The crucial role of the nitrogen substituent in the desymmetrisation of cyclic meso-imides using B-Me and B-OMe oxazaborolidine catalysts

Article abstract of DOI:10.1016/j.tet.2006.09.051

Various cyclic meso-imides have been desymmetrised via enantioselective reduction using two chiral oxazaborolidine catalysts derived from (1R,2S)-cis-1-amino-indan-2-ol followed by the reduction of the hydroxylactam product to give the γ-lactam. The enant

Full text of DOI:10.1016/j.tet.2006.09.051

Tetrahedron 62 (2006) 11663–11669
The crucial role of the nitrogen substituent in the
desymmetrisation of cyclic meso-imides using B-Me
and B-OMe oxazaborolidine catalysts
c
Mike D. Barker,a Rachel A. Dixon,b Simon Jonesb,c, and Barrie J. Marsh
*
aGlaxoSmithKline Research & Development Ltd, Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertfordshire SG1 2NY, UK
bSchool of Natural Sciences, University of Newcastle upon Tyne, Bedson Building, Newcastle upon Tyne, NE1 7RU, UK
cDepartment of Chemistry, University of Sheffield, Dainton Building, Brook Hill, Sheffield, South Yorkshire S3 7HF, UK
Received 13 July 2006; accepted 15 September 2006
Available online 17 October 2006
Abstract—Various cyclic meso-imides have been desymmetrised via enantioselective reduction using two chiral oxazaborolidine catalysts
derived from (1R,2S)-cis-1-amino-indan-2-ol followed by the reduction of the hydroxylactam product to give the g-lactam. The enantiomeric
excesses were shown to be 27–99% by chiral HPLC and chiral GC of the g-lactam products with the nitrogen substituent playing a pivotal role
in determining yield and selectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
related systems.3 In this case, N-aryl groups gave better
selectivities than N-benzyl at catalyst loading of 20 mol %,
with N-phenyl providing the better ee over the more steri-
cally demanding N-2,6-dichlorophenyl (86% ee vs 50% ee).
Desymmetrisation of meso-compounds is a powerful and
versatile strategy in asymmetric synthesis as the differentia-
tion of two enantiotopic groups facilitates the formation of
multiple stereocentres in a single transformation.1 There
have been several previous reports of the catalytic desym-
metrisation of meso-imides using oxazaborolidines derived
from a,a-diphenylprolinol (CBS catalyst, Scheme 1).2
Previous work from this group has described the use of
various B-substituted oxazaborolidines 2 and 3 derived
from (1R,2S)-cis-1-amino-indan-2-ol as catalysts for the
asymmetric reduction of prochiral ketones (Fig. 1).4 Follow-
ing from this work, various N-substituted oxazaborolidines 4
(R¼Me, Et and Bn) were probed as possible catalysts for
the catalytic desymmetrisation of meso-imides. The results
showed that the unsubstituted oxazaborolidine 2 proved to
be the most efficient.5
O
O
H
H
H
Ph
Ph
H
(i) 50 mol% 1
N
N
.
N
O
BH3 THF
Ph
Ph
B
(ii) EtOH, H+
H
O
OEt
1
Me
73% over 2 steps
Although B-OMe oxazaborolidines such as catalyst 3 have
been shown to be successful in the asymmetric reduction
of various prochiral ketones,6 their use in imide reduction
has not yet been explored. Herein we describe their appli-
cation in the desymmetrisation of various cyclic meso-
imides and further investigate the effect that the changing
75% ee
Scheme 1. Desymmetrisation of meso-imides using a CBS catalyst.
Loadings of catalyst 1 of 50 mol % were required to main-
tain high yields and selectivities although lower loadings
could be used but this was sensitive to the nature of the nitro-
gen substituent, N-phenyl substrates requiring 10 mol %
catalyst to achieve an ee of 68%. The role played by the
nitrogen substituent on the ee was also noted by Kang et al.
who used catalytic thiazazincolidine complexes to reduce
R
N
H
N
H
N
Me
Me
OMe
B
O
B
B
O
O
2
3
4
Keywords: Asymmetric reduction; Oxazaborolidine; Catalysis; Imides.
* Corresponding author. Tel.: +44 114 222 9483; fax: +44 114 222 9346;
e-mail: simon.jones@sheffield.ac.uk
R=Me, Et, Bn
Figure 1. cis-1-Amino-indan-2-ol derived oxazaborolidines.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.051

11664
M. D. Barker et al. / Tetrahedron 62 (2006) 11663–11669
Table 2. meso-Imide synthesis via microwave promoted conditions
N-substituent has on the enantioselectivity of this type of
asymmetric reduction.
Entry
Amine
Time (min)
Product
Yield (%)
1
2
3
4
5
BnNH2
PhNH2
(p-OMe)PhNH2
CH2]CHCH2NH2
t-BuNH2
15
25
25
10
20
5a
5b
5c
5e
5f
50
60
33
48
17
2. Results and discussion
2.1. Substrate synthesis
Various N-substituted hexahydroisolidine-1,3-diones 5a–f
were prepared via two different methods starting from either
the corresponding dicarboxylic acid or the carboxylic acid
anhydride. This methodology, however, could not be applied
to the N-methyl 5g derivative, which was prepared from the
corresponding N-methylmaleimide by Diels–Alder reaction
with 1,3-butadiene followed by hydrogenation (Scheme 2).
Imide 5d could not be prepared in this manner, since micro-
wave irradiation caused rapid heating and volatilisation of
the aniline, presumably due to the ability of this dipolar
molecule to efficiently absorb this radiation. Use of the
microwave procedure enabled large amounts of the desired
starting materials to be prepared quickly and efficiently in
comparison to the ZnCl2/HMDS promoted conditions, which
took considerably longer due to prolonged purification pro-
cedures to remove impurities. However, the yield of the
microwave reactions was considerably reduced, providing
a trade-off between yield of product and speed of synthesis.
O
O
H
H
5% Pd/C, H2
EtOH
N Me
N Me
5g
O
O
N
Me
toluene
rt
H
H
O
O
60% over 2 steps
Scheme 2.
2.2. Desymmetrisation
The first method involved application of a previously re-
ported procedure for the Lewis acid and hexamethyldisila-
zane (HMDS) promoted condensation between a primary
amine and cyclohexane-1,2-dicarboxylic acid anhydride
(Scheme 3, Table 1).7 This method proved to be useful in
the synthesis of all the required substrates, however, with
bulky and highly electron deficient amines the yield was
reduced considerably. However, this method accessed the
required products in good yields.
Both oxazaborolidine catalysts vary in the method of prepa-
ration prior to their use in the reaction. Catalyst 2 is made
separately prior to use from trimethylboroxine and cis-1-
amino-indan-2-ol but is only stable for approximately 48 h
under a nitrogen atmosphere. Conversely catalyst 3 can be
made in situ from trimethyl borate and cis-1-amino-indan-
2-ol. Hexahydroisolidinediones 5a–g were firstly treated
with 10 mol % of either catalyst 2 or 3 and 1 equiv of
BH3$THF at 25 ꢀC for 18 h to yield a mixture of the optically
active 5-hydroxy-2-pyrrolidinones 6 (Scheme 5). In order to
simplify analysis, the crude mixture was immediately treated
with TFA and Et3SiH to give the g-lactam 7, which was
isolated after silica gel chromatography. The enantiomeric
excess was then established via either chiral HPLC or
chiral GC.
O
O
O
H
H
1 eq. RNH2
toluene
1.5 eq. HMDS
NHR
OH
O
N R
1.0 eq. ZnCl2
Δ, 2 h
H
H
5a-f
O
O
O
Scheme 3.
Table 1. meso-Imide preparation using ZnCl2/HMDS promoted conditions
O
OH
H
H
H
Entry
Amine
Product
Yield (%)
TFA
Et3SiH
CH2Cl2
10 mol.% 2 or 3
N R
N R
N R
.
1 eq. BH3 THF
1
2
3
4
5
6
BnNH2
PhNH2
(p-OMe)PhNH2
(p-NO2)PhNH2
CH2]CHCH2NH2
t-BuNH2
5a
5b
5c
5d
5e
5f
55
81
88
15
69
33
H
5a-g
H
6
H
7a-g
THF
O
O
O
a
Scheme 5.
Results indicated that both catalysts were as equally effec-
tive in terms of enantioselectivity of the lactam obtained
(Table 3), but in all cases there was a marked difference in
the yield of the reaction with the B-OMe catalyst 3 in com-
parison to the B-Me catalyst 2. This is probably due to the
reduced Lewis acidity of the boron centre by the additional
oxygen substituent, therefore, retarding the rate of reduction.
As previously observed, no background reaction was
observed with BH3$THF, although this was not the case
with BH3$DMS.5
a
Reflux overnight instead of 2 h.
The second method employed for the synthesis of the meso-
imides 5 used a microwave promoted condensation between
various primary amines and cis-cyclohexane-1,2-dicarb-
oxylic acid (Scheme 4).8 For this a mixture of both the amine
and dicarboxylic acid were subjected to microwave radiation
in a domestic microwave oven for various periods of time
(Table 2).
O
H
CO2H
RNH2
Several important points were observed in terms of the yield
of product. For alkyl substituents 5a,e–g low yields were
obtained for both allyl 5e and tert-butyl 5f groups, probably
resulting in competitive hydroboration of the alkene for the
former. In the case of the large tert-butyl group 5f, poor
N
R
μw
CO2H
H
5a-c,e,f
O
Scheme 4.

M. D. Barker et al. / Tetrahedron 62 (2006) 11663–11669
11665
Table 3. Reductions of meso-imides 5a–g using catalysts 2 and 3
O
OH
N
H
H
H
(i) NaBH4
10 mol.% 2
Entry
Imide
Catalyst 2
Yield of 7 (%)a
Catalyst 3
Yield of 7 (%)a
N
R
R
O
(ii) 2M H2SO4
.
1 eq. BH3 THF
ee
ee
H
5a-g
H
6
THF
H
9
O
O
O
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
57
49
41
24
24
19
52
84b
99b
99b
99b
33c
0c
53
23
28
9
24
21
30
82b
99b
99b
99b
32c
0c
Scheme 6.
Table 5. Formation of lactone 9 using catalyst 2
5g
75c
70c
Entry
Imide
Yield of 9 (%)a
eeb
a
Refers to yield after two-step procedure.
ee Determined by HPLC.
ee Determined by GC.
b
c
1
2
3
4
5
5a
5b
5e
5f
62
40
25
23
37
88
99
31
0
5g
75
binding to the catalyst due to the steric bulk may be respon-
sible for the low yield, which is also reflected in the poor
enantioselectivity observed for this substrate. Both benzyl
5a and methyl 5g gave comparable yields, which is not sur-
prising since the benzyl group can adopt a conformation
which places the phenyl group away from the catalyst, effec-
tively mimicking a methyl group.
a
Refers to yield after two-step procedure.
ee Determined by GC.
b
Although the enantioselectivities observed with either cata-
lyst are nearly identical, a significant variation in ee was ob-
served with different nitrogen substituents. In general, little
variation of ee was observed with alkyl substituents 5a and
5e, since each of these groups appear identical when bound
to the catalyst, the selectivity with the benzyl imide 5a again
resulting from this substrate adopting a conformation that
locates the aromatic ring away from the catalyst.
Those substrates with N-Ph and N-p-MeOPh groups gave
slightly reduced yields, while N-p-NO2Ph was very dis-
appointing. With all of these substrates a significant amount
of a doubly reduced product 8 (Fig. 2) was obtained, with
more being isolated from the reaction with N-p-NO2Ph
imide 5d (Table 4). The lower yield for all of these N-aryl
substrates is probably a reflection of the ability of the aro-
matic ring to engage the lone pair of the nitrogen atom,
reducing the amide character of the imide, making these
more ‘ketone-like’ and more prone to reduction. In the case
of the p-NO2Ph substituent, the additional electron with-
drawing group further accentuates this effect. This was
confirmed from the 1H NMR spectrum of the crude hydroxy-
lactam 6d, where approximately 10% of double reduction
product was observed, demonstrating the susceptibility of
this system to reduction.
The lower ee with the allyl group 5e probably results from
hydroboration of the alkene, which can then act as a compet-
itive reagent and/or hydride source for reduction. Somewhat
surprisingly, the more bulky tert-butyl group 5f gave race-
mic material. As previously noted, the large steric bulk of
this substrate probably inhibits tight binding to the catalyst
thus resulting in a looser transition state and hence non-
selective reduction. More pleasingly though, all of the
N-phenyl substrates 5b–d gave a single enantiomer of prod-
uct irrespective of the electronic nature of the phenyl group.
The selectivities at first appear to support the previously pro-
posed model with the prolinol derived catalyst (Fig. 3).2 In
this model, the fused ring system is considered as the small
substituent (Rs) with the nitrogen moiety considered the
large group (RL). The N-phenyl substrates have sufficient
free rotation to allow them to adopt a conformation ortho-
gonal to the carbonyl groups similar to that proposed by
Kang,3 thus allowing optimum binding to the catalyst. It is
important to note that the previously proposed model should
not be blindly adopted, since making the nitrogen substituent
as big as possible should result in excellent selectivity, while
H
N
X
H
8b-d
Figure 2.
Table 4. Yield of double reduction product with catalysts 2 and 3a
Entry
Substrate
Product
Catalyst 2
1
2
3
5b
5c
5d
8b
8c
8d
16
18
52
a
Refers to yield of 8b–d after the two-step procedure depicted in Scheme 5.
H
O
H
H
H
H
B
O
H2B
N
O
N
R
O
HO
N
R
The identity of the major enantiomer formed in each case
was determined by comparison of the specific rotation
with those in the literature and by conversion of the inter-
mediate hydroxylactam 6 to the lactone 9 via an established
protocol (Scheme 6, Table 5). This additionally allowed the
ee of the asymmetric reduction to be confirmed by a second
independent method. In all these cases the major enantiomer
formed was found to be the (3aS,7aR).
H
H
H
When R=t-Bu increased
steric interactions result
in poor binding
N
R
O
Figure 3. Model for the proposed selectivity.

11666
M. D. Barker et al. / Tetrahedron 62 (2006) 11663–11669
in reality the tert-butyl substrate gives by far the worst selec-
tivity and yield.
column chromatography eluting with 30% EtOAc/petroleum
ether (40:60) gave the title compound as colourless crystals
(1.2 g, 60% yield); mp 44–46 ꢀC (lit.9 47–48 ꢀC); 1H NMR
(250 MHz; CDCl3) dH 1.32–1.49 (4H, m, CH2), 1.65–1.83
(4H, m, CH2), 2.76–2.84 (2H, m, CHC]O), 2.91 (3H, s,
CH3); 13C NMR (250 MHz; CDCl3) dC 21.9 (CH2), 24.0
(CH2), 25.0 (CH3), 40.1 (CHC]O), 180.3 (C]O). NMR
data was broadly in accordance with the literature (literature
multiplicities appear to have been misinterpreted).
3. Conclusion
We have shown oxazaborolidines 2 and 3 to be effective cat-
alysts for the enantioselective reduction of a series of meso-
imides, with the B-methyl catalyst 2 providing better yields
of product. More importantly we have also demonstrated
that varying the nitrogen substituent on the imide greatly
affects the level of enantioselectivity observed with N-aryl
groups providing single enantiomers of product, the selectiv-
ities far exceeding those ever previously obtained with
similar catalysts and conditions.
4.2. General procedure A for the preparation of
N-substituted cis-hexahydro-isoindole-1,3-diones 5a–f
A solution of cyclohexane-1,2-carboxylic acid anhydride
(25 mmol) in toluene (70 cm3) was treated with amine
(25 mmol) and allowed to stir at room temperature for 1 h.
Dry zinc (II) chloride (25 mmol) was added, the reaction
warmed to 80 ꢀC and hexamethyldisilazane (37 mmol)
was added over a 40 min period. The reaction was heated
to reflux for a further 2 h, allowed to cool to room tempera-
ture and added to 1 M HCl (30 cm3). The product was ex-
tracted with EtOAc (3ꢂ15 cm3) and the combined organic
extracts were washed with saturated NaHCO3 (3ꢂ15 cm3),
brine (3ꢂ15 cm3) and dried over MgSO4. The solvent was
removed by rotary evaporation under vacuum and the imide
recrystallised from EtOAc/petroleum ether (60:80).
4. Experimental
4.1. General
All solvents were obtained dry from a Grubbs dry solvent
system and glassware was flame dried and cooled under
vacuum before use. All reactions were carried out under
nitrogen. TLC was carried out using Merck aluminium TLC
sheets (silica gel 60 F254), visualisation of TLC plates was
performed using a UV lamp or by dipping in KMnO4 then
exposure to heat. Flash column chromatography was carried
out with Silica Gel 40–63u 60A (Fluorochem Ltd.). 1H and
13C NMR spectra were measured using CDCl3 as a solvent
unless otherwise stated, on a Bruker AC250 machine with an
automated sample changer. Chemical shifts for carbon and
hydrogen are given on the d scale relative to TMS (tetra-
methylsilane, d¼0 ppm). Coupling constants were measured
in hertz. 13C NMR spectra were recorded using the JMOD
method. Specific rotations were performed on an Optical
Activity Ltd. AA-10 automatic polarimeter at 589 nm (Na
D-Line) and measured at 20 ꢀC unless otherwise stated.
[a]D Values are given in 10ꢁ1 deg cm2 gꢁ1. Infrared spectra
were recorded on a Perkin–Elmer 1600 FT-IR machine using
0.5 mm NaCl cells and mass spectra were recorded on a Kra-
tos instrument. HPLC was carried out on a Gilson analytical
system using a Chiralcel OD (4.8 mmꢂ250 mm) column
with 8% IPA in heptane as the solvent (unless otherwise
stated). The flow rate was 1.00 cm3 per minute and the detec-
tor was set at 254 nm. GC analysis was carried out using a
Perkin–Elmer Autosystem XL gas chromatograph fitted with
a Supleco fused silica capillary column (ALPHA DEXÔ
120) (30 mꢂ0.25 mmꢂ0.25 mm film thickness) using
nitrogen as the carrier gas and detection by standard FID.
All chemicals were used as received without further
purification except (1R,2S)-cis-1-amino-2-indanol, which
was recrystallised from hot toluene prior to use.
4.3. General procedure B for the preparation of
N-substituted cis-hexahydro-isoindole-1,3-diones
5a–c, e and f
A
mixture of cis-cyclohexane-1,2-dicarboxylic acid
(25 mmol) and amine (25 mmol) were heated in a domestic
microwave oven (750 W 70% of total power) until no start-
ing materials were observed by TLC. The imide was purified
via flash column chromatography eluting with 20% EtOAc/
petroleum ether (40:60).
4.3.1. cis-2-Benzyl-hexahydro-isoindole-1,3-dione 5a.2b
The title compound was obtained as colourless needles
either using general procedure A (55%) or B (50%); mp
1
58–60 ꢀC (lit.2b 71–72 ꢀC); H NMR (250 MHz; CDCl3)
dH 1.31–1.51 (4H, m), 1.60–1.91 (4H, m), 2.77–2.89 (2H,
m, 2ꢂCHC]O), 4.65 (2H, s, NCH2), 7.26–7.39 (5H, m,
ArCH); 13C NMR (63 MHz; CDCl3) dC 22.0 (CH2), 24.1
(CH2), 40.2 (CHC]O), 42.5 (CH2Ph), 128.2 (ArCH),
129.0 (ArCH), 136.5 (ArC), 179.8 (C]O). All NMR data
was in accordance with the literature.
4.3.2. cis-2-Phenyl-hexahydro-isoindole-1,3-dione 5b.2b
The title compound was obtained as white crystals either
using general procedure A (81%) or B (60%); mp 134–
1
135 ꢀC (lit.2b 70.5–72.5 ꢀC); H NMR (250 MHz; CDCl3)
dH 1.48–1.56 (4H, m), 1.82–2.02 (4H, m), 2.98–3.11 (2H,
m, 2ꢂCHC]O), 7.25–7.51 (5H, m, ArCH); 13C NMR
(63 MHz; CDCl3) dC 22.3 (CH2), 24.4 (CH2), 40.5
(CHC]O), 126.7 (ArCH), 128.7 (ArCH), 129.5 (ArCH),
132.5 (ArC), 179.0 (C]O). All NMR data was in accor-
dance with the literature.
4.1.1. cis-2-Methyl-hexahydro-isoindole-1,3-dione 5g.9
1,3-Butadiene was bubbled through a solution of N-methyl-
maleimide (1.38 g, 12 mmol) in toluene (30 cm3) and the
reaction stirred for 2 h. The solution was then cooled to
ꢁ5 ꢀC and the resulting white precipitate collected. This
was dissolved in ethanol (5 cm3) and 5% Pd/C was added.
The suspension was left to stir for 24 h under a balloon
pressure of H2, the solution filtered through Celite and the
solvent removed under vacuum to give a crude oil. Flash
4.3.3. cis-2-(p-Methoxyphenyl)-hexahydro-isoindole-1,3-
dione 5c.10 The title compound was obtained as white crys-
tals either using general procedure A (88%) or B (33%);

M. D. Barker et al. / Tetrahedron 62 (2006) 11663–11669
11667
mp 154–157 ꢀC (lit.10 161.5–162.5 ꢀC); 1H NMR (250 MHz;
CDCl3) dH 1.46–1.55 (4H, m), 1.79–2.00 (4H, m), 2.97–3.07
(2H, m, 2ꢂCHC]O), 3.81 (3H, s, OCH3), 6.96 (2H,
AA0BB0, ArCH), 7.19 (2H, AA0BB0, ArCH); 13C NMR
(63 MHz; CDCl3) dC 21.9 (CH2), 24.0 (CH2), 40.1
(CHC]O), 55.5 (CH3), 114.6 (ArCH), 124.7 (ArC), 127.5
(ArCH), 159.3 (ArC), 178.9 (C]O). 1H NMR data reported
previously was recorded in DMSO-d6.
(3ꢂ15 cm3), the combined organic extracts were washed
with1 MHCl(3ꢂ15 cm3)anddriedoverMgSO4. Thesolvent
was removed under vacuum to give the crude hydroxylactam
that was immediately redissolved in CH2Cl2 (30 cm3) and
treated with TFA (1 cm3) and triethylsilane (1 cm3) in
CH2Cl2 (5 cm3). This was allowed to stir at rt for 1 h and
the solution was added to an ice–water mixture (15 cm3) fol-
lowed by extraction with CH2Cl2 (3ꢂ15 cm3). The combined
organic extracts were washed with saturated NaHCO3
(3ꢂ15 cm3) and dried over MgSO4. The solvent was removed
under vacuum and purified via flash column chromatography
eluting with 20% EtOAc/petroleum ether (40:60).
4.3.4. cis-2-(p-Nitrophenyl)-hexahydro-isoindole-1,3-
dione 5d. The title compound was obtained as white crystals
using only general procedure A (15%); mp 186–189 ꢀC
(EtOH); (Found: C, 61.46; H, 5.05; N, 9.85. C14H14N2O4 re-
quires C, 61.31; H, 5.14; N, 10.21%); nmax (KBr disc)/cmꢁ1
4.5. General procedure D for the reduction of imides
using catalyst 3
1
1781, 1610, 1494; H NMR (250 MHz; CDCl3) dH 1.51–
1.54 (4H, m), 1.83–2.03 (4H, m), 3.05–3.13 (2H, m,
2ꢂCHC]O), 7.61 (2H, AA0BB0, ArCH), 8.34 (2H,
AA0BB0, ArCH); 13C NMR (63 MHz; CDCl3) dC 22.3
(CH2), 24.4 (CH2), 40.6 (CHC]O), 124.7 (ArCH), 126.9
(ArCH), 138.1 (ArC), 147.1 (ArC), 178.1 (C]O); m/z (EI)
274.0948 (100% M+ C14H14N2O4 requires 274.0954), 109
(6, C7H9O+), 82 (37), 67 (35), 54 (18).
A solution of (1R,2S)-cis-1-aminoindan-2-ol (0.25 mmol) in
dry THF (20 cm3) was treated with trimethyl borate
(0.25 mmol) and the resulting solution allowed to stir at
room temperature for 30 min. BH3$THF (1 M, 2.5 mmol)
was added, followed by a solution of meso-imides 5a–g
(2.5 mmol) in THF (5 cm3) and the solution was allowed
to stir at rt for 18 h. The crude reaction mixture was extracted
with CH2Cl2 (3ꢂ15 cm3), the combined organic extracts
were washed with 1 M HCl (3ꢂ15 cm3) and dried over
MgSO4. The solvent was removed under vacuum to give
the crude hydroxylactam that was immediately redissolved
in CH2Cl2 (30 cm3) and treated with TFA (1 cm3) and tri-
ethylsilane (1 cm3) in CH2Cl2 (5 cm3). This was allowed
to stir at rt for 1 h and the solution was added to an ice–water
mixture (15 cm3) followed by extraction with CH2Cl2
(3ꢂ15 cm3). The combined organic extracts were washed
with saturated NaHCO3 (3ꢂ15 cm3) and dried over MgSO4.
The solvent was removed under vacuum and purified via flash
column chromatography eluting with 20% EtOAc/petroleum
ether (40:60).
4.3.5. cis-2-Allyl-hexahydro-isoindole-1,3-dione 5e.11 The
title compound was obtained a colourless oil either using
general procedure A (69%) or B (48%); nmax (film)/cmꢁ1
1785, 1703; 1H NMR (250 MHz; CDCl3) dH 1.33–1.51
(4H, m), 1.65–1.93 (4H, m), 2.79–2.89 (2H, m,
2ꢂCHC]O), 4.05 (2H, dt, J 5.9, 1.4, NCH2), 5.07–5.16
(2H, m, CH]CH2), 5.64 (1H, ddt, J 17.3, 9.8 and 5.9,
CH]CH2); 13C NMR (63 MHz; CDCl3) dC 21.6 (CH2),
23.7 (CH2), 39.7 (CHC]O), 40.4 (NCH2), 118.0
(CH]CH2), 130.9 (CH]CH2), 179.2 (C]O); m/z (EI)
193 (100% M+), 82 (46), 67 (55), 54 (30). No NMR data
were reported in the literature.
4.3.6. cis-2-tert-Butyl-hexahydro-isoindole-1,3-dione
5f.12 The title compound was obtained as a white powder
either using general procedure A (33%) or B (17%); mp
4.5.1. (3aS,7aR)-2-Benzyl-octahydro-isoindol-1-one 7a.5
The title compound was obtained as a colourless oil with
imide 5a either using general procedure C (57%, ee 84%)
or D (53%, ee 82%); [a]D +15.0 (c 1, CHCl3; ee 84%),
1
58–61 ꢀC (lit.12 54–55 ꢀC); H NMR (250 MHz; CDCl3)
dH 1.41–1.86 (4H, m), 1.55 (9H, s, 3ꢂCH3), 1.62–1.83
(4H, m), 2.65 (2H, m, 2ꢂCHC]O); 13C NMR (63 MHz;
CDCl3) dC 21.9 (CH2), 24.0 (CH2), 27.4 (CH3), 40.2
(CHC]O), 58.2 [NC(CH3)3], 180.7 (C]O). All NMR
data were in accordance with the literature.
1
lit.5 +19.6 (c 0.5, CHCl3; ee 91%); H NMR (250 MHz;
CDCl3) dH 0.97–1.26 (3H, m), 1.32–1.62 (4H, m), 1.92–
2.05 (1H, m), 2.15–2.27 (1H, m), 2.37–2.46 (1H, m,
CHC]O), 2.66 (1H, dd, J 9.5, 2.5, 1ꢂCH2N), 3.16 (1H,
dd, J 9.5, 6.0, 1ꢂCH2N), 4.29 (1H, d, J 14.5, 1ꢂCH2Ph),
4.45 (1H, d, J 14.5, 1ꢂCH2Ph), 7.12–7.27 (5H, m, ArCH);
13C NMR (63 MHz; CDCl3) dC 23.0 (CH2), 23.5
(2ꢂCH2), 27.9 (CH2), 32.3 (CH), 41.9 (CHC]O), 46.8
(NCH2), 50.7 (NCH2Ph), 127.1 (ArCH), 128.3 (ArCH),
128.6 (ArCH), 136.8 (ArC), 175.9 (C]O); Chiral HPLC:
CHIRALCEL OD, 10% i-PrOH in hexane, tR 8.06 min
and 10.09 min. All NMR data were in accordance with the
literature.
4.4. General procedure C for the reduction of imides
using catalyst 3
(1R,2S)-cis-1-Aminoindan-2-ol (0.25 mmol) was suspended
in dry toluene (2 cm3 mmolꢁ1) and treated with trimethyl-
boroxine (0.08 mmol). After stirring at room temperature
for 30 min, toluene (5 cm3) was added and the resulting
solution was concentrated to approximately 2 cm3 by distil-
lation. This process was repeated twice after which the tolu-
ene was removed under reduced pressure to give the catalyst
as a white solid. THF (5 cm3) was added and the active
catalyst 2 was used immediately. Thus no analytical data
was obtained for this species. BH3$THF (1 M, 2.5 mmol)
was added and the solution allowed to stir at rt for 30 min.
A solution of meso-imide 5a–g (2.5 mmol) in THF (5 cm3)
was added and the solution was allowed to stir at rt for
18 h. The crude reaction mixture was extracted with CH2Cl2
4.5.2. (3aS,7aR)-2-Phenyl-octahydro-isoindol-1-one 7b.10
The title compound was obtained as a white powder with
imide 5b either using general procedure C (49%, ee 99%)
or D (23%, ee 99%); mp 88–90 ꢀC (lit.10 87.5–89 ꢀC);
[a]D +4.0 (c 0.5, CHCl3; ee 99%), lit.10 ꢁ4.8 (c 0.5,
1
CHCl3; (3aR,7aS) ee 93%); H NMR (250 MHz; CDCl3)
dH 1.17–1.34 (3H, m), 1.51–1.63 (3H, m), 1.69–1.77 (1H,
m), 2.07–2.25 (1H, m), 2.37–2.45 (1H, m), 2.59–2.65 (1H,

11668
M. D. Barker et al. / Tetrahedron 62 (2006) 11663–11669
m, CHC]O), 3.29 (1H, dd, J 9.4, 2.2, 1ꢂCH2N), 3.52 (1H,
dd, J 9.4, 5.8, 1ꢂCH2N), 7.23–7.54 (5H, m, ArCH);
13C NMR (63 MHz; CDCl3) dC 23.1 (CH2), 23.9 (CH2),
24.1 (CH2), 28.4 (CH2), 32.3 (CH), 43.8 (CHC]O), 53.0
(CH2N), 119.9 (ArCH), 124.5 (ArCH), 129.5 (ArCH),
129.2 (ArCH), 140.5 (ArC), 175.5 (C]O); Chiral HPLC:
CHIRALCEL OD, 8% i-PrOH in hexane, tR 10.94 min
27.9 (CH2), 32.3 (CH), 41.9 (CHC]O), 41.9
(NCH2CH]CH2), 50.8 (NCH2CH), 117.9 (]CH), 132.7
(]CH2), 175.7 (C]O); m/z (EI) 179.1309 (100%, M+
C11H17NO requires 179.1310), 164 (30), 152 (15), 136 (18),
124 (22), 95 (24), 70 (38), 67 (30); Chiral GC: b-DEX,
135 ꢀC, tR 43.52 min and 43.78 min.
1
and 12.22 min. H NMR data were in accordance with the
literature (no 13C NMR data were reported).
4.5.6. cis-tert-Butyl-octahydro-isoindol-1-one 7f. The title
compound was obtained as a colourless oil with imide 7f
either using general procedure C (19%, ee 0%) or D (17%,
ee 0%); nmax (film)/cmꢁ1 2925, 2852, 1638, 1559; 1H
NMR (250 MHz; CDCl3) dH 1.16–1.22 (4H, m), 1.35 (9H,
s, 3ꢂCH3), 1.48–1.53 (2H, m), 1.59–1.67 (1H, m), 1.91–
1.99 (1H, m), 2.14–2.19 (1H, m, CH), 2.33–2.39 (1H, m,
CHC]O), 2.96 (1H, dd, J 9.5, 2.1, 1ꢂNCH2), 3.34 (1H,
dd, J 9.5, 5.8, 1ꢂNCH2); 13C NMR (63 MHz; CDCl3) dC
21.8 (CH2), 23.3 (CH2), 23.6 (CH2), 27.6 (CH3), 27.7
(CH2), 31.7 (CH), 43.2 (CHC]O), 49.6 (NCH2), 53.4
[NC(CH3)3], 175.9 (C]O); m/z (EI) 195.1631 (12%, M+
C12H21NO requires 195.1623), 180 (100), 178 (15), 152
(25), 140 (10), 124 (12), 95 (15); Chiral GC: a-DEX,
105 ꢀC, tR 67.28 min and 68.59 min.
4.5.3. (3aS,7aR)-2-(p-Methoxyphenyl)-octahydro-iso-
indol-1-one 7c.10 The title compound was obtained as
a white powder with imide 7c either using general procedure
C (41%, ee 99%) or D (28%, ee 99%); mp 76–77 ꢀC (lit.10
77–78 ꢀC); [a]D +6.6 (c 0.6, CHCl3; ee 99%), lit.10 +4.4
(c 0.5, CHCl3; ee 87%); nmax (film)/cmꢁ1 1705, 1509;
1H NMR (250 MHz; CDCl3) dH 1.23–1.39 (3H, m), 1.50–
1.68 (3H, m), 1.73–1.85 (1H, m), 2.09–2.23 (1H, m),
2.39–2.51 (1H, m), 2.64–2.75 (1H, m, CHC]O), 3.36
(1H, dd, J 9.4, 2.2, 1ꢂCH2N), 3.80–3.84 (4H, m, CH3 and
1ꢂCH2N), 6.93 (2H, d, J 6.9, ArCH), 7.56 (2H, d, J 6.9,
ArCH); 13C NMR (75 MHz; CDCl3) dC 23.1 (CH2), 23.8
(CH2), 23.9 (CH2), 28.2 (CH2), 32.4 (CH), 43.4
(CHC]O), 53.3 (CH2N), 55.7 (OCH3), 114.2 (ArCH),
121.5 (ArCH), 133.7 (ArC), 156.5 (ArC), 175.0 (C]O);
Chiral HPLC: CHIRALCEL OD, 8% i-PrOH in hexane, tR
4.5.7. (3aS,7aR)-2-Methyl-octahydro-isoindol-1-one 7g.13
The title compound was obtained as a colourless oil with
imide 7g either using general procedure C (52%, ee 75%)
or D (30%, ee 70%); [a]D ꢁ17.0 (c 1, CHCl3; ee 75%); 1H
NMR (250 MHz; CDCl3) dH 1.05–1.25 (3H, m) 1.31–1.55
(3H, m), 1.59–1.70 (1H, m), 1.86–1.99 (1H, m), 2.16–2.28
(1H, m), 2.32–2.40 (1H, m, CHC]O), 2.84 (3H, s, CH3),
2.74 (1H, dd, J 9.4, 2.2, 1ꢂNCH2), 3.30 (1H, dd, J 9.4,
5.8, 1ꢂNCH2); 13C NMR (63 MHz; CDCl3) dC 23.1
(CH2), 23.8 (CH2), 23.9 (CH2), 28.3 (CH2), 30.2 (CH),
32.6 (CH3), 41.9 (CHC]O), 54.0 (CH2N), 176.2 (C]O);
Chiral GC: a-DEX, 100 ꢀC, tR 58.85 min and 59.60 min.
Only racemic material was reported in the literature.
1H NMR data were in accordance with the literature (no
13C NMR data were reported).
1
9.81 min and 10.73 min. H NMR data were in accordance
with the literature (no 13C NMR data were reported).
4.5.4. (3aS,7aR)-2-(p-Nitrophenyl)-octahydro-isoindol-1-
one 7d. The title compound was obtained as a yellow powder
with imide 7d either using general procedure C (24%, ee
99%) or D (9%, ee 99%); mp 189–191 ꢀC; [a]D ꢁ15.0
(c 0.4, CHCl3; ee 99%), nmax (KBr disc)/cmꢁ1 2935, 1707,
1593, 1500, 1469, 1387, 1291; 1H NMR (250 MHz;
CDCl3) dH 1.14–1.27 (3H, m), 1.45–1.64 (3H, m), 1.78–
1.89 (1H, m), 2.10–2.22 (1H, m), 2.45–2.57 (1H, m),
2.69–2.80 (1H, m, CHC]O), 3.39 (1H, dd, J 9.4, 2.2,
1ꢂCH2N), 3.80 (1H, dd, J 9.4, 5.8, 1ꢂCH2N), 7.80 (2H,
d, J 7.2, ArCH), 8.20 (2H, d, J 7.2, ArCH); 13C NMR
(63 MHz; CDCl3) dC 23.0 (CH2), 23.7 (CH2), 23.9 (CH2),
28.4 (CH2), 32.1 (CH), 44.0 (CHC]O), 52.9 (CH2N),
118.7 (ArCH), 125.1 (ArCH), 143.5 (ArC), 146.1 (ArC),
176.4 (C]O); m/z (EI) 260.1150 (100%, M+ C14H16N2O3
requires 260.1161), 217 (6), 206 (6), 151 (28), 135 (8),
120 (10), 105 (9), 95 (14), 67 (22); Chiral HPLC:
CHIRALCEL OD, 8% i-PrOH in hexane, tR 9.70 min and
12.40 min.
4.5.8. cis-2-Phenyl-octahydro-isoindole 8b.14 The title
compound was obtained as a by-product using general pro-
cedure C (30%) or D (29%); H NMR (250 MHz; CDCl3)
1
dH 1.23–1.66 (8H, m) 2.20–2.31 (2H, m), 3.09 (1H, dd,
J 8.9, 5.2, 1ꢂCH2N), 3.21 (1H, dd, J 8.9, 6.7, 1ꢂCH2N),
6.43 (2H, d, J 7.5, ArCH), 6.55 (1H, t, J 7.5, ArCH), 7.10–
7.18 (2H, m, ArCH); 13C NMR (63 MHz; CDCl3) dC 23.2
(CH2), 26.5 (CH2), 37.4 (CH), 51.7 (CH2), 111.1 (ArCH),
114.9 (ArCH), 129.1 (ArCH), 148.2 (ArC). No NMR data
were reported in the literature.
4.5.5. (3aS,7aR)-2-Allyl-octahydro-isoindol-1-one 7e. The
title compound was obtained as a colourless oil with imide
7e either using general procedure C (24%, ee 33%) or D
(24%, ee 32%); [a]D ꢁ0.14 (c 1, CHCl3; ee 32%), nmax
(film)/cmꢁ1 2929, 2843, 1640; 1H NMR (250 MHz;
CDCl3) dH 1.10–1.20 (3H, m), 1.38–1.68 (4H, m), 1.89–
1.99 (1H, m), 2.22–2.30 (1H, m), 2.37–2.44 (1H, m,
CHC]O), 2.81 (1H, dd, J 9.5, 2.1, 1ꢂNCH2), 3.24 (1H,
dd, J 9.5, 5.8, 1ꢂNCH2), 3.76 (1H, dd, J 15.2, 6.1,
1ꢂCH2CH]CH2), 3.88 (1H, ddt, J 15.2, 6.1, 1.3,
1ꢂCH2CH]CH2), 5.14 (1H, dq, J 10.1, 1.3, 1ꢂCH2CH]
CH2), 5.17 (1H, dq, J 17.3, 1.3, 1ꢂCH2CH]CH2), 5.76
(1H, ddt, J 17.3, 10.2, 5.8, CH2CH]CH2); 13C NMR
(63 MHz; CDCl3) dC 22.8 (CH2), 23.5 (CH2), 23.6 (CH2),
4.5.9. cis-2-(4-Methoxyphenyl)-octahydro-isoindole 8c.
The title compound was obtained as a by-product using
general procedure C (33%) or D (33%); nmax (film)/cmꢁ1
2922, 2851, 1599, 1511, 1482; 1H NMR (250 MHz;
CDCl3) dH 1.34–1.64 (8H, m), 2.18–2.30 (2H, m), 3.06
(1H, dd, J 8.9, 5.2, 1ꢂCH2N), 3.14–3.23 (1H, m,
1ꢂCH2N), 3.68 (3H, s, OCH3), 6.38 (2H, br d, J 8.8,
ArCH), 6.74–6.81 (2H, AA0BB0, ArCH); 13C NMR
(63 MHz; CDCl3) dC 23.2 (CH2), 26.5 (CH2), 37.5 (CH),
52.2 (CH2), 56.1 (CH3O), 111.6 (ArCH), 115.2 (ArCH),
126.2 (ArC), 143.4 (ArC); m/z (EI) 231.1625 (100%, M+
C15H21NO requires 231.1623), 216 (50), 149 (10), 134
(12), 121 (21).

M. D. Barker et al. / Tetrahedron 62 (2006) 11663–11669
11669
4.5.10. cis-2-(4-Nitrophenyl)-octahydro-isoindole 8d. The
title compound was obtained as a by-product using general
References and notes
procedure C (30%) or D (30%); mp 110–111 ꢀC; nmax
1. Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765–1784.
2. (a) Romagnoli, R.; Roos, E. C.; Hiemstra, H.; Moolenaar, M. J.;
Speckamp, W. N. Tetrahedron Lett. 1994, 35, 1087–1090; (b)
Ostendorf, M.; Romagnoli, R.; Pereiro, I. C.; Roos, E. C.;
Moolenaar, M. J.; Speckamp, W. N.; Hiemstra, H. Tetrahedron:
Asymmetry 1997, 8, 1773–1789.
1
(film)/cmꢁ1 2925, 2852, 1603, 1462; H NMR (250 MHz;
CDCl3) dH 1.33–1.68 (8H, m), 2.26–2.39 (2H, m), 3.20 (1H,
dd, J 10.1, 5.5, 1ꢂCH2N), 3.34 (1H, dd, J 10.1, 7.0,
1ꢂCH2N), 6.37 (2H, AA0BB0, ArCH), 8.05 (2H, AA0BB0,
ArCH); 13C NMR (63 MHz; CDCl3) dC 22.8 (CH2), 26.0
(CH2), 37.1 (CH), 52.1 (CH2), 110.2 (ArCH), 126.3 (ArCH),
132.2 (ArC), 152.4 (ArC); m/z (EI) 246.1363 (100%, M+
C14H18N2O2 requires 246.1368), 164 (27), 151 (5), 136 (30).
3. Kang, J.; Lee, J. W.; Kim, J. I.; Pyun, C. Tetrahedron Lett. 1995,
36, 4265–4268.
4. (a) Jones, S.; Atherton, J. C. C. Tetrahedron: Asymmetry 2000,
11, 4543–4548; (b) Glimore, N. J.; Jones, S. Tetrahedron:
Asymmetry 2003, 14, 2115–2118; (c) Gilmore, N. J.; Jones,
S.; Muldowney, M. P. Org. Lett. 2004, 6, 2805–2808.
5. Jones, S.; Dixon, R. A. Tetrahedron: Asymmetry 2002, 13,
1115–1119.
6. (a) Masui, M.; Takayuki, S. Synlett 1997, 273–274; (b) Ponzo,
V. L.; Kaufman, T. S. Molecules 2000, 5, 495–496; (c) Lagasse,
F.; Tsukamoto, M.; Welch, C. J.; Kagan, H. B. J. Am. Chem.
Soc. 2003, 125, 7490–7491; (d) Xu, J.; Su, X.; Zhang, Q.
Tetrahedron: Asymmetry 2003, 14, 1781–1786; (e) Duquette,
J.; Zhang, M.; Lei, Z.; Reeves, R. S. Org. Process Res. Dev.
2003, 7, 285–288.
4.5.11. (3aS,7aR)-Hexahydroisobenzofuran-1-one 9.10
A
solution of hydroxylactam (1.25 mmol) in 60% ethanol
(10 cm3) was treated with sodium borohydride (2.5 mmol)
and the resulting solution was stirred at 50 ꢀC for 4 h.
Once cooled EtOAc (10 cm3) was added followed by 5%
HCl (5 cm3), upper organic layer was extracted and solvent
was removed under vacuum to give crude amide. Crude
product was suspended in 2 M H2SO4 and heated at 80 ꢀC
for 2 h. Product was extracted with CH2Cl2 (3ꢂ15 cm3).
Combined organic extracts were dried over MgSO4. Solvent
was removed under vacuum and purified via flash column
chromatography eluting with 30% EtOAc/petroleum ether
(40:60). Title compound was obtained as a clear oil (62%);
[a]D ꢁ63.0 (c 0.4, CHCl3; ee 99%), lit.10 ꢁ43.2 (c 1,
7. Reddy, P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org. Chem. 1997,
62, 2652–2654.
ꢀ
´
ꢀ
8. Seijas, J. A.; Vazquez-Tato, M. P.; Martınez, M. M.; Nun˜ez-
Corredoira, G. J. Chem. Res. 1999, 420–421.
9. Bailey, B.; Haworth, R. D.; McKenna, J. E. J. Chem. Soc. 1954,
967–976.
1
CHCl3; ee 89%); H NMR (250 MHz; CDCl3) dH 1.09–
1.27 (3H, m), 1.41–1.63 (3H, m), 1.71–1.80 (1H, m),
1.98–2.10 (1H, m), 2.33–2.46 (1H, m), 2.50–2.61 (1H, m,
CHC]O), 3.88 (1H, dd, J 8.9, 1.2, 1ꢂCH2O), 4.13 (1H,
dd, J 8.9, 4.9, 1ꢂCH2O); Chiral GC: a-DEX, 100 ꢀC, tR
10. Matsuki, K.; Inoue, H.; Ishida, A.; Takeda, M.; Nakagawa, M.;
Hino, T. Chem. Pharm. Bull. 1994, 42, 9–18.
11. Newman, S. S.; Magerlein, B. J.; Wheatley, W. B. J. Am. Chem.
Soc. 1946, 68, 2112, 2114–2115.
1
39.893 min and 40.658 min. H NMR data were in accor-
dance with the literature.
12. Bilyard, K. G.; Garratt, P. J.; Hunter, R.; Lete, E. J. Org. Chem.
1982, 47, 4731–4736.
Acknowledgements
13. Milewska, M. J.; Bytner, T.; Polonski, T. Synthesis 1996, 1485–
1488.
14. Khandewal, G. D.; Swan, G. A.; Roy, R. B. J. Chem. Soc.,
Perkin Trans. 1 1974, 891–896.
We would like to thank the EPSRC and GlaxoSmithKline for
a studentship and Rhodia-Chirex for the generous donation
of (1R,2S)-cis-1-aminoindan-2-ol.