Discovery and application of doubly quaternized cinchona-alkaloid-based phase-transfer catalysts

Article abstract of DOI:10.1002/anie.201404084

We report the discovery of novel N,N'-disubstituted cinchona alkaloids as efficient phase-transfer catalysts for the assembly of stereogenic quaternary centers. In comparison to traditional cinchona-alkaloid-based phase-transfer catalysts, these new catal

Full text of DOI:10.1002/anie.201404084

Angewandte
Chemie
DOI: 10.1002/anie.201404084
Phase-Transfer Catalysis
Discovery and Application of Doubly Quaternized Cinchona-Alkaloid-
Based Phase-Transfer Catalysts**
Bangping Xiang,* Kevin M. Belyk, Robert A. Reamer, and Nobuyoshi Yasuda*
Dedicated to Ulf-H. Dolling and Edward J. J. Grabowski on the 30th anniversary of their first report of an asymmetric alkylation
under phase-transfer catalysis
Abstract: We report the discovery of novel N,N’-disubstituted
cinchona alkaloids as efficient phase-transfer catalysts for the
assembly of stereogenic quaternary centers. In comparison to
traditional cinchona-alkaloid-based phase-transfer catalysts,
these new catalysts afford substantial improvements in enan-
tioselectivity and reaction rate for intramolecular spirocycliza-
tion reactions with catalyst loadings as low as 0.3 mol% under
mild conditions.
trial settings.[4] The structures of cinchona-alkaloid-based
PTCs have been modified by functionalization of the C9
hydroxy group or quaternization of the bridgehead amine;
however, to our knowledge, there are no examples of PTCs in
which the quinoline nitrogen was also quaternized. Herein,
we report the discovery of N,N’-disubstituted cinchona
alkaloids, wherein both the quinuclidine nitrogen (N) and
the quinoline nitrogen (N’) are quaternized, as a new
generation of phase-transfer catalysts.
A
symmetric phase-transfer catalysis has been established as
During our studies directed toward the practical synthesis
of calcitonin gene-related peptide (CGRP) antagonist candi-
dates MK-8825 and MK-3207 for the treatment of migraines
(Figure 1),[5] we again faced the challenge of developing an
a powerful, yet practical method for challenging enantiose-
lective transformations, and is of great relevance to the
industrial application of green chemistry.[1] The first indus-
trial-scale asymmetric alkylation reaction, mediated by a cin-
chona-alkaloid-based phase-transfer catalyst (PTC), was
reported in 1984 by Merck for the construction of the
stereogenic quaternary carbon center in 2 with remarkable
enantioselectivity (92% ee; Scheme 1).[2,3] Since then, cin-
chona-alkaloid-based PTCs have been applied to many
practical asymmetric syntheses in both academic and indus-
Figure 1. CGRP-antagonist candidates for the treatment of migraines.
enantioselective synthesis of a stereogenic quaternary carbon
center, this time in a 3,3-spiro-7-azaoxindole. Although this
and related structural motifs are common in both naturally
derived and biologically active compounds,[6] there have been
few reports of their preparation by practical asymmetric
synthesis, despite numerous developments in the field of
phase-transfer catalysis.[7]
Among several synthetic routes we evaluated, the spiro-
cyclization of benzyl chloride 4 under phase-transfer catalysis
was the most attractive for constructing the stereogenic
quaternary center in MK-8825 (Scheme 2). Unfortunately,
Scheme 1. The first industrial application of an asymmetric PTC at
Merck.
[*] B. Xiang, K. M. Belyk, R. A. Reamer, N. Yasuda
Department of Process Chemistry, Merck and Co., Inc.
P.O. Box 2000, Rahway, NJ 07065 (USA)
E-mail: bangping_xiang@merck.com
nobuyoshi_yasuda@merck.com
[**] We acknowledge Zhijian Liu, Brian T. Kim, and Szilvia Kiss for the
preparation of substrates and useful discussions. We also
acknowledge Joe Armstrong, Kevin R. Campos, John Y. L. Chung,
Cameron Cowden, Stephen M. Dalby, Ian Davies, David L. Hughes,
Shen-chun Kuo, Jinchu Liu, Michael R. Luzung, Carmela Molinaro,
Benjamin D. Sherry, David Thaisrivongs, and Jianguo Yin for critical
discussions.
Scheme 2. Initial screening of the asymmetric alkylation. Screening
conditions: 4 (1 mg) in toluene (0.075 mL, 0.027m), NaOH (0.025 mL,
0.3 n), 08C, PTC (20 mol%), 19 h.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404084.
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Table 1: Introduction of additional functional groups on the PTC.
PTC
ee [%] Conv. [%]
6[a]
none
none
none
58
34
67
92
80
90
7[a]
none
8[a]
80
Figure 2. Comparison of the 1H NMR spectra of 6 and 9a in
[D6]dimethyl sulfoxide (blue: pure 6; red: original batch of 6; black:
9a).
9a[b]
100[c]
a majority of phase-transfer catalysts examined in the
spirocyclization of 4 did not show complete conversion after
19 h, and the enantioselectivity was generally modest.[8]
However, we observed unique
[a] PTC: 20 mol%. [b] PTC: 1 mol%. [c] The reaction was complete
within 1 h.
results with PTC 6, which afforded
the desired product 5 in high yield
with 92% ee.
Table 2: Selected results from the screening of doubly quartenized phase-transfer catalysts.
As new batches of PTC 6 were
prepared for the demonstration of
this reaction on a larger scale, we
were surprised to find that the
reaction proceeded at a slower rate
(80% conversion, 19 h) and with
lower enantioselectivity (58% ee)
than results in our initial screening.
A 1H NMR spectrum of the batch of
PTC 6 used in the original screen
revealed several significant impuri-
ties (Figure 2). We speculated that
the unknown components were gen-
erated during the preparation of 6
by overalkylation of the cinchona
alkaloid. After extensive NMR
spectroscopic analysis, we were
able to conclude that no O-alkylated
impurities were present; however,
evidence supporting a quaternized
quinoline nitrogen was inconclusive.
To understand the reactivity of these
hypothesized compounds, we inde-
pendently prepared and screened
each as a catalyst in the spirocycli-
zation of 4 (Table 1). We found that
catalyst 9a, a unique cinchona alka-
loid containing both a quaternized
quinuclidine nitrogen and a quater-
nized quinoline nitrogen,[9] afforded
results that were consistent with
Cinchonine series (R3 =H)
Quinidine series (R3 =OMe)
R1 R2
PTC
R1
R2
ee [%]
PTC
ee [%]
9a
92
9g
94
9b
78
80
47
9h
9i
89
84
90
9c[a]
9d
Me
9j
9e
9 f
allyl
70
42
9k[b]
46
9l
67
81
9m[b]
those observed in the original reac- [a] Mixed BrÀ/IÀ salt. [b] Catalysts 9k and 9m are the dihydroquinidine derivatives.
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Table 3: Application of PTC 9g to other substrates.
tion. Moreover, PTC 9a exhibited a remarkable rate accel-
eration in the spirocyclization and afforded complete con-
version at only 1 mol% loading in 1 h (92% ee). Complete
conversion was not observed with the other catalysts even at
20 mol% loading after 19 h.
Owing to the improved reactivity and enantioselectivity
observed with the N,N’-doubly quaternized cinchona-alka-
loid-based catalyst 9a, a collection of similar catalysts was
prepared with different substituents at N and N’, and each was
examined in the spirocyclization of 4 (Table 2).[10] In every
case, N’-quaternization accelerated the reaction, resulting in
100% conversion within 2 h at 1 mol% loading. N,N’-Doubly
quaternized cinchona-alkaloid-based catalysts generally dem-
onstrated improved enantioselectivity in the spirocyclization
versus the traditional cinchona-alkaloid-based phase-transfer
catalysts. In fact, the introduction of even a methyl group at
the N’ position dramatically improved the enantioselectivity
(9c; 80% ee). Although the best enantioselectivities in the
spirocyclization of 4 were observed with catalysts containing
a 2-bromo-5-methoxybenzyl substituent as R1, respectable
selectivities could be achieved with other R1 substituents by
modification of the cinchona-alkaloid scaffold and/or the R2
substituent (9e and 9m). The effect of changes to the
counterion on both rate and enantioselectivity was minor.
For example, with catalyst 9a, the bis-bromide, bis-iodide, and
mixed salts all provided the product with 90% ee.
10
R1
Cl
R2
R3 R4
X
Y
11
ee [%]
10a
10b (4) Br
tBu
tBu
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
11a
11b (5) 92
11c
11d
94
10c
10d
10e
10 f
10g
10h
CO2Me tBu
92
96
Cl
Cl
Cl
Cl
H
tBu
tBu
Ph
Me
tBu
CH 11e
CH 11 f
CH 11g
90[a]
85[a]
65[a]
56[a]
CF3 CH
N
11h
[a] The absolute configuration was assigned by analogy to 5.
optimize the catalyst for each substrate. For example, the
enantioselectivity in the spirocyclization of 10h in Table 3
(56% ee) was improved to 85% ee by changing the cinchona-
alkaloid core from cinchonine to cinchonidine (Scheme 4).[12]
The traditional cinchona-alkaloid-based PTC 12, which is not
quaternized at N’, induced almost no enantioselectivity, thus
highlighting the unique reactivity and selectivity of this new
class of catalysts in enantioselective spirocyclization reactions
under phase-transfer catalysis.
The impact of the leaving group in 4 on the stereochemical
course of the reaction was studied (Scheme 3). Consistent
with the observations of Dolling et al., when the leaving
group was changed from a chloride to either a bromide or
a tosylate (OTs) group, the enantioselectivity of the spirocyc-
lization decreased significantly.[2,11]
Scheme 3. Effect of the leaving group.
To explore the potential of these novel catalysts, several
structurally related substrates were synthesized and evaluated
under similar spirocyclization conditions. In general, the
reactions proceeded smoothly in consistently high yield with
varying levels of enantioselectivity (Table 3). Various func-
tional groups at the C3 position of the pyridine ring (10a–c)
were well-tolerated; however, the replacement of the pyri-
dine ring with a substituted phenyl group led to a significant
decrease in the enantioselectivity (10h). In contrast, both
azaindoline and indoline substrates provided similar levels of
enantioselectivity (10a versus 10e). Notably, modification of
the R2 substituent (10e–g) had a profound effect on the
enantioselectivity, whereby a tert-butyl substituent consis-
tently afforded the highest level of selectivity.
Scheme 4. Optimization of the spirocyclization of 10h. [a] The abso-
lute configuration was assigned by analogy to 5.
As a testament to the remarkable reactivity of this new
class of catalysts, the loading of catalyst 9g in the spirocyc-
lization of 10a was reduced to as low as 0.30 mol% with
1.1 equivalents of a weak base while still achieving 100%
conversion in 3 h at about 08C, with no decrease in
enantioselectivity (Scheme 5). This catalyst loading is unpre-
cedented in reactions under cinchona-alkaloid phase-transfer
catalysis, which usually require 10–20 mol% of the catalyst.
Furthermore, the substrate concentration and stirring rate do
not appear to have a significant effect on the reaction yield
and ee value; thus, the reaction can be performed at high
concentration with gentle agitation. Optimized conditions
With three structural components that can be independ-
ently modified (the cinchona-alkaloid core, the N-substituent,
and the N’-substituent), there is tremendous opportunity to
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dron Lett. 1997, 38, 8595; d) E. J. Corey, F.-Y. Zhang, Org. Lett.
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[5] I. M. Bell, C. A. Stump, S. N. Gallicchio, D. D. Staas, C. B.
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Scheme 5. Optimized asymmetric alkylation.
[7] For reviews on phase-transfer catalysis, see: a) T. Ooi, K.
Maruoka, Angew. Chem. 2007, 119, 4300; Angew. Chem. Int.
Ed. 2007, 46, 4222; b) S.-s. Jew, H.-g. Park, Chem. Commun.
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M. Waser, Tetrahedron 2014, 70, 1935.
[8] Enantioselectivity of product 5 ranged from 0 to 58% ee.
Selected results are presented in the Supporting Information
for an initial cyclization with PTCs, including a Maruoka catalyst
and dimeric monoquaternized cinchona-alkaloid catalysts devel-
oped by Park, Jew, and co-workers: a) T. Ooi, M. Kameda, K.
Maruoka, J. Am. Chem. Soc. 1999, 121, 6519; b) H.-g. Park, B.-S.
Jeong, M.-S. Yoo, J.-H. Lee, M.-k. Park, Y.-J. Lee, M.-J. Kim, S.-s.
Jew, Angew. Chem. 2002, 114, 3162; Angew. Chem. Int. Ed. 2002,
41, 3036.
have been successfully applied at a large scale to demonstrate
the robustness and practicality of this catalyst.
In summary, we have discovered a new class of cinchona-
alkaloid-based phase-transfer catalysts, which are quaternized
at both the quinuclidine nitrogen and the quinoline nitrogen.
These catalysts demonstrate unprecedented reactivity and
enantioselectivity in the spirocyclization of substrates such as
compound 4. The reaction is robust, mild, and environ-
mentally friendly. These catalysts are readily prepared from
commercially available cinchona alkaloids and alkyl halides,
and preliminary experiments in our laboratories suggest that
they may open new avenues in the area of asymmetric
transformations. Detailed studies on the mechanism/kinetics
of this catalysis and applications to other reactions will be
reported in due course.
[9] Although studies have been reported on N,N’-doubly quater-
nized cinchona alkaloids, there is no precedent for their
application as phase-transfer catalysts (references are listed in
the Supporting Information).
Received: April 9, 2014
[10] All of the N,N’-doubly quaternized cinchona-alkaloid-based
catalysts were readily prepared from commercially available
cinchona alkaloids in one or two steps. All cinchona alkaloids
had a mixture of ethyl and vinyl functional groups at C3 of the
quinuclidine moiety, unless specifically mentioned. We observed
no difference in reactivity or enantioselectivity between 9g with
a mixture of ethyl and vinyl groups at C3 and the corresponding
pure C3-ethyl-substituted compound 9g.
[11] Recently, new calculated transition state modeling of the PTC
including the leaving group effect was reported: E. de Freitas,
J. R. Pliego, Jr., ACS Catal. 2013, 3, 613.
[12] Owing to the pseudoenantiomeric nature of cinchonidine with
respect to cinchonine, the absolute configuration of product 11
was opposite to that of the product obtained with 9g; A.
Bhattacharya, U.-H. Dolling, E. J. J. Grabowski, S. Karady,
K. M. Ryan, L. M. Weinstock, Angew. Chem. 1986, 98, 442;
Angew. Chem. Int. Ed. Engl. 1986, 25, 476.
Published online: && &&, &&&&
Keywords: asymmetric synthesis · enantioselectivity ·
.
organocatalysis · phase-transfer catalysis · spiro compounds
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[3] The first asymmetric application of a cinchona-alkaloid-based
PTC was reported for the enantioselective oxidation of unsatu-
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4
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Communications
Phase-Transfer Catalysis
B. Xiang,* K. M. Belyk, R. A. Reamer,
N. Yasuda*
&&&& — &&&&
Discovery and Application of Doubly
Quaternized Cinchona-Alkaloid-Based
Phase-Transfer Catalysts
A doubly positive development: N,N’-
Disubstituted cinchona alkaloids were
found to be highly efficient phase-transfer
catalysts for the assembly of stereogenic
quaternary centers. In comparison to
traditional cinchona-alkaloid phase-
transfer catalysts they afforded substan-
tial improvements in enantioselectivity
and reactivity in intramolecular spirocyc-
lization reactions at catalyst loadings as
low as 0.3 mol% under mild conditions
(see example).
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