“This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright © American
Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see
https://pubs.acs.org/doi/full/10.1021/acscatal.7b04001 .”

Acylative Kinetic Resolution of Alcohols Using a Recyclable
Polymer-Supported Isothiourea Catalyst in Batch and Flow
Rifahath Mon Neyyappadath,† Ross Chisholm,† Mark D. Greenhalgh,† Carles Rodríguez-Escrich,‡ Miquel A. Pericàs,*,‡,§ Georg Hähner*,† and Andrew D. Smith*,†
†

EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, U.K.
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain
§
Department de Química Inorgànica i Orgànica, Universitat de Barcelona, 08080 Barcelona, Spain
kinetic resolution, isothioureas, Lewis base catalysis, polymer-supported catalysts, catalyst recyclability, acyl transfer reactions, enantioselective catalysis, continuous flow
‡

ABSTRACT: A polystyrene-supported isothiourea catalyst, based on the homogeneous catalyst HyperBTM, has been prepared and
used for the acylative kinetic resolution of secondary alcohols. A wide range of alcohols, including benzylic, allylic and propargylic
alcohols, cycloalkanol derivatives and a 1,2-diol, has been resolved using either propionic or isobutyric anhydride with good to
excellent selectivity factors obtained (28 examples, s up to 622). The catalyst can be recovered and reused by a simple filtration and
washing sequence, with no special precautions needed. The recyclability of the catalyst was demonstrated (15 cycles) with no significant loss in either activity or selectivity. The recyclable catalyst was also used for the sequential resolution of 10 different alcohols
using different anhydrides with no cross-contamination between cycles. Finally, successful application in a continuous flow process
demonstrated the first example of an immobilized Lewis base catalyst used for the kinetic resolution of alcohols in flow.

INTRODUCTION
Catalytic kinetic resolution (KR) processes allow the separation
of a racemate into its two enantiomeric forms through the selective reaction of one enantiomer promoted by a chiral catalyst.1
The efficiency of a KR is commonly characterized by its selectivity factor (s), defined as the rate constant for the fast reacting
enantiomer divided by the rate constant for the slow reacting
enantiomer (s = kfast/kslow).2 KRs with an s of greater than 10 are
generally considered to be synthetically useful. The preparation
of enantioenriched compounds is of general interest in both academia and industry and as such a tremendous number of KR
processes have been devised. Of these methods, the catalytic
acylative KR of alcohols is a powerful method to prepare highly
enantioenriched alcohols (Scheme 1).3 Chiral Lewis base catalysis is most commonly applied for this transformation, with a
range of excellent catalysts reported for the KR of many classes
of secondary alcohols. A current limitation of this method is that
the Lewis base catalyst is rarely recovered from the reaction.
This is particularly problematic for methods that require high
catalyst loadings (> 5 mol%) or use expensive catalysts.
A common strategy to facilitate catalyst recovery is catalyst immobilization on an insoluble solid support.4 The mild reaction
conditions commonly required for organocatalysis makes the
use of polymer resins an attractive option due to good chemical
stability and efficient swelling in organic solvents. Although
many solid-supported organocatalysts have been reported, there
are very few examples of application in the acylative KR of alcohols (Scheme 2a).5 Janda, Anson and Ishihara have used polymer-supported Lewis base catalysts 1-3 for the KR of secondary alcohols.6–8 Although good selectivity factors were obtained
for cycloalkanols and N-protected
Scheme 1. Catalytic Acylative KR of Secondary Alcohols

1,2-aminoalcohols, the resolution of benzylic alcohols was inefficient (s ≤ 2) and application to other substrate classes was
not reported. In all cases the catalysts were recycled up to 5
times, with either none or only minimal catalyst deactivation
observed. In an alternative approach, Connon prepared chiral
DMAP derivative 4 on the surface of magnetic Fe3O4 nanoparticles (Scheme 2a).9 The catalyst was recycled an impressive 32
times, and used for the resolution of 6 different alcohols. Unfortunately the substrate scope was limited to cycloalkanols,
and the selectivity factors obtained were generally low (s = 3–
11).10 Additionally, there are currently no examples in which
immobilized Lewis base catalysts have been applied for the kinetic resolution of alcohols in a continuous flow process.11,12
Based on these current limitations, this manuscript reports the
development of a recyclable polymer-supported Lewis base catalyst capable of resolving a diverse range of secondary alcohols
in both batch and flow. Considering the additional time and cost
required to prepare polymer-supported catalysts, we considered
catalyst recycling of more than 10 cycles necessary to show acceptable recyclability. In addition, the ideal catalyst would be
capable of sequentially resolving different
Scheme 2. Solid-Supported Lewis Base Catalysts used for
KR of Alcohols

Synthesis of Polystyrene-Supported HyperBTM. The synthesis of a polystyrene-supported variant of HyperBTM 6, began with the coupling of the HCl salt of (R)-2-((R)-amino(phenyl)methyl)-3-methylbutan-1-ol 719 with 2-chloro-6-methoxybenzo[d]thiazole 8 followed by in situ cyclization to give 8MeO-HyperBTM 9 in 71% yield (Scheme 3). Demethylation,
followed by propargylation gave alkyne-substituted HyperBTM derivative 11 (68% over 2 steps), which could be attached
to a Merrifield resin-derived azidomethyl polystyrene support
by a Cu-catalyzed azide-alkyne cycloaddition reaction.20 The
nitrogen content of polymer 6, determined by elemental analysis, was used to calculate the functionalization of 6 (0.88 mmol
g−1).21,22 This value of functionalization was used to calculate
the catalyst loading in subsequent KRs.
Scheme 3. Synthesis of Polystyrene-Supported HyperBTM
6

alcohols using different acylating agents without loss in activity
or cross-contamination of products.
Isothioureas have been successfully applied as Lewis base catalysts for a range of enantioselective processes,13 building upon
Birman’s initial application as enantioselective acylation catalysts.14 They have proven useful in the KR of a wide range of
secondary alcohols including benzylic, allylic and propargylic
alcohols, cycloalkanols and a-hydroxy alkanoates.14–16 Recently Pericàs reported the synthesis of the first polymer-supported isothiourea 5, and applied it as a catalyst for formal
[4+2], [2+2] and [8+2] cycloaddition reactions (Scheme 2a).17
A range of heterocyclic products were obtained in good yields
and with excellent diastereo- and enantiocontrol, with the catalyst used in both batch and continuous flow processes. It was
noted however that the catalyst was inefficient for the KR of
(±)-1-phenylethanol, with only a low conversion and minimal
selectivity obtained after an extended reaction time.17a This is in
contrast to the homogenous variant of this catalyst, benzotetramisole (BTM), which has been successfully applied for this
transformation.14
An alternative isothiourea catalyst, HyperBTM,18 developed in
our laboratory has also been applied for the KR of benzylic, allylic and propargylic alcohols.16 Herein we describe the synthesis of a polystyrene-supported variant of the isothiourea catalyst
HyperBTM 6, and demonstrate its application as a catalyst for
the KR of a range of secondary alcohols (Scheme 2b). The durability of the catalyst is demonstrated in recycling studies using
either the same alcohol and anhydride or different alcohols and
anhydrides, and through application in a continuous flow procedure.

RESULTS AND DISCUSSION

Reaction Optimization. Initial studies focused on the KR of a
model secondary alcohol, (±)-1-(naphthalen-2-yl)ethan-1-ol 12,
using polystyrene-supported HyperBTM 6 (1 mol%) as catalyst
(Table 1). Using propionic anhydride as acyl donor (0.55
equiv.) in chloroform at room temperature resulted in an efficient KR of (±)-12, giving 51% conversion within 4 h and a
selectivity factor of 44 (entry 1).23 Increasing the steric bulk of
the anhydride, from propionic to isobutyric, gave an improved
selectivity factor of 79 (entry 2). As the choice of solvent is
known to have a significant effect on the swelling properties of
polymer supports,4c a range of solvents were tested for applicability in the developed KR process (entries 2-7). With the exception of acetonitrile (entry 3) all other solvents provided ideal
conversion of ~50%, with chloroform and toluene giving the
highest selectivity factors (79 and 69 respectively, entries 2 and
7). Notably, industrially-preferable solvents such as EtOAc also
gave good conversion and selectivity (s = 42),24 however chloroform and toluene were chosen for further optimization. Lowering the reaction temperature to 0 °C further improved selectivity (entries 8–9), with

Table 1. KR of (±)-12 using Polystyrene-Supported HyperBTM 6: Optimizationa

Figure 1. Recycling of 6 for the KR of (±)-12

Cat.

1
2
3
4
5
6
7
8
9
10
11

6
6
6
6
6
6
6
6
6
9
14

13
erc
94:6
96:4
92:8
93:7
95:5
94:6
95:5
98:2
98:2
95:5
95:5

s
44
79
18
38
51
42
69
80
104
103
108

a

Reaction conditions: alcohol (0.2 mmol), Catalyst 6, 9 or 14 (1 mol%),
Pr2NEt (0.6 equiv.), anhydride (0.55 equiv.), solvent (0.2 M), 4-7 h. Conversion and er determined by chiral HPLC analysis. Selectivity factors (s)
calculated using er of 12 and reaction conversion (see ref. 2). b R:S. c S:R.
i

chloroform out-performing toluene in terms of both reaction
conversion and selectivity factor (conversion = 47%, s = 105).
To provide a direct comparison with homogenous isothiourea
catalysts, the KR of (±)-12 using 8-OMe-HyperBTM 9 and HyperBTM 14 was performed under analogous reaction conditions
(entries 10-11). Both homogenous catalysts gave slightly higher
conversion (52%), but essentially equal selectivity (s = 103–
108), suggesting that the 8-alkoxy substituent and polystyrene
support of 6 do not have detrimental effects on catalyst selectivity.
Catalyst Recyclability. Encouraged by the excellent activity
and selectivity obtained using polystyrene-supported HyperBTM 6, the recyclability and robustness of the catalyst was investigated. The catalyst could be recovered by filtration, followed by washing sequentially with CHCl3, MeOH and THF
and finally drying under high vacuum for 2 h. Using the KR of
(±)-12 in chloroform at 0 °C for 7 h as standard, the catalyst was
recovered and reused in 15 consecutive KRs (Figure 1). Reaction conversion remained very consistent over all 15 cycles (47
± 3%) indicating the activity of the catalyst remained unaltered,
and corresponding to a combined turnover number (TON) of
over 700. The selectivity factor was more variable (90 ± 12),
however there was no overall loss in selectivity, with the selectivity factor for the 15th cycle (s = 95) essentially equal to that
obtained for the 1st cycle (s = 89). The variability observed in s
may result from a combination of slight inconsistencies in catalyst regeneration after each cycle, and the inherent error present when calculating selectivity factors for highly selective
KRs.1,2

80

80

60

60

40

40

20

20

Selectivity Factor

Entry

T Conv. 12
R Solvent
(°C) (%)
erb
Et CHCl3 r.t.
51
95:5
i
Pr CHCl3 r.t.
50
95:5
i
Pr MeCN r.t.
36 73:27
i
Pr CH2Cl2 r.t.
50
93:7
i
Pr
THF
r.t.
50
94:6
i
Pr EtOAc r.t.
50
93:7
i
Pr PhMe
r.t.
52
98:2
i
Pr PhMe
0
41 83:17
i
Pr CHCl3
0
47
92:8
i
Pr CHCl3
0
52 >99:1
i
Pr CHCl3
0
52 >99:1

100

0

Conversion (%)

100

0
1

3

5

7

9

11

13

15

Catalyst Recycle
Selectivity Factor
% Conversion

Substrate Scope and Limitations. The limited range of secondary alcohols previously resolved using polymer-supported
Lewis base catalysts inspired us to probe the scope of the current method. In particular, different classes of structurally-diverse secondary alcohols were targeted. The KR of secondary
benzylic alcohols is considered a ‘benchmark’ reaction for
Lewis base catalyzed acylative KR, however previous polymersupported variants have proved ineffective for this substrate
class (highest reported s = 3). The KR of benzylic alcohols bearing various substituents at the a-position and on the aromatic
ring was therefore investigated (Table 2). Applying the previously optimized conditions, the KR of (±)-1-phenylethanol 15
was achieved with good conversion and selectivity (s = 46). Increasing the steric bulk of the a-alkyl substituent (15→18) resulted in improved selectivity, although increased catalyst loading (5 mol%) and reaction time (30 h) were required for good
conversion with t-Bu-substituted benzylic alcohol 18. Although
a-trifluoromethyl benzyl alcohol 19 was resolved with only low
selectivity, the a-chloromethyl-substituted analogue 20 was resolved with a good s of 31. The introduction of both electrondonating (OMe, 21) and withdrawing substituents (F, CF3, 22
and 23) on the aromatic ring was tolerated, however lower selectivity factors were obtained for substrates 22 and 23 bearing
electron-withdrawing groups. This is in keeping with previous
reports of isothiourea-catalyzed KR of alcohols and is consistent with a p-cation interaction between the benzylic alcohol
and the acyl isothiouronium playing a significant role in substrate recognition.15g ortho-Substitution on the aromatic ring
was also tolerated, with substrates 24–26 resolved with good
selectivity (s = 14–77), although the KR of sterically-hindered
26 did require resolution at room temperature to obtain good
conversion. An exceptionally high selectivity factor of > 600
was obtained for the resolution of 2-naphthyl derivative 27. The
KR of heteroaromatic alcohols was also briefly studied. 2Thienyl alcohol 28 was resolved with good selectivity (s = 25),
however 2-pyridyl analogue 29 was resolved with very poor selectivity (s = 2), highlighting a current limitation.

Table 2. KR of Benzylic Alcohols

Table 3. KR of Allylic and Propargylic Alcohols

Conversion and er determined by chiral HPLC analysis. Selectivity factors
(s) calculated using alcohol er and reaction conversion (see ref. 2). Alcohol
er given as R:S, ester er given S:R. a Conversion determined by 1H NMR
spectroscopy. b er could not be determined by chiral HPLC or GC.

Consistent with the work of Birman,15b propionic anhydride
gave improved conversion and selectivity factors relative to isobutyric anhydride.22 Both diastereoisomers underwent effective
KR, with trans-phenylcyclohexanol 35 giving the higher selectivity factor (s = 51).25 Indole-substituted cyclohexanol 39 was
also efficiently resolved (s = 51), whilst
Table 4. KR of Cycloalkanol derivatives

Conversion and er determined by chiral HPLC analysis. Selectivity factors
(s) calculated using alcohol er and reaction conversion (see ref. 2). Alcohol
er given as R:S, ester er given S:R. a 5 mol% 6, r.t., 30 h. b r.t.

The substrate scope was extended to allylic and propargylic alcohols, with p-cation interactions between the substrate and catalyst again expected to enable enantiodiscrimination (Table 3).
Cinnamyl alcohol derivative 30 underwent effective KR (s =
17).23 The resolution of a potentially-challenging aryl-alkenyl
alcohol 31, where the catalyst would be required to differentiate
between two p-systems, was also attempted.16b An efficient KR
was still achieved (s = 25), with the enantiodiscrimination obtained consistent with the naphthalene unit acting as the dominant recognition motif in this case.23,16b Propargylic alcohols 32
and 33 were also resolved with good selectivity (s = 23–26).23
The resolution of an aryl-alkynyl alcohol 34 was also attempted
to again probe catalyst differentiation between two p-systems.
In this example very low selectivity was obtained (s = 3), consistent with the respective p-cation interactions between the
phenyl and acetylene units and an acyl-isothiouronium intermediate being comparable in magnitude.23
The KR of cycloalkanols was next studied (Table 4). Previous
isothiourea-catalyzed methods have demonstrated the need for
an adjacent substituent (generally aryl) which can interact with
the catalyst to provide effective enantiodiscrimination.15b,c With
this pre-requisite in mind, the resolutions of trans- and cis-phenylcyclohexanol 35 and 37 were first studied.

Conversion and er determined by chiral HPLC analysis. Selectivity factors
(s) calculated using alcohol er and reaction conversion (see ref. 2). a
(iPrCO)2O (0.55 equiv.) used in place of (EtCO)2O. b 7 h

reducing the ring size to trans-phenylcyclopentanol 41 was also
well tolerated (s = 72). Interestingly, for the resolution of transphenylcyclopentanol 41, isobutyric anhydride proved the optimal acyl donor, with propionic anhydride providing significantly lower selectivity (s = 36).22 An acyclic analogue, homobenzylic alcohol 43, was resolved with low selectivity (s = 7),
suggesting that the conformational rigidity of the cycloalkanol
derivatives may be beneficial for effective recognition by the
catalyst.15g
The KR of a 1,2-diol, (±)-1,2-diphenylethane-1,2-diol 45, was
next investigated (Table 5). Under standard conditions a mixture of diol (S,S)-45,26 monoester (R,R)-46 and diester (R,R)-47
was obtained (entry 1). The selectivity factor for the KR of diol
(±)-45 was determined to be 20,27 however, diester (R,R)-47
was obtained in highly enantioenriched form (99:1), indicating
an amplification in enantiopurity through operation of a second
KR of monoester 46. A control KR using racemic monoester
(±)-46 revealed this second KR proceeds with very high selectivity (conversion = 47%, s = 108) and the same sense of enantiodiscrimination,22 consistent with the observed amplification
in enantiopurity of diester (R,R)-47. This effect was exploited
for the KR of diol (±)-45 by using 1.5 equiv. of anhydride to
increase reaction conversion and allow the isolation of highly
enantioenriched diol (S,S)-45 and diester (R,R)-47 (both > 99:1
er) (entry 2). A similar effect was recently reported in the isothiourea-catalysed KR of 1,3-diols,28a however, to the best of our
knowledge, this is the first example of an isothiourea-catalyzed
KR of a 1,2-diol.28
Table 5. KR of a 1,2-Diol

Entry
1
2

(iPrCO)2O 45 (R,R:S,S)
equiv.
(yield, %)
16:84 er
0.55
(54%)
< 1:99 er
1.5
(20%)

46 (R,R:S,S)
(yield, %)
89:11 er
(34%)
18:82 er
(27%)

47 (R,R:S,S)
(yield, %)
> 99:1 er
(7%)
> 99:1 er
(43%)

Conversion and er determined by chiral HPLC analysis. Selectivity factor
(s) calculated using alcohol er and reaction conversion (see ref. 2).

The developed method was next applied to the enantioselective
synthesis of the (S)-enantiomer of b-blocker pronethalol (S)-49
(Scheme 5).29 The KR of 1,2-azidoalcohol 48 was achieved
with an excellent s of 96, allowing recovery of (S)-48 in 42%
yield and > 99:1 er. Subsequent reduction of the azide and in
situ reductive amination of acetone provided (S)-pronethalol in
81% yield. The excellent selectivity factor obtained for the KR
of 1,2-azidoalcohol 48 indicates this method could be successfully applied more generally to the synthesis of enantiopure 1,2aminoalcohols.

Scheme 5. KR of 1,2-Azidoalcohol 48 and Synthesis of (S)Pronethalol (S)-49

Conversion and er determined by chiral HPLC analysis. Selectivity factor
(s) calculated using alcohol er and reaction conversion (see ref. 2).

Having demonstrated the KR of a range of classes of secondary
alcohols, the recyclability of polystyrene-supported HyperBTM
6 was finally tested for the sequential KR of 10 different alcohols (Table 6). Significantly either propionic or isobutyric anhydride could be used without any cross-contamination between cycles. Generally, slightly lower conversions and selectivity factors were obtained compared to the results obtained
using fresh catalyst (data shown italicized in square brackets),
however there was no overall drop in activity over the course of
the cycling, with the final cycle (entry 10) providing a similar
conversion and identical selectivity factor to that obtained using
fresh catalyst.
Application in Continuous Flow. The exceptional recyclability and versatility of polystyrene-supported catalyst 6 prompted
application in a continuous flow set-up. Polystyrene-supported
catalyst 6 (600 mg, 0.54 mmol) was swollen in CHCl3 in a sizeadjustable, medium pressure borosilicate glass column to create
a packed bed reactor. A cooling jacket was attached to maintain
a constant reaction temperature and solutions of racemic alcohol (0.4 M) and a mixture of anhydride (0.24 M) and base (0.26
M) in CHCl3 were passed through the vertical packed bed reactor using a syringe pump. Improved selectivity factors were obtained at 0 °C relative to room temperature; and a combined
flow rate of 0.1 mL min−1, providing a residence time of 30 min,
was found to be optimal to achieve >50% conversion (Scheme
6). The KR of 1-phenylethanol (±)-15 using isobutyric anhydride was highly reproducible, with 54–56% conversion and s
of 27–30 obtained in five consecutive 4 mmol scale reactions.22
The robustness of the same packed bed reactor was exemplified
by the KR of 28.8 mmol of 1-phenylethanol (±)-15 over a 24 h
period in a continuous flow process (Scheme 6). A conversion
of 55% and s of 28 were obtained, with (R)-1-phenylethanol
(R)-15 recovered in 40% yield (11.5 mmol) and 97:3 er.
To further demonstrate the applicability of the continuous flow
process, the same packed bed reactor that had been used for optimization studies and the resolution of 1-phenylethanol was
then used for sequential KRs using 9 different alcohol/anhydride combinations (Table 7). Each KR was carried out on a 4
mmol scale, with the packed bed reactor simply flushed with
CHCl3 or CHCl3/MeOH (9:1) between reactions.30 A selection
of benzylic, allylic, propargylic and cycloalkanol derivatives
were resolved with optimal conversion (49–63%) and good to
excellent selectivity factors (s = 11–175), allowing isolation of
the enantioenriched alcohol in

Table 6. Recycling of Polystyrene-Supported HyperBTM 6
for the KR 10 Different Substrates

Cycle

Substrate

R

Scheme 6. KR of 1-Phenylethanol in Continuous Flow

Conv. alc. er
Est. er
sa
(%)a (yield, %) (yield, %)

1

i

Pr

50
[47]

96:4
(47)

97:3
(48)

94
[105]

2

i

Pr

55
[54]

93:7
(39)

85:15
(49)

16
[23]

Et

54
[54]

98:2
(41)

91:9
(44)

37
[51]

b

3

4

i

Pr

34
[39]

73:27
(65)

95:5
(33)

28
[31]

5

i

Pr

52
[54]

91:9
(37)

88:12
(45)

50
[46]

93:7
(50)

93:7
(45)

36
[51]

7

i

Pr

38
[45]

81:19
(54)

99:1
(35)

238
[622]

8

i

Pr

45
[51]

88:12
(50)

96:4
(39)

61
[72]

9

i

Pr

50
[57]

95:5
(45)

95:5
(46)

62
[96]

10

i

40
[47]

77:23
(56)

91:9
(37)

Table 7. Continuous Flow KR of Different Alcohols using
the Same Packed Bed Reactor

18
[26]

Et

Conversion and er determined by chiral HPLC analysis. Selectivity factor
(s) calculated using alcohol er and reaction conversion (see ref. 2).

18
[17]

6b

Pr

Conversion and er determined by chiral HPLC analysis. Selectivity factors
(s) calculated using alcohol er and reaction conversion (see ref. 2). a Conversion and s data for resolutions using fresh catalyst (from Tables 1-4)
shown in italics in square brackets. b r.t., 16 h.

92:8–99:1 er in each case. Significantly, the use of different alcohols and anhydrides with the same packed bed reactor gave
spectroscopically-pure products in each case with no evidence
of cross-contamination or catalyst deactivation observed. Remarkably, all the flow experiments described in this paper, including optimization and repeat reactions, were performed with
the same sample of polystyrene-supported catalyst 6, resulting
in a total operation time in excess of 100 h.

Conversion and er determined by chiral HPLC analysis. Selectivity factor
(s) calculated using alcohol er and reaction conversion (see ref. 2). a
(iPrCO)2O used. b (EtCO)2O used.

CONCLUSION
The synthesis of polystyrene-supported isothiourea catalyst 6
was achieved in four steps from (R)-2-((R)-amino(phenyl)methyl)-3-methylbutan-1-ol in 48% overall yield. The KR of a
range of secondary alcohols was demonstrated using 6 as catalyst (1 mol%), with the substrate scope including benzylic, allylic and propargylic alcohols, cycloalkanol derivatives and a
1,2-diol (28 examples). The majority of examples were resolved
with good to excellent selectivity factors (s up to > 600), showing this process has a broad substrate scope, well beyond that of
other solid-supported Lewis base catalysts reported to date. The
recyclability of the catalyst was demonstrated for the resolution
of a single alcohol (15 cycles), and for the sequential resolution
of 10 different alcohols using different anhydrides, with no significant loss in activity or selectivity and with no cross-contamination observed. Based on the high catalyst activity and recyclability, a continuous flow process was developed which was
applied for the efficient KR of 9 different alcohols and also utilized on a 28.8 mmol scale. Current work is focused on using
this new catalyst for other isothiourea-catalyzed reactions
through application in batch and continuous flow processes.31

ASSOCIATED CONTENT
Supporting Information. Experimental procedures; characterization data for novel compounds; 1H and 13C NMR spectra and HPLC
traces. This material is available free of charge via the Internet at
http://pubs.acs.org.

AUTHOR INFORMATION
Corresponding Author
* mapericas@iciq.es (M.A.P.)
* gh23@st-andrews.ac.uk (G.H.)
* ads10@st-andrews.ac.uk (A.D.S.)

Author Contributions
All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT
We 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.). The European
Research Council under the European Union’s Seventh Framework
Programme (FP7/2007-2013) ERC Grant Agreement No. 279850
is also acknowledged. 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 (CTQ201569136-R, AEI/MINECO/FEDER, UE and Severo Ochoa Excellence Accreditation 2014–2018, SEV-2013-0319) and DEC Generalitat de Catalunya (Grant 2014SGR827).

REFERENCES
(1) For reviews see: (a) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N.
Adv. Synth. Catal. 2001, 343, 5-26. (b) Vedejs, E.; Jure, M. Angew.
Chem. Int. Ed. 2005, 44, 3974-4001. (c) Pellissier, H. Adv. Synth. Catal.
2011, 353, 1613-1666.
(2) Kagan, H. B.; Fiaud, J. C. Topics in Stereochemistry 1988, 18,
249-330.
(3) For reviews see: (a) Murray, J. I.; Heckenast, Z.; Spivey, A. C.
Chiral Lewis Base Activation of Acyl and Related Donors in Enantioselective Transformations (n → p*). In Lewis Base Catalysis in

Organic Synthesis; Vedejs, E., Denmark, S. E., Eds.; Wiley-VCH:
Weinheim, 2016; Vol. 2, pp 459-526. (b) Muller, C. E.; Schreiner, P.
R. Angew. Chem. Int. Ed. 2011, 50, 6012-6042.
(4) (a) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103,
3401-3429. (b) Trindade, A. F.; Gois, P. M. P.; Alfonso, C. A. M.
Chem. Rev. 2009, 109, 418-514. (c) Lu, J.; Toy, P. H. Chem. Rev. 2009,
109, 815-838.
(5) In addition, immobilized peptides and transition metal catalysts
have been used for the KR of alcohols: (a) Copeland, G. T.; Miller, S.
J. J. Am. Chem. Soc. 2001, 123, 6496-6502. (b) Gissibl, A.; Finn, M.
G.; Reiser, O. Org. Lett. 2005, 7, 2325-2328. (c) Gissibl, A.; Padié, C.;
Hager, M.; Jaroschik, F.; Rasappan, R.; Cuevas-Yañez, E.; Turrin, C.O.; Caminade, A.-M.; Majoral, J.-P.; Reiser, O. Org. Lett. 2007, 9,
2895-2898. (d) Schätz, A.; Hager, M.; Reiser, O. Adv. Funct. Mater.
2009, 19, 2109-2115. (e) Schätz, A.; Grass, R. N.; Kainz, Q.; Stark, W.
J.; Reiser, O. Chem. Mater. 2010, 22, 305-310.
(6) Clapham, B.; Cho, C.-W.; Janda, K. D. J. Org. Chem. 2001, 66,
868-873.
(7) Pelotier, B.; Priem, G.; Campbell, I. B.; Macdonald, S. J. F.; Anson, M. S. Synlett, 2003, 5, 679-683
(8) (a) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc.
2004, 126, 12212-12213. (b) Kosugi, Y.; Akakura, M.; Ishihara, K. Tetrahedron 2007, 63, 6191-6203.
(9) Gleeson, O.; Tekoriute, R.; Gun’ko, Y. K.; Connon, S. J. Chem.
Eur. J. 2009, 15, 5669-5673.
(10) In addition, the equivalents of anhydride and base were incrementally increased over the recycling process, indicating some catalyst
degradation.
(11) For reviews on the use of solid-supported chiral catalysts in
continuous flow processes see: (a) Puglisi, A.; Benaglia, M.; Chiroli,
V. Green Chem. 2013, 15, 1790-1813. (b) Rodríguez-Escrich, C.; Pericàs, M. A. Eur. J. Org. Chem. 2015, 2015, 1173-1188. (c) Atodiresei,
I.; Vila, C.; Rueping, M. ACS Catal. 2015, 5, 1972-1985.
(12) The KR of a 1,2-diol using a Cu(II)-azabis(oxazoline) catalyst
supported on a Co/C nanoparticle has been reported in continuous flow,
see ref 5e. For the non-catalytic acylative parallel KR of amines in continuous flow see: Kreituss, I.; Bode, J. W. Nature Chem. 2017, 9, 446452.
(13) For a review see: Merad, J.; Pons, J.-M.; Chuzel, O.; Bressy,
C.; Eur. J. Org. Chem. 2016, 2016, 5589-5610.
(14) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351-1354.
(15) (a) Birman, V. B.; Guo, L. Org. Lett. 2006, 8, 4859-4861. (b)
Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115-1118. (c) Zhang, Y.;
Birman, V. B. Adv. Synth. Catal. 2009, 351, 2525-2529. (d) Xu, Q.;
Zhou, H.; Geng, X.; Chen, P. Tetrahedron 2009, 65, 2232-2238. (e)
Shiina, I.; Nakata, K.; Ono, K.; Sugimoto, M.; Sekiguchi, A.. Chem.
Eur. J. 2010, 16, 167-172. (f) Shiina, I.; Ono, K.; Nakata, K. Chem.
Lett. 2011, 40, 147-149. (g) Li, X.; Jiang, H.; Uffman, E. W.; Guo, L.;
Zhang, Y.; Yang, X.; Birman, V. B. J. Org. Chem. 2012, 77, 17221737. (h) Nakata, K.; Gotoh, K.; Ono, K.; Futami, K.; Shiina, I. Org.
Lett. 2013, 15, 1170-1173. (i) Shiina, I.; Ono, K.; Nakahara, T. Chem.
Commun. 2013, 49, 10700-10702.
(16) (a) Belmessieri, D.; Joannesse, C.; Woods, P. A.; MacGregor,
C.; Jones, C.; Campbell, C. D.; Johnston, C. P.; Duguet, N.; Concellón,
C.; Bragg, R. A.; Smith, A. D. Org. Biomol. Chem. 2011, 9, 559-570.
(b) Musolino, S. F.; Ojo, O. S.; Westwood, N. J.; Taylor J. E.; Smith
A. D. Chem. Eur. J. 2016, 22, 18916-18922.
(17) (a) Izquierdo, J.; Pericàs, M. A. ACS Catal. 2016, 6, 348-356.
(b) Wang, S.; Izquierdo, J.; Rodríguez-Escrich, C.; Pericàs, M. A. ACS
Catal. 2017, 7, 2780-2785. (c) Wang, S.; Rodríguez-Escrich, C.;
Pericàs, M. A. Angew. Chem. Int. Ed. 2017, 56, 15068-15072.
(18) (a) Joannesse, C.; Johnson, C. P.; Concellón, C.; Simal, C,
Philp, D.; Smith, A. D. Angew. Chem. Int. Ed. 2009, 48, 8914-8918.
(b) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith,
A. D. J. Am. Chem. Soc. 2011, 133, 2714-2720. (c) Maji, B.; Joannesse,
C.; Nigst. T. A.; Smith, A. D.; Mayr, H. J. Org. Chem. 2011, 76, 51045112. (d) Robinson, E. R. T.; Fallan, C.; Smial, C.; Slawin, A. M. Z.;
Smith, A. D. Chem. Sci. 2013, 4, 2193-2200. (e) Matviiksuk, A.;
Greenhalgh, M. D.; Antúnez, D.-J. B.; Slawin, A. M. Z.; Smith, A. D.
Angew. Chem. 2017, 129, 12450-12455.

(19) Morrill, L. C.; Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox D.
J.; Smith A. D. Chem. Sci. 2013, 4, 4146-4155.
(20) For a review see: (a) Fernandez, A. E.; Jonas, A. M.; Riant, O.
Tetrahedron 2014, 70, 1709-1731. For seminal reports see: (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem. Int. Ed. 2002, 41, 2596−2599. (c) Tornøe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057−3064.
(21) Bastero, A.; Font, D.; Pericàs, M. A. J. Org. Chem. 2007, 72,
2460-2468.
(22) See the Supporting Information for full details
(23) The absolute configuration of recovered alcohol was assigned
as (R) through comparison of its specific rotation with literature, see
Supporting information for details.
(24) (a) Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevid, T.; Jennings, S.;
Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.;
Stefaniak, M. Green Chem. 2008, 10, 31-36. (b) Henderson, R. K.; Jiménez-González, C.; Constable, D. J. C.; Alston, S. R.; Inglis, G. G.
A.; Fisher, G.; Sherwood, J.; Binks, S. P.; Curzona, A. D. Green Chem.
2011, 13, 854-862. (c) Prat, D.; Pardigon, O.; Flemmin, H.-W.; Letestu,
S.; Ducandas, V.; Isnard, P.; Guntrum, E.; Senec, T.; Ruisseau, S.; Cruciani, P.; Hosek, P. Org. Process Res. Dev. 2013, 17, 1517-1525.
(25) The absolute configuration of recovered alcohol was assigned
as (1R,2S) through comparison of its specific rotation with literature,
see Supporting information for details.
(26) The absolute configuration of recovered alcohol was assigned
as (S,S) through comparison of its specific rotation with literature, see
Supporting information for details.
(27) The selectivity factor for the KR of (±)-45 was calculated using
the er of isolated (S,S)-45, and the er of ‘product’, calculated by combining the ers of monoester (R,R)-46 and diester (R,R)-47, with their
contributions weighted according to their ratio measured by 1H NMR
spectroscopy of the crude reaction product. If the contribution from the
minor component of diester (R,R)-47 is omitted from the calculation an
s of 17 is obtained.
(28) For the isothiourea-catalyzed KR of a 1,3-diol see: (a) Merad,
J.; Borkar, P.; Caijo, F.; Pons, J.-M.; Parrain, J.-L.; Chuzel, O.; Bressy,
C. Angew. Chem. Int. Ed. 10.1002/anie.201709844. For the isothiourea-catalyzed desymmetrization of meso-diols see: (b) Birman, V. B.;
Jiang, H.; Li, X. Org. Lett. 2007, 9, 3237-3240. (c) Merad, J.; Borkar,
P.; Yenda, T. B.; Roux, C.; Pons, J.-M.; Parrain, J.-L.; Chuzel, O.;
Bressy, C. Org. Lett. 2015, 17, 2118-2121.
(29) (a) Black, J. W.; Stephenson, J. S. Lancet 1962, 280, 311-314.
(b) Howe, R. Nature 1965, 207, 594-595. (c) Howe, R.; Crowther, A.
F.; Stephenson, J. S.; Rao, B. S.; Smith, L. H. J. Med. Chem. 1968, 11,
1000-1008.
(30) When using different alcohol substrates, CHCl3 was pumped at
0.1 mL min−1 for 45 min. When using different anhydrides,
CHCl3/MeOH (9:1) was pumped at 0.1 mL min−1 for 45 min.
(31) The research data underpinning this publication can be found at
DOI:
http://dx.doi.org/10.17630/5c945e1a-44ac-4c1a-8cb1a154bcefa4c6.