Isothiourea-Catalyzed Acylative Kinetic Resolution of Tertiary α-Hydroxy Esters

Article abstract of DOI:10.1002/anie.202004354

A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous-flow process using a polymer-supported variant of the catalyst.

Full text of DOI:10.1002/anie.202004354

A Journal of the Gesellschaft Deutscher Chemiker
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Chemie
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Accepted Article
Title: Isothiourea-Catalyzed Acylative Kinetic Resolution of Tertiary α-
Hydroxy Esters
Authors: Shen Qu, Sam Smith, Victor Laina, Rifahath M
Neyyappadath, Mark Greenhalgh, and Andrew David Smith
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10.1002/anie.202004354
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RESEARCH ARTICLE
Isothiourea-Catalyzed Acylative Kinetic Resolution of Tertiary α-
Hydroxy Esters
Shen Qu,† Samuel M. Smith,† Víctor Laina-Martín, Rifahath M. Neyyappadath, Mark D. Greenhalgh
and Andrew D. Smith*
Abstract: A highly enantioselective isothiourea-catalyzed acylative
kinetic resolution (KR) of acyclic tertiary alcohols has been
developed. Selectivity factors of up to 200 were achieved for the KR
of tertiary alcohols bearing an adjacent ester substituent, with both
reaction conversion and enantioselectivity found to be sensitive to
the steric and electronic environment at the stereogenic tertiary
carbinol centre. For more sterically-congested alcohols, the use of a
recently-developed isoselenourea catalyst was optimal, with
equivalent enantioselectivity but higher conversion achieved in
comparison to the isothiourea HyperBTM. Diastereomeric acylation
transition state models are proposed to rationalize the origins of
enantiodiscrimination in this process. This KR procedure has also
been translated to a continuous flow process using a polymer-
supported variant of the catalyst.
and Ma[5f] using Cu and co-operative Pd/phosphoric acid
catalysis, respectively. The acylative KR of alcohols is a
particularly attractive option as simple separation of products,
coupled with facile ester hydrolysis, provides straightforward
access to both enantiomers of the alcohol. The Lewis base-
catalyzed acylative KR of heterocyclic tertiary alcohols has been
achieved by Zhao[5g] and our group[5h] using oxidative NHC
catalysis[7] and isothiourea catalysis, respectively. To date, the
only example of the catalytic acylative KR of acyclic alcohols
was reported by Miller using a pentapeptide catalyst.[5i,5j]
Relatively high catalyst loading (10 mol%) and excess anhydride
(50 equiv.) was required for the KR of seven amino alcohol
substrates, demonstrating the remaining challenge associated
with the acylative KR of this important class of tertiary alcohol.
Introduction
Tertiary alcohols and their derivatives are present within many
natural products and bioactive molecules, however, their
synthesis in enantiopure form remains a significant challenge.[1]
Towards this goal, the most commonly investigated method is
the enantioselective addition of carbon-centred nucleophiles to
ketones.[1a–e] Challenging facial differentiation and the potential
for unwanted side-reactions currently impacts the scope and
effectiveness of these methods. The catalytic kinetic resolution
(KR)[2,3] of tertiary alcohols therefore represents a potentially
attractive option. KRs are equally applicable to racemic and
scalemic substrates, allowing for KRs to be used as either
alternative or complimentary processes. In contrast to the
catalytic KR of secondary alcohols,[4] there are currently very few
efficient methods for the KR of tertiary alcohols. The challenges
associated with the KR of tertiary alcohols are two-fold: i) tertiary
alcohols are sterically hindered, reducing their nucleophilicity;
and ii) the catalyst is required to differentiate between three non-
hydrogen substituents at the stereogenic carbinol centre.
To date, only nine methods have been reported for the
non-enzymatic catalytic KR of tertiary alcohols in which an
enantioenriched chiral product is obtained (Figure 1).[5,6] Chiral
phosphoric acid catalysis has been exploited by List[5a,5b] and
Yang[5c,5d] in intra- and intermolecular approaches for the KR of
tertiary alcohols, amino-alcohols and diols; whilst the KR of
tertiary propargylic alcohols has been reported by Oestreich[5e]
Figure 1. Approaches reported for the catalytic KR of tertiary alcohols
Lewis basic isothiourea catalysts[8] have been applied for
the acylative KR of a wide range of alcohols, including primary
alcohols[9], secondary alcohols[10] and diols.[11] We recently
reported an isothiourea-catalyzed KR of tertiary heterocyclic
alcohols,[5h]
in
which
coordinated
experimental
and
computational studies were used to identify the origins of
enantiodiscrimination (Figure 2a). Interrogation of the acylation
transition state structure for the fast-reacting enantiomer of the
alcohol revealed three key interactions: 1) an O•••S
interaction,[12] which holds the acyl group of the acylated catalyst
syn-coplanar to the isothiouronium core; 2) chelation of the
carboxylate counterion through non-classical C−H•••O hydrogen
bonding;[13] and 3) a C=O•••isothiouronium interaction, which is
[*]
S. Qu, Dr S. M. Smith, V. Laina-Martín, Dr R. M. Neyyappadath, Dr
M. D. Greenhalgh, 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
These authors contributed equally
Supporting information for this article is given via a link at the end of
the document.
[†]
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10.1002/anie.202004354
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RESEARCH ARTICLE
primarily electrostatic in nature. The transition state structure for
the slow-reacting enantiomer lacked the C=O•••isothiouronium
interaction, and therefore it was hypothesized this interaction
was critical for effective enantiodiscrimination.
through variation of solvent, temperature, base and anhydride
(see SI for full details). Improved selectivity was obtained when
the reaction was conducted in Et2O (s = 15, entry 5), with
additional optimization to s = 60 achieved by using isobutyric
anhydride as the acylating agent (entry 6). Finally, in the
absence of an auxiliary base (NEt3) good conversion and
excellent selectivity was maintained (entry 7). Under these
optimized conditions, variation of the ester group was
investigated, with the highest selectivity obtained using benzyl
ester 8 (c = 50%, s = 130, entry 10).[16] The scalability of the
method was demonstrated, with comparable conversion and
selectivity obtained when conducting the KR on a gram scale (c
= 50%, s = 120, entry 11).
Table 1: Carbonyl group screening
Entry
R1
R2 (x)
Base
Solvent
c
s
(equiv.)
TMP (10)
TMP (2)
NEt3 (5)
NEt3 (1)
NEt3 (1)
NEt3 (3)
none
none
none
none
none
1[a,b]
2[a]
3[a,c]
4
5
6
7
8
9
10
11[d]
NMe2 (2)
NHPh (3)
Ph (4)
OMe (5)
OMe (5)
OMe (5)
OMe (5)
OEt (6)
Me (5)
i-Pr (5)
Me (3)
Me (1)
Me (1)
i-Pr (2)
i-Pr (2)
i-Pr (2)
i-Pr (2)
i-Pr (2)
i-Pr (2)
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Et2O
Et2O
Et2O
Et2O
0
-
7
3
3
15
60
70
60
7
59
36
44
43
47
41
32
15
50
50
Figure 2. Proposed transition state models
In contrast to our previous work on the KR of heterocyclic
alcohols,[5h] the additional conformational flexibility of acyclic
substrates (Figure 2b) presents additional challenges to
overcome: i) increased steric hindrance at the carbinol centre
attenuating the rate of acylation; and ii) the potential for the other
carbinol substituents to act as competitive recognition motifs,
resulting in reduced enantiodiscrimination. We report herein the
development of the acylative KR of acyclic tertiary alcohols
using isothiourea catalysis. Key to this transformation is the
incorporation of a suitable carbonyl donor adjacent to the tertiary
stereogenic carbinol centre to act as a recognition motif for the
acylated catalyst.
Ot-Bu (7)
OBn (8)
OBn (8)
Et2O
Et2O
130
120
Conversion (c) and selectivity factor (s) calculated using the enantiomeric
ratios of recovered alcohol and ester (see ref. 3a). s values rounded according
to estimated errors (see ref. 3b). Reactions performed on 0.16–0.32 mmol
scale, see SI for full details. TMP = 2,2,6,6-tetramethylpiperidine. [a] 10 mol%
catalyst used. [b] Reaction at 50 °C. [c] Reaction at 40 °C. [d] 1.02 g (4 mmol)
scale.
We recently reported isoselenourea HyperSe 9 as a highly
efficient catalyst for a range of processes, including the KR of
heterocyclic tertiary alcohols at catalyst loadings as low as 500
ppm.[17] Applying this catalyst to the current KR procedure
allowed reduction in both catalyst loading and equivalents of
anhydride, whilst maintaining comparable conversion and
selectivity (Scheme 1). Despite this improved activity, the
reaction scope was initially investigated using the commercially
available isothiourea, HyperBTM,[18] with isoselenourea HyperSe
9 reserved for the KR of particularly challenging substrates.
Results and Discussion
Initial studies probed the feasibility of the acylative KR of acyclic
α-hydroxy carbonyl derivatives, using the isothiourea HyperBTM
1 as catalyst (Table 1). The attempted KR of tertiary amide 2 led
to no conversion (entry 1), however the use of different
secondary amide derivatives provided some promise.[14]
Following optimization the KR of secondary amide 3 was
achieved with good conversion but moderate selectivity (s =
7),[15] which could not be improved upon further (entry 2). Next,
the KR of α-hydroxy ketones and esters was investigated
(entries 3 and 4). Whilst low selectivities were obtained for both
substrates (s = 3), the KR of α-hydroxy ester 5 was achieved
using lower catalyst loading and with fewer equivalents of
anhydride, indicating greater potential for further optimization
Scheme 1. KR of (±)-8 using isoselenourea catalyst HyperSe 9
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10.1002/anie.202004354
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RESEARCH ARTICLE
The scope and limitations of the newly developed KR
process was first evaluated through incorporation of
electronically- and sterically-differentiated aryl substituents at the
carbinol centre (Table 2). The KR of substrates 11–15 bearing
electron-neutral and electron-donating aromatic substituents
(naphthyl, tolyl, anisolyl) was achieved with good conversion and
high selectivity (s = 60–140). The incorporation of a sterically-
demanding ortho-anisolyl substituent however resulted in only
6% conversion. This is consistent with our previous work on the
KR of heterocyclic tertiary alcohols,[5h] where sterically-
encumbered substrates were less efficiently acylated. By
applying the newly-developed isoselenourea catalyst HyperSe 9
for the KR of 16, significantly improved conversion (c = 35%)
and good selectivity (s = 20) was obtained. The KR of 17
bearing an electron-withdrawing aromatic substituent was
successful using HyperBTM 1, with high conversion, but
reduced selectivity obtained (s = 12). Substrates bearing
heterocycles were also well tolerated, with 2-thienyl- and 2-
pyridyl-substituted tertiary alcohols 18 and 19 resolved with
good conversion and excellent selectivity (s = 46–60).
PrCO)2O. For example, the KR of homoallylic alcohol 20 under
the standard KR conditions provided only 4% conversion. By
replacing (i-PrCO)2O with (MeCO)2O, good conversion and
reasonable selectivity was obtained (c = 42%, s = 9). The
introduction of an ethyl or n-butyl substituent at the carbinol
centre also resulted in very low conversion (< 2%), however a
combination of isoselenourea HyperSe
(EtCO)2O allowed the KR of 21 and 22 with good conversion
and selectivity (c 56–57%, 9–10). The KR of
9 (2 mol%) and
=
s =
trifluoromethyl-substituted tertiary alcohol 23 also benefitted
from the use of isoselenourea HyperSe 9 to increase reaction
conversion from 26% to 48%. The catalytic system was further
challenged through the introduction of an additional π-system at
the carbinol centre to provide substrates with three potential
recognition motifs. The KR of allylic tertiary alcohol 24 was
achieved with good selectivity (s = 20), with the use of
isoselenourea HyperSe 9 as catalyst again proving beneficial for
increasing conversion. Finally, the KR of propargylic alcohol 25
was achieved with slightly reduced selectivity (s = 6). Consistent
with the lower steric hindrance of this substituent, good
conversion was obtained when using HyperBTM 1.
Table 2: Substrate Scope I: Aromatic substituent variation
Table 3: Substrate Scope II: Alkyl substituent variation
Conversion (c) and selectivity factor (s) calculated using the enantiomeric
ratios of recovered alcohol and ester (see ref. 3a). Reactions performed on
0.2–0.32 mmol scale, see SI for full details. [a] (i-PrCO)2O used; [b] (MeCO)2O
used; [c] (2R,3S)-HyperSe 9 (2 mol%), (EtCO)2O, and NEt3 (2 equiv.) used. [d]
The alcohol and ester were obtained in the opposite enantiomeric series to
that shown in the scheme due to the (2R,3S) configuration of HyperSe 9; [e]
(2R,3S)-9 (2 mol%) and (i-PrCO)2O used. [f] (i-PrCO)2O (0.55 equiv.) used.
Conversion (c) and selectivity factor (s) calculated using the enantiomeric
ratios of recovered alcohol and ester (see ref. 3a). s values rounded according
to estimated errors (see ref. 3b). Reactions performed on 0.16–0.64 mmol
scale, see SI for full details. [a] (2R,3S)-HyperSe 9 (5 mol%) used; the alcohol
and ester were obtained in the opposite enantiomeric series to that shown in
the scheme due to the (2R,3S) configuration of HyperSe 9; [b] (i-PrCO)2O (1
equiv.) used; separation of the ester enantiomers was not possible by HPLC,
conversion based on 1H NMR spectroscopic analysis of crude reaction product
mixture.
Based on the lower selectivities obtained for the KR of
substrates bearing longer alkyl chains (Table 3), it was
hypothesized that catalyst discrimination between the aryl and
alkyl substituents may predominantly originate from steric
differences.[19] To investigate this hypothesis, the aryl substituent
was replaced by a series of sterically-differentiated groups
(Table 4). As expected, the KR of alcohols 26 and 27, bearing
small alkynyl or vinyl substituents at the carbinol centre were
Next, the effect of varying the alkyl substituent at the
carbinol centre was evaluated (Table 3). Replacing the methyl
group with more sterically-demanding substituents led to
significantly lower conversion when using HyperBTM and (i-
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10.1002/anie.202004354
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RESEARCH ARTICLE
achieved with relatively low selectivity (s = 2–7).[20] Increasing
the steric hindrance of the vinyl substituent through the
proved to be optimal, with excellent conversion and selectivity
obtained for the KR of 8 (c = 50%, s = 50). A collection of a
further four structurally-diverse substrates were applied under
the optimal conditions. Variation of the aryl substituent was well
tolerated, with 13 and 15 resolved with good conversion and
good to excellent selectivity (c ≈ 50%, s = 29–80). The KR of
allylic alcohols 24 and 29 was also successful. Although slightly
lower conversion was observed under the standard continuous
flow conditions, good to excellent selectivity was obtained in
each case (s = 21–60). To the best of our knowledge, this work
represents the first example of the KR of acyclic tertiary alcohols
in a continuous flow process.
introduction of two β-methyl groups resulted in
a small
improvement selectivity (s = 10); however the introduction of an
α-methyl group had a significant effect, with alcohol 29 resolved
with excellent selectivity (s > 200). Based on these results, the
KR of substrates bearing two sterically-differentiated alkyl
substituents at the carbinol centre was investigated. The
introduction of a cyclopentyl or cyclohexyl group at this position
resulted in only moderate conversion under the standard KR
conditions (c ≈ 20%); however the use of isoselenourea
HyperSe 9 allowed the KR of 30 and 31 with good conversion
and selectivity (c = 40–47%, s = 19–24). The importance of
steric differentiation between the carbinol substituents was
further supported by the attempted KR of an electronically-
differentiated di-aryl-substituted alcohol, which resulted in
essentially no selectivity.[14]
Table 5: KR in continuous flow
Table 4: Substrate Scope III: Further structural variation
Conversion (c) and selectivity factor (s) calculated using the enantiomeric
ratios of recovered alcohol and ester (see ref. 3a). s values rounded according
to estimated errors (see ref. 3b). Reactions performed on 0.2–0.22 mmol
scale, see SI for full details.
Conversion (c) and selectivity factor (s) calculated using the enantiomeric
ratios of recovered alcohol and ester (see ref. 3a). s values rounded according
to estimated errors (see ref. 3b). Reactions performed on 0.13–0.32 mmol
scale, see SI for full details. [a] (i-PrCO)2O (0.55 equiv.) used. [b] separation of
enantiomers not possible by HPLC analysis, conversion based on 1H NMR
spectroscopic analysis of crude reaction product mixture; [c] (2R,3S)-HyperSe
9 (2 mol%) used; [d] Alcohol and ester obtained in the opposite enantiomeric
series to that shown in the scheme; [e] (2R,3S)-HyperSe 9 (5 mol%) used.
Finally, the importance of the carbonyl recognition motif
was investigated to provide insight into the origins of
enantiodiscrimination in this KR process (Figure 2). Attempted
KR of benzyl ether 33 or homologated benzyl ester 34 resulted
in essentially no conversion under the standard KR conditions.
The resolution of these substrates could be achieved by
switching to (MeCO)2O as the acyl donor, however low
selectivities were obtained (s < 3) (Figure 3a). In contrast, the
KR of ester 8 under analogous conditions was achieved with s =
19. This demonstrates that the presence and proximity of the
ester functionality is essential to promote acylation and allow
effective enantiodiscrimination. The absolute configuration of the
recovered alcohol within each substrate class [aryl/alkyl (5,20);
alkenyl/alkyl (29); alkyl/alkyl (31)] was determined by
comparison of specific rotations to literature values.[14] Based on
these data, and previous computational studies,[5h,9h,9q] we
propose that the ester functionality operates as a recognition
A common perceived drawback of organocatalysis is the
use of relatively high loadings of the catalyst, which is typically
discarded following a given reaction. One potentially general
solution is immobilization of the organocatalyst on
a
heterogeneous support, provided that the catalyst maintains
activity and displays high stability.[21,22] We recently addressed
this issue through the development of a polymer-supported
isothiourea catalyst 32, which could be applied for the KR of
alcohols in batch and flow with no reduction in either activity or
selectivity observed upon recycling.[23] Application of this
continuous flow technology to the KR of acyclic tertiary alcohols
was therefore targeted (Table 5). As Merrifield resin-supported
catalyst 32 does not swell in Et2O, process optimization focused
on the application of alternative solvents.[14] The use of toluene
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10.1002/anie.202004354
Angewandte Chemie International Edition
RESEARCH ARTICLE
motif within the acylation transition states of this KR by engaging
products with conservation of er will allow access to further
tertiary alcohol containing motifs using this methodology.[26]
in
a stabilizing C=O•••isothiouronium interaction with the
acylated catalyst (Figure 3b). The preferential acylation of the
fast-reacting enantiomer for each substrate class can then be
rationalized through minimization of unfavourable steric contacts
between the substrate and the acyl group of the acylated
catalyst. This model helps explain why substrates bearing alkyl
substituents larger than methyl at the carbinol centre were
challenging to resolve and required the use of less sterically-
hindered anhydrides as the acyl donor.[24]
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 no.
279850. The Chinese Scholarship Scheme and University of St
Andrews are thanked for
a CSC Scholarship (S. Q.).
Universidad Autónoma de Madrid is thanked for a predoctoral
fellowship (V. L.-M.). We thank the EPSRC Centre for Doctoral
Training in Critical Resource Catalysis (CRITICAT, grant code
EP/L016419/1) for funding (R. M. N.). 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.
Keywords: kinetic resolution • enantioselectivity • acyl transfer •
organocatalysis • tertiary alcohol
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Conclusion
In conclusion, a highly enantioselective isothiourea-catalyzed
acylative kinetic resolution (KR) of acyclic tertiary alcohols has
been developed. Through utilizing an adjacent carbonyl
substituent as a recognition motif for the acylated catalyst, the
KR of 25 α-hydroxy ester derivatives was achieved with
selectivity factors of up to > 200. Increased steric hindrance at
the tertiary carbinol centre resulted in low conversion; however
this issue was circumvented by performing the KR of these
substrates using a recently-developed isoselenourea catalyst
HyperSe 9. This new KR procedure was also applied in
continuous flow using a polymer-supported isothiourea catalyst
to resolve acyclic tertiary alcohols with good to excellent
selectivity. Based on mechanistic control reactions, and previous
computational studies, it is proposed that stabilization and
enantiodiscrimination within the acylation transition state
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structure
originates
through
maximization
of
a
C=O•••isothiouronium interaction between the α-hydroxy ester
substrate and acylated catalyst. Although not demonstrated in
this manuscript, the known derivatization[25] of structurally related
[6] For isolated examples of non-enzymatic catalytic KR of tertiary alcohols
as a part of an alternative methodological study, see: a) Z. Li, V.
Boyarskikh, J. H. Hansen, J. Autschbach, D. G. Musaev, H. M. L. Davis, J.
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Y. Tosaki, K. Hara, V. Gnanadesikan, H. Morimoto, S. Harada, M. Sugita,
N. Yamagiwa, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2006, 128,
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[14] See the Supporting Information for more details.
[15] 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 using the reaction conversion and either
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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 ref. 3 for more details.
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[26] The research data underpinning this publication can be found at DOI:
https://doi.org/10.17630/df9887af-d9c0-433b-a7c0-1dbe06a96be8
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10.1002/anie.202004354
Angewandte Chemie International Edition
RESEARCH ARTICLE
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Shen Qu, Samuel M. Smith, Víctor
Laina-Martín, Rifahath M.
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Andrew D. Smith*
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Isothiourea-Catalyzed Acylative
Kinetic Resolution of Tertiary α-
Hydroxy Esters
The Lewis base-catalyzed kinetic resolution of tertiary α-hydroxy esters has been
achieved with selectivity factors of up to 200. Enantiodiscrimination is proposed to
be reliant on the alcohol substrate containing an adjacent carbonyl recognition
motif. The procedure has also been translated to continuous flow using a solid-
supported variant of the catalyst.
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