Counterion-Induced Asymmetric Control in Ring-Opening of Azetidiniums: Facile Access to Chiral Amines

Article abstract of DOI:10.1002/anie.201712395

Counterion-induced stereocontrol is a powerful tool in organic synthesis. However, such enantiocontrol on tetrahedral ammonium cations remains challenging. Described here is the first example of using chiral anion phase-transfer catalysis to achieve intermolecular ring-opening of azetidiniums with excellent enantioselectivity (up to 97 % ee). Precise control over the formation and reaction of the chiral ion pair as well as inhibition of the background reaction by the biphasic system is key to the success of the reaction.

Full text of DOI:10.1002/anie.201712395

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Accepted Article
Title: Counterion-Induced Asymmetric Control on Azetidiniums: A
Facile Access to Chiral Amines
Authors: Deyun Qian, Min Chen, Alex C. Bissember, and Jianwei Sun
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712395
Angew. Chem. 10.1002/ange.201712395
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10.1002/anie.201712395
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Counterion-Induced Asymmetric Control on Azetidiniums: A
Facile Access to Chiral Amines**
Deyun Qian, Min Chen, Alex C. Bissember and Jianwei Sun*
Abstract: Counterion-induced stereocontrol is a powerful tool in
organic synthesis. However, such enantiocontrol on tetrahedral
ammonium cations remains challenging. Herein we demonstrate the
first example of using chiral anion phase-transfer catalysis to
achieve intermolecular ring-opening of azetidiniums with excellent
enantioselectivity (up to 97% ee). Precise control over the formation
and reaction of the chiral ion pair as well as inhibition of the
background reaction by the biphasic system is key to success.
use of a chiral ion pair.[9,10] However, ion pair interaction is
weaker than hydrogen bonding and thus expected to be more
challenging in asymmetric induction relative to neutral azetidine
opening.[11] Moreover, previous examples of chiral counter
anion-directed asymmetric catalysis on prochiral electrophiles
have mainly featured iminium and oxocarbenium cations with
planar configuration in the reactive center, in which facial
differentiation is relatively defined.[9,10] In contrast, the cationic
center of azetidiniums is tetrahedral and the position of the
counter anion is elusive. Furthermore, the clean exchange of the
substrate counter anion by the catalytic chiral anion is required
for exclusive asymmetric control, and background reaction
should be inhibited (Fig. 1B). Finally, precise cooperation
between the chiral ion pair and the nucleophile is required to
achieve excellent enantioselectivity. Therefore, synergistic
control on every stage of the process is needed.
Quaternary ammonium salts have attracted considerable
attention and found many applications in organic synthesis,
including asymmetric catalysis. However, these species have
been employed mainly as catalysts (e.g., cinchona alkaloid-
derived phase-transfer catalysts)[1] or reagents (e.g., Selectfluor
as an electrophilic fluorine source).[2] In contrast, the direct use
of quaternary ammonium salts as substrates for catalytic
asymmetric synthesis is rare.[3]
Azetidiniums are versatile synthons for the preparation of
bioactive and organic targets.[4,5] They are susceptible to ring
opening by nucleophiles due to inherent ring strain. Compared
to neutral azetidines and oxetanes, their reactivity is much
higher and may allow more mild conditions and more compatible
nucleophiles. Enantioenriched azetidiniums are typically
employed to furnish β-chiral amines by ring-opening, but
unfortunately, the synthesis of these substrates is not
straightforward.[4,5] Consequently, catalytic strategies that permit
easy conversion of the readily available azetidinium species to
enantioenriched amine products are particularly desirable.
Indeed, enantioselective desymmetrization of the prochiral 3-
substituted azetidiniums has not been developed. Such
transformations would provide expedient access to β-chiral
amines, a family of privileged structures present in a range of
bioactive molecules, including various notable drug molecules.[6]
Although several metal-catalyzed strategies have been devised
to directly access β-chiral amines in an enantioselective
manner,[7] few examples by organocatalytic methods have been
developed.[8]
Figure 1. Counterion-induced asymmetric opening of azetidiniums.
With the above analysis, we envisioned chiral anion phase-
transfer (CAPT) catalysis.[3,9,10] With this approach, a non-polar
solvent should be employed so that the azetidinium salt
substrate should be essentially insoluble. The catalyst would
then provide a chiral organic counter anion, such as chiral
phosphate, to pair with the azetidinium, and in the meanwhile
increase the solubility of the chiral ion pair. In this scenario, the
organic nucleophile then reacts in the solution phase to achieve
both reactivity and asymmetric control. The background reaction
of the insoluble substrate is thus inhibited due to ineffective
contact with nucleophile.
The cationic nature of azetidinium substrates suggests that the
most straightforward tool for asymmetric induction would be the
We employed azetidinium 1a as the model substrate and
mercaptobenzothiazole 2a as the nucleophile (Table 1). A
chiral phosphoric acid catalyst was employed in conjunction
with a suitable base to provide chiral anion.[12] In the presence
of Na2HPO4 and a catalytic amount of (R)-TRIP (A1), the
reaction in toluene proceeded smoothly at room temperature to
give the desired product with good conversion, albeit with low
enantioselectivity (24% ee, entry 1). Other SPINOL-derived
chiral phosphoric acid (S)-B4 provided the highest but still
moderate selectivity (43% ee, entry 7). Next, using PhCF3 as
solvent led to slight improvement (58% ee, entry 8). Finally,
evaluation of other nucleophiles identified thiol 2d as the best
reaction partner (90% ee, entry 12). Notably, other bases
proved inferior (entries 12–14).
[]
Dr. D. Qian,[+] Dr. M. Chen[+] and Prof. J. Sun
Shenzhen Research Institute, The Hong Kong University of Science
and Technology (HKUST), Shenzhen, China; Department of
Chemistry, HKUST, Clear Water Bay, Kowloon, Hong Kong, China
E-mail: sunjw@ust.hk
Dr. A. C. Bissember
School of Natural Sciences – Chemistry
University of Tasmania, Hobart, Australia
[+]
These authors contributed equally to this work.
[]
Financial support was provided by Shenzhen STIC
(JCYJ20160229205441091) and Hong Kong RGC (16304115,
ECS605812, 16302617, 16311616). We thank Dr. Herman Sung for
assistance in structure determination.
Table 1: Reaction optimization.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
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10.1002/anie.201712395
Angewandte Chemie International Edition
COMMUNICATION
configuration of 3r’ was confirmed by X-ray crystallography.
Finally, the benzydryl (Bp) group could be easily cleaved.
conv
[%][a]
entry
cat.
2
base
solvent
ee [%][b]
1
A1
A2
A3
B1
B2
B3
B4
B4
B4
B4
B4
B4
B4
B4
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2d
2d
2d
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na3PO4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
76
24
9
2
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
3
6
4
38
26
22
43
58
47
42
90
31
16
12
5
6
7
8
9
10
11
12
13
14
K2HPO4
Na2CO3
[a] Determined by 1H NMR analysis of the crude mixture. [b] Determined by
HPLC on chiral stationary phase. Bp = Ph2CH.
A wide range of 3-azetidiniums smoothly participated in the
mild desymmetrization process, directly providing a diverse set
of densely functionalized β-chiral amines with good to excellent
enantioselectivity (Scheme 1). Aryl-, alkenyl-, alkyl-, and hetero-
substituents at the 3-position all worked well. Notably,
nucleophile 2b was also excellent, provided that catalyst B2 is
used for this nucleophile (3q-3z). 3,3-Disubstituted azetidiniums
successfully lead to the formation of quaternary stereocenters
(4a-c). The reaction conditions could tolerate a range of
functional groups, including acetals, nitriles, esters, Weinreb
amide, ethers, etc. Substrates featuring various N-alkyl and N-
aryl substituents provided access to a range of chiral amine
products (3w–3ab) that can be readily functionalized or
derivatized. Other thiols, such as benzoxazole-2-thiol, 1,3,4-
thiadiazole-2-thiol, and quinolone-2-thiol, are all useful
nucleophiles. Although some of the substrates were used as
mixtures of two diastereoisomers (3g–j, 3l–n, 3q–s, 3u–z, 3ab–
ae, and 4b–c), excellent stereocontrol could still be achieved,
demonstrating extraordinary robustness of our process.[8–11]
The reaction products could be readily derivatized (Scheme 2).
A one-pot reaction from the commercially available azetidine S1i
efficiently furnished product 3i. Furthermore, oxidation of
thioether 3r by H2O2 generated Julia olefination reagent 3r’,
which was used to synthesize alkene 5. The absolute
Scheme 1. Reaction scope. [a] Reaction conditions: 1 (0.2 mmol), 2 (0.4
mmol), catalyst (0.02 mmol); (S)-B2 for 3q–3z, 3ad, and 4a; (S)-B5 for 4b;
(R)-B4 for all others, PhCF3 (8.0 mL), RT, 96 h. [b] Isolated yield. [c]
Determined by HPLC with a chiral stationary phase. [d] Run with cis-1 at RT,
6–24 h. [e] Run at 5 oC, 96 h.
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10.1002/anie.201712395
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Scheme 2. Product transformations.
We carried out control experiments to understand the reaction
mechanism. The background reaction of 1d and 2d did not
proceed in the absence of catalyst (Eq. 1). In contrast, an
aqueous-organic biphasic system smoothly promoted the
background reaction. The results indicate the standard liquid-
solid biphasic system is effective and critically important for
clean ion exchange to ensure exclusive enantiocontrol via the
chiral ion pair intermediate. Mixing iodide 7d with silver
phosphate salt Ag-A1 provided chiral azetidinium phosphate salt
IP-A1.[13] Treating this salt with nucleophile 2d in PhCF3 directly
led to the formation of the ring-opening product (83% yield, 42%
ee, Eq. 2). For direct comparison, the standard protocol from
azetidinium 1d with catalyst A1 provided essentially the same
level of enantiocontrol. These results agree well with the
mechanistic proposal involving chiral ion pair.
In conclusion, we have developed the first catalytic
enantioselective desymmetrization of azetidiniums. The reaction
provides rapid access to a wide range of β-chiral amine
derivatives with high enantioselectivity under mild conditions.
These highly enantioenriched and densely functionalized
products can be easily transformed to other useful chiral building
blocks. Mechanistically, a suitable chiral anion phase transfer
(CAPT) catalytic system is critically important for precise control
over each stage of the process. It also represents a rare
example of excellent asymmetric induction by chiral counter
anions on tetrahedral cations.
Keywords: asymmetric catalysis • phase-transfer catalysis •
small ring systems • chirality • organocatalysis
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10.1002/anie.201712395
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D. Qian, M. Chen, A. C. Bissember and
J. Sun*
Page No. – Page No.
Counterion-Induced Asymmetric
Control on Azetidiniums: A Facile
Access to Chiral Amines
Counterion-induced asymmetric induction over tetrahedral ammonium cations is useful but remains challenging. Herein we
demonstrate the use of chiral anion phase transfer catalysis to achieve ring-opening reactions of tetrahedral azetidiniums with
enantioselectivity (up to 97% ee). Precise control over the formation and reaction of the key chiral ion pair as well as inhibition of the
background reaction by the biphasic system is key to success.
This article is protected by copyright. All rights reserved.