A novel and highly stereoselective route for the synthesis of non-racemic 3-substituted isoindolin-1-one targets

Article abstract of DOI:10.1016/j.tet.2018.11.050

A new, versatile and highly stereoselective approach for the synthesis of non-racemic 3-substituted isoindolin-1-ones is described from a readily available chiral template. The potential of this new protocol is demonstrated through the synthesis of an enantiomerically enriched 3-alkyl N-H isoindolin-1-one target with an e.e. of 98%.

Full text of DOI:10.1016/j.tet.2018.11.050

Accepted Manuscript
A novel and highly stereoselective route for the synthesis of non-racemic 3-
substituted isoindolin-1-one targets
Ryan A. Hemming, Megan Bell, Liam J. Duffy, Jonathan Bristow, John D. Wallis,
Steven M. Allin, Philip C. Bulman Page
PII:
S0040-4020(18)31405-4
https://doi.org/10.1016/j.tet.2018.11.050
TET 29961
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 September 2018
Revised Date: 13 November 2018
Accepted Date: 23 November 2018
Please cite this article as: Hemming RA, Bell M, Duffy LJ, Bristow J, Wallis JD, Allin SM, Bulman Page
PC, A novel and highly stereoselective route for the synthesis of non-racemic 3-substituted isoindolin-1-
one targets, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.11.050.
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ACCEPTED MANUSCRIPT
Graphical Abstract
A Novel and Highly Stereoselective Route for the Synthesis of Non-racemic 3-
Substituted Isoindolin-1-one Targets
Ryan A. Hemming,1 Megan Bell,1 Liam J. Duffy,1 Jonathan Bristow,1 John D. Wallis,1
Steven M. Allin1* and Philip C. Bulman Page2
1Department of Chemistry and Forensics, School of Science and Technology, Nottingham
Trent University, Nottingham NG11 8NS
2School of Chemistry, University of East Anglia, Norwich NR4 7TJ
Corresponding author: steve.allin@ntu.ac.uk (ORCHID: 0000-0001-5198-9339)
Abstract
A new, versatile and highly stereoselective approach for the synthesis of non-racemic 3-
substituted isoindolin-1-ones is described from a readily available chiral template. The
potential of this new protocol is demonstrated through the synthesis of an enantiomerically
enriched 3-alkyl N-H isoindolin-1-one target with an e.e. of 98%.
Keywords: Isoindolinone, N-Acyliminium, Stereoselective Synthesis
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1. Introduction
The synthesis of non-racemic 3-substituted isoindolin-1-one targets remains an area of
significant interest due to the wide range of biological activities exhibited by this class of
compound. Typical examples of bioactive targets include compounds 1-3 (Figure 1). (S)-PD-
172938, 1, shows affinity for dopamine D4 receptors,1 whilst (S)-pagoclone, 2, is known to
display anxiolytic activity2 and JM-1232, 3, is a benzodiazepine receptor agonist also being
investigated for the treatment of anxiety related conditions.3 Selected biological activities of
other, related, 3-substituted isoindolin-1-one derivatives include affinity for 5-HT receptors,4
as inhibitors of the MDM2-p53 protein-protein interaction,5 and as Kv1.5 ion channel
blockers.6
Figure 1. Biologically Active 3-Substituted Isoindolin-1-ones.
Deprotonation and subsequent benzylic C-alkylation of the parent isoindolinone template has
been previously explored as a route to such targets in racemic form.7 This approach has been
extended to include chiral auxiliary based approaches for the asymmetric synthesis of non-
racemic 3-substituted isoindolin-1-ones: for example in Couture’s application of an
aminoprolinol-derived template,8 Royer’s use of phenylglycinol,9 and Comins’ approach
using TCC esters for control of asymmetric alkylation.10
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In our own previous contribution to this area we pioneered the use of readily accessible
Meyers-type tricyclic lactams, 4, as versatile asymmetric building blocks, and reported the
successful synthesis of non-racemic 3-alkyl and 3-aryl isoindolin-1-ones.11 Appropriately
substituted chiral templates, 4, were used as novel N-acyliminium precursors which could be
activated towards subsequent reaction with carbon nucleophiles (Scheme 1, path 1), or with
hydride (Scheme 1, path 2) in order to deliver the desired 3-substituted isoindolin-1-one
targets.
Although pathway 1 was found to suffer from low levels of product diastereoselectivity, we
discovered that a complementary approach, pathway 2, delivered up to exclusive levels of
product diastereoselectivity. We have also demonstrated two effective methods for removal
of the phenylglycinol chiral auxiliary to deliver the corresponding enantio-enriched 3-alkyl
and 3-aryl substituted NH-isoindolinones, 5, with minimal loss of stereochemical integrity at
the newly created chiral centre.11
Scheme 1. Approaches to Non-racemic 3-Substituted Isoindolin-1-one Targets Using a
Tricyclic Lactam Template.
We were intrigued by the subsequent work from the aforementioned groups of Couture,8
Royer9 and Comins10 which have each approached this challenge by generating an anion at
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the benzylic position of suitably derivatized, non-racemic isoindolinone intermediates,
followed by an asymmetric alkylation protocol - a complementary approach to our own
routes.
In this present paper we describe a novel application of the “Meyers’” tricyclic lactams in an
analogous anionic approach to the targets of interest (Scheme 1, path 3), which significantly
extends our earlier work in this area by overcoming a number of potentially limiting factors,
such as the lack of availability of appropriate ketoacid building blocks, and so allows for the
preparation of a wider range of the intermediate templates, 4.
2. Results and Discussion
In the new approach described in this paper we have utilized the (R)-phenylglycinol derived
template, 6, readily prepared as previously described by us in 75% yield as a single
diastereoisomer through Dean-Stark condensation of the commercially available enantiopure
aminoalcohol with 2-carboxybenzaldeyde.11
In our exploratory work (Scheme 2), template 6 was deprotonated using 1.1 eq. of LHMDS at
-78 oC in dry THF and the intermediate anion was then alkylated with 1.2 eq. MeI to generate
the alkylated template 7 as a 1:1 mixture of diastereoisomers, as determined by 400 MHz 1H-
NMR spectroscopy on the crude reaction mixture (Step 1).
The lack of any diastereoselectivity observed in the synthesis of intermediate 7 is of no
consequence to our ultimate goal, since the subsequent step of this new approach involves the
generation of a planar N-acyliminium species on activation of 7, where any stereochemistry
that was established during the initial alkylation step would be lost. followed by the second
stage of the process, a stereoselective reduction of the non-racemic N-acyliminium
intermediate with a silane-based hydride reagent, which would be expected to induce high
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levels of diastereoselectivity in the final product, based on our previous experience with these
templates.11
Our results are presented in Table 1 for alkylation of template 6 using a representative range
of alkyl halides. For allyl bromide, which gave the highest level of diastereoselectivity when
using LiHMDS as the base, alternative bases were investigated due to the significance of the
counterion on the diastereoisomeric product ratio in related studies.9
Scheme 2. (i) 1.1 eq. Base, THF, -78 oC; (ii) 1.2 eq. Alkyl halide, THF, -78 oC to R.T. (12 h),
then H3O+; (iii) 1.5 eq. TiCl4, DCM, -78 oC; (iv) 1.5 eq. Et3SiH, THF, -78 oC to R.T.
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Table 1. Diastereoselective Alkylation of Tricyclic Lactam, 6.
Base
Alkyl halide
Diastereoisomeric
Ratioa
% conversiona
LiHMDS
LiHMDS
LiHMDS
NaHMDS
KHMDS
Me-I
50:50
75:25
80:20
90:10
86:14
50
94
96
50
57
Benzyl-Br
Allyl-Br
Allyl-Br
Allyl-Br
adetermined by 400 MHz 1H-NMR spectroscopy on the crude reaction mixture.
As can be seen from Table 1, the highest level of diastereoselectivity achieved with allyl
bromide as the electrophile was in the presence of sodium as the counterion, although this
1
base (NaHMDS) gave the poorest conversion (50%) by 400 MHz H NMR. A significantly
higher conversion of 96% was achieved with LiHMDS. In examples where the conversion
was observed to be low, the 400 MHz 1H NMR spectra of the crude product mixture showed
only the presence of non-alkylated starting material as a by-product. Variation of the number
of equivalents of both base and alkyl halide did not improve the observed outcome.
As noted by Couture,8 the deprotonated species 6a may undergo delocalization to form the
alternative extended enolate 6b. It may be tempting to suggest that a preference for one
enolate form over the other (6a : 6b) in the presence of a given base may help to rationalize
the observed diastereoselectivities of the alkylation step, although there may be other factors
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at play and so we would prefer not to speculate further at this juncture, particularly as the
stereoselective outcome of this initial alkylation reaction is of no consequence to the overall
success of this new approach to the 3-substituted isonidolino-1-one targets.
We were pleased to find that reductive ring-opening of intermediate 7 using 1.5 eq.
triethylsilane in the presence of 1.5 eq. TiCl4 in dry DCM gave the desired 3-methyl
isoindolino-1-one, 8a, in 32% yield (over 2 steps) as a ≥95:5 mixture of diastereoisomers by
1H NMR spectroscopy (Scheme 2, Table 2).
Access to compound 8a, prepared by us in our previous research efforts,11 allowed us to
determine that the relative stereochemistry of the major diastereoisomer was as shown in
1
Scheme 2, by comparison of H NMR data. The observed stereochemical outcome can be
rationalized by reference to our usual conformational model (Scheme 2).
Having established that this new approach to the synthesis of 3-substituted isoindolin-1-one
targets had significant potential, we explored the application of a range of alkylating agents
(Table 2). Based on the model study outlined in Table 1, we chose to use LiHMDS as the
base, since this base gave highest conversions. Although the initial diastereoselectivity for
alkylation of the template using LiHMDS was the lowest for those bases explored, this would
be of no consequence to the formation of the desired non-racemic 3-substituted isoindolin-1-
one targets with high levels of diastereoselectivity. The alkylated intermediate from Step 1
was not isolated during this reaction sequence, but instead was subjected to the reductive ring
opening in Step 2.
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Table 2. Template Derivatization and Diastereoselective Ring Opening.
Alkyl halide
Step 1
conversion
(%)a
diastereoisomeric
ratio
product
diastereoisomeric
ratio
yield
(%)b
(step 1)a
50:50
50:50
66:34
80:20
60:40
(step 2) a
≥95:5
≥95:5
≥95:5
≥95:5
≥95:5
methyl iodide
ethyl iodide
50
81
78
96
94
32
47
32
49
35
8a
8b
8c
8d
8e
propyl iodide
allyl bromide
benzyl bromide
2-fluorobenzyl
bromide
94
96
83:17
80:20
≥95:5
≥95:5
65
61
8f
3-methoxybenzyl
bromide
8g
a determined by 400 MHz 1H NMR spectroscopy on the crude reaction mixture.
b overall isolated yield after 2 steps, following purification by flash column chromatography.
As can be seen from Table 2, alkylation of the parent template could be achieved with
variable levels of diastereoselectivity at the intermediate stage of the synthetic sequence (Step
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1). In all cases, the reductive ring-opening of the intermediate proceeded to deliver excellent
levels of product diastereoselectivity (Step 2) for all final target compounds. Although the
overall yields of the desired products are only low to moderate, the yields quoted for products
8a-g in Table 2 are over the two reaction steps from template 6, following purification by
column chromatography. In all cases, the major by-product of the two-step procedure was
formation of the corresponding ring-opened product from the presence of unalkylated
template 6 following Step 1, which was readily separable from the desired products by
column chromatography.
Figure 2. Single Crystal X-Ray Structure of Compound 8e.
X-Ray crystal structures were obtained for the major diastereoisomers of products 8b, 8d and
8e; with that of benzyl-substituted product 8e shown in Figure 2. Interestingly, the relative
stereochemistry of the allyl-substituted product 8d is, as expected from our rationale,
opposite to that observed when accessing the same compound via our alternative,
complementary approach using a carbon-centred nucleophile (allyl trimethylsilane, Scheme
1, path 1), thus further supporting the conformational model that we have proposed to
rationalize the stereochemical induction that is observed on ring opening of such tricyclic
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lactam substrates (Scheme 2). The induced relative stereochemistry in the reaction sequence
is governed by the approach of the corresponding nucleophile: hydride in this current study,
but allyl in our previous work, thus leading to the observed opposite relative
stereochemistry.11
One major advantage of our new approach, described herein, is the significant increase in
product diastereoselectivity that can be achieved for a wider range of 3-position substituents:
for example, allyl derivative 8d was isolated as a ≥95:5 ratio of diastereoisomers using our
new approach, whereas our previously reported methodology delivered this target compound
with a diastereoisomeric ratio of only 2:1.11
In order to demonstrate the synthetic potential of this new methodology as a potential route to
access enantiomerically enriched 3-substituted NH-isoindolin-1-one targets, we then
subjected major diastereoisomer 8a to our previously developed method for cleavage of the
chiral auxiliary group (Scheme 3).11 Thus, treatment of 8a with 96% sulfuric acid over a
reaction time of just 2 minutes at 95 oC gave a 38% yield of (R)-3-methyl isoindolino-1-one,
9, with 98% e.e. (as determined by chiral HPLC).12
O
O
96% H2SO4
95 oC, 2 min.
Ph
N
NH
H
H
Me
OH
Me
9
8a
Scheme 3. Access to Enantiomerically Enriched 3-Substituted Isoindolin-1-one Target, 9.
3. Conclusion
Our previously reported approach to the synthesis of non-racemic 3-substituted isoindolin-1-
ones relied upon the availability of appropriate keto-acid substrates, which could be a
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limiting factor in the introduction of structural diversity to the chiral templates. Given the
ready availability of a wide range of alkylating agents, our new approach described herein
now circumvents this issue, since it allows for the synthesis of an extended range of 3-
substituted isoindolin-1-one targets from a common, readily available lactam template (4, R =
H), itself accessed as a crystalline intermediate in high yield in one step from commercially
available substrates. Further applications of this methodology in target synthesis are
underway, and will be reported in due course.
4. Experimental
Materials and Methods
13
1H and C nuclear magnetic resonance (NMR) were measured on a Jeol eclipse 400 MHz
1
13
spectrometer using CDCl3, at 400 MHz for H NMR and 100 MHz for C NMR. Chemical
shifts are quoted in ppm downfield from TMS; coupling constants (J) are quoted in Hertz
1
(Hz). TMS was defined as 0 ppm in H NMR and the residual chloroform triplet as 77.10
13
ppm in C NMR. The following abbreviations were used in analysis; broad (br), singlet (s),
doublet (d), triplet (t), quartet (q), double doublet (dd), doublet of doublet of doublets (ddd),
doublet of triplets (dt) and multiplet (m). Mass spectra were obtained from the EPSRC
National Mass Spectrometry Centre at Swansea University using electron spray ionisation
(ES). Infra-red spectra were recorded in the range 4000-600 cm-1 using a Perkin Elmer
spectrum 100 FT-IR spectrometer. Optical rotation measurements were obtained from a
Bellingham and Stanley ADP440+ Polarimeter, at 24 oC, at a concentration of 0.5 g/100 ml-1,
with a cell length of 5cm. Melting points were measured on a Stuart SMP10 melting point
apparatus.
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Reagents and solvents were purchased from Sigma-Aldrich, Acros Organics and Alfa Aesar,
and were used without further purification. Anhydrous solvents (used where specified) were
purchased from Sigma-Aldrich and used without further drying. Reactions were carried out
under a flow of nitrogen gas, where specified. Dry ice/acetone baths were used to cool
reactions to -78 ̊C.
The progress of the reactions was monitored by thin layer chromatography (TLC), using
glass pre-coated silica gel plates (Merck) visualized by UV irradiation at a wavelength of 254
nm. Flash column chromatography was carried out on silica gel 60 (43-60 mesh)
(Fluorochem).
(3R,9bS)-3-phenyl-2,3-dihydrooxazolo[2,3-a]isoindol-5(9bH)-one, (6).11c
(R)-Phenylglycinol, (5.00g, 36 mmol, 1 eq.) was heated with 2-carboxybenzaldehyde (6.02g,
40 mmol, 1.1 eq.) in toluene (300 mL) under Dean-Stark conditions for 48 hours. The crude
reaction mixture was then evaporated to yield an oil, which was purified by flash column
chromatography (50:50 Et2O/petroleum ether (40-60)). Evaporation of the solvents under
reduced pressure afforded a white crystalline solid. Yield: 75% (5.50 g); Mp: 117-119 ̊C
1
(DCM/hexanes); H NMR (400 MHz, CDCl3) δ 7.97 - 7.78 (m, 1H), 7.71 - 7.55 (m, 3H),
7.51 - 7.29 (m, 5H), 6.06 (s, 1H), 5.23 (t, J = 7.4 , 1H), 4.85 (dd, J = 7.4, 8.8, 1H), 4.17 (dd, J
= 7.4, 8.8, 1H).
(R)-2-((R)-2-hydroxy-1-phenylethyl)-3-methylisoindolin-1-one, 8a.
Compound 6, (1.00g, 3.96 mmol, 1.0 eq.) was dissolved in dry THF (15 mL, dry) under
nitrogen and the solution cooled to -78 ̊C. LiHMDS (1M in THF) (4.36 mL, 4.36 mmol, 1.1
12

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eq.) was then added drop-wise and the resulting mixture stirred for 30 minutes. Methyl iodide
(0.30 mL, 4.77 mmol, 1.2 eq.) was then added drop-wise and the solution was allowed to
warm to room temperature overnight. Saturated NH4Cl aq. (20mL) was then added to quench
the reaction, and the reaction mixture was then further diluted with H2O (20 mL). The
mixture was then extracted with 5 x 30 mL portions of Et2O and the combined organic
extracts were washed with 1 x 30 mL brine, dried over anhydrous MgSO4, filtered and
evaporated under reduced pressure to yield the crude product as a light brown oil which was
used in the next step without any further purification. Analysis of the crude reaction mixture
by 1H NMR spectroscopy (400 MHz) confirmed a conversion of 50% of starting material in
this synthetic step.
The crude product (1.06 g, 3.96 mmol, 1.0 eq.) was stirred in dry DCM (15 mL), under
nitrogen and cooled to -78
̊
drop-wise to the solution and left to stir for 30 minutes at -78
̊
5.94 mmol, 1.5 eq.) was added drop-wise to the mixture, which was then allowed to warm to
room temperature overnight. The reaction was quenched by the addition of saturated NH4Cl
aq. (20 mL) and then diluted further with H2O (20 mL). The mixture was extracted with 3 x
40 mL portions of DCM and the organic extracts combined and washed with 30 mL brine,
dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give a light
brown residue. This was then purified by flash column chromatography (100% petroleum
ether (40-60)) to afford a yellow oil. Yield: 32% (0.34 g); [α]D = + 244 (c 0.5, 24 oC, DCM);
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.4, 1H), 7.62 - 7.44 (m, 2H), 7.39 - 7.26 (m, 6H),
5.00 - 4.89 (m, 1H), 4.77 (dd, J = 3.4, 8.0, 1H), 4.53 - 4.43 (m, 1H), 4.34 (q, J = 6.7, 1H),
4.18 - 4.05 (m, 1H), 1.46 (d, J = 6.7, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 147.1, 137.9,
132.1, 128.9, 128.4, 128.1, 127.3, 123.9, 122.0, 64.7, 62.5, 57.1, 18.4; νmax (solid): 3333,
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1658, 1469, 1404, 1353 cm-1; HRMS (ESI, m/z): calcd. for C17H17NO2 (M + H+) 268.1332,
found: 268.1334.
(R)-3-ethyl-2-((R)-2-hydroxy-1-phenylethyl)isoindolin-1-one, (8b).
Compound 6, (0.50g, 1.98 mmol, 1.0 eq.) was dissolved in dry THF (15 mL) under nitrogen
and the solution cooled to -78 ̊C. LiHMDS (1M in THF) (2.18 mL, 2.18 mmol, 1.1 eq.) was
added drop-wise and the resulting mixture stirred for 30 minutes. Ethyl iodide (0.19 mL, 2.39
mmol, 1.2 eq.) was then added drop-wise and the solution was allowed to warm to room
temperature overnight. Saturated NH4Cl aq. (15 mL) was then added to quench the reaction,
which was then diluted further with H2O (20 mL). The mixture was then extracted with 5 x
30 mL portions of Et2O and the organic extracts were combined and washed with 1 x 30 mL
brine, dried over anhydrous MgSO4, filtered and evaporated to give the crude intermediate as
an orange oil, which was used in the next step without any further purification. Analysis of
1
the crude reaction mixture by H NMR spectroscopy (400 MHz) confirmed a conversion of
81% of starting material in this synthetic step.
The crude product (0.55 g, 1.98 mmol, 1.0 eq.) was stirred in dry DCM (10 mL), under
nitrogen and cooled to -78
̊
drop-wise and the solution left to stir for 30 minutes at -78
̊
mmol, 1.5 eq.) was added drop-wise to the mixture, which was then allowed to warm to room
temperature overnight. The reaction was quenched by addition of saturated NH4Cl aq. (20
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mL) and the mixture further diluted with H2O (20 mL). The mixture was then extracted with
3 x 30 mL portions of DCM and the combined organic extracts washed with 1 x 30 mL brine,
dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give a light
brown residue which was purified by flash column chromatography (80:20 EtOAc/ petroleum
ether (40-60)) to afford the target compound as a yellow crystalline solid. Yield: 47% (0.26
o
⁰
g); Mp: 101-104 C (DCM/hexanes); [α]D = + 180 (c 0.5, 24 C, DCM); νmax (solid): 3345,
1
2995, 2876, 1659, 1469, 1407, 1214 cm-1; H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.5,
1H), 7.62 - 7.40 (m, 2H), 7.38 - 7.26 (m, 6H), 7.38 - 7.21 (m, 1H), 5.07 - 4.99 (m, 1H), 4.62
(dd, J = 3.3, 8.0, 1H), 4.48 (dt, J = 7.9, 12.5, 1H), 4.40 (dd, J = 2.7, 5.1, 1H), 4.11 (ddd, J =
3.3, 7.0, 12.5, 1H), 2.13 - 1.90 (m, 2H), 0.55 (t, J = 7.4, 3H); 13C NMR (100 MHz, CDCl3) δ
170.4, 144.9, 138.0, 132.9, 132.0, 128.9, 128.4, 128.1, 127.3, 123.8, 122.0, 64.8, 62.8, 61.1,
22.9, 5.9; HRMS (ESI, m/z): calcd. for C18H19NO2 (M + H+) 282.1489, found 282.1489.
(R)-2-((R)-2-hydroxy-1-phenylethyl)-3-propylisoindolin-1-one, (8c).
Compound 6, (0.50 g, 1.98 mmol, 1.0 eq.) was dissolved in dry THF, (15 mL), under
nitrogen and the solution cooled to -78 ̊C. LiHMDS (1M in THF) (2.18 mL, 2.18 mmol, 1.1
eq.) was then added drop-wise and the resulting mixture stirred for 30 minutes. 1-
Iodopropane (0.23 mL, 2.39 mmol, 1.2 eq.) was then added drop-wise and the solution was
allowed to warm to room temperature overnight. Saturated NH4Cl aq. (15 mL) was then
added to quench the reaction, which was then diluted further with H2O (20 mL). The mixture
was then extracted with 5 x 30 mL portions of Et2O and the organic extracts were combined
and washed with 1 x 30 mL brine, dried over anhydrous MgSO4, filtered and evaporated
under reduced pressure to give the crude intermediate as a light brown oil, which was used in
1
the next step without any further purification. Analysis of the crude reaction mixture by H
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NMR spectroscopy (400 MHz) confirmed a conversion of 78% of starting material in this
synthetic step.
The crude product (0.58 g, 1.98 mmol, 1.0 eq.) was stirred in dry DCM (10 mL), under
nitrogen and cooled to -78
̊
drop-wise and the solution left to stir for 30 minutes at -78
̊
mmol, 1.5 eq.) was added drop-wise to the mixture, which was then allowed to warm to room
temperature overnight. The reaction was quenched by addition of saturated NH4Cl aq.
(20mL) and the mixture further diluted with H2O (20 mL). The mixture was then extracted
with 3 x 30 mL portions of DCM and the combined organic extracts washed with 1 x 30 mL
brine, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give a
light brown residue which was purified by flash column chromatography (80:20 EtOAc/
petroleum ether (40-60)) to afford the target compound as white crystalline solid. Yield: 32%
o
⁰
(0.19 g); Mp: 149-151 C (DCM/hexanes); [α]D = + 132 [c 0.5, 24 C, DCM]; νmax (solid):
1
3300, 2998, 2875, 1660, 1413, 1305, 1216 cm-1; H NMR (400 MHz, CDCl3) δ 7.87 (d, J =
7.5, 1H), 7.61 - 7.42 (m, 2H), 7.38 - 7.15 (m, 6H), 5.08 - 4.94 (m, 1H), 4.66 (dd, J = 3.4, 8.0,
1H), 4.47 (dt, J = 7.9, 12.5, 1H), 4.42 - 4.31 (m, 1H), 4.09 (ddd, J = 3.4, 7.3, 12.4, 1H), 2.02 -
1.79 (m, 2H), 1.29 - 1.09 (m, 1H), 0.88 - 0.68 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 170.2,
145.4, 137.9, 132.5, 131.8, 128.8, 128.2, 127.9, 127.1, 123.7, 121.9, 64.7, 62.6, 60.5, 32.3,
15.1, 13.9; HRMS (ESI, m/z): calcd. for C19H21NO2 (M + H+) 296.1645, found 296.1644.
(R)-3-allyl-2-((R)-2-hydroxy-1-phenylethyl)isoindolin-1-one, (8d).
Compound 6, (1.00 g, 3.96 mmol, 1.0 eq.) was dissolved in dry THF, (15 mL), under
nitrogen and the solution cooled to -78 ̊C. LiHMDS (1M in THF) (4.36 mL, 4.36 mmol, 1.1
eq.) was then added drop-wise and the resulting mixture stirred for 30 minutes. Allyl bromide
16

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(0.41 mL, 4.77 mmol, 1.2 eq.) was then added drop-wise and the solution was allowed to
warm to room temperature overnight. Saturated NH4Cl aq. (15mL) was then added to quench
the reaction, which was then diluted further with H2O (20 mL). The mixture was then
extracted with 5 x 30 mL portions of Et2O and the organic extracts were combined and
washed with 1 x 30 mL brine, dried over anhydrous MgSO4, filtered and evaporated under
reduced pressure to give the crude intermediate as an orange oil, which was used in the next
1
step without any further purification. Analysis of the crude reaction mixture by H NMR
spectroscopy (400 MHz) confirmed a conversion of 96% of starting material in this synthetic
step.
The crude product (1.15 g, 3.96 mmol, 1.0 eq.) was stirred in dry DCM (10 mL), under
nitrogen and cooled to -78
̊
drop-wise and the solution left to stir for 30 minutes at -78
̊
mmol, 1.5 eq.) was added drop-wise to the mixture, which was then allowed to warm to room
temperature overnight. The reaction was quenched by addition of saturated NH4Cl aq.
(20mL) and the mixture further diluted with H2O (20 mL). The mixture was then extracted
with 3 x 30 mL portions of DCM and the combined organic extracts washed with 1 x 30 mL
brine, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give a
light brown residue which was purified by flash column chromatography (80:20 EtOAc/
petroleum ether (40-60)) to afford the target compound as a yellow solid. Yield: 49% (0.57
o
⁰
g); Mp: 109-112 C (DCM/hexanes); [α]D = + 104 (c 0.5, 24 C, DCM); νmax (solid): 3381,
2924, 1725, 1646, 1406 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.4, 1H), 7.60 - 7.44
(m, 2H), 7.41 - 7.21 (m, 6H), 5.56 - 5.15 (m, 1H), 5.12 - 4.96 (m, 3H), 4.74 (dd, J = 3.2, 7.7,
1H), 4.49 - 4.36 (m, 2H), 4.13 (m, 1H), 2.80 - 2.48 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
170.1, 144.8, 137.8, 132.3, 131.8, 130.4, 128.8, 128.3, 127.9, 127.1, 123.7, 122.2, 119.7,
17

ACCEPTED MANUSCRIPT
64.5, 62.6, 59.9, 34.9; HRMS (ESI, m/z): calcd. for C19H19NO2 (M + H+) 294.1489, found
294.1490.
(R)-3-benzyl-2-((R)-2-hydroxy-1-phenylethyl)isoindolin-1-one, (8e).
Compound 6, (0.50 g, 1.98 mmol, 1.0 eq.) was dissolved in dry THF, (15 mL), under
nitrogen and the solution cooled to -78 ̊C. LiHMDS (1M in THF) (2.18 mL, 2.18 mmol, 1.1
eq.) was then added drop-wise and the resulting mixture stirred for 30 minutes. Benzyl
bromide (0.31 mL, 2.39 mmol, 1.2 eq.) was then added drop-wise and the solution was
allowed to warm to room temperature overnight. Saturated NH4Cl aq. (15mL) was then
added to quench the reaction, which was then diluted further with H2O (20 mL). The mixture
was then extracted with 5 x 30 mL portions of Et2O and the organic extracts were combined
and washed with 1 x 30 mL brine, dried over anhydrous MgSO4, filtered and evaporated
under reduced pressure to give the crude intermediate as a light orange solid, which was used
in the next step without any further purification. Analysis of the crude reaction mixture by 1H
NMR spectroscopy (400 MHz) confirmed a conversion of 94% of starting material in this
synthetic step.
The crude product (0.68 g, 1.98 mmol, 1.0 eq.) was stirred in dry DCM (10 mL), under
nitrogen and cooled to -78
̊
drop-wise and the solution left to stir for 30 minutes at -78
̊
mmol, 1.5 eq.) was added drop-wise to the mixture, which was then allowed to warm to room
temperature overnight. The reaction was quenched by addition of saturated NH4Cl aq.
(20mL) and the mixture further diluted with H2O (20 mL). The mixture was then extracted
with 3 x 30 mL portions of DCM and the combined organic extracts washed with 1 x 30 mL
brine, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give a
18

ACCEPTED MANUSCRIPT
light brown residue which was purified by flash column chromatography (80:20 EtOAc/
petroleum ether (40-60)) to afford the target compound as a white crystalline solid. Yield:
̊
o
35% (0.24 g); Mp: 174-177 C (EtOAc/hexanes); [α]D = + 124 (c 0.5, 24 C, DCM); νmax
1
(solid): 3380, 2924, 2885, 1649, 1408 cm-1; H NMR (400 MHz, CDCl3) δ 7.84 - 7.74 (m,
1H), 7.51 - 7.14 (m, 10H), 6.98 - 6.91 (m, 2H), 6.88 - 6.78 (m, 1H), 5.10 - 4.95 (m, 1H), 4.87
(dd, J = 3.4, 7.8, 1H), 4.54 (dd, J = 4.5, 7.8, 1H), 4.46 (dt, J = 7.7, 12.5, 1H 1H), 4.09 (ddd, J
= 3.3, 6.9, 12.4, 1H), 3.37 (dd, J = 4.4, 13.9, 1H), 2.88 (dd, J = 7.8, 13.8, 1H); 13C NMR (100
MHz, CDCl3) δ 169.9, 144.9, 137.9, 135.4, 132.0, 131.4, 129.4, 128.9, 128.4, 128.3, 128.0,
127.1, 127.1, 123.7, 122.8, 64.6, 63.1, 61.7, 38.1; HRMS (ESI, m/z): calcd. for C23H21NO2
(M + H+) 344.1645, found 344.1643.
(R)-3-(2-fluorobenzyl)-2-((R)-2-hydroxy-1-phenylethyl)isoindolin-1-one, (8f).
Compound 6, (0.50 g, 1.98 mmol, 1.0 eq.) was dissolved in dry THF, (15 mL), under
nitrogen and the solution cooled to -78 ̊C. LiHMDS (1M in THF) (2.18 mL, 2.18 mmol, 1.1
eq.) was then added drop-wise and the resulting mixture stirred for 30 minutes. 2-
Fluorobenzyl bromide (0.29 mL, 2.39 mmol, 1.2 eq.) was then added drop-wise and the
solution was allowed to warm to room temperature overnight. Saturated NH4Cl aq. (15mL)
was then added to quench the reaction, which was then diluted further with H2O (20 mL).
The mixture was then extracted with 5 x 30 mL portions of Et2O and the organic extracts
were combined and washed with 1 x 30 mL brine, dried over anhydrous MgSO4, filtered and
evaporated under reduced pressure to give the crude intermediate as a light orange oil, which
was used in the next step without any further purification. Analysis of the crude reaction
19

ACCEPTED MANUSCRIPT
1
mixture by H NMR spectroscopy (400 MHz) confirmed a conversion of 94% of starting
material in this synthetic step.
The crude product (0.71 g, 1.98 mmol, 1.0 eq.) was stirred in dry DCM (10 mL), under
nitrogen and cooled to -78
̊
drop-wise and the solution left to stir for 30 minutes at -78
̊
mmol, 1.5 eq.) was added drop-wise to the mixture, which was then allowed to warm to room
temperature overnight. The reaction was quenched by addition of saturated NH4Cl aq. (20
mL) and the mixture further diluted with H2O (20 mL). The mixture was then extracted with
3 x 30 mL portions of DCM and the combined organic extracts washed with 1 x 30 mL brine,
dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give a light
brown residue which was purified by flash column chromatography (70:30 EtOAc/ petroleum
ether (40-60)) to afford the target compound as an off-white crystalline solid. Yield: 65%
o
(0.465 g); Mp: 140-143
̊
3313, 2871, 1657, 1491, 1230 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.85 - 7.77 (m, 1H), 7.50 -
6.88 (m, 12H), 4.96 - 4.82 (m, 2H), 4.59 (dd, J = 4.3, 7.7, 1H), 4.48 (dt, J = 7.8, 12.5, 1H),
4.13 (ddd, J = 3.4, 7.0, 12.5, 1H), 3.43 (dd, J = 4.2, 14.0, 1H), 2.93 (dd, J = 7.7, 14.0, 1H);
13C NMR (100 MHz, CDCl3) δ 170.0, 161.2 (d, 1JC-F = 245.4 Hz), 144.9, 137.9, 132.1, 131.7
(d, 3JC-F = 4.8 Hz), 131.5, 129.1 (d, 2JC-F = 7.7 Hz), 128.9, 128.4, 128.0, 127.2, 124.0 (d, 3JC-F
4
2
= 3.8 Hz), 123.8, 122.8, 122.7 (d, JC-F = 15.3 Hz), 115.4 (d, JC-F = 22.0 Hz), 64.6, 63.0,
60.5, 31.6; HRMS (ESI, m/z): calcd. for C23H20FNO2 (M + H+) 362.1551 found, 362.1550.
(R)-2-((R)-2-hydroxy-1-phenylethyl)-3-(3-methoxybenzyl)isoindolin-1-one, (8g).
Compound 6, (0.50 g, 1.98 mmol, 1.0 eq.) was dissolved in dry THF, (15 mL), under
nitrogen and the solution cooled to -78 ̊C. LiHMDS (1M in THF) (2.18 mL, 2.18 mmol, 1.1
20

ACCEPTED MANUSCRIPT
eq.) was then added drop-wise and the resulting mixture stirred for 30 minutes. 3-
Methoxybenzyl bromide (0.33 mL, 2.39 mmol, 1.2 eq.) was then added drop-wise and the
solution was allowed to warm to room temperature overnight. Saturated NH4Cl aq. (15mL)
was then added to quench the reaction, which was then diluted further with H2O (20 mL).
The mixture was then extracted with 5 x 30 mL portions of Et2O and the organic extracts
were combined and washed with 1 x 30 mL brine, dried over anhydrous MgSO4, filtered and
evaporated under reduced pressure to give the crude intermediate as a light orange oil, which
was used in the next step without any further purification. Analysis of the crude reaction
1
mixture by H NMR spectroscopy (400 MHz) confirmed a conversion of 96% of starting
material in this synthetic step.
The crude product (0.74 g, 1.98 mmol, 1.0 eq.) was stirred in dry DCM (10 mL), under
nitrogen and cooled to -78
̊
drop-wise and the solution left to stir for 30 minutes at -78
̊
mmol, 1.5 eq.) was added drop-wise to the mixture, which was then allowed to warm to room
temperature overnight. The reaction was quenched by addition of saturated NH4Cl aq. (20
mL) and the mixture further diluted with H2O (20 mL). The mixture was then extracted with
3 x 30 mL portions of DCM and the combined organic extracts washed with 1 x 30 mL brine,
dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to give a light
brown residue which was purified by flash column chromatography (70:30 EtOAc/ petroleum
ether (40-60)) to afford the target compound as an off-white crystalline solid. Yield: 61%
(0.45 g); Mp: 94-96 ̊
C (EtOAc/hexanes); [α]D = + 40 (c 0.5, 24 oC, DCM); νmax (solid): 2868,
1715, 1616, 1361, 1311 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.84 - 7.76 (m, 1H), 7.49 - 7.40
(m, 2H), 7.38 - 7.28 (m, 3H), 7.27 - 7.20 (m, 2H), 7.14 (t, J = 7.9, 1H), 6.96 - 6.88 (m, 1H),
6.76 (dd, J = 2.0, 8.2, 1H), 6.56 (d, J = 7.5, 1H), 6.45 - 6.39 (m, 1H), 5.07 - 5.00 (m, 1H),
4.85 (dd, J = 3.1, 7.8 , 1H), 4.54 (dd, J = 4.4, 7.7, 1H), 4.45 (dt, J = 7.7, 12.5, 1H), 4.08 (ddd,
21

ACCEPTED MANUSCRIPT
J = 3.3, 7.2, 12.4, 1H), 3.68 (s, 3H), 3.34 (dd, J = 4.3, 13.9, 1H), 2.86 (dd, J = 7.8, 14.0, 1H);
13C NMR (100 MHz, CDCl3) δ 169.9, 159.5, 145.0, 137.9, 136.9, 132.1, 131.5, 129.4, 128.9,
128.3, 128.0, 127.2, 123.7, 122.8, 121.8, 114.8, 112.7, 64.6, 63.1, 61.6, 55.1, 38.1; HRMS
(ESI, m/z): calcd. for C24H23NO3 (M + H+) 374.1751 found, 374.1749.
(R)-3-methylisoindolin-1-one, (9).11c
(R)-2-((R)-2-hydroxy-1-phenylethyl)-3-methylisoindolin-1-one, 8a, (0.05g, 0.20 mmol, 1.0
eq.) was dissolved in conc. H2SO4 (96%, 2 mL) in a test tube. This was then immediately
heated for two minutes over a steam bath, then cooled to room temperature. Cold H2O (20
mL) was then added and the mixture extracted using 3 x 20mL portions of DCM. The
combined organic extracts were dried over anhydrous MgSO4, filtered and evaporated under
reduced pressure to obtain a pale yellow oil. The crude product was then purified using
preparative layer chromatography eluting with 80:20 EtOAc/ petroleum ether (40-60), to
1
obtain the product as a clear, colourless oil. Yield: 38% (0.011 g); H NMR (400 MHz,
CDCl3) δ 7.89 - 7.77 (m, 1H), 7.63 - 7.52 (m, 1H), 7.52 - 7.39 (m, 2H), 4.70 (q, J = 6.5, 1H),
1.51 (d, J = 6.7, 3H). Enantiomeric excess (e.e) was determined independently by Reach
Separations Ltd., (BioCity Nottingham, NG1 1GF). Analysis was carried out using a chiral
stationary phase, Chiralpak IC column, 4.6mm x 250mm, 5µm, (Daicel Chemical Industries,
Ltd., Tokyo, Japan). The isocratic mobile phase comprised of 20:80 MeOH:CO2 (0.2% v/v
NH3). The flow rate of the mobile phase was 4.0 mL min-1. A detector wavelength of 210-
o
400nm was utilised. The column temperature was maintained at 40 C and the injection
volume was 1.0 µL. Under these conditions the enantiomeric excess of compound 9 was
found to be 98 %, when compared to a racemic sample.
X-Ray Crystallography.
22

ACCEPTED MANUSCRIPT
O
Suitable crystals were obtained by slow evaporation in ether/petrol (40-60 C). Diffraction
data (Mo-Kα) were collected on a Rigaku Oxford Diffraction Excalibur diffractometer at T =
150-158 K using graphite-monochromated Mo-Kα radiation. The structures were solved and
refined using the SHELXS-2016 and SHELXL-2016 programs.13
8b, R = ethyl, Crystal data: C18H16NO2, Mr = 281.34 g mol-1, orthorhombic, P212121, a =
6.3679(2), b =7.1844(2), c = 32.8776(12) Å, V = 1504.14(9) Å3, T = 150 K, Z = 4, R[F2 >
2σ(F2)] = 0.048 for 2711 reflections with I > 2σ(I), wR(F2) = 0.093 for all 3135 independent
data, GOF = 1.045, 192 refined parameters.
8d, R = allyl, Crystal data: C19H19NO2, Mr = 293.35 g mol-1, orthorhombic, P212121, a =
9.4566(4), b =9.6198(3), c = 16.9868(7) Å, V = 1545.30(10) Å3, T = 158 K, Z = 4, R[F2 >
2σ(F2)] = 0.042 for 3072 reflections with I > 2σ(I), wR(F2) = 0.090 for all 3364 independent
data, GOF = 1.083, 208 refined parameters.
8e, R = benzyl, Crystal data: C23H21NO2, Mr = 343.41 g mol-1, orthorhombic, P212121, a =
8.6454(3), b =10.5715(3), c = 20.1931(6) Å, V = 1845.55(10) Å3, T = 150 K, Z = 4, R[F2 >
2σ(F2)] = 0.053 for 3401 reflections with I > 2σ(I), wR(F2) = 0.097 for all 3860 independent
data, GOF = 1.104, 239 refined parameters.
The crystallographic data are deposited as CCDC 1583682, 1878667-1878668. These data
can be obtained free of charge from The Cambridge Crystallographic Data Centre via via
www.ccdc.cam.ac.uk/data_request/cif.
Conflicts of interest
There are no conflicts of interest to declare.
23

ACCEPTED MANUSCRIPT
Acknowledgements
The authors would like to acknowledge the support of Nottingham Trent University and the
School of Science and Technology at NTU for facilities and financial assistance for this
research project (Vice-Chancellors Scholarship to RAH), the EPSRC UK National Mass
Spectrometry Facility at Swansea University, and Charnwood Molecular Ltd for additional
financial support of this research.
References and Notes
1. T.R. Belliotti, W.A. Brink, S.R. Keston, J.R. Rubin, D.J. Wustrow, K.T. Zoski, A.S.
Whetzel, Z.E. Corbin, T.A. Pugsley, Heffner T.G., L.D. Wise, Bioorg. Med. Chem. Lett. 8
(1998) 1499.
2. R.J. Kavoussi, A.C. Pande, R.B. Lydiard, L. Pap, T.A. Pigott, K. Rickels, Int. J.
Neuropsychopharmacol. 3(S1). (2000), Abstract P09042.
3. N. Kanamitsu, T. Osaki, Y. Itsuji, M. Yoshimura, H. Tsujimoto, M. Soga, Chem. Pharm.
Bull. 55 (2007) 1682.
4. Z.-P. Zhuang, M.-P. Kung, M. Mu, H.F. Kung, J. Med. Chem. 41 (1998) 157.
24

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5. I.R. Hardcastle, J. Liu, E. Valeur, A. Watson, S.U. Ahmed, T.J. Blackburn, K. Bennaceur,
W. Clegg, C. Drummond, J.A. Endicott, B.T. Golding, R.J. Griffin, J. Gruber, K. Haggerty,
R.W. Harrington, C. Hutton, S. Kemp, X. Lu, J.M. McDonnell, D.R. Newell, M.E.M. Noble,
S.L. Payne, C.H. Revill, C.Riedinger, Q. Xu, J. Lunec, J. Med. Chem. 54 (2011) 1233.
6. J. Kajanus, I. Jacobsen, A. Astrand, R.I. Olsson, U. Gran, A. Bjore, O. Fjellstrom, O.
Davidsson, H. Emtenas, A. Dahlen, B. Lofberg, Z.-Q. Yuan, J. Sundell, J. Cassel, J. Gyll, T.
Iliefski, A. Hogberg, E. Lindhardt, J. Malmberg, Bioorg, Med. Chem. Lett. 26 (2016) 2023.
7. A. Couture, E. Deniau, D. Ionescu and P. Grandclaudon, Tetrahedron Lett. 39 (1998)
2319; Z. Guo, A.G. Schultz, J. Org. Chem. 66 (2001) 2154; E. Deniau, D. Enders,
Tetrahedron 57 (2001) 2581.
8. V. Agouridas, F. Capet, A. Couture, E. Deniau, P. Grandclaudon, Tetrahedron Asymmetry
22 (2011) 1441.
9. J. Perard-Viret, T. Prange, A. Tomas, J. Royer, Tetrahedron 58 (2002) 5103.
10. D.L. Comins, S. Schilling, Y. Zhang, Org. Lett. 7 (2005) 95; D.L. Comins, A.-C.Hiebel,
Tetrahedron Lett. 46 (2005) 5639.
11. (a) S.M. Allin, C.J. Northfield, M.I. Page, A.M.Z. Slawin, Tetrahedron Lett. 40 (1999)
141; (b) S.M. Allin, C.J. Northfield, M.I. Page, A.M.Z. Slawin, Tetrahedron Lett. 40 (1999)
143; (c) S.M. Allin, C.J. Northfield, M.I. Page, A.M.Z. Slawin, J. Chem. Soc., Perkin Trans.
1 (2000) 1715.
12. Enantiomeric excess (e.e.) was determined independently by Reach Separations Ltd.,
(BioCity Nottingham, NG1 1GF). Analysis was carried out using a chiral stationary phase,
Chiralpak IC column, 4.6mm x 250mm, 5µm, (Daicel Chemical Industries, Ltd., Tokyo,
Japan). The isocratic mobile phase comprised of 20:80 MeOH:CO2 (0.2% v/v NH3). The
25

ACCEPTED MANUSCRIPT
flow rate of the mobile phase was 4.0 mL min-1. A detector wavelength of 210-400nm was
o
utilised. The column temperature was maintained at 40 C and the injection volume was 1.0
µL. Under these conditions the enantiomeric excess of compound 10 was found to be 98 %,
when compared against a racemic sample.
13. G. M. Sheldrick, http://shelx.uni-ac.gwdg.de/SHELX/, University of Göttingen,
Germany.
Supplementary Information available: NMR (1H and 13C) spectra for compounds: 6, 8a-
g, 9.
26