Enantioselective Cycloaddition of Styrenes with Aldimines Catalyzed by a Chiral Magnesium Potassium Binaphthyldisulfonate Cluster as a Chiral Br?nsted Acid Catalyst

Article abstract of DOI:10.1021/jacs.7b04795

A chiral magnesium potassium binaphthyldisulfonate cluster, as a chiral Br?nsted acid catalyst, was shown to catalyze an enantioselective cycloaddition of styrenes with aldimines for the first time. The strong Br?nsted acidity of the catalyst precursors,

Full text of DOI:10.1021/jacs.7b04795

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Communication
Enantioselective Cycloaddition of Styrenes with
Aldimines Catalyzed by a Chiral Magnesium Potassium
Binaphthyldisulfonate Cluster as a Chiral Brønsted Acid Catalyst
Manabu Hatano, Keisuke Nishikawa, and Kazuaki Ishihara
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 30 May 2017
Downloaded from http://pubs.acs.org on May 30, 2017
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Enantioselective Cycloaddition of Styrenes with Aldimines
Catalyzed by a Chiral Magnesium Potassium Binaphthyldisul-
fonate Cluster as a Chiral Brønsted Acid Catalyst
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Manabu Hatano, Keisuke Nishikawa, Kazuaki Ishihara*
Graduate School of Engineering, Nagoya University, Furoꢀcho, Chikusa, Nagoya 464ꢀ8603, Japan
Supporting Information Placeholder
reported (Eq. 1).10 We envisioned that, to promote the
ABSTRACT: A chiral magnesium potassium binaphꢀ
reaction of interest, chiral strong Brønsted acids should
be effective, since (1) simple styrenes, which are regardꢀ
ed as relatively weak nucleophiles,11 could be used
without direct activation by the catalysts and (2) fragꢀ
mentation of the tꢀBu moiety is involved.
thyldisulfonate cluster, as a chiral Brønsted acid catalyst,
was shown to catalyze an enantioselective cycloaddition
of styrenes with aldimines for the first time. The strong
Brønsted acidity of the unoptimized catalystꢀprecursors,
which might dissolve drying agents and take up the
leached Mg2+ and K+, led to serendipitous results.
Mechanistic aspects were supported by Xꢀray and ESIꢀ
MS analysis of the catalyst and a kinetics study of the
reaction. Useful transformations to optically active 1,3ꢀ
amino alcohols on a gram scale were also demonstrated.
We initially examined the reaction of styrene 3a with
NꢀBoc aldimine 2a through the use of (R)ꢀ3,3’ꢀ(4ꢀtꢀ
BuC6H4)2ꢀBINSA 1a (5 mol%) in 1,2ꢀdichloroethane at
0 °C for 5 h (Table 1, also see the SI). With the use of
(R)ꢀ1a alone, the reaction was slow and synꢀ4a was obꢀ
tained with poor enantioselectivity along with antiꢀ4a,
double adduct 5a, and hydrolyzed 7a (entry 1). When
we used MgSO4 to prevent the hydrolysis to 7a by adꢀ
ventitious water, the enantioselectivity of synꢀ4a was
temporarily improved, although reproducibility was not
observed and 6a and 7a were still obtained by overreacꢀ
tion and hydrolysis, respectively (entry 2). We then susꢀ
pected that Mg2+ was being leached from MgSO4 due to
the strong acidity of (R)ꢀ1a. Therefore, we used a
In modern asymmetric catalysis, chiral Brønsted acid
catalysts with (R)ꢀ or (S)ꢀbinaphthyl skeletons have been
used as practical organocatalysts.1 Since the suitable
Brønsted acidity of the catalysts is different for each
substrate and reagent to promote the desired reactions,
fine tuning of the acidity as well as fine stereoꢀtuning of
the catalysts are very important. In this regard, we have
recently developed a practical synthesis of chiral 3,3’ꢀ
Ar2ꢀBINSA (1,1’ꢀbinaphthaleneꢀ2,2’ꢀdisulfonic acid) 1,2
which might have both strong Brønsted acidity3 and sufꢀ
ficient bulkiness for asymmetric induction. Here, we
report for the first time an asymmetric catalysis that uses
chiral 3,3’ꢀAr2ꢀBINSAs 1 in the presence of magnesium
and potassium sources through a somewhat interesting
scenario.4,5 In particular, we focused on the enantioseꢀ
lective cycloaddition of styrenes with NꢀBoc aldimines,
which has been originally developed by Hossain in an
achiral manner using HBF4·Et2O (Eq. 1).6 Indeed, chiral
oxazinanones sometimes have biological activities,7 and
are useful as chiral auxiliaries and precursors of chiral
1,3ꢀamino alcohols.8 Nevertheless, while catalytic enanꢀ
tioselective oxazinanone synthesis has not been reportꢀ
ed,9 a few examples of a catalytic enantioselective
iminoꢀene reaction of αꢀmethylstyrenes have been
Table 1. Optimization of the catalystsa
yield
of 4
(%)
ee of
syn-4a of 5
(%)
yield yield yield
additive
(mol%)
syn:anti
of 4a
entry
of 6
(%)
of 7
(%)
(%)
1
2
3
–
52
76:24
–4
4
0
13
MgSO4
38~59 89:11~93:7 28~70 5~10 5~10 15~20
73
Mg(OEt)2 (5)
Mg(OEt)2 (5)
MS 3A
Mg(OEt)2 (3.3)
KOtꢀBu (10)
Mg(OEt)2 (3.3)
KOt-Bu (10)
MS 3A
92:8
48
0
0
0
4
5
90
94:6
78
4
0
0
56
>99:<1
95
0
0
20
6
91
>99:<1
96
4
0
0
a The reaction was carried out with (R)ꢀ1a (10 mol%), 2a (0.2 mmol),
3a (4 mmol), and additives in 1,2ꢀdichloroethane at 0 °C for 5 h.
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Scheme 1. Reactions of simple styrene 3a with a variety of
Scheme 2. Reactions of a variety of styrene derivatives 3b–
g with NꢀBoc aldimines 2.
NꢀBoc aldimines 2.a
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2
3
4
5
6
7
8
Products synꢀ4, yield, ratio of syn:anti, and enantioselectivity of synꢀ4.
Products 8, reaction time, yield, and enantioselectivity.
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yields (80–100%). In particular, the tolerance of steriꢀ
cally hindered orthoꢀsubstituted compounds such as 2e
(oꢀCF3C6H5), 2f (oꢀBrC6H5), 2g (oꢀIC6H5), 2k (1ꢀ
naphthyl), and 2n (3ꢀbenzothienyl) was remarkable.
Moreover, we examined the scope of styrene derivatives
3b–g (Scheme 2). As a result, not only simple 4ꢀ
methylstyrene (3b) and sterically hindered 2ꢀ
methylstyrene (3c), but also 4ꢀ(chloromethyl)styrene
(3d) and less nucleophilic 4ꢀbromostyrene (3e) could be
used. The steric effect of 1ꢀvinylnaphthalene (3f) did
not affect the yield, syn/antiꢀratio, or enantioselectivity.
Moreover, heteroaromatic 3ꢀvinylthiophene (3g) could
also be used successfully.
a
The reaction was carried out with (R)ꢀ1a (10 mol%), 2 (0.2 mmol),
and 3a (4 mmol) in 1,2ꢀdichloroethane with MS 3A at 0 °C for 5 h.
catalyst, which was prepared from (R)ꢀ1a (10 mol%)
and Mg(OEt)2 (5 mol%). As a result, synꢀ4a was obꢀ
tained reproducibly in moderate yield with 48% ee (enꢀ
try 3). Interestingly, the addition of MS 3A to the cataꢀ
lyst provided synꢀ4a with 78% ee (entry 4). Again, we
suspected that K+ was being leached due to the strong
acidity of the (R)ꢀ1a–Mg complex, since MS 3A is
K9Na3[(AlO2)12(SiO2)12] (see the SI). Therefore, we
used a catalyst prepared from (R)ꢀ1a (10 mol%),
Mg(OEt)2 (3.3 mol%), and KOtꢀBu (10 mol%). As a
result, synꢀ4a was obtained in 56% yield with 95% ee
without the generation of antiꢀ4a (entry 5). Finally, the
use of MS 3A prevented the generation of undesired 7
(see the SI including ICPꢀOES analysis), synꢀ4a was
exclusively obtained in 91% yield with 96% ee (entry 6).
Overall, strong acids may trigger unexpected excellent
results or invalidate the evaluations in the presence of
common drying agents.4,12
Next, the αꢀ or βꢀMeꢀsubstituent effect on the vinyl
moiety of styrene was examined (also see the SI). The
reaction of αꢀmethylstyrene 9 with aldimine 2g provided
the corresponding cycloadduct 10 in 81% yield (syn:anti
= 95:5) with 85% ee for synꢀ10 (Eq. 2). Moreover,
transꢀβꢀmethylstyrene
(transꢀ11)
and
cisꢀβꢀ
methylstyrene (cisꢀ11) were examined (Eq. 3). As a reꢀ
sult, from transꢀ11, 1,3ꢀsyn-2,3ꢀantiꢀ12 was obtained
exclusively in 62% yield with 99% ee. In contrast, the
We next examined the scope of NꢀBoc aldimines 2b–n
in the presence of the optimized 3:1:3 complex of (R)ꢀ
1a/Mg/K (Scheme 1). As a result, 2b–j with a variety of
orthoꢀ, metaꢀ, or paraꢀsubstituted aryl moieties, 2k with
a 1ꢀnapththyl moiety, 2l with a 2ꢀnaphthyl moiety, and
2k and 2l with a heteroaryl moiety could be used, and
the corresponding synꢀ4a–n were exclusively obtained
with excellent enantioselectivities (91–99% ee) in high
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Scheme 3. Transformations to 1,3ꢀamino alcohols.
reaction of cisꢀ11 with 2g was sluggish, and 1,3ꢀsyn-2,3ꢀ
synꢀ12 was obtained as a sole product, although enantiꢀ
oselectivity was not induced. These trans/cisꢀretention
results strongly indicated that the reaction might proceed
via a concerted pathway as seen Eq. 1, and a stepwise
pathway involving a benzyl cation is unlikely.
1
2
3
4
5
6
As another application of styrene derivatives, indene
13 was examined (Eq. 4). As a result, the corresponding
product synꢀ14 was obtained with good enantioselectiviꢀ
ty in the presence of the (R)ꢀ1aꢀderived catalyst (77%
ee). The use of (R)ꢀ1bꢀderived catalyst (Ar = 4ꢀPhC6H4)
improved the enantioselectivity (82% ee). Fortunately,
recrystallization of synꢀ14 increased the enantioꢀpurities
to 98% ee without any serious loss of yield.
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Next, we performed some transformations to synthetiꢀ
cally useful 1,3ꢀamino alcohols8b to validate our catalytꢀ
ic system (Scheme 3, Eqs. 5–7). First, transformations
to synꢀ and antiꢀ1,3ꢀamino alcohols 15 were demonstratꢀ
ed. Hydrolysis of synꢀ4a afforded corresponding synꢀ15
in 98% yield without a loss of optical purity (Eq. 5). On
the other hand, transformation to antiꢀ15 was also
achieved in five steps in good yields (Eq. 6). A key step
is the Mitsunobu reaction, in which diꢀ2ꢀmethoxyethyl
showed no catalytic activity in a probe reaction (Eq. 8).
However, addition of TfOH (see the SI) restored the catꢀ
alytic activity through H+ꢀexchange, and synꢀ4a was
obtained in 58% yield with 90% ee (Eq. 9). Actually,
the Brønsted acid part of the optimized 3:1:3 complex of
(R)ꢀ1a/Mg/K might be essential, since the addition of
methallyltrimethylsilane or sterically hindered 2,6ꢀtꢀBu2ꢀ
pyridine, both of which would selectively react on H+,
completely deactivated the catalytic activity in the probe
reaction (Eq. 10). In contrast, the use of (R)ꢀ1a (10
mol%), Mg(OEt)2 (3.3 mol%), and KOtꢀBu (6.6 mol%)
which would lead to the corresponding 3:1:2 complex of
(R)ꢀ1a/Mg/K with two Brønsted acid parts, still showed
high catalytic activity (85% yield and 89% ee of synꢀ4a)
(Eq. 11), although the result was slightly inferior to that
with the optimized catalyst. Overall, the Xꢀrayꢀanalyzed
cluster 22 might be an inactive species, and a similar
structural cluster with active H+ in place of inactive K+
might be considered to be an active catalyst in situ.
azodicarboxylate
(DMEAD)13
and
Nꢀ
hydroxyphthalimide were carefully selected to suppress
an undesired spontaneous elimination reaction that
would give undesired β,γꢀunsaturated amide. Moreover,
we performed a formal total synthesis of bioactive 1,3ꢀ
amino alcohol 21,14 which is a drug candidate for neuroꢀ
pathic pain due to its NMDA receptor antagonistic activꢀ
ity (Eq. 7).15 Actually, a 1.5 gꢀscale cycloaddition of 3b,
which used only 2 molar equivalents to 2g, was conꢀ
ducted with a reduced amount of catalyst (5 mol%). As
a result, the desired synꢀ8d was obtained with 96% ee.
Consequently, Manabe’s palladiumꢀcatalyzed carbocyꢀ
clization16 of synꢀ8d provided tricyclic amide 18 quantiꢀ
tatively. After the hydrolysis of 18, the Mitsunobu reacꢀ
tion of 19 followed by N–O bond cleavage afforded 0.70
g of the key compound 20 with 98% ee.
Figure 1. Xꢀray analysis of a 3:1:4 complex of (R)ꢀ1a/Mg/K 22.
Finally, we turn our attention to mechanistic aspects.
We tried to crystallize the optimized 3:1:3 complex of
(R)ꢀ1a/Mg/K for Xꢀray structural analysis.5 As a result,
we instead obtained a 3:1:4 aqua complex of (R)ꢀ
1a/Mg/K (22) (Figure 1, also see the SI). The obtained
cluster 22 could be formally assembled by 2:2:1 and
1:0:2 complexes of (R)ꢀ1a/Mg/K and adventitious water.
As expected, due to the lack of a Brønsted acid part (i.e.,
SO3H), the cluster 22 itself (or the use of (R)ꢀ1a (10
mol%), Mg(OEt)2 (3.3 mol%), and KOtꢀBu (13.3mol%))
Ar
Ar
O
OH2
K
O
O
S
S
O
O
O
O
O
Mg
O
O
S
S
O
O
K
Ar
Ar
OH2
K
K
O
O
O
O
S
S
Ar
Ar
OO
Mg
S
K
O
Ar = 4-t-BuC6H4
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Funding Sources
1
2
The authors declare no competing financial interest.
3
4
ACKNOWLEDGMENT
Dedicated to Prof. Teruaki Mukaiyama in celebration of his
90th birthday (Sotsuju). This work was financially supꢀ
ported by JSPS KAKENHI Grant Numbers JP26105723,
JP17H03054 and JP15H05810 in Precisely Designed Cataꢀ
lysts with Customized Scaffolding.
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To consider the active species in situ, ESIꢀMS analysis
of the catalyst was carried out. As a result, a variety of
BINSA trimers [m/z = 2150–2230], possibly with cluster
structures, were exclusively observed (see the SI).
Moreover, a kinetics study was conducted for a 3:1:3
complex of (R)ꢀ1a/Mg/K, 2a, and 3a. The results
showed firstꢀorder dependency for the catalyst as well as
zeroꢀorder dependency for 2a and firstꢀorder dependenꢀ
cy for 3a (Figure 2, also see the SI). This may support
the presence of a 3:1:3 complex of (R)ꢀ1a/Mg/K, and the
rateꢀdetermining step might be the addition of 3a to acꢀ
tivated 2a. At this preliminary stage, possible transition
states cannot be considered, since the position of the
active site (H+) has not been specified, although the
Brønsted acid center itself should be essential.
(2) (a) Hatano, M.; Sugiura, Y.; Ishihara, K. Tetrahedron: Asymmetry
2010, 21, 1311. (b) Hatano, M.; Ozaki, T.; Nishikawa, K.; Ishihara, K. J.
Org. Chem. 2013, 78, 10405. (c) Hatano, M.; Ishihara, K. Asian J. Org.
Chem. 2014, 3, 352. Also see our original paper of 3,3’ꢀunsubstituted
BINSA. (d) Hatano, M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara,
K. J. Am. Chem. Soc. 2008, 130, 16858. (e) Hatano, M.; Sugiura, Y.;
Akakura, M.; Ishihara, K. Synlett 2011, 2011, 1247. (f) Hatano, M.; Ozaꢀ
ki, T.; Sugiura, Y.; Ishihara, K. Chem. Commun. 2012, 48, 4986.
(3) pKa (DMSO) of (R)ꢀ3,3’ꢀunsubstituted BINSA is –9.06. Yang,
C.; Xue, X.ꢀS.; Li, X.; J.ꢀP. Cheng, J. Org. Chem. 2014, 79, 4340.
(4) We had a similar experience during the development of chiral
calcium phosphates (a) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara,
K. Angew. Chem. Int. Ed. 2010, 49, 3823. Also see, (b) Klussmann, M.;
Ratjen, L.; Hoffmann, S.; Wakchaure, V.; Goddard, R.; List, B. Synlett
2010, 2010, 2189. (c) Terada, M.; Kanomata, K. Synlett 2011, 2011,
1255. (d) Akiyama, T. Synlett 2016, 27, 542.
(5) Shibasaki pioneeringly developed chiral heterobimetallic
M3[Ln(binol)3] catalysts for a variety of asymmetric reactions. See a
review, Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
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Daniliuc, C.ꢀG.; Mancheño, O. G. Angew. Chem. Int. Ed. 2012, 51,
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Figure 2. Kinetics study for the catalyst, 2a, and 3a.
y = 1.18x – 1.82
y = 0.0135x – 3.17
y = 0.978x – 8.24
ln [3:1:3 catalyst (mM)]
ln [2a (mM)]
ln [3a (mM)]
In summary, we have developed for the first time a
chiral magnesium potassium binaphthyldisulfonate clusꢀ
ter, which can catalyze a highly enantioselective cyꢀ
cloaddition of styrenes with aldimines. We serendipiꢀ
tously discovered that the strong Brønsted acidity of
unoptimized catalysts dissolved drying agents and took
up leached Mg2+ and K+. Mechanistic insights were
supported by Xꢀray, ESIꢀMS and ICPꢀOES analyses of
the clusters, a kinetics study, and control experiments.
Moreover, synthetically useful transformations to optiꢀ
cally active 1,3ꢀamino alcohols on a gram scale were
demonstrated.
(11) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
(12) We investigated chiral BINSAꢀcatalyses in our previous reports
(refs. 2d–f). However, no leaching effect was observed. See the SI.
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dron 2009, 65, 6109.
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ASSOCIATED CONTENT
Experimental procedures and characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: ishihara@cc.nagoyaꢀu.ac.jp
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ACS Paragon Plus Environment