Evaluating polymer-supported isothiourea catalysis in industrially-preferable solvents for the acylative kinetic resolution of secondary and tertiary heterocyclic alcohols in batch and flow

Article abstract of DOI:10.1039/c8gc02020e

Polymer-supported Lewis base catalysts, based on the homogeneous isothioureas HyperBTM and BTM, have been synthesised and applied for the acylative kinetic resolution of secondary and tertiary heterocyclic alcohols. In batch, the use of industrially-preferable solvents was investigated, with dimethyl carbonate proving to be most generally-applicable. Significantly, the HyperBTM-derived immobilised catalysts were readily recycled, with no loss in either activity or selectivity. In addition to the kinetic resolution of secondary benzylic, propargylic, allylic and cycloalkanol derivatives, a range of 22 tertiary heterocyclic alcohols, based on privileged 3-hydroxyoxindole and 3-hydroxypyrrolidinone substructures, were resolved with up to excellent selectivity (s = 7-190). Finally, the immobilised isothiourea catalysts were applied in a packed bed reactor to demonstrate the first example of the kinetic resolution of tertiary heterocyclic alcohols in a continuous flow process. High selectivities were obtained for the resolution of 3-hydroxyoxindole derivatives in ethyl acetate (s up to 70); and for 3-hydroxypyrrolidinones derivatives in toluene (s up to 42).

Full text of DOI:10.1039/c8gc02020e

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Evaluating polymer-supported isothiourea catalysis in industrially-
preferable solvents for the acylative kinetic resolution of
secondary and tertiary heterocyclic alcohols in batch and flow†
Received 00th January 20xx,
Accepted 00th January 20xx
Nitul Ranjan Guha,‡a Rifahath M. Neyyappadath,‡a Mark D. Greenhalgh,a Ross Chisholm,a Samuel
M. Smith,a Megan L. McEvoy,a Claire M. Young,a Carles Rodríguez-Escrich,b Miquel A. Pericàs,bc
Georg Hähnera and Andrew D. Smith*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Polymer-supported Lewis base catalysts, based on the homogeneous isothioureas HyperBTM and BTM, have been
synthesised and applied for the acylative kinetic resolution of secondary and tertiary heterocyclic alcohols. In batch, the
use of industrially-preferable solvents was investigated, with dimethyl carbonate proving to be most generally-applicable.
Significantly, the HyperBTM-derived immobilised catalysts were readily recycled, with no loss in either activity or
selectivity. In addition to the kinetic resolution of secondary benzylic, propargylic, allylic and cycloalkanol derivatives, a
range of 22 tertiary heterocyclic alcohols, based on privileged 3-hydroxyoxindole and 3-hydroxypyrrolidinone
substructures, were resolved with up to excellent selectivity (s = 7–190). Finally, the immobilised isothiourea catalysts
were applied in a packed bed reactor to demonstrate the first example of the kinetic resolution of tertiary heterocyclic
alcohols in a continuous flow process. High selectivities were obtained for the resolution of 3-hydroxyoxindole derivatives
in ethyl acetate (s up to 70); and for 3-hydroxypyrrolidinones derivatives in toluene (s up to 42).
In this area, we recently reported the synthesis of a Merrifield
resin-derived polymer-supported chiral isothiourea based
upon a homogeneous Lewis basic catalyst, HyperBTM, and
Introduction
Enantioselective organocatalysis has become a diverse and
vibrant research area over recent decades, with many highly
efficient and selective methods having been developed.1 In the
context of sustainability and potential industrial applicability,
one common criticism of the area is the use of relatively high
loadings of the organocatalyst, which is typically neither
applied this immobilised catalyst for the kinetic resolution (KR)
of secondary alcohols (Scheme 1).4–8 A range of alcohols,
including benzylic, allylic and propargylic alcohols, as well as
cycloalkanol derivatives and a 1,2-diol, were resolved with up
to excellent selectivity factors [where selectivity factor (s) is
defined as the rate constant for the fast reacting enantiomer
divided by the rate constant for the slow reacting enantiomer
(s = kfast/kslow)].9 Significantly, this immobilised catalyst could
be recycled at least 15 times with no appreciable loss in either
activity or selectivity. The broad scope and excellent catalyst
recyclability in comparison to previously reported KRs using
immobilised catalysts indicated substantial potential of this
catalyst for future applications.4,5
reisolated nor recycled following
a given reaction. One
potential general solution is the immobilisation of the
organocatalyst onto a heterogeneous polymer support.2 In
principle, recovery of the catalyst can be achieved following
the reaction by a simple filtration; alternatively the polymer-
supported catalyst can be incorporated into a continuous flow
set-up, improving the ease of catalyst recycling even further.3
To compensate the additional time and energy costs
associated with catalyst synthesis, the immobilised catalyst
must be obtained via a straightforward and high yielding
route, and be sufficiently stable to allow recycling multiple
Prior work: Polymer-supported HyperBTM-catalysed KR of 2° alcohols
N
• KR of a range of
secondary alcohols
• Excellent catalyst
recyclability
N
N
O
= Merrifield resin
times without any loss in activity or selectivity.
• Chloroform as solvent
iꢀPr
a EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St
Andrews, KY16 9ST, U.K. E-mail: ads10@st-andrews.ac.uk
N
O
S
b Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of
Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain.
c Department de Química Inorgànica i Orgànica, Universitat de Barcelona, 08080
Barcelona, Spain.
H
OH
R2
H
OH
R2
H
O
Ph
N
R3
(1 mol%)
(R3CO)2O (0.55 equiv.)
CHCl3, 0 °C
+
R1
R1
R1
R2
(±)
28 examples; s up to > 600
†
Electronic Supplementary Information (ESI) available: experimental procedures,
α]D, HPLC,), traces (NMR,
Scheme 1 Previous work on the KR of secondary alcohols using a Merrifield resin-
product characterisation data (mpt, NMR, IR, HRMS, [
HPLC). See DOI: 10.1039/x0xx00000x.
supported isothiourea catalyst.
‡
These authors contributed equally to this work.
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Although demonstrating proof-of-concept in this area, one
potential obstacle for industrial application of this method was
the reliance upon using chloroform as the reaction solvent. As
the solvent typically constitutes the majority of the mass in
any synthetic transformation, the nature of the solvent has a
substantial impact on the sustainability of the process. These
considerations are of particular importance in the chemical
industry. Over the last 15 years, considerable effort has been
made to identify the suitability of different solvents, taking
into account environmental impact, health and safety, cost
and life-cycle management considerations. This has resulted in
a range of reports from pharmaceutical companies that have
broadly categorised solvents into a number of groupings, that
for simplicity and the purpose of this manuscript we have
classified as “best to avoid”, “usable” and “preferred”.10
Results and discussion
Synthesis of polymer-supported isothiourea catalysts
The synthesis of immobilised HyperBTM derivatives 2–4 was
achieved through a Cu-catalysed azide-alkyne cycloaddition
between alkyne-substituted HyperBTM derivative and azide-
1
functionalised Merrifield, TentaGel and Wang resins (Scheme
3).12 Elemental analysis of each immobilised catalyst allowed
calculation of polymer functionalisation based on nitrogen
content,13,14 with these values used to determine catalyst
loading in all subsequent KRs.15 A Merrifield resin-supported
derivative of the isothiourea BTM
similar procedure starting from alkyne-substituted BTM
derivative . In all cases the isothiourea-functionalised
6 was also synthesised by a
5
polystyrene resins were obtained in high yield.
In order to enhance the potential industrial-applicability of our
polymer-supported isothiourea catalyst, we recognised that
solvent compatibility with industrially-preferable solvents was
of paramount importance.
A variety of differentially-
functionalised polymer supports are commercially-available
due to their application in solid phase peptide synthesis
(Scheme 2a),11 where modulation of the polymer functionality
is known to have a substantial effect on the stability and
swelling properties of the polymer in different solvents. The
synthesis of isothiourea catalysts immobilised on different
polymer supports was therefore envisioned to allow
assessment of solvent compatibility and sustainability. In
addition, the change in chemical environment around the
Lewis basic isothiourea in each immobilised catalyst could be
expected to lead to changes in both activity and selectivity.
Herein, we report the synthesis of a range of polymer-
supported isothiourea catalysts and demonstrate their
application and recyclability for the KR of secondary and
tertiary alcohols in both batch and continuous flow, with a
particular focus on the compatibility of industrially-preferable
solvents (Scheme 2b).
Scheme 3 Preparation of solid-supported HyperBTM and BTM catalysts.
KR of secondary alcohols: solvent compatibility
Investigations began by comparing the activity and selectivity of
HyperBTM-derived immobilised catalysts 2–4 for the KR of (±)-1-
(naphthalen-2-yl)ethan-1-ol
7 using isobutyric anhydride in a
range of solvents (Table 1).14,16 All KRs were conducted at room
temperature to aid practically and to enable future application. The
KRs were first performed in chloroform to provide a direct
comparison with the previously-reported methodology.4 All
immobilised isothioureas catalysed the KR of alcohol
7 with
excellent selectivity (s = 45–80, entries 1–3). The use of
industrially-preferable solvents was next investigated.10,17
Excellent selectivities were obtained with all catalysts in
toluene (s = 60–70), with Merrifield and TentaGel-derived
catalysts
2 and 3 providing optimal conversion (entries 4–5),
whilst lower conversion was obtained using Wang derivative
4
Scheme 2 a) Commercially-available polymer supports used in this study; b) KR of
secondary and tertiary alcohols using a range of supported isothiourea catalysts in
batch and flow using industrially-preferable solvents.
(entry 6). A more significant solvent effect was observed when
using tert-amyl alcohol, with high conversion and selectivity
only obtained with TentaGel-derived catalyst 3 (entries 7–9).
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Table 1 KR of (±)-7 using supported catalysts 2–4 and 6: Effect of solvent
and CH2Cl2 before drying under high vacuum for 2 h. The
secondary alcohols were selected from the scope previously
reported in chloroform,4 with these five alcohols chosen to
probe catalyst versatility for the KR of benzylic, allylic,
propargylic and cycloalkanols.16 Differences in catalyst activity
and selectivity for the KR of each substrate, in addition to
changes in activity following catalyst recycling, were assessed.
Entry Catalyst
Solvent
CHCl3
c (%)
50
40
32
52
52
32
17
49
3
7 era
95:5
8 erb
96:4
96:4
97:3
95:5
94:6
98:2
93:7
94:6
87:13
93:7
94:6
90:10
94:6
96:4
96:4
4:96
s
First, the KR of 1,2-azidoalcohol
catalysts (Table 2). Each of the HyperBTM derivatives
similar conversions and selectivities (c = 46–52%; s = 22–29);
however BTM derivative provided only low conversion and
9
was performed with all four
1c
2
3
4
2
3
4
2
3
4
2
3
4
2
3
4
6
80
45
50
70
60
70
16
43
7
A
V
O
I
2–4
gave
2
CHCl3
81:19
72:28
98:2
D
3
4c
CHCl3
6
PhMe
selectivity (c = 16%; s = 3). Each catalyst was then recovered
and applied for the KR of propargylic alcohol 10. All of the
5
PhMe
97:3
U
S
A
B
L
6
PhMe
72:28
59:41
89:11
51:49
97:3
HyperBTM-derived catalysts
however more variation in selectivity was observed, with
Wang-derived catalyst providing the highest selectivity (s =
15). In contrast, BTM derivative was completely inactive.
Next, the KR of trans-phenylcyclopentanol 11 with each
HyperBTM-derived catalyst provided similar conversions
2–4 provided optimal conversion,
7
t-AmOH
t-AmOH
t-AmOH
i-PrOAc
i-PrOAc
i-PrOAc
(MeO)2CO
(MeO)2CO
(MeO)2CO
(MeO)2CO
E
8
9
4
10
11
12
13
14
15
16
52
47
44
50
46
45
27
49
39
16
45
60
49
38
6
P
R
E
F
89:11
81:19
94:6
2–4
E
R
R
E
and selectivities (c = 48–53%; s = 27–29), whilst BTM-derived
89:11
88:12
33:67
D
Table 2 Recycling supported catalysts 2–4 and 6 for the sequential KR of five secondary
alcohols (±)-9–13
‘Avoid’, ‘Usable’ and ‘Preferred’ indicate the industrial applicability of the
solvent.10 Conditions: (±)-7 (0.2 mmol), 2 or 6 (5 mol%), or 3 or 4 (3 mol%), (i-
PrCO)2O (0.55 equiv.), i-Pr2NEt (0.6 equiv.), solvent (0.2 M), r.t., 16 h. Conversion
(c) and er determined by chiral HPLC analysis. Selectivity factors (s) calculated
using er of 7 and reaction conversion (see ref. 9a), and rounded according to
estimated associated errors (see ref. 9b). a R:S. b S:R. c Data taken from ref. 4.
This solvent effect is consistent with the expected swelling of
each polymer support in tert-amyl alcohol, with the
polyethylene glycol linker present in TentaGel providing
enhanced swelling in polar protic solvents. The use of acetate
solvents was also tolerated, with good conversions obtained in
isopropyl acetate using each catalyst (entries 10–12). The
selectivity obtained using each catalyst was more variable
Catalyst
2
Cycle Substrate c (%)
Alc. era Est. erb
s
25
10
27
14
140
22
7
however; with Merrifield-derived catalyst
2
providing an s
providing
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
1
2
3
9
52
55
53
48
52
46
52
48
47
43
50
51
49
47
44
16
0
6:94
89:11
95:5c
85:15
> 99:1
13:87
81:19
90:10c
85:15
87:13
10:90
88:12
91:9c
85:15
88:12
54:46
-
10:90
81:19
90:10d
87:13
96:4
value of 49 (entry 10), but Wang-derived catalyst
4
10
11
12
13
9
an s value of only 16 (entry 12). More consistent data were
obtained when using dimethyl carbonate, with 45–50%
conversion and s = 45–60 obtained for all three catalysts
(entries 13–15). The use of immobilised BTM catalyst
6 also
9:91
proved reasonably effective, with good selectivity (s = 38) and
10
11
12
13
9
79:21
92:8d
90:10
99:1
3
29
18
170
29
15
29
16
190
3
moderate conversion obtained (27%). Although less effective
than immobilised HyperBTM derivatives 2–4, the activity of
this BTM derivative is promising when compared to a
previously-reported polymer-supported variant of BTM, which
was shown to be ineffective for KRs (s = 3 for the KR of 1-
phenylethanol in CDCl3).8a Based on these results, the use of
dimethyl carbonate was further investigated for the KR of a
range of secondary alcohols using each immobilised catalyst.
8:92
10
11
12
13
9
87:13
92:8d
89:11
> 99:1
70:30
-
4
6
10
11
-
Catalyst recycling
0
-
-
-
The recyclability and robustness of each polymer-supported
isothiourea catalyst was investigated through the sequential
KR of five different secondary alcohols in dimethyl carbonate
(Table 2). In each case, the catalyst was recovered by filtration
and washed sequentially with CH2Cl2/MeOH (1:1), MeOH, THF
Conditions: 9–13 (0.2–0.4mmol), 2 or 6 (5 mol%), or 3 or 4 (3 mol%), (i-PrCO)2O
(0.55 equiv.), i-Pr2NEt (0.6 equiv.), (MeO)2CO (0.2 ), r.t., 24 h. Conversion (c) and
M
er determined by chiral HPLC analysis. Selectivity factors (s) calculated using
alcohol er and reaction conversion (see ref. 9a), and rounded according to
estimated associated errors (see ref. 9b). a R:S. b S:R. c 1R,2S:1S,2R. d 1S,2R:1R,2S.
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catalyst
6
again proved to be completely inactive. Based on (entries 4–5). Finally, the KR of 14 was examined in dimethyl
in these carbonate with all three immobilised HyperBTM catalysts
recycling experiments was discontinued. The KR of the next (entries 6–8). TentaGel-supported catalyst gave the highest
substrate, aryl-alkenyl-substituted carbinol 12 7l
was achieved selectivity (s = 29; entry 7), however significantly better
using all HyperBTM derivatives , with similar conversions conversion was obtained using Merrifield resin-supported
and selectivities obtained once more (c = 47–48%; s = 14–18). HyperBTM (entry 6). As conversions of > 50% are desirable in
Finally, the KR of benzylic alcohol 13 using each HyperBTM- KRs to allow isolation of substrate in highly enantioenriched
derived catalyst was achieved with good conversions and form, further optimisation using Merrifield resin-supported
exceptional selectivities (s = 140–190). It should be noted that HyperBTM in dimethyl carbonate was targeted. Although
these results, the use of BTM-derived catalyst
6
2–4
3
,
2–4
2
2–4
2
the s values obtained in these experiments using dimethyl similar conversions and selectivites were obtained using both
carbonate are lower than those previously-reported for the ethyl acetate and dimethyl carbonate, the use of dimethyl
same substrates in chloroform.4 Nonetheless, these carbonate was considered preferrable due to its reduced
experiments demonstrate the feasibility of using an flammability, increased stability and lower environmental
industrially-prefererable solvent to obtain synthetically-useful impact.10b,d,e The reaction conversion in dimethyl carbonate
levels of selectivity. It is noteworthy that all of the immobilised was improved to 53% by increasing the equivalents of
HyperBTM derivatives
2
–
4
are readily recycled and are anhydride, to provide the optimised conditions for this KR
using Merrifield resin-supported HyperBTM (entry 9).
considerably more robust than BTM analogue
6.
2
Decomposition of the homogeneous isothiourea catalyst BTM Consistent with our work using the homogeneous analogues of
has been reported in the presence of anhydrides and these isothiourea catalysts, the use of Merrifield resin-
alcohols,7i with the operation of a similar deactivation pathway supported BTM derivative
for the immobilised analogue consistent with the results of selectivity (entry 10).7m
these recycling experiments.
6 led to very low conversion and
Table 3 Reaction optimisation for the KR of 3-allyl-3-hydroxyoxindole derivative (±)-14
KR of tertiary alcohols: reaction optimisation and scope
To expand the scope and impact of this method, the polymer-
supported catalysts 2–4 and 6 were investigated for the KR of
tertiary heterocyclic alcohols in industrially-preferable solvents
in both batch and continuous flow. The acylative KR of tertiary
alcohols is a significant challenge due to the sterically-hindered
nature of the substrates, and the requirement for the catalyst
to differentiate between three substituents at the stereogenic
carbinol centre. As such, only three methods have been
previously reported,7m,18 including a recent example from
ourselves using the homogeneous version of HyperBTM.7m The
KR of a range of tertiary heterocyclic alcohols was reported,
however chloroform was used as the optimal solvent and the
ability to recover or recycle the catalyst was not
demonstrated, thus limiting industrial applicability.
Entry Catalyst
Solvent
CHCl3
c (%)
22
46
47
42
47
48
38
36
53
1
14 era
64:36
85:15
87:13
88:12
86:14
88:12
77:23
74:26
93:7
15 erb
98:2
s
1
2
2
2
2
3
4
2
3
4
2
6
60
21
22
13
20
21
29
19
20
2
PhMe
91:9
U
S
A
B
L
3
EtOAc
91:9
4
EtOAc
78:22
90:10
90:10
94:6
E
5
EtOAc
P
R
E
F
6
(MeO)2CO
(MeO)2CO
(MeO)2CO
(MeO)2CO
(MeO)2CO
7
E
R
R
E
8
9c
92:8
88:12
66:34
D
10
50:50
‘Usable’ and ‘Preferred’ indicate the industrial applicability of the solvent.10
Optimisation studies began with the KR of 3-allyl-3-
hydroxyoxindole derivative 14 using Merrifield resin-supported
Conditions: 14 (0.1 mmol), 2, 3, 4 or 6 (5 mol%), (i-PrCO)2O (0.55 equiv.), i-Pr2NEt
2
and isobutyric anhydride in batch (Table 3).16,19
(0.6 equiv.), solvent (0.2 M), r.t., 24 h. Conversion (c) and er determined by chiral
HyperBTM
HPLC analysis. Selectivity factors (s) calculated using alcohol er and reaction
conversion (see ref. 9a), and rounded according to estimated associated errors
(see ref. 9b). a S:R. b R:S. c 0.7 equiv. of (i-PrCO)2O used.
Initially, the use of chloroform, which proved most effective in
the homogeneous system,7m was investigated. After 24 h at
room temperature only 22% conversion was observed,
however encouragingly high selectivity was obtained (s = 60)
(Table 3, entry 1). To provide context, the KR of alcohol 14 in
chloroform at room temperature using homogeneous
HyperBTM (1 mol%) provided a conversion of 53% and an s
value of 90.7m This indicates the polymer-supported variant of
the catalyst displays reduced activity, but still provides
similarly high enantiodiscrimination. The use of more
industrially-preferable solvents was investigated next.10,17
Using either toluene or ethyl acetate resulted in significantly
improved conversion, albeit with lower selectivity (entries 2–
3). The KR of 14 in ethyl acetate was also investigated using
Encouraged by the promising results using Merrifield resin-
supported HyperBTM
2 in dimethyl carbonate at room
temperature, the scope of the KR was investigated (Table 4).16
The introduction of a sterically-hindered i-Pr group or an
electron- withdrawing CF3 group at C(3) were both tolerated,
with 17 and 18 resolved with good selectivity (s = 13–21). The
incorporation of an aromatic group at C(3) was also successful,
with phenyl-substituted alcohols 19–21 resolved with optimal
conversion and excellent selectivity (s = 60–70) allowing
recovery of the alcohol in highly enantioenriched form in each
case. Aromatic substituents at C(3) bearing both electron-
donating and -withdrawing groups were tolerated, as was the
TentaGel and Wang resin-supported HyperBTM
3 and 4, with
introduction of heteroaromatic substituents, with alcohols 22
–
similar conversions and selectivities obtained in each case
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Table 5 Recycling of polymer-supported HyperBTM 2
25 all resolved with good selectivity (s = 13–36). The method
was equally applicable for the KR of 3-alkenyl-substituted
alcohol 26 (s = 24). It is noteworthy that these examples
demonstrate the immobilised isothiourea catalyst can
differentiate between three sp2-hybridised substituents at the
tertiary carbinol centre (two
π
-systems and a carbonyl).20
Finally, substitution of the benzenoid ring was generally
tolerated, with 4-chloro- and 5-methyl-substituted oxindole
derivatives 27 and 28 resolved with good selectivity (s = 16–
27); however 6- and 7-chloro-substituted derivatives 29 and 30
Alcohol
er;b yield
Ester
Cycle
Substrate
c (%)a
s a
er;c yield
56
[56]
> 99:1; 43% 90:10; 51%
60
[60]
1
Table 4 Substrate Scope for the KR of 3-substituted-3-hydroxyoxindole derivatives
2 (5 mol%)
(iꢀPrCO)2O
HO
HO
iꢀPr(O)CO
R1
R1
R1
(0.7 equiv.)
R3
O
R3
O
R3
+
O
iꢀPr2NEt
(0.6 equiv.)
(MeO)2CO, r.t.
54
[54]
> 99:1; 46% 92:8; 49%
> 99:1; 43% 92:8; 51%
80
[70]
N
R2
N
R2
N
R2
2
3
4
5
HO
HO
HO
iꢀPr
CF3
54
[56]
70
[60]
O
O
O
19
N
N
N
Boc
Bn
Bn
18, c = 62; s = 21
16, c = 64; s = 14
alc: 99:1 er; 31%
est: 77:23 er; 53%
17, c = 45; s = 13
alc: 80:20 er; 53%
est: 87:13 er; 42%
alc: > 99:1 er; 36%
est: 80:20 er; 42%
52
[53]
99:1; 47%
99:1; 45%
95:5; 50%
94:6; 48%
90
[70]
HO
Ph
HO
Ph
HO
Ph
O
O
O
N
N
N
Bn
Allyl
Me
53
[56]
70
[60]
19
19, c = 51; s = 60
alc: 96:4 er; 43%
est: 90:10 er; 51%
20, c = 54; s = 70
alc: > 99:1 er; 41%
est: 92:8 er; 54%
21, c = 53; s = 70
alc: 99:1 er; 46%
est: 94:6 er; 48%
OMe
F3C
60
[59]
>99:1;c 39% 84:16;b 57%
44
6
[26]
HO
HO
HO
S
CF3
O
O
O
N
N
N
54
[56]
> 99:1; 45% 93:7; 50%
70
[80]
Allyl
Allyl
Allyl
7
8
9
19
22, c = 57; s = 36
alc: > 99:1 er; 41%
est: 87:13 er; 55%
23, c = 59; s = 13
alc: 95:5 er; 37%
est: 82:18 er; 59%
24, c = 57; s = 34
alc: 99:1 er; 41%
est: 88:12 er; 53%
55
[53]
99:1; 44%
89:11; 52%
37
[27]
Cl
N
HO
HO
HO
Me
O
O
O
N
N
N
Allyl
Bn
Bn
54
[56]
80
[60]
19
> 99:1; 45% 92:8; 53%
25, c = 59; s = 26
alc: 99:1 er;a 34%
est: 84:16 er;b 56%
26, c = 44; s = 24
alc: 83:17 er; 55%
est: 92:8 er; 41%
27, c = 41; s = 16
alc: 78:22 er; 56%
est: 90:10 er; 39%
HO
Ph
HO
Ph
HO
Me
Me
49
[44]
89:11; 48%
92:8; 48%
26
[24]
O
O
O
10
N
N
N
Cl
Bn
Bn
Bn
Cl
28, c = 53; s = 27
alc: 95:5 er; 46%
est: 90:10 er; 50%
29, c = 52; s = 9
alc: 81:19 er; 37%
est: 79:21 er; 48%
30, c = 62; s = 7
alc: 91:9 er; 38%
est: 76:24 er; 50%
Conditions: alcohol (0.25–0.4 mmol), 2 (5 mol%), (i-PrCO)2O (0.7 equiv.), i-Pr2NEt
(0.6 equiv.), (MeO)2CO (0.2 ), 18–48 h. Conversion (c) and er determined by
M
Conditions: alcohol (0.1 mmol), 2 (5 mol%), (i-PrCO)2O (0.7 equiv.), i-Pr2NEt (0.6
equiv.), (MeO)2CO (0.2 ), 24–48 h. Conversion (c) and er determined by chiral
chiral HPLC analysis. Selectivity factors (s) calculated using alcohol er and reaction
conversion (see ref. 9a), and rounded according to estimated associated errors
(see ref. 9b). a Conversion (c) and s data for resolutions using fresh catalyst shown
in italics in brackets. b S:R. c R:S.
M
HPLC analysis. Selectivity factors (s) calculated using alcohol er and reaction
conversion (see ref. 9a), and rounded according to estimated associated errors
(see ref. 9b). Alcohol er given as S:R, ester er given R:S. a R:S. b S:R.
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Journal Name
Table
6 Continuous flow KR of 3-substituted-3-hydroxyoxindole derivatives in
provided relatively low selectivity (s = 7–9). Overall, substrates
bearing a variety of N-substituents were successfully applied,
including N-tert-butoxycarbonyl (Boc), N-benzyl, N-allyl and N-
methyl-substituted 3-hydroxyoxindole derivatives. Although
slightly lower than those previously reported using
homogeneous HyperBTM in chloroform,7m synthetically-useful
levels of selectivity were obtained in the majority of cases.
chloroform using the same packed bed reactor
Catalyst recycling
The robustness and reusability of Merrifield resin-supported
HyperBTM catalyst
2 was further probed through a recycling
experiment in which the catalyst was recovered and reused
ten times (Table 5). In this experiment, six different tertiary
alcohol substrates were applied, with the KR of N-benzyl-3-
phenyl-substituted hydroxyoxindole 19 performed on
alternate cycles. This approach was adopted to: (i) investigate
if the same sample of catalyst could be used to resolve
different substrates without cross-contamination, and (ii)
provide insight into whether there is any loss in activity or
selectivity of the catalyst upon recycling. All six substrates
were resolved with very comparable conversion and selectivity
to when fresh catalyst was used (this data is provided italicized
and in square brackets in table 5 for clarity). The KR of 19 was
also remarkably consistent, with conversions of 53–56% and s
values of 60–80 obtained for the five cycles. These
experiments indicate excellent stability of Merrifield resin-
supported HyperBTM catalyst
2 over the course of this
recycling protocol. Significantly, no cross-contamination
between KRs was observed in any case, demonstrating
excellent potential for further applications.
Application in continuous flow
Based on the excellent recyclability of Merrifield resin-
supported HyperBTM catalyst
2 for the KR of tertiary alcohols,
application in a continuous flow set-up was investigated. To
the best of our knowledge the KR of tertiary alcohols in
continuous flow has not been reported previously. We
therefore initially investigated the feasibility of the process
under the conditions used previously for the KR of secondary
alcohols in continuous flow using chloroform as solvent.4 The
Conversion and er determined by chiral HPLC analysis. Selectivity factor (s)
calculated using alcohol er and reaction conversion (see ref. 9a), and rounded
according to estimated associated errors (see ref. 9b). Alcohol er given as S:R,
ester er given R:S. a R:S. b S:R.
Next, the use of industrially-preferable solvents for the KR of
3-substituted-3-hydroxyoxindole derivatives was investigated.
immobilised catalyst
2 (600 mg, 0.53 mmol) was swollen in a
medium pressure borosilicate glass column in chloroform to
create a packed bed reactor, and solutions of racemic tertiary
Optimisation studies using Merrifield-supported HyperBTM
2
and hydroxyoxindole derviative 14 found that low selectivities
were obtained using dimethyl carbonate (s = 9), and that
alcohol (0.1
(0.08 ) were passed through using a syringe pump. Based on
optimisation studies using hydroxyoxindole derviative 14 14
M) and a mixture of anhydride (0.08 M) and base
M
toluene was unsuitable due to the low solubility of 14 14
The
.
,
a
use of ethyl acetate was relatively successful however, with a
reaction temperature of 0 °C and an elution rate of 0.1 mL
1
min− , to provide a residence time of 30 min, was chosen and
moderate s and good conversion obtained at 0 °C, albeit when
using an increased concentration of anhydride (0.2
swelling of Merrifield-supported HyperBTM was inefficient in
ethyl acetate and therefore the use of TentaGel-supported
M). The
applied in each case. The packed bed reactor was used for the
sequential KR of six different 3-substituted-3-hydroxyoxindole
2
derivatives 14, 19, 25, 30, 20 and 28 using isobutyric anhydride
HyperBTM
3 was also investigated, however only low
(Table 6, entries 1–6). Good conversions and exceptional
selectivities were obtained in each case (s = 50–190). Each KR
was carried out on a 0.5 mmol scale, with the packed bed
reactor flushed with a solution of 10% methanol in chloroform,
followed by pure chloroform between KRs to regenerate the
catalyst and avoid any cross-contamination.
conversion and selectivity were obtained (c = 10%; s = 9).14 The
scope of the KR of 3-substituted-3-hydroxyoxindole derivatives
using Merrifield-supported HyperBTM
2 in ethyl acetate was
therefore investigated in more detail (Table 7). The same
packed bed reactor that had been used in the previous studies
6 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
was used for the sequential KR of six different 3-substituted-3- The KR of a second class of tertiary alcohol, 3-substituted-3-
hydroxyoxindole derivatives 14 19 25 28
22 and 30. The hydroxypyrrolidin-2-ones,7m,21 was next investigated in
,
,
,
,
diminished swelling of the polymer support in ethyl acetate continuous flow using the same packed bed reactor. In line
resulted in a shorter residence time of 15 min. The resolution with the previously-reported KR using homogeneous
of 3-allyl-substituted derivative 14 proceeded with high HyperBTM,7m the use of acetic anhydride as acylating agent
conversion and good selectivity (s = 14; entry 1) to provide the was required for high conversions. Good solubility of the
recovered alcohol with high enantioenrichment (98:2 er). The substrates in toluene allowed effective resolution, despite the
resolution of 3-aryl-substituted 3-hydroxyindolin-2-one diminished swelling of the polymer support resulting in a
derivatives 19
,
25
,
28 and 22 proceeded with optimal residence time of only 20 min. The sequential KR of six 3-
36 was
conversions and high selectivities in each case (s = 29–70; substituted-3-hydroxypyrrolidin-2-one derivatives 31
–
entries 2–5). In contrast, the KR of 3-methyl-substituted performed, with very good conversions and selectivities
analogue 30 only provided an s value of 8, albeit still allowing obtained in each case (c = 40–53%; s = 18–42) (Table 8).16 The
for the isolation of recovered alcohol (S)-30 with excellent robustness of the same packed bed reactor was further
enantiopurity (> 99:1 er) at 76% conversion (entry 6).
exemplified by the 7.25 mmol-scale KR of N-benzyl-3-hydroxy-
3-phenylpyrrolidin-2-one 33 in a continuous flow process over
a 24 h period (Scheme 4). Significantly, all continuous flow
experiments described in this manuscript, including
Table 7 Continuous flow KR of 3-substituted-3-hydroxyoxindole derivatives in ethyl
acetate using the same packed bed reactor
Table 8 Continuous flow KR of pyrrolidin-2-one derivatives in toluene using the same
packed bed reactor
HO
Me(O)CO
+
R1
R1
1
Flow rate: 0.1 mL min
Residence time: 20 min
Total reaction time: 2 h
O
O
N
N
R2
R2
HO
R1
O (0.1 M)
N
R2
0.5 mmol
PhMe
Coolant
(0 °C)
syringe pumps
O
N
N
iꢀPr
N
N
S
Ph
N
(MeCO)2O (0.1 M)
iꢀPr2NEt (0.1 M)
PhMe
1
2 (600 mg, f = 0.89 mmol g
)
Cl
1.
2.
3.
S
HO
HO
HO
Ph
O
O
O
N
N
N
Allyl
Allyl
Bn
31, c = 40; s = 42
alc: 80:20 er; 57%
est: 96:4 er; 33%
32, c = 45; s = 29
alc: 85:15 er; 50%
est: 93:7 er; 41%
33, c = 52; s = 27
alc: 93:7 er; 43%
est: 91:9 er; 46%
OMe
4.
5.
6.
HO
S
HO
Ph
HO
O
O
O
N
N
N
Allyl
Ph
Allyl
34, c = 52; s = 25
alc: 94:6 er;a 41%
est: 90:10 er;b 48%
35, c = 52; s = 29
alc: 94:6 er; 42%
est: 91:9 er; 45%
36, c = 53; s = 18
alc: 92:8 er; 40%
est: 87:13 er; 44%
Conversion and er determined by chiral HPLC analysis. Selectivity factor (s)
calculated using alcohol er and reaction conversion (see ref. 9a), and rounded
Conversion and er determined by chiral HPLC analysis. Selectivity factor (s)
according to estimated associated errors (see ref. 9b). Alcohol er given as S:R, calculated using alcohol er and reaction conversion (see ref. 9a), and rounded
ester er given R:S. a R:S. b S:R. c 0.25 mmol scale. d 30 (0.07
(0.14 ).
M), (i-PrCO)2O, i-PrNEt2
according to estimated associated errors (see ref. 9b). Alcohol er given as R:S,
ester er given S:R. a S:R. b R:S.
M
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ARTICLE
optimisation studies, were performed with the same sample of
Journal Name
Acknowledgements
Merrifield resin-supported HyperBTM catalyst
total operation time of over 100 h.
2, resulting in a
We thank the Royal Society and the Science and Engineering
Board of India (SERB) for the award of a Royal Society-SERB
Newton International Fellowship (N.R.G.). We also thank the
EPSRC Centre for Doctoral Training in Critical Resource
Catalysis (CRITICAT, grant code EP/L016419/1, R.M.N.P.) for
funding. Financial support from the EPSRC (EP/K000411/1) is
gratefully acknowledged (R.C.). We thank the European
Research Council under the European Union's Seventh
Framework Programme (FP7/2007-2013) ERC grant agreement
no. 279850 (A.D.S). A.D.S. thanks the Royal Society for a
Wolfson Research Merit Award. We also thank the EPSRC UK
National Mass Spectrometry Facility at Swansea University.
C.R.-E. and M.A.P. acknowledge the financial support from
CERCA Programme/Generalitat de Catalunya, MINECO
(CTQ2015-69136-R, AEI/MINECO/FEDER, UE and Severo Ochoa
Excellence Accreditation 2014–2018, SEV-2013-0319) and DEC
Generalitat de Catalunya (Grant 2014SGR827).
Notes and references
1
P. I. Dalko, Comprehensive Enantioselective Organocatalysis:
Catalysts, Reactions, and Applications, Wiley-VCH,
Weinheim, 2013.
Scheme 4 Continuous flow KR of N-benzyl-3-hydroxy-3-phenylpyrrolidin-2-one (±)-33.
2
(a) M. Benaglia, A. Puglisi and F. Cozzi, Chem. Rev., 2003,
103, 3401–3429; (b) A. F. Trindade, P. M. P. Gois and C. A. M.
Alfonso, Chem. Rev., 2009, 109, 418–514; (c) J. Lu and P. H.
Toy, Chem. Rev., 2009, 109, 815–838; (d) T. E. Kristensen and
T. Hansen, Eur. J. Org. Chem., 2010, 3179–3204; (e) B. Altava,
M. I. Burguete, E. Garcia-Verdugo and S. V. Luis, Chem. Soc.
Rev., 2018, 47, 2722–2771.
(a) A. Puglisi, M. Benaglia and V. Chiroli, Green Chem., 2013,
15, 1790–1813; (b) C. Rodríguez-Escrich and M. A. Pericàs,
Eur. J. Org. Chem., 2015, 2015, 1173–1188; (c) I. Atodiresei,
Conclusions
The synthesis of polymer-supported Lewis base catalysts,
based on the homogeneous isothioureas HyperBTM and BTM,
was achieved, and these catalysts were applied for the
acylative kinetic resolution of a range of secondary and tertiary
heterocyclic alcohols. In batch, the use of industrially-
preferable solvents was investigated, with dimethyl carbonate
proving the most generally applicable. Notably, the HyperBTM-
derived immobilised catalysts were readily recycled, with no
loss in either activity or selectivity. In contrast, the polymer-
supported BTM derivative showed diminished reactivity, with
the catalyst being deactivated following a single experiment.7i
In addition to the kinetic resolution of secondary benzylic,
propargylic, allylic and cycloalkanol derivatives, a range of 22
tertiary heterocyclic alcohols, based on privileged 3-
hydroxyoxindole and 3-hydroxypyrrolidinone substructures,
were resolved with up to excellent selectivity (s = 7–190). The
immobilised HyperBTM catalysts were applied in a packed bed
reactor to demonstrate the first example of the kinetic
resolution of tertiary alcohols in a continuous flow process.
Although using chloroform as solvent gave the highest
selectivities in flow, high selectivities were also obtained for
3
C. Vila and M. Rueping, ACS Catal., 2015, 5, 1972–1985.
4
5
R. M. Neyyappadath, R. Chisholm, M. D. Greenhalgh, C.
Rodríguez-Escrich, M. A. Pericàs, G. Hähner and A. D. Smith,
ACS Catal., 2018, 8, 1067–1075.
For other examples of solid-supported catalysts used for the
acylative kinetic resolution of secondary alcohols see: (a) B.
Clapham, C.-W. Cho and K. D. Janda, J. Org. Chem., 2001, 66
,
868–873; (b) G. T. Copeland and S. J. Miller, J. Am. Chem.
Soc., 2001, 123, 6496–6502; (c) B. Pelotier, G. Priem, I. B.
Campbell, S. J. F. Macdonald and M. S. Anson, Synlett, 2003,
5
, 679–683; (d) K. Ishihara, Y. Kosugi, M. Akakura, J. Am.
Chem. Soc., 2004, 126, 12212–12213; (e) A. Gissibl, M. G.
Finn and O. Reiser, Org. Lett., 2005, , 2325–2328; (f) A.
7
Gissibl, C. Padié, M. Hager, F. Jaroschik, R. Rasappan, E.
Cuevas-Yañez, C,-O. Turrin, A.-M. Caminade, J.-P. Majoral
and O. Reiser, Org. Lett., 2007, 9, 2895–2898; (g) A. Schätz,
M. Hager and O. Reiser, Adv. Funct. Mater., 2009, 19, 2109–
2115; (h) O. Gleeson, R. Tekoriute, Y. K. Gun’ko and S. J.
Connon, Chem. Eur. J., 2009, 15, 5669–5673; (i) A. Schätz, R.
N. Grass, Q. Kainz, W. J. Stark and O. Reiser, Chem. Mater.,
2010, 22, 305–310.
the
resolution
of
3-hydroxyoxindole
and
3-
hydroxypyrrolidinone derivatives in the industrially-preferable
solvents of ethyl acetate and toluene.22
6
7
For a review on isothiourea catalysis see: J. Merad, J.-M.
Pons, O. Chuzel and C. Bressy, Eur. J. Org. Chem., 2016, 2016,
5589–5610.
For examples of isothiourea-catalysed acylative KR of
Conflicts of interest
alcohols see: (a) V. B. Birman and X. Li, Org. Lett., 2006,
1351–1354; (b) V. B. Birman and L. Guo, Org. Lett., 2006,
4859–4861; (c) V. B. Birman and X. Li, Org. Lett., 2008, 10
8
8
,
,
,
There are no conflicts to declare.
1115–1118; (d) Y. Zhang and V. B. Birman, Adv. Synth. Catal.,
8 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
2009, 351, 2525–2529; (e) Q. Xu, H. Zhou, X. Geng and P.
Chen, Tetrahedron, 2009, 65, 2232–2238; (f) I. Shiina, K.
W.-Y. Siau and Y. Zhao, Angew. Chem. Int. Ed., 2013, 52,
1731–1734.
Nakata, K. Ono, M. Sugimoto and A. Sekiguchi, Chem. Eur. J., 19 For
a
review on the bioactivity of 3-substituted-3-
hydroxyoxindole derivatives see: S. Peddidhotla, Curr. Bioact.
Compd., 2009, , 20–38.
2010, 16, 167–172; (g) D. Belmessieri, C. Joannesse, P. A.
Woods, C. MacGregor, C. Jones, C. D. Campbell, C. P.
5
Johnston, N. Duguet, C. Concellón, R. A. Bragg and A. D. 20 For a computational model of alcohol acylation transition
Smith, Org. Biomol. Chem., 2011,
Ono and K. Nakata, Chem. Lett., 2011, 40, 147–149; (i) X. Li,
9
, 559–570; (h) I. Shiina, K.
state structures that rationalise this enantiodiscriminiation,
see ref 7m.
H. Jiang, E. W. Uffman, L. Guo, Y. Zhang, X. Yang and V. B. 21 For examples documenting the bioactivity of 3-
Birman, J. Org. Chem., 2012, 77, 1722–1737; (j) K. Nakata, K.
Gotoh, K. Ono, K. Futami and I. Shiina, Org. Lett., 2013, 15
hydroxypyrrolidinone derivatives, see: (a) F. Damiani, D.
Hamprecht, A. A. Jaxa-Chamiec, F. Micheli, A. Pasquarello
and G. Tedesco, Int. Pat., WO 03/089409 A1, 2003; (b) K.-K.
Ho, W. Quan and J. Zhou, Int. Pat., WO 2017/005069 A1,
2017; (c) J. L. Castro Pineiro, K. Dinnell, J. M. Elliott, G. J.
Hollingworth, D. E. Shaw and J. C. Swain, Int. Pat., WO
02/102372 A1, 2002; (d) P.-H. Liang, L.-W. Hsin and C.-Y.
Cheng, Bioorganic Med. Chem., 2002, 10, 3267–3276.
,
1170–1173; (k) I. Shiina, K; Ono and T. Nakahara, Chem.
Commun., 2013, 49, 10700–10702; (l) S. F. Musolino, O. S.
Ojo, N. J. Westwood, J. E. Taylor and A. D. Smith, Chem. Eur.
J., 2016, 22, 18916–18922; (m) M. D. Greenhalgh, S. M.
Smith, D. M. Walden, J. E. Taylor, Z. Brice, E. R. T. Robinson,
C. Fallan, D. B. Cordes, A. M. Z. Slawin, H. C. Richardson, M.
A. Grove, P. H.-Y. Cheong and A. D. Smith, Angew. Chem. Int. 22 The research data underpinning this publication can be
Ed., 2018, 57, 3200–3206.
found at DOI: http://dx.doi.org/10.17630/131807b4-8473-
434e-a77d-ee950ac25464.
8
9
For previous examples of polymer-supported isothiourea
catalysts see: (a) J. Izquierdo and M. A. Pericàs, ACS Catal.,
2016,
Escrich, and M. A. Pericàs, ACS Catal., 2017,
6, 348–356; (b) S. Wang, J. Izquierdo, C. Rodríguez-
7, 2780–2785;
(c) S. Wang, C. Rodríguez-Escrich and M. A. Pericàs, Angew.
Chem. Int. Ed., 2017, 56, 15068–15072.
(a) H. B. Kagan and J. C. Fiaud, in Topics in Stereochemistry,
ed. E. L. Eliel and S. H. Wilen, John Wiley & Sons, 1988, vol.
18, pp. 249–330; (b) M. D. Greenhalgh, J. E. Taylor and A. D.
Smith, Tetrahedron, DOI:10.1016/j.tet.2018.05.069
10 (a) K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevid, S. Jennings, T. A.
Johnson, H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry and
M. Stefaniak, Green Chem., 2008, 10, 31–36; (b) R. K.
Henderson, C. Jiménez-González, D. J. C. Constable, S. R.
Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks and
A. D. Curzona, Green Chem., 2011, 13, 854–862; (c) D. Prat,
O. Pardigon, H.-W. Flemmin, S. Letestu, V. Ducandas, P.
Isnard, E. Guntrum, T. Senec, S. Ruisseau, P. Cruciani and P.
Hosek, Org. Process Res. Dev., 2013, 17, 1517–1525; (d) H. E.
Eastman, C. Jamieson and A. J. B. Watson, Aldrichimica Acta,
2015, 48, 51–55; (e) D. Prat, A. Wells, J. Hayler, H. Sneddon,
C. R. McElroy, S. Abou-Shehada and P. J. Dunn, Green Chem.
2016, 18, 288–296.
11 (a) B. Merrifield, Science, 1983, 232, 341–347; (b) E. Bayer,
Angew. Chem. Int. Ed. Engl., 1991, 30, 113–129; (c) I. W.
James, Tetrahedron, 1999, 55, 4855–4946; (d) F. Guillier, D.
Orain and M. Bradley, Chem. Rev., 2000, 100, 2091–2157.
12 For a review see: (a) A. E. Fernandez, A. M. Jonas and O.
Riant, Tetrahedron, 2014, 70, 1709–1731. For seminal
reports see: (b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K.
B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596−2599; (c)
C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem.,
2002, 67, 3057−3064.
13 A. Bastero, D. Font and M. A. Pericàs, J. Org. Chem., 2007,
72, 2460–2468.
14 See the Supporting Information for full details.
15 Each polymer-supported catalyst was only prepared at a
single functionalisation, and therefore any effect of polymer
functionalisation on catalytic performance cannot be
assessed.
16 The absolute configurations of the ester product and
recovered alcohol were assigned by comparison of specific
rotation values with the literature, see Supporting
Information.
17 For the full range of solvents investigated see the Supporting
Information.
18 (a) E. R. Jarvo, C. A. Evans, G. T. Copeland and S. J. Miller, J.
Org. Chem., 2001, 66, 5522–5527; (b) M. C. Angione and S. J.
Miller, Tetrahedron, 2006, 62, 5254–5261; (c) S. Lu, S. B. Poh,
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DOI: 10.1039/C8GC02020E
Highly recyclable isothiourea catalysts on various polymer supports are reported for the kinetic
resolution of secondary and tertiary alcohols using industrially-preferable solvents.