Fluxionally chiral DMAP catalysts: Kinetic resolution of axially chiral biaryl compounds

Article abstract of DOI:10.1002/anie.201406684

Can organocatalysts that incorporate fluxional groups provide enhanced selectivity in asymmetric transformations? To address this issue, we have designed chiral 4-dimethylaminopyridine (DMAP) catalysts with fluxional chirality. These catalysts were found

Full text of DOI:10.1002/anie.201406684

Angewandte
Chemie
DOI: 10.1002/anie.201406684
Asymmetric Organocatalysis
Fluxionally Chiral DMAP Catalysts: Kinetic Resolution of Axially
Chiral Biaryl Compounds**
Gaoyuan Ma, Jun Deng, and Mukund P. Sibi*
Abstract: Can organocatalysts that incorporate fluxional
groups provide enhanced selectivity in asymmetric transfor-
mations? To address this issue, we have designed chiral 4-
dimethylaminopyridine (DMAP) catalysts with fluxional chir-
ality. These catalysts were found to be efficient in promoting
the acylative kinetic resolution of secondary alcohols and
axially chiral biaryl compounds with selectivity factors of up to
genic center to the catalytic center of DMAP. We report
herein the synthesis of novel fluxionally chiral DMAP
catalysts and their application in the acylative kinetic
resolution of secondary alcohols and axially chiral biaryl
compounds.
The design of our chiral DMAP catalysts is highly
modular and consists of three components: a 4-(N,N-dialkyl-
amino)pyridine (DMAP analogue) as the catalytic site,
a chiral pyrazolidinone as a chirality element, and a fluxional
substituent whose size can readily be varied as a blocking
3
7 and 51, respectively.
O
ver the past two decades, acylative kinetic resolution
1
through the use of non-enzymatic catalysts has become
group (Scheme 1). Conceptually, the R group dictates the
[
1]
2
important. Research in this field has focused on the
orientation of the CH R group, which in turn both influences
2
development of nucleophilic catalysts, such as chiral 4-
the orientation of the DMAP group and provides steric
discrimination during acylation. The 4-(N,N-dialkylamino)-
pyridine is connected to the chiral pyrazolidinone at the meta
position. Additionally, the nucleophilicity of the pyridine can
be tuned by varying the dialkylamino substituent. The
synthesis of these catalysts was straightforward (see the
Supporting Information for details). Six novel chiral DMAP
catalysts were prepared.
[
2]
[3]
dimethylaminopyridines (DMAPs) and others, for the
kinetic resolution of alcohols and amines with high catalytic
activity and enantioselectivity. Chiral biaryl skeletons are
prolific among useful organic molecules, such as biologically
[
4]
[5]
active natural compounds, chiral ligands, and chiral
[
6]
Brønsted acid catalysts. C -symmetric dihydroxy-substituted
2
biaryl derivatives have been applied extensively in a variety of
[
6]
enantioselective catalysts. Thus, the development of cata-
lysts which can resolve a variety of biaryl compounds
efficiently is significant. Several research groups have
reported the catalytic kinetic resolution of biaryl compounds,
[
7]
mostly by the use of biaryl-derived catalysts. There is only
one example of the acylative kinetic resolution of 1,1’-
binaphthyl derivatives with a chiral DMAP catalyst, and the
reaction proceeded with only modest selectivity (s = 1.4–
[
8]
4
.4).
Our research group has designed useful templates, ligands,
and additives with fluxional groups to control and/or enhance
Scheme 1. Novel fluxionally chiral DMAP catalysts.
[9]
stereoselectivity in a variety of asymmetric transformations.
We initiated the evaluation of these novel chiral DMAP
catalysts L1–L6 for the kinetic resolution of secondary
alcohols by using 1-(2-naphthyl)ethanol (rac-1a) as a test
substrate and isobutyric anhydride as the acylation reagent
(Table 1). Catalyst L1 bearing an isopropyl group at the
asymmetric C5 position and a benzyl fluxional group gave low
selectivity for the resolution (s = 4; Table 1, entry 1). The
selectivity factor (s) was considerably influenced by the
substituent at the asymmetric center; the replacement of the
isopropyl group in L1 with a larger tert-butyl group (catalyst
L2) raised the s factor from 4 to 15 (Table 1, entry 2). An
increase in the size of the relay group from benzyl to 1-
naphthylmethyl (in L3) gave the best result: s = 23 (Table 1,
entry 3). However, an even larger 9-methylanthracenyl flux-
ional group (in L4) reduced the selectivity from that observed
with L3 (s = 14; Table 1, entry 4). The dialkylamino group on
the pyridine unit of the catalyst was also investigated and
found to impact selectivity: L3 bearing a dimethylamino
group gave higher selectivity (s = 23) than L5 (s = 11) and L6
A key feature of this strategy is that the size of the fluxional
substituent can be varied readily. As an extension of this
strategy, we became interested in developing efficient,
broadly applicable, and tunable DMAP catalysts. In our
design, we surmised that a fluxional group would be effective
in relaying stereochemical information from the fixed stereo-
[
*] G. Ma, Dr. J. Deng, Prof. Dr. M. P. Sibi
Department of Chemistry and Biochemistry
North Dakota State University
Fargo, ND 58108 (USA)
E-mail: mukund.sibi@ndsu.edu
[**] We acknowledge the NSF (CHM-0709061) and an A. C. Cope
Scholar Award for financial support. We also thank NSF-CRIF (CHE-
0946990) for the purchase of a departmental X-ray diffractometer
and Dr. Angel Ugrinov for solving the single-crystal XRD structures.
DMAP=4-dimethylaminopyridine.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406684.
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Table 1: Optimization of the reaction conditions for the resolution of
[
a]
1
-(2-naphthyl)ethanol.
[
b]
[b–d]
Entry
Catalyst
T [8C]
Conv. [%]
s factor
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L3
L3
L3
0
0
0
0
0
53
54
56
49
52
51
57
47
47
4
15
23
14
11
9
24
37
22
0
À10
À50
À50
[
e]
9
[a] Reaction conditions: racemic alcohol (0.1 mmol, 1 equiv), isobutyric
anhydride (0.06 mmol, 0.6 equiv), chiral catalyst (10 mol%), Et O
2
(
2 mL), 48 h. [b] The following equations were used to calculate
Scheme 2. Substrate scope for the kinetic resolution of secondary
alcohols. For reaction conditions, see the Supporting Information. See
Table 1 for the calculation of the conversion and s factor. The ee values
were determined by HPLC analysis. Absolute configurations were
[
1a]
conversion and selectivity factors: conv=eealcohol/(eeester+eealcohol);
s factor=ln[1Àconv(1+ee )]/ln[1Àconv(1Àeeester)]. [c] The ee value
ester
was determined by HPLC analysis. [d] The absolute configuration was
[
10]
assigned by comparison with literature data. [e] 2,6-Di-tert-butylpyr-
idine (0.06 mmol, 0.6 equiv) was added.
[10]
assigned by comparison with literature data.
(
s = 9) with a pyrrolidine and di-n-butylamino substituent,
ligands and also serve as precursors for the synthesis of many
important biaryl compounds.
[11]
respectively (Table 1, entries 3, 5, and 6). The results of
catalyst screening thus demonstrate that L3 is the best catalyst
for the kinetic resolution of rac-1a.
We examined the kinetic resolution of monomethylated
bi-2-naphthol (binol), rac-7a, under various conditions with
catalyst L3 and isobutyric anhydride (0.6 equiv). In the
presence of 5 mol% of the catalyst at room temperature,
after 72 h, rac-7a was resolved with an s factor of 9. Lowering
of the reaction temperature led to increased selectivity
(Table 2, entries 1–3), and at À508C, catalytic resolution
gave s = 33, although the acylation proceeded slowly with
24% conversion. The use of higher amounts of the catalyst
improved conversion (Table 2, entries 3–5). With 15 mol% of
L3, (R)-7a was produced with increased selectivity (s = 38,
49% conversion; Table 2, entry 5).
We speculated that the addition of a base might lead to
a higher acylation rate, because a base could remove the by-
product isobutyric acid and thus prevent deactivation of the
catalyst. Bulky 2,6-di-tert-butylpyridine was the most effective
of the tested bases (Table 2, entries 6–9), and provided
sufficient selectivity (s = 36) and 41% conversion in 84 h
with 15 mol% of L3. We observed a diminished s value with
1,8-bis(dimethylamino)naphthalene (proton sponge). The
absolute configuration of the product alcohol was assigned
by comparison of the HPLC trace of an authentic sample of
monomethylated enantiomerically pure binol.
The effect of temperature was also investigated (Table 1).
Lowering of the temperature from 0 (s = 23) to À108C (s =
2
4) showed limited improvement. However, when the reac-
tion was carried out at À508C, the s factor increased
dramatically to 37 (Table 1, entry 8). The addition of a base,
such as 2,6-di-tert-butylpyridine, was detrimental to the
selectivity (s = 22; Table 1, entry 9). Further reaction screen-
ing included different acylation reagents and solvents (see the
Supporting Information).
On the basis of these investigations, we conducted the
kinetic resolution of various racemic secondary alcohols with
isobutyric anhydride (0.6 equiv) and L3 (10 mol%) at À508C
(
Scheme 2). The 2-naphthyl-substituted and propargylic alco-
hols rac-1a and rac-6a, respectively, could be efficiently
resolved within 48 h with s = 17–37. In contrast, resolution of
1
-naphthyl-substituted alcohol 2a proceeded with lower
selectivity (s = 6). The steric bulk of the alkyl group on
secondary alcohols 3a–5a had a significant impact on the
selectivity factor. The presence of bulkier tert-butyl and ethyl
groups led to higher s factors of 10 and 12, respectively, than
that observed for methyl-substituted benzyl alcohol (s = 6).
Encouraged by the results of the kinetic resolution of
secondary alcohols, we proceeded to study the kinetic
resolution of biaryl compounds. Our investigation started
with the acylation of derivatives of dihydroxy aryl com-
pounds. Optically active 2,2’-dihydroxy-1,1’-biaryls have
received significant attention, as they are highly effective as
The scope of the kinetic resolution was investigated under
the optimal conditions (Scheme 3). A variety of substrates
(rac-7a–rac-16a) were resolved effectively. A number of 2-
hydroxy-1,1’-biaryl analogues were resolved with good to
excellent selectivity (s = 10–51). The biaryl compound rac-8a
without a substituent at the b’-position gave a reduced s factor
2
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[
a]
Table 2: Optimization of the reaction conditions for the resolution of monomethylated bi-2-naphthol.
proceeded with s values higher
than 18. In contrast, compounds
with electron-deficient groups at
the b’-position gave lower selectiv-
ities (rac-13a, rac-14a). Pyridine
was used for substrates with bulkier
substituents, such as rac-12a and
rac-13a, to increase conversion.
The catalytic kinetic resolution
of 2-amino-2’-hydroxy-1,1’-binaph-
thyl (nobin) derivatives remains
a challenging problem, and only
limited examples have been repor-
[
c]
[c]
[b,d]
Entry L3
mol%]
T [8C] Additive (0.6 equiv)
t [h] Conv. ee [%]
ee [%]
s factor
[
b]
[
[%]
(ester) (alcohol)
1
2
3
4
5
6
7
8
9
5
5
5
10
15
15
15
15
15
RT
–
72
72
144
120
120
84
60
60
60
44
46
24
39
49
41
45
50
50
69
82
92
90
87
90
88
84
81
54
71
30
56
84
62
71
84
79
9
À30
À50
À50
À50
À50
À50
À50
À50
–
–
–
–
20
33
34
38
36
34
31
21
[
7c,8]
ted.
Among them, the reported
2,6-di-tert-butylpyridine
2,6-lutidine
pyridine
chiral DMAP acylation showed
[
8]
only modest selectivity.
To
proton sponge
expand the utility of our DMAP
catalysts, we synthesized and
resolved nobin derivative rac-15a.
[
a] Reaction conditions: racemic alcohol (0.1 mmol, 1 equiv), anhydride (0.06 mmol, 0.6 equiv), L3,
CH Cl (2 mL), with or without an additive. The effects of different catalysts, acylation reagents, and
2
2
solvents are shown in the Supporting Information. [b,c] See Table 1. [d] The absolute configuration was To our surprise, the kinetic resolu-
assigned by comparison with HPLC data of authentic samples.
tion afforded the acylation product
with 35% conversion and a high
s factor (s = 21). Remarkably, sub-
(
s = 10). Notably, compounds with an electron-rich group at
strate rac-16a with a biaryl structure was resolved with very
high selectivity and an s factor of 51 with 50% conversion.
To get insight into the origin of the catalytic activity
and stereoselectivity, we
the b’-position gave higher s factors: The resolution of
substrates rac-7a, rac-9a, rac-10a, rac-11a, and rac-12a
obtained the single-crystal
X-ray structure of catalyst
[
12]
L3 (Figure 1).
According
to the X-ray crystal structure,
the pyridine ring lies at the
top of the fluxional naphtha-
lene ring. In analogy with our
prior observation, the tert-
butyl group and the fluxional
naphthylmethyl substituent
are on opposite faces of the
five-membered ring owing to
steric interactions. The flux-
ional group blocks the back
side as well as the bottom
side of the pyridine ring.
Thus, on the basis of the
experimental results and
structure analysis, we pro-
pose
model for selectivity as
shown Scheme 4. The
a
stereochemical
DMAP ring and the acyl
group of the acylpyridinium
ion lie approximately in
a single plane. Naphthalene
ring A with the hydroxy
group attacks the N-acyl
group from the top face,
and the other ring, B,
approaches from the back
side. To minimize steric
Scheme 3. Substrate scope for the resolution of binol derivatives. For conditions, see the Supporting
Information. See Table 1 for the calculation of the conversion and s factor. Configurations were assigned by
comparing HPLC data with those of authentic samples; see the Supporting Information. [a] Pyridine
(
0.6 equiv) was used instead of 2,6-di-tert-butylpyridine. Bn=benzyl.
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Communications
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[
Figure 1. X-ray crystallographic analysis of L3.
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[
3] For kinetic resolution catalyzed by non-DMAP catalysts, see:
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Scheme 4. Stereochemical model for the kinetic resolution of biaryl
compounds.
[
4] For biaryl natural products, see: a) J. Chang, J. Reiner, J. Xie,
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B ring, the OR’ side of the B ring prefers to approach the
catalyst; thus, the (S)-binol derivative is more favored than
5
63.
[
5] For the use of chiral biaryl ligands in asymmetric catalysis, see:
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ever, bulky substituents on the B ring show relatively strong
repulsion and therefore decreased selectivity. The high
selectivity exhibited by b’-OR’-substituted biaryl compounds
possibly results from the intervention of an attractive p–p
interaction between the N-acyl and OR’ groups.
[
In summary, we have established that novel fluxionally
chiral DMAP molecules serve as effective acylation catalysts
for the kinetic resolution of racemic secondary alcohols and
biaryl compounds. This study adds a new family of DMAP-
based organocatalysts to the field of nucleophilic acylation
catalysis. Biaryl substrates were resolved with s factors of up
to 51 by using this catalyst system. To the best of our
knowledge, the selectivities observed for the kinetic resolu-
tion of biaryl compounds are better than those for previously
reported asymmetric acylation catalysts. We have proposed
a stereochemical model to explain the enantioselectivity
observed in this process. Further applications of the chiral
DMAP catalysts in other asymmetric transformations are
under investigation.
3
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684.
Received: June 29, 2014
Published online: && &&, &&&&
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Keywords: acylation · biaryls · fluxionality · kinetic resolution ·
.
organocatalysis
[
1] For reviews on acylative kinetic resolution, see: a) J. M. Keith,
J. F. Larrow, E. N. Jacobsen, Adv. Synth. Catal. 2001, 343, 5; b) E.
4
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[
10] The absolute configuration was determined by the comparison
of HPLC retention times with those reported in the literature;
see Ref. [2i] and V. B. Birman, L. Guo, Org. Lett. 2006, 8, 4859.
[11] For the synthesis and use of binol catalysts, see: J. M. Brunel,
Chem. Rev. 2005, 105, 857.
[12] See the Supporting Information for details.
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Communications
Asymmetric Organocatalysis
G. Ma, J. Deng,
M. P. Sibi*
&&&& — &&&&
Fluxionally Chiral DMAP Catalysts:
Kinetic Resolution of Axially Chiral Biaryl
Compounds
A catalyst for kinetic resolution: Chiral 4-
dimethylaminopyridine catalysts with
a fluxional group to relay stereochemical
information from a fixed stereogenic
center to the catalytic center promoted
the acylative kinetic resolution of secon-
dary alcohols and axially chiral biaryl
compounds with high enantioselectivity
(see scheme). The highly modular design
of the chiral DMAP catalysts enables
significant variation of their structure.
6
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