Approaches to the synthesis of non-racemic 3-substituted isoindolinone derivatives

Article abstract of DOI:10.1039/b001569p

New methodology for the synthesis of non-racemic isoindolinone targets has been developed through application of tricyclic γ-lactam substrates as N-acyliminium ion precursors in reactions with carbon and hydride nucleophiles. Removal of the phenylglycinol

Full text of DOI:10.1039/b001569p

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Approaches to the synthesis of non-racemic 3-substituted
isoindolinone derivatives
Steven M. Allin,*a Christopher J. Northfield,ab Michael I. Pageb and Alexandra M. Z. Slawina†
1
a Department of Chemistry, Loughborough University, Loughborough, Leicestershire,
UK LE11 3TU
b Department of Chemical & Biological Sciences, University of Huddersfield, Queensgate,
Huddersfield, UK HD1 3DH
Received (in Cambridge, UK) 25th February 2000, Accepted 18th April 2000
Published on the Web 16th May 2000
New methodology for the synthesis of non-racemic isoindolinone targets has been developed through application
of tricyclic γ-lactam substrates as N-acyliminium ion precursors in reactions with carbon and hydride nucleophiles.
Removal of the phenylglycinol derived chiral auxiliary can be achieved without loss of stereochemical integrity at
the newly created asymmetric centre, and we report a novel method for this key step using conc. sulfuric acid.
Introduction
Results and discussion
The chemistry and reactivity of the isoindolinone ring system is
currently an area of interest for many research groups due to
its biological activitiy. It has been recognized that 3-substi-
tuted isoindolinones of general structure 11 possess anxio-
We have recently reported a novel synthesis of tricyclic
γ-lactams based on the isoindolinone ring system by conden-
sation of aminoalcohol substrates with 2-formylbenzoic acid, 6
(Scheme 1). Tricyclic lactams such as 7 are produced in good
Scheme 1 Synthesis of tricyclic lactams.
yield and as single diastereoisomers; the relative stereo-
chemistry has been confirmed by single crystal X-ray analysis.7
In this paper we describe our studies towards the stereo-
selective synthesis of 3-substituted isoindolinone targets
through application of tricyclic lactam substrates as N-acyl-
iminium ion precursors, providing full experimental details,
and we report a novel deprotection method for removal of the
phenylglycinol template from an isoindolinone substrate.
The synthetic potential of N-acyliminium species is now well
documented.8 Bicyclic lactams have been investigated by the
groups of Meyers9 and others10 as N-acyliminium ion pre-
cursors in the synthesis of a wide range of enantiomerically
enriched products.
The tricyclic lactam 7, derived from (R)-phenylglycinol was
prepared as previously reported,7 and was subjected to an
aminal ring-opening reaction using allyl(trimethyl)silane as the
nucleophile. In general, the substrate was cooled to Ϫ78 ЊC in
dichloromethane and treated with 1 equivalent of TiCl4 fol-
lowed by 1 equivalent of allyl(trimethyl)silane. The reaction mix-
ture was allowed to warm to room temperature overnight
before dilute acid work-up (Scheme 2).
lytic activity and are of interest as sedatives, hypnotics and
muscle relaxants,2 including the anxiolytic pazinaclone 23
and the anxiolytic/anticonvulsant zopiclone 3.4 Other bioactive
3-substituted isoindolinone derivatives include the 5-HT
antagonist 4,5 and the non-nucleosidic HIV-reverse tran-
scriptase inhibitor 5.6
Compounds 2–5 contain an asymmetric centre within the
isoindolinone ring system and, although the importance of
chirality in drug design is now well established, a stereo-
selective route for the synthesis of non-racemic 3-substituted
isoindolinones has yet to be reported.
† Present address: School of Chemistry, University of St. Andrews,
Fife, UK KY16 9AL.
DOI: 10.1039/b001569p
J. Chem. Soc., Perkin Trans. 1, 2000, 1715–1721
This journal is © The Royal Society of Chemistry 2000
1715

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Table 1 Ring opening of lactam 7
Lewis acid
Yield (%)
8:9a
TiCl4
BF3ؒOEt2
SnCl4
86
95
90
90
1:1
1.6:1
1.5:1
2:1
TMSOTf
a Determined by 270 MHz 1H NMR spectroscopy.
Fig. 1 X-Ray crystal structure of 8.
Scheme 2 Reagents and conditions: i, Lewis acid, CH2Cl2, Ϫ78 ЊC;
ii, allyl(trimethyl)silane.
We first chose to apply titanium() chloride as the activator,
and were disappointed to find that although the reaction
proceeded in high yield (86%) to give the desired 3-allyliso-
indolinone product, analysis of the crude reaction mixture by
Scheme 3
1
270 MHz H NMR showed that the product was formed as a
1:1 mixture of diastereoisomers 8 and 9. This level of diastereo-
selectivity was significantly lower than that observed by Meyers
using the same combination of Lewis acid and nucleophile
with the corresponding phenylglycinol-derived bicyclic lactam
(reported diastereoselectivity: >9:1).11
Based on the precedent that the diastereoselectivity obtained
in allylsilane–acetal addition reactions is known to vary with
the Lewis acid activator, and that TiCl4 proved to be least selec-
tive when compared to alternatives in these related studies,12 we
chose to investigate the effect of the Lewis acid component on
product diastereoselectivity in the aminal ring-opening reaction
described in Scheme 2. Table 1 summarises our results with a
range of Lewis acid activators.
Scheme 4
The substrate was cooled to Ϫ78 ЊC in dichloromethane and
treated with TiCl4 followed by triethylsilane (Scheme 5, Table
2). The reaction mixture was allowed to warm to room tem-
perature overnight before acidic work-up.
As can be appreciated from Table 1, variation of the Lewis
acid component had little effect on the level of product
diastereoselectivity. The relative stereochemistry of the major
product diastereoisomer 8 was confirmed by X-ray crystal
analysis (Fig. 1) following its isolation in diastereoisomerically
pure form by flash-column chromatography.13 The major isomer
is therefore formed with retention of configuration at the
asymmetric (aminal) centre. Our rationalisation of the stereo-
chemical outcome of the ring-opening reaction is described
below.
An alternative, yet complementary, approach to non-racemic
3-substituted isoindolinone target molecules can be envisaged
(Scheme 3). Our initial attempts to prepare the 3-substituted
isoindolinone targets had involved using a carbon nucleophile
in order to introduce the 3-substituent during the aminal ring-
opening reaction (Scheme 3, Pathway A). We recognised that
the 3-substituent could be introduced during lactam prepar-
ation, and the aminal ring could subsequently be opened stereo-
selectively using a source of hydride (Scheme 3, Pathway B).
To investigate this approach, substrate 10 was prepared as a
single diastereoisomer by condensation of (S)-phenylglycinol14
with the corresponding ketoacid in toluene under Dean–Stark
conditions (Scheme 4). The relative stereochemistry of the
product was confirmed by single crystal X-ray analysis.15
Scheme 5 Reagents and conditions: i, Lewis acid, CH2Cl2, Ϫ78 ЊC;
ii, Et3SiH.
As can be appreciated from Table 2, much higher levels of
diastereoselectivity can be achieved using this alternative
protocol than with the Lewis acid–allyl(trimethyl)silane system
described above. This route allows essentially complete
diastereocontrol depending on the Lewis acid activator used.
One might predict that the relative stereochemistry of the major
diastereoisomer would be formed with retention of configur-
1716
J. Chem. Soc., Perkin Trans. 1, 2000, 1715–1721

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Table 2 Diastereoselective ring opening of lactam 10
ments, where R = H, the N-acyliminium species suffers from
free rotation about the extraannular N–C bond with little pref-
erence for the competing transition state conformations during
nucleophilic attack. When R = Ph, the steric effect provided by
this substituent is sufficient to favour one transition state inter-
mediate, that leading to retention of configuration at the new
asymmetric centre (in turn leading to product 11). Interestingly
this conformation places the Lewis acid-complexed oxymethyl
substituent in a suitable orientation to allow chelation to
occur with the amide oxygen atom. This “chelation effect” also
appears to be significant, since use of an activator that is not
capable of multi-point coordination (TMSOTf) sees a fall in
product diastereoselectivity from 98:2 to only 4:1. These pos-
tulates are further supported by the results obtained with the
methyl-substituted substrate 13 (Scheme 6). The angular methyl
R
Lewis acid
Yield (%)
11:12a
Ph
Ph
TiCl4
TMSOTf
90
80
>98:2
4:1
a Determined by 270 MHz 1H NMR spectroscopy.
Scheme 6 Reagents and conditions: i, Lewis acid, CH2Cl2, Ϫ78 ЊC;
ii, Et3SiH.
group leads to a high diastereoselectivity (98:2) with chelation
control, again in favour of the product of retention of
configuration, but with only low stereoselection (1.5:1) when
chelation cannot be a contributing factor.
One might also expect the reactivity of the nucleophile to be
a factor. Since the Si–H bond is significantly weaker than the
Si–C bond17 the nucleophilic addition might take place more
rapidly with triethylsilane, and at lower temperature where
interconversion between competing transition state conform-
ations is slowed, again contributing to an increased level of
diastereoselection.
Fig. 2 X-Ray crystal structure of 11.
To summarise the study of nucleophilic aminal ring-open-
ings, although only a low level of diastereoselectivity was
observed on Lewis acid induced ring-opening of the tricyclic
lactam substrates with carbon nucleophiles, we have achieved
almost exclusive diastereoselectivity by a complementary
approach involving hydride ring-opening of an alkyl-
substituted γ-lactam. The relative size of the alkyl substituent is
a major factor in determining product diastereoselectivity, as
seems to be the ability of the Lewis acid activator to form a
chelated intermediate.
As one main aim of our study was to demonstrate a novel
route to non-racemic 3-substituted 2H-isoindolin-1-one mole-
cules, we have attempted removal of the chiral auxiliary. Due to
the benzylic nature of the newly created asymmetric centre
within the isoindolinone ring, we believed that deprotection of
the phenylglycinol-derived chiral auxiliary by traditional means
(e.g. hydrogenolysis) could prove futile. This problem has
recently been addressed by Vernon and Fains on an achiral
isoindolinone substrate using a three step (can be one-pot) pro-
cedure.18 In this method, the alcohol moiety is first converted to
the corresponding mesylate to allow base-induced elimination
to generate the enamide. Acid hydrolysis then liberates the
desired deprotected isoindolin-1-one target.
Fig. 3 Proposed transition states for reaction of tricyclic lactam
substrate with nucleophile.
ation at the asymmetric centre, based on related studies by
Meyers.16 This was indeed found to be the case and we were able
to obtain confirmation of the structure of the major isomer by
X-ray analysis of the crystalline major product diastereoisomer
11 (Fig. 2).
The remarkable increase in diastereoselectivity for the aminal
ring-opening reaction can be rationalised by the transition state
models presented in Fig. 3. The “size” of the angular substitu-
ent (R) appears to be a significant factor contributing to the
observed level of diastereoselectivity. In the previous experi-
We were pleased to find that this new method also worked
well with one of our own non-racemic substrates (used as a 2:1
mixture of diastereoisomers), to provide the desired 3-substi-
tuted isoindolinone 15 in good yield and without loss of
stereochemical integrity at the 3-position of the isoindolinone
ring (Scheme 7). The enantiomeric excess of the product was
determined by chiral HPLC analysis.19
This procedure also worked well for substrate 14 providing
enantiomerically pure isoindolinone 16 (Scheme 8). With sub-
strate 11, however, complete racemisation was observed using
J. Chem. Soc., Perkin Trans. 1, 2000, 1715–1721
1717

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Table
3
Acid-mediated removal of the 2-hydroxy-1-phenylethyl
group from 11
t/min
Yield (%)
Eea
30
16
11
6
42
65
64
71
74
65
68
77
85
96
2
a Determined by chiral HPLC.
lysed in situ to the corresponding 3-substituted 2H-isoindolin-
1-one product.
As can be appreciated from Table 3, essentially no loss in
ee is observed with a reaction time of only 2 minutes. Over
time, however, racemisation and degradation of the product is
observed.
To our knowledge the use of sulfuric acid as a one-step
method for removal of the 2-hydroxy-1-phenylethyl substituent
from chiral phenylglycinol templates has not been previously
reported. The method is extremely convenient and easy to carry
out, and proves particularly useful with this isoindolinone
substrate.
Scheme 7 Reagents and conditions: i, MeSO2Cl, Et3N; ii, NaOEt,
EtOH; iii, 3 M HCl, EtOH–H2O, 80 ЊC.
This paper describes what we believe to be the first asym-
metric synthesis of 3-substituted isoindolinones. In summary,
although only a low level of diastereoselectivity was observed
on Lewis acid induced ring-opening of the tricyclic lactam
substrates with allyl(trimethyl)silane, we have achieved almost
complete diastereoselectivity via a complementary approach
involving hydride ring-opening of an alkyl-substituted lactam.
Both routes outlined represent novel approaches to non-
racemic 3-substituted isoindolin-1-one targets. We have also
demonstrated that cleavage of the chiral auxiliary can be
achieved without racemisation at the newly created asymmetric
centre and have developed a new method for removal of the
chiral auxiliary from a sensitive isoindolinone substrate.
Scheme 8 Reagents and conditions: i, MeSO2Cl, Et3N; ii, NaOEt,
EtOH; iii, 3 M HCl, EtOH–H2O, 80 ЊC.
this base-mediated process. Variation of the leaving group
(e.g. chloro, bromo, iodo, mesylate) and base showed no
increase in product ee with this same reaction sequence.
In our search for an alternative strategy for removal of the
2-hydroxy-1-phenylethyl substituent from base-sensitive sub-
strates such as 11, we discovered a report for removal of an
N-benzyl substituent from an achiral isoindolinone substrate.20
We were initially skeptical about the success of this approach
with our own non-racemic substrate, since the literature method
called for prolonged heating of the substrate in concentrated
sulfuric acid.
Experimental
Where necessary, solvents were dried, distilled and stored over
4 Å molecular sieves prior to use. Reagent chemicals were
purchased from Lancaster Synthesis Ltd. and Aldrich Chemical
Co. Ltd., and were purified where necessary before use.
Flash-column chromatography was carried out using Merck
silica gel (70–230 Mesh ASTM). Analytical thin layer chrom-
atography (TLC) was carried out using aluminium-backed
plates coated with 0.2 mm silica. Plates were visualised under
UV light (at 254 nm) or by staining with either potassium per-
manganate solution or iodine. Yields quoted are for isolated,
purified products.
The substrate under investigation, compound 11, was added
to concentrated sulfuric acid and the reaction mixture heated
in a boiling water bath for a 30 minute period, followed by
dilution with excess water and extraction into dichloromethane
to yield the desired target, 17, in 42% yield and, somewhat
surprisingly, with an ee of 65% (Scheme 9).
Infra-red spectra were recorded in the range 4000–600 cmϪ1
,
using a Perkin-Elmer Paragon 100 FT-IR spectrometer, as
Nujol mulls or as liquid films. 1H NMR spectra were recorded
using either a Bruker Avance 400 MHz Spectrometer or a
Bruker AC 270 MHz Spectrometer. 13C NMR spectra were
recorded at 100 MHz or 67.5 MHz on the same instruments
respectively. NMR samples were made up in deuterated
solvents with all values quoted in ppm relative to TMS as refer-
ence. Coupling constants (J values) are reported in hertz (Hz).
Diastereoisomer ratios were calculated from the integration of
suitable peaks in the proton NMR spectra. Mass spectra were
recorded using a Fisons VG Quattro II SQ instrument and
accurate-mass mass spectra were recorded using a Kratos MS80
instrument. Melting points were determined on a Gallenkamp
Melting Point apparatus. Elemental analyses were carried out
on a Perkin-Elmer 2400 CHN Elemental Analyser. Optical
rotations were performed using an Optical Activity AA – 10
Automatic Polarimeter. Chiral HPLC analyses were conducted
using a Thermal Separation Products system, fitted with a
Scheme 9 Reagents and conditions: i, conc. H2SO4; ii, H2O.
Since compound 17 was the only organic product to be
1
isolated during the extraction procedure (by crude H NMR),
we believed that destruction of product material might be
occurring the longer the reaction was left to run. Indeed, the
original procedure20 called for heating in the concentrated acid
only until dissolution was observed; in our case this required
only a matter of minutes. We performed a study in which the
reaction time was gradually reduced in order to observe the
effect on product yield and enantiomeric excess (measured by
chiral HPLC). Our results are summarized in Table 3.
It is likely that the deprotection mechanism proceeds in a
similar manner to that reported for the Vernon deprotection
sequence,18 but via acid catalysed dehydration to yield a similar
enamide intermediate (as in Scheme 7), which is then hydro-
1718
J. Chem. Soc., Perkin Trans. 1, 2000, 1715–1721

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Chiralcel OJ column, using various combinations of iso-
propyl alcohol and hexane as eluent. X-Ray crystallography
was carried out using a Rigaku AFC7S diffractometer with
graphite monochromated Cu-Kα radiation.
(1.65 g, 85%). Mp 119–122 ЊC; [α]D = Ϫ123.7 [c = 3.07, CH2Cl2]
(Found: C, 76.92; H, 5.63; N, 5.22. C17H15NO2 requires C,
76.96; H, 5.70; N, 5.29%); νmax/cmϪ1 (Nujol) 1708, 1464, 1377,
1018, 766; δH (CDCl3, 270 MHz) 1.72 (3H, s, CH3), 4.32–4.38
(1H, dd, J 8.6, 7, CH(Ph)-CH-O), 4.81 (1H, t, J 8.6, CH(Ph)-
CH-O), 5.31 (1H, t, J 7, CH-Ph), 7.08–7.39 (5H, m, Ar), 7.54–
7.63 (3H, m, Ar), 7.80–7.83 (1H, d, J 7.3, Ar); δC (CDCl3, 67.5
MHz) 22.1, 58.1, 76.0, 99.1, 122.2, 124.4, 125.8 (2C), 127.4,
128.7 (2C), 130.3, 131.5, 133.3, 140.2, 146.9, 174.2; m/z (EI)
265 [Mϩ, 18%], 235 (100%) (Found: Mϩ, 265.1103. C17H15NO2
requires 265.1102).
Synthesis of tricyclic lactams 7, 10 and 13
(3R,9bS)-3-Phenyl-2,3,5,9b-tetrahydro[1,3]oxazolo[2,3-a]-
isoindol-5-one, 7. (R)-Phenylglycinol (2.0 g, 14.6 mmol) and
2-carboxybenzaldehyde (2.19 g, 14.6 mmol) were slurried in
toluene (150 ml). The mixture was heated at reflux under Dean–
Stark conditions for 24 hours. The resultant yellow solution
was allowed to cool and the toluene removed under reduced
General procedure for nucleophilic ring-openings
1
pressure to yield a yellow oil. H NMR analysis of this crude
product indicated the formation of only one product diastereo-
isomer. The oil was adsorbed onto silica and purified by flash-
column chromatography using a 1:1 mixture of light petroleum
ether and ether as eluent to afford the target compound as a
white powder, a portion of which was recrystallised from
dichloromethane and hexanes to yield clear, colourless needles
(3.54 g, 96%). Mp 112–116 ЊC; [α]D = Ϫ137.1 [c = 2.20, CH2Cl2]
(Found: C, 76.50; H, 5.20; N, 5.60. C16H13NO2 requires C,
76.48; H, 5.21; N, 5.58%); νmax/cmϪ1 (Nujol) 1712, 1463, 1377,
753; δH (CDCl3, 270 MHz) 4.11–4.17 (1H, dd, J 8.7, 7.5,
CH(Ph)-CH2-O), 4.79–4.85 (1H, dd, J 8.7, 7.5, CH(Ph)-CH2-O),
5.19–5.24 (1H, t, J 7.5, CH-Ph), 6.02 (1H, s, N-CH-O), 7.29–
7.41 (5H, m, Ar), 7.54–7.63 (3H, m, Ar), 7.83 (1H, d, J 5.27,
Ar); δC (CDCl3, 100 MHz) 57.8, 77.8, 91.7, 123.9, 124.3, 125.8
(2C), 127.5, 128.7 (2C), 130.6, 132.8, 133.0, 139.5, 141.9, 173.5;
m/z (EI) 251 (Mϩ, 5%), 221 (100%) (Found: Mϩ, 251.0951.
C16H13NO2 requires 251.0946).
The desired substrate was dissolved in dry dichloromethane (20
ml) under a nitrogen atmosphere and cooled to Ϫ78 ЊC. The
Lewis acid was then added dropwise by syringe. After stirring at
this temperature for 10 minutes, the nucleophile (allyl(tri-
methyl)silane, triethylsilane) was added by syringe and the mix-
ture stirred at this temperature for a further 30 minutes. The
mixture was then allowed to reach room temperature over 20
hours. The reaction mixture was quenched by the addition of
saturated ammonium chloride solution (20 ml), extracted with
dichloromethane (3 × 30 ml), dried over anhydrous magnesium
sulfate, filtered, and evaporated under reduced pressure to yield
1
the crude product mixture which was analysed by H NMR
spectroscopy.
(3S)-3-Allyl-2-[(1R)-2-hydroxy-1-phenylethyl]-2,3-dihydro-
1H-isoindol-1-one, 8. (3R,9bS)-3-Phenyl-2,3,5,9b-tetrahydro-
[1,3]oxazolo[2,3-a]isoindol-5-one, 7 (1.0 g, 7.3 mmol) was
treated as described above with TiCl4 (7.3 ml, 7.3 mmol)
and allyl(trimethyl)silane (0.63 g, 7.3 mmol) to yield a 1:1
mixture of product diastereoisomers in an overall yield of
98%. The major diastereoisomer from more diastereoselective
reactions was isolated following flash column chromatography
using ethyl acetate–hexanes as eluent as off-white crystals, a
portion of which was recrystallised from dichloromethane and
hexanes to yield clear, colourless crystals. Mp 112–114 ЊC
(Found: C, 78.0; H, 6.30; N, 4.57. C19H19NO2 requires C, 77.80;
H, 6.52; N, 4.77%); [α]D (Major isomer) = ϩ152.2 [c = 2.68,
CH2Cl2]; νmax/cmϪ1 (Nujol) 3241, 1657, 1463, 1376, 1061, 928,
(3S,9bR)-3,9b-Diphenyl-2,3,5,9b-tetrahydro[1,3]oxazolo-
[2,3-a]isoindol-5-one, 10. (S)-Phenylglycinol (1.21 g, 8.84 mmol)
and benzophenone-2-carboxylic acid (2.0 g, 8.84 mmol) were
slurried in toluene (150 ml). The mixture was heated at reflux
under Dean–Stark conditions for 24 hours. The resultant yel-
low solution was allowed to cool and the toluene removed
under reduced pressure to yield a yellow oil. 1H NMR analysis
of this crude product indicated the formation of only one
diastereoisomer. The oil was adsorbed onto silica and purified
by flash-column chromatography using a 1:1 mixture of light
petroleum ether and ether as eluent to afford the target com-
pound as a white powder, a portion of which was recrystallised
from dichloromethane and hexanes to yield clear, colourless
needles (2.9 g, 98%). Mp 104–106 ЊC; [α]D = ϩ282.0 [c = 1.90,
CH2Cl2] (Found: C, 80.75; H, 5.18; N, 4.18. C22H17NO2 requires
C, 80.71; H, 5.23; N, 4.27%); νmax/cmϪ1 (Nujol) 1724, 1463, 1301,
756; δH (CDCl3, 400 MHz) 4.25 (1H, t, J 8.5, CH2-O), 4.94 (1H,
t, J 8.5, CH2-O), 5.3 (1H, t, J 8.5, N-CH-Ph), 7.20–7.41 (9H, m,
Ar), 7.50–7.54 (2H, m, Ar), 7.64–7.67 (2H, m, Ar), 7.88–7.91
(1H, m, Ar); δC (CDCl3, 67.5 MHz) 59.9, 76.9, 101.7, 123.6,
124.4, 125.9 (2C), 126.6 (2C), 127.4, 128.4 (2C), 128.6, 128.7
(2C), 130.2, 130.8, 133.4, 138.2, 138.8, 147.3, 175.4; m/z (EI)
327 (Mϩ, 15%), 297 (100%) (Found: Mϩ, 327.1255. C22H17NO2
requires 327.1259).
733; δH (CDCl , 400 MHz) 2.62–2.67 (2H, m, CH ᎐CH-CH -),
᎐
3
2
2
4.10–4.16 (1H, dd, J 12.3, 3.5, Ph-CH(N)-CH2-O), 4.37–
4.44 (2H, m, Ph-CH(N)-CH2O), 4.76–4.80 (1H, dd, J 7.4, 3.2,
CH ᎐CH-CH -CH(Ar)N), 4.92–5.01 (2H, m, CH ᎐CH-),
᎐
᎐
2
2
2
5.21–5.36 (1H, m, CH ᎐CH-), 7.22–7.31 (5H, m, Ar), 7.34–7.52
᎐
2
(3H, m, Ar), 7.82 (1H, d, J 7.4, Ar), OH not visible; δC (CDCl3,
100 MHz) 34.8, 59.7, 61.9, 64.0, 119.3, 122.0, 123.3, 127.0
(2C), 127.6, 128.0, 128.5 (2C), 130.3, 131.6, 132.0, 137.7, 144.7,
169.9; m/z (CI) 294 [Mϩ ϩ 1, 100%] (Found: Mϩ, 293.1416.
C19H19NO2 requires 293.1415).
(3S)-3-Phenyl-2-[(1S)-2-hydroxy-1-phenylethyl]-2,3-dihydro-
1H-isoindol-1-one, 11. (3S,9bR)-3,9b-Diphenyl-2,3,5,9b-tetra-
hydro[1,3]oxazolo[2,3-a]isoindol-5-one, 10 (0.1 g, 7.3 mmol)
was treated as described in the general procedure using TiCl4 in
dichloromethane (10.95 ml, 10.95 mmol, 1 M solution) and
triethylsilane (1.75 ml, 10.95 mmol) to yield the target com-
pound, a single diastereoisomer, as off-white crystals, a portion
of which was recrystallised from dichloromethane and hexanes
to yield clear, colourless crystals (0.09 g, 90%). Mp 115–116 ЊC
(Found: C, 79.99; H, 5.83; N, 4.26. C22H19NO2 requires C,
(3R,9bS)-9b-Methyl-3-phenyl-2,3,5,9b-tetrahydro[1,3]-
oxazolo[2,3-a]isoindol-5-one, 13. (R)-Phenylglycinol (1 g, 7.3
mmol) and 2-acetylbenzoic acid (1.2 g, 8.1 mmol) were slurried
in toluene (100 ml). The mixture was heated at reflux under
Dean–Stark conditions for 24 hours. The resultant yellow
solution was allowed to cool and the toluene removed under
reduced pressure to yield a yellow oil. 1H NMR analysis of this
crude product indicated the formation of only one diastereo-
isomer. The oil was adsorbed onto silica and purified by flash-
column chromatography using a 1:1 mixture of light petroleum
ether and ether as eluent to afford the target compound as a
white powder, a portion of which was recrystallised from
dichloromethane and hexanes to yield clear, colourless needles
80.22; H, 5.81; N, 4.25%); [α]D = ϩ84.8 [c = 3.28, CH2Cl2]; νmax
/
cmϪ1 (Nujol) 3482, 1669, 1464, 1377, 1059, 741; δH (CDCl3, 270
MHz) 4.0–4.10 (1H, m, N-CH(Ph)-CH2O), 4.29–4.37 (2H, m,
N-CH(Ph)CH2O), 5.2 (1H, s, CH(Ar)-N), 7.05–7.49 (13H, m,
Ar), 7.91–7.94 (1H, m, Ar), OH not visible; δC (CDCl3, 67.5
MHz) 62.9, 64.5, 65.9, 123.0, 123.7, 127.3 (2C), 127.7 (2C),
127.9, 128.5, 128.8 (2C), 128.9, 129.2 (2C), 131.4, 132.3, 136.4,
J. Chem. Soc., Perkin Trans. 1, 2000, 1715–1721
1719

View Article Online
137.9, 146.3, 170.2; m/z (EI) 329 [Mϩ, 3%], 301 (100%) (Found:
CH-CH ), 2.64–2.74 (1H, m, CH ᎐CH-CH ), 4.62–4.67 (1H,
᎐
2 2 2
dd, J 7.7, 4.9, -N-CH), 5.11–5.18 (2H, m, CH ᎐CH), 5.71–5.87
᎐
2
Mϩ, 329.1408. C22H19NO2 requires 329.1415).
(1H, m, CH ᎐CH-), 7.42–7.57 (3H, m, Ar), 7.82 (1H, d, J 8.2,
᎐
2
Ar), OH not visible; δC (CDCl3, 67.5 MHz) 38.9, 56.2, 119.2,
122.6, 123.8, 128.2, 131.8, 132.0, 133.0, 146.8, 171.0;
m/z (EI) 173 [Mϩ, 2%], 132 (100%) (Found: Mϩ, 173.0839.
C11H11NO requires 173.0841).
(3R)-3-Methyl-2-[(1R)-2-hydroxy-1-phenylethyl]-2,3-
dihydro-1H-isoindol-1-one, 14. (3R,9bS)-9b-Methyl-3-phenyl-
2,3,5,9b-tetrahydro[1,3]oxazolo[2,3-a]isoindol-5-one, 13 (1.0 g,
7.3 mmol) was treated as described in the general procedure
using TiCl4 (11.0 ml, 11.0 mmol) and triethylsilane (1.8 ml, 11.0
mmol) to yield the target compound, a single diastereoisomer,
as a colourless oil which was further purified by flash-column
chromatography using a 1:1 mixture of ethyl acetate and
hexanes as eluent (1.0 g, 99%). [α]D = ϩ21.3 [c = 2.34, CH2Cl2];
νmax/cmϪ1 (Nujol) 3379, 1667, 1469, 1073, 726; δH (CDCl3, 400
MHz) 1.43 (3H, d, J 6.7, CH3), 4.18–4.22 (1H, dd, J 11.3, 5.5,
CH2OH), 4.54–4.58 (1H, q, J 6.7, CHCH3), 4.87–4.92 (1H, dd,
J 11.2, 10.0, CH-Ph), 5.05–5.09 (1H, dd, J 9.9, 5.5, CH2OH),
7.29–7.39 (5H, m, Ar), 7.46–7.55 (3H, m, Ar), 8.64 (1H, d,
J 7.6, Ar), OH not visible; δC (CDCl3, 100 MHz) 18.8, 43.8,
56.0, 59.4, 121.8, 123.6, 127.4 (2C), 128.1, 128.2, 128.7 (2C),
131.3, 131.7, 138.0, 146.9, 169.1; m/z (EI) 267 [Mϩ, 7%], 236
(100%) (Found: Mϩ, 267.1255. C17H17NO2 requires 267.1259).
(3R)-3-Methyl-2,3-dihydro-1H-isoindol-1-one, 16. (3R)-3-
Methyl-2-[(1R)-2-hydroxy-1-phenylethyl]-2,3-dihydro-1H-iso-
indol-1-one, 14 (0.50 g, 1.87 mmol) was treated as described in
Method A to yield a crude brown crystalline residue which
was recrystallised from ethyl acetate to yield the target com-
pound as a yellow powder. Chiral HPLC experiments17 showed
that the crude product mixture had an enantiomeric excess of
ca. 96%. Mp 129–133 ЊC; [α]D = Ϫ89.7 [c = 1.7, MeOH]; νmax
/
cmϪ1 (Nujol) 3380, 1668, 1610; δH (CDCl3, 400 MHz) 1.46 (3H,
d, J 6.7, -CH3), 4.64–4.69 (1H, q, J 6.7 -CH-CH3), 7.20–7.30
(1H, m, Ar), 7.38–7.43 (1H, m, Ar), 7.50–7.54 (1H, m, Ar), 7.81
(1H, d, J 7.5, Ar), 8.5 (1H, br s, NH); δC (CDCl3, 100 MHz)
19.8, 52.6, 121.9, 123.3, 127.5, 131.5, 137.8, 146.9, 171.1;
m/z (EI) 147 [Mϩ, 85%], 132 (100%) (Found: Mϩ, 147.0683.
C9H9NO requires 147.0684).
Removal of phenylglycinol auxiliary: Method A18
(3S)-3-Allyl-2,3-dihydro-1H-isoindol-1-one, 15. Following
the three step (one-pot) method of Vernon and Fains,18 (3S)-
3-allyl-2-[(1R)-2-hydroxy-1-phenylethyl]-2,3-dihydro-1H-iso-
indol-1-one (as a 2:1 mixture of diastereoisomers 8 and 9)
(1.0 g, 3.41 mmol) was dissolved in dry dichloromethane
(20 ml) under a nitrogen atmosphere. The mixture was cooled
to 0 ЊC and triethylamine (0.72 ml, 5.12 mmol) was added.
Methanesulfonyl chloride (0.84 ml, 10.24 mmol) was then
added dropwise and the mixture was stirred at this temperature
for 3 hours. Cold water (30 ml) was then added and the mixture
extracted with dichloromethane (3 × 30 ml). The combined
organic extracts were washed successively with 2 M HCl and
water, dried (NaSO4), and concentrated under reduced pressure
to yield the crude product as an off-white powder (0.8 g, 63%).
1H NMR of this chiral mesylate intermediate showed no epim-
erisation, and it was used in the subsequent step without further
purification.
The mesylate was dissolved in dry ethanol under a nitrogen
atmosphere and sodium ethoxide (0.95 g, 13.96 mmol) in dry
ethanol (20 ml) was added by syringe and the mixture stirred at
room temperature for 4 hours. The reaction mixture was con-
centrated under reduced pressure and dissolved in dichloro-
methane. Water (20 ml) was added and the mixture extracted
with dichloromethane (3 × 20 ml). The combined organic
extracts were then washed with saturated sodium bicarbonate
solution, dried and then concentrated under reduced pressure
to yield the intermediate enamide (0.44 g, 74%). Due to the
sensitive nature of this compound no further purification was
attempted, and the crude product was promptly used in the
subsequent reaction.
The enamide was dissolved in a 1:1 mixture of ethanol and
6 M HCl (50 ml). The mixture was then heated at reflux for
4 hours and then allowed to cool. The reaction mixture was
then concentrated under reduced pressure and extracted with
dichloromethane (3 × 20 ml). The combined organic extracts
were then washed with saturated sodium bicarbonate solution,
dried and concentrated under reduced pressure to yield a brown
crystalline residue which was recrystallised from ethanol and
hexanes to yield colourless needles (0.21 g, 90%). Chiral HPLC
experiments17 showed that the crude product mixture was
composed of a 2:1 mix of enantiomers, showing that the
stereochemical integrity of the 2:1 mixture of substrate
diastereoisomers had not been adversely affected throughout
the deprotection sequence. Mp 105–106 ЊC; [α]D = ϩ17.8
[c = 0.87, CH2Cl2]; νmax/cmϪ1 (Nujol) 3157, 1691, 1673, 1612,
Removal of phenylglycinol auxiliary: Method B, concentrated
sulfuric acid cleavage
(3S)-3-Phenyl-2,3-dihydro-1H-isoindol-1-one, 17. (3S)-3-
Phenyl-2-[(1S)-2-hydroxy-1-phenylethyl]-2,3-dihydro-1H-iso-
indol-1-one, 11, (0.36 g, 1.09 mmol) was added to 98% sulfuric
acid (20 ml) in a boiling tube on a water bath heated at 90 ЊC.
The mixture was heated in this manner until all the solid had
dissolved. From this point, heating was continued for 2 minutes.
The acid mixture was then carefully cooled before being added
to cold water (40 ml). The resulting green solution was then
cooled quickly and was extracted with dichloromethane (3 × 50
ml). The combined organic extracts were washed with water,
dried and concentrated under reduced pressure to yield a brown
crystalline residue. Chiral HPLC experiments17 showed that the
crude product mixture had an enantiomeric excess of 96%. The
crude material was recrystallised from ethanol and hexanes to
yield colourless needles (0.17 g, 74%). Mp 221–224 ЊC (Found:
C, 80.20; H, 5.25; N, 6.60. C14H11NO requires C, 80.36; H, 5.30;
N, 6.69%); [α]D = ϩ230.0 [c = 2.0, DMSO]; νmax/cmϪ1 (Nujol)
3401, 1709, 1464, 1012, 766; δH (d6-DMSO, 400 MHz) 5.74
(1H, s, Ar-CH-NH), 7.28–7.32 (5H, m, Ar), 7.35–7.37 (1H, m,
Ar), 7.46–7.55 (2H, m, Ar), 7.73 (1H, d, J 7.2, Ar), 9.08 (1H, br
s, -NH); δC (d6-DMSO, 100 MHz) 59.5, 122.8, 123.4, 126.5
(2C), 127.8, 128.1, 128.7 (2C), 131.3, 131.8, 139.5, 148.1, 169.7;
MS (EI) m/z 209 [Mϩ, 5%], 207 (100%) (Found: Mϩ, 209.0845.
C14H11NO requires 209.0840).
X-Ray data‡
Compound 8. Clear needle; orthorhombic, space group
P21212, a = 21.713(4), b = 8.530(3), c = 8.770(4) Å, V = 1624(1)
Å3, T = 293 K, Z = 4, Dcalc = 1.200 g cmϪ3, µ(Cu-Kα) = 5.82
cmϪ1, F000 = 624.00. The structure was solved by direct methods
and refined by full matrix least squares, with a final R and Rw of
0.052 and 0.030 respectively, for 1441 reflections.
Compound 10. Colourless plate; monoclinic, space group
P21(#4), a = 9.171(3), b = 10.530(4), c = 18.069(3) Å, β =
93.06(2)Њ, V = 1742.5(9) Å3, T = 293 K, Z = 4, Dcalc = 1.248 g
cmϪ3, µ(Cu-Kα) = 6.37 cmϪ1, F000 = 688.00. The structure was
solved by direct methods and refined by full matrix least
squares, with a final R and Rw of 0.052 and 0.032 respectively,
for 2960 reflections.
1070, 921; δH (CDCl , 270 MHz) 2.31–2.43 (1H, m, CH ᎐
‡ CCDC reference number 207/428.
᎐
3
2
1720
J. Chem. Soc., Perkin Trans. 1, 2000, 1715–1721

View Article Online
7 S. M. Allin, C. J. Northfield, M. I. Page and A. M. Z. Slawin,
Tetrahedron Lett., 1997, 38, 3627.
8 H. Hiemstra and W. N. Speckamp, in Comprehensive Organic
Synthesis, eds. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991,
vol. 2, p. 1047; A. I. Meyers and G. P. Brengel, Chem. Commun.,
1997, 1.
9 For examples see: A. I. Meyers and L. E. Burgess, J. Org. Chem.,
1991, 56, 2294; L. E. Burgess and A. I. Meyers, J. Org. Chem., 1992,
57, 1656; A. I. Meyers and G. P. Brengel, Chem. Commun., 1997, 1;
M. D. Groaning and A. I. Meyers, Tetrahedron Lett., 1999, 40, 4639.
10 For examples see: R. P. Polniaszek and S. E. Belmont, J. Org. Chem.,
1990, 55, 4688; R. P. Polniaszek and S. E. Belmont, J. Org. Chem.,
1991, 56, 4868; A. A. Bahajaj, P. D. Bailey, M. H. Moore, K. M.
Morgan and J. M. Vernon, J. Chem. Soc., Chem. Commun., 1994,
2511; M. Amat, N. Llor and J. Bosch, Tetrahedron Lett., 1994, 35,
2223; M. Amat, N. Llor, J. Bosch and X. Solans, Tetrahedron, 1997,
53, 719; S. G. Kim and K. H. Ahn, Synth. Commun., 1998, 28, 1387;
N. Yamazaki, T. Itoh and C. Kibayashi, Tetrahedron Lett., 1999, 40,
739.
Compound 11. Colourless prism; orthorhombic, space group
P212121, a = 10.726(5), b = 17.794(5), c = 8.945(4) Å, V =
1707(1) Å3, T = 293 K, Z = 4, Dcalc = 1.281 g cmϪ3, µ(Cu-Kα) =
6.13 cmϪ1, F000 = 696.00. The structure was solved by direct
methods and refined by full matrix least squares, with a final R
and Rw of 0.047 and 0.046 respectively, for 1502 reflections.
Acknowledgements
We thank the Universities of Loughborough and Huddersfield
for facilities and financial support. We also thank Dr Neil
McLay (Huddersfield) and Dr Tim Smith (Loughborough) for
assistance with NMR spectroscopy, and Professor Harry
Heaney (Loughborough) and Dr John Vernon (York) for
helpful discussions.
11 A. I. Meyers and L. E. Burgess, J. Org. Chem., 1991, 56, 2294.
12 S. E. Denmark and T. M. Willson, J. Am. Chem. Soc., 1989, 111,
3475; S. Kim, J. Yun Do, S. H. Kim and D. Kim, J. Chem. Soc.,
Perkin Trans. 1, 1994, 2357.
13 S. M. Allin, C. J. Northfield, M. I. Page and A. M. Z. Slawin,
Tetrahedron Lett., 1999, 40, 141.
References
1 K. Hiraga and Y. Saji, PCT Int. Appl. 1984, WO 8303 410 (Chem.
Abstr., 1984, 100, 51451p).
2 H. P. Rang, M. M. Dale and J. M. Ritter, in Pharmacology, 3rd edn.,
Churchill-Livingstone, London, 1995.
3 I. Takahashi, T. Kawakami, E. Hirano, H. Yokota and H. Kitajima,
Synlett, 1996, 353.
4 M. Anzini, A. Cappelli, S. Vomero, G. Giorgi, T. Langer, G. Bruni,
M. R. Romeo and A. S. Basile, J. Med. Chem., 1996, 36, 4275;
V. Gotor, F. Limeres, R. Garcia, M. Bayod and R. Brieva,
Tetrahedron: Asymmetry, 1997, 8, 995.
5 Z. P. Zhuang, M. P. Kung, M. Mu and H. F. King, J. Med. Chem.,
1998, 41, 157.
6 W. Schafer, W.-G. Friebe, H. Leinert, A. Mertens, T. Poll, W. von der
Saal, H. Zilch, B. Nuber and N. L. Ziegler, J. Med. Chem., 1993, 36,
726; A. Mertens, H. Zilch, B. Konig, W. Schafer, T. Poll, W. Kampe,
H. Seidel, U. Leser and H. Leinert, J. Med. Chem., 1993, 36, 2526;
E. De Clercq, J. Med. Chem., 1995, 38, 2491.
14 We wish to thank Dr Dave Ager (NSC Technologies) for the
generous gift of phenylglycinol used in this study.
15 S. M. Allin, C. J. Northfield, M. I. Page and A. M. Z. Slawin,
Tetrahedron Lett., 1999, 40, 143.
16 L. E. Burgess and A. I. Meyers, J. Org. Chem., 1992, 57, 1656
17 D. R. Lide, in Handbook of Chemistry and Physics, 72nd edn.,
CRC Press, Boston, 1991.
18 O. Fains and J. M. Vernon, Tetrahedron Lett., 1997, 38, 8265.
19 Chiral HPLC study carried out using Chiracel-OJ column eluting
with a 3% IPA–97% hexanes solvent mixture. Racemic samples of
the targets under study were prepared and investigated prior to the
enantiomerically enriched products.
20 A. Marsili and V. Scartoni, Gazz. Chim. Ital., 1972, 102, 806.
J. Chem. Soc., Perkin Trans. 1, 2000, 1715–1721
1721