Isothiourea-Catalysed Regioselective Acylative Kinetic Resolution of Axially Chiral Biaryl Diols

Article abstract of DOI:10.1002/chem.201805631

An operationally simple isothiourea-catalysed acylative kinetic resolution of unprotected 1,1′-biaryl-2,2′-diol derivatives has been developed to allow access to axially chiral compounds in highly enantioenriched form (s values up to 190). Investigation of the reaction scope and limitations provided three key observations: i) the diol motif of the substrate was essential for good conversion and high s values; ii) the use of an α,α-disubstituted mixed anhydride (2,2-diphenylacetic pivalic anhydride) was critical to minimize diacylation and give high selectivity; iii) the presence of substituents in the 3,3′-positions of the diol hindered effective acylation. This final observation was exploited for the highly regioselective acylative kinetic resolution of unsymmetrical biaryl diol substrates bearing a single 3-substituent. Based on the key observations identified, acylation transition state models have been proposed to explain the atropselectivity of this kinetic resolution.

Full text of DOI:10.1002/chem.201805631

A Journal of
Accepted Article
Title: Isothiourea-Catalyzed Regioselective Acylative Kinetic Resolution
of Axially Chiral Biaryl Diols
Authors: Shen Qu, Mark Greenhalgh, and Andrew David Smith
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Isothiourea-Catalyzed Regioselective Acylative Kinetic
Resolution of Axially Chiral Biaryl Diols
Shen Qu, Mark. D. Greenhalgh and Andrew. D. Smith*[a]
Abstract: An operationally-simple isothiourea-catalyzed acylative
kinetic resolution of unprotected 1,1′-biaryl-2,2′-diol derivatives has
been developed to allow access to axially chiral compounds in highly
enantioenriched form (s values up to 190). Investigation of the
reaction scope and limitations provided three key observations: i) the
diol motif of the substrate was essential for good conversion and
high s values; ii) the use of an a,a-disubstituted mixed anhydride
(2,2-diphenylacetic pivalic anhydride) was critical to minimize
diacylation and give high selectivity; iii) the presence of substituents
in the 3,3′-positions of the diol hindered effective acylation. This final
observation was exploited for the highly regioselective acylative
kinetic resolution of unsymmetrical biaryl diol substrates bearing a
single 3-substituent. Based on the key observations identified,
acylation transition state models have been proposed to explain the
atropselectivity of this kinetic resolution.
regioisomeric ester products when using unsymmetrically-
substituted diol substrates.
1. Introduction
Axially chiral biaryl structures are present in many natural
products and pharmaceuticals,[1] and have been used as chiral
ligands and auxiliaries in a range of applications.[2] Axially chiral
biaryl compounds derived from 1,1′-bi-2-naphthol (BINOL),
including 2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN) and 2,2′-
bis(diphenylphosphino)-1,1′-binaphtyl (BINAP), have found
particularly widespread use in asymmetric catalysis.[3]
Enantiopure samples of these axially chiral biaryl compounds
are typically prepared through classical stoichiometric resolution
methods, and as such there is current interest in the
development of alternative routes to these important
compounds.[4] The catalytic enantioselective synthesis of BINOL
derivatives can be achieved through the oxidative homocoupling
of naphthols,[5] however some limitations in substrate scope and
enantioselectivity makes the development of alternative methods
attractive. Recently a number of catalytic methods have been
reported for the kinetic resolution (KR)[6] of O- and/or N-
protected BINOL and NOBIN derivatives[7] using enzymes,[8]
transition metals,[9] and organocatalysts.[10] Despite this interest,
small molecule Lewis base catalyzed acylative KRs of these
substrates has not been widely explored.[11] Sibi has reported
Scheme 1. Lewis based-catalyzed acylative KRs of biaryl diol derivatives.
Lewis basic isothioureas catalysts,[15] first reported for acyl
transfer reactions by Birman and Okamoto,[16] have been applied
for the acylative KR of primary,[17] secondary[18] and tertiary[19]
alcohols bearing point chirality. The KR of secondary alcohols
has been most widely explored, with exceptional selectivities
obtained in many cases. Computational studies have been used
to probe the origin of enantiodiscrimination in these KRs, with
acylation transition state structure (TS) models proposed for the
fast- and slow-reacting enantiomers (Scheme 2a).[18h–j,m,n,p,q,19a,20]
Three key features are generally highlighted: i) a 1,5-S•••O
interaction, which locks the acyl group syn-coplanar with the
isothiouronium core;[21] ii) chelation of the carboxylate counterion,
which engages in a non-classical C-H•••O hydrogen bond with
the acidic C(2)-H of the acylated catalyst and simultaneously
deprotonates the alcohol;[20,22] and iii) electrostatic stabilization of
the isothiouronium ion by an electron-rich substituent on the
alcohol (commonly a p-system or a substituent bearing a lone
pair of electrons). The preferential acylation of the fast-reacting
enantiomer of the alcohol is then generally rationalized based on
reduced steric hindrance in the acylation transition state.
Based on this mechanistic model, we hypothesized that
isothiourea catalysis may be applicable for the atropselective
acylative KR of axially chiral biaryl diols (Scheme 2b).
Considering possible TSs for the acylation of each enantiomer of
BINOL, it was expected that the extended p-system of BINOL, in
addition to the potential for the formation of additional hydrogen
bonding interactions (present in TS-I), may provide an
opportunity for enantiodiscrimination. Herein we report the
development of this method for the highly regio- and
the acylative KR of mono-protected biaryl diols using
a
fluxionally chiral DMAP catalyst with moderate to good
selectivity factors[12] (Scheme 1a, s = 10–50),[13] however the KR
of unprotected chiral biaryl diols remains surprisingly
underdeveloped. To the best of our knowledge, only one such
method has been reported by Zhao by utilizing NHC redox
catalysis (Scheme 1b).[14] Although proceeding with excellent
selectivity in many examples, this method provided a mixture of
[a]
S. Qu, Dr M. D. Greenhalgh, Prof. Dr 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
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201805631
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atropselective KR of unprotected 1,1′-biaryl-2,2′-diol derivatives
to provide access to biaryl diols in highly enantioenriched form.
18, entry 10), and in particular tert-amyl alcohol (s = 34, entry
11) provided good to high levels of selectivity. Notably, the
choice of solvent not only affected the selectivity of the KR, but
also had a significant effect on the amount of diester 3a
produced. Very little diester (1-2%) was obtained when using
halogenated or hydrocarbon solvents, however the use of ethers,
esters, alcohols and ketones provided significantly higher
quantities of diester (up to 10%), suggesting that diester
formation may be promoted by the hydrogen bond acceptor
ability of the solvent.[26]
Further control studies found that high conversions were still
obtained in the absence of catalyst, indicating the possibility of a
competitive racemic base-mediated acylation pathway.[24] The
KR of BINOL in the absence of i-Pr2NEt was therefore
investigated in both tert-amyl alcohol and CHCl3. The KR in tert-
amyl alcohol provided very similar conversion and selectivity in
comparison to the reaction in the presence of base (c = 50, s =
37, entry 12). In contrast, the KR in chloroform was significantly
improved in the absence of base, with good conversion (c =
49%) and high selectivity (s = 40) obtained. Notably, the
formation of diester 3a was also inhibited under these conditions.
Table 1: Reaction optimization I: Variation of catalyst and solvent.
Scheme 2. Proposed transition state structures (TSs) for the acylation of point
chiral secondary alcohols (a) and axially chiral biaryl diols (b).
2. Results and Discussion
2.1. Reaction optimization
Method development began with the KR of commercially-
available (±)-BINOL
1
using three isothiourea catalysts:
HyperBTM 4,[23] tetramisole (TM·HCl) 5 and BTM 6,[16a] all at 1
mol% catalyst loading (Table 1). Initial investigations used
isobutyric anhydride 7a as the acyl donor, i-Pr2NEt as auxiliary
base and chloroform as solvent, as this combination is
commonly optimal for the KR of point chiral alcohols.[16–19] All
three catalysts provided good conversion (c = 54–58%, entries
1-3), however only BTM 6 provided good selectivity (s = 26,
entry 3). When using (R)-BTM 6 as catalyst, the recovered
BINOL was enriched in the (R)-enantiomer (R)-1, consistent with
the proposed acylation TS models (Scheme 2b). In addition to
BINOL 1 and the expected monoester product 2a, small
amounts (~1%) of diester 3a, enriched in the (S)-enantiomer,
were also obtained. Control reactions found that acylation of
monoester 2a to give diester 3a takes place via a second KR,
albeit with low selectivity (s < 2).[24] Due to the operation of this
second KR, all subsequent s values were calculated using the er
of recovered BINOL 1 and the reaction conversion, which was
determined by 1H NMR spectroscopic analysis of the crude
reaction product mixture.
The use of alternative reaction solvents was examined next
(entries 4–11). In contrast to chloroform, the use of
dichloromethane provided only low selectivity (s = 5, entry 4).
The use of ethereal solvents provided mixed results: THF gave
low selectivity (s = 9, entry 5), however diethyl ether and
diisopropyl ether provided good levels of selectivity (s = 20–22,
entries 6–7), albeit still slightly lower than that obtained using
chloroform. The use of industrially-preferable solvents was
investigated next.[25] Whilst ethyl acetate and acetone provided
relatively low selectivities (s = 11–12, entries 8–9), toluene (s =
1 er
Entry
Cat.
solvent
c
1:2a:3a
s
(R:S)
1
2
4
5
6
6
6
6
6
6
6
6
6
6
6
CHCl3
CHCl3
54
56
58
52
49
47
48
47
50
52
51
50
49
46:53:1
44:55:1
42:57:1
48:51:1
51:44:5
53:40:7
52:42:6
53:42:5
50:40:10
48:50:2
49:47:4
50:47:3
51:49:0
21:79
8:92
5
12
26
5
3
CHCl3
99:1
4
CH2Cl2
THF
78:22
81:19
87:13
87:13
82:18
84:16
91:9
5
9
6
Et2O
22
20
12
11
18
34
37
40
7
iPr2O
8
EtOAc
acetone
toluene
t-amyl-OH
t-amyl-OH
CHCl3
9
10
11
12[a]
13[a]
94:6
93:7
92:8
Conversion (c) and product ratio determined by 1H NMR spectroscopic
analysis of the crude reaction product mixture. er determined by chiral HPLC
analysis. s calculated using equations given in ref. 6. [a] no i-Pr2NEt used.
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The choice of anhydride is known to have a significant effect on
enantiodiscrimination in the KR of point chiral alcohols. This
effect is most commonly rationalized by a change in the steric
nature of the acyl group undergoing transfer; however the role of
the carboxylate counterion in aiding preorganization of the
acylation TS and promoting deprotonation of the alcohol should
not be overlooked (highlighted in Scheme 2).[20,22] Due to the
lack of fundamental studies on the acylative KR of axially chiral
alcohols, a broad investigation of anhydride structure for the KR
of BINOL 1 was conducted. These studies were performed using
both chloroform and tert-amyl alcohol as solvent, with similar
selectivities obtained in both solvent systems. As such, only the
results obtained using chloroform are discussed in the following
section, with the results obtained using tert-amyl alcohol
available in the Supporting Information.[24]
KR protocol that gave excellent selectivity (s = 50–60) but
inconsistent reaction conversion in our hands (c = 8–42%).[24]
This irreproducibility was circumvented by using the isolated
mixed anhydride, 2,2-diphenylacetic pivalic anhydride 7r, which
can be readily prepared and stored as a bench-stable solid.
Good conversion and excellent selectivity were reproducibly
obtained for the KR of BINOL (c = 50%, s = 50) (Table 2, entry
17).[28] Further investigation of reaction temperatures in the
range of −40 to 45 °C confirmed the highest selectivity was
obtained at room temperature.[24]
Table 2: Reaction optimization II: Variation of anhydride.
The effect of anhydride choice was investigated under the
conditions previously optimized for isobutyric anhydride 7a,
which had provided good conversion and high selectivity (c = 49,
s = 40) (Table 1, entry 13). Decreasing the steric bulk of the
anhydride to propionic anhydride 7b led to reduced selectivity (s
= 14, table 2, entry 1); whilst increasing the steric bulk to pivalic
anhydride 7c resulted in a loss in activity, with only 2%
conversion obtained (entry 2). As the branched nature of
isobutyric anhydride appeared advantageous, the use of
homoanhydrides with alkyl substituents at the b- or g-carbon was
investigated (entries 3–4). In each case, selectivities similar to
that observed when using propionic anhydride were obtained (s
= 8–11), consistent with branching at the a-carbon being most
influential for inducing high selectivity. The introduction of an
aromatic substituent at the a- or b-carbon was also investigated.
The use of dihydrocinnamic anhydride 7g provided similar
results to propionic anhydride (s = 11, entry 6), however
improved selectivity was obtained using phenylacetic anhydride
7f (s = 21, entry 5), again consistent with increased steric
hindrance at the a-carbon leading to improved selectivity.
Homoanhydrides bearing an sp2-hybridized carbon at the a-
position were next tested. Cinnamic anhydride 7h provided very
poor selectivity (s = 3, entry 7), however improved selectivities
were obtained using benzoic anhydride derivatives 7i–7k and
nicotinic anhydride 7l (s = 15–21, entries 8–11).
As isobutyric anhydride 7a had provided the highest selectivity
and the lowest amount of diester 3a, the use of alternative a,a-
disubstituted homoanhydrides was investigated. While both
diethyl acetic anhydride 7m and dipropyl acetic anhydride 7n
provided relatively low conversions (c = 12–15%, entries 12–13),
similar selectivities to that obtained when using isobutyric
anhydride were achieved (s = 34–37). Diphenyl acetic anhydride
7o provided an improvement in selectivity (s = 43), and crucially
also provided excellent conversion (c = 52%). Cyclic anhydrides
were also tested, however neither cyclopentane carboxylic
anhydride 7p nor cyclohexane carboxylic anhydride 7q provided
any further improvement (s = 23–34, entries 15–16).
Entry
R1 = R2
Et 7b
c
59
2
1:2:3
41:56:3
98:2:0
1 er (R:S)
s
14
-
1
2
96:4
-
t-Bu 7c
3
4
48
30
52:46:2
70:30:0
79:21
67:33
8
11[a]
5
6
7
8
48
42
33
36
52:47:1
58:41:1
67:32:1
64:36:0
88:12
77:23
61:39
73:27
21
11
3
Ph 7i
15[a]
9
54
51
54
46:53:1
49:51:0
46:52:2
92:8
89:11
94:6
16
16[a]
21
10
11
12
13
14
15
12
52
85:15:0
88:12:0
48:52:0
58:42
57:43
96:4
34[a]
37[a]
43[a]
15
16
Cyclopentyl 7p
Cyclohexyl 7q
53
45
47:52:1
55:44:1
94:6
23
34
86:14
The optimal conversion and high selectivity obtained using
diphenylacetic anhydride 7o, and the lack of reactivity using
pivalic anhydride 7c, presented the possibility of using the mixed
anhydride 2,2-diphenylacetic pivalic anhydride 7r. Mixed
anhydrides have been reported to be advantageous in some
R1
R2
17
50
50:50:-
95:5
50[a]
t-Bu 7r
cases
for
the
KR
of
point
chiral
secondary
Conversion (c) and product ratio determined by 1H NMR spectroscopic
analysis of the crude reaction product mixture. er determined by chiral HPLC
alcohols.[18b,d,h,j,m,n,p,q,20b,27] Generating the mixed anhydride in
situ from diphenylacetic acid and pivalic anhydride provided a
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analysis. s calculated using equations given in ref. 6. [a] As no diester
formation observed, s was calculated using the ers of recovered 1 and 2.
acylation transition state, which may resemble TS-II (Scheme
2b). It is worth noting that the pseudo-enantiomeric forms of the
To showcase the applicability of the optimized KR procedure,
the resolution of (±)-BINOL was conducted on a preparative
scale (Scheme 3). The KR of 1.43 g of BINOL 1 was achieved
with comparable conversion and selectivity as that obtained on
an analytical scale (c = 50%, s = 50), allowing enantioenriched
(R)-BINOL (R)-1 to be recovered in 46% yield (0.66 g, 95:5 er).
Table 3. Scope: Symmetrically-substituted binaphthyl diol derivatives.
Scheme 3. Gram-scale KR of (±)-BINOL 1.
2.2. Reaction scope and limitations
The generality of the KR procedure was explored using a
collection of biaryl diols (Tables 3 and 4). In each case no
formation of any diester products was observed and therefore s
values were calculated using the er of the recovered diol and
monoester
products.
7,7′-Dimethoxy-substituted
BINOL
derivative 8 underwent KR with ideal conversion and excellent
selectivity (Table 3, s = 60). Whilst 7,7′-dibromo-substituted
derivative 9 underwent resolution with good conversion (c =
54%), significantly lower selectivity was observed (s = 10),
indicating the selectivity of this KR procedure is sensitive to the
electronic effects of the substituents. Introduction of the bromo
substituents at the 6,6′-positions however led to much improved
selectivity (10, s = 25), whilst maintaining good conversion. The
KR of BINOL derivatives with 3/3′-substitution proved more
Conversion (c) and er determined by chiral HPLC analysis. s calculated using
equations given in ref. 6. [a] 10 mol% (R)-BTM 6 used. [b] Using either 10
mol% (R)-BTM 6 or (2R,3S)-HyperBTM 4 with 2,2-diphenylacetic pivalic
anhydride 7r or (MeCO)2O at up to 65 °C.
challenging.
[9,9′-Biphenanthrene]-10,10′-diol
11
was
significantly more difficult to acylate, with only 23% conversion
obtained when using 10 mol% catalyst loading, albeit with an
acceptable s value of 11. The attempted KR of 3,3′-dimethyl
ester-substituted BINOL derivative 12 proved unsuccessful, with
no conversion observed using either HyperBTM 4 or BTM 6 at
up to 10 mol% catalyst loading. The use of higher reaction
temperatures and less sterically-hindered anhydrides also failed
to promote the acylation of diol 12. This difficultly in acylating
3,3′-disubstituted BINOL derivatives is consistent with the
proposed acylation TS models, where a 3/3′-substituent would
be expected to introduce an unfavourable steric contact with the
acyl group of the acylated catalyst (Scheme 2b).
Table 4. Scope: Symmetrically-substituted biphenyl diol derivatives.
Next, the KR of biphenyl diol derivatives was investigated (Table
4). The KR of H8-BINOL 13 using (R)-BTM 6 provided only low
selectivity (s = 3), and required a 10 mol% catalyst loading to
achieve good conversion (see Supporting Information).[24] This
can be rationalized considering the proposed transition state
models (Scheme 2b), with the semi-hydrogenation of BINOL
leading to increased steric hindrance and a loss of the stabilising
p-isothiouronium interactions present in proposed TS-I.
Significantly improved results were obtained when using the
alternative isothiourea catalyst (2R,3S)-HyperBTM 4 (1 mol%, c
= 38, s = 10), Interestingly, the pseudo-enantiomeric isothiourea
catalysts (R)-BTM 6 and (2R,3S)-HyperBTM 4 both preferentially
acylated (S)-H8-BINOL 13. This indicates the KR of H8-BINOL 13
using (2R,3S)-HyperBTM 4 proceeds via a different favoured
Conversion (c) and er determined by chiral HPLC analysis. s calculated using
equations given in ref. 6. [a] 1 mol% (2R,3S)-HyperBTM 4 used. [b] Using
either 10 mol% (R)-BTM 6 or (2R,3S)-HyperBTM 4 with 2,2-diphenylacetic
pivalic anhydride 7r or (MeCO)2O at up to 65 °C.
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catalysts gave the ‘expected’ opposite enantiodiscrimination for
the acylative KR of BINOL 1, indicating that comparable
transition state models may be proposed in this case (see Table
1, entries 1 and 3). The scope was explored further through the
KR of biphenyl diol derivatives 14 and 15, which were resolved
with good conversion and selectivity (c = 48%, s = 13–37). For
the KR of these substrates, BTM 6 proved the optimal choice of
catalyst, with (R)-BTM 6 displaying enantiodiscrimination for
acylation of the (S)-enantiomer of the substrate in each case.[29]
To better understand the origin of selectivity in this KR process,
the KR of a selection of mono-protected BINOL derivatives was
investigated (Table 5). The KR of racemic monoester 2o was
inefficient, with only 11% conversion and an s value of 1.1
obtained under the standard reaction conditions. This low
conversion is consistent with the observation that diester 3o was
not obtained under standard conditions for the KR of BINOL
(Table 2, entry 17). Next, the KR of O-methyl-BINOL derivative
16 was investigated. Under standard conditions only 20%
conversion was obtained, with up to 39% conversion achievable
when using a 5 mol% catalyst loading. Once again the selectivity
of this KR was very low (s = 3). These results suggest that the
presence of two hydroxyl groups in the substrate may be
required to facilitate both good reactivity and selectivity. It was
hypothesized that these hydroxyl groups may operate as
hydrogen bond donors, and therefore the KR of N-Boc protected
NOBIN derivative 17, which contains a free N-H bond, was
investigated. Under the standard KR conditions excellent
conversion (c = 49%) and reasonable selectivity (s = 17) were
obtained, consistent with the requirement for two hydrogen bond
donors in the substrate. These results indicate that this
additional hydrogen bond donor may be essential for
stabilization of the acylation TS-I to promote effective acylation
and enantiodiscrimination (Scheme 2b).
selectivity (s = 49). Only a single ester product was obtained,
with regioselective acylation taking place at the less sterically-
hindered alcohol. Notably, the acylation of BINOL derivative 18
using 4-dimethylaminopyridine (DMAP) in our hands, or
according to Zhao’s previous KR methodology,[14] provides a
mixture of both monoester constitutional isomers. The scope of
the current method was therefore further probed. 3-Phenyl-
substituted BINOL derivative 19 also underwent regioselective
acylation, with the KR achieved with good conversion (c = 51%)
and exceptional selectivity (s = 190), allowing (R)-19 to be
recovered in essentially enantiopure form (> 99:1 er). Finally, the
KR of 3-methyl ester-substituted BINOL derivative 20 was
investigated. Although highly regioselective acylation was
observed, a significantly lower s value of 4 was obtained. 1H
NMR spectroscopic analysis of diol 20 reveals a significant
downfield signal for the hydroxyl group ortho to the ester
substituent (dH = 10.9 ppm), indicative of an intramolecular
hydrogen bond. We hypothesize that the low s value obtained
for this substrate is therefore consistent with the proposal that
this hydroxyl group is required to operate as a hydrogen bond
donor
in
acylation
TS-I
to
promote
effective
enantiodiscrimination (Scheme 2b).
Table 6. Scope: Unsymmetrically-substituted BINOL derivatives.
Table 5. Scope: Mono-protected BINOL derivatives.
Conversion (c) and er determined by chiral HPLC analysis. s calculated using
equations given in ref. 6. [a] PhMe used as solvent
Intrigued by the apparent differences in the regioselectivity of
acylation of 3-bromo-substituted BINOL 18 using BTM 6, DMAP
and an NHC catalyst,[14] further control studies were performed
(Scheme 4). Treatment of an enantioenriched sample of
monoester constitutional isomer (S)-21 (93:7 er) with i-Pr2NEt
(10 mol%) resulted in equilibration to give
constitutional isomers 21 and 22 in a 77:23 ratio (Scheme 4a).
HPLC analysis using chiral support revealed both
a mixture of
Conversion (c) and er determined by chiral HPLC analysis. s calculated using
equations given in ref. 6. [a] 5 mol% (R)-BTM 6 used.
a
constitutional isomers were obtained with the same enantiomeric
enrichment (93:7 er), indicating no racemization takes place
during this acyl transfer process. To provide further insight, 21
was treated under various conditions, with the time taken to
reach equilibrium assessed by H NMR spectroscopy (Scheme
4b). Equilibration in the presence of i-Pr2NEt (10 mol%) was
Based on the significantly lower conversions obtained when
using BINOL derivatives bearing 3,3′-substituents, it was
hypothesized that regioselective acylation may be possible for
the KR of asymmetrically-substituted biaryl diols bearing just a
single 3-substituent. 3-Bromo-substituted BINOL 18 underwent
efficient KR with good conversion (c = 52%) and excellent
1
achieved after 15 minutes, whilst the use of DMAP (10 mol%)
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required an extended reaction time of
1 hour to reach
thanks the Royal Society for a Wolfson Research Merit Award.
We thank the EPSRC UK National Mass Spectrometry Facility at
Swansea University.
equilibrium. This difference in rate suggests equilibration most
likely takes place through a Brønsted base-catalyzed process.[30]
Considering an equivalent of i-Pr2NEt was used in the NHC-
catalyzed KR of biaryl diols (Scheme 1b),[14] the mixture of
constitutional isomers reported for the KR of 18 may not be
representative of the regioselectivity of acylation using the NHC
catalyst, but rather the position of equilibrium between the
constitutional isomers. Finally, when monoester 21 was treated
with rac-BTM 6 (10 mol%) significantly slower equilibration was
observed, with one week required to reach a 78:22 ratio of 21:22.
The fact that constitutional isomer 22 was not observed under
KR conditions may therefore be rationalized by the lower loading
of BTM 6 used (1 mol%), in addition to the formation of pivalic
acid over the reaction course, which presumably inhibits this
Brønsted base-catalyzed process.
Keywords: biaryl • kinetic resolution • enantioselectivity •
regioselectivity • axial chirality
[1]
a) G. Bringmann, C. Günther, M. Ochse, O. Schupp, S. Tasler in
Progress in the Chemistry of Organic Natural Products, Vol. 82 (Eds.:
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3. Conclusions
In summary, we have developed an operationally-simple method
for the atropselective acylative KR of axially chiral biaryl diols
using an isothiourea organocatalyst (generally 1 mol%) and a
bench-stable mixed anhydride (2,2-diphenylacetic pivalic
anhydride). The KR of a range of binaphthyl and biphenyl diols,
in addition to a NOBIN derivative, is reported (s up to 190).
Significant to the success of this method is the presence of two
hydrogen bond donors in the substrate, with low conversion and
selectivity observed in the attempted resolution of mono-
protected diols. In addition, the acylation of 3,3′-disubstituted
BINOL derivatives proved challenging, leading to the
development of the regioselective acylation of unsymmetrically-
substituted BINOL derivatives bearing only a single 3-substituent.
A transition state model for acylation has been proposed to help
rationalize the observed reactivity and enantiodiscrimination.
The insights obtained through this work provides great promise
for the development of other atropselective processes using
isothiourea catalysis, with some of these avenues of research
currently being explored within our group.[31]
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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. The Chinese Scholarship Scheme and University of St
Andrews are thanked for a CSC Scholarship (S.Q.). A.D.S.
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Isothiourea-Catalyzed Regioselective
Acylative Kinetic Resolution of
Axially Chiral Biaryl Diols
Problem Resolved! The kinetic resolution of unprotected 1,1′-biaryl-2,2′-diol
derivatives is reported, in which a combination of a bench-stable mixed anhydride
and 1 mol% of a commercially-available isothiourea catalyst is required. This
operationally simple process provides access to axially-chiral diols in highly
enantioenriched form (s values up to 190).
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