Chiral Phosphoric Acid Catalyzed Enantioselective Synthesis of α-Tertiary Amino Ketones from Sulfonium Ylides

Article abstract of DOI:10.1021/jacs.0c07210

Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-Amino ketones, which is particularly useful for the less accessible acyclic α-Tertiary cases. By a protonation-Amination sequence, our approach represents a rare asymmetric H-heteroatom bond insertion by α-carbonyl sulfonium ylides, an attractive surrogate of diazocarbonyls. The mild intermolecular C-N bond formation was catalyzed by chiral phosphoric acids with excellent efficiency and enantioselectivity. The products are precursors to other important chiral amine derivatives, including drug molecules and chiral ligands. The enantioselectivity was controlled by dynamic kinetic resolution in the amination step, rather than the initial protonation. This process opens up a new platform for the development of other related insertion reactions.

Full text of DOI:10.1021/jacs.0c07210

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Article
Chiral Phosphoric Acid Catalyzed Enantioselective Synthesis
of #-Tertiary Amino Ketones from Sulfonium Ylides
Wengang Guo, Yuzheng Luo, Herman H. Y. Sung, Ian D. Williams, Pingfan Li, and Jianwei Sun
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07210 • Publication Date (Web): 22 Jul 2020
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Chiral Phosphoric Acid Catalyzed Enantioselective Synthesis of
α-Tertiary Amino Ketones from Sulfonium Ylides
Wengang Guo,§‡ Yuzheng Luo,§† Herman H.-Y. Sung,‡ Ian D. Williams,‡ Pingfan Li,†* and Jianwei
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Sun‡*
† State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, College of Chemistry, Beijing
University of Chemical Technology, Beijing 100029, China;
‡ Department of Chemistry, the Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
SAR, China
ABSTRACT: Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-amino ketones, which is
particularly useful for the less accessible acyclic α-tertiary cases. By a protonation-amination sequence, our approach represents a
rare asymmetric H−heteroatom bond insertion by α-carbonyl sulfonium ylides, an attractive surrogate of diazocarbonyls. The mild
intermolecular C–N bond formation was catalyzed by chiral phosphoric acids with excellent efficiency and enantioselectivity. The
products are precursors to other important chiral amine derivatives, including drug molecules and chiral ligands. The
enantioselectivity was controlled by dynamic kinetic resolution in the amination step, rather than the initial protonation. This process
opens up a new platform for the development of other related insertion reactions.
INTRODUCTION
asymmetric intramolecular C–H insertion with α-ester
sulfonium ylides,
Chiral α-amino ketones are substructures present in
numerous important molecules of pharmaceutical relevance
Scheme 1. Introduction and Reaction Design
(Scheme 1a).1 They also serve as important precursors to β-
aminol alcohols, widely used as chiral ligands.2 As a result,
efficient asymmetric synthesis of such important chiral amines
has been a constant pursuit of organic chemists. In the past
decades, a few catalytic enantioselective approaches have been
devised for this purpose.3-5 Among them, direct electrophilic α-
amination of ketone enolates represents the most general
approach (Scheme 1b).4 However, this elegant method has its
limitations. For example, the majority of current examples dealt
with cyclic ketones or activated ketones (such as β-ketoesters),
whose stereocontrol might benefit from the restricted
conformation of cyclic enolates or interaction with the
additional carbonyl group. Moreover, they are mainly limited to
the construction of quaternary stereocenters, which likely
avoids epimerization of the otherwise labile tertiary
stereocenter.4b-f Another point probably worthy of note is that
currently known approaches rarely employ free amines as the
nitrogen source. Instead, masked and protected amines (e.g.,
diazocarboxylate, azide, amides) were typically needed to be
compatible with the catalytic systems.3-6 While recent progress
by other ingenious strategies have been achieved, catalytic
asymmetric approaches for the synthesis of acyclic α-tertiary
(a) Selected -amino ketone drug molecules

O
O
O
Me
Cl
Me
Me
N
NHtBu
NH2
Me
cathinone
pyrovalerone
bupropion
(b) Catalytic asymmetric electrophilic amination (typical approach)
mainly on
cyclic substrates
chiral
catalyst
O
O
(fix enolate conformation)
 activated substrates
(easy enolization, e.g., ketoester)
 quaternary stereocenter
(avoid racemization)
R2
"N+"
R2
+
R1
R1
*
R3
R3 NR2
(c) Intramolecular C H insertion to -ester sulfonium ylides


O
O
Rh2[(2S)-mepy)]4
O
cis/trans = 2.7:1
cis: 93% ee
trans: 85% ee
O
SPh2
DCE, reflux
a single example
9% yield
(d) Asymmetric S H insertion to -ester sulfoxonium ylides


chiral
thiourea
O
O
O
amino ketones remain scarce. Herein we introduce
a
SAr
S
*
RO
Me
Me
+ ArSH
RO
completely different approach to address these challenges.
R'
R'
4595% ee
α-Carbonyl sulfonium ylides are versatile species in organic
synthesis, serving as attractive surrogates to α-diazocarbonyl
compounds.7 However, so far, their application in catalytic
asymmetric synthesis has been mainly focused on cycloaddition
reactions.8 Their utilization for asymmetric H–heteroatom bond
insertion has been rarely exploited. In 1999, Müller and
(e) Asymmetric N H insertion to -keto sulfonium ylides (this work)


O
O
O
HA* (cat.)
RNH2
R2
R'
R2
 acyclic
 monocarbonyl
 -tertiary
R2
SR'2
R1
*
R1
R1
A*
SN
2
S
NHR
R'
 amino esters OK
DKR
coworkers reported
a
single example of Rh-catalyzed
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but with very low efficiency (9% yield, Scheme 1c).9 During
the preparation of this manuscript, Burtoloso and coworkers
reported an elegant S–H insertion of arylthiols to α-ester
sulfoxonium ylides with chiral thiourea catalysis, leading to a
range of α-arylthio esters in 45–95% ee.10 Notably, in contrast
to the α-ester sulfur ylides, asymmetric insertion using α-keto
sulfur ylides has not been realized. We envisioned that these
reactions may remedy some of the drawbacks encountered with
α-diazoketones.5e Specifically, metal carbene complexes
generated from diazoketones have poor stability due to easy
decomposition (e.g., β-elimination).11 Moreover, the resulting
metal ylides can easily lose enantiocontrol due to facile
detachment of the metal/L* part off the molecule.5e,6c In this
context, an organocatalytic approach with α-keto sulfonium
ylides for this purpose would be a highly desirable alternative.
8
(S)-A4
(S)-A4
(S)-A4
(S)-A4
(S)-A4
25
25
1
toluene
Et2O
54
46
34
80
83
1
2
3
4
5
6
7
8
9
36
1
10
11
12
25
CHCl3
toluene
toluene
–30
–40
72
96
a
Reaction scale: 1a (0.10 mmol), 2a (0.11 mmol), catalyst (0.01
mmol), solvent (1.0 mL). b Determined by chiral HPLC.
Aiming to further enhance the product enantiopurity, we then
resorted to a post-reaction operation. After complete conversion,
a substiochiometric amount of Cu(OAc)2 was added to the
reaction mixture (Scheme 2). Stirring the mixture under air
atmosphere at room temperature for 3 h led to the isolation of
product 3a in 72% yield in enantiopure form! The minor
enantiomer was selectively consumed (oxidized by air), which
was catalyzed by the in-situ generated Cu/CPA complex.16 It is
remarkable that same (S)-A4 has the matched absolute
configuration for the subsequent ee enhancement through
kinetic resolution, which is key to the success of this one-pot
operation.
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The relative basicity of sulfonium ylide inspired us to
envision that protonation with a chiral acid would lead to a
chiral sulfonium ion pair, in which the labile α-tertiary
stereocenter bearing a good leaving group (organosulfide)
would be susceptible to nucleophilic substitution (Scheme 1e).
Depending on the relative rates of its epimerization and
subsequent substitution, the ultimate asymmetric control could
be from either asymmetric protonation12a or dynamic kinetic
resolution (DKR) in amination.12b,c Notably, the nucleophilic
nature of the nitrogen source would permit free amines to be
directly used.13
Scheme 2. One-pot ee Enhancement with Cu(OAc)2
Cu(OAc)2
(10 mol%)
A4
(S)-
(10 mol%)
1a
full
conversion
3a
+
toluene, 40 o
C
r.t., 3 h, air
before work-up
2a
72% isolated yield
>99% ee
96 h
one-pot
RESULTS AND DISCUSSION
We then examined the scope of this formal N–H insertion
process. A range of sulfonium ylides and anilines, including
electron-poor and electron-rich examples, all participated in the
reaction to form the corresponding α-amino ketone products
with excellent enantioselectivity (Table 2). The mild conditions
tolerated a range of functional groups. Notably, the late-stage
oxidation condition is compatible with the p-methoxyphenyl
(PMP) and thiophene functionalities, which are known to be
labile toward oxidation.
We began our study with sulfonium ylide 1a, which was
readily prepared as a mixture of s-cis and s-trans isomers.14
A
range of chiral phosphoric acids (CPAs) were examined for the
reaction with aniline (Table 1).15 To our delight, all these
reactions proceeded cleanly in DCM to form the desired amino
ketone 3a, albeit with low enantioselectivity. Among them, (S)-
A4 exhibited the best performance (44% ee, entry 4). SPINOL-
derived CPAs and chiral thioureas proved inferior (see the SI
for more details). With (S)-A4, further condition screening
revealed that 3a could be generated with 83% ee in toluene at –
40 oC (entry 12).
While the post-reaction Cu-catalyzed kinetic resolution
provided an alternative to boost the product enantiopurity, we
also further examined the protocol without this additional
operation. For example, with A6 and a new catalyst A7 (shown
in Table 1), the reactions could directly afford the desired
products with good to excellent enantioselectivity (3r-w).
Table 1. Evaluation of Reaction Conditionsa
O
O
The nucleophilicity of the anilines was also important to
Me
Ph
Me
CPA (10 mol %)
solvent, T
ensure successful reactivity. Anilines with electron-donating
+
PhNH2
S
–
NHPh
and slightly electron-withdrawing groups, such as p-Cl (p
=
Ph
1a
–
3a
all >95% NMR yield
2a
+0.19), p-CF3 (p = +0.65), were suitable nucleophiles.
However, strongly electron-withdrawing groups, such as p-NO2,
p-CN, led to no reactivity, even at an elevated temperature (see
SI for more details). The low nucleophilicity not only directly
led to poor amination reactivity, but also resulted in relatively
faster catalyst deactivation (vide infra). Finally, in addition to
primary amine nucleophiles, we found that secondary amines,
such as indolines, were also excellent nucleophiles that
furnished the desired tertiary amine products with excellent
enantioselectivity (3u-w). However, aliphatic amines resulted
in either low reactivity or low enantioselectivity (see the SI for
details), which is likely related to their relatively higher basicity
that might be incompatible with the acid catalyst. The absolute
configuration of the p-trifluoromethylaniline product 3r was
determined by single crystal X-ray crystallography to be (S), as
(7:1 isomeric mixture)
R =
R
A1
, R = 1-naphthyl
O
O
A2
A3
A4
A5
, R = 9-phenanthrenyl
, R = 1-pyrenyl
P
X
OH
O
, R = 9-anthracenyl
A6
A7
(X = Ph)
i
, R = 2,4,6- Pr3C6H2
R
i
(X = 3,5- Pr2C6H3)
entry
cat.
T/oC
25
t/h
1
solvent
DCM
DCM
DCM
DCM
DCM
ee (%)b
24
1
2
3
4
5
(S)-A1
(S)-A2
(S)-A3
(S)-A4
(S)-A5
25
1
24
25
1
0
25
1
44
25
1
43
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was that of the indoline product 3v via its indolyl derivative 13
1
(see Scheme 3).
2
3
4
5
6
7
Table 2. Synthesis of α-Amino Propiophenonesa
O
A4
(S)-
(10 mol%)
O
Me
toluene, 40 oC, 96 h
Me
X
then
+
ArNHR
X
S
Ph
Ph
NRAr
Cu(OAc)2 (10 mol%)
r.t., t
1
2
3
(s-cis & s-trans mixture)
8
9
O
c
O
Reactions with (S)-A6 at 50 oC without Cu(OAc)2

3a
3b
3c
3d
3e
O
(R = H), 3 h, 70%, 99% ee
Me
Me
Ph
O
Me
Ph
(R = Cl), 3 h, 75%, 99% ee
Ph
10
11
12
13
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HN
Me
t
Me
HN
(R = Bu), 3 h, 64%, 96% ee
(R = Me), 3 h, 69%, 98% ee
(R = OMe), 0.5 h, 61%, 96% ee
HN
HN
Br
R
Me
, 4.5 h, 58%, 90% ee
CF3
3g
, 5 h, 65%, 80% ee
3f
d
3r
, 61%, 96% ee
O
O
O
F
O
3h
3i
(R = Br), 3 h, 73%, 99% ee
(R = F), 2 h, 70%, 96% ee
(R = CF3), 1.4 h, 79%, 99% ee
(R = Me), 2 h, 68%, 92% ee
(R = OMe), 2 h, 63%, 90% ee
Me
Me
O
Cl
Me
Me
Me
NHPh
HN
HN
NHPh
Br
NHPh
Br
3j
3k
3l
R
F
OMe
F
3n
b
, 3 h, 69%, 93% ee
3m
, 3 h, 40%, 99% ee
e
3s
, 53%, 78% ee
3t
, 59%, 82% ee
O
O
O
O
O
O
Me
Ph
Me
Me
Me
Me
S
Me
NHPh
N
N
N
HN
NHPh
Br
Br
NC
OMe
Br
3w
, 51%, 95% ee
f
3v
, 75%, 91% ee
3p
3q
3o
, 2.5 h, 60%, 96% ee
, 1.8 h, 55%, 88% ee
3u
, 70%, 92% ee
, 2.5 h, 70%, 92% ee
a Reaction scale: 1 (0.5 mmol, 2 (0.55 mmol), (S)-A4 (10 mol%), toluene (5.0 mL). b Run with A4 (20 mol%), –40 oC, 72 h, followed
by 24 h at r.t. after addition of Cu(OAc)2. c (S)-A6 (10 mol%), 4 Å MS (100 mg), –50 oC, 120 h. d (S)-A6 (15 mol%), –30 oC. e (S)-
A6 (20 mol %), –40 oC, 120 h. f (R)-A7 (10 mol %).
O
Ph
S
O
While excellent results were obtained with α-methyl
sulfonium ylides, further study indicated that those bearing a
NHPMP
A6
(S)-
(10 mol %)
Ph
+
PMPNH2
R
R
toluene, 4Å MS
50 oC, 120 h
higher
alkyl
substituent
reacted
with
moderate
1
enantioselectivity. Importantly, the post-reaction kinetic
resolution with Cu(OAc)2 no longer improved the enantiopurity,
but became mismatched scenario, leading to ee erosion. More
importantly, we found that the sense of asymmetric induction
was opposite to the cases in Table 2, which might be the cause
of the mismatched kinetic resolution. This observation also
indicated that increasing the size of the α-substituent from
methyl group had dramatic influence on the enantiodetermining
transition state. Next, various catalysts were screened again.
Gratifyingly, A6 (Table 1) was identified as the superior one
(Table 3). After slight modification of reaction parameters,
these α-amino ketones bearing various alkyl chains could be
obtained with good to excellent enantioselectivity without post-
reaction kinetic resolution. Cyclic α-amino ketones, such as
aminotetralones,17 could also be synthesized. Some of these
products resembles commercial drugs (e.g, 3z vs. pyrovalerone
in Scheme 1a). The absolute configuration of 3ab was
determined by single crystal X-ray crystallography of its
derivative (see the SI for details). Notably, α-ethyl substitution
also led to 70% ee (see the SI for details).
3
PMP = (p-MeO)C6H4
(s-cis & s-trans mixture)
O
O
O
Me
nHex
nDec
Ph
NHPMP
NHPMP
NHPMP
Me
Br
3x
3y
3z
, 94%, 96% ee
O
, 86%, 96% ee
, 89%, 98% ee
O
O
CN
X
NHPMP
Ph
NHPMP
3ab
, 54%, 93% ee
NHPMP
, 90%, 97% ee
Me
3ac
3ad
(X = H), 49%, 81% ee
(X = Br), 52%, 80% ee
3aa
a Reaction scale: 1 (0.5 mmol), 2 (0.55 mmol), (S)-A6 (10 mol%),
and 4 Å MS (250 mg), toluene (5.0 mL).
With the success on α-amino ketones, we were curious about
the potential of this approach for the synthesis of α-amino esters.
However, the previous catalysts of choice were not suitable for
these substrates. Nevertheless, we managed to achieve good to
excellent enantioselectivity with A7 and another new SPINOL-
derived catalyst B (Table 4). Similarly, α-methyl and other α-
alkyl esters required different catalysts. However, the sense of
asymmetric induction of these two types of products remained
same, in contrast to the scenario for α-amino ketones.
Table 3. Scope for α-Non-methyl Aminoketonesa
Table 4. Synthesis of Chiral α-Amino Estersa
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(a) BH3-SMe2, THF, 0 oC, 12 h, >50:1 dr, 99% yield; (b)
O
A7
B
or (R)-
(S)-
(10 mol %)
R2
R2 CO2R1
NHPMP
1
2
3
4
5
6
7
OR1
PhMgBr, THF, 0 oC, 15 min, 65% yield; (c) AcCl, THF, 25 oC, 12
+
PMPNH2
h, 75% yield; (d) super-hydride, THF, –20 oC, 1 h; (e)
toluene, 4Å MS
50 oC, 120 h
S
Ph
Ph
o
KOH/MeOH, 65 C, 30 min, 15:1 dr, 65% yield (2 steps); (f)
4
5
PMP = (p-MeO)C6H4
Ph3PMeBr, tBuOK, THF, 0 oC to r.t., 12 h; (g) KOH/MeOH, 65 oC,
30 min, 59% yield (2 steps); (h) DDQ, 0 oC to r.t., 71% yield.
(s-cis & s-trans mixture)
A7
with (S)-
Me
:
CO2iPr
CO2Me
NHPMP
5a
Me
CO2Et
Me
NHPMP
NHPMP
MECHANISTIC STUDIES
8
9
5b
5c
It is proposed that the reaction begins with protonation of
sulfonium ylide 1, typically a mixture of s-cis and s-trans
isomers with the enolate resonance form 1′. The ratio of s-cis
and s-trans isomers varies with temperature (see the SI for
details). The resulting IM is a diastereomeric mixture of
sulfonium ions paired with a chiral phosphate anion. Its labile
α-stereogenic center makes these two isomers in rapid
equilibrium. Subsequent amine substitution delivers the product
and regenerates the catalyst (Scheme 4). Indeed, IM was found
to be the catalyst resting state, which permits extensive
epimerization of the labile tertiary stereocenter in IM. Thus,
even though the initial protonation step could be highly
enantioselective, the established chirality is lost during
epimerization. This is also consistent with the excellent
enantioselectivity even with an isomeric mixture of substrates.
Thus, the enantioselectivity is controlled during amination by
pseudo dynamic kinetic resolution.19
69% yield, 86% ee
60% yield, 84% ee
55% yield, 78% ee
10
11
12
13
14
15
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Ar =
Ar
B
with (R)-
:
Me
CO2Ph
Me NHPMP
5e
Me
CO2Ph
NHPMP
O
O
O
P
OH
Ar
5d
69% yield, 90% ee
50% yield, 95% ee
Me
Me
B
(R)-
a Reaction scale: 1 (0.2 mmol), 2 (0.22 mmol), (S)-A7 or (R)-B (10
mol%), and 4 Å MS (100 mg), toluene (2.0 mL).
Our products are precursors to other useful chiral amine
derivatives (Scheme 3). For example, oxidative PMP-
deprotection in 3e immediately furnished chiral drug cathinone
(6).1a Further Boc-protection delivered 7, a known precursor
toward bioactive molecules 8 and 9.18 Next, a gram-scale
synthesis of 3a was performed with recovery of catalyst A4 and
diphenylsulfide. Furthermore, product 3a were converted to
both diastereomers of amino alcohol 10 and alcohol 11, which
are useful chiral ligands.2 Wittig olefination led to chiral
allylamine 12. Finally, indoline 3v could be easily oxidized by
DDQ to form -N-indolyl ketone 13. Notably, in all these
transformations, no obvious erosion in enantiopurity was
observed.
Scheme 4. Proposed Mechanism
O
O
O
O
O
P
Me
Me
HA*
*
ArNH2
Ph
Ph
OH
1
1'
SPh2
SPh2
HA*
Z/E mixture
product
Ph2S
fast
saturation
slow
no rxn
Scheme 3. Product Transformations
r.d.s.
(
)
x
ArNH2
O
O
O
ArNH2
epimerization
Boc2O, Et3N
TCCA
O
Me
O
Me
O
Me
Ph
Ph
Ph
Ph2S
Me
Me
SPh2
Me
*
CH3CN
H2O
NHPMP
88% yield
NHBoc
Ph
NH2HCl
Ph
Ph
x
(two steps)
O
*
O
O
3e
(92% ee)
7
(91% ee)
SPh2
cathinone
6
)
(
P
irreversible
A*
A*
dynamic kinetic
resolution
enantiodetermining
14
O
IM
IM
(S)-
(R)-
Ref 18b
Ref 18a
inactive
catalyst resting state
O
Me
Me
O2
Cl
O
Ph
S
N
H
O
To further understand the ion pair intermediate IM, we mixed
substrate 1 and catalyst (S)-A4 in toluene-d8. This immediately
generated IM, whose broad peak at 4.2 ppm in 31P NMR
matched that observed in the standard reaction (Figure 1b).19b
Interestingly, in the absence of amine, this intermediate
gradually turned into phosphate ester 14 (Figure 1c). 14 was
ultimately obtained as a 1.3:1 diastereomeric mixture (Figure
1d), whose identity was confirmed by isolation and full
characterization (eq. 1). The formation of 14 is a result of
phosphate O-substitution of the sulfonium motif in IM. This
prompted us to speculate 14 as a potential intermediate, which
might be substituted by amine to form the same product.20
However, treating 14 with PhNH2 resulted in no reaction, even
with additional (S)-A4. Similarly, treating 14 with Ph2S (with
or without A4) also did not reverse to IM, thus excluding its
role as either an active catalyst or a viable intermediate.
Although it is an off-cycle dead end, fortunately, its generation
in the standard reaction was very slow relative to the
substitution of IM by amine, which is the key to successful
turnover (Figure 1e). We also carried out a competition
experiment with deuterated anilines. The absence of kinetic
F3C
N
N
H
NH
Ph
O
HN
N
O
9
8
Nonsteroidal glucocorticoid
receptor modulator
Metalloproteinase inhibitor
F
1a 2a
+
OH
OH
a
c-e
Ph
Me
Me
Ph
NHPh
NHPh
O
10
(1R,2S)- (91% ee)
10
(1S,2S)- (89% ee)
Me
Ph
NHPh
Ph OH
c, f-g
b
3a
(92% ee)
Me
Me
Ph
Ph
1.6 g
(75% yield)
NHPh
NHPh
catalyst recovery: 71%
Ph2S recovery: 94%
11
(93% ee)
O
12
(91% ee)
O
Me
Me
h
N
N
Br
Br
3v
(91% ee)
13
(91% ee)
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Page 5 of 8
Journal of the American Chemical Society
Figure 2. (a) Non-linear effects. (b) Catalyst solubility in toluene
isotope effect ((kH/kD = 1.0) indicated that the protonation step
is not rate-determining, which is consistent with the proposed
mechanism (eq. 2)
1
2
(–40 oC) over time.
3
4
CONCLUSION
toluene-d8, r.t.
A4
(a) (S)-
In summary, we have developed a new catalytic asymmetric
synthesis of chiral α-amino ketones, whose access has been
limited and challenging particularly for acyclic α-tertiary cases.
This is also a rare demonstration of asymmetric insertion
reactions of α-carbonyl sulfonium ylides, a family of versatile
and safe surrogates of diazocarbonyl compounds. With the
proper choice of chiral phosphoric acids, the mild
intermolecular C–N bond formation process proceeds
efficiently with free amines to provide a wide range of highly
enantioenriched α-amino ketones. Post-reaction enhancement
of the product enantiopurity was also demonstrated by an
operationally simple, stereochemically matched, Cu-CPA-
catalyzed kinetic resolution. The design of new chiral catalysts
also enabled the extension to α-amino esters. The products are
precursors to a range of important chiral amine derivatives,
including drug molecules and chiral ligands. Mechanistic
studies indicated that the enantioselectivity is controlled by
dynamic kinetic resolution in the rate-determining amination
step, rather than the initial protonation. Finally, the privileged
chiral phosphoric acids are now being applied to a new type of
substrates and reactions. This process also opens up a new
platform for the development of other related insertion reactions.
5
6
7
8
4.2 ppm
1a
(2 min)
A4
A4
(b)
(c)
+ (S)-
IM
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1a
+ (S)-
(7 min)
14
(d) standard sample of
1a 2a
A4
(standard reaction mixture at partial conversion)
(e)
+
+ (S)-
Figure 1. 31P NMR study of the reaction species involved (all with
10 mol% of A4).
O
O
A4
(S)-
(1 equiv)
ASSOCIATED CONTENT
Supporting Information.
Me
*
+ArNH2
Me
Ph
Ph
1a
No rxn
(1)
O
*
O
toluene-d8
r.t.
SPh2
P
A*
O
O
w. or w/o.
additional
14
, 1.3:1 dr
(fully characterized)
The Supporting Information is available free of charge on the
ACS Publications website.
IM
(observed)
A4
(S)-
51% D
Experimental procedures and compound characterization (PDF)
X-ray crystallography data (CIF)
ND2
O
NH2
H(D)
Me
A4
(S)-
(1 mol%)
Ph
(D)H
3a
1a
(0.2 mmol)
+
+
D5
D5
(2)
toluene-d8
r.t., 3h
N
AUTHOR INFORMATION
D5
2a
-d7
(1.0 mmol)
2a
-d5
(1.0 mmol)
k
H/kD = 1.0
-d
Corresponding Author
*lipf@mail.buct.edu.cn, sunjw@ust.hk.
Next, we also studied non-linear effects and observed
significant chirality amplification (Figure 2a). This prompted us
to examine the catalyst solubility. Surprisingly, stirring the
solution of racemic A4 in toluene at –40 oC resulted in obvious
precipitation over time, but the solution from enantiopure A4
remained clear (Figure 2b). It is believed that the formation of
less soluble hetero-aggregates in the racemic sample resulted in
precipitation. This might be responsible for the observed
dramatic chirality amplification, since the precipitation of a
racemic (or low ee) aggregate would enhance the catalyst
enantiopurity in solution.21
Author Contributions
§
These authors contributed equally to this work.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by National Natural Science
Foundation of China (21402005, 91956114), Beijing Municipal
Natural Science Foundation (2202040), Fundamental Research
Funds for the Central Universities (XK-1802-6, 12060093063),
and the Research Grants Council of Hong Kong (16302617,
16302318). We also thank Chao Yuan and Jun Li for initial studies
and Prof. Shou-Fei Zhu for helpful discussion.
(b)
(S)-A4
(±)-A4
(a)
0 h
(±)-A4
(S)-A4
ABBREVIATIONS
48 h
Super-hydride,
lithium
triethylborohydride;
TCCA,
trichloroisocyanuric acid; DDQ, 2,3-dichloro-5,6-dicyano-1,4-
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Page 6 of 8
Reaction of α-Aryl α-Diazoketones: An Efficient Route to Chiral α-
benzoquinone; TEA, triethyl amine; DCM, dichloromethane; THF,
tetrahydrofuran.
Aminoketones. Angew. Chem., Int. Ed. 2014, 53, 3913. Photoredox
catalysis: (f) Huang, X.; Webster, R. D.; Harms, K.; Meggers, E.
Asymmetric Catalysis with Organic Azides and Diazo Compounds
Initiated by Photoinduced Electron Transfer. J. Am. Chem. Soc. 2016,
138, 12636. Nucleophilic amination: (g) Miles, D. H.; Guasch, J.;
1
2
3
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(15) Pioneering studies and recent reviews of CPA-related catalysis:
(18) (a) Hemmerling, M.; Nilsson, S.; Edman, K.; Eirefelt, S.;
Russell, W.; Hendrickx, R.; Johnsson, E.; Mårdh, C. K.; Berger, M.;
Rehwinkel, H.; Abrahamsson, A.; Dahmén, J.; Ericsson, A. R.; Gabos,
B.; Henriksson, K.; Hossain, N.; Ivanova, S.; Jansson, A.-H.; Jensen,
T. J.; Jerre, A.; Johansson, H.; Klingstedt, T.; Lepistö, M.; Lindsjö, M.;
Mile, I.; Nikitidis, G.; Steele, J.; Tehler, U.; Wissler, L.; Hansson, T.
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(19) (a) Racemic 3a remained racemic upon treatment with (S)-A4
in toluene at room temperature, excluding the product deracemization
mechanism. (b) Although the free CPA was drawn in the catalytic cycle
for clarity, its adduct with amine is the actual form in the reaction
system. (c) Only a single broad peak at 4.2 ppm in 31P NMR was
observed for IM at room temperature, which is consistent with the rapid
equilibrium between the two stereo isomers. (d) The use of sulfonium
tetrafluoroborate salt can also directly generate IM under phase-
transfer condition, but the reactivity of the type of sulfonium salts is
much lower than that of sulfonium ylides.
(a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Enantioselective
Mannich-type Reaction Catalyzed by a Chiral Brønsted Acid. Angew.
Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. Chiral
Brønsted Acid-catalyzed Direct Mannich Reactions via Electrophilic
Activation. J. Am. Chem. Soc. 2004, 126, 5356. (c) Parmar, D.; Sugiono,
E.; Raja, S.; Rueping, M. Complete Field Guide to Asymmetric
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Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev.
2014, 114, 9047. (d) Akiyama, T.; Mori, K. Stronger Brønsted Acids:
Recent Progress. Chem. Rev. 2015, 115, 9277. (e) James, T.; van
Gemmeren, M.; List, B. Development and Applications of
Disulfonimides in Enantioselective Organocatalysis, Chem. Rev. 2015,
115, 9388.
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(16) The matched kinetic resolution was confirmed by the following
two experiments. Cu-catalyzed oxidation of amino ketones is known,
but we are not aware of a kinetic resolution with this system.
O
A4
(S)-
(10 mol%)
Me
+
3a
(S)-
3a
Cu(OAc)2 (10 mol %)
toluene (0.1 M)
air, 3 h
Ph
50% ee
O
racemic
37% conv., s = 21
(20) Tay, J. H.; Arguelles, A. J.; DeMars, M. D., II; Zimmerman, P.
M.; Sherman, D. H.; Nagorny, P. Regiodivergent Glycosylations of 6-
Deoxy-erythronolide B and Oleandomycin-Derived Macrolactones
Enabled by Chiral Acid Catalysis. J. Am. Chem. Soc. 2017, 139, 8570.
(21) For another example of non-linear effects due to CPA catalyst
solubility: Li, N.; Chen, X.-H.; Zhou, S.-M.; Luo, S.-W.; Song, J.; Ren,
L.; Gong, L.-Z. Asymmetric Amplification in Phosphoric Acid
Catalyzed Reactions. Angew. Chem., Int. Ed. 2010, 49, 6378.
as above
as above
A4
with (S)-
A4
with (R)-
3a
3a
3a
(S)-
(S)-
(S)-
87% ee
>99% ee
48% ee
(17) α-Aminotetralones are important precursors to a range of
biologically important molecules. For an example: Reifenrath, W. G.;
Fries, D. S. Aminotetralins as Narcotic Antagonists. Synthesis and
Opiate-Related Activity of l-Phenyl-2-aminotetralin Derivatives, J.
Med. Chem. 1979, 22, 204.
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TOC
1
O
O
2
3
4
HA*
(cat.)
R2
R2
R1
R'
*
R1
+ RNH2
S
NHR
R'
5
isomeric mixture
up to 99% ee
6
7
8
9
O
 -tertiary
 acyclic substrates
 monocarbonyl
via
dynamic
kinetic
R2
SR'2
R1
resolution
 amino esters OK
A*
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