Synthesis of quaternary stereogenic centres via stereoselective intermolecular Friedel-Crafts reactions

Article abstract of DOI:10.1039/c1ob05129f

Highly stereoselective Friedel-Crafts reactions have been performed using a chiral anthracene template to control the selectivity of the reaction. In the case of additions to fully substituted N-acyliminium ions, competitive elimination and condensation r

Full text of DOI:10.1039/c1ob05129f

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PAPER
Synthesis of quaternary stereogenic centres via stereoselective intermolecular
Friedel–Crafts reactions†
Jennifer C. Ball,a Robert Gleaveb and Simon Jones*a
Received 24th January 2011, Accepted 22nd March 2011
DOI: 10.1039/c1ob05129f
Highly stereoselective Friedel–Crafts reactions have been performed using a chiral anthracene template
to control the selectivity of the reaction. In the case of additions to fully substituted N-acyliminium
ions, competitive elimination and condensation reactions were observed. Retro-Diels–Alder reaction of
one of the reaction products led to a precursor that could be used for the construction of pyroglutamic
acids bearing quaternary stereogenic centres.
Introduction
Results & Discussion
In recent years, chiral anthracenes have been shown to undergo
highly diastereoselective Diels–Alder cycloadditions with a range
of dienophiles such as N-methylmaleimide and maleic anhydride,1
and more recently p-benzoquinone.2 These cycloadducts are then
able to undergo further transformations utilising the anthracene
template to control the stereoselectivity, followed by a retro-Diels–
Alder reaction to liberate a product with high enantiopurity. In
2005, Snyder et al. demonstrated the addition of allyltrimethyl-
silane to fully substituted N-acyliminium ions derived from
maleimide cycloadducts to form quaternary stereocentres used for
the synthesis of bicyclic alkaloidal systems.1f However, attempts
to add other carbon nucleophiles, such as Grignard reagents,
to these species led to deprotonation and formation of N-
acyl enamines. It was therefore surmised that a non-basic C–
C bond process, such as a Friedel–Crafts reaction, may give
superior results. Intra-molecular variants of this process have been
previously reported,3 and recent work from our own laboratory
has used this strategy with chiral anthracene templates.1a Several
reports have detailed the stereoselective inter-molecular Friedel–
Crafts reaction of un-substituted N-acyl iminium ions leading
to products with tertiary stereogenic centres using chiral pool4 or
catalytic methods.5 However, there are fewer reports of performing
an inter-molecular reaction that would lead to products bearing
quaternary stereogenic centres.6 Having recently established a
strategy to construct pyroglutamic acids using an inter-molecular
Friedel–Crafts reaction of un-substituted N-acyliminium ions
with furan,7 we now report our findings of the generality of this
process and application to the synthesis of quaternary stereogenic
centres.
Hydroxy-lactam 1 was prepared in 2 steps from (R)-9-
(methoxyethyl)anthracene as previously reported.1a Treatment of
this with TFA and an aromatic nucleophile led to formation of
a single diastereoisomer in nearly every case studied (Scheme
1, Table 1). The identity of these isomers was confirmed by the
small coupling constant of the proton of the tertiary stereocentre
(around J ª 3), that correlates with the modelled dihedral
angle and coupling constant for this isomer (135◦ and 6.0 Hz,
respectively).8 The modelled dihedral angle of the other isomer
(27◦) would have resulted in a larger coupling constant (J ª 9.6 Hz).
This data is therefore in-line with previous studies and confirms
that the nucleophile attacks the Si face of the N-acyliminium ion
(Fig. 1).
Scheme 1 Reagents and conditions: i. TFA, ArCH, CH2Cl2.
1,3,5-Trimethylbenzene did not react under these conditions,
but TiCl4 provided the desired product in moderate yield (Table
1, entry 5). Addition of 2-ethoxythiazole gave the somewhat
unexpected result of an O-aryl product (Table 1, entry 6). Under
the acidic conditions of the reaction, the 2-ethoxy thiazole is most
likely protonated (pKaH ~ 2.5), rendering this extremely electron
deficient. Under equilibrating conditions, the more thermodynam-
ically stable (S)-configured hydroxy-lactam is formed which then
undergoes nucleophilic attack at the 2-position of a thiazolium
intermediate (Scheme 2). Attempts to extend this chemistry to
other related heterocyclic aromatics such as 2-methoxy-pyridines
or their N-oxides were unsuccessful both under Brønsted acid
aDepartment of Chemistry, University of Sheffield, Dainton Building, Brook
Hill, Sheffield, S3 7HF, UK. E-mail: simon.jones@sheffield.ac.uk; Tel: +44
(0)114 22 29483
bGlaxoSmithKline, New Frontiers Park, Third Avenue, Harlow, CM19 5AW,
UK
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra. See DOI: 10.1039/c1ob05129f
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Table 1 Friedel–Crafts reactions of hydroxy-lactam 1
Entry
1
Ar
Yield (%)
48
2
3
4
100
98
Fig. 1 Modelled dihedral angles and observed J values for product 2.
97
5
54a
6
7
68
59b
Scheme 3 Reagents and conditions. i. TFA, ArH, CH2Cl2, reflux 24 h.
a Reaction conditions: TiCl4 (2 eq), CH2Cl2, -78 ◦C. b Reaction yielded an
inseparable mixture of isomers.
Application of the Friedel–Crafts methodology described
above, gave good yields and selectivities for furan and in-
dole (Table 2, entries 1–3), but in the case of other aromatic
species, side-products were observed. Attempted addition of 1,2-
dimethoxybenzene to hydroxy-lactam 9 or 10 using TFA or
TiCl4 resulted in elimination product 16 and 17 being formed,
respectively. Re-subjecting this isolated product to the reaction
conditions did not lead to the desired product. Reaction of
hydroxy-lactams 9 and 10 with thiophene gave a 1 : 1 mixture of
desired products 14 and 15 and the unexpected (E)-trifluoroacetyl
products 18 and 19.11
conditions (TFA) and Lewis acid conditions (TiCl4). In these
cases, it is likely that they are too electron deficient to undergo
the Friedel–Crafts reaction, yet not sufficiently electrophilic to
perform nucleophilic aromatic substitution as in the case of the
thiazole. Addition of 2-methoxynaphthalene gave an inseparable
mixture of isomers (about 2 : 1 ratio) in good yield (Table 1, entry
7).9
This approach was extended to the Grignard addition adducts
9 and 10 where successful introduction of another carbon-carbon
bond would allow generation of a quaternary stereogenic centre
(Scheme 3).10 Hydroxy-lactam 9 was prepared as previously
reported,1a the N-allyl analogue 10 also being prepared by
application of the same procedure.
Presumably, the extended reaction times for this process must
generate small quantities of trifluoroacetic anhydride that can
then undergo condensation with the N-acyl-enamine. Similar
products have also been observed by Rashatasakhon and Padwa
in transformations of related hydroxy-lactams, although in their
study, the authors note that direct use of trifluoroacetic anhydride
Scheme 2 Proposed mechanism of formation of hydroxy-lactam 7.
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Table 2 Friedel–Crafts reactions of hydroxy-lactams 9 and 10
From this data, it appears that the formation of the N-acyl
enamine 16 is incredibly fast during this reaction as after one hour,
essentially all starting material has been consumed. Formation
of the desired Friedel–Crafts product 14 then slowly increases
with time, but at a very similar rate to the formation of the
trifluoroacetyl adduct 18. This implies that there is a limit to
the quantity of desired product that may be prepared under
these reaction conditions with less reactive aromatics, since the
competing formation of the trifluoroacetyl compound removes
starting material at approximately the same rate as that which
provides the product.
Component, yield (%)
Entry
1
R
Me
Ar
11–15
11, 100
16/17
0
18/19
0
2
3
Allyl
Allyl
12, 99
13, 98
0
0
0
0
In order to complete the cycle and free the chiral anthracene
template from the transformed product, a retro-Diels–Alder was
performed using flash vacuum pyrolysis (FVP). Recent work
within our group has found that if a substrate with a tertiary
stereocentre has an acidic proton in this position, racemisation
may occur in the product during the FVP process.1a,7 In order to
thus exemplify the process with a substrate bearing a quaternary
stereogenic centre, the retro-Diels–Alder reaction of cycloadduct
11 was carried out, providing substituted maleimide 20 in high
yield and ee, the latter confirmed by HPLC (Scheme 4). Auxiliary
21 was also regenerated in high yield with no loss in enantiopurity;
[a]2D2 -45 (c 1 in CHCl3 ee >99%) before Diels–Alder cycloaddition
and [a]2D2 -45 (c 1 in CHCl3) after FVP. This methodology is
particularly applicable for the preparation of enantiomerically
enriched substituted pyroglutamic acid analogues by application
of our previously reported methodology for the synthesis of
pyroglutamates by transforming the furan into a carboxylic acid
group.7 This still retains the alkene may that can be further
functionalised to prepare more complex derivatives.
4
Me
0
16, 80
0
5
6
Allyl
Me
0
17, 44
0
0
14, 50
18, 50
7
Allyl
15, 52
0
19, 48
Table 3 Formation of products as a function of time from reaction of
hydroxy-lactam 9 with thiophene
Product distribution (%)a
Entry
Time (h)
1
4
9
12
27
14
11
10
11
23
52
16
89
85
78
54
0
18
0
5
11
23
48
1
2
3
4
5
a Ratio’s obtained by integration of the appropriate signals in the 1H-NMR
spectrum of the crude reaction mixture.
to effect this transformation leads to a different by-product.12
To further investigate the formation of product 18, a study was
conducted to monitor the progress of the reaction of hydroxy-
lactam 9 with thiophene with time (Table 3 and Fig. 2).
Scheme 4 Reagents and conditions. i. FVP (180 ◦C inlet, 510 ◦C furnace,
0.02 mmHg).
Conclusions
We have reported a method to combine intermolecular Friedel–
Crafts reactions to N-acyliminium ions derived from maleimide
cycloadducts and a Diels–Alder/retro-Diels–Alder methodology
to prepare quaternary stereocentres in high yield and enan-
tiopurity. Further work into demonstrating the applicability to
preparing pyroglutamic acid analogues containing quaternary
stereocentres is now being undertaken.
Fig. 2 Graphical representation of data in Table 3.
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111.0 (ArCH), 119.3 (ArCH), 123.4 (ArCH), 124.1 (ArCH),
125.1 (ArCH), 125.5 (ArCH), 125.8 (ArCH), 125.9 (ArCH), 126.3
(ArCH), 126.7 (ArCH), 134.2 (ArC), 139.5 (ArC), 139.9 (ArC),
140.3 (ArC), 143.7 (ArC), 149.0 (ArC), 149.8 (ArC) and 172.6
(CO); m/z (EI) 469.2273 (M+. C30H31NO4 requires 469.2253), 454
(20%), 234 (100), 221 (40), 205 (25) and 178 (23).
Experimental
All solvents were obtained dry from a Grubbs dry solvent system.
When required, glassware was flame-dried and cooled under
vacuum. All other reagents were used as supplied without any
purification unless stated. Column chromatography was carried
out on Silica Gel 40–63u 60A (Fluorochem Ltd.) and thin layer
chromatography on Merck aluminium sheets coated with silica
(3aR,9aR,3R)-2,3,3a,4,9,9a-Hexahydro-4-[(1R)-1-methoxye-
thyl]-3-(2-furanyl)-2-methyl-4,9-[1¢,2¢]benzeno-1H -benz[f ]isoin-
dol-1-one 3. The title compound was prepared according to
general procedure A and purified by recrystallisation from
CH2Cl2/petroleum ether (40–60) to give a brown solid (114 mg,
100%); [a]2D2 -57.5 (c 1 in CHCl3); mp 152–154 ◦C; nmax(ATR)/cm-1
2936, 2821 and 1681; dH (400 MHz; CDCl3) 1.86 (3 H, d, J
6.4, CH3CH), 2.57 (3 H, s, NCH3), 2.75 (1H, dt, J 9.9 and 3.0,
COCHCH), 3.58 (1 H, d, J 9.9, COCHCH), 3.74 (3 H, s, OCH3),
3.84 (1 H, d, J 3.0, CH), 4.24 (1 H, d, J 3.0, CH), 5.45 (1 H, q,
J 6.4, CH3CH), 6.18 (1 H, d, J 3.1, ArCH), 6.29 (1 H, dd, J 3.1
and 1.9, ArCH), 7.04–7.41 (8 H, m, ArCH) and 7.87–7.92 (1H, m,
ArCH); dC (100 MHz; CDCl3) 17.0 (CH3CH), 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), 107.6 (ArCH), 110.2 (ArCH), 123.4 (ArCH),
124.1 (ArCH), 124.9 (ArCH), 125.6 (ArCH), 125.8 (ArCH), 125.9
(ArCH), 126.4 (ArCH), 126.8 (ArCH), 139.2 (ArC), 139.9 (ArC),
140.3 (ArC), 142.8 (ArCH), 143.6 (ArC), 153.3 (ArC) and 172.4
(CO); m/z (EI) 399.1846 (M+. C26H25NO3 requires 399.1834), 384
(27%), 236 (84), 221 (52), 205 (26), 178 (31), 164 (100) and 152 (7).
gel 60 F254.
1H NMR and 13C NMR spectra were measured
using CDCl3 as a solvent unless otherwise stated, on a Bruker
AC250 machine and an AC400 with automated sample changers.
Chemical shifts for carbon and hydrogen are given on the d scale
relative to TMS (tetramethylsilane, d = 0 ppm). J values are given
in Hz. 13C NMR spectra were recorded using the JMOD method.
Optical 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 10-1 deg cm2
g-1. Infrared spectra were recorded on a Perkin–Elmer 1600 FT-IR
machine using KBr discs. Low resolution mass spectra (m/z) were
recorded on Kratos MS 25 or MS 80 spectrometer supported by
DS 55 system, operating in EI, CI or FAB mode. High resolution
mass spectra (HRMS) recorded for accurate mass analysis, were
performed on either MicroMass LCT operating in Electrospray
mode (TOF ES); or a MicroMass Prospec operating in either
FAB, EI or CI mode. HPLC was carried out using a Spectra
Physics Analytical system (consisting of a P4000 pump, a UV2000
detector and using PC 1000 version 2.0 software). Compounds 1
and 9 were prepared by established literature methods.1a
(3aR,9aR,3R)-2,3,3a,4,9,9a-Hexahydro-4-[(1R)-1-methoxy-
ethyl]-3-(2-thienyl)-2-methyl-4,9-[1¢,2¢]benzeno-1H-benz[f ]isoin-
dol-1-one 4. The title compound was prepared according to
general procedure A. A viscous, colourless oil was obtained which
solidified upon standing to give a white solid (117 mg, 98%); [a]D22
-61.9 (c 1 in CHCl3); mp 216–217 ◦C; nmax(ATR)/cm-1 3044, 2979,
2939, 2820, 1681 and 1468; dH (400 MHz; CDCl3) 1.86 (3 H, d,
J 6.4, CH3CH), 2.17 (3 H, s, NCH3), 2.70 (1 H, dt, J 9.9 and
3.0, COCHCH), 3.60 (1 H, d, J 9.9, COCHCH), 3.75 (3 H, s,
OCH3), 4.03 (1 H, d, J 3.0, CH), 4.27 (1 H, d, J 3.0, CH), 5.47
(1 H, q, J 6.4, CH3CH), 6.89–6.96 (2 H, m, ArCH), 7.04–7.31
(7H, m, ArCH), 7.39–7.41 (1 H, m, ArCH) and 7.88 (1 H, d, J
7.5, ArCH); dC (100 MHz; CDCl3) 17.0 (CH3CH), 27.5 (NCH3),
47.8 (CH), 49.0 (2 ¥ CH), 54.7 (9-C), 57.3 (OCH3), 62.2 (CH),
73.4 (CHOCH3), 123.5 (ArCH), 124.1 (ArCH), 125.0 (ArCH),
125.3 (ArCH), 125.6 (ArCH), 125.7 (ArCH), 125.9 (ArCH), 126.0
(ArCH), 126.4 (ArCH), 126.8 (2 ¥ ArCH), 139.2 (ArC), 139.9
(ArC), 140.2 (ArC), 143.5 (ArC), 145.9 (ArC) and 172.1 (CO);
m/z (EI) 415.1592 (M+. C26H25NO232S requires 415.1606), 400
(17%), 236 (96), 221 (77), 205 (37), 180 (100), 178 (49) and 84 (16).
General procedure A for the synthesis of substituted malemide
cycloadducts via N-acyliminium ions
Trifluoroacetic acid (0.11 mL, 1.43 mmol) was added to a stirred
solution of hydroxy-lactam 1 (100 mg, 0.29 mmol) and aromatic
compound (0.57 mmol) in dichloromethane (2 mL) and heated to
reflux for 4 h. The reaction was followed by LCMS, cooled and
quenched with a saturated aqueous solution of Na2CO3 (5 mL),
extracted with CH2Cl2 (3 ¥ 5 mL), washed with brine (3 ¥ 5 mL)
and dried (Na2SO4). The solvent was removed to give the crude
material. Purification was carried out as detailed in individual
experiments.
(3aR,9aR,3R)-2,3,3a,4,9,9a-Hexahydro-4-[(1R)-1-methoxy-
ethyl]-3-(3,4-dimethoxyphenyl)-2-methyl-4,9-[1¢,2¢]benzeno-1H-
benz[f ]isoindol-1-one 2. The title compound was prepared ac-
cording to general procedure A and purified by recrystallisation
from CH2Cl2/petroleum ether (40–60) to give a white solid
(65 mg, 48%); [a]2D2 -67.6 (c 1 in CHCl3); mp 135 ◦C [from
CH2Cl2/petroleum ether (40–60)]; nmax(ATR)/cm-1 3058, 2937,
2835, 1674, 1594 and 1516; dH (400 MHz; CDCl3) 1.87 (3 H, d,
J 6.4, CH3CH), 2.12 (3 H, s, NCH3), 2.57 (1 H, dt, J 9.9 and
3.0, COCHCH), 3.61 (1 H, d, J 9.9, COCHCH), 3.65 (1 H, d,
J 3.0, NCH), 3.76 (3 H, s, OCH3), 3.82 (3 H, s, OCH3), 3.86
(3 H, s, OCH3), 4.25 (1 H, d, J 3.0, 10-H), 5.50 (1 H, q, J 6.4,
CH3CH), 6.52 (1 H, d, J 2.0, ArCH), 6.69–6.75 (1 H, m, ArCH),
6.77–6.83 (1 H, m, ArCH), 7.05–7.17 (2 H, m, ArCH), 7.18–
7.33 (4 H, m, ArCH), 7.42–7.44 (1 H, m, ArCH) and 7.87 (1
H, d, J 7.2, ArCH); dC (100 MHz; CDCl3) 17.0 (CH3CH), 27.5
(NCH3), 48.3 (CH), 48.5 (CH), 49.2 (CH), 54.7 (9-C), 56.0 (2 ¥
OCH3), 57.2 (OCH3), 67.0 (CH), 73.5 (CHOCH3), 108.6 (ArCH),
(3aR,9aR,3R)-2,3,3a,4,9,9a-Hexahydro-4-[(1R)-1-methoxy-
ethyl]-3-(3-indolyl)-2-methyl-4,9-[1¢,2¢]benzeno-1H-benz[f ]isoin-
dol-1-one 5. The title compound was prepared according to
general procedure A as a yellow solid (132 mg, 100%); [a]2D2 -56.6
(c 1 in CHCl3); mp >230 ◦C (decomp.); nmax(ATR)/cm-1 3450,
3059, 2929, 1660 and 1551; dH (400 MHz; CDCl3) 1.88 (3 H, d,
J 6.4, CH3CH), 2.16 (3 H, s, NCH3), 2.83 (1 H, dt, J 10.1 and
3.0, COCHCH), 3.70 (1 H, d, J 10.1, COCHCH), 3.80 (3 H, s,
OCH3), 4.02 (1 H, d, J 3.0, CH), 4.26 (1 H, d, J 3.0, CH), 5.53 (1
H, q, J 6.4, CH3CH), 7.02–7.15 (3 H, m, ArCH), 7.16–7.29 (5 H,
m, ArCH), 7.28–7.48 (4 H, m, ArCH), 7.89 (1 H, d, J 7.5, ArCH)
4356 | Org. Biomol. Chem., 2011, 9, 4353–4360
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and 8.12 (1 H, br s, NH); dC (100 MHz; CDCl3) 17.0 (CH3CH),
27.4 (NCH3), 47.2 (CH), 48.9 (CH), 49.2 (CH), 54.8 (9-C), 57.3
(OCH3), 59.7 (CH), 73.6 (CHOCH3), 111.4 (ArCH), 116.2 (ArC),
119.0 (ArCH), 120.2 (ArCH), 122.6 (ArCH), 122.8 (ArCH),
123.5 (ArCH), 124.1 (ArCH), 124.9 (ArC), 125.2 (ArCH), 125.5
(ArCH), 125.8 (ArCH), 125.9 (ArCH), 126.3 (ArCH), 126.6
(ArCH), 136.9 (ArC), 139.9 (ArC), 140.2 (ArC), 140.4 (ArC),
143.8 (ArC) and 172.2 (CO); m/z (EI) 448.2165 (M+. C30H28N2O2
requires 448.2151), 433 (23%), 236 (65), 221 (52), 213 (100), 205
(23), 178 (18) and 83 (23).
1H -benz[f ]isoindol-1-one and (3aR,9aR,3R)-2,3,3a,4,9,9a-hex-
ahydro-4-[(1R)-1-methoxyethyl]-3-(2-methoxy-3-naphthalenyl)-2-
methyl-4,9-[1¢,2¢]benzeno-1H-benz[f ]isoindol-1-one 8. The title
compound was prepared according to general procedure A.
Attempted purification by flash column chromatography (30%
ethyl acetate, 70% hexane followed by 50% ethyl acetate, 50%
hexane) gave an inseparable mixture of isomers as a pale yellow
oil in a 2 : 1 ratio (41 mg, 59%); nmax(ATR)/cm-1 3027, 2932, 1678,
1592 and 1515; dH (400 MHz; CDCl3) Major isomer: 2.04 (3 H,
s, NCH3), 2.93 (1 H, dt, J 10.0 and 3.0, COCHCH), 3.62 (1 H,
d, J 10.0, COCHCH), 3.82 (3 H, s, OCH3), 3.85 (3 H, s, OCH3),
4.26 (1 H, d, J 3.0, 10-H) and 4.86 (1 H, d, J 3.0, NCH); Minor
isomer: 2.12 (3 H, s, NCH3), 2.93 (1 H, ddd, J 10.5, 4.9 and 3.0,
COCHCH), 3.78–3.82 (1 H, m, COCH), 3.84 (3 H, s, OCH3),
4.12 (3 H, s, OCH3), 4.30 (1 H, d, J 3.0, 10-H) and 5.06 (1 H, d, J
4.9, NCH); Both isomers: 1.92 (3 H, d, J 6.4, CH3CH), 5.52–5.60
(1 H, m, CH3CH), 7.04–8.17 (14 H, m, ArCH); dC (100 MHz;
CDCl3) Major isomer: 17.2 (CH3CH), 27.0 (NCH3), 46.7 (CH),
49.5 (CH), 50.3 (CH), 54.7 (C-9), 56.3 (OCH3), 57.1 (OCH3),
58.4 (NCH), 73.7 (CHOCH3), 113.1 (ArCH), 119.9 (ArC), 144.0
(ArC), 156.0 (ArC) and 173.3 (CO); Minor isomer: 17.0 (CH3CH),
27.4 (NCH3), 46.4 (CH), 48.5 (CH), 49.7 (CH), 54.6 (C-9),
57.1 (OCH3), 57.2 (OCH3), 57.4 (NCH), 73.6 (CHOCH3), 113.2
(ArCH), 119.5 (ArC), 143.7 (ArC), 156.1 (ArC) and 172.6 (CO);
Both isomers: 120.78 (ArCH), 122.4 (ArCH), 123.4 (ArCH), 123.5
(ArCH), 123.7 (ArCH), 123.9 (ArCH), 124.1 (ArCH), 124.2
(ArCH), 125.0 (ArCH), 125.4 (ArCH), 125.7 (ArCH), 125.9
(ArCH), 126.3 (ArCH), 126.5 (ArCH), 127.4 (ArCH), 128.8
(ArC), 129.0 (ArCH), 129.2 (ArCH), 129.7 (ArC), 130.3 (ArCH),
130.6 (ArCH), 131.8 (ArC), 133.5 (ArC), 140.3 (ArC), 140.5
(ArC), 140.6 (ArC) and 140.8 (ArC); m/z (TOF ES+) 490.2369
(MH+. C33H32NO3 requires 490.2382).
(3aR,9aR,3R)-2,3,3a,4,9,9a-Hexahydro-4-[(1R)-1-methoxy-
ethyl] - 3 - (2,4,6 - trimethylphenyl) - 2 - methyl - 4,9 - [1¢,2¢]benzeno-
1H-benz[f ]isoindol-1-one 6. The title compound was prepared
according to general procedure A as a white solid after purification
by column chromatography on silica gel eluting with 10% ethyl
acetate/90% hexane to 40% ethyl acetate/6◦0% hexane (70 mg,
54%); [a]2D2 -63.2 (c 1 in CHCl3); mp 251–253 C; nmax(ATR)/cm-1
3060, 2937, 2834, 1681, 1594 and 1516; dH (400 MHz; CDCl3) 1.86
(3 H, d, J 6.4, CH3CH), 2.02 (3 H, s, CH3), 2.08 (3 H, s, CH3),
2.25 (3 H, s, CH3), 2.48 (3 H, s, NCH3), 2.70 (1 H, ddd, J 10.3,
3.1 and 4.4, COCHCH), 3.52 (1 H, d, J 10.3, COCHCH), 3.76 (3
H, s, OCH3), 4.22 (1 H, d, J 3.1, CH), 4.31 (1 H, d, J 4.4, CH),
5.47 (1 H, q, J 6.4, CH3CH), 6.80 (1H, s, ArCH), 6.90 (1H, s,
ArCH), 7.04–7.24 (5 H, m, ArCH), 7.28–7.33 (1 H, m, ArCH),
7.40–7.46 (1 H, m, ArCH) and 7.88 (1 H, d, J 7.2, ArCH); dC
(100 MHz; CDCl3) 17.0 (CH3CH), 19.7 (CH3), 20.8 (CH3), 21.5
(CH3), 27.1 (NCH3), 46.3 (CH), 49.0 (CH), 50.1 (CH), 54.5 (9-
C), 57.2 (OCH3), 61.0 (CH), 73.4 (CHOCH3), 123.7 (ArCH),
124.2 (ArCH), 125.1 (ArCH), 125.5 (ArCH), 125.9 (2 ¥ ArCH),
126.4 (ArCH), 126.5 (ArCH), 129.6 (ArCH), 131.7 (ArCH), 132.8
(ArC), 136.8 (2 ¥ ArC), 137.5 (ArC), 140.2 (ArC), 140.3 (ArC),
140.4 (ArC), 143.5 (ArC) and 172.4 (CO); m/z (EI) 451.2499 (M+.
C31H33NO2 requires 451.2511), 436 (33%), 236 (55), 221 (47), 216
(100), 205 (23), 178 (20) and 96 (8).
Preparation of (3R,3aR,9aR)-2,3,3a,4,9,9a-Hexahydro-3-hydr-
oxy-9-[(1R)-1-methoxyethyl]-2-(2-propen-1-yl)-3-methyl-4,9[1¢,2¢]-
benzeno-1H-benz[f ]isoindol-1-one 10. Prepared by application of
known literature procedures in three steps as outlined below.
(3aR,9aR,3R)-2,3,3a,4,9,9a-Hexahydro-4-[(1R)-1-methoxy-
ethyl]-3-(2-thiazolyloxy)-2-methyl-4,9-[1¢,2¢]benzeno-1H -benz
[f ]isoindol-1-one 7. The title compound was prepared according
to general procedure A as a colourless oil after purification by
column chromatography on silica gel eluting with 50% ethyl
acetate, 50% petroleum ether (82 mg, 68%); [a]2D2 -59.0 (c 1 in
CHCl3); nmax(ATR)/cm-1 3026, 2934, 1678 and 1515; dH (400
MHz; CDCl3) 1.87 (3 H, d, J 6.4, CH3CH), 2.22 (3 H, s, NCH3),
2.58 (1 H, dt, J 9.4 and 2.2, COCHCH), 3.61 (1 H, d, J 9.4,
COCHCH), 3.74 (3 H, s, OCH3), 4.47 (1 H, d, J 2.2, H-10),
5.22 (1 H, d, J 2.2, NCH), 5.38 (1 H, q, J 6.4, CH3CH), 6.15
(1 H, d, J 5.4, ArCH), 6.26 (1 H, d, J 5.4, ArCH), 7.14–7.24
(5 H, m, ArCH), 7.32–7.36 (1 H, m, ArCH), 7.48–7.51 (1 H, m,
ArCH) and 7.88–7.90 (1 H, m, ArCH); dC (100 MHz; CDCl3)
16.8 (CH3), 26.8 (CH3), 46.8 (CH), 47.6 (CH), 48.1 (CH), 54.7 (9-
C), 57.2 (OCH3), 71.4 (NCH), 73.2 (CHOCH3), 103.4 (NCHO),
119.7 (ArCH), 123.7 (ArCH), 124.0 (ArCH), 125.2 (ArCH), 125.8
(ArCH), 126.2 (ArCH), 126.5 (ArCH), 126.7 (ArCH), 126.8
(ArCH), 138.5 (ArC), 139.4 (ArC), 139.6 (ArC), 143.0 (ArC),
171.8 (SC N) and 172.7 (CO); m/z (TOF EI+) 471 (M++K, 5%),
433.1565 (MH+. C25H25N2O332S requires 433.1586), 332 (12).
N-Allyl maleimide. Allylamine (1.30 mL, 17.5 mmol) and
maleic anhydride (3.43 g, 35.0 mmol) were heated to reflux in
toluene (15 mL) for 2 h. Acetic acid (30 mL, 525 mmol) was then
added and the reaction heated to reflux for 5 h. The resulting
mixture was cooled to RT and the solvent removed. Water (50 ml)
was added and the mixture extracted with CH2Cl2 (3 ¥ 50 mL),
dried (MgSO4) and solvent was removed to give a yellow oil. This
was purified by flash column chromatography on silica gel eluting
with (20% ethyl acetate, 80% hexane) to give a white solid (735
mg, 31%) as the title compound; mp 42–44 ◦C (Lit.13 42–44 ◦C);
n
max(ATR)/cm-1 3459, 3162, 3087, 2925, 1771, 1707 and 1651; dH
(400 MHz; CDCl3) 4.13 (2 H, dt, J 5.6, 1.4, NCH2), 5.12–5.24 (2
H, m, C CH2), 5.73–5.88 (1H, m, CH CH2) and 6.72 [2 H, s,
C(O)CH].
(3aR,9aR)-3a,4,9,9a-Tetrahydro-4-[(1R)-1-methoxyethyl]-2-(2-
propen-1-yl)-4,9-[1¢,2¢]benzeno-1H -benz[f ]isoindole-1,3-(2H)-
dione. 9-(1R)-Methoxyethyl anthracene1 (300 mg, 1.27 mmol)
and N-allylmaleimide (174 mg, 1.27 mmol) were dissolved in
CH2Cl2 (15 mL) and heated to reflux for 9 h. The reaction mixture
was allowed to cool to RT and the solvent was removed to give a
pale yellow solid. This was recrystallised from CH2Cl2/petroleum
(3aR,9aR,3R)-2,3,3a,4,9,9a-Hexahydro-4-[(1R)-1-methoxy-
ethyl]-3-(2-methoxy-1-naphthalenyl)-2-methyl-4,9-[1¢,2¢]benzeno-
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ether (40–60) to give a white solid as the title compound (435 mg,
92%); mp 175–176 ◦C (from CH2Cl2/petroleum ether); [a]2D2 -34.0
(c 1 in CHCl3); nmax (ATR)/cm-1 2934, 2825, 1770, 1699 and 1645;
dH (400 MHz; CDCl3) 1.86 (3 H, d, J 6.4, CH3CH), 3.13 (1 H,
dd, J 8.3 and 3.1, COCHCH), 3.62 (1 H, d, J 8.3, COCHCH),
3.65–3.68 (2 H, m, CH2), 3.71 (3 H, s, OCH3), 4.55 (1 H, app. dd,
J 17.0 and 1.3, 1 ¥ C CH2), 4.72 (1 H, d, J 3.1, 10-H), 4.81 (1
H, app. dd, J 10.2 and 1.3, 1 ¥ CH CH2), 4.93 (1 H, ddt, J 17.0,
10.2 and 4.4, CH CH2), 5.12 (1 H, q, J 6.4, CH3CH), 7.12–7.21
(5 H, m, ArCH), 7.28–7.33 (1 H, m, ArCH), 7.35–7.40 (1 H, m,
ArCH) and 7.84–7.90 (1 H, m, ArCH); dC (100 MHz; CDCl3) 16.9
(CH3), 40.5 (CH2), 46.4 (CH), 46.9 (CH), 48.7 (CH), 54.7 (9-C),
57.1 (OCH3), 73.8 (CHOCH3), 117.6 (HC CH2), 123.8 (ArCH),
123.9 (ArCH), 125.3 (ArCH), 125.9 (ArCH), 126.4 (ArCH), 126.7
(ArCH), 126.8 (2 ¥ ArCH), 130.2 (HC CH2), 138.5 (ArC), 139.0
(ArC), 139.4 (ArC), 142.5 (ArC), 175.9 (CO) and 176.4 (CO); m/z
(EI) 373.1680 (M+. C24H23NO3 requires 373.1678), 358 (18), 235
(100), 221 (85), 205 (50), 178 (42) and 59 (24).
hydroxy-lactam 9 and furan afforded a white solid as the title
compound (341 mg, 100%); [a]2D2 +19 (c 1 in CHCl3); mp 205 ◦C;
n
max(ATR)/cm-1 3050, 2980, 2942, 2819, 1681 and 1502; dH (400
MHz; CDCl3) 1.72 (3 H, s, CH3), 1.89 (3 H, d, J 6.4, CH3CH),
2.23 (3 H, s, NCH3), 2.58 (1 H, dd, J 9.3 and 2.1, COCHCH),
3.76 (3 H, s, OCH3), 3.89 (1 H, d, J 9.3, COCHCH), 4.47 (1 H, d,
J 2.1, 10-H), 5.60 (1 H, q, J 6.4, CH3CH), 6.06 (1 H, dd, J 3.2 and
0.7, ArCH), 6.21 (1 H, dd, J 3.2 and 1.7, ArCH), 7.08–7.25 (5H,
m, ArCH), 7.25–7.29 (2 H, m, ArCH), 7.33–7.39 (1 H, m, ArCH)
and 7.86–7.88 (1 H, m, ArCH); dC (100 MHz; CDCl3) 17.2 (CH3),
17.3 (CH3), 24.8 (CH3), 46.5 (CH), 47.6 (CH), 50.0 (CH), 54.9 (9-
C), 57.5 (OCH3), 61.4 (NCCH3), 73.9 (CHOCH3), 105.3 (ArCH),
109.8 (ArCH), 122.9 (ArCH), 124.3 (ArCH), 125.4 (ArCH), 125.6
(2 ¥ ArCH), 125.7 (ArCH), 125.8 (ArCH), 126.9 (ArCH), 140.0
(ArC), 140.1 (ArC), 141.3 (ArC), 142.2 (ArCH), 145.2 (ArC),
157.8 (ArC) and 173.8 (CO); m/z (EI) 413.2008 (M+, C27H27NO3
requires 413.1991), 398 (38), 236 (35), 221 (32), 205 (20), 178 (100),
147 (10) and 110 (12).
(3aR,9aR,3R)-3a,4,9,9a-Tetrahydro-4-[(1R)-1-methoxyethyl]-
2-(2-propen-1-yl)-3-(2-furanyl)-3-methyl-4,9-[1¢,2¢]benzeno-1H-
benzo[f ]isoindole-1-(1H)-one 12. UsinggeneralprocedureB with
hydroxy-lactam 10 (150 mg, 0.39 mmol) and furan gave an orange
oil which solidified upon standing. This was recrystallised from
CH2Cl2/petroleum ether (40–60) giving an orange solid (359 mg,
99%◦) as the title compound; [a]2D2 -26 (c 1 in CHCl3); mp 170–
173 C; nmax(ATR)/cm-1 3069, 3040, 2970, 2940, 2818, 1679 and
1502; dH (400 MHz; CDCl3) 1.71 (3 H, s, CH3), 1.89 (3 H, d,
J 6.4, CH3CH), 2.59 (1 H, dd, J 9.5 and 2.1, COCHCH), 2.95
(1 H, dd, J 16.6 and 5.6, 1 ¥ CH2), 3.75 (3 H, s, OCH3), 3.77–
3.83 (2 H, m, COCHCH and 1 ¥ CH2), 4.07 (1 H, dd, J 17.3
and 1.9, 1 ¥ C CH2), 4.48 (1 H, d, J 2.1, 10-H), 4.65 (1H, dd,
J 10.5 and 1.9, 1 ¥ C CH2), 5.02 (1 H, dddd, J 17.3, 10.5, 5.6
and 4.3, CH CH2), 5.60 (1 H, q, J 6.4, CH3CH), 6.05 (1 H,
dd, J 3.3 and 0.7, ArCH), 6.21 (1 H, dd, J 3.3 and 1.7, ArCH),
7.10–7.32 (7 H, m, ArCH), 7.37–7.42 (1 H, m, ArCH), and 7.84–
7.89 (1 H, m, ArCH); dC (100 MHz; CDCl3) 17.3 (CH3CH), 17.9
(CH3), 42.2 (CH2), 46.5 (CH), 47.4 (CH), 50.1 (CH), 54.9 (9-C),
57.5 (OCH3), 62.2 (NCCH3), 73.8 (CHOCH3), 105.3 (ArCH),
109.8 (ArCH), 115.0 (C CH2), 122.9 (C CH2), 124.5 (ArCH),
125.5 (ArCH), 125.7 (ArCH), 125.8 (2 ¥ ArCH), 125.9 (ArCH),
126.9 (ArCH), 133.5 (ArCH), 140.1 (2 ¥ ArC), 141.6 (ArC), 142.2
(ArCH), 145.2 (ArC), 158.3 (ArC) and 174.2 (CO); m/z (EI)
439.2160 (M+, C29H29NO3 requires 439.2147), 424 (45), 236 (34),
221 (30), 204 (100), 178 (24), 147 (16), 136 (8), 91 (10) and 59 (8).
(3aR,9aR,3R)- 3a,4,9,9a-Tetrahydro-4-[(1R)-1-methoxyethyl]-
2-(2-propen-1-yl)-3-hydroxy-3-methyl-4,9-[1¢,2¢]benzeno-1H-ben-
zo[f ]isoindole-1-(1H)-one 10. MeMgBr (0.9 ml, 2.68 mmol, 3 M
in THF) was added to the N-allyl cycloadduct (prepared above)
◦
(200 mg, 0.54 mmol) in THF (10 mL) at 0 C. The reaction was
stirred at 0 ◦C for 30 min then allowed to warm to RT and stirred
for 18 h. The reaction was quenched with a saturated aqueous
solution of NH4Cl (10 mL) and extracted with CH2Cl2 (3 ¥
10 mL). The organic phase was dried (Na2SO4) and the solvent was
removed to give a white solid as the title compound (198 mg, 95%);
mp 130 ◦C; [a]2D2 +39.0 (c 1 in CHCl3); nmax(ATR)/cm-1 3373, 2941,
2820, 1665 and 1456; dH (400 MHz; CDCl3) 1.36 (3 H, s, CH3),
1.86 (3 H, d, J 6.4, CH3CH), 2.34 (1 H, d, J 1.0, OH), 2.61 (1 H, dd,
J 9.8 and 2.6, COCHCH), 3.30 (1 H, dd, J 15.7 and 5.9, 1 ¥ CH2),
3.55 (1 H, d, J 9.8, COCHCH), 3.72 (3 H, s, OCH3), 3.75–3.77 (1
H, m, 1 ¥ CH2), 4.41 (1 H, dd, J 17.4 and 1.3, C CHH), 4.64 (1
H, d, J 2.6, 10-H), 4.75 (1 H, dd, J 10.3 and 1.3, C CHH), 5.09–
5.18 (1 H, m, CH CH2), 5.49 (1 H, q, J 6.4, CH3CH), 7.15–7.24
(4 H, m, ArCH), 7.31–7.40 (3 H, m, ArCH) and 7.86–7.89 (1 H,
m, ArCH); dC (100 MHz; CDCl3) 17.1 (CH3CH), 28.4 (CH3), 41.0
(CH2), 45.6 (CH), 48.0 (CH), 51.1 (CH), 55.0 (C-9), 57.2 (OCH3),
73.8 (CHOCH3), 89.0 (COH), 115.7 (CH CH2), 123.2 (ArCH),
124.2 (ArCH), 125.2 (ArCH), 125.6 (ArCH), 126.0 (ArCH), 126.4
(ArCH), 126.8 (ArCH), 126.9 (ArCH), 134.0 (CH CH2), 140.0
(ArC), 140.6 (ArC), 141.5 (ArC), 144.1 (ArC) and 171.0 (CO);
m/z (TOF ES+) 390.2063 (MH+, C25H28NO3 requires 390.2069).
(3aR,9aR,3R)-3a,4,9,9a-Tetrahydro-4-[(1R)-1-methoxyethyl]-
2-(2-propen-1-yl)-3-(indol-3-yl)-3-methyl-4,9-[1¢,2¢]benzeno-1H-
benzo[f ]isoindole-1-(1H)-one 13. UsinggeneralprocedureB with
hydroxy-lactam 10 and indole afforded the title compound as a
yellow solid (395 mg, 98%); [a]2D2 -29 (c 1 in CHCl3); mp 230
◦C; nmax(ATR)/cm-1 3418, 3286, 3058, 2982, 2944 and 1661; dH
(400 MHz; CDCl3) 1.88–1.91 (6 H, m, CH3 and CH3CH), 2.74
(1 H, dd, J 9.3 and 1.9, COCHCH), 3.20 (1 H, dd, J 16.1 and
6.0, 1 ¥ CH2), 3.60 (1 H, d, J 9.5, COCHCH), 3.71 (3 H, s,
OCH3), 4.09–4.15 (1 H, m, 1 ¥ CH2), 4.18 (1 H, dd, J 17.1 and
1.4, 1 ¥ C CH2), 4.67 (1 H, d, J 1.9, 10-H), 4.70 (1 H, dd, J
10.3 and 1.2, 1 ¥ C CH2), 4.91–5.01 (1 H, dddd, J 17.1, 10.3,
6.0 and 4.3, CH CH2), 5.65 (1 H, q, J 6.4, CH3CH), 6.67 (1 H,
d, J 2.7, ArCH), 7.07–7.36 (9 H, m, ArCH), 7.45–7.48 (1H, m,
General procedure B to synthesise quaternary stereocentres via
N-acyliminium ions
Trifluoroacetic acid (0.32 mL, 4.13 mmol) was added to hydroxy-
lactam 9 or 10 (0.83 mmol) and aromatic (0.83 mmol) in
dichloromethane (2 mL) and heated to reflux for 24 h. The reaction
was quenched with saturated Na2CO3 (4 mL), extracted with
CH2Cl2 (3 ¥ 5 mL), washed with brine (3 ¥ 5 mL) and dried
(Na2SO4). The solvent was removed to give the target compound
which was purified as appropriate.
(3aS,9aS,3S)-3a,4,9,9a-Tetrahydro-4-[(1S)-1-methoxyethyl]-
2-methyl-3-(2-furanyl)-3-methyl-4,9-[1¢,2¢]benzeno-1H-benzo[f ]-
isoindole-1-(1H)-one 11. Using general procedure
B with
4358 | Org. Biomol. Chem., 2011, 9, 4353–4360
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ArCH), 7.60 (1 H, d, J 7.8, ArCH), 7.80–7.82 (1 H, m, ArCH)
and 8.14 (1 H, s, ArCH); dC (100 MHz; CDCl3) 17.3 (CH3CH),
21.1 (CH3), 43.2 (CH2), 47.1 (CH), 47.3 (CH), 52.0 (CH), 54.9 (9-
C), 57.4 (OCH3), 63.7 (NCCH3), 73.8 (CHOCH3), 111.6 (ArCH),
115.1 (C CH2), 119.5 (ArCH), 119.9 (ArCH), 120.2 (ArCH),
122.2 (ArCH), 122.8 (C CH2), 124.0 (2 ¥ ArC), 124.1 (ArCH),
125.2 (ArCH), 125.6 (ArCH), 125.8 (ArCH), 125.9 (ArCH), 126.1
(ArCH), 126.9 (ArCH), 133.9 (ArCH), 137.3 (ArC), 140.0 (ArC),
140.5 (ArC), 141.7 (ArC), 145.6 (ArC) and 174.1 (CO); m/z (TOF
ES+) 489.2556 (MH+, C33H33N2O2 requires 489.2542).
(3aS,9aS)-3a,4,9,9a-Tetrahydro-4-[(1S)-1-methoxyethyl]-2-
methyl - 3 - methylene - 4,9 - [1¢,2¢]benzeno - 1H - benzo[f ]isoindole-
1-(1H)-one 16. Using general procedure B with hydroxy-lactam
9 and 1,2-dimethoxy benzene afforded a white solid as the title
compound (0.225 mg, 80%); [a]2D2 +63 (c 1 in CHCl3); mp 180 ◦C;
n
max(ATR)/cm-1 2938, 1699 and 1661; dH (400 MHz; CDCl3) 1.87
(3 H, d, J 6.4, CH3CH), 2.43 (3 H, s, NCH3), 3.23 (1 H, ddt,
J 9.2, 2.9 and 1.8, CHCHCO), 3.45 (1 H, d, J 9.2, CHCHCO),
3.74 (3 H, s, OCH3), 4.09 (1 H, app. t, J 1.8, C CHH), 4.29
(1 H, app. t, J 1.8, C CHH), 4.31 (1 H, d, J 2.9, 10-H), 5.32
(1 H, q, J 6.4, CH3CH), 7.09–7.23 (6 H, m, ArCH), 7.36–7.38
(1 H, m, ArCH) and 7.88–7.91 (1 H, m, ArCH); dC (100 MHz;
CDCl3) 17.0 (CH3CH), 25.6 (NCH3), 44.7 (CH), 47.0 (CH), 50.7
(CH), 54.5 (9-C), 57.2 (OCH3), 73.8 (CHOCH3), 83.5 (C CH2),
123.4 (ArCH), 123.6 (ArCH), 125.4 (ArCH), 125.6 (ArCH), 125.8
(ArCH), 126.0 (2 ¥ ArCH), 126.7 (ArCH), 139.1 (ArC), 139.4
(ArC), 139.9 (ArC), 143.2 (ArC), 149.0 (C CH) and 173.6 (CO);
m/z (TOF ES+) 346.1803 (MH+, C23H24NO2 requires 346.1807).
(3aS,9aS,3S)-3a,4,9,9a-Tetrahydro-4-[(1S)-1-methoxyethyl]-2-
methyl-3-(2-thienyl)-3-methyl-4,9-[1¢,2¢]benzeno-1H-benzo[f ]iso-
indole-1-(1H)-one 14. Using general procedure B with hydroxy-
lactam 9 and thiophene afforded the title compound as a white
solid after column chromatography on silica gel eluting with 20%
ethyl acetate, 80% hexane as a white solid (177 mg, 50%); [a]D22
+20 (c 1 in CHCl3); mp 184–185 ◦C; nmax(ATR)/cm-1 3041, 2979,
2941, 2818, 1681 and 1502; dH (400 MHz; CDCl3) 1.84 (3 H, s,
CH3), 1.89 (3 H, d, J 6.4, CH3CH), 2.32 (3 H, s, NCH3), 2.58 (1
H, dd, J 9.3 and 2.0, COCHCH), 3.72–3.75 (4 H, m, OCH3 and
COCHCH), 4.51 (1 H, d, J 2.0, 10-H), 5.61 (1 H, q, J 6.4, CH3CH),
6.70 (1 H, dd, J 3.4 and 1.0, ArCH), 6.86 (1H, dd, J 3.9 and 3.7,
ArCH), 7.08–7.21 (5 H, m, ArCH), 7.27–7.30 (2 H, m, ArCH),
7.36–7.38 (1 H, m, ArCH) and 7.83–7.85 (1 H, m, ArCH); dC (100
MHz; CDCl3) 17.3 (CH3), 20.3 (CH3), 25.1 (CH3), 46.7 (CH),
46.8 (CH), 53.6 (CH), 54.9 (9-C), 57.5 (OCH3), 63.6 (NCCH3),
73.9 (CHOCH3), 122.7 (ArCH), 122.9 (ArCH), 124.4 (2 ¥ ArCH),
125.4 (ArCH), 125.6 (2 ¥ ArCH), 125.7 (ArCH), 125.8 (ArCH),
126.8 (ArCH), 126.9 (ArCH), 139.9 (ArC), 140.0 (ArC), 141.3
(ArC), 145.1 (ArC), 152.5 (ArC) and 173.2 (CO); m/z (TOF ES+)
430.1855 (MH+, C27H28NO232S requires 430.1841).
(3aR,9aR)-3a,4,9,9a-Tetrahydro-4-[(1R)-1-methoxyethyl]-2-(2-
propen-1-yl)-3-methylene-4,9-[1¢,2¢]benzeno-1H-benzo[f ]isoindole-
1-(1H)-one 17. Using general procedure B with hydroxy-lactam
10 and 1,2-dimethoxy benzene afforded a pale orange solid
after recrystallisation from CH2Cl2–hexane as the title compound
(0.133 mg, 43%); [a]D22 -78 (c 1 in CHCl3); mp 147 ◦C (from
CH2Cl2–hexane); nmax(ATR)/cm-1 3061, 3020, 2933, 1709 and
1660; dH (400 MHz; CDCl3) 1.85 (3 H, d, J 6.4, CH3CH), 3.20–
3.23 (1 H, m, COCHCH), 3.38 (1 H, dd, J 16.1 and 5.6, NCHH),
3.46 (1 H, d, J 9.4, COCHCH), 3.71 (3 H, s, OCH3), 3.93 (1
H, ddt, J 16.1, 5.6 and 1.3, 1 ¥ NCHH), 4.08 (1 H, s, 10-H),
4.27–4.33 (2 H, m, NC CH2), 4.37 (1 H, app. dd, J 17.1 and
1.3, C CHH), 4.79 (1 H, app. dd, J 10.3 and 1.3, C CHH),
4.85–4.97 (1 H, m, CH CH2), 5.29 (1 H, q, J 6.4 CH3CH), 7.07–
7.24 (6 H, m, ArCH), 7.31–7.37 (1 H, m, ArCH), 7.84–7.89 (1
H, m, ArCH); dC (100 MHz; CDCl3) 17.0 (CH3), 42.0 (CH2),
44.8 (CH), 46.9 (CH), 50.7 (CH), 54.5 (9-C), 57.2 (OCH3), 73.7
(CHOCH3), 84.5 (CH2), 116.4 (C CH2), 123.6 (2 ¥ ArCH), 125.6
(C CH2), 125.7 (ArCH), 125.9 (ArCH), 126.0 (ArCH), 126.1
(ArCH), 126.7 (ArCH), 130.7 (C CH2), 139.3 (ArCH), 139.7
(ArC), 140.0 (ArC), 143.5 (ArC), 147.5 (ArC) and 173.4 (CO);
m/z (TOF ES+) 372.1951 (MH+, C25H26NO2 requires 372.1964).
(3aR,9aR,3R)-3a,4,9,9a-Tetrahydro-4-[(1R)-1-methoxyethyl]-
2-(2-propen-1-yl)-3-(2-thienyl)-3-methyl-4,9-[1¢,2¢]benzeno-1H-
benzo[f ]isoindole-1-(1H)-one15. Using generalprocedure B with
hydroxy-lactam 10 and thiophene afforded a yellow solid. This was
purified by column chromatography on silica gel (5% ethyl acetate,
95% hexane to 20% ethyl acetate, 80% hexane) giving a white solid
as the title compound (18 mg, 52%); [a]2D2 -27 (c 1 in CHCl3); mp
191 ◦C; nmax(ATR)/cm-1 3071, 2979, 2939, 2819 and 1681; dH (400
MHz; CDCl3) 1.80 (3 H, s, CH3), 1.86 (3 H, d, J 6.4, CH3CH), 2.56
(1 H, dd, J 9.3 and 2.1, COCHCH), 2.95 (1 H, dd, J 16.4 and 5.9,
1 ¥ CH2), 3.72–3.74 (4 H, m, OCH3 and COCHCH), 3.91–3.96
(1 H, m, 1 ¥ CH2), 4.05 (1 H, dd, J 17.1 and 1.3, 1 ¥ C CH2),
4.50 (1 H, d, J 2.1, 10-H), 4.63 (1 H, app. dd, J 12.0 and 4.0, 1 ¥
(3E,3aS,9aS)-3a,4,9,9a-Tetrahydro-4-[(1S)-1-methoxyethyl]-2-
(methyl)-3-(3,3,3-trifluoro-2-oxopropylidene)-4,9-[1¢,2¢]benzeno-
1H-benzo[f ]isoindole-1-(1H)-one 18. Using general procedure B,
with hydroxy-lactam 9 and thiophene and heating to reflux for 24
h afforded a white solid as the title compound after purification
by silica gel eluting with 20% ethyl acetate, 80% hexane (183 mg,
50%); [a]2D2 +169 (c 0.5 in CHCl3); mp 195–196 ◦C; nmax(ATR)/cm-1
2982, 2937, 2825, 1744, 1691 and 1568; dH (400 MHz; CDCl3) 1.90
(3 H, d, J 6.4, CH3CH), 2.57 (3 H, s, NCH3), 3.60 (1 H, d, J 8.3,
COCHCH), 3.71 (3 H, s, OCH3), 3.97–3.99 (1 H, m, COCHCH),
4.87 (1 H, d, J 2.7, 10-H), 5.20 (1 H, q, J 6.4, CH3CH), 5.64 [1 H,
s, CHC(O)CF3], 7.13–7.25 (6 H, m, ArCH), 7.55–7.57 (1 H, m,
ArCH) and 7.88–7.89 (1 H, m, ArCH); dC (100 MHz; CDCl3) 16.7
(CH3), 26.6 (CH3N), 46.3 (CH), 46.5 (CH), 47.2 (CH), 54.1 (9-
C), 54.8 (CH3O), 73.4 (CHOCH3), 90.7 (CH C), 116.66 (q, JC–F
291.8, CF3), 123.3 (ArCH), 124.4 (ArCH), 125.1 (ArCH), 125.9
(ArCH), 126.5 (ArCH), 126.6 (2 ¥ ArCH), 126.8, 143.0 (ArC),
139.0 (ArC), 138.9 (ArC), 138.5 (ArC), 169.1 (NC CH), 175.1
C
CH2), 4.98 (1 H, dddd, J 17.1, 12.0, 5.9 and 4.1, CH CH2),
5.59 (1 H, q, J 6.4, CH3CH), 6.68 (1 H, dd, J 3.5 and 1.1, ArCH),
6.83 (1 H, dd, J 5.0 and 3.5, ArCH), 7.03–7.21 (5 H, m, ArCH),
7.24–7.32 (2 H, m, ArCH), 7.34–7.42 (1 H, m, ArCH) and 7.78–
7.84 (1H, m, ArCH); dC (100 MHz; CDCl3) 17.3 (CH3CH), 21.3
(CH3), 42.9 (CH2), 46.6 (CH), 46.8 (CH), 53.6 (CH), 54.9 (9-C),
57.5 (OCH3), 64.7 (NC–CH3), 73.7 (CHOCH3), 115.1 (C CH2),
122.7 (ArCH), 122.9 (C CH2), 124.5 (ArCH), 124.6 (ArCH),
125.4 (ArCH), 125.7 (ArCH), 125.8 (ArCH), 125.9 (ArCH), 126.0
(ArCH), 126.8 (ArCH), 126.9 (ArCH), 133.4 (ArCH), 140.0 (2 ¥
ArC), 141.5 (ArC), 145.1 (ArC), 153.4 (ArC) and 173.6 (CO);
m/z (EI) 455.1938 (M+, C29H29NO2S requires 455.1919), 440 (45),
236 (43), 220 (100), 205 (27), 178 (25), 163 (15) and 136 (14).
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Org. Biomol. Chem., 2011, 9, 4353–4360 | 4359
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(CO) and 178.2 (q, JC–F 34.0, CF3CO); dF (235 MHz; CDCl3)
-77.94 (CF3); m/z (TOF ES+) 442.1617 (MH+, C25H23F3NO3
requires 442.1630).
mm Cellulose-1, 10% IPA in hexane, flow rate 1 mL min-1, tR (S)
enantiomer 10.3 min (R) enantiomer 11.5 min.
Acknowledgements
(3E,3aR,9aR)-3a,4,9,9a-Tetrahydro-4-[(1R)-1-methoxyethyl]-
2-(2-propen-1-yl)-3-(3,3,3-trifluoro-2-oxopropylidene)-4,9-[1¢,2¢]
benzeno-1H-benzo[f ]isoindole-1-(1H)-one 19. Using general
procedure B with hydroxy-lactam 10 and thiophene and heating to
reflux for 27 h afforded a yellow solid that was purified by column
chromatography on silica gel (5% ethyl acetate, 95% hexane to
20% ethyl acetate, 80% hexane) giving a white solid as the title
We would like to thank GlaxoSmthKline and EPSRC for funding.
Notes and references
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31–34; (f) K. L. Burgess, M. S. Corbett, P. Eugenio, N. J. Lajkiewicz,
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J. K. Snyder, Tetrahedron Lett., 2003, 44, 931–935; (h) J. C. Christian
Atherton and S. Jones, J. Chem. Soc., Perkin Trans. 1, 2002, 2166–2173;
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9100; (j) J. C. C. Atherton and S. Jones, J. Chem. Soc., Perkin Trans. 1,
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Trevitt and D. J. Dixon, J. Am. Chem. Soc., 2009, 131, 10796–10797;
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10, 745–748; (c) I. T. Raheem, P. S. Thiara, E. A. Peterson and E. N.
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Temprano, I. Osante, E. Lete and N. Sotomayor, J. Org. Chem., 2004,
69, 3875–3885.
◦
compound (184 mg, 48%); mp 187–188 C; [a]2D2 -124 (c 1 in
CHCl3); nmax(ATR)/cm-1 2936, 2827, 1742, 1692 and 1567; dH
(400 MHz; CDCl3) 1.88 (3 H, d, J 6.4, CH3CH), 3.48 (1 H, dd,
J 16.0 and 6.1, 1 ¥ NCH2), 3.58 (1 H, d, J 8.3, COCHCH),
3.70 (3 H, s, OCH3), 3.96 (1 H, dd, J 8.3 and 1.3, COCHCH),
4.06 (1 H, dd, J 16.0 and 4.6, 1 ¥ NCH2), 4.57 (1 H, d, J 17.1,
1 ¥ C CH2), 4.75–4.90 (2 H, m, 10-H and CH CH2), 4.90–
4.99 (1 H, m, 1 ¥ C CH2), 5.19 (1 H, q, J 6.4, CH3CH), 5.64
[1 H, s, CHC(O)CF3], 7.08–7.29 (6 H, m, ArCH), 7.49–7.57 (1
H, m, ArCH) and 7.80–7.91 (1 H, m, ArCH); dC (100 MHz;
CDCl3) 16.8 (CH3CH), 42.7 (CH2), 46.3 (CH), 46.5 (CH), 47.1
(CH), 54.8 (9-C), 57.2 (OCH3), 73.4 (CHOCH3), 91.5 (CH C),
118.5 (CH CH2), 116.6 (q, JC–F 178.2, CF3), 123.5 (ArCH and
CH CH2), 124.4 (ArCH), 125.4 (ArCH), 125.9 (ArCH), 126.5
(2 ¥ ArCH), 126.6 (ArCH), 128.7 (ArCH), 138.7 (ArC), 139.2
(2 ¥ ArC), 143.1 (ArC), 168.1 (C CH), 174.9 (CO), 178.4 (q,
J
C–F 34.2, CF3CO); dF (377 MHz; CDCl3) -78.1 (CF3); m/z (TOF
ES+) 468.1804 (MH+, C27H25F3NO3 requires 468.1787).
(S)-5-(Furan-2-yl)-1,5-dimethyl-1H-pyrrol-2(5H)-one 20.
A
4 M. Ostendorf, J. Dijkink, F. P. J. T. Rutjes and H. Hiemstra, Eur. J. Org.
Chem., 2000, 115–124.
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Int. Ed., 2007, 46, 1893–1896; (b) E. A. Peterson and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2009, 48, 6328–6331.
6 (a) M. Rueping and B. J. Nachtsheim, Synlett, 2009, 2010, 119–122;
(b) I. T. Raheem, P. S. Thiara and E. N. Jacobsen, Org. Lett., 2008, 10,
1577–1580.
50 cm quartz thermolysis tube was connected to a 25 mL flask
containing cycloadduct 11 (190 mg, 0.46 mmol), and the other
end to a cold trap. The thermolysis tube was heated at 510 ◦C
under vacuum◦(0.02 mmHg) and the starting material was then
heated to 180 C for 0.5 h. The system was then allowed to cool
to room temperature. The crude material was collected from the
U-tube (100% conversion) and the desired compound 20 was
separated from the auxiliary 21 by flash column chromatography
on silica gel (50% ethyl acetate, 50% petroleum ether) affording
pale yellow crystals (64 mg, 79%); (Found: C, 67.87; H, 6.31; N,
7.75. C10H11NO2 requires C, 67.78; H, 6.26; N, 7.90%); [a]2D2 -268
(c 1 in CHCl3, ee 97%); mp 38–39 ◦C; nmax(ATR)/cm-1 3116, 2984,
2936, 1690 and 1594; dH (400 MHz; CDCl3) 1.64 (3 H, s, CH3),
2.76 (3 H, s, NCH3), 6.17 (1 H, d, J 5.8, CH CH), 6.23 (1 H, dd,
J 3.3 and 0.9, ArCH), 6.33 (1 H, dd, J 3.3 and 1.8, ArCH), 7.02 (1
H, d, J 5.8, CH CH) and 7.36 (1 H, dd, J 1.8 and 0.9, ArCH);
dC (100 MHz; CDCl3) 20.0 (CH3), 24.4 (NCH3), 65.5 (CH3C),
107.6 (CH), 110.4 (CH), 125.9 (CH), 142.9 (CH), 150.5 (CH),
151.2 (ArC) and 170.2 (CO); m/z (TOF ES+) 178.0863 (MH+,
C10H12NO2 requires 178.0868); Chiral HPLC, Phenomenex Lux 3
7 S. Jones and S. A. Hasbullah, Tetrahedron: Asymmetry, 2010, 21, 2719–
2725.
8 Dihedral angles were measured from molecular models obtained using
Spartan 06 (1.0.2) using the B3LYP functional method and the 6-
311+G** basis set. Coupling constants were then modelled with the
Smith-Barfield equation using MestReJ v1.1, freely available from
http://mestrelab.com/software/mestrej/.
9 A variable temperature 1H NMR experiment to determine the nature of
these isomers (regioisomers or atropisomers) gave no significant change
in the ratios of signals upon heating that unfortunately precludes any
closure on this matter.
10 Note that for these transformations, the opposite enantiomer of
anthracene template was employed to prepare the N-methyl series. The
absolute stereochemistry of the N-allyl series is the same as depicited
in Scheme 1.
11 Alkene geometry determined by nOe studies.
12 P. Rashatasakhon and A. Padwa, Org. Lett., 2003, 5, 189–191.
13 T. F. Braish and D. E. Fox, Synlett, 1992, 979–980.
4360 | Org. Biomol. Chem., 2011, 9, 4353–4360
This journal is
The Royal Society of Chemistry 2011
©