Evaluating the use of chiral anthracene templates to access pyroglutamic acids

Article abstract of DOI:10.1016/j.tetasy.2010.10.021

An approach for the asymmetric synthesis of pyroglutamic acid derivatives is described based on an anthracene chiral auxiliary. The introduction of a furan ring as a masked carboxylic acid moiety proceeded with excellent levels of diastereo-selectivity, followed by conversion into a carboxylate ester. The ensuing retro-Diels-Alder procedure using flash vacuum pyrolysis (FVP) followed by reduction gave pyroglutamate esters in good yield but poor enantioselectivity, the latter of which was found to be dependant on the electronic nature of the N-protecting group.

Full text of DOI:10.1016/j.tetasy.2010.10.021

Tetrahedron: Asymmetry 21 (2010) 2719–2725
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Evaluating the use of chiral anthracene templates to access pyroglutamic acids
⇑
Siti Aishah Hasbullah, Simon Jones
Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An approach for the asymmetric synthesis of pyroglutamic acid derivatives is described based on an
anthracene chiral auxiliary. The introduction of a furan ring as a masked carboxylic acid moiety pro-
ceeded with excellent levels of diastereo-selectivity, followed by conversion into a carboxylate ester.
The ensuing retro-Diels–Alder procedure using flash vacuum pyrolysis (FVP) followed by reduction gave
pyroglutamate esters in good yield but poor enantioselectivity, the latter of which was found to be
dependant on the electronic nature of the N-protecting group.
Received 4 October 2010
Accepted 21 October 2010
Available online 22 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
OH
O
H
N
Pyroglutamic acid, 2-oxo-tetrahydropyrrole-5-carboxylic acid
1, is recognized as an internally protected glutamic acid and has
been used as an important building block in numerous syntheses,
making use of the differing stereo-electronic properties of the
two carbonyl entities to allow independent functionalisation.1
Pyroglutamates are also found embedded in the core-structures
of numerous biologically active natural products including lactacy-
stin, omuralide, salinosporamide A and dysibetaine (Fig. 1).2
Recent studies on the use of chiral anthracene templates from
our group and others have established efficient protocols for the
highly stereoselective construction of carbon–carbon bonds, facili-
tating the preparation of densely functionalized small molecule
building blocks.3,4 These reactions are particularly applicable to
N-acyl iminium ions derived from pyrrolidinones,5 lending them-
selves as particularly appealing targets for the preparation of
pyroglumatate analogues using a nucleophilic carboxylic acid syn-
thon. Furan has been used in this way, to prepare (2S,3S)-3-
hydroxypipecolic acid.6 We therefore sought to exemplify this in
the preparation of pyroglutamic acid itself as a prelude to the prep-
aration of more complex target molecules.
OH
S
O
O
HO2C
O
N
O
O
N
H
NHAc
CO2H
H
O
HO
1
Omuralide
Lactacystin
HO
Cl
O
NMe3
OH
O
N
O
N
H
H
O
HO
H
Lactacystin
Salinosporamide A
Figure 1. Naturally occurring pyroglutamates.
either p-methoxy benzylamine or benzylamine gave the desired
p-methoxy benzylamine and N-benzylamine cycloadducts 3c and
3d in 76% and 90% yield, respectively, over two steps (Scheme 1).
With anthracene cycloadducts 3a–d in hand, reduction with
diisobutylaluminium hydride (DIBAL-H) in CH2Cl2 at ꢀ78 °C for
3 h gave hydroxy-lactams 5a–d in quantitative yield without the
need for further purification. In all cases, the reaction proceeded
with complete regio- and diastereo-selectivity, reduction occurring
at the carbonyl group distal to the stereogenic centre from the least
hindered Si face. The identity of these products was confirmed by
analysis of the coupling constants for the ddd bridgehead signal
in the 1H NMR spectrum, corresponding well to results previously
obtained for these classes of compound. The regioselectivity
observed is also in good agreement with our model previously de-
scribed for the addition of Grignard reagents to these imides, with
DIBAL-H pre-co-ordination being less favored at the carbonyl prox-
imal to the stereogenic centre due to increased steric interactions
2. Results and discussion
The anthracene adducts 3a and 3b were prepared as previously
described from ether 2 (>98% ee) and the corresponding maleimide
derivatives in excellent yield (Scheme 1).5 The synthesis of sub-
strates 3c and 3d was achieved via the diastereoselective Diels–
Alder reaction between ether 2 and maleic anhydride to furnish
the cycloadduct 4 in quantitative yield.3d Treatment of this with
⇑
Corresponding author. Tel.: +44 (0) 114 222 9483; fax: +44 (0) 114 222 9346.
E-mail address: simon.jones@sheffield.ac.uk (S. Jones).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.021

2720
S. A. Hasbullah, S. Jones / Tetrahedron: Asymmetry 21 (2010) 2719–2725
The next step was the retro-Diels–Alder reaction by flash vac-
O
R
O
uum pyrolysis (FVP). Initially, the retro-Diels–Alder reaction of
compound 7a was conducted at 180 °C (inlet) and 510–530 °C (fur-
nace). However, the reaction only gave the elimination product 9 in
a quantitative yield (Scheme 4).
N
O
O
N
R
Toluene
reflux, 4 - 6 hr
Me
OMe
Judging that the acidity of the carboxylic acid may be promoting
E1 elimination at the stereogenic centre of the ether 2, methyl es-
ter 8a was next subjected to FVP at 180 °C (inlet) and 500–540 °C
(furnace), providing a 1:1 ratio of the desired dihydro-oxo-pyrrole
9a and ether 2 in 100% conversion. The separation of the crude
compounds was difficult due to decomposition upon column chro-
matography. Immediate hydrogenation of the reaction mixture ob-
tained from FVP (2 and 9a) was performed allowing separation of
the desired N-methyl pyroglutamate 10a in 21% yield. However,
the product completely racemised due to the high acidity of H-2
proton. Rapid racemisation of the corresponding N-BOC ethyl ester
in just 2 h at room temperature has previously been observed by
Ezquerra et al.8 Nevertheless, esters 8b–d were also subjected to
the same procedure, with esters 10c and 10d being returned as
racemates, while ester 10b was obtained in 24% ee, confirmed by
HPLC (Scheme 5).
MeO
H
2
Me
Toluene
reflux, 4 - 6 hr
>99%
3a R = Me (95%)
3b R = PMP (91%)
3c R = PMB (76%)
3d R = Bn (90%)
O
O
O
O
O
PMBNH2 or BnNH2
AcOH, 24 hr
reflux
O
H
MeO
4
Me
Scheme 1. Preparation of substrates 3a–d.
Esters 10a, 10c and 10d all behaved similarly since they all
essentially bear N-alkyl substituents. The rate of racemisation of
ester 10b is slightly slower since the p-methoxyphenyl group pre-
sumably decreases the acidity of the C-2 proton through electron
donation to the nitrogen atom. Thus, it may be possible to further
tune the electronic nature of the nitrogen protecting group to sup-
press racemisation further.
and disruption of stabilizing interactions between the carbonyl
group and substituents forming the stereogenic centre in the start-
ing material (Scheme 2).5
O
H
HO
R
O
R
O
N
N
DIBAL-H
CH2Cl2
3. Conclusion
-78 ºC, 3 h
MeO
H
MeO
H
In conclusion, an approach for the synthesis of pyroglutamates
has been developed using furan as a masked carboxylic acid. The
final products from these reactions are highly prone to racemisa-
tion although this can be suppressed by the use of electron rich
nitrogen protecting groups. This means that the strategy described
herein would be particularly suited for the synthesis of analogues
where the racemisation pathway becomes less viable.
Me
Me
3a R = Me
5a R = Me (>99%)
5b R = PMP (89%)
5c R = PMB (98%)
5d R = Bn (96%)
3b R = PMP
3c R = PMB
3d R = Bn
H
i-Bu
i-Bu
Al
O
O
Loss of
R
O
R
stabilizing
N
N
4. Experimental
4.1. General
H
interactions
O Al i-Bu
i-Bu
MeO
H
MeO
H
Dry solvents from Grubbs system were used unless otherwise
stated. Glassware was flame dried and cooled under nitrogen be-
fore use. Commercially available compounds were obtained from
the Aldrich chemical company, Lancaster Synthesis and Alfa Aeser
and were used without further purification. TLC was carried out
using Merck aluminium sheets and was visualised by UV light
(254 nm) or by dipping in KMnO4 or molybdophosphoric acid solu-
tion followed by exposure by heating. Purification of crude materi-
als was performed using flash column chromatography utilising
different sized columns packed with silica gel (Merck Kieselgel
60; 230–400 mesh). 1H NMR spectra were performed on a Bruker
Avance 250 and 400 MHz spectrometers as solvent and TMS as
an internal standard. 13C NMR spectra were recorded on the same
instrument using JMOD method. Coupling constants were mea-
sured in Hz. Infra-red spectra were recorded in solid state on a
Perkin–Elmer 1600 FT-IR machine. Mass spectra were recorded
on a Kratos instrument using Electron Impact mode at 70 eV.
Elemental analysis was performed in Micro Analytical Services in
the department. Microwave reactions were conducted using a
Smith Creator unit with personal chemistry software. The machine
had a continuous microwave power delivery system with a power
output of 0–300 W and a pressure of 0.2 mm Hg. All microwave
Me
Me Increased steric
interaction
Scheme 2. Stereoselective reduction of imides 3a–d.
Hydroxy-lactam 5a was used as a model compound to optimize
the installation of the carboxylic acid. Thus, treatment with furan
and boron trifluoride etherate in THF at ꢀ78 °C for 2 h followed
by stirring at room temperature overnight gave the desired furan
anthracene adduct 6a in 89% yield after purification by flash col-
umn chromatography. Subsequent oxidation of the furan ring to
the carboxylic acid using RuCl3/NaIO4 required careful modulation
of the reaction conditions. Adopting the optimized conditions rec-
ommended by Noji et al.7 whereby a solvent mixture of Hex/
EtOAc/H2O in a ratio of 4.5/3.5/2 is employed, gave 100% conver-
sion of furan 6a to carboxylic acid 7a after 45 min. Any longer oxi-
dation led to oxidative cleavage and the formation of imide 3a as a
by-product. At this stage purification was difficult and the crude
carboxylic acid was esterified with TMSCHN2 in MeOH/toluene to
afford the ester 8a in 80% yield after column chromatography.
The remaining hydroxy-lactams 5b–d were transformed using this
protocol in excellent yield (Scheme 3).

S. A. Hasbullah, S. Jones / Tetrahedron: Asymmetry 21 (2010) 2719–2725
2721
O
HO2C
H
MeO2C
MeO
HO
R
O
R
O
R
O
R
O
N
N
N
N
Furan,
RuCl3 / NaIO4
BF3.OEt2
TMSCHN2
Hex / AcOEt / H2O
rt, 45 mins
MeOH / toluene
rt
THF, 0 ºC
MeO
H
MeO
H
MeO
H
H
Me
Me
Me
Me
5a R = Me
6a R = Me (89%)
6b R = PMP (85%)
6c R = PMB (88%)
6d R = Bn(81%)
7a-d
8a R = Me (80%)
5b R = PMP
5c R = PMB
5d R = Bn
8b R = PMP (78%)
8c R = PMB (71%)
8d R = Bn (74%)
Scheme 3. Transformation to methyl esters 8a–d.
and the resulting white suspension was heated at reflux overnight.
Once cooled to rt, the solution was added to an ice water mixture
(20 cm3) and stirred vigorously. The off-white precipitate was col-
lected and washed with 1 M NaOH (10 cm3) and water (10 cm3).
The precipitate was dissolved in CH2Cl2 (20 cm3) and washed with
water (3 ꢁ 10 cm3), dried over magnesium sulfate and evaporated.
The imide 3c was obtained as a white precipitate (3.1 g, 76%) that
HO2C
Me
O
HO2C
H
N
N
FVP
+
Me
180 °C (inlet)
510-530 °C
(furnace)
O
MeO
7a
H
not isolated
9
Me
did not require further purification; [
a]
D = ꢀ42 (c 1, CHCl3); mp
199 °C; mmax (film)/cmꢀ1 2935, 2834, 1738, 1698, 1612, 1514; 1H
NMR (400 MHz; CDCl3) dH 1.87 (3H, J 6.4, CH3), 3.12 (1H, dd, J 8.6
and 3.2, COCHCHCH), 3.65 (1H, d, J 8.6, COCHCHCH), 3.74 (3H, s,
COCH3), 3.80 (3H, s, COCH3), 4.17 (1H, d, J 15.0, 1 ꢁ ArCH2), 4.21
(1H, d, J 15.0, 1 ꢁ ArCH2), 4.72 (1H, d, J 3.2, 10-H), 5.13 (1H, q, J 6.4,
CH3CH), 6.68–6.74 (4H, m, ArCH), 6.99–7.22 (6H, m, ArCH), 7.35–
7.42 (1H, m, ArCH), 7.85–7.92 (1H, m, ArCH); 13C NMR (100 MHz;
CDCl3) dC 16.9 (CH3), 41.4 (CH2), 46.3 (CH), 46.8 (CH), 48.6 (CH),
54.6 (9-C), 55.3 (OCH3), 57.1 (OCH3), 73.8 (CH), 113.7 (2 ꢁ ArCH),
123.5 (ArCH), 123.9 (ArCH), 125.0 (ArCH), 125.9 (ArCH), 126.3
(ArCH), 126.7 (ArCH), 126.8 (2 ꢁ ArCH), 127.5 (ArC), 129.4
(2 ꢁ ArCH), 138.2 (ArC), 138.7 (ArC), 139.5 (ArC), 142.7 (ArC), 158.8
(ArC), 175.9 (CO), 176.5 (CO); m/z (EI+) 453.1947 (12%, M+,
Scheme 4. Retro-Diels–Alder reaction of carboxylic acid 7a.
MeO2C
R
O
N
FVP
Me
OMe
180 ºC (inlet)
500-540 ºC
(furnace)
not
+
MeO
H
isolated
CO2Me
Me
H
N
8a R = Me (80%)
8b R = PMP (78%)
8c R = PMB (71%)
8d R = Bn (74%)
9a R = Me
9b R = PMP
9c R = PMB
9d R = Bn
R
C29H27NO4 requires 453.1940), 438 (14), 235 (100), 221 (75), 205
O
(48), 178 (32), 136 (12), 121 (40).
H2, Pd/C
MeOH, rt
4.2.2. (3aS,9aS)-3a,4,9,9a-Tetrahydro-4-[(1S)-1-methoxyethyl]-
2-(N-phenylmethyl)-4,9-[10,20]benzeno-1H-benzo[f]isoindole-
1,3-(2H)-dione 3d
CO2Me
Anhydride 4 (2.0 g, 6 mmol) was suspended in AcOH (20 cm3)
followed by the addition of benzylamine (1.3 g, 12 mmol) and
the resulting white suspension was heated at reflux overnight.
Once cooled to rt, the solution was added to an ice water mixture
(15 cm3) and stirred vigorously. The off-white precipitate was col-
lected and washed with 1 M NaOH (15 cm3) and water (5 cm3). The
precipitate was dissolved in CH2Cl2 (20 cm3) and washed with
water (3 ꢁ 10 cm3), dried over magnesium sulfate and evaporated.
The imide 3d was obtained as a white precipitate (2.2 g, 90%) that
H
10a R = Me (21%, 0% ee)
10b R = PMP (32%. 24% ee)
10c R = PMB (23%, 0% ee)
10d R = Bn (26%, 0% ee)
N
R
O
Scheme 5. FVP of methyl esters 8a–d.
reactions were performed in 10 mL glass vessels sealed with a
septum.
did not require further purification; [
a
]
D = ꢀ36 (c 1, CHCl3); mp
230 °C; mmax (film)/cmꢀ1 2934, 1770, 1699, 1457; 1H NMR
(400 MHz; CDCl3) dH 1.85 (3H, J 6.4, CH3), 3.16 (1H, dd, J 8.6 and
3.2, COCHCHCH), 3.66 (1H, d, J 8.6, COCHCHCH), 3.73 (3H, s,
OCH3), 4.23 (1H, d, J 14.1, 1 ꢁ ArCH2), 4.29 (1H, d, J 14.1,
1 ꢁ ArCH2), 4.73 (1H, d, J 3.2, 10-H), 5.12 (1H, q, J 6.4, CH3CH),
6.68–6.71 (2H, m, ArCH), 6.98–7.10 (8H, m, ArCH), 7.39–7.41 (1H,
m, ArCH), 7.84–7.93 (1H, m, ArCH); 13C NMR (100 MHz; CDCl3)
dC 16.9 (CH3), 42.0 (CH2), 46.3 (CH), 46.9 (CH), 48.7 (CH), 54.6
(9-C), 57.1 (OCH3), 73.8 (CHOCH3), 123.6 (ArCH), 123.9 (ArCH),
125.1 (ArCH), 125.9 (ArCH), 126.4 (ArCH), 126.7 (ArCH), 126.8
(ArCH), 126.9 (ArCH), 127.3 (ArCH), 127.8 (2 ꢁ ArCH), 128.4
(2 ꢁ ArCH), 135.1 (ArC), 138.3 (ArC), 138.8 (ArC), 139.6 (ArC),
4.2. Synthesis of substrates
Several key starting materials were prepared according to
established literature methods; ether 2, imides 3a and 3b;5 anhy-
dride 4;3d N-p-methoxyphenyl-maleimide.9
4.2.1. (3aS,9aS)-3a,4,9,9a-Tetrahydro-4-[(1S)-1-methoxyethyl]-
2-(N-40-methoxyphenylmethyl)-4,9-[10,20]benzeno-1H-benzo[f]-
isoindole-1,3-(2H)-dione 3c
Anhydride4 (3.0 g, 9 mmol) wassuspendedinAcOH(20 cm3)fol-
lowed by the addition of p-methoxybenzylamine (2.5 g, 18 mmol)

2722
S. A. Hasbullah, S. Jones / Tetrahedron: Asymmetry 21 (2010) 2719–2725
142.7 (ArC), 175.9 (CO), 176.5 (CO); m/z (EI+) 423.1847 (6%, M+,
28H25NO3 requires 423.1834), 408 (24), 368 (6), 235 (100), 221
(77), 205 (38), 178 (32).
cmꢀ1 3425, 1633, 1455; 1H NMR (400 MHz; CDCl3) dH 1.89 (3H,
d, J 6.4, CH3), 2.80 (1H, ddd, J 10.3, 8.2 and 2.5, HOCHCH), 3.53
(1H, d, J 10.3, COCHCH), 3.75 (3H, s, OCH3), 3.79 (3H, s, OCH3),
3.99 (1H, d, J 14.8, 1 ꢁ ArCH2), 4.24 (1H, d, J 14.8, 1 ꢁ ArCH2),
4.63 (1H, d, J 2.5, 10-H), 5.01 (1H, dd, J 12.0 and 8.2, CHOH), 5.47
(1H, q, J 6.4, CHCH3), 6.63 (2H, d, J 8.8, 2 ꢁ ArCH), 6.71 (2H, d, J
8.8, 2 ꢁ ArCH), 7.13–7.22 (3H, m, ArCH), 7.25–7.29 (1H, m, ArCH),
7.32–7.37 (3H, m, ArCH), 7.87–7.90 (1H, m, ArCH); 13C NMR
(63 MHz; CDCl3) dC 17.2 (CH3), 43.9 (CH), 44.0 (CH2), 45.0 (CH),
48.8 (CH), 55.0 (9-C), 55.3 (OCH3), 57.2 (OCH3), 73.9 (CHOCH3),
83.5 (CHOH), 113.8 (2 ꢁ ArCH), 123.3 (ArCH), 124.4 (ArCH), 125.0
(ArCH), 125.6 (ArCH), 126.0 (ArCH), 126.3 (ArCH), 126.8 (ArCH),
126.9 (ArCH), 128.5 (2 ꢁ ArCH), 129.3 (ArC), 140.3 (ArC), 141.4
(ArC), 141.5 (ArC), 144.2 (ArC), 158.6 (ArC), 171.7 (CO); m/z (EI+)
455.2082 (46%, M+, C29H29NO4 requires 455.2097), 440 (45), 379
(5), 236 (82), 221 (72), 205 (36), 178 (26), 136 (56), 121 (100),
112 (58).
C
4.2.3. General procedure A for the reduction of imides 3a–d
Imide (0.29 mmol) was dissolved in CH2Cl2 (20 cm3) under dry
nitrogen and cooled to ꢀ78 °C. Next, DIBAL-H (0.60 cm3 of a 1.0 M
solution in CH2Cl2, 0.58 mmol) was added drop-wise and the reac-
tion was left to stir for 30 min before warming to room temperature
for 3 h. The reaction mixture was quenched with 1 M HCl (10 cm3)
and water (10 cm3), and extracted with CH2Cl2 (3 ꢁ 10 cm3). The
combined organic extracts were washed with brine (5 cm3), dried
over MgSO4, filtered and the solvent was evaporated. The hydro-
xy-lactams were found to be of sufficient purity to proceed directly
to the next step; purification by column chromatography on silica
gel led to a loss of mass through decomposition.
4.2.4. (3S,3aS,9aS)-9-[(1S)-1-Methoxyethyl]-2,3,3a,4,9,9a-
hexahydro-3-hydroxy-2-methyl-4,9 [10,20]-benzeno-1H-
benz[f]isoindol-1-one 5a5
4.2.7. (3S,3aS,9aS)-9-[(1S)-1-Methoxyethyl]-2,3,3a,4,9,9a-hexa-
hydro-3-hydroxy-2-[N-phenylmethyl]-4,9 [10,20]-benzeno-1H-
benz[f]isoindol-1-one 5d
The hydroxy-lactam 5d was obtained as a white solid (96%)
using general procedure A. The crude was purified by recrystalliza-
The hydroxy-lactam 5a was obtained as a white solid (>99%)
using general procedure A. The crude material was purified by
recrystallization using CH2Cl2;5
[a]
D = ꢀ24 (c 1, CHCl3), lit.5 ꢀ31.0
(c 1, CHCl3); mp 199–200 °C, lit.5 197–199 °C; mmax (film)/cmꢀ1
3238, 2928, 1644, 1456; 1H NMR (400 MHz; CDCl3) dH 1.86 (3H, J
6.4, CH3), 2.16 (1H, d, J 12.5, OH), 2.50 (3H, s, NCH3), 2.87 (1H,
ddd, J 10.0, 8.1 and 2.7, HOCHCH), 3.47 (1H, d, J 10.0, COCHCH),
3.73 (3H, s, COCH3), 4.66 (1H, d, J 2.7, 10-H), 4.95 (1H, dd, J 8.1
and 12.5, OHCH), 5.41 (1H, q, J 6.4, CH3CH), 7.05–7.14 (4H, m,
4 ꢁ ArCH), 7.42–7.44 (3H, m, 3 ꢁ ArCH), 7.92–7.94 (1H, m, ArCH);
13C NMR (100 MHz; CDCl3) dC 17.0 (CH3), 26.7 (NCH3), 43.9 (CH),
45.0 (CH), 48.8 (CH), 54.8 (9-C), 57.2 (OCH3), 73.8 (CHOCH3), 84.2
(CHOH), 123.4 (ArCH), 123.8 (ArCH), 125.1 (ArCH), 125.6 (ArCH),
126.0 (ArCH), 126.5 (ArCH), 126.8 (ArCH), 126.9 (ArCH), 140.3
(ArC), 141.2 (ArC), 141.4 (ArC), 143.8 (ArC), 171.6 (CO); m/z (EI+)
349.1673 (<1%, M+, C22H23NO3 requires 349.1678), 334 (55), 273
(30), 236 (100), 221 (95), 205 (60), 178 (50), 114 (85).
tion using CH2Cl2; [a]D = +9 (c 1, CHCl3); mp 180 °C; mmax (film)/
cmꢀ1 3312, 1658, 1454; 1H NMR (400 MHz; CDCl3) dH 1.89 (3H,
d, J 6.4, CH3), 2.83 (1H, ddd, J 10.2, 7.8 and 2.5, HOCHCH), 3.52
(1H, d, J 10.2, COCHCH), 3.73 (3H, s, OCH3), 4.02 (1H, d, J 14.9,
1 ꢁ ArCH2), 4.37 (1H, d, J 14.9, 1 ꢁ ArCH2), 4.62 (1H, d, J 2.5,
10-H), 5.04 (1H, d, J 7.8, CHOH), 5.48 (1H, q, J 6.4, CHCH3), 6.60–
6.67 (2H, m, ArCH), 7.10–7.39 (10H, m, ArCH), 7.89 (1H, d, J 7.1,
ArCH); 13C NMR (100 MHz; CDCl3) dC 17.2 (CH3), 44.9 (CH), 44.8
(CH2), 44.9 (CH), 48.8 (CH), 54.9 (9-C), 57.2 (OCH3), 73.8 (CHOCH3),
83.9 (CHOH), 123.3 (ArCH), 124.3 (ArCH), 125.1 (ArCH), 125.6
(ArCH), 126.0 (ArCH), 126.3 (ArCH), 126.8 (ArCH), 126.9 (ArCH),
127.0 (2 ꢁ ArCH), 127.1 (ArCH), 128.4 (2 ꢁ ArCH), 137.2 (ArC),
140.3 (ArC), 141.3 (ArC), 141.5 (ArC), 144.1 (ArC), 171.8 (CO); m/z
(EI+) 466 (21%), 425.1997 (<1%, M+, C28H27NO3 requires
425.1991), 407 (32), 392 (22), 349 (36), 246 (25), 236 (83), 221
(76), 205 (53), 190 (47), 91 (100).
4.2.5. (3S,3aS,9aS)-9-[(1S)-1-Methoxyethyl]-2,3,3a,4,9,9a-
hexahydro-3-hydroxy-2-[N-40-methoxyphenyl]-4,9 [10,20]-
benzeno-1H-benz[f]isoindol-1-one 5b
The hydroxy-lactam 5b was obtained as white solid (89%) using
general procedure A. The crude material was purified by recrystal-
4.2.8. General procedure B for the addition of furan to hydroxy-
lactams 5a–d
At first, BF3ꢂOEt (2.0 cm3, 15 mmol) was added dropwise to a
solution of hydroxy-lactam (5.0 mmol) and furan (1.7 cm3,
25.0 mmol) in THF (20 cm3) at 0 °C under a nitrogen atmosphere.
After 24 h, the reaction was quenched by the addition of saturated
aqueous NH4Cl (5 cm3) and water (5 cm3). The mixture was ex-
tracted with CHCl2 (3 ꢁ 15 cm3) and the combined organic layers
dried with MgSO4. Filtration and evaporation yielded a residue of
the crude material that was purified by flash column chromatogra-
phy on silica gel using EtOAc/petroleum ether 40–60.
lization using CH2Cl2; [
a]
D = ꢀ44 (c 1, CHCl3); mp 190–200 °C; mmax
(film)/cmꢀ1 3424, 1751, 1692; 1H NMR (400 MHz; CDCl3) dH 1.89
(3H, J 6.4, CH3), 2.37 (3H, d, J 10.8, OH), 2.96 (1H, ddd, J 10.0, 8.0
and 2.4, HOCHCH), 3.63 (1H, d, J 10.0, COCHCH), 3.70 (3H, s,
OCH3), 3.75 (3H, s, OCH3), 4.76 (1H, d, J 2.4, 10-H), 5.47–5.59 (2H,
m, CHOH and CH3CH), 6.63 [2H, (AX)2, 2 ꢁ ArCH], 6.79 [2H, (AX)2,
2 ꢁ ArCH], 7.16–7.17 (2H, m, ArCH), 7.27–7.29 (2H, m, ArCH),
7.30–7.37 (2H, m, ArCH), 7.44–7.46 (1H, m, ArCH), 7.90–7.92 (1H,
m, ArCH); 13C NMR (100 MHz; CDCl3) dC 17.0 (CH3), 44.0 (CH),
44.9 (CH), 48.8 (CH), 55.2 (9-C), 55.4 (OCH3), 57.3 (OCH3), 73.8
(CHOCH3), 83.2 (CHOH), 114.3 (2 ꢁ ArCH), 123.4 (ArCH), 124.7
(ArCH), 124.9 (ArCH), 125.7 (ArCH), 126.0 (ArCH), 126.2 (ArCH),
126.7 (ArCH), 126.8 (ArCH), 126.9 (2 ꢁ ArCH), 128.4 (ArC), 140.0
(ArC), 141.2 (ArC), 141.3 (ArC), 144.0 (ArC), 158.3 (ArCO), 171.2
(CO); m/z (EI+) 441.1950 (4%, M+, C28H27NO4 requires 441.1940),
426 (10), 236 (57), 221 (85), 206 (100), 178 (37).
4.2.9. (3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxy-
ethyl]-3-(2-furanyl)-2-methyl-4,9-[10,20]benzeno-1H-benz[f]iso-
indol-1-one 6a
The title compound 6a was obtained in 89% yield using general
procedure B with hydroxy-lactam 5a; [a]D = +59 (c 1, CHCl3); mp
153 °C; mmax (film)/cmꢀ1 3045, 2938, 2821, 1680, 1468; 1H NMR
(400 MHz; CDCl3) dH 1.88 (3H, J 6.4, CH3), 2.20 (3H, s, NCH3), 2.80
(1H, dt, J 9.8, and 2.8, COCHCH), 3.63 (1H, d, J 9.8, COCH), 3.79
(3H, s, COCH3), 3.89 (1H, d, J 2.8, NCH), 4.28 (1H, d, J 2.8, 10-H),
5.50 (1H, q, J 6.4, CHOCH3), 6.21 (1H, d, J 3.2, ArCH), 6.30–6.32
(1H, m, ArCH), 7.19–7.24 (4H, m, ArCH), 7.31–7.40 (3H, m, ArCH),
7.41–7.43 (1H, m, ArCH), 7.92–7.94 (1H, m, ArCH); 13C NMR
(100 MHz; CDCl3) dC 17.0 (CH3), 27.4 (NCH3), 45.0 (CH), 48.0
(CH), 49.1 (CH), 54.7 (9-C), 57.3 (OCH3), 59.8 (CH), 73.4 (CHOCH3),
4.2.6. (3S,3aS,9aS)-9-[(1S)-1-Methoxyethyl]-2,3,3a,4,9,9a-
hexahydro-3-hydroxy-2-[N-40-methoxyphenylmethyl]-4,9
[10,20]-benzeno-1H-benz[f]isoindol-1-one 5c
The hydroxy-lactam 5c was obtained as a white solid (98%)
using general procedure A. The crude was purified by recrystalliza-
tion using CH2Cl2; [a]D = +8 (c 1, CHCl3); mp 180 °C; mmax (film)/

S. A. Hasbullah, S. Jones / Tetrahedron: Asymmetry 21 (2010) 2719–2725
2723
107.6 (CH), 110.3 (CH), 123.4 (ArCH), 124.1 (ArCH), 124.9 (ArCH),
125.6 (ArCH), 125.9 (ArCH), 126.0 (ArCH), 126.4 (ArCH), 126.9
(ArCH), 139.2 (ArC), 139.9 (ArC), 140.3 (ArC), 142.9 (ArCH), 143.6
(ArC), 153.3 (ArC), 172.4 (CO); m/z (EI+) 399.1852 (4%, M+,
d, J 7.6, ArCH); 13C NMR (100 MHz; CDCl3) dC 17.3 (CH3), 43.8 (CH2),
44.9 (CH), 48.2 (CH), 48.7 (CH), 54.6 (9-C), 56.4 (OCH3), 57.2 (CH),
73.5 (CHOCH3), 108.8 (ArCH), 110.2 (ArCH), 123.4 (ArC), 124.2
(ArC), 125.4 (ArC), 125.5 (ArC), 125.9 (ArC), 126.3 (ArC), 126.4
(ArC), 126.8 (ArC), 126.9 (ArC), 127.8 (2 ꢁ ArCH), 128.3 (2 ꢁ ArCH),
135.1 (ArC), 139.6 (ArC), 140.3 (ArC), 140.6 (ArC), 143.1 (ArCH),
144.1 (ArC), 152.5 (ArC), 172.5 (CO); m/z (TOF ES+) 476.2247
(100%, MH+, C32H30NO3 requires 476.2226), 462 (40).
C26H25NO3 requires 399.1852), 384 (20), 236 (80), 221 (43), 205
(20), 178 (16), 164 (100).
4.2.10. (3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro 4-[(1S)-1-methoxy-
ethyl]-3-(2-furanyl)-2-(N-40-methoxyphenyl)-4,9[10,20]benzeno-
1H-benz[f]isoindol-1-one 6b
4.2.13. General procedure C for the oxidation and esterification
of lactams 6a–d
The title compound 6b was obtained in 85% yield using general
At first, RuCl3ꢂH2O (0.002 g, 0.01 mmol) was added to a solution
of NaIO4 (3.0 g, 14 mmol) in EtOAc (8.0 cm3), hexane (8 cm3) and
H2O (4.0 cm3). After 10 min, lactam 6a–d (2.0 mmol) was added.
The resultant mixture was stirred at rt for 45 min and then
quenched with brine (10 cm3). The aqueous phase was extracted
with EtOAc (3 ꢁ 15 cm3) and the combined organic phases washed
with brine (3 ꢁ 10 cm3), dried over MgSO4 and concentrated. The
crude material was taken up in toluene/MeOH (9 cm3, 1:3) and ex-
cess TMSCHN2 (approximately 0.1 cm3) was added until the yellow
colour just persisted. The reaction was stirred for 1 h and solvents
were removed. Purification of the crude material was carried out
by flash column chromatography on silica gel using EtOAc/petro-
leum ether 40–60.
procedure B with hydroxy-lactam 5b; [a]D = +8 (c 1, CHCl3); mp
141 °C; mmax (film)/cmꢀ1 3359, 2934, 2834, 1660, 1513; 1H NMR
(400 MHz; CDCl3) dH 1.88 (3H, d, J 6.4, CH3), 2.92 (1H, dt, J 9.6
and 2.7, COCHCH), 3.70 (3H, s, OCH3), 3.74 (3H, s, OCH3), 3.79
(1H, d, J 9.6, COCH), 4.21 (1H, d, J 2.7, NCH), 4.34 (1H, d, J 2.7,
10-H), 5.48 (1H, q, J 6.4, CHCH3), 6.08–6.12 (3H, m, ArCH), 6.25–
6.27 (1H, m, ArCH), 6.62–6.66 (2H, m, ArCH), 7.14–7.22 (2H, m,
ArCH), 7.30–7.36 (4H, m, ArCH), 7.49–7.51 (1H, m, ArCH), 7.95–
7.98 (1H, m, ArCH); 13C NMR (100 MHz; CDCl3) dC 17.0 (CH3),
45.1 (CH), 48.3 (CH), 49.2 (CH), 55.0 (9-C), 55.3 (CH), 57.3 (OCH3),
61.4 (CH), 73.3 (CHOCH3), 108.2 (ArCH), 110.3 (ArCH), 114.1
(2 ꢁ ArCH), 123.5 (ArCH), 124.4 (ArCH), 125.2 (ArCH), 125.7 (ArCH),
126.0 (ArCH), 126.1 (ArCH), 126.5 (ArCH), 126.9 (ArCH), 127.6
(2 ꢁ ArCH), 130.0 (ArC), 139.6 (ArC), 139.8 (ArC), 140.6 (ArC),
142.7 (ArCH), 143.5 (ArC), 153.5 (ArC), 158.4 (ArC), 172.7 (CO);
m/z (EI+) 491.2103 (30%, M+, C32H29NO4 requires 491.2097), 256
(100), 236 (50), 221 (62), 205 (26), 178 (20).
4.2.14. (3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxy-
ethyl]-2-methyl-4,9-[10,20]benzeno-1H-benz[f]isoindol-1-one-3-
carboxylic acid methyl ester 8a
Oxidation of lactam 6a using general procedure C gave the title
compound 8a in good yield (80%); [a]D = +21 (c 1, CHCl3); mp
4.2.11. (3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro 4-[(1S)-1-methoxy-
ethyl]-3-(2-furanyl)-2-(N-40-methoxyphenylmethyl)-4,9[10,20]-
benzeno-1H-benz[f]isoindol-1-one 6c
The title compound 6c was obtained in 88% yield using general
procedure B with hydroxy-lactam 5c; [a]D = +8 (c 1, CHCl3); mp
200 °C; mmax (film)/cmꢀ1 2929, 1750, 1677; 1H NMR (400 MHz;
CDCl3) dH 1.85 (3H, d, J 6.4, CH3), 2.31 (3H, s, NCH3), 2.65 (1H, dt,
J 9.8 and 2.7, COCHCH), 3.45–3.48 (2H, m, COCH and NCH), 3.73
(3H, s, OCH3), 3.74 (3H, s, OCH3), 4.32 (1H, d, J 2.7, 10-H), 5.40
(1H, q, J 6.4, CH3CH), 7.15–7.25 (5H, m, ArCH), 7.33–7.37 (2H, m,
ArCH), 7.88–7.92 (1H, m, ArCH); 13C NMR (100 MHz; CDCl3) dC
16.9 (CH3), 28.4 (NCH3), 43.2 (CH), 47.5 (CH), 49.4 (CH), 52.5
(CH), 54.6 (9-C), 57.2 (OCH3), 64.0 (OCH3), 73.2 (CHOCH3), 123.6
(ArCH), 124.1 (ArCH), 124.9 (ArCH), 125.7 (ArCH), 126.0 (ArCH),
126.1 (ArCH), 126.5 (ArCH), 126.9 (ArCH), 138.7 (ArC), 139.7
(ArC), 140.0 (ArC), 143.2 (ArC), 172.1 (CO), 172.8 (CO); m/z (EI+)
391.1796 (<1%, M+, C24H25NO4 requires 391.1784), 376 (25), 332
(8), 274 (12), 236 (100), 221 (82), 205 (35), 178 (34), 156 (87),
124 (20), 96 (47).
198–200 °C; mmax (film)/cmꢀ1 2935, 1679, 1612, 1513; 1H NMR
(400 MHz; CDCl3) dH 1.93 (3H, J 6.4, CH3), 2.84 (1H, dt, J 10.3 and
3.1, COCHCH), 3.05 (1H, d, J 14.9, 1 ꢁ ArCH2), 3.78–3.85 [8H, m,
2 ꢁ (OCH3), COCH and NCH], 4.16 (1H, d, J 2.7, 10-H), 4.72 (1H, d,
J 14.9, 1 ꢁ ArCH2), 5.56 (1H, q, J 6.4, CH3CH), 6.15 (1H, d, J 3.2,
ArCH), 6.20 (2H, d, J 8.6, ArCH), 6.33 (1H, dd, J 3.2 and 2.0, ArCH),
6.69 (2H, d, J 8.6, ArCH), 7.10–7.41 (8H, m, ArCH), 7.93 (2H, d, J
7.6, ArCH); 13C NMR (100 MHz; CDCl3) dC 17.3 (CH3), 43.2 (CH2),
44.8 (CH), 48.2 (CH), 48.7 (CH), 54.6 (9-C), 55.3 (OCH3), 56.3 (CH),
57.2 (CH), 73.5 (CHOCH3), 108.6 (ArCH), 110.2 (ArCH), 113.7
(2 ꢁ ArCH), 123.4 (ArCH), 124.2 (ArCH), 125.4 (ArCH), 125.5 (ArCH),
125.8 (ArCH), 126.2 (ArCH), 126.3 (ArCH), 126.8 (ArCH), 127.1
(ArC), 129.1 (2 ꢁ ArCH), 139.6 (ArC), 140.3 (ArC), 140.6 (ArC),
143.0 (ArCH), 144.1 (ArC), 152.6 (ArC), 158.5 (ArC), 172.3 (CO);
m/z (EI+) 505.2275 (45%, M+, C33H31NO4 requires 505.2253), 490
(40), 270 (72), 236 (55), 221 (50), 205 (32), 178 (22), 162 (52),
134 (55), 121 (100).
4.2.15. (3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxy-
ethyl]-2-(N-40-methoxyphenyl)-4,9-[10,20]benzeno-1H-benz[f]-
isoindol-1-one-3-carboxylic acid methyl ester 8b
Oxidation of lactam 6b using general procedure C gave the title
compound 8b in good yield (78%); [a]D = +13 (c 1, CHCl3); mp
141 °C; mmax (film)/cmꢀ1 2936, 1749, 1693, 1512; 1H NMR
(400 MHz; CDCl3) dH 1.85 (3H, d, J 6.4, CH3), 2.73 (1H, dt, J 9.8
and 2.9, COCHCH), 3.65 (1H, d, J 9.8, COCH), 3.70 (3H, s, OCH3),
3.72 (3H, s, OCH3), 3.74 (3H, s, OCH3), 3.92 (1H, d, J 2.9, NCH),
4.42 (1H, d, J 2.9, 10-H), 5.40 (1H, q, J 6.4, CH3CH), 6.47 (2H, d, J
9.0, ArCH), 6.72 (2H, d, J 9.0, ArCH), 7.27–7.39 (6H, m, ArCH),
7.48 (1H, d, J 6.1, ArCH), 7.93–7.95 (1H, m, ArCH); 13C NMR
(100 MHz; CDCl3) dC 16.9 (CH3), 43.4 (CH), 48.0 (CH), 49.5 (CH),
52.5 (CH), 54.9 (9-C), 55.4 (OCH3), 57.2 (OCH3), 65.5 (CH), 73.1
(CHOCH3), 114.2 (2 ꢁ ArCH), 123.6 (ArCH), 124.5 (ArCH), 125.1
(ArCH), 125.9 (ArCH), 126.1 (ArCH), 126.2 (ArCH), 126.8 (ArCH),
126.9 (2 ꢁ ArCH), 127.0 (ArCH), 130.1 (ArC), 139.1 (ArC), 139.7
(ArC), 140.3 (ArC), 143.1 (ArC), 158.5 (ArC), 172.4 (CO), 172.9
(CO); m/z (EI+) 483.2052 (15%, M+, C30H29NO5 requires 483.2046),
468 (5), 248 (100), 236 (65), 221 (65), 188 (47), 178 (25).
4.2.12. (3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxy-
ethyl]-2-(N-phenylmethyl)-3-(2-furanyl)-2-methyl-4,9[10,20]benz-
eno-1H-benz[f]isoindol-1-one 6d
The title compound 6d was obtained in 81% yield using general
procedure B with hydroxy-lactam 5d; [a]D = +21 (c 1, CHCl3); mp
153 °C; mmax (film)/cmꢀ1 2939, 1655, 1448; 1H NMR (400 MHz;
CDCl3) dH 1.93 (3H, d, J 6.4, CH3), 2.86 (1H, dt, J 10.6 and 3.0,
COCHCH), 3.03 (1H, d, J 14.9, 1 ꢁ ArCH2), 3.80 (1H, d, J 10.6, COCH),
3.82 (3H, s, OCH3), 3.86 (1H, d, J 3.0, NCH), 4.17 (1H, d, J 3.0, 10-H),
4.77 (1H, d, J 14.9, 1 ꢁ ArCH2), 5.56 (1H, q, J 6.4, CH3CH), 6.14 (1H,
d, J 3.2, ArCH), 6.22 (2H, d, J 7.4, ArCH), 6.33 (1H, dd, J 3.2 and 2.0,
ArCH), 7.10–7.37 (10H, m, ArCH), 7.40 (1H, d, J 7.4, ArCH), 7.91 (1H,

2724
S. A. Hasbullah, S. Jones / Tetrahedron: Asymmetry 21 (2010) 2719–2725
4.2.16. (3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxy-
ethyl]-2-(N-40-methoxyphenylmethyl)-4,9-[10,20]benzeno-1H-
benz[f]isoindol-1-one-3-carboxylic acid methyl ester 8c
Oxidation of lactam 6c using general procedure C gave the title
gas at 14 psi, tR 11.94 min and 13.04 min. 1H NMR data was in
accordance with the literature.
4.2.20. (S)-1-(4-Methoxyphenyl)-5-oxo-proline methyl ester
10b11
compound 8c in good yield (71%); [a]D = +10 (c 1, CHCl3); mp
180–200 °C; mmax (film)/cmꢀ1 2932, 1744, 1688, 1611; 1H NMR
(400 MHz; CDCl3) dH 1.88 (3H, d, J 6.4, CH3), 2.62 (1H, dt, J 10.3
and 3.0, COCHCH), 3.37 (1H, d, J 3.0, NCH), 3.53 (1H, d, J 14.9,
1 ꢁ ArCH2), 3.59 (1H, d, J 10.3, COCH), 3.71 (3H, s, OCH3), 3.76
(3H, s, OCH3), 3.82 (3H, s, OCH3), 4.21 (1H, d, J 3.0, CHN), 4.69
(1H, d, J 14.9, 1 ꢁ ArCH2), 5.47 (1H, q, J 6.4, CH3CH), 6.26 (2H, d, J
8.0, 2 ꢁ ArCH), 6.67 (2H, d, J 8.0, 2 ꢁ ArCH), 7.12–7.20 (4H, m,
ArCH), 7.28–7.34 (3H, m, ArCH), 7.87 (1H, d, J 7.2, ArCH); 13C
NMR (100 MHz; CDCl3) dC 17.1 (CH3), 43.3 (CH), 44.4 (CH2), 47.8
(CH), 49.1 (CH), 52.4 (CH), 54.5 (9-C), 55.3 (OCH3), 57.2 (OCH3),
60.6 (CH), 73.3 (CHOCH3), 113.8 (2 ꢁ ArCH), 123.5 (ArCH), 124.2
(ArCH), 125.3 (ArCH), 125.7 (ArCH), 125.9 (ArCH), 126.4 (2 ꢁ ArC),
125.5 (ArCH), 126.9 (ArCH), 129.4 (2 ꢁ ArCH), 139.1 (ArC), 140.1
(ArC), 140.3 (ArC), 143.6 (ArC), 143.1 (ArC), 143.6 (ArC), 158.8
(ArC), 172.1 (CO), 172.6 (CO); m/z (TOF EI+) 498.2281 (100%, MH+,
Using general procedure D, the desired product 10b was ob-
tained in low yield (32%); [
a]
D = ꢀ6 (c 0.8, CHCl3, ee 23%); 1H
NMR (400 MHz; CDCl3) dH 2.16–2.24 (1H, m, 1 ꢁ CH2), 2.48–2.62
(2H, m, CH2), 2.70–2.80 (1H, m, 1 ꢁ CH2), 3.74 (3H, s, OCH3), 3.82
(3H, s, OCH3), 4.68 (1H, dd, J 8.8 and 3.0, CHN), 6.91 [2H, (AX)2,
2 ꢁ ArCH], 7.35 [2H, (AX)2, 2 ꢁ ArCH]; 13C NMR (100 MHz; CDCl3)
dC 23.3 (CH2), 30.5 (CH2), 52.6 (OCH3), 55.4 (OCH3), 62.3 (CHN),
114.4 (2 ꢁ ArCH), 124.4 (2 ꢁ ArCH), 130.9 (ArC), 157.6 (ArC),
172.4 (CO), 174.4 (CO); Chiral HPLC: Phenomenex Lux Cellulose
1, 20% IPA in hexane @ 1 mL/min, tR 18.4 min (major) and
19.9 min (minor). 1H NMR was in accordance with the literature.
Previously reported in racemic form.
4.2.21. ( )-l-(4-Methoxybenzyl)-5-oxo-proline methyl ester
10c12
C31H32NO5 requires 498.2280), 470 (50).
Using general procedure D, the desired product 10b was ob-
tained in low yield (23%); 1H NMR (400 MHz; CDCl3) dH 2.07 (1H,
ddt, J 13.2, 9.4 and 3.2, 1 ꢁ CHCH2), 2.25 (1H, dq, J 13.2 and 9.4,
1 ꢁ CHCH2), 2.42 (1H, ddd, J 16.9, 9.4 and 3.2, 1 ꢁ COCH2), 2.54–
2.66 (1H, m, 1 ꢁ COCH2), 3.71 (3H, s, OCH3), 3.81 (3H, s, OCH3),
3.96 (1H, d, J 14.4, 1 ꢁ ArCH2), 3.98 (1H, dd, J 9.1 and 3.2, CHN),
3.98–4.01 (1H, m, NCOCHH), 4.96 (1H, d, J 14.4, 1 ꢁ ArCH2), 6.86
(2H, d, J 8.6, 2 ꢁ ArCH), 7.15 (2H, d, J 8.6, 2 ꢁ ArCH); 13C NMR
(100 MHz; CDCl3) dC 22.8 (CH2), 29.7 (CH2), 45.0 (CH2), 52.4
(OCH3), 55.3 (OCH3), 58.7 (CH), 114.1 (2 ꢁ ArCH), 127.8 (ArC),
129.9 (2 ꢁ ArCH), 159.2 (ArC), 171.5 (CO), 174.9 (CO); Chiral HPLC:
Phenomenex Lux Cellulose 2, 5% IPA in hexane @ 1 mL/min, tR
6.9 min and 10.1 min. NMR was in general accordance with the lit-
erature. An additional un-assignable signal at d 1.25 ppm was re-
ported in the literature 1H NMR data.12
4.2.17. (3aS,9aS,3S)-2,3,3a,4,9,9a-Hexahydro-4-[(1S)-1-methoxy-
ethyl]-2-(N-phenylmethyl)-4,9-[10,20]benzeno-1H-benz[f]isoindol-
1-one-3-carboxylic acid methyl ester 8d
Oxidation of lactam 6d using general procedure C gave the title
compound 8d in good yield (74%); [a]D = +2 (c 1, CHCl3); mp
190 °C; mmax (film)/cmꢀ1 2936, 1745, 1687; 1H NMR (400 MHz;
CDCl3) dH 1.90 (3H, d, J 6.4, CH3), 2.67 (1H, dt, J 10.3 and 3.1,
COCHCH), 3.42 (1H, d, J 3.1, NCH), 3.62 (1H, d, J 10.3, COCH), 3.64
(1H, d, J 14.9, 1 ꢁ ArCH2), 3.72 (3H, s, OCH3), 3.79 (3H, s, OCH3),
4.24 (1H, d, J 3.1, CHN), 4.81 (1H, d, J 14.9, 1 ꢁ ArCH2), 5.49 (1H,
q, J 6.4, CH3CH), 6.32 (2H, d, J 6.5, 2 ꢁ ArCH), 7.12–7.39 (10H, m,
ArCH), 7.90 (1H, d, J 6.9, ArCH); 13C NMR (100 MHz; CDCl3) dC
17.2 (CH3), 43.4 (CH), 45.0 (CH2), 47.7 (CH), 49.1 (CH), 52.5 (CH),
54.5 (9-C), 55.3 (OCH3), 57.2 (OCH3), 60.7 (CH), 73.3 (CHOCH3),
123.5 (ArCH), 124.2 (ArCH), 125.4 (ArCH), 126.2 (ArCH), 126.4
(ArCH), 126.6 (ArCH), 126.8 (ArCH), 126.9 (ArCH), 127.3 (ArCH),
128.0 (2 ꢁ ArCH), 128.5 (2 ꢁ ArCH), 134.5 (ArC), 139.1 (ArC),
140.1 (ArC), 140.3 (ArC), 143.6 (ArC), 172.0 (CO), 172.8 (CO); m/z
(EI+) 467.2102 (<1% M+, C30H29NO4 requires 467.2097), 452 (35),
350 (10), 236 (90), 232 (100), 221 (70), 205 (35), 178 (30), 172
(25), 91 (100).
4.2.22. ( )-l-Benzyl-5-oxo-proline methyl ester 10d13
Using general procedure D, the desired product 10d was ob-
tained in low yield (26%); 1H NMR (400 MHz; CDCl3) dH 2.10 (1H,
ddt, J 13.2, 9.5 and 3.5, 1 ꢁ CHCH2), 2.27 (1H, dq, J 13.2 and 9.5,
1 ꢁ CHCH2), 2.45 (1H, ddd, J 16.9, 9.5 and 3.5, 1 ꢁ COCH2), 3.22–
3.29 (1H, m, 1 ꢁ COCH2), 3.70 (3H, s, OCH3), 4.00 (1H, dd, J 9.5
and 3.5, CHN), 4.02 (1H, d, J 14.8, 1 ꢁ ArCH2), 5.04 (1H, d, J 14.8,
1 ꢁ ArCH2), 7.22 (2H, d, J 6.4, 2 ꢁ ArCH), 7.32–7.38 (3H, m,
3 ꢁ ArCH); 13C NMR (100 MHz; CDCl3) dC 22.8 (CH2), 29.5 (CH2),
45.6 (CH2), 52.4 (OCH3), 58.7 (CH), 127.8 (ArCH), 128.5 (2 ꢁ ArCH),
128.7 (2 ꢁ ArCH), 134.1 (ArC), 172.3 (CO), 175.0 (CO); Chiral HPLC:
Phenomenex Lux Cellulose 1, 5% IPA in hexane @ 1 mL/min, tR
9.65 min and 11.48 min. 1H NMR was in accordance with the
literature.
4.2.18. General procedure D for flash vacuum pyrolysis (FVP)
A 50 cm quartz thermolysis tube was connected with ‘O’-ring
joints to a 25 cm3 flask containing the carboxy-lactam 8a–d, and
the other end to a cold trap. The thermolysis tube was heated at
500–550 °C under vacuum (0.05–0.01 mm/Hg) and the lactam
was heated to 180–210 °C until no more cycloadduct was observed
(15–30 min). The system was cooled to room temperature, the vac-
uum released and the residue in the trap was immediately treated
with 10% Pd/C and H2 gas (balloon) in MeOH (10 cm3). The reaction
was stirred at rt for 24 h, filtered through Celite and the solvent
was removed.
Acknowledgments
We would like to thank the Ministry of Higher Education of
Malaysia and the National University of Malaysia for financial
support.
4.2.19. ( )-1-Methyl-5-oxo-proline methyl ester 10a10
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Using general procedure D, the desired product 10a was
obtained in low yield (21%); 1H NMR (400 MHz; CDCl3) dH 2.05–
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