A C=O???Isothiouronium Interaction Dictates Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary Heterocyclic Alcohols

Article abstract of DOI:10.1002/anie.201712456

A combination of experimental and computational studies have identified a C=O???isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

Full text of DOI:10.1002/anie.201712456

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: C=O***Isothiouronium Interaction Dictates Enantiodiscrimination
in Acylative Kinetic Resolution of Tertiary Heterocyclic Alcohols
Authors: Mark Greenhalgh, Samuel Smith, Daniel Walden, James
Taylor, Zamira Brice, Emily Robinson, Charlene Fallan, David
Cordes, Alexandra Slawin, Hannah Camille Richardson,
Markas Grove, Paul Cheong, and Andrew David Smith
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712456
Angew. Chem. 10.1002/ange.201712456
Link to VoR: http://dx.doi.org/10.1002/anie.201712456
http://dx.doi.org/10.1002/ange.201712456

10.1002/anie.201712456
Angewandte Chemie International Edition
COMMUNICATION
C=O•••Isothiouronium Interaction Dictates Enantiodiscrimination
in Acylative Kinetic Resolution of Tertiary Heterocyclic Alcohols
Mark D. Greenhalgh,[a] Samuel M. Smith,[a] Daniel M. Walden,[b] James E. Taylor,[a] Zamira Brice,[a]
Emily R. T. Robinson,[a] Charlene Fallan,[a] David B. Cordes,[a] Alexandra M. Z. Slawin,[a] H. Camille
Richardson,[b] Markas A. Grove,[b] Paul Ha-Yeon Cheong*[b] and Andrew D. Smith*[a]
Abstract: A combination of experimental and computational studies
have identified a C=O•••isothiouronium interaction as key to efficient
enantiodiscrimination in the kinetic resolution of tertiary heterocyclic
alcohols bearing up to three potential recognition motifs at the
stereogenic tertiary carbinol center. This discrimination was
exploited in the isothiourea-catalyzed acylative kinetic resolution of
tertiary heterocyclic alcohols (38 examples, s up to > 200). The
reaction proceeds at low catalyst loadings (generally 1 mol%) using
either isobutyric or acetic anhydride as the acylating agent under
mild conditions.
high selectivity is only commonly observed for stereogenic
carbinols bearing one of these motifs in combination with an
alkyl substituent and a hydrogen atom.[10] An unmet challenge
within acylative KR is the ability to resolve alcohols bearing
multiple recognition motifs, with the relative strength of the
different interactions only poorly understood. For example, the
KR of ethyl mandelate, which contains two recognition motifs (-
system and carbonyl), is ineffective (s < 2).[7c]
The catalytic kinetic resolution (KR) of racemates offers an
effective approach to the separation of enantiomers,[1] with an
enormous range of processes and catalysts developed for
applications in academia and industry.[2] Among the most
popular methods is the acylative KR of alcohols,[3] as this
approach allows simple separation of the enantiomerically-
enriched alcohol and ester products. Within this area, the use of
small molecule Lewis base catalysts is well developed for the
catalytic acylative KR of secondary alcohols (Scheme 1a).[1,3] In
such processes, enantiodiscrimination is dictated by the relative
ability of the two non-hydrogen substituents at the stereogenic
carbinol center to stabilize the catalytic cationic acyl transfer
intermediate. Therefore, a common prerequisite for the selective
KR of an alcohol substrate is the presence of one electron-rich
sp2-hybridized substituent (e.g. aryl, carbonyl), which acts as a
cation recognition motif,[4] and one non-stabilizing sp3-hybridized
alkyl substituent (Scheme 1b).
Scheme 1. Lewis base-catalyzed acylative KR of secondary alcohols.
In this context, this work investigates such cases through the
isothiourea-catalyzed acylative KR of tertiary alcohols (Scheme
2a). The efficient KR (s > 20) of tertiary alcohols is particularly
challenging as: 1) they are difficult to acylate due to their
hindered nature; and 2) the catalyst must distinguish between
three substituents at the reactive carbinol center. The presence
of multiple recognition motifs (e.g. aryl and carbonyl) provides an
additional challenge, as the acylation of both substrate
enantiomers may be promoted by different carbinol substituents,
resulting in poor selectivity (Scheme 2b).
Lewis basic isothiourea catalysts, first developed for acyl
transfer reactions by Birman[5] and Okamoto,[6] have emerged as
exceptional catalysts for the acylative KR of secondary
alcohols[7] and KR or desymmetrization of diols,[8] amongst other
applications.[9] The high selectivity factors (s) obtained for the
KR of secondary alcohols are attributed to the presence of an
effective recognition motif on the racemic alcohol, allowing one
antipode to react preferentially with a chiral acyl isothiouronium
intermediate. Established recognition motifs in isothiourea-
catalyzed KR include aryl,[5,7a-c,h,i] heteroaryl,[7e] alkenyl,[7a,h]
alkynyl,[7a,h] C=O,[7d,f] and P=O[7g] substituents. Consequently,
[a]
Dr M. D. Greenhalgh, S. M. Smith, Dr J. E. Taylor, Z. Brice, E. R. T.
Robinson, Dr C. Fallan, Dr D. B. Cordes, Prof. A. M. Z. Slawin, Prof.
A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews, North
Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
D. M. Walden, H. C. Richardson, M. A. Grove, Prof. P. H.-Y.
Cheong
Department of Chemistry, Oregon State University, 153 Gilbert Hall,
Corvallis, OR 97331 (USA)
E-mail: cheongh@oregonstate.edu
Scheme 2. KR of tertiary alcohols.
For the KR of tertiary alcohols, the situation is further
complicated if three recognition motifs are present, with potential
for competition between six stabilized transition states for
acylation (three for each substrate enantiomer). As such, only
two non-enzymatic acylative KRs of tertiary alcohols have been
reported to date, using either a bespoke pentapeptide catalyst or
[b]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201712456
Angewandte Chemie International Edition
COMMUNICATION
through oxidative NHC catalysis.[11] In both cases high catalyst
loadings (10 mol%) are required. Herein, the isothiourea-
catalyzed acylative KR of tertiary 3-hydroxyoxindole and 3-
hydroxypyrrolidin-2-one derivatives,[12] in which either two or
three of the carbinol substituents can potentially act as a
recognition motif, is investigated (Scheme 2c). The key
structural features of catalyst-substrate recognition that allow
effective enantiodiscrimination are explored both experimentally
and computationally.
potentially act as competitive recognition motifs, were also
resolved with good selectivity (s = 26 and 30). Nitrile-containing
3-hydroxyoxindole derivatives, including 11, are intermediates in
the synthesis of bioactive pyrrolidinoindoline alkaloid natural
products, such as CPC-1 and flustraminol-B.[18] For the KR of
this substrate, improved selectivity factors were obtained in the
presence of isobutyric acid and without i-Pr2NEt as a surrogate
base. This effect can be attributed to suppression of a non-
selective base-promoted background acylation, identified by
control studies (Table S5).[13] Substitution around the benzenoid
ring in every position with both electron-donating and
withdrawing groups was also tolerated, albeit with substitution in
the 4-position leading to reduced reactivity, presumably due to
increased steric hindrance. For the KR of 12 a higher catalyst
loading of 10 mol% was therefore required. A current limitation
of this method is that exceptionally sterically-hindered 3-tert-
butyl-substituted derivatives were unreactive.
Optimization studies focused on the KR of 3-allyl-3-
hydroxyoxindole 2, which bears two potential recognition motifs
at the tertiary carbinol center: an aryl -system and a carbonyl. A
highly efficient KR process was identified (s > 100) using
isothiourea catalyst HyperBTM 1 (1 mol%) and isobutyric
anhydride in CHCl3 at 0 °C (Figure 1a).[13,14] The use of less
sterically-hindered anhydrides provided lower s values, whilst
alternative
isothiourea
catalysts,
tetramisole
4
and
Table 1: 3-Alkyl-3-hydroxyoxindole derivatives (sp2 vs sp2 vs sp3)
benzotetramisole 5, were ineffective in terms of both conversion
and selectivity (s < 2).[13] Industrially-preferable solvents [EtOAc,
i-PrOAc, (MeO)2CO, PhMe] also provided synthetically-useful
levels of selectivity (s = 34–41),[13,15] albeit lower than those
obtained in CHCl3. The robustness of the process was
demonstrated through 12 repeat reactions, in which comparable
conversions and selectivities were obtained in each case (Figure
1b). Monitoring the temporal change in er of alcohol and ester in
a KR at r.t. and applying a linear regression analysis confirmed s
was independent of conversion, thus validating its use as a
descriptor for the efficiency of the process (Figure 1c).[1c,13,16,17]
b) Reproducibility[b]
c) Validation of s[c]
ln[(1−c)(1+ee)]
-0.025
100
-0.05
0
0
80
60
40
20
0
-1
-2
-3
-4
Conversion (c) and er determined by chiral HPLC analysis. s calculated using
equations given in ref. 1a, and rounded as detailed in ref. 17. See SI for
reaction concentration and time. [a] 2 mol% (2S,3R)-1. [b] −40 °C. [c] 5 mol%
(2S,3R)-1. [d] 0.6 equiv. (i-PrCO)2O, 0.5 equiv. i-PrCO2H, no i-Pr2NEt used. [e]
10 mol% (2S,3R)-1.
y = 91.062x
R² = 0.9997
1 2 3 4 5 6 7 8 9 101112
Conversion
The developed method was next challenged in the KR of 3-aryl-
substituted 3-hydroxyoxindole derivatives, in which all three
carbinol substituents could act as competitive recognition motifs
(two aryl -systems and a carbonyl) (Table 2). Notably, these
derivatives were resolved with excellent selectivity (s up to >
200), indicating exceptional enantiodiscrimination by the
isothiourea catalyst. The resolution of oxindole derivatives 15–
18 bearing phenyl, 2-naphthyl and aryl groups bearing both
electron-withdrawing and -donating at the 3-position gave
excellent selectivity (s = 60–200).[19] The resolution of 4-N,N-
dimethylaminophenyl-substituted alcohol 19 allowed the
isolation of highly enantiomerically-enriched (R)-19 (97:3 er) at
49% conversion; however the isobutyric ester was obtained as a
s
Figure 1. KR of 3-hydroxyoxindole (±)-2. Conversion (c) determined by chiral
HPLC analysis. s calculated using equations given in ref. 1a. [a] Mean of 12
repeat reactions (see part b); errors given as 2 standard deviations of mean.
[b] 12 repeat KRs of (±)-2 at 0 °C. [c] Linear regression analysis of the KR of
(±)-2 at r.t. by determination of temporal alcohol and ester er data.
The scope and limitations of the KR process was first evaluated
for a range of 3-alkyl-substituted 3-hydroxyoxindole derivatives,
through variation of the 3-alkyl-, N- and benzenoid ring
substituents (Table 1). Simple alkyl chains, including an -
branched i-Pr and perfluorinated CF3 group, were well tolerated
(6–9, s = 32–110), as were a range of N-substituents, including
benzyl, allyl, and tert-butyloxycarbonyl (Boc). Alcohols 10 and 11
bearing Lewis basic amide and nitrile substituents, which could
This article is protected by copyright. All rights reserved.

10.1002/anie.201712456
Angewandte Chemie International Edition
COMMUNICATION
racemate (52:48 er). This phenomenon is attributed to
racemization of the ester by reversible ionization promoted by
the presence of the electron-donating NMe2 group. Various
heteroaromatic substituents were successfully incorporated
including furyl, benzoxazolyl and Brønsted and Lewis basic 2-
and 3-pyridyl groups (20–23, s = 15–70). The method was
equally applicable for the KR of 3-alkenyl-substituted 3-
hydroxyoxidinole derivatives 24–26, in which the catalyst was
again capable of differentiating between three potential
recognition motifs at the carbinol stereocenter. Excellent s
values were obtained in each case (s = 50–80), however
incorporation of an alkyne substituent at the tertiary alcohol
center (sp2 vs sp2 vs sp) resulted in very low selectivity (s = 2).[13]
the carbonyl oxygen is replaced with sulfur, were both resolved
with excellent selectivity (s = 41 and 39 respectively). The effect
of removing the carbonyl completely was simulated using
indenol derivative 29. No acylation was observed using
isobutyric anhydride, while using acetic anhydride gave a
selectivity factor of just 5. This is consistent with the carbonyl
moiety playing a significant role in facilitating both reactivity and
enantiodiscrimination. -Hydroxy--lactam 30, which lacks the
benzannulation present in all other substrates, was unreactive
using isobutyric anhydride; however, the use of acetic anhydride
allowed resolution of 30 with excellent selectivity (s = 110),
indicating that benzannulation has minimal effect on
selectivity.[20,21] -Substituted--hydroxylactams possess
a
Table 2: 3-Aryl- and alkenyl-3-hydroxyoxindole derivatives (sp2 vs sp2 vs sp2)
range of biological activities; however there are few general
methods for their enantioselective synthesis.[22] The KR of this
substrate class was therefore further investigated. The KR of -
lactams 31–33, bearing electron-donating, electron-withdrawing
and heteroatomic substituents at the tertiary alcohol center was
achieved with excellent selectivity (s = 60–200). The scope was
further expanded to include -lactam and -lactam derivatives 34
and 35. A reaction temperature of 90 °C was required for the
acylation of -lactam 35; however even at this temperature an
impressive s value of 25 was obtained.
Table 3: Tertiary alcohol structure-selectivity relationships
Conversion (c) and er determined by chiral HPLC analysis. s calculated using
equations given in ref. 1a, and rounded as detailed in ref. 17. See SI for
reaction concentration and time. [a] 1 mol% (2S,3R)-1. [b] (i-PrCO)2O. [c] 5
mol% (2S,3R)-1. [d] PhMe used as solvent. [e] 20 mol% (2S,3R)-1, 90 °C.
Conversion (c) and er determined by chiral HPLC analysis. s calculated using
equations given in ref. 1a, and rounded as detailed in ref. 17. See SI for
reaction concentration and time. [a] 2 mol% (2S,3R)-1. [b] 10 mol% (2S,3R)-1.
Conversion determined by 1H NMR spectroscopy. [c] 5 mol% (2S,3R)-1.
Computational studies on the KR of 3-methyl- and 3-phenyl-3-
hydroxyoxindole derivatives 6 and 15 were used to further
elucidate the mechanism and origin of enantiodiscrimination in
this KR process.[23] The stereodetermining acylation transition
states were calculated following the established Lewis base-
promoted acylative pathway described by Zipse and Spivey.[24]
The lowest energy diastereomeric transition state structures
(TSs) for the acylation of the (S)-enantiomer ((S)-TS-II) and (R)-
enantiomer ((R)-TS-II) of each substrate are shown in Figure
The broad substrate scope of this KR process had demonstrated
good selectivities for a range of C(3) substituents, indicating that
this substituent was unlikely to act as a dominant recognition
motif in this resolution. To provide further insight, the core
heterocyclic structure was systematically varied to probe the
effect of the carbonyl group and benzannulation (Table 3).
Benzothiophenone derivative 27, in which the lactam nitrogen is
replaced with sulfur, and indoline-2-thione derivative 28, in which
This article is protected by copyright. All rights reserved.

10.1002/anie.201712456
Angewandte Chemie International Edition
COMMUNICATION
2.[13] Significantly, the conformation of the acylation TSs of the
(S)- and (R)-enantiomers are independent of the alcohol
substrate, allowing a general model to be proposed. The
predicted ΔΔG‡ of 2.0 kcal/mol for the KR of 6 is in good
agreement with the experimental s value of 50 (ΔΔG‡ = 2.1
kcal/mol). The increased value of ΔΔG‡ calculated for the KR of
15 (3.5 kcal/mol) is in qualitative agreement with experiment (2.6
kcal/mol), albeit the magnitude of this ΔΔG‡ is overestimated.[25]
The significance of the C=O•••isothiouronium interaction for
enantiodiscrimination indicated that modulation of the Lewis
basicity of the amide oxygen should affect the relative energies
of the diastereomeric acylation TSs. To investigate this
hypothesis, a series of 3-phenyl-3-hydroxyoxindole derivatives
36–41
were prepared
with electronically-differentiated
substituents at the 5-position, with the C=O stretching frequency
of each substrate used as a proxy for the Lewis basicity of the
amide oxygen (Table 4).[28] The KR of this series followed the
expected trend, with the highest selectivity obtained for the
resolution of the 5-NMe2-substituted derivative 36 (s = 140) and
the lowest selectivity obtained for the 5-NO2-substituted
derivative 41 (s = 11). This trend in selectivity is consistent with
the ability of the amide of the fast reacting enantiomer to engage
in a TS-stabilizing C=O•••isothiouronium interaction.
Table 4: Effect of 5-substiuent on C=O stretching frequency and KR selectivity
Figure 2. Computed TSs for the acylation of (R)- and (S)-6 and 15. Energies
given in kcal/mol.
We hypothesize that three critical interactions govern
enantiodiscrimination:
i) S•••O Interaction: The most stable conformation of acylated
HyperBTM exhibits syn-coplanarity of the 1,5-O and S atoms.
This arrangement is favored by 6.5 kcal/mol over the anti
conformation (Figure S4).[13,26] With the acyl group held rigid a
single prochiral face is exposed, with the opposite face blocked
by the stereodirecting Ph group of the catalyst.
ii) Chelation by isobutyrate: The isobutyrate counterion
simultaneously deprotonates the alcohol and engages in a non-
classical H-bond to the catalyst +NC-H group.[24,27]
iii) Isothiouronium interaction: The diastereomeric TSs for the
acylation of both enantiomers of the alcohol share the S•••O
interaction and the two-point isobutyrate binding. NBO analyses
show that the isothiouronium carbon bears a partial positive
charge (Figure S5).[13] The high selectivity of this resolution is
then a result of effective discrimination between the three
carbinol center substituents by their ability to stabilize the partial
carbocation character within the heavily preorganized acylated
HyperBTM (Figure S8-S10).[13] In (S)-TS-II, the substrate
carbonyl is in close proximity to the isothiouronium carbon. NBO
analyses show no bonding character between the
isothiouronium carbon and the carbonyl oxygen (bond order of
0.01) which, in addition to partial charge calculations, suggests
the C=O•••isothiouronium interaction is primarily electrostatic in
nature.[14] In contrast, the critical stabilizing interaction in the
disfavored (R)-TS-II is a •••isothiouronium interaction involving
the substrate benzenoid. This model is in agreement with the
experimental findings (Table 3). Alternative TSs for the acylation
of 15 in which the 3-phenyl substituent acts as the recognition
motif were significantly higher in energy [(R): ΔG‡ = 17.8
kcal/mol; (S): ΔG‡ = 22.8 kcal/mol] consistent with this group not
being instrumental for enantiodiscrimination.[13]
Conversion (c) and er determined by chiral HPLC analysis. s calculated using
equations given in ref. 1a, and rounded as detailed in ref. 17. See SI for
reaction concentration and time. [a] 5 mol% (2S,3R)-1. [b] 2 mol% (2S,3R)-1.
Finally, the developed method was applied in the
enantioselective synthesis of 5-HT2C antagonist 42 (Scheme
3).[22a] By taking advantage of the non-destructive nature of
acylative KR, and the readily availability of both enantiomers of
HyperBTM 1, both enantiomers of the target compound were
accessed. Racemic bioactive target (±)-42 was synthesized in
five steps from commercially-available reagents in an overall
64% yield.[13] Gram-scale KR using 5 mol% (2S,3R)-HyperBTM
1 gave (S)-42 in 45% yield and with excellent enantioenrichment
(97:3 er). The recovered (R)-isobutyrate ester (R)-43 (48% yield,
90:10 er) underwent facile hydrolysis with NaOH, and the
enantiopurity of the resulting (R)-alcohol (R)-42 (90:10 er) was
enhanced by performing a second KR. Enantiomeric (2R,3S)-
HyperBTM 1 was used to selectively acylate the remaining (S)-
enantiomer, requiring only 11% conversion to obtain highly
enantiomerically-enriched (R)-42 (97:3 er). Overall, both (S)-
and (R)-42 were isolated in highly enantioenriched form in a
combined 84% yield from (±)-42, demonstrating the powerful
nature of the developed KR methodology.
In conclusion, a C=O•••isothiouronium interaction has been
identified as the key recognition motif that leads to efficient
enantiodiscrimination in the KR of a number of heterocyclic
tertiary alcohols. By exploiting this interaction, a combination of
This article is protected by copyright. All rights reserved.

10.1002/anie.201712456
Angewandte Chemie International Edition
COMMUNICATION
Scheme 3. Application in the synthesis of both enantiomers of 5-HT2C antagonist 42. Conversion (c) and er determined by chiral HPLC analysis. s calculated
using equations given in ref. 1a.
[7] a) X. Li, H. Jiang, E. W. Uffman, L. Guo, Y. Zhang, X. Yang, V. B. Birman, J.
isothiourea catalyst HyperBTM 1 (generally 1 mol%) and either
isobutyric or acetic anhydride allows the KR of a range of
heterocyclic tertiary alcohols with excellent selectivity (38
Org. Chem. 2012, 77, 1722; b) Q. Hu, H. Zhou, X. Geng, P. Chen,
Tetrahedron 2009, 65, 2232; c) P. Chen, Y. Zhang, H. Zhou, Q. Xu, Acta
Chim. Sinica 2010, 68, 1431; d) I. Shiina, K. Nakata, K. Ono, M. Sugimoto,
examples, s up to > 200). Significantly, the substrate scope
A. Sekiguchi, Chem. Eur. J. 2010, 16, 167; e) I. Shiina, K. Ono, K. Nakata,
includes tertiary alcohol substrates which contain up to three
recognition motifs at the stereogenic tertiary carbinol center. The
Chem. Lett. 2011, 40, 147; f) K. Nakata, K. Gotoh, K. Ono, K. Futami, I.
Shiina, Org. Lett. 2013, 15, 1170; g) I. Shiina, K. Ono, T. Nakahara, Chem.
interactions identified as a requirement for selectivity in this KR
process should be readily applicable to other enantioselective
transformations, and work is currently underway to exploit these
in alternative catalytic processes.[29]
Commun. 2013, 49, 10700; h) D. Belmessieri, C. Joannesse, P. A.
Woods, C. MacGregor, C. Jones, C. D. Campbell, C. P. Johnson, N.
Duguet, C. Concellón, R. A. Bragg, A. D. Smith, Org. Biomol. Chem. 2011,
9, 559; i) S. F. Musolino, O. S. Ojo, N. J. Westwood, J. E. Taylor, A. D.
Smith, Chem. Eur. J. 2016, 22, 18916.
[8] a) V. B. Birman, H. Jiang, X. Li, Org. Lett. 2007, 9, 3237; b) J. Merad, P.
Borkar, T. B. Yenda, C. Roux, J.-M. Pons, J.-L. Parrain, O. Chuzel, C.
Bressy, Org. Lett. 2015, 17, 2118; c) J. Merad, P. Borkar, F. Caijo, J.-M.
Pons, J.-L. Parrain, O. Chuzel, C. Bressy, Angew. Chem. Int. Ed. 2017,
56, 16052; Angew. Chem. 2017, 129, 16268.
Acknowledgements
The research leading to these results has received funding from
the ERC under the European Union's Seventh Framework
Programme (FP7/2007-2013)/E.R.C. grant agreement n°
279850 and the EPSRC (EP/J500549/1). A.D.S. thanks the
Royal Society for a Wolfson Research Merit Award. We thank
the EPSRC UK National Mass Spectrometry Facility at Swansea
University. P.H.-Y.C. is the Bert and Emelyn Christensen
Professor and gratefully acknowledges financial support from
the Stone Family of OSU. Financial support from the National
Science Foundation (NSF) (CHE-1352663) is acknowledged.
D.M.W. acknowledges the Bruce Graham and Johnson
Fellowships of OSU. D.M.W. and P.H.-Y.C. acknowledge
computing infrastructure in part provided by the NSF Phase-2
CCI, Center for Sustainable Materials Chemistry (CHE-1102637).
[9] J. Merad, J.-M. Pons, O. Chuzel, C. Bressy, Eur. J. Org. Chem. 2016, 2016,
5589.
[10] For the KR of aryl-alkenyl substituted secondary alcohols, see ref. 7i.
[11] a) E. R. Jarvo, C. A. Evans, G. T. Copeland, S. J. Miller, J. Org. Chem.
2001, 66, 5522; b) M. C. Angione, S. J. Miller, Tetrahedron 2006, 62,
5254; c) S. Lu, S. B. Poh, W.-Y. Siau, Y. Zhao, Angew. Chem. Int. Ed.
2013, 52, 1731; Angew. Chem. 2013, 125, 1775.
[12] For
a review on the bioactivity of 3-substituted-3-hydroxyoxindole
derivatives see: S. Peddidhotla, Curr. Bioact. Compd. 2009, 5, 20.
[13] See Supporting Information for details.
[14] The absolute configuration of recovered 2 was assigned as (R) by
comparison of its specific rotation with the literature, see SI.
[15] R. K. Henderson, C. Jiménez-González, D. J. C. Constable, S. R. Alston,
G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks, A. D. Curzons, Green
Chem. 2011, 13, 854.
[16] D. G. Blackmond, J. Am. Chem. Soc. 2001, 123, 545.
Keywords: Kinetic resolution • Lewis bases • Organocatalysis •
Tertiary alcohols • Acylation
[17] The analytical error associated with s has been estimated for each KR
and is detailed in full in the SI. Based on these estimations of error the
following rules have been applied: i) for s < 50, s is given to the closest
integer; ii) for s = > 50, s is given to the closest 10.
[1] a) H. B. Kagan, J. C. Fiaud, in Topics in Stereochemistry, Vol. 18 (Eds.: E.
L. Eliel, S. H. Wilen), John Wiley & Sons, 1988, pp. 249–330; b) J. M.
Keith, J. F. Larrow, E. N. Jacobsen, Adv. Synth. Catal. 2001, 343, 5; c) E.
Vedejs, M. Jure, Angew. Chem. Int. Ed. 2005, 44, 3974; Angew. Chem.
2005, 117, 4040.
[18] a) A. Singh, G. P. Roth, Org. Lett. 2011, 13, 2118; b) A. Singh, G. P. Roth,
Tetrahedron Lett. 2012, 53, 4889.
[19] The absolute configuration of recovered 15 was assigned as (R) by X-ray
crystallographic analysis (CCDC 1570446).
[2] a) J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol. Chem.
2006, 4, 2337; b) S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54,
3451.
[20] Under analogous conditions [(MeCO)2O, CHCl3, 0 °C], -hydroxy--lactam
30 and benzannulated analogue 15 were resolved with comparable
selectivity and with the same sense of enantiodiscrimination, see SI.
[21] The absolute configuration of recovered 30 was assigned as (S) by X-ray
crystallographic analysis (CCDC 1570447).
[3] a) C. E. Müller, P. R. Schreiner, Angew. Chem. Int. Ed. 2011, 50, 6012;
Angew. Chem. 2011, 123, 6136; b) J. I. Murray, Z. Heckenast, A. C.
Spivey, in Lewis Base Catalysis in Organic Synthesis, Vol. 2, (Eds.: E.
Vedejs, S. E. Denmark), Wiley-VCH, Weinheim, 2016, pp. 459–526.
[4] For a review on cation- interactions in organocatalysis see: S. Yamada, J.
S. Fossey, Org. Biomol. Chem. 2011, 9, 7275.
[22] a) F. Damiani, D. Hamprecht, A. A. Jaxa-Chamiec, F. Micheli, A.
Pasquarello, G. Tedesco (Glaxo Group Ltd.), WO 03/089409 A1, 2003; b)
K.-K. Ho, W. Quan, J. Zhou (Eli Lilly and Company), WO 2017/005069 A1,
2017; c) N. Ishida, D. Nečas, Y. Masuda, M. Murakami, Angew. Chem. Int.
Ed. 2015, 54, 7418; Angew. Chem. 2015, 127, 7526; d) W. J. Brouillette,
G. L. Grunewald, J. Med. Chem. 1984, 27, 202.
[5] V. B. Birman, X. Li, Org. Lett. 2006, 8, 1351.
[6] M. Kobayashi, S. Okamoto, Tetrahedron Lett. 2006, 47, 4347.
This article is protected by copyright. All rights reserved.

10.1002/anie.201712456
Angewandte Chemie International Edition
COMMUNICATION
[23] Geometries and energies were computed at the M06-2X/6-
311++G(2df,p)/PCM(CHCl3)//M06-2X/6-31G(d)/PCM(CHCl3)
level
of
theory, see: a) M. J. Frisch, et al. Gaussian 09 (Gaussian, Inc. Walling-
ford, Connecticut, 1973); b) Y. Zhao, D. G. Truhlar, Theor. Chem. Acc.
2008, 120, 215; c) W. J. Hehre, R. Ditchfield, J. A. Pople, J. Chem. Phys.
1972, 56, 2257; d) P. C. Hariharan, J. A. Pople, Theor. Chim. Acta. 1973,
28, 213; e) S. Miertuš, E. Scrocco, J. Tomasi, Chem. Phys. 1981, 55, 117.
[24] E. Larionov, M. Mahesh, A. C. Spivey, Y. Wei, H. Zipse, J. Am. Chem.
Soc. 2012, 134, 9390.
[25] Overestimation of calculated ΔΔG‡ in KR processes has been previously
reported, see ref. 7e, 24, 27a, b and: X. Li, P. Liu, K. N. Houk, V. L.
Birman, J. Am. Chem. Soc. 2008, 130, 13836.
[26] a) B. R. Beno, K.-S. Yeung, M. D. Bartberger, L. D. Pennington, N. A.
Meanwell, J. Med. Chem. 2015, 58, 4383; b) V. B. Birman, X. Li, Z. Han,
Org. Lett. 2007, 9, 37; c) M. E. Abbasov, B. M. Hudson, D. J. Tantillo, D.
Romo, J. Am. Chem. Soc. 2014, 136, 4492; d) T. H. West, D. M. Walden,
J. E. Taylor, A. C. Brueckner, R. C. Johnson, P. H.-Y. Cheong, G. C.
Lloyd-Jones, A. D. Smith, J. Am. Chem. Soc. 2017, 139, 4366; e) E. R. T.
Robinson, D. M. Walden, C. Fallan, M. D. Greenhalgh, P. H.-Y. Cheong,
A. D. Smith, Chem. Sci. 2016, 7, 6919; f) D. J. Pascoe, K. B. Ling, S. L.
Cockroft, J. Am. Chem. Soc. 2017, 139, 15160.
[27] a) P. Liu, X. Yang, V. B. Birman, K. N. Houk, Org. Lett. 2012, 14, 3288; b)
X. Yang, P. Liu, K. N. Houk, V. B. Birman, Angew. Chem. Int. Ed. 2012,
51, 9638; Angew. Chem. 2012, 124, 9776; c) R. C. Johnston, P. H.-Y.
Cheong, Org. Biomol. Chem. 2013, 11, 5057; d) C. E. Cannizzaro, K. N.
Houk, J. Am. Chem. Soc. 2002, 124, 7163; e) V. Lutz, J. Glatthaar, C.
Würtele, M. Serafin, H. Hausmann, P. R. Schreiner, Chem. Eur. J. 2009,
15, 8548; f) S. Xu, I. Held, B. Kempf, H. Mayr, W. Steglich, H. Zipse,
Chem. Eur. J. 2005, 11, 4751.
[28] J. P. Idoux, R. Zarrillo, J. Org. Chem. 1975, 40, 1519.
[29] The research data underpinning this publication can be found at DOI:
http://dx.doi.org/10.17630/e8b7bd1c-15d2-4ea3-9f34-02d87ad0435c
This article is protected by copyright. All rights reserved.

10.1002/anie.201712456
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Mark D. Greenhalgh,[a] Samuel M.
Smith,[a] Daniel M. Walden,[b] James E.
Taylor,[a] Zamira Brice,[a] Emily R. T.
Robinson,[a] Charlene Fallan,[a] David B.
Cordes,[a] Alexandra M. Z. Slawin,[a] H.
Camille Richardson,[b] Markas A.
Grove,[b] Paul Ha-Yeon Cheong*[b] and
Andrew D. Smith*[a]
Page No. – Page No.
Experimental and computational studies have identified a C=O•••isothiouronium
interaction as key to efficient enantiodiscrimination in the kinetic resolution (KR) of
tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the
stereogenic tertiary carbinol center. The KR of a range of tertiary heterocyclic
alcohols was achieved using low loadings of an isothiourea catalyst and either
isobutyric or acetic anhydride, with excellent selectivity factors obtained (38
examples, s up to > 200).
C=O•••Isothiouronium Interaction
Dictates Enantiodiscrimination in
Acylative Kinetic Resolution of
Tertiary Heterocyclic Alcohols
This article is protected by copyright. All rights reserved.