Isothiourea-Catalysed Acylative Kinetic Resolution of Aryl–Alkenyl (sp2vs. sp2) Substituted Secondary Alcohols

Article abstract of DOI:10.1002/chem.201604788

The non-enzymatic acylative kinetic resolution of challenging aryl–alkenyl (sp²vs. sp²) substituted secondary alcohols is described, with effective enantiodiscrimination achieved using the isothiourea organocatalyst HyperBTM (1 mol %) and isobutyric anhydride. The kinetic resolution of a wide range of aryl–alkenyl substituted alcohols has been evaluated, with either electron-rich or naphthyl aryl substituents in combination with an unsubstituted vinyl substituent providing the highest selectivity (S=2–1980). The use of this protocol for the gram-scale (2.5 g) kinetic resolution of a model aryl–vinyl (sp²vs. sp²) substituted secondary alcohol is demonstrated, giving access to >1 g of each of the product enantiomers both in 99:1 e.r.

Full text of DOI:10.1002/chem.201604788

A Journal of
Accepted Article
Title: Isothiourea-Catalysed Acylative Kinetic Resolution of Aryl-Alkenyl
(sp2 vs sp2) Substituted Secondary Alcohols
Authors: Andrew David Smith, Stefania Musolino, James Taylor,
Nicholas Westwood, and Stephen Ojo
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10.1002/chem.201604788
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Isothiourea-Catalysed Acylative Kinetic Resolution of Aryl-
Alkenyl (sp2 vs sp2) Substituted Secondary Alcohols
Stefania F. Musolino, O. Stephen Ojo, Nicholas J. Westwood, James E. Taylor*, and Andrew D.
Smith*[a]
Abstract: The non-enzymatic acylative kinetic resolution of
challenging aryl-alkenyl (sp2 vs sp2) substituted secondary alcohols
is described, with effective enantiodiscrimination achieved using the
isothiourea organocatalyst HyperBTM (1 mol%) and isobutyric
anhydride. The kinetic resolution of a wide range of aryl-alkenyl
substituted alcohols has been evaluated, with either electron-rich or
naphthyl aryl substituents in combination with an unsubstituted vinyl
substituent providing the highest selectivity (S = 2-1980). The
demonstration of this protocol for the gram-scale (2.5 g) kinetic
resolution of a model aryl-vinyl (sp2 vs sp2) substituted secondary
alcohol is demonstrated, giving access to >1 g of each of the product
enantiomers both in 99:1 e.r.
Introduction
Non-enzymatic, acylative kinetic resolution (KR) is a powerful
method for the preparation of enantiomerically enriched
alcohols.[1] In this regard, enantioselective Lewis base-catalysed
acylations are one of the most widely employed methodologies,
with various catalyst structures and acyl transfer agents having
been developed. In terms of substrate scope, non-enzymatic
acylative KRs are most commonly trialed on benzylic secondary
alcohols where the catalytic acylating agent must differentiate
Figure 1. Lewis base-catalysed KR of secondary alcohols.
between the enantiomers of alcohols bearing a planar aryl (sp2)
and a tetrahedral alkyl (sp3) substituent in order to obtain high
selectivity (Figure 1a).
To date there are very few examples of the KR of
Although less common, highly selective methods have also
secondary allylic alcohols bearing both planar alkenyl and planar
been developed for the KR of both alkynyl-alkyl (sp vs sp3) and
aryl substituents (sp2 vs sp2).[8] This is likely to be due to the
alkenyl-alkyl (sp2 vs sp3) substituted secondary alcohols. In
challenge of the catalytic acylating agent differentiating between
enantiomeric alcohols with two planar sp2 hybridized
these systems the acylating agent must differentiate between
the enantiomers of alcohols with a planar π-system and a
substituents during the selectivity-determining acylation step. To
tetrahedral sp3 hybridized substituent. For example, a number of
this end, Connon and co-workers have studied the KR of a
range of Morita-Baylis-Hillman (MBH) adducts 8 bearing aryl
substituents, obtaining moderate selectivity (S up to 13) using
chiral DMAP derivative 3 and isobutyric anhydride (Scheme
1a).[9] Mandai and Suga have also reported a single example of
Lewis base organocatalysts has been utilized for the acylative
KR of alkenyl-alkyl (sp2 vs sp3) allylic alcohols (Figure 1b).[2-7] Fu
used planar-chiral DMAP catalyst 1 and acetic anhydride for the
KR of a range of allylic alcohols, including two that had served
as intermediates in natural product synthesis, with high
the KR of an aryl MBH adduct using a chiral phosphoric acid
selectivity factors, S (up to 80).[2] Vedejs has also achieved high
catalyst alongside acetyl chloride and DABCO.[10] Deng and co-
workers have used amidine 7 as a catalyst for the acylative KR
selectivity for the KR of allylic alcohols using chiral phosphine 2
and isobutyric anhydride (S up to 82).[3] More recently, both
of aryl-alkenyl substituted alcohols 10, with moderate to good
Birman[4] and Deng[5] have used amidine catalysts 4-6 for the
selectivity (S up to 24) obtained for a range of aryl substituents
acylative KR of alkenyl-alkyl (sp2 vs sp3) alcohols with moderate
and simple 1,1-disubstituted alkenes (Scheme 1b).[11]
to good selectivity obtained across a range of substrates.
Herein, the challenge of resolving aryl-alkenyl (sp2 vs sp2)
substituted secondary alcohols is addressed using an
[a]
S. F. Musolino, Dr O. S. Ojo, Prof. N. J. Westwood, Dr J. E. Taylor,
Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews, North
Haugh, St Andrews, KY16 9ST (UK)
isothiourea-based organocatalyst (Scheme 1c).[12,13] Isothioureas
have previously been used as catalysts for the acylative KR of
various secondary alcohols,[14] as well as the desymmetrization
of meso-diols.[15] In this report, we demonstrate that the
isothiourea HyperBTM 12 can differentiate between the
E-mail: jet20@st-andrews.ac.uk, ads10@st-andrews.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Reaction optimization.
Cat.
Conv.
15
16
Entry
R
Solvent T (°C)
S[c]
(%)[a] e.r.[b] e.r.[b]
(mol%)
12 (1)
17 (1)
18 (1)
1
2
Et CHCl3
Et CHCl3
Et CHCl3
0
0
0
44
6
76:24 83:17
52:48 68:32
(ent)
8
2
2
(ent)
3
21
52
51
50
50
53
52:48 58:42
4[d]
5[d]
6[d]
7
12 (1) i-Pr CHCl3 –40
12 (1) i-Pr THF –40
12 (1) i-Pr PhMe –40
12 (1) i-Pr PhMe –78
12 (0.25) i-Pr PhMe –78
88:12 86:14 14
90:10 87:13 16
90:10 90:10 21
92:8
92:8 29
8
94:6 89:11 22
Scheme 1. Lewis base-catalysed acylative KR of aryl-alkenyl alcohols.
[a] Calculated by HPLC analysis. [b] e.r. determined by HPLC analysis. [c]
Calculated using the equations developed by Kagan.[17] [d] 0.6 eq of anhydride
used.
enantiomers of aryl-alkenyl (sp2 vs sp2) substituted secondary
alcohols. The selectivity of the KR has been assessed across a
wide range of allylic alcohols, with good to excellent
enantiodiscrimination observed for substrates bearing either
electron-rich or naphthyl substituents alongside an unsubstituted
vinyl substituent.
conversion or selectivity (Table 1, entry 8), although for
practicality 1 mol% HyperBTM 12 was used to assess the
reaction scope.
The optimized conditions for the KR of (±)-15 were then
tested for a range of vinyl alcohols bearing various aryl
substituents (Tables 2-4). Initial investigations probed the effect
of varying the steric and electronic nature of the aryl group
bearing a single substituent in either the para-, meta-, or ortho-
position (Table 2). Unsubstituted and aryl rings bearing electron-
donating methoxy substituents in either para-, meta-, or ortho-
positions worked well, with excellent selectivity obtained in all
cases (Table 2, entries 1, 2, 6 and 9, S = 29-59). In contrast, the
presence of an electron-withdrawing CF3 substituent in any of
the positions around the aryl ring led to a noticeable drop in
selectivity (Table 2, entries 3, 7 and 10, S = 7-11). For example,
while 3-methoxy substituted alcohol (±)-23 gave S = 59, the
analogous 3-CF3 substituted (±)-24 gave S = 11. Various
halogen substituents were tolerated, allowing KR of alcohols 21,
22 and 25 with moderate levels of selectivity (Table 2, entries 4,
5 and 8, S = 8-17). This observation is consistent with previous
proposals for the acylative KR of aryl-alkyl (sp2 vs sp3)
substituted secondary alcohols using isothioureas, which
typically give higher selectivity in the resolution of alcohols
bearing electron-rich aryl substitutents.[14] In these processes,
the aryl unit is thought to be the key recognition motif for
enantiodiscrimination, being involved in -stacking with an
electron-deficient acyl ammonium intermediate during the
acylation step.
Results and Discussion
The reaction of (±)-1-(4-methoxyphenyl)prop-2-en-1-ol 15 with
propanoic anhydride (0.5 eq) and i-Pr2NEt (0.5 eq) in CHCl3 was
chosen as the starting point to identify suitable reaction
conditions for the acylative KR of aryl-alkenyl (sp2 vs sp2)
substituted alcohols. The commercially available and readily
prepared isothiourea HyperBTM 12 (1 mol%) was identified as
the most promising in an initial screen of readily available
catalysts, giving 44% conversion into ester 16 with S = 8,[16-18]
whereas both tetramisole 17 and BTM 18 gave poor conversion
and lower selectivity (Table 1, entries 1-3). The absolute
configuration of the major enantiomer of recovered alcohol (S)-
15 was confirmed by comparison of its specific rotation with
literature values.[19] Further optimization revealed that using
isobutyric anhydride and lowering the reaction temperature to –
40 °C gave improved selectivity (Table 1, entry 4). A solvent
screen showed that both THF (S = 16) and in particular toluene
(S = 21) gave improvements in selectivity (Table 1, entries 5 and
6). Further lowering the reaction temperature to –78 °C led to
the efficient KR of (±)-15 with excellent selectivity (S = 29)
considering the challenging aryl-alkenyl (sp2 vs sp2) alcohol
substitution (Table 1, entry 7). The catalyst loading could also be
lowered to 0.25 mol% without an appreciable drop in either
Subsequent studies aimed to exploit this observation
through testing the KR of aryl-vinyl alcohols bearing either poly-
substituted electron-rich aryl-substitutents or extended aromatic
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Table 2. KR of substituted aryl-vinyl (sp2 vs sp2) secondary alcohols.
Table 3. KR of poly-substituted aryl-vinyl (sp2 vs sp2) secondary alcohols.
Conv. Alcohol e.r.[b] Ester e.r.[b]
Conv. Alcohol e.r.[b] Ester e.r.[b]
Entry
1
Substrate
S[c]
29
Entry
1[d]
Substrate
S[c]
(%)[a]
(yield, %)]
(yield, %)
(%)[a] (yield, %)
(yield, %)
92:8
(40)
92:8
(34)
78:22
(40)
99:1
(26)
50
37
110
82:18
(48)
95:5
(35)
>99:1
(39)
80:20
(50)
2
3
4
41
52
35
8
2
3
60
44
33
83:17
(37)
82:18
(41)
94:6
(43)
92:8
(47)
51
87:13
(31)
91:9
(30)
48[d]
17
61:39
(51)
90:10
(17)
4
5
22
11
68:32
(56)
84:16
(28)
5
6
7
8
35
43
8
97:3
(47)
>99:1
(45)
49
1980[e]
86:14
(46)
96:4
(40)
59
15
12
92:8
(41)
98:2
(31)
6
7
8
9
46
108
5
86:14
(46)
88:12
(50)
50
72:28
(31)
75:25
(37)
47
89:11
(33)
84:16
(34)
54[d]
78:22
(50)
88:12
(37)
42
13
26
95:5
(44)
N/D[e]
(35)
9
52[d]
37
36
7
89:11
(34)
92:8
(29)
48
68:32
(59)
82:18
(30)
[a] Calculated by HPLC analysis. [b] e.r. determined by HPLC analysis. [c]
Calculated using the equations developed by Kagan.[17] [d] 48 h reaction time.
[e] Determined by linear regression analysis (see text).
10
[a] Calculated by HPLC analysis. [b] e.r. determined by HPLC analysis. [c]
Calculated using the equations developed by Kagan.[17] [d] Conversion
determined by 1H NMR analysis. [e] Enantiomers of ester inseparable by
HPLC.
and 30 to be isolated with high e.r. This demonstrates that the
methodology can be used to access enantiomerically pure
synthetic building blocks from renewable monomers derived
from lignin, which is important for the continued drive for
valorization of such feedstocks.[18] Mesityl substituted allylic
alcohol (±)-31 also gave lower conversion into the corresponding
ester, but the KR selectivity was reasonable (Table 3, entry 4, S
= 11). The KR of 2-naphthyl substituted vinyl alcohol (±)-32 gave
exceptional selectivity, with the remaining alcohol 32 (97:3 e.r.)
and the corresponding isobutyric ester (>99:1 e.r.) isolated with
excellent e.r. at 50% conversion (Table 3, entry 5). The
presence of a 1-naphthyl substituent also led to excellent
naphthyl units (Table 3). Excellent selectivity was observed with
electron-rich 2,6-dimethoxy substituted aryl-alkenyl alcohol (±)-
28 (S = 110), although the presence of two ortho-substituents
resulted in lower, but still acceptable, conversion over an
extended 48 h reaction time due to the slower rate of acylation
(Table 3, entry 1). The methodology was then applied to the KR
of lignin-derived alcohols (±)-29 and (±)-30 bearing methoxy-
substituted aryl rings (Table 3, entries 2 and 3). Pleasingly, the
resolutions proceeded with excellent selectivity in both cases (S
= 44 and 33, respectively), allowing the recovered alcohols 29
selectivity (S
=
108) under the standard conditions
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Table 4. KR of heteroaryl-vinyl (sp2 vs sp2) secondary alcohols.
Conv. Alcohol e.r.[b] Ester e.r.[b]
Entry
1
Substrate
S[c]
3
(%)[a] (yield, %)
(yield, %)
67:33
(42)
68:32
(45)
49
69:31
(46)
73:27
(39)
2
3
46
4
9
76:24
(49)
84:16
(44)
44
[a] Calculated by HPLC analysis. [b] e.r. determined by HPLC analysis. [c]
Calculated using the equations developed by Kagan.[17]
Figure 2. Determination of the selectivity factor for the KR of (±)-32 using
linear regression.
Table 5. Effect of alkene substitution.
(Table 3, entry 6). The selectivity observed with naphthyl
substituents was surprisingly sensitive to further substitution on
the naphthylene ring. For example, 6-methoxy substituted
naphthyl alcohol (±)-34 gave dramatically lower selectivity (S =
5) compared with the unsubstituted analogue (Table 3, entry 7).
To probe the origin of the high selectivity using unsubstituted
naphthyl alcohols, the KR protocol was tested on aryl substrates
(±)-35 and (±)-36 containing 4-phenyl and 3-vinyl substituents,
respectively (Table 3, entries 8 and 9). In both cases the KR
gave good selectivity (S = 13 and 26), although neither match
the levels of enantiodiscrimination observed with the extended
conjugation within the unsubstituted naphthyl examples.
Conv. Alcohol e.r.[b] Ester e.r.[b]
Entry
1
Substrate
S[c]
10
(%)[a] (yield, %)
(yield, %)
79:21
(48)
84:16
(42)
45
73:27
(42)
65:35
(33)
2[d]
57
N/D
For the resolution of (±)-32, the exceptionally high
selectivity, coupled with the accuracy of the HPLC analysis used
to measure the e.r. values of both alcohol and ester, makes the
calculation of an exact selectivity factor difficult. To validate the
reported S value, repeat experiments were performed and
product enantioselectivities measured at varying reaction
conversions. The data obtained was plotted as shown in Figure
2, allowing the selectivity factor to be determined using linear
regression.[19] Good linear correlation of the data over a range of
reaction conversions suggests that S = 1980 for the KR of (±)-32.
Next, the use of heteroaryl-vinyl (sp2 vs sp2) secondary
alcohols in the KR was briefly assessed. Both 2- and 3-pyridyl
substituted alcohols (±)-38 and (±)-39 gave poor selectivity
(Table 4, entries 2 and 3, S = 3 and 4, respectively), while 2-
thiophenyl alcohol (±)-40 gave better, but still moderate, results
(Table 4, entry 3, S = 9).
The effect of substitution on the alkene portion was then
explored under the standard conditions (Table 5). The KR of 1,1-
disubstituted alkene (±)-41 showed good reactivity and
reasonable selectivity (Table 5, entry 1), although the selectivity
was lower (S = 10) than for the corresponding vinyl analogue
(±)-15 (S = 29). The reaction with 1,2-disubstituted alkene (±)-42
did not proceed at –78 °C and gave a complex mixture of
62:38
(64)
70:30
(34)
3
4
5
6
38
3
24
11
8
86:14
(45)
92:8
(37)
47
81:19
(51)
85:15
(38)
47
84:16
(45)
80:20
(48)
53
[a] Calculated by HPLC analysis. [b] e.r. determined by chiral HPLC analysis.
[c] Calculated using the equations developed by Kagan.[17] [d] Reaction
performed at 0 °C.
products when performed at 0 °C. However, the recovered
alcohol and ester were bot obtained in low e.r. so the selectivity
is likely to be minimal (Table 5, entry 2). The use of 1,1,2-
trisubstituted alkene (±)-43 also gave low levels of selectivity
(Table 5, entry 3, S = 3). As the 2-naphthyl aryl substituent led to
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extremely high levels of enantiodiscrimination with unsubstituted
allylic alcohol (±)-32, the effect of alkene substitution within this
series was also investigated. In this case, 1,1-disubstituted
alkene (±)-44 gave higher selectivity (S = 24, Table 5, entry 4)
compared with (±)-41, although again this was significantly lower
than for vinyl substituted (±)-32. The reactions of 1,2-
disubstituted (±)-45 and 1,1,2-trisubstituted (±)-46 followed the
same trend as previously and both gave relatively low selectivity
(Table 5, entries 5 and 6, S = 11 and 8). These results
demonstrate that levels of enantiodiscrimination between the
two enantiomers of aryl-alkenyl (sp2 vs sp2) secondary alcohols
decreases with increasing substitution on the alkenyl moiety.
Finally, as the catalytic system can effectively discriminate
between the two planar sp2 hybridized substituents within aryl-
alkenyl alcohols, the KR of some alternative classes of
secondary alcohol were compared under the same reaction
conditions (Table 6). Interestingly, the KR of aryl-vinyl
substituted alcohol (±)-32 (sp2 vs sp2) gave higher levels of
enantiodiscrimination than the analogous aryl-alkyl substituted
alcohol (±)-47 (sp2 vs sp3), although in both cases the selectivity
is excellent (Table 6, entries 1 and 2). However, the use of aryl-
alkynyl alcohol (±)-48 (sp2 vs sp) gave poor selectivity (S = 3) in
the KR process (Table 6, entry 3). The catalytic system was also
only poorly selective for the KR of vinyl-alkyl alcohol (±)-49 (sp2
vs sp3) (Table 6, entry 4, S = 3). This suggests that both aryl
(sp2) and alkynyl (sp) groups are effective recognition motifs for
enantiodiscrimination and may interact with the proposed acyl
ammonium intermediate (vide infra) during the acylation step.
Conversely, vinyl (sp2) and alkyl (sp3) substituents are poor
recognition units and are unlikely to interact with the catalytic
intermediate. Consequently, combining an effective recognition
motif (such as aryl (sp2) and alkynyl (sp) groups) with a poor one
(such as vinyl (sp2) and alkyl (sp3) units) leads to high
enantiodiscrimination
during
KR,
whereas
alternative
combinations result in low selectivity.
To demonstrate the synthetic utility of this KR process to
facilitate the separation of the two enantiomers of a racemic
alcohol, the KR was performed on a preparative laboratory scale
using 2.5 g (13.6 mmol) of (±)-32 and 1 mol% of HyperBTM
(Scheme 2). This highly selective reaction proceeded to 50%
conversion, allowing unreacted (S)-32 to be recovered in 43%
yield (1.08 g) and 99:1 e.r. Isolated ester (R)-37 was readily
hydrolyzed under basic conditions to give (R)-32 in 45% yield
(1.12 g) over the two steps and >99:1 e.r.
Scheme 2. Preparative-scale KR for the separation of (±)-32.
The proposed catalytic cycle starts with
a reversible
acylation of HyperBTM 12 with isobutyric anhydride to form acyl
ammonium intermediate 50 (Scheme 3a). Turnover-limiting
acylation of the favoured enantiomer of the aryl-alkenyl alcohol
is thought to occur with concomitant proton transfer to the
carboxylate anion.[20,21] The i-Pr2NEt may possibly act as a
shuttle base to regenerate the catalyst and remove isobutyric
acid. The sense of enantioselectivity observed can be
rationalized by considering the interactions of the incoming
alcohol with acyl ammonium 50 during the selectivity-
determining step (Scheme 3b). Acyl ammonium 50 is thought to
be conformationally locked due to a stabilizing non-bonding O-S
interaction (nO to σ*C-S),[22] with the Re face blocked by the
pseudo-axial phenyl group. The fast-reacting enantiomer of the
aryl-alkenyl alcohol can adopt a conformation that has a
potentially stabilizing aryl π-cation interaction with the
isothiourea (52), which is favoured over the potential alkenyl π-
cation interaction in the slow reacting enantiomer (53).[23] This
model is consistent with the higher selectivity observed for
substrates bearing electron-rich aryl rings due to the increased
strength of the proposed cation-π interaction in the favoured
transition state in these cases.[24] Conversely, increasing the
substitution on the alkene makes this π-system more electron
rich, which decreases the difference in energy between the
diastereomeric transition states and accounts for the lower
selectivity obtained for these examples. A possible explanation
for the enhanced selectivity with naphthyl substituents is the
presence of an additional stacking interactions with the
benzenoid ring of acyl ammonium 50 for the fast reacting
enantiomer. Substitution of the naphthyl ring with electron-
donating substituents may destabilise these additional
Table 6. KR of different classes of secondary alcohols.
Conv. Alcohol e.r.[b] Ester e.r.[b]
Entry
1
Substrate
S[c]
(%)[a] (yield, %)
(yield, %)
>99:1
(37)
96:4
(39)
52
152
97:3
(47)
>99:1
(45)
2
49
1980[d]
66:34
(35)
64:36
(36)
3
4
53
3
3
61:39
(35)
68:32
(25)
40
[a] Calculated by HPLC analysis. [b] e.r. determined by chiral HPLC analysis.
[c] Calculated using the equations developed by Kagan.[17] [d] Determined by
linear regression analysis (see text).
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interactions,[25]
enantiodiscrimination.
resulting
in
the
observed
loss
in
Representative procedure for the KR of aryl-alkenyl alcohols: The
appropriate alcohol (1 eq) was dissolved in PhMe (0.35 M) and the
solution cooled to –78 °C. HyperBTM 12 (1 mol%), i-Pr2NEt (0.6 eq) and
isobutyric anhydride (0.5 eq) were added and the solution stirred at –
78 °C for 16 h. The reaction was quenched with 1 M HCl, the solution
diluted with EtOAc and washed successively with 1 M HCl (×2), NaHCO3
(×2) and brine. The organic layer was dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The alcohol and ester
were purified by column chromatography and analysed by chiral HPLC
Acknowledgements
We would like to thank the Engineering and Physical Sciences
Research Council and CRITICAT Centre for Doctoral Training
[Ph.D. studentship to SFM; Grant code: EP/L016419/1 and
EP/J018139/1] and The Leverhulme Trust [Early Career
Fellowship to JET; ECF-2014-005] for financial support. ADS
thanks the Royal Society for a Wolfson Merit Award. We also
thank the EPSRC UK National Mass Spectrometry Facility at
Swansea University.
Keywords: Kinetic resolution • acylation • organocatalysis •
isothiourea • renewable resources
[1]
For reviews on non-enzymatic acylative KR, see: a) A. C. Spivey, P.
McDaid, in Enantioselective Organocatalysis, (Ed.: P. I. Dalko), Wiley-
VCH Verlag GmbH & Co. KGaA, Weinheim, 2007, pp. 287-329; b) A. C.
Spivey, S. Arseniyadis, in Asymmetric Organocatalysis (Ed.: B. List),
Springer, Heidelberg, 2009, pp. 233-280; c) C. E. Muller, P. R.
Schreiner, Angew. Chem. Int. Ed. 2011, 50, 6012-6042; d) H. Pellissier,
Adv. Synth. Catal. 2011, 353, 1613-1666.
Scheme 3. a) Proposed mechanism. b) Stereochemical rationale.
Conclusions
The isothiourea HyperBTM 12 (1 mol%) can catalyze the
acylative KR of a range of aryl-alkenyl (sp2 vs sp2) substituted
secondary alcohols with isobutyric anhydride. The catalytic
system achieves effective enantiodiscrimination between the
enantiomers of secondary alcohols bearing two planar sp2
hybridized substituents. The efficiency of the KR process has
been assessed for a range of substituted aryl and heteroaryl
moieties and various alkene substitution patterns. The highest
selectivity is obtained when either electron-rich or naphthyl aryl
substituents are present in combination with a vinyl substituent.
Conversely, the presence of either electron-deficient aryl rings or
substituted alkenes leads to lower levels of selectivity. The
optimized KR process can be used to separate the two
enantiomers of synthetically useful aryl-vinyl alcohols with high
enantioselectivity (up to >99:1 e.r.) on a preparative scale at low
catalyst loading (1 mol%). Ongoing work within this laboratory is
focused upon the development of practical KR processes of
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c)(1-eealcohol)] / [(1-c)(1+eealcohol)]}.
[18] Authentic racemic samples of all isobutyric esters were synthesised
using a DMAP-catalysed acylation, see the Supporting Information.
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S. F. Musolino, O. S. Ojo, N. J.
Westwood, J. E. Taylor*, A. D. Smith*
Page No. – Page No.
Isothiourea-Catalysed Acylative
Kinetic Resolution of Aryl-Alkenyl
(sp2 vs sp2) Substituted Secondary
Alcohols
Face to face: The isothiourea HyperBTM catalyses the acylative kinetic resolution
of challenging aryl-alkenyl (sp2 vs sp2) substituted secondary alcohols with high
levels of selectivity.
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