b-diazacyclo-penta[a]fluoren-10-one 11.
Table 1
Compounds prepared
Compd
R
X
Yield (%)
18a
18b
18c
18d
18e
18f
Me
Pr
iPr
Allyl
I
I
I
Br
Br
—
—
—
91a
87a
72a
98a
76a
56a
78b
92
Bn
p-MeO–C6H4–CHOH
Pr
Pr
20
(R)-1
a
de >95%.
Figure 3. ORTEP view of the crystal structure of (3aS,5aR)-5a-propyl-2,3,3a,4-
tetrahydro-1H-5aH-5-oxa-10a,10b-diazacyclopenta[a]fluoren-10-one 18b.
b
70:30 Mixture of diastereoisomers.

1444
V. Agouridas et al. / Tetrahedron: Asymmetry 22 (2011) 1441–1447
diastereoselectivity for this carbanionic approach to 3-alkylisoind-
olinones was observed by Comins et al. for N-acylated models
flash column chromatography. Removal of the chiral auxiliary with-
out racemization was readily achieved by oxidative cleavage of the
N–N bond promoted by magnesium monoperoxyphthalate hexahy-
drate (MMPP).18 This deamination method afforded the virtually
enantiopure 3-propylisoindolinone (R)-1 with excellent yield
(Scheme 2, Table 1). The stereochemical integrity at the C-3 position
of the isoindolinone ring and enantiopurity of the synthetic com-
pound were clearly established from the sign and value of the spe-
cific rotation value and from spectroscopic data which matched
those reported for the same product synthesized by other means.6c
Owing to difficulties associated with the aminal ring opening reac-
tion of adduct 18 and to the very moderate level of diastereoselectiv-
ity usually observed for the reactions performed with a combination
of Lewis acid and carbon nucleophile,7f,g,17 we were rather pessimis-
tic about the chance of success of the alternative approach depicted
in Scheme 1 (Method B, path b). As anticipated, when compound 11
was subjected to the aminal ring opening reaction with titanium(IV)
chloride as the Lewis acid activator and allyltrimethylsilane as the
nucleophile the starting compound was recovered unchanged. Forc-
ing reaction conditions led to hardly isolable and identifiable com-
pounds and consequently, this alternative was no longer developed.
bearing (ꢀ)-trans-2-(a-cumyl)cyclohexanol (TCC) as the chiral
auxiliary.7c It is worth noting that the reaction performed with
p-methoxybenzaldehyde as the electrophile delivered an almost
exclusive diastereoisomer, which was shown to possess an
(S,S,S)-configuration as determined unequivocally by X-ray crystal-
lographic analysis of adduct 18f obtained in the pure form (>99%)
by simple recrystallization from EtOH (Fig. 4). The high degree of
stereoselectivity observed may be tentatively rationalized by sta-
bilization of the alkoxide by chelation of the metal counterion
embedded in a five-membered hetero ring system in the primary
adduct 18 (Fig. 5).
3. Conclusion
In conclusion, we have identified an efficient and highly diaste-
reoselective route to an architecturally new ring-fused isoindoli-
none system that can be regarded as a novel Meyers’ tetracyclic
lactam. In only two synthetic steps involving phthalic anhydride
and enantiopure aminoprolinol, we have prepared a highly fused
polyheterocyclic system with complete stereocontrol. Excellent
yields and diastereoselectivites were obtained upon an unusual
metallation/electrophilic alkylation sequence applied to this mod-
el. Although a moderate level of diastereoselectivity was observed
afterward upon Lewis acid-induced hydride ring opening of the
C-alkylated tetracyclic lactam we have demonstrated a new route
to non-racemic 3-substituted-1H-isoindol-1-one targets.
Figure 4. ORTEP view of the cystal structure of (3aS,5aS)-5a-[(S)-hydroxy-(4-
methoxyphenyl)methyl]-2,3,3a,4-tetrahydro-1H-5aH-5-oxa-10a,10b-diazacyclo-
penta[a]fluoren-10-one 18f.
O
H
4. Experimental
4.1. General
O
MeO
N
N
K
O
N
N
O
H
Melting points were determined on a Reichert-Thermopan appara-
tus and are uncorrected. NMR spectra were recorded on Bruker AM 300
and Bruker AMX 400 spectrometers. They were referenced against
internal tetramethylsilane; coupling constants (J) are given in Hz and
rounded to the nearest 0.1 Hz. IR absorption spectra were run on a Per-
kin–Elmer 881. Infrared spectra were recorded on a Nicolet FTIR spec-
trometer. Optical rotations were recorded on Perkin–Elmer 343 digital
polarimeter at 589 nm. Elemental analyses were obtained using a Car-
lo-Erba CHNS-11110 equipment. Flash chromatography was per-
HO
O
MeO
18f
Figure 5. Chelation controlled facial selectivity for the assembly of adduct 18f.
The subsequent stereoselective ring opening of the cyclic aminal
18 was more problematic than we anticipated. The C-propyl com-
pound 18b was chosen as a model study and to ensure the optimal
formation of the opened model with the Lewis acid (TFA, TiCl4,
BF3ꢁOEt2, SnCl4), solvent (neat TFA, CH2Cl2), temperature profile
(ꢀ78 °C, 0 °C, rt) all being screened in the presence of a standard hy-
dride source (Et3SiH). We found that although the reaction pro-
ceeded in high yield upon treatment of compound 18b in TFA
followed by the addition of Et3SiH at low temperature, NMR analysis
of the crude reaction mixture showed that the opened C-propylated
20 was formed as a 7:3 mixture of diastereoisomers (Scheme 2,
Table 1). The level of diastereoselectivity for this Lewis acid cata-
lyzed reductive dihydroxylation was significantly lower than that
observed by other groups using alternative combinations of Lewis
acid and Et3SiH.7g This is probably due to the high degree of stability
of the hydrazide-derived aminal 18 and due to the harsh conditions
required to ensure the aminal ring opening reaction. The relative
stereochemistry of the major diastereoisomer was assigned as
(R,S) following its isolation in diastereochemically pure form by
formed on Sorbent Technologies 32–63 lm 60 Å silica gel. Reactions
were monitored by thin layer chromatography with Sorbent Technol-
ogies 0.20 mm silica gel 60 Å plates. Dry glassware was obtained by
oven-drying and assembly under Ar. Dry Ar was used as the inert atmo-
sphere. The glassware was equipped with rubber septa and reagent
transfer was performed by syringe techniques. Tetrahydrofuran
(THF) was distilled from sodium benzophenone ketyl immediately
before use. Methanol was distilled over magnesium turning, CH2Cl2
over CaH2 and toluene over sodium.
4.2. X-Ray structure determination
Single crystal X-ray diffraction data of compounds 11, 18f, and
18a were collected at room temperature on a Bruker APEX-II CCD
three-circle diffractometer with graphite monochromatized Mo

V. Agouridas et al. / Tetrahedron: Asymmetry 22 (2011) 1441–1447
1445
K
a
radiation (k = 0.71073 Å) and equipped with a CCD two-dimen-
at ꢀ78 °C. The deep red solution was allowed to warm to ꢀ50 °C
over 30 min, and then was cooled down to ꢀ78 °C. A solution of
alkylhalide 17a-e (1.2 mmol) in THF (1 mL) was added dropwise.
The crude mixture was allowed to warm from ꢀ78 °C to rt over
1.5 h and stirred for an additional 2 h. Finally the resulting mixture
was quenched with aq satd NH4Cl solution (10 mL). The separated
aqueous layer was extracted with Et2O (2 ꢂ 10 mL). The organic
layers were combined, washed with water, brine, dried (MgSO4),
and concentrated under reduced pressure. Purification by flash col-
umn chromatography on silica gel (hexanes–acetone; 90:10 to
80:20 as eluent) finally afforded the targeted compound 18a-f.
sional detector. The structures were solved by direct methods and
expanded using Fourier maps. All non hydrogen atoms were
refined anisotropically. Hydrogen atoms’ positions were refined
but their temperature coefficients were fixed to 1.2 times the Ueq
of the atoms they are bound to. The SHELX-97 crystallographic
software package was used for all calculations. Crystallographic
data have been deposited with the Cambridge Crystallographic
Data Centre with the deposition numbers CCDC 829354–829356
and can be obtained free of charge via http://www.ccdc.cam.
ac.uk/conts/retrieving.html.
4.3. Synthesis of adduct 11
4.4.1. (3aS,5aR)-5a-Methyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-
10a,10b-diazacyclopenta[a]fluoren-10-one 18a
4.3.1. 2-[(S)-2-Hydroxymethylpyrrolidin-1-yl]-isoindole-1,3-
dione 12
Colorless needles, 222 mg (91%); mp 203–205 °C; ½a D25
¼ þ10:5
ꢃ
(c 0.60, MeOH); 1H NMR (300 MHz, CDCl3) d 1.60–1.66 (m, 1H),
1.91 (s, 3H), 1.95–2.13 (m, 3H), 3.41–3.59 (m, 4H), 3.82 (dd,
J = 11.3, 12.7 Hz, 1H), 7.49 (t, J = 8.1 Hz, 2H), 7.61 (t, J = 7.5 Hz,
1H), 7.86 (d, J = 7.5 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) d
22.1 (CH2), 22.6 (CH3), 25.5 (CH2), 51.2 (CH2), 55.6 (CH), 61.3
(CH2), 86.2 (C), 121.5 (CH), 124.1 (CH), 129.7 (C), 129.8 (CH),
To a solution of phthalic anhydride (8.3 g, 56 mmol) in toluene
(70 mL) were added successively N-aminoprolinol (7.05 g,
60 mmol) and PTSA (10 mg). The mixture was stirred at reflux
for 5 h until completion of the reaction, and then quenched with
water (50 mL). The separated aqueous layer was extracted with
CH2Cl2 (3 ꢂ 20 mL). The organic layers were combined, washed
with water (20 mL), dried (MgSO4), and concentrated under re-
duced pressure. The crude product was recrystallized from toluene,
filtered, and washed with Et2O: 13.3 g, (94%). Colorless crystals;
132.9 (CH), 146.2 (C) ppm; IR (m) 2974, 2875, 1707, 1469,
1361 cmꢀ1. Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N,
11.47. Found: C, 68.96; H, 6.82; N, 11.67.
mp 144–146 °C; ½a D25
ꢃ
¼ ꢀ42:0 (c 0.50, CHCl3); 1H NMR (300 MHz,
4.4.2. (3aS,5aR)-5a-Propyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-
10a,10b-diazacyclopenta[a]fluoren-10-one 18b
CDCl3) d 1.80–2.00 (m, 2H), 2.02–2.21 (m, 2H), 3.07 (br. t,
J = 6.4 Hz, 1H), 3.30–3.54 (m, 3H), 3.59–3.67 (m, 2H), 7.73–7.79
(m, 2H), 7.80–7.85 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) d
23.4 (CH2), 26.2 (CH2), 52.6 (CH2), 62.9 (CH2), 64.1 (CH), 123.4
Colorless crystals; 225 mg (87%); mp 101–103 °C; ½a D25
¼ þ19:7
ꢃ
(c 0.66, MeOH); 1H NMR (300 MHz, CDCl3) d 0.68–0.82 (m, 4H),
1.11–1.23 (m, 1H), 1.54–1.62 (m, 1H), 1.90–2.11 (m, 4H), 2.46–
2.60 (m, 1H), 3.30 (dd, J = 8.7, 15.7 Hz, 1H), 3.46–3.55 (m, 3H),
3.82 (dd, J = 10.4, 13.3 Hz, 1H), 7.41–7.49 (m, 2H), 7.57 (dt,
J = 1.2, 7.5 Hz, 1H), 7.83 (dt, J = 1.0, 7.5 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3) d 13.8 (CH3), 16.7 (CH2), 21.9 (CH2), 25.2 (CH2),
36.1 (CH2), 50.3 (CH2), 55.7 (CH), 60.8 (CH2), 88.9 (C), 121.2 (CH),
123.9 (CH), 129.6 (CH), 130.4 (C), 132.7 (CH), 144.9 (C), 168.7 (C)
(2 ꢂ CH), 130.1 (2 ꢂ C), 134.6 (2 ꢂ CH), 159.8 (2 ꢂ C) ppm; IR (
m)
2912, 2875, 1698, 1412 cmꢀ1. Anal. Calcd for C13H14N2O3: C,
63.40; H, 5.73; N, 11.38. Found: C, 63.41; H, 5.89; N, 11.55.
4.3.2. (3aS,5aR)-2,3,3a,4-Tetrahydro-1H,5aH-5-oxa-10a,10b-
diazacyclopenta[a]fluoren-10-one 11
At first, NaBH4 (763 mg, 20.1 mmol, 1 equiv; ip to an additional
0.25 equiv of hydride might be necessary to complete the monore-
duction) was added portionwise at 0 °C to a solution of 12 (5.0 g,
20.3 mmol) in MeOH (100 mL). After 30 min of stirring at 0 °C,
the crude mixture was concentrated to approximatively 1/3rd of
the initial volume and diluted with ethyl acetate (50 mL) and water
(30 mL). The separated aqueous layer was extracted with ethyl
acetate (2 ꢂ 30 mL). The organic layers were combined, washed
with water (2 ꢂ 10 mL), dried (MgSO4), and the solvent was evap-
orated to afford an oily product which was used without further
purification in the next step. The crude oil was dissolved in toluene
(60 mL) and PTSA (50 mg) was added. The mixture was refluxed
overnight in a flask equipped with a Dean-Stark apparatus. The
resulting solution was evaporated to dryness to give 11 as a white
solid, which was recrystallized from toluene–hexanes: 3.82 g
ppm; IR (
16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.70; H, 7.19;
N, 10.05.
m
) 2953, 2878, 1711, 1464, 1365 cmꢀ1. Anal. Calcd for
C
4.4.3. (3aS,5aR)-5a-Isopropyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-
10a,10b-diazacyclopenta[a]fluoren-10-one 18c
Colorless needles, 196 mg (72%); mp 156–158 °C; ½a D25
¼ þ9:0
ꢃ
(c 0.58, MeOH); 1H NMR (300 MHz, CDCl3) d 0.59 (d, J = 6.9 Hz,
3H), 1.29 (d, J = 6.9 Hz, 3H), 1.53–1.62 (m, 1H), 1.91–2.11 (m,
3H), 3.00 (sept., J = 6.9 Hz, 1H), 3.36 (dd, J = 8.0, 15.1 Hz, 1H),
3.49–3.64 (m, 3H), 3.79 (dd, J = 10.7, 13.0 Hz, 1H), 7.45–7.56 (m,
3H), 7.85 (dt, J = 1.2, 8.2 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 16.8 (2 ꢂ CH3), 22.2 (CH2), 25.5 (CH2), 30.7 (CH), 50.9 (CH2),
55.4 (CH), 61.2 (CH2), 91.6 (C), 122.0 (CH), 123.9 (CH), 129.5
(CH), 131.3 (C), 131.9 (CH), 142.9 (C), 168.1 (C) ppm; IR (m) 2977,
(82%). Colorless crystals; mp 223–225 °C; ½a D25
ꢃ
¼ þ81:6 (c 0.57,
2864, 1710, 1467, 1366 cmꢀ1. Anal. Calcd for C16H20N2O2: C,
70.56; H, 7.40; N, 10.29. Found: C, 70.66; H, 7.57; N, 10.20.
MeOH); 1H NMR (300 MHz, CDCl3) d 1.50–1.42 (m, 1H), 1.88–
2.18 (m, 3H), 3.20 (q, J = 8.7 Hz, 1H), 3.35–3.42 (m, 1H), 3.54–
3.62 (m, 1H), 3.74 (s, 1H), 3.76 (d, J = 5.0 Hz, 1H), 5.70 (s, 1H),
7.50–7.62 (m, 3H), 7.88 (dt, J = 1.1, 7.2 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3) d 20.6 (CH2), 23.6 (CH2), 49.0 (CH2), 55.2 (CH),
65.4 (CH2), 76.8 (CH), 123.5 (CH), 124.0 (CH), 130.2 (CH), 131.5
4.4.4. (3aS,5aR)-5a-Allyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-
10a,10b-diazacyclopenta[a]fluoren-10-one 18d
White solid; 265 mg (98%); mp 115–117 °C; ½a D25
¼ þ12:2 (c
ꢃ
0.55, MeOH); 1H NMR (300 MHz, CDCl3) d 1.57–1.63 (m, 1H),
1.99–2.13 (m, 3H), 2.94 (dd, J = 6.3, 14.5 Hz, 1H), 3.21 (dd, J = 7.3,
14.5 Hz, 1H), 3.40 (q, J = 8.4 Hz, 1H), 3.48–3.58 (m, 3H), 3.81 (dd,
J = 10.1, 13.0 Hz, 1H), 4.91–4.99 (m, 2H), 5.25–5.39 (m, 1H), 7.46
(t, J = 7.3 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.81 (d, J = 7.4 Hz, 1H)
ppm; 13C NMR (75 MHz, CDCl3) d 22.0 (CH2), 25.3 (CH2), 38.4
(CH2), 50.5 (CH2), 55.6 (CH), 61.0 (CH2), 88.1 (C), 119.7 (CH2),
121.8 (CH), 123.8 (CH), 129.6 (CH), 130.3 (C), 130.4 (CH), 132.6
(C), 132.3 (CH), 139.4 (C), 170.8 (C) ppm; IR (m) 2914, 2875,
1709, 1410 cmꢀ1. Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13;
N, 12.17. Found: C, 68.03; H, 6.01; N, 11.93.
4.4. General procedure for the alkylation of Meyers’ adduct 11
A solution of KHMDS (2.2 mL, 1.1 mmol, 0.5 M in toluene) was
added to a solution of adduct 11 (230 mg, 1 mmol) in THF (7 mL)
(CH), 144.3 (C), 168.5 (C) ppm; IR (m) 2956, 2879, 1716, 1465,

1446
V. Agouridas et al. / Tetrahedron: Asymmetry 22 (2011) 1441–1447
1365 cmꢀ1. Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36.
Found: C, 71.31; H, 6.46; N, 10.39.
4.6. (R)-3-Propyl-2,3-dihydro-isoindol-1-one (R)-1
Magnesium monoperoxyphthalate hexahydrate (MMPP,
741 mg, 1.49 mmol, 3 equiv) was added to a solution of adduct
(R,S)-20 (120 mg, 0.49 mmol) in MeOH (5 mL). After stirring for
12 h, the crude mixture was diluted with water (5 mL) and CH2Cl2
(10 mL). The separated aqueous layer was extracted with CH2Cl2
(2 ꢂ 10 mL). The organic layers were combined, washed with
water, brine, dried (MgSO4), and concentrated under reduced pres-
sure. Flash column chromatography on silica gel (hexanes–ethyl
acetate; 70:30 as eluent) finally afforded isoindolinone (R)-1 as a
white solid (77 mg, 92%). mp 106–108 °C (lit.6c 108–109 °C);
4.4.5. (3aS,5aR)-5a-Benzyl-2,3,3a,4-tetrahydro-1H,5aH-5-oxa-
10a,10b-diazacyclopenta[a]fluoren-10-one 18e
Colorless crystals, 243 mg (76%); mp 153–155 °C; ½a D25
¼ þ21:0
ꢃ
(c 0.67, MeOH); 1H NMR (300 MHz, CDCl3) d 1.68–1.72 (m, 1H),
1.98–2.12 (m, 3H), 3.44–3.73 (m, 6H), 3.95 (dd, J = 8.4, 11.9 Hz,
1H), 6.97–7.03 (m, 3H), 7.10–714 (m, 3H), 7.39 (m, 2H), 7.69 (m,
1H) ppm; 13C NMR (75 MHz, CDCl3) d 22.1 (CH2), 25.6 (CH2), 40.6
(CH2), 51.1 (CH2), 56.2 (CH), 61.6 (CH2), 89.2 (C), 122.7 (CH),
123.6 (CH), 126.7 (CH), 127.8 (2 ꢂ CH), 129.5 (CH), 130.0
(2 ꢂ CH), 130.4 (C), 132.0 (CH), 134.3 (C), 144.0 (C), 172.2 (C)
½
a 2D5
ꢃ
¼ þ48:7 (c 0.58, MeOH) {lit.6c
½
a 2D5
ꢃ
¼ þ57:2 (c 0.7, MeOH)}.
ppm; IR (
20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 74.87; H, 6.11;
N, 8.55.
m
) 2975, 2925, 1710, 1502, 1354 cmꢀ1. Anal. Calcd for
C
Acknowledgments
This research was supported by the Centre National de la
Recherche Scientifique. The authors are grateful to M. Dubois for
technical assistance.
4.4.6. (3aS,5aS)-5a-[(S)-Hydroxy-(4-methoxyphenyl)methyl]-
2,3,3a,4-tetrahydro-1H,5aH-5-oxa-10a,10b-
diazacyclopenta[a]fluoren-10-one 18f
References
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¼ ꢀ3:3
ꢃ
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m) 3372, 2958, 2873, 1671,
1468 cmꢀ1
.

V. Agouridas et al. / Tetrahedron: Asymmetry 22 (2011) 1441–1447
1447
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