Kinetic resolution of secondary alcohols catalyzed by chiral phosphoric acids

Article abstract of DOI:10.1002/anie.201304281

Acid instead of base: Kinetic resolution of secondary alcohols is realized using chiral Bronsted acid catalyzed acylation instead of the conventional basic conditions. A broad range of functional groups are tolerated, such as aldehydes, carboxylic acids, and enoates. The selectivity factor (s) reaches up to 215 at ambient temperature. Copyright

Full text of DOI:10.1002/anie.201304281

Angewandte
Chemie
DOI: 10.1002/anie.201304281
Kinetic Resolution
Kinetic Resolution of Secondary Alcohols Catalyzed by Chiral
Phosphoric Acids**
Shingo Harada, Satoru Kuwano, Yousuke Yamaoka, Ken-ichi Yamada,* and Kiyosei Takasu*
Of the many methods to separate enantiomeric constituents
from racemic materials, kinetic resolution offers distinct
advantages, especially when a chiral catalyst is involved.
Kinetic resolution of racemic alcohols by esterification is an
important process in synthetic chemistry, and many artificial
catalysts as well as enzymatic methods have been developed
for this purpose.[1] Their catalytic mechanisms are classified
into two types: 1) Enhancement of the nucleophilicity of
alcohols as a metal alkoxide bearing a chiral ligand[2]
(Scheme 1, class a); and 2) in situ generation of chiral
acylating reagents by nucleophilic chiral organocatalysts[3]
(Scheme 1, class b).[4]
Scheme 2. cis-2-Arylcycloalkanol motifs in bioactive compounds.
Although Brønsted acids promote the acylation of
alcohols with an acid anhydride,[12] a systematic study of
their catalytic activity has not been reported. At the outset of
this study, several Brønsted acids were tested in the acylation
of cis-2-phenylcyclohexanol (5a) with isobutyric anhydride
(6a).[13] Acylation did not occur in chloroform at ambient
temperature after 24 h in the absence or presence of
isobutyric acid. In contrast, stronger acids, such as phosphoric
acid, accelerated acylation. With highly acidic triflic imide,
acylation was complete within 0.5 h with only 0.5 mol% of the
catalyst. These results show that isobutyric acid does not
Scheme 1. Activation and enantiomer-discrimination modes in acyla-
tion-based kinetic resolution of secondary alcohols.
catalyze background acylation to give a racemic product, but
an appropriately strong acid catalyzes acylation from 6a in
accordance to the acid strength of the catalyst.
As a new mechanistic class, we expect that a chiral
Brønsted acid will activate the acylating agent by hydrogen
bonding and simultaneously discriminate the enantiomers of
alcohols (Scheme 1, class c).[5] Herein we present the first
kinetic resolution of secondary alcohols by chiral phosphoric
acid catalyzed acylation.[6] This method provides effective
access to optically pure 2-arylcycloalkanols,[7] which are
structural motifs of biologically significant compounds, such
as lycorine (1),[8] epicatechin (2),[9] PF-998,425 (3),[10] and L-
733,060 (4)[11] (Scheme 2).
Since the pioneering work of Akiyama and Terada,[14]
chiral phosphoric acids have emerged as powerful Brønsted
acid catalysts for various organic transformations.[15] How-
ever, acylation reactions catalyzed by this type of catalyst
have rarely been reported.[6] Nevertheless, in the presence of
chiral phosphoric acid (R)-TRIP (7a)[16,17] (5 mol%), a solu-
tion of (Æ)-5a and 6a (1.5 equiv) in chloroform was stirred at
ambient temperature. Acylation proceeded slowly, and
reached 47% conversion after 48 h to give (+)-8aa with
good enantioselectivity (s = 24;[18] Table 1, entry 1). Although
the reaction was greatly accelerated (41–64% conversion
after 0.5–5 h) using more acidic 7b–7d, the selectivity
decreased (s = 1–17; entries 2–4). TRIP-based phosphoric
acid 7e,[19] which bore bromine atoms at the 6,6’-positions,
enhanced the selectivity as well as the reaction rate (s = 45,
50% conversion after 24 h; entry 5). Finally, a new catalyst 7 f,
which had nitro groups at the 6,6’-positions, was the best
catalyst, exhibiting a sufficient s value and reaction rate (s =
110, 32% conversion after 5 h; entry 6). Even with
a decreased amount of 6a (0.7 equiv), the reaction with
catalyst 7 f proceeded with a similar selectivity (s = 113) and
reached 51% conversion after 24 h (entry 7).[13]
[*] Dr. S. Harada, S. Kuwano, Dr. Y. Yamaoka, Prof. Dr. K. Yamada,
Prof. Dr. K. Takasu
Graduate School of Pharmaceutical Sciences, Kyoto University
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: yamak@pharm.kyoto-u.ac.jp
kay-t@pharm.kyoto-u.ac.jp
[**] We thank MEXT (Japan) for financial support (Grants-in-Aid for
Scientific Research and Platform for Drug Design, Discovery, and
Development).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304281.
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Table 1: Optimization of reaction conditions.[a]
Table 2: Substrate scope.[a]
Entry
Recovered 5
5
8
s
Yield [%],[b] er
Yield [%],[b] er
(À)-5a
(+)-8aa
52%, 95:5
1[c]
116
215
48%,>99:1
(À)-5b
(+)-8b
49%, 98:2
2
51%, 97:3
Entry
6
7
Solvent
Time [h]
Conversion [%]
s
(À)-5c
(+)-8c
47%, 98:2
3
4
5
135
120
126
47 (48)[b]
52
41
64
50
32
51
37
25
48
44
27
15
24
2
17
1
45
110
113
6
30
35
68
43
22
48%, 95:5
1
2
3
4
5
6
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6a
6a
6a
7a
7b
7c
7d
7e
7 f
7 f[d]
7 f
7 f
7 f
7 f
7 f
7 f
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
MeNO2
MeCN
Et2O
48
1
5
0.5
24
5
24
5
96
5
24
24
24
(+)-5d
48%, 98:2
(À)-8d
50%, 97:3
7[c]
8
9
10
11[c]
12[c]
13[c]
(À)-3 (=5e)
48%,>99:1
(+)-8e
52%, 96:4
(À)-5 f
(+)-8 f
51%, 94:6
6
7
55
49%, 96:4
(À)-5g
(+)-8g
50%, 96:4
151
48%,>99:1
[a] With 5a (0.1 mmol) and 6 (1.5 equiv) in CHCl3 (0.2 mL). Absolute
configuration was determined based on the specific rotation. [b] Yield of
isolated product in parentheses. [c] With 6a (0.7 equiv) in solvent
(0.1 mL). [d] Recovered 7 f was used.
(À)-5i
(+)-8i
55%, 90:10
8
39
23
45%, 99:1
(+)-5l
44%, 92:8
(À)-8l
9
47%, 90:10
Next, we tested other anhydrides and solvents. With acetic
anhydride (6b), the selectivity significantly decreased (s = 6;
entry 8). Notably, methacrylic anhydride (6c) was applicable
to this reaction, and (+)-8ac was obtained in a lower but
acceptable selectivity (s = 30; entry 9). Acylation with suc-
cinic anhydride (6d) also proceeded with good selectivity (s =
35) to yield (+)-8ad, which bore a carboxylic acid moiety and
was easily separated from (À)-5a by alkaline extraction
(entry 10).
Replacing chloroform with nitromethane, acetonitrile, or
diethyl ether decreased the enantioselectivity and the reac-
tion rate (entries 11–13). The observed selectivity (s = 113, 68,
43, and 22 for CHCl3, MeNO2, MeCN, and Et2O, respectively)
and the reaction rate (51%, 44%, 27%, and 15% conversion
after 24 h) seem to be correlated with the basicity of the
solvents (donor numbers = 0, 2.7, 14, and 19),[20] suggesting
that hydrogen bonding plays a critical role in the transition
state.
With the optimal conditions (Table 1, entry 7), the scope
of alcohols was investigated (Table 2). cis-Alcohol (Æ)-5b,
which possessed an electron-rich aryl group, was successfully
resolved (s = 215) at ambient temperature to give (À)-5b
(51%, 97:3 er) and ester (+)-8b (49%, 98:2 er; entry 2).
Alcohols (Æ)-5c, 5d, and 3 with an electron-deficient aryl
group were also good substrates, affording a high selectivity
(s = 120–135; entries 3–5). PF-998,425 (3)[10] was obtained
with a high optical purity in an almost ideal yield (entry 5).
cis-Arylcycloalkanols with different ring sizes, such as (Æ)-5 f
and (Æ)-5g, were also resolved with a high selectivity (s = 55
(À)-5m
(+)-8m
52%, 94:6
10
128
46%,>99:1
(À)-5n
(+)-8n
43%, 95:5
11[d]
39
55%, 85:15
[a] With 5 (0.25 mmol) and 6a (0.7 equiv) in CHCl3 (0.25 mL). The
absolute configurations were determined based on specific rotation,
except for entries 2–4, 7, and 8, which were assigned by analogy. [b] Yield
of isolated product. [c] With 5a (1 mmol) in CHCl3 (0.1 mL) for 15 h.
[d] With 6a (1.5 equiv) in MeNO2 (0.1 mL).
and 151; entries 6 and 7, respectively). trans-Isomers as well as
acyclic alcohol were also resolved in a practical level of
selectivity (s = 23–39; entries 8 and 9).[13] Importantly, 7 f was
quantitatively recovered and recycled.
Piperidinol (Æ)-5m was an appropriate substrate (s =
128), and (À)-5m, a known intermediate for L-733,060
(4),[11] with 99:1 er was recovered in 46% yield (entry 10).
For lactam alcohol (Æ)-5n, which had a poor solubility in
chloroform, nitromethane was a substitute solvent, although
the selectivity was lower (s = 39, entry 11). An a,b-unsatu-
rated ester (Table 1, entry 9), a formyl group (Table 2,
entry 3), nitromethane (Table 2, entry 9), carboxylic acid,
aryl acetate, and 1,3-dione,[13] which are potentially sensitive
to nucleophilic catalysts providing side reactions, were inert
under these conditions.
Chiral phosphoric acid would catalyze acylation not only
as a Brønsted acid to activate acid anhydride as an electro-
2
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phile by protonation, but also as a general base[21] to enhance
the nucleophilicity of alcohol. However, another possibility
was that nucleophilic catalysis occurred. Namely, phosphoric
acid might react with acid anhydride to form the correspond-
ing acyl phosphate (mixed anhydride), which then acylates
alcohols.
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To exclude this possibility, equimolar mixtures of 6a with
1
7a or 7 f in deuterochloroform were monitored by H and
31P NMR. Only signals of 6a and 7a or 7 f appeared,
respectively, and no formation of acyl phosphates was
observed for 48 h.[22] Therefore, the high performances of 7e
and 7 f can be explained by the stronger acidity, which allows
stronger hydrogen bonds, increasing the reaction rate and
selectivity (Table 1, entry 1 vs. entries 5 and 6).
The geometry of the proposed transition state was
calculated at the B3LYP/6-31G** level of theory (Figure 1).
=
À
=
The distances of P O···H, P O···H, and H···O C were 1.41,
1.26, and 1.15 ꢀ, respectively, clearly indicating that the
expected hydrogen-bond network was operative. The activa-
tion energy was reasonably low (22.6 kcalmolÀ1), supporting
the plausibility of the model. The decreased selectivity with
7b–d (Table 1, entries 2–4) and the above-mentioned solvent
effect (Table 1, entries 11–13) also suggest the importance of
hydrogen bonding in the transition state.
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Figure 1. Perspective view of the calculated transition-state model (the
À
H atoms of the C H bonds are omitted for clarity).
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In conclusion, we have developed the kinetic resolution of
secondary alcohols by chiral phosphoric acid-catalyzed acy-
lation. New electronically tuned binaphthyl-based phosphoric
acid 7 f was developed by installing nitro groups at the 6,6’-
positions of TRIP, enabling the resolution of cis-2-arylcy-
cloalkanols with a high selectivity even at ambient temper-
ature. Hydrogen bonding most likely plays a crucial role in the
selectivity and acceleration of the acylation. Facile access to
biologically significant compounds highlights the utility of this
reaction. The reaction procedure is simple and does not
require additives, such as a stoichiometric amount of base,
which was required for the conventional methods. This acid-
catalyzed reaction provides complementary functional group
compatibility to already-known methods.
[16] a) S. Hoffmann, A. M. Seayad, B. List, Angew. Chem. 2005, 117,
7590; Angew. Chem. Int. Ed. 2005, 44, 7424; b) T. Akiyama, WO
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[17] Compounds 7 were washed with aqueous HCl before use to
remove metals.
Received: May 18, 2013
Revised: June 27, 2013
Published online: && &&, &&&&
[18] Enantioselectivity in kinetic resolution is expressed by selectiv-
ity factor “s”, which is defined as the ratio of reaction rates for
the fast- and the slow-reacting enantiomers of the starting
Keywords: asymmetric acylation · chiral alcohols ·
kinetic resolution · organocatalysis
.
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material. In simple first-order kinetics, s = kfast/kslow = ln[(1ÀC)
(1Àee’)]/ln[(1ÀC)(1+ee’)] = ln[1ÀC(1+ee)]/ln[1ÀC(1Àee)] and
C = ee’/(ee’+ee), where C is conversion, and ee and ee’ are
enantiomeric excesses of the product, and the recovered starting
material, respectively: H. B. Kagan, J. C. Fiaud, Top. Stereochem.
1988, 18, 249.
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Solvents (Ed.: G. Wypych), ChemTec, Toronto, 2001.
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Soc. 2007, 129, 6756.
[22] The acyl phosphates should have a 31P signal at about À20 ppm,
1
and a double septet H signal that is due to characteristic JH-P
[19] T. Akiyama, Y. Honma, J. Itoh, K. Fuchibe, Adv. Synth. Catal.
2008, 350, 399.
coupling at about 2.65 ppm: C. Blonski, H. Belghith, A. Klaebe,
J.-J. Perie, J. Chem. Soc. Perkin Trans. 2 1987, 1369.
4
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Kinetic Resolution
S. Harada, S. Kuwano, Y. Yamaoka,
K. Yamada,* K. Takasu*
&&&& — &&&&
Kinetic Resolution of Secondary Alcohols
Catalyzed by Chiral Phosphoric Acids
Acid instead of base: Kinetic resolution of
secondary alcohols is realized using
chiral Brønsted acid catalyzed acylation
instead of the conventional basic condi-
tions. A broad range of functional groups
are tolerated, such as aldehydes, carbox-
ylic acids, and enoates. The selectivity
factor (s) reaches up to 215 at ambient
temperature.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!