Asymmetric Aminalization via Cation-Binding Catalysis

Article abstract of DOI:10.1002/chem.201703800

Asymmetric cation-binding catalysis, in principle, can generate “chiral” anionic nucleophiles, where the counter cations are coordinated within chiral environments. Nitrogen nucleophiles are intrinsically basic, therefore, its use as nucleophiles is often challenging and limiting the scope of the reaction. Particularly, a formation of configurationally labile aminal centers with alkyl substituents has been a formidable challenge due to the enamine/imine equilibrium of electrophilic substrates. Herein, we report enantioselective nucleophilic addition reactions of potassium phthalimides to Boc-protected alkyl- and aryl-substituted α-amido sulfones. In situ generated imines smoothly reacted with the nitrogen nucleophiles to corresponding aminals with good to excellent enantioselectivitiy under mild reaction conditions. In addition, transformation of aminal products gave biologically relevant pyrrolidinone-fused hexahydropyrimidine scaffold with excellent stereoselectivity and good yield.

Full text of DOI:10.1002/chem.201703800

A Journal of
Accepted Article
Title: Asymmetric Aminalization via Cation-Binding Catalysis
Authors: Sang Yeon Park, Yidong Liu, Joong Suk Oh, Yoo Kyung
Kweon, Yong Bok Jeong, Yu Tan, Ji-Woong Lee, Hailong
Yan, and Choong Eui Song
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To be cited as: Chem. Eur. J. 10.1002/chem.201703800
Link to VoR: http://dx.doi.org/10.1002/chem.201703800
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COMMUNICATION
Asymmetric Aminalization via Cation-Binding Catalysis
Sang Yeon Park,+[a] Yidong Liu,+[b] Joong Suk Oh,[a] Yoo Kyung Kweon,[a] Yong Bok Jeong,[a] Mengying
Duan,[b] Yu Tan,[b] Ji-Woong Lee,*[c] Hailong Yan*[b] and Choong Eui Song*[a]
Abstract: Asymmetric cation-binding catalysis, in principle, can
generate “chiral” anionic nucleophiles, where the counter cations are
coordinated within chiral environments. Nitrogen-nucleophiles are
intrinsically basic, therefore, its use as nucleophiles is often
challenging and limiting the scope of the reaction. Particularly, a
formation of configurationally labile aminal centers with alkyl
be highly valuable in syntheses of numerous enanioenriched
nitrogen-based heterocycles.
a)
HO
O
O
H
H
N
H
H
H
H
R
H
N
H
H
HO
H
N
N
N
N
substituents has been
a formidable challenge due to the
H
N
N
O
H
Me
O
OH
H
enamine/imine equilibrium of electrophilic substrates. Herein, we
report enantioselective nucleophilic addition reactions of potassium
phthalimides to Boc-protected alkyl- and aryl-substituted α-amido
sulfones. In-situ generated imines smoothly reacted with the nitrogen
nucleophiles to corresponding aminals with good to excellent
enantioselectivitiy under mild reaction conditions. In addition,
transformation of aminal products gave biologically relevant
pyrrolidinone-fused hexahydropyrimidine scaffold with excellent
stereoselectivity and good yield.
OMe
palcernuine
(±)-tetraponerines
lycopalhine A
vernavosine
b)
C6H4OH
CH2
S
CH3
O
O
H
H
H
H
H
N
H
R
O
O
H
N
N
N
H
CH3COO H3N
N
H
N
N
H
H
H
H
CH3
H
O
O
O
C6H5
retro-inverso-analog of Enkephalin
PMRI
(-Glyy(NHCO)gly-)
Figure 1. a) Natural products with pyrrolidine-fused hexahydropyrimidines with
aminal stereogenic centers. b) Examples of PMRI.
Chiral aminals, or geminal diamines, are attractive structural
motifs in numerous natural products and pharmaceuticals.[1] For
example, pyrrolidine-fused hexahydropyrimidine frameworks
with aminal stereogenic centers are found in the skeletons of
many natural products (Figure 1a).[2] Acyclic N-protected chiral
aminals have also often been incorporated into peptide chains to
provide partially modified retro-inverso (PMRI) peptide mimics,
which can alter physical and chemical properties of
pharmacologically active peptides (Figure 1b).[3] Chiral Brønsted
acid can catalyze aminal formation reactions in high
enantioselectivity with aromatic imine substrates and nitrogen
nucleophiles (i.e. sulfonamides[4a] and imides[4b]).[4–6] However,
aminal stereogenic centers are difficult to access particularly
with aliphatic imine substrates due to the acidic a-protons and
rapid tautomerization under acidic conditions. Therefore, chiral
and strong Brønsted acids are presumably impotent to
generating aminal stereogenic centers for aliphatic imines.[7] It is
noteworthy that aminals with saturated carbons are more
pertinent structural motifs in biologically active molecules, since
their predominant aminal stereogenic centers are correspondent
to aliphatic substrates (see Fig. 1a). In addition, to the best of
our knowledge, there is no examples of functional group
transformation with enantioenriched aminal products, which can
In this study, we describe an asymmetric aminal formation
reaction from a-amido sulfones[8] as in-situ equivalents of
imines[9] with potassium phthalimides using our cation-binding
catalyst 1 (Figure 2).[10] The scope of this new catalytic protocol
was not limited to aromatic or heteroaromatic imines. Aliphatic
substrates, regardless the degree of branching, also provided
the desired aminals with excellent yields and ees. To the best of
our knowledge, this is the first successful preparation of chiral
primary, secondary, and tertiary aliphatic acyclic aminal
derivatives
in
high
enantiopurity.
Derivatization
of
enantioenriched aminals were also realized, showing the
unprecedented application potential of the enantiopure aminals
in asymmetric syntheses of natural products and biologically
active molecules.
Song's chiral oligoEGs
X
X
n
O
O
O
O
OH
HO
X
X
(R)-1: X = I, n = 1
[a]
[b]
[c]
[+]
S. Y. Park,[+] J. S. Oh, Y. K. Kweon, Y. B. Jeong, Prof. C. E. Song
Department of Chemistry, Sungkyunkwan University
Suwon, 440-746 (Korea)
Figure 2. Song’s chiral oligo ethylene glycol(EG)s.
E-mail: s1673@skku.edu
Y. Liu,[+] M. Duan, Y. Tan, Prof. H. Yan
Innovative Drug Research Centre, Chongqing University
Chongqing 401331 (China)
Asymmetric cation-binding catalysis is to generate reactive
"chiral" anions (nucleophiles) from achiral salts by binding to
their counter cations with a catalyst in the “chiral cage” of the
catalyst.[11] Recently, we have successfully expanded the scope
of cation-binding catalysis by employing Song’s chiral oligoEGs
(Figure 2),[10] in which the ether oxygens act as Lewis base to
coordinate metal ions such as K+, thus generating a soluble
chiral anion in a confined chiral space. Moreover, the terminal
phenol groups are capable of simultaneously activating
electrophiles by hydrogen bonding interactions. The resulted
E-mail: yhl198151@cqu.edu.cn
Prof. J. W. Lee
Department of Chemistry, University of Copenhagen
Universitetsparken 5, 2100 Copenhagen, (Denmark)
E-mail: jiwoong.lee@chem.ku.dk
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/chem.201703800
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self-assembled transition state leads to excellent stereoinduction
in asymmetric reactions; for example, in desilylative kinetic
resolution of silyl-protected secondary alcohols,[10b] asymmetric
Strecker reaction using potassium cyanide,[10c] kinetic resolution
of b-sulfonyl ketones through enantioselective b-elimination,[10d]
organocatalytic asymmetric synthesis of chiral dioxazinanes and
leaving group (-SO2Ph) is critical in both enhancing the reaction
rate and the enantioselectivity.[13] Therefore, we decided to use
the imine precursor for further study of aminal formation
reactions.
Boc
K
N
Boc
Boc
1
dioxazepanes
enantioselective
with
synthesis
in
situ
of
generated
anti−syn-trihalides
nitrones,[10e]
and
(R)-
HN
O
N
HN
(10 mol%)
O
O
or
N
SO2Ph
toluene
25 oC, 48 h
anti−syn−anti-tetrahalides via asymmetric β‑elimination,[10f] and
enantioselective glyoxalase I mimic catalytic isomerization of in-
situ generated hemithioacetals,[10g] etc. The vast application
potential of this catalytic system stimulated us to explore other
challenging asymmetric transformations with nucleophilic
anions.[10h] It is worth noted here that there was no cation-
binding catalysis with nitrogen-based nucleophiles prior to this
study. We presumed that cation-binding catalysis could be
suitable for the reaction of potassium phthalimide with α-amido
sulfones 2, in which potassium phthalimide, upon the activation
by the chiral cation-binding catalyst, may effectively serve as
both the base and the nucleophile for addition reactions.
O
2
3l
4l-1
25%, <5% ee with 2
99%, 98% ee with 3l
Scheme 1. Catalytic reaction with imine
2 and a-amido sulfone 3l as
substrates.
As mentioned previously, aliphatic substrates are
challenging with Brønsted acid catalysis, because of the facile
enamine formation and related by-products formed under acidic
environments.[7] To our delight, our reaction condition turned out
to be highly tolerant to the encarbamate formation. All
investigated alkyl chain substituted substrates including highly
challenging primary alkyl substituted substrates gave good to
excellent chemical yields and enantioselectivities (see 4a–4k in
Scheme 2). Moreover, the highly enantiomerically enriched
primary alkyl-substituted products (4b, 4e and 4f) were obtained
by a single recrystallization step similar to most of other aminal
First, we examined the bimolecular complexation; nitrogen
nucleophiles and catalyst (R)-1. 13C Spin-lattice relaxation time
(T1) decreased dramatically upon the complexation of 1 with
potassium phthalimide (Table 1). This indicates that the
complexation of the potassium cation with catalyst 1 reduced the
mobility of the ether units on the host (1). [12] Further evidence of
the complexation of the catalyst (1) with potassium phthalimide
was observed by ESI-HRMS (positive ion mode, calculated for
products
4 (see Supporting Information). However, highly
sterically demanding tertiary alkyl substrate 3k showed slower
reaction rates when potassium phthalimide was used (4k-1, 12%
conversion after 48 h) compared to other aliphatic substrates.
The reaction rate, however, was dramatically increased by
+
C46H34I4KO6 : 1228.8166; observed: 1228.8167) (see Supporting
Information, Figure S1).
Table 1. 13C Spin-lattice relaxation measurements[a]
changing the sterically bulky potassium phthalimide to
a
sterically less demanding potassium succinimide, (4k-2, 80%
conversion after 48 h). These results implies that the catalysis
proceeds in a sterically congested chiral cage, generated by
binding a potassium cation with the polyether backbone,
ensuring high enantio-induction. To the best of our knowledge,
this is the first catalytic preparation of chiral primary, secondary,
and tertiary aliphatic aminal derivatives, presumably due to the
mild acidity of the catalyst. The acitidty of the catalyst might be
enough to activate the substrates but not to facilitate the
tautomerization. For aromatic substrates, both the electron-
donating (3o–3u) and electron-withdrawing substituents (3v–3x)
on the aromatic ring were equally tolerated under the reaction
conditions. Electron-donating substituents in ortho-, meta-, or
para-positions were all shown to be excellent substrates for the
addition. Likewise, the use of electron withdrawing substituents
on the para-position of the phenyl-substituted imines also
afforded high yields and enantiomeric excess of the addition
products. Sterically demanding imine 3m was also smoothly
converted to the corresponding aminal 4m (91%, 95% ee).
Heteroaromatic substrates such as 3-thienyl (3y) and 3-pyridyl
(3z) also gave excellent yields and enantioselectivities. The
absolute configuration of 4v was unambiguously determined by
a single crystal X-ray structure analysis.[14] Moreover, X-ray
crystal structure can explain the configurational stability of
acyclic aminals obtained in this study. The aminals are stabilized
by intramolecular hydrogen bonding between BocNH proton and
T1 [s]
Sample (0.075 M)
C1
C2
C3
(R)-1
0.364
0.163
2.23
0.397
0.223
1.78
0.604
0.203
2.97
(R)-1/K+ salt (1/1)
T1 ((R)-1)/T1 (complex)
[a] The NMR experiments were performed in CDCl3 at 22 oC.
Confirming that a phthalimide anion can be associated
within the chiral ologoEGs, we performed catalytic reactions with
imine 2 as a model substrate. However, we observed only low
yield and disappointing enantioselectivity (25% yield, <5% ee,
Scheme 1). Notably, a-amido sulfone 3a – imine precursor –
showed complete conversion and excellent enantioselectivity
(99% yield, 98% ee) under same reaction conditions (see
Supporting Information for catalyst screening and reaction
conditions optimization). This result indicates that the sulfinate
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[a] Unless otherwise indicated, the reactions were performed with 3 (0.1–0.5
mmol), 1.1 equiv. of potassium phthalimide and (R)-1 catalyst (10 mol%) in
toluene at 25 oC. See Supporting Information for reaction condition
optimization study including catalyst screening. [b] Recrystallization from
methylcyclohexane. [c] Using (S)-1 catalyst. [d] Reaction was performed on a
1.2 gram scale.
carbonyl oxygen atom of phthaimide group (length: NH---O =
2.705 Å, see SI for structural information of 4v).[15]
Scheme 2. Substrate scope of the 1,2-addition of imide with aliphatic and
aromatic a-amido sulfones 3a–3z[a]
Boc
O
HN
O
To demonstrate the synthetic utility of the obtained chiral
aminals, we attempted asymmetric syntheses of pyrrolidine-
fused hexahydropyrimidine scaffold, which are found in the
skeletons of many natural alkaloids (Figure 1a).[2] Chemo-
selective reductions of 4l-1, 4n and 4w with NaBH4 afforded
N,O-hemiaminals 5 with low diastereoselectivity (dr = 1.6:1 –
2:1). However, in the reaction mixture, compounds 5 are in
equilibrium between N,O-acetal and aldehyde, which will be
consumed selectivity when it is in the aldehyde form. Gratifyingly,
upon the addition of Wittig reagents (Ph3P=CHC(O)OMe or
Ph3P=CHC(O)SEt) to aldehyde form, the resulting products
rapidly underwent tandem diastereoselective 1,4-addition
reaction, affording single diastereomeric β-amino ester 6 and β-
amino thioesters 7. In the case of thioesters 7, we observed
Boc
(R)-1 (10 mol%)
HN
R
N
+
K N
toluene
25 oC, 48 h
R
SO2Ph
O
O
3a-3z
Boc
4a-4z
Boc
Boc
O
HN
HN
HN
O
O
N
N
Ph
N
O
O
O
4a
4b
4c
49%, 77% ee
92%, 94% ee
84%, 76% ee
60%, 98% ee[b]
Boc
Boc
O
Boc
HN
HN
HN
O
O
Cl
I
N
Cl
N
N
O
O
O
4d
4e
4f
91%, 81% ee
90%, 84% ee
92%, 83% ee
68%, 99% ee[b]
Boc
62%, 93% ee[b]
Boc
O
Boc
HN
HN
HN
O
O
simultaneously
cyclized
in-situ
to
furnish
N
N
N
hexahydropyrimidinopyrrolidines 8 as a single diastereomer in
good yields (58–65% yields over 2 steps, see Supporting
Information for experimental and calculation details) (Scheme 3).
Furthermore, we performed the deprotection of Boc group of
compound 8n using 1M HCl in Et2O solution afforded the free
amine compound without epimerization (see Supporting
Information for details). The tricyclic core of aminals 8 can be a
valuable synthon, recognizing that further derivatization is
amenable on two differentiated carbonyls, Boc-protecting group
and the secondary amine. The absolute configuration of 6n was
determined to be (S,S) by X-ray single crystallography. The
absolute configuration of 7 was assigned by analogy.[16]
O
4g
O
O
4h
4i
98%, 87% ee
99%, 86% ee
91%, 96% ee
70%, 99% ee[b]
Boc
Boc
Boc
HN
O
HN
O
HN
O
N
N
N
O
O
O
4k-2
80%, 75% ee
4j
4k-1
12%, 74% ee
71%, 91% ee
Boc
Boc
Boc
HN
O
HN
O
HN
O
N
N
N
O
O
O
4l-2
70%, 99% ee
4l-1
4m
99%, 98% ee
91%, 95% ee
99%, -98% ee[c]
Boc
O
Boc
O
Boc
O
HN
HN
HN
Boc
Boc
Boc
N
HN
HN
HN
OH
O
N
N
N
H
O
NaBH4
R
R
R
N
NH
THF/MeOH
0 oC, 2 h
91-93%
O
O
O
O
O
O
4n
4o
4p
90%, 99% ee
89%, 99% ee[d]
Boc
96%, 99% ee
91%, 93% ee
dr = 1.6:1–2:1
96% ee, 99% ee
5n,
99% ee, 99% ee
5l-1,
4l-1 (R=Ph) = 98% ee
Boc
Boc
4n
(R=2-Naph) = 99% ee
4w (R=4-Cl-Ph) = 95% ee
HN
NH
O
O
HN
O
5w, 91% ee, 91% ee
N
N
N
O
O
EtS
NH
O
Boc
NH
Boc
O
O
HN
Boc
O
PPh3
N
O
EtS
4q
4r
4s
R
R
N
96%, 92% ee
95%, 91% ee
94%, 93% ee
R
N
toluene
reflux, 96 h
SEt
Boc
O
O
Boc
Boc
HN
O
HN
HN
O
O
O
N
N
N
stereoselective
conjugat addition
7
8,
58–65% yields
a single diastereomer
(over 2 steps from 5)
= Ph, 2-Naph, 4-Cl-Ph
not isolated
O
MeO
F
O
O
OMe
R
4t
4u
4v
94%, 97% ee
97%, 95% ee
Boc
90%, 89% ee
Boc
Boc
NH
O
CO2Me
HN
HN
O
O
PPh3
MeO
N
O
N
N
toluene
reflux, 48 h
Cl
Br
O
O
4w
4x
6n,
91%
a single diastereomer
89%, 94% ee
95%, 90% ee
Boc
O
Boc
O
HN
HN
Scheme 3. Utility of chiral aminals in the enantioselective synthesis of some
N
N
pyrrolidine-fused hexahydropyrimidines.
S
N
O
O
4y
90%, 91% ee
4z
99%, 93% ee
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Boc
Boc
Our proposed catalytic mechanism depicted in Fig. 3
involves initial simultaneous activation of potassium phthalimide
and amido sulfone by the catalyst. Subsequently, the
coordinated phthalimide anion can eliminate the potassium
sulfinate from the substrate, generating a catalyst-bound imine
(H-bonded). We confirmed the formation of imine by 1H-NMR
spectroscopy (see Supporting Information, Figure S2).
Subsequently, phthalimide 9 (HNR2 in Figure 3) is able to react
with the imine, with high enantioselectivity, providing aminals (up
to 99% ee). The coordination of potassium sulfinate within the
catalyst cavity seems vital, based on the experimental data and
previous mechanistic studies.
(R)-1
(10 mol%)
HN
O
N
+
conditions
N
toluene
25 oC, 48 h
O
2
4l-1
O
O
+ HSO2Ph
+ KSO2R (10)
73%, >99% ee
68%, 94% ee (100 mol% of 10a)
89%, 94% ee (10 mol% of 10b)
N
H
NK
no additive
25%, <5% ee
O
O
9
C12H25
KSO2
10a
KSO2
I
10b
O
O
I
O
K+
O
Scheme 4. Critical effects of potassium sulfinate for the catalysis.
O
H
O
I
H
NR2
I
O
O
H
S
Ph
N
O
According to the above experimental results, an
incorporation of the potassium sulfinate is critical. As
R
OtBu
a
cocatalyst, sulfinate anions induced high reactivity and high
enantioselectivity, perhaps by increasing the proximity of
substrates. The complexation of potassium sulfinate with the
catalyst was also confirmed in the measurements of 13C spin-
lattice relaxation (T1) and ESI-HRMS (see Supporting
Information, Table S2 and Figure S3). Furthermore, a linear
relationship was observed between the optical purity of catalyst
(R)-1 and product 4i (see Supporting Information, Figure S4),
I
O
O
I
O
K+
O
O
O
H
O
H
H
I
I
O
NR2
S
N
O
Ph
OtBu
R
indicating that
a single catalyst involves in the enantio-
Figure 3. Plausible reaction transition state.
determining step, supporting our proposed model shown in
Figure 3.
In summary, we developed a new asymmetric nucleophilic
addition of potassium phthalimide with α-amido sulfones as
imine surrogates, catalyzed by Song’s chiral oligoEGs 1 as a
cation-binding catalyst. Diverse chiral acyclic aminals were
prepared in excellent yields and enatioselectivities (up to 99%
ee). In particular, our protocol renders unprecedented and
challenging substrate scope, particularly, aliphatic substrates,
which are predominant in molecular scaffold of many natural
products. A densely confined chiral space can be formed in-situ
by the incorporation of potassium salt, which enables highly
enantio- and chemoselective catalysis. We demonstrated
synthetic utility of the current methodology by preparing
biologically relevant product, possessing aminal and
polyheterocyclic cores.
To support this hypothesis, pre-isolated imine 2 were
reacted with phthalimide 9 in the presence of additional
potassium arene sulfinates 10. Potassium sulfinate salts are in
general not soluble in organic solvents, however, the
complexation of cation-binding catalyst 1 and the sulfinate salt is
expected in catalytic amounts. We obtained 94% ee of the
desired product with 100 mol% of insoluble sulfinate 10a,
mimicking the optimized reaction conditions. In addition, catalytic
amounts (10 mol%) of soluble sulfinate 10b was found to be
effective to afford identical enantioselectivity (94% ee, Scheme
4). These reactions indicate that the nucleophile of the
enantioselective reaction is phthalimide 9. Also, under otherwise
identical reaction conditions, imine 2 failed to give observable
conversion and enantioselectivity without the addition of
sulfinate ion. Lastly, but not the least, the pre-mixture of
potassium phthalimide and sulfinic acid furnished 99% ee of the
product (73% yield) under catalytic conditions, which highlight
the importance of the sulfinate anion in the enantiodetermining
step and catalytic activity as well.
Experimental Section
General catalytic procedure. An ordinary vial equipped with a magnetic
stirring bar, was charged with α-amido sulfone 3 (0.10 mmol), potassium
phthalimide (40.7 mg, 0.11 mmol) and the catalyst (R)-1 (11.9 mg, 0.01
mmol). Toluene (1.0 mL) was added at room temperature. After stirring
for 48 h, the mixture was filtered and purified by silica gel
chromatography (acetone/hexanes = 1/8) to afford the corresponding
chiral aminal 4.
Acknowledgements
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10.1002/chem.201703800
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[8]
[9]
For reviews, a) M. Petrini, Chem. Rev. 2005, 105, 3949–3977; b) B. Yin,
Y. Zhang, L. W. Xu, Synthesis 2010, 3583–3595.
This study was supported by the Ministry of Science, ICT and
Future Planning in Korea (NRF-2014R1A2A1A01005794 and
NRF-2016R1A4A1011451), the Fundamental Research Funds
for the Central Universities in China (Grant No: 0236015205004)
and the Scientific Research Foundation in China (Grant No:
0236011104404).
For
a review on catalytic asymmetric reactions with carbamate-
protected imines, see: J. Vaseley, R. Rios, Chem. Soc. Rev. 2014, 43,
611–630.
[10] a) J.-W. Lee, H. Yan, H. B. Jang, H. K. Kim, S. W. Park, S. Y. Lee, D. Y.
Chi, C. E. Song, Angew. Chem., Int. Ed. 2009, 48, 7683–7686; b) H.
Yan, H. B. Jang, J.-W. Lee, H. K. Kim, S. W. Lee, J. W. Yang, C. E.
Song, Angew. Chem., Int. Ed. 2010, 49, 8915–8917; c) H. Yan, J. S.
Oh, J.-W. Lee, C. E. Song, Nat. Commun. 2012, 3, 1212; d) L. Li, Y. Liu,
Y. Peng, L. Yu, X. Wu, H. Yan, Angew. Chem., Int. Ed., 2016, 55, 331–
335; e) Y. Liu, J. Ao, S. Paladhi, C. E. Song, H. Yan, J. Am. Chem.
Soc., 2016, 138, 16486–16492; f) Y. Tan, S. Luo, D. Li, N. Zhang, S.
Jia, Y. Liu, W. Qin, C. E. Song, H. Yan, J. Am. Chem. Soc., 2017, 139,
6431–6436; g) S. Y. Park, I. S. Hwang, H. J. Lee, C. E. Song, Nat.
Commun. 2017, 8, 14877; h) S. Y. Park, J. W. Lee, C. E. Song, Nat.
Commun. 2015, 6, 7512; i) V. Vaithiyanathan, M. J. Kim, Y. Liu, H. Yan,
C. E. Song, Chem. Eur. J., 2017, 23, 1268–1272; j) M. J. Kim, L. Xue, Y.
Liu, S. Paladhi, S. J. Park, H. Yan, C. E. Song, Adv. Synth. Catal., 2017,
359, 811–823; k) L. Yu, X. Wu, M. J. Kim, V. Vaithiyanathan, Y. Liu, Y.
Tan, W. Qin, C. E. Song, H. Yan, Adv. Synth. Catal., 2017, 359, 1879–
1891; l) M. Duan, Y. Liu, J. Ao, L. Xue, S. Luo, Y. Tan, W. Qin, C. E.
Song, H. Yan, Org. Lett., 2017, 19, 2298–2301; m) S. Paladhi, Y. Liu, B.
S. Kumar, M.-J. Jung, S. Y. Park, H. Yan, C. E. Song, Org. Lett., 2017,
19, 3279–3282.
Keywords: cation-binding catalysis • chiral oligoethylene glycol
catalyst • a-amido sulfones • N,N-acetals • chiral acyclic aminals
[1]
[2]
Book without editor: C. Ko, Synthesis Methods Using Cyclic Acetals
and Aminals, ProQuest, Ann Arbor, 2011.
a) A. Rouchaud, J.-C. Braekman, Eur. J. Org. Chem. 2009, 16, 2666–
2674; b) I. Bosque, J. C. Gonzalez-Gomez, M. I. Loza, J. Brea, J. Org.
Chem. 2014, 79, 3982–3991; c) C.-E. Nge, C.-Y. Gan, K.-H. Lim, K.-N.
Ting, Y.-Y. Low, T.-S. Kam, Org. Lett. 2014, 16, 6330–6333; d) Y. Tang,
J. Xiong, Y. Zou, B. Nay, L.-J. Wang, J.-F. Hu, Chinese Chemical
Letters 2016, 27, 969–973; e) B. M. Williams, D. Trauner, Angew.
Chem. Int. Ed. 2016, 55, 2191–2194; f) Y. Ochi, S. Yokoshima, T.
Fukuyama, Org. Lett. 2016, 18, 1494–1496.
[3]
[4]
M. D. Fletcher, M. M. Campbell, Chem. Rev. 1998, 98, 763−795.
a) G. B. Rowland, H. Zhang, E. B. Rowland, S. Chennamadhavuni, Y.
Wang, J. C. Antilla, J. Am. Chem. Soc. 2005, 127, 15696–15697; b) Y.
Liang, E. B. Rowland, G. B. Rowland, J. A. Perman, J. C. Antilla, Chem.
Commun. 2007, 43, 4477–4479.
[11] K. Brak, E. N. Jacobsen, Angew. Chem. Int. Ed. 2013, 52, 534–561.
[12] Y. Li, L. Echegoyen, J. Org. Chem. 1994, 59, 6539–6542.
[13] Similar results were also observed in the asymmetric Strecker reactions.
See the reference [9c].
[5]
[6]
M. Hatano, T. Ozaki, Y. Sugiura, K. Ishihara, Chem. Commun. 2012, 48,
4986−4988.
Representative examples for catalytic enantioselective synthesis of
cyclic aminals, see: a) X. Cheng, S. Vellalath, R. Goddard, B. List, J.
Am. Chem. Soc. 2008, 130, 15786–15787; b) M. Rueping, A. P.
Antonchick, E. Sugiono, K. Grenader, Angew. Chem. Int. Ed. 2009, 48,
908–910.
[14] CCDC 1556761 contains the supplementary crystallographic data for
compound 4v. (see Supporting Information).
[15] For examples for acyclic aminals stabilized by intramolecular hydrogen
bonding, see: a) G. Koz, D. Astley, S. T. Astley, Z. Naturforsch. 2013,
68b, 57–63; b) E. Galvez, I. Iriepa, A. Lorente, J. M. Mohedano, F.
Florencio, S. Garcia-Blanco, Can. J. Chem. 1987, 65, 687–692; c) E.
Galvez, A. Lorente, I. Iriepa, F. Florencio, S. Garcia-Blanco, J. Mol.
Struct. 1986, 142, 447–450.
[7]
Spontaneous tautomerization of N-Boc alkyl imines into the
corresponding enamines readily occurs even at -20 °C. For the details
please see: J. Song, H. W. Shih, L. Deng, Org. Lett. 2007, 9, 603–606.
[16] CCDC 1555424 contains the supplementary crystallographic data for
compound 6n. (see Supporting Information).
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10.1002/chem.201703800
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Author[s] and Corresponding Author[s]
Page No. – Page No.
Title
Layout 2:
COMMUNICATION
Sang Yeon Park,+[a] Yidong Liu,+[b] Joong
Suk Oh,[a] Mengying Duan,[b] Yoo Kyung
Kweon,[a] Yong Bok Jeong,[a] Yu Tan,[b]
Ji-Woong Lee,*[c] Hailong Yan,*[b] and
Choong Eui Song*[a]
Boc
Boc
I
O
Boc
HN
HN
O
O
HN
O
O
I
Boc
Ar
O
K
N
N
Ar
N
O
O
K
N
SO2Ph
or
O
O
O
H
O
NR2
R
H
N
R
O
O
I
I
Boc
O
S
H
N
HN
Ph
up to 92% yield up to 99% yield
up to 99% ee up to 99% ee
after single recrystallization
for alkyl substrates
O
O
58–65% yields
over 2 steps
cation-binding
catalysis
R
Ar
SO2Ph
OtBu
Diverse chiral acyclic aminals were prepared in excellent yields and
enatioselectivities (up to 99% ee) via cation-binding catalysis. In particular, the
present protocol renders unprecedented and challenging substrate scope,
particularly, aliphatic substrates, which are predominant in molecular scaffold of
many natural products. The synthetic utility of the current methodology was also
demonstrated by preparing biologically relevant product, possessing aminal and
polyheterocyclic cores.
Page No. – Page No.
Asymmetric Aminalization via Cation-
Binding Catalysis
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