Isothiourea-Catalysed Sequential Kinetic Resolution of Acyclic (±)-1,2-Diols

Article abstract of DOI:10.1055/s-0037-1610721

The isothiourea-catalysed acylative kinetic resolution of a range of acyclic (±)-1,2-diols using 1 molpercent of catalyst under operationally simple conditions is reported. Significantly, the bifunctional nature of (±)-1,2-diols was exploited in a sequential double kinetic resolution, in which both kinetic resolutions operate synergistically to provide access to highly enantioenriched products. The principles that underpin this process are discussed, and selectivity factors for the individual kinetic resolution steps are reported in a model system.

Full text of DOI:10.1055/s-0037-1610721

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
A
en
S. Harrer et al.
Letter
Synlett
Isothiourea-Catalysed Sequential Kinetic Resolution of Acyclic
(±)-1,2-Diols
Siegfried Harrer
i-Pr
N
Mark D. Greenhalgh
Rifahath M. Neyyappadath
Andrew D. Smith*
S
Ph
N
OH
OH
OCOi-Pr
OCOi-Pr
1 mol% catalyst
R
R
R
R
+
+
R
R
R
R
(i-PrCO)2O, i-Pr2NEt
OH
OH
(1R,2R)
OH
OCOi-Pr
EaStCHEM, School of Chemistry, University of St Andrews,
St Andrews, Fife, KY16 9ST, UK
CHCl3, 0 °C
(1S,2S)
racemate
ads10@st-andrews.ac.uk
combined yield: 36–49%
44–50%
reinforcement of enantioselectivity
all products highly enantioenriched
R = aryl, alkenyl,
alkynyl
Received: 30.05.2019
Accepted after revision: 12.06.2019
Published online: 10.07.2019
sense of enantiodiscrimination (e.g. k1 > k3 and k2 > k4), the
enantiomer of monoester preferentially formed from the
first KR is rapidly consumed in the second KR. This process
is related to the principles of Horeau amplification,9 and
leads to the final diester product being obtained in highly
enantioenriched form. By exploiting this effect, highly en-
antioenriched compounds can be obtained even if each in-
dividual KR step displays only moderate selectivity.
DOI: 10.1055/s-0037-1610721; Art ID: st-2019-d0295-l
Abstract The isothiourea-catalysed acylative kinetic resolution of a
range of acyclic (±)-1,2-diols using 1 mol% of catalyst under operation-
ally simple conditions is reported. Significantly, the bifunctional nature
of (±)-1,2-diols was exploited in a sequential double kinetic resolution,
in which both kinetic resolutions operate synergistically to provide ac-
cess to highly enantioenriched products. The principles that underpin
this process are discussed, and selectivity factors for the individual ki-
netic resolution steps are reported in a model system.
O
O
OH
R2
O
R2
O
k1
k2
R1
R1
OH
R1
O
Key words kinetic resolution, isothiourea, 1,2-diols, enantioselectivi-
ty, acylation
R1
R1
R1
OH
O
R2
(S,S)
(S,S)
(S,S)
Chiral 1,2-diols are important intermediates in organic
synthesis; are present in a range of bioactive compounds;
and have found application as chiral auxiliaries, ligands and
organocatalysts.1 The most common approaches to access
chiral 1,2-diols include enantioselective Sharpless dihydrox-
ylation of alkenes,1a,2 pinacol coupling of aldehydes,1a,3 reduc-
tion of ketones1a,4 and hydrolysis of epoxides.1a,5 Although in-
credibly powerful, these methods are generally reliant on the
use of toxic or expensive transition metals as stoichiometric
reagents or catalysts. The organocatalytic kinetic resolution
(KR) of (±)-1,2-diols therefore represents a potentially attrac-
tive alternative.6 KR processes provide access to enantioen-
riched compounds with unrivalled control of enantiopurity
through simply modulating the reaction conversion.7 In addi-
tion, products from enantioselective synthetic methods are
often only obtained as a scalemic mixture, and therefore a
suitable KR can also be applied as a subsequent complemen-
tary process to improve product enantiopurity.
O
O
OH
R2
O
R2
O
k3
k4
R1
R1
R1
O
R1
R1
R1
OH
(R,R)
OH
(R,R)
O
R2
(R,R)
1st KR
s1 = k1/k3
2nd KR
s2 = k2/k4
Scheme 1 Sequential kinetic resolution (KR) of C2-symmetric (±)-1,2-diols
To date, there have been four approaches reported for
the organocatalytic acylative KR of C2-symmetric (±)-1,2-
diols.10 In each of these examples only minimal formation
of the diester product was observed, and therefore these
methods could be simply considered as a single KR process
(i.e. k1 > k3 >> k2 ≈ k4). The efficiency of these KRs was there-
fore reported by only calculating the selectivity factor (s)11
of the first KR process. Fujimoto reported the first of these
methods using a bifunctional phosphinite-derived cincho-
na alkaloid catalyst.10a The KR of a small selection of cyclic
and acyclic diols was achieved with up to excellent selectiv-
The acylative KR of C2-symmetric (±)-1,2-diols embod-
ies an interesting class of KRs, where, by virtue of the bis-
functionality of the substrate, two sequential KR processes
can operate (Scheme 1).8 Where both KRs display the same
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Harrer et al.
Letter
Synlett
ity (six substrates, s = 11 to >200). Schreiner has since pub-
lished a series of seminal studies on the KR of cyclic (±)-1,2-
diols using oligopeptide catalysts (seven substrates, s = 4 to
>50);10b–g whilst Takasu and Yamada have demonstrated the
successful use of N-heterocyclic carbene (NHC) redox catal-
ysis for the KR of cyclic (±)-1,2-diols (five substrates, s = 18
to >200).10h,i Arguably the most general method for the KR
of (±)-1,2-diols was reported recently by Suga.10j,k In this
work, a bifunctional chiral 4-(N,N-dimethylamino)pyridine
(DMAP) derivative was applied for the KR of a broad range
of cyclic and acyclic (±)-1,2-diols with up to excellent selec-
tivity (22 substrates, s = 2 to 180). The selective mono-acy-
lation reported in these literature examples, although im-
pressive, negates the opportunity to use a sequential KR
process to enhance the enantiopurity of the products in
both antipodal series.
Lewis basic isothioureas have emerged as versatile cata-
lysts for the acylative KR of primary,12 secondary13 and ter-
tiary alcohols14 and the acylative desymmetrisation of
meso-diols,15 amongst other applications.16 Recently, iso-
thiourea catalysis has also been applied for the acylative KR
of (±)-1,3-diols17 and axially chiral biaryl diols.18 Herein we
report the development of the catalytic acylative KR of C2-
symmetric acyclic (±)-1,2-diols using HyperBTM 1, in
which a synergistic sequential KR process is exploited to
enable the highly efficient separation of the 1,2-diol enan-
tiomers (Scheme 2).
diester (1S,2S)-4 (97:3 er), with the isolated diol 2 and
monoester 3 both enriched in the 1R,2R enantiomer (both
>98:2 er) (entry 3). These results demonstrate the elegance
of using a sequential KR process for the highly efficient sep-
aration of enantiomers.
Table 1 Reaction Optimisation I: Variation of Anhydride Equivalents
1 (5 mol%)
(i-PrCO)2O
(x equiv.)
OH
OH
OCOi-Pr
Ph
OCOi-Pr
Ph
Ph
Ph
+
+
Ph
Ph
Ph
Ph
i-Pr2NEt
CHCl3
r.t., 7 h
OH
)-2
OH
(1R,2R)-2
OH
(1S,2S)-3
OCOi-Pr
(1S,2S)-4
(
Entry
x
Ratioa
2 erb
3 erb
4 erb
(1R,2R):(1S,2S) (1S,2S):(1R,2R) (1S,2S):(1R,2R)
1
2
3
0.55 54:41:5
83:17
88:12
65:35
2:98
>99:1
99:1
97:3
1.0
1.5
36:40:24 99:1
13:36:51 >99:1
a Determined by 1H NMR spectroscopic analysis of the crude reaction product.
b Determined by HPLC analysis using a chiral support.
To provide further insight into this process, s values for
the individual KR steps were calculated. An s value for the
KR of (±)-1,2-diphenylethane-1,2-diol 2 was evaluated on
the basis of the data obtained when using 0.55 equivalents
of isobutyric anhydride (Table 1, entry 1). Using the enan-
tiomeric purity of the recovered diol, and the reaction con-
version determined by 1H NMR spectroscopy, an s value of
16 was calculated for this first KR step.21 The s value of the
second KR process was simply determined by performing
the KR of (±)-monoester 3 (Scheme 3). This KR provided an
s value of 60, demonstrating that the second KR is signifi-
cantly more selective than the first KR. Both KR steps dis-
played selectivity for acylation of the 1S,2S enantiomer of
substrates 2 and 3, confirming the synergistic nature of the
overall sequential KR process. These results directly con-
trast the work of Suga on the KR of (±)-1,2-diols, where se-
lectivity was solely attributable to a highly selective first
KR, with essentially no operation of, or selectivity associat-
ed with, the second KR.10j
i-Pr
N
S
OH
(
OH
OCOi-Pr
OCOi-Pr
Ph
N
1 (1 mol%)
R
R
R
R
+
+
R
R
R
R
(i-PrCO)2O
i-Pr2NEt
CHCl3, 0 °C
OH
)
OH
OH
OCOi-Pr
All products highly enantioenriched
Scheme 2 This work: isothiourea-catalysed KR of C2-symmetric acyclic
(±)-1,2-diols
Initial studies focussed on the KR of (±)-1,2-dipheny-
lethane-1,2-diol 219 using isobutyric anhydride as the acyl
donor unit and HyperBTM 1 as the isothiourea catalyst (Ta-
ble 1).20 The use of 0.55 equivalents of isobutyric anhydride
allowed isolation of diol (1R,2R)-2 and monoester (1S,2S)-3
in good enantiopurity, along with a small quantity of essen-
tially enantiopure diester (1S,2S)-4 (Table 1, entry 1). This
result indicated that both KR processes were in operation,
and therefore we attempted to exploit this sequential KR by
driving the reaction to higher conversion through increas-
ing the equivalents of isobutyric anhydride. Use of one
equivalent of isobutyric anhydride provided both diol
(1R,2R)-2 and diester (1S,2S)-4 in very high enantiopurity
(99:1 er), although the major reaction component (40%)
was monoester (1S,2S)-3, which was isolated with low en-
antiopurity (65:35 er) (entry 2). Increasing the equivalents
of isobutyric anhydride to 1.5 provided 51% conversion to
1 (5 mol%)
(i-PrCO)2O
(0.55 equiv.)
OH
OH
OCOi-Pr
Ph
Ph
Ph
+
Ph
Ph
Ph
i-Pr2NEt
(0.6 equiv.)
CHCl3, r.t., 7 h
OCOi-Pr
)-3
OCOi-Pr
OCOi-Pr
(1S,2S)-4
96:4 er
(
(1R,2R)-3
88:12 er
conv. = 45%, s = 60
Scheme 3 KR of racemic monoester (±)-3
These s values were then applied in the SeKiRe software,
developed by Faber,8g to simulate the variation in enantio-
enrichment of the diol, monoester and diester over the
course of the reaction (Figure 1).22 Plotting the conversion
to diester 4 on the x-axis provides insight into how varying
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C
S. Harrer et al.
Letter
Synlett
the reaction conversion, through modulation of the equiva-
lents of anhydride used, affects the enantioenrichment of
each reaction component. It also provides a useful visual
guide to show how the level of enantioenrichment, and the
absolute configuration, of the monoester 3 is particularly
sensitive to reaction conversion. For example, by using this
simulation the change in the configuration of the isolated
monoester 3 from the 1S,2S enantiomer (Table 1, entries 1
and 2), to the 1R,2R enantiomer (Table 1, entry 3), can be
understood. The complex kinetic scenario of this sequential
KR clearly highlights the challenge associated with direct
comparison between reactions run under different condi-
tions and to different conversions.
Further reaction optimisation was targeted through
variation of the isothiourea catalyst, reaction solvent and
temperature (Table 2). As demonstrated above, the calcula-
tion of s values for both KR processes is a relatively labor-
intensive process. It was therefore considered to be imprac-
tical to calculate these values for each set of conditions
during reaction optimisation. It has previously been pro-
posed that the overall selectivity of a sequential KR can be
represented by using the conversion to, and enantiomeric
purity of, the final product to calculate the s value that
would be required in a hypothetical single-step KR to give
the product with the observed enantiopurity.8d,e,f,23 Whilst
this approach may allow more straightforward comparison
between experiments, we found this value to be dependent
on the reaction conversion and therefore did not consider it
as a meaningful metric in this case.24
Reaction optimisation was therefore assessed by aiming for
~50% conversion to diester, and comparing the enantiopuri-
ty of the diester. By using this approach, alternative iso-
thiourea catalysts, BTM 5 and tetramisole 6, gave useful
product selectivities but were considered to be less selec-
tive than HyperBTM 1 (Table 2, entries 2–3). Studying the
KR using HyperBTM 1 in a range of solvents demonstrated
that THF provided low selectivity and conversion (entry 4);
whilst PhMe, EtOAc, MeCN and DMSO provided good con-
version and high enantiopurity of the diester (entries 5–8).
However, the original results using CHCl3 as solvent were
still considered to be optimal. Further studies showed that
performing the KR in CHCl3 at 0 °C, and using 1 mol% Hy-
perBTM 1, provided 51% conversion to diester and gave all
Figure 1 Simulation of evolution of %ee of diol 2, monoester 3 and di-
ester 4 over the course of the sequential KR at room temperature (entry
numbers refer to Table 1)
Table 2 Reaction Optimisation II: Variation of Catalyst, Solvent and Temperature
catalysts:
catalyst (x mol%)
(i-PrCO)2O (1.5 equiv.)
OH
OH
OCOi-Pr
Ph
OCOi-Pr
N
i-Pr
Ph
Ph
Ph
Ph
Cl
N
N
+
+
Ph
Ph
Ph
Ph
Ph
i-Pr2NEt (1.6 equiv.)
N
S
H
S
OH
)-2
OH
(1R,2R)-2
OH
(1R,2R)-3
OCOi-Pr
solvent, r.t., 7 h
N
S
Ph
N
(1S,2S)-4
(2S,3R)-HyperBTM 1
(R)-BTM 5
(
(S)-TM⋅HCl 6
Entry
Catalyst (mol%)
Solvent
Product ratio (2:3:4)a
2 er (1R,2R):(1S,2S)b
3 er (1R,2R):(1S,2S)b
4 er (1S,2S):(1R,2R)b
1
2
3
4
5
6
7
8
9c
1 (5)
5 (5)
6 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (1)
CHCl3
CHCl3
CHCl3
THF
13:36:51
7:40:53
>99:1
>99:1
1:99
98:2
97:3
99:1
94:6
18:42:40
49:36:15
12:34:54
10:36:54
14:33:53
28:20:52
13:36:51
30:70
10: 90
>99:1
>99:1
>99:1
99:1
6:94
94:6
93:7
PhMe
EtOAc
MeCN
DMSO
CHCl3
>99:1
>99:1
>99:1
>99:1
>99:1 (8%)d
92:8
91:9
93:7
96:4
>99:1 (31%)d
97:3 (50%)d
a Determined by 1H NMR spectroscopic analysis of the crude reaction product.
b Determined by HPLC analysis using a chiral support.
c Reaction temperature 0 °C.
d Isolated yield.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F

D
S. Harrer et al.
Letter
Synlett
three products in highly enantioenriched form (entry 9).
Overall, this process allowed isolation of (1S,2S)-diester
4 in 50% yield and 97:3 er and the 1R,2R enantiomer of both
the diol 2 and monoester 3 in a combined 39% yield and
>99:1 er. Under the optimised conditions at 0 °C, the indi-
vidual s values for each KR step were also measured.22 Per-
forming the KR of (±)-1,2-diphenylethane-1,2-diol 2 using
0.55 equivalents of anhydride, to limit reaction conversion,
allowed calculation of the s value for the first KR as 36. The
KR of (±)-monoester 3 was used to calculate an s value of 80
for the second KR. The fact that both of these s values were
higher than those calculated previously at room tempera-
ture confirmed the advantage of performing this synergis-
tic sequential KR process at 0 °C.
At this point we were intrigued to investigate further (i)
the influence of the diol motif on the selectivity of the KR
and (ii) the origin of the higher selectivity obtained in the
second KR process. It has been demonstrated previously for
the KR of simple benzylic alcohols that substrates bearing
larger  substituents are generally resolved with higher s
values.13 To provide some insight towards answering both
questions outlined above, the KRs of sterically differentiat-
ed monoalkylated derivatives of 1,2-diphenylethane-1,2-di-
ol, (±)-7 and (±)-9, were performed (Scheme 4). The KR of
(±)-7, bearing the small methyl substituent, was achieved
with an s value of 10; whilst the KR of (±)-9, bearing the
larger isopropyl substituent, was achieved with an s value
of 34. These experiments highlight a beneficial effect of in-
creasing the size of the  substituent; however, both s val-
ues were lower than those obtained for the KR of diol (±)-2
and monoester (±)-3. This suggests that the additional hy-
drogen bond donor and/or acceptor abilities of the diol and
monoester may also have an influential role in enhancing
the selectivities observed in this sequential KR.
donating and -withdrawing substituents on the aryl units
were resolved with good conversion and, with the excep-
tion of dimethyl ester-substituted derivative 14, excellent
selectivity. In general, the KR of derivatives bearing elec-
tron-donating groups provided products of higher enantio-
meric purity than the KR of substrates bearing electron-
withdrawing groups. These observations are consistent
with selectivity trends observed for the KR of secondary
benzylic alcohols, and can be rationalised by the more elec-
tron-rich aromatic substituents providing more effective
stabilisation of the positively charged acylated catalyst in-
termediate in the acylation transition state.13h It was there-
fore hypothesised that this method may be extended for
the KR of other (±)-1,2-diols bearing adjacent -donor
systems.13a,b,g,h,l The KRs of allylic and propargylic diols 17
and 18 were achieved with moderate selectivity; however,
1 (1 mol%)
(i-PrCO)2O
OH
(
OH
OCOi-Pr
OCOi-Pr
(1.5 equiv.)
R
R
R
R
+
+
R
R
R
R
i-Pr2NEt
(1.6 equiv.)
CHCl3, 0 °C, 7 h
OH
)
OH
OH
OH
OCOi-Pr
OMe
Me
OH
OH
OH
MeO
Me
11; ratioa = 16:33:51
diol: >99:1 er; 14%
monoester: 99:1 er; 28%
diester: 98:2 er; 44%
12; ratioa = 9:39:52
diol: >99:1 er; 8%
monoester: >99:1 er; 36%
diester: 96:4 er; 48%
CO2Me
Cl
OH
OH
OH
OH
MeO2C
Cl
13; ratioa = 8:40:52
diol: >99:1 er, 7%
monoester: 99:1 er, 36%
diester: 95:5 er, 48%
14; ratioa = 12:37:51
diol: 87:13 er; 10%
monoester: 94:6 er; 34%
diester: 90:10 er; 48%
a)
1 (1 mol%)
(i-PrCO)2O
(0.55 equiv.)
OH
OH
OCOi-Pr
Ph
Ph
Ph
+
CF3
Ph
Ph
Ph
OH
OH
i-Pr2NEt
(0.6 equiv.)
CHCl3, 0 °C, 7 h
OMe
)-7
OMe
OMe
(
(1R,2R)-7
(1S,2S)-8
78:22 er; 52%
82:18 er; 41%
OH
OH
F3C
conv. = 45%, s = 10
15; ratioa = 7:42:51
diol: >99:1 er; 7%
16; ratioa = 13:35:52
diol: >99:1 er; 13%
b)
1 (1 mol%)
(i-PrCO)2O
(0.55 equiv.)
OH
OH
OCOi-Pr
monoester: 99:1 er; 38%
diester: 96:4 er; 50%
monoester: >99:1 er; 35%
diester: 95:5 er; 50%
Ph
Ph
Ph
Ph
Ph
+
Ph
i-Pr2NEt
(0.6 equiv.)
CHCl3, 0 °C, 7 h
OH
OH
Ph
Oi-Pr
)-9
Oi-Pr
Oi-Pr
Ph
(
(1R,2R)-9
61:39 er; 77%
(1S,2S)-10
96:4 er; 18%
Ph
OH
Ph
OH
conv. = 20%, s = 34
17; ratioa = 0:52:48
18; ratioa = 8:41:51
diol: >99:1 er; 5%
diol: N/Ab
Scheme 4 KRs of model monoalkylated compounds (±)-7 and (±)-9
monoester: 77:23 er; 49%
diester: 79:21 er; 48%
monoester: 85:15 er; 31%
diester: 83:17 er; 50%
Finally, the generality of this sequential KR process was
investigated using a selection of electronically and sterically
differentiated (±)-1,2-diols (Scheme 5).20 (±)-1,2-Diary-
lethane-1,2-diol derivatives 11–16 bearing both electron-
Scheme 5 Reaction scope. a Ratio of diol/monoester/diester deter-
mined by 1H NMR spectroscopic analysis of the crude reaction product.
b N/A = not applicable.
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S. Harrer et al.
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Synlett
these chiral diols would be challenging to synthesise
through alternative enantioselective methods such as dihy-
droxylation.
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In conclusion, we have reported a synergistic sequential
acylative KR of (±)-1,2-diols using Lewis base organocataly-
sis, which provides access to C2-symmetric 1,2-diols in
highly enantioenriched form. Optimal selectivities were ob-
tained using a readily prepared and commercially available
isothiourea Lewis base catalyst (HyperBTM)25,26 and re-
agents (isobutyric anhydride, Hünig’s base) at 0 °C, making
this KR process operationally simple to perform.27
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Wanka, L.; Schreiner, P. R. Chem. Commun. 2012, 48, 2498.
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Schuler, S. M.; Schreiner, P. R. J. Org. Chem. 2013, 78, 8465.
(f) Hofmann, C.; Schuler, S. M. M.; Wende, R. C.; Schreiner, P. R.
Chem. Commun. 2014, 50, 1221. (g) Hofmann, C.; Schümann, J.
M.; Schreiner, P. R. J. Org. Chem. 2015, 80, 1972. (h) Kuwano, S.;
Harada, S.; Kang, B.; Oriez, R.; Yamaoka, Y.; Takasu, K.; Yamada,
K.-I. J. Am. Chem. Soc. 2013, 135, 11485. (i) Iwahana, S.; Iida, H.;
Yashima, E. Chem. Eur. J. 2011, 17, 8009. (j) Fujii, K.; Mitsudo, K.;
Mandai, H.; Suga, S. Adv. Synth. Catal. 2017, 359, 2778.
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Funding Information
We thank the EPSRC Centre for Doctoral Training in Critical Resource
Catalysis (CRITICAT, grant code EP/L016419/1, R.M.N.) for funding.
We thank the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007–2013) ERC grant agree-
ment 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 Service at Swansea.
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Acknowledgment
We thank Prof. Kurt Faber (University of Graz) for a number of useful
discussions and for providing us access to his SeKiRe software.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610721.
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References and Notes
(1) (a) Bhowmick, K. C.; Joshi, N. N. Tetrahedron: Asymmetry 2006,
17, 1901. (b) Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021.
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(2) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483. (b) Zaitsev, A. B.; Adolfsson, H. Synthesis 2006,
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(b) Takenaka, N.; Xia, G.-Y.; Yamamoto, H. J. Am. Chem. Soc.
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(11) Selectivity factor (s) is the most commonly used metric to
report the efficiency of a KR, is defined as the rate constant for
the fast reacting enantiomer divided by the rate constant for the
slow reacting enantiomer (s = kfast/kslow) and is calculated by
using the reaction conversion and either the ee of the recovered
substrate
{s = ln[(1−c)(1−eesubstrate)]/ln[(1−c)(1+eesubstrate)]}
or ee of the reaction product
{s = ln[(1−c(1+eeproduct)]/ln[(1−c(1−eeproduct)]}
See references 7a and 7c for more details. For biocatalysed pro-
cesses an analogous metric, E (enantiomeric ratio), is used, see
reference 7b.
(12) Burns, A. S.; Wagner, A. J.; Fulton, J. L.; Young, K.; Zakarin, A.;
Rychnovsky, S. D. Org. Lett. 2017, 19, 2953.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F

F
S. Harrer et al.
Letter
Synlett
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Neyyappadath, R. M.; Greenhalgh, M. D.; Chisholm, R.; Smith, S.
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Biotage flash silica column chromatography (0→40% EtOAc in
n-hexane) to give a colourless solid, which was further purified
by recrystallisation: the material was dissolved hot PhMe/hex-
ane (1:1), allowed to cool to r.t. and then cooled in a freezer
overnight. The product was filtered and washed with cold
hexane to give (±)-1,2-diphenylethane-1,2-diol as colourless
crystals (single diastereoisomer, 768 mg, 3.59 mmol, 72% yield).
Mp 121 °C (Lit.25 mp 121 °C); 1H NMR (500 MHz, CDCl3):  =
2.84 (s, 2 H, OH), 4.72 (s, 2 H, HCOH), 7.10–7.16 (m, 4 H, ArH),
7.21–7.27 (m, 6 H, ArH). Spectral data in accordance with the
literature.28
(20) KR of (±)-1,2-Diols: General Procedure
HyperBTM 1 (x mol%), (i-PrCO)2O (y equiv.) and i-Pr2NEt (z
equiv.) were added to a solution of the appropriate (±)-1,2-diol
(1 equiv.) in the given solvent (0.2 M) and at the given tempera-
ture, and the mixture allowed to stir for 7 h. HCl (1 M) was
added and the mixture extracted with EtOAc (3 times). The
combined organic fractions were washed sequentially with sat-
urated NaHCO3 and brine, dried (Na2SO4), filtered and concen-
trated to give a residue, which was purified by Biotage flash
silica column chromatography (0→40% EtOAc in hexane) to
give the diester, monoester and diol products, which were anal-
ysed by HPLC using a chiral support – see Supporting Informa-
tion for more details.
(21) This s value was calculated by using
s = ln[(1−c)(1−eesubstrate)] / ln[(1−c)(1+eesubstrate)]
and assumes the reaction is irreversible and the er of the diol
substrate is exclusively determined by the selectivity associated
with the first KR process.
(17) Merad, J.; Borkar, P.; Caijo, F.; Pons, J.-M.; Parrain, J.-L.; Chuzel,
O.; Bressy, C. Angew. Chem. Int. Ed. 2017, 56, 16052.
(18) Qu, S.; Greenhalgh, M. D.; Smith, A. D. Chem. Eur. J. 2019, 25,
2816.
(22) See Supporting Information for more details.
(23) Macfarlane, E. L. A.; Roberts, S. M.; Turner, N. J. J. Chem. Soc.,
Chem. Commun. 1990, 569.
(24) In contrast, the selectivity factor (s) of a single step KR is, by
definition, independent of conversion. See references 7a and 7b.
(25) Morrill, L. C.; Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox, D. J.;
Smith, A. D. Chem. Sci. 2013, 4, 4146.
(26) Both enantiomers are available from Apollo Scientific {(2S,3R)
CAS Reg. No. [1203507-02-1]; (2R,3S) CAS Reg. No. [1699751-
03-5]}.
(19) (±)-1,2-Diphenylethane-1,2-diol (2)
THF (4 equiv.) was added to a solution of TiCl4 (1 equiv.) in
anhydrous CH2Cl2 (0.5 M) under an N2 atmosphere at r.t. and
was allowed to stir for 30 s. Zinc powder (0.5 equiv.) was added,
and after a further 30 s N,N,N′,N′-tetramethylethylenediamine
(1.5 equiv.) was added. After 30 s, a solution of benzaldehyde (1
mL, 10 mmol, 1 equiv.) in CH2Cl2 (1 M) was added and the
mixture allowed to stir at r.t. for 1 h. HCl (1 M) was added and
the mixture extracted with EtOAc (3 times). The combined
organic fractions were washed with brine, dried (Na2SO4), fil-
tered and concentrated to give a residue, which was purified by
(27) The research data underpinning this publication can be found
at:
https://doi.org/10.17630/45a265c9-c200-47ef-979d-
cb3ed157e4c0.
(28) Jahn, E.; Smrček, J.; Pohl, R.; Cisařovà, I.; Jones, P. G.; Jahn, U. Eur.
J. Org. Chem. 2015, 7785.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F