Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium-Catalyzed Enantio-, Chemo- and Diastereoselective Methylene C(sp3)?H arylation

Article abstract of DOI:10.1002/ange.202008952

The enantioselective desymmetrizing C?H activation of α-gem-dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp³)?H bonds and increased rotational freedoms of the acyclic systems add tremendous difficulties for chemo- and stereocontrol. We have developed a method for the synthesis of acyclic aliphatic amides with α,β-contiguous stereogenic centers via Pd^II-catalyzed asymmetric arylation of unbiased methylene C(sp³)?H, in good yields and with high levels of enantio-, chemo- and diastereoselectivity (up to >99 % ee and >20:1 d.r.). Successive application of this method enables the sequential arylation of the gem-dialkyl groups with two different aryl iodides, giving a range of β-Ar¹-β′-Ar²-aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity.

Full text of DOI:10.1002/ange.202008952

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Titel: Synthesis of Acyclic Aliphatic Amides with Contiguous
Stereogenic Centers via Pd-Catalyzed Enantio-, Chemo- and
Diastereoselective Methylene C(sp3)-H arylation
Autoren: Ye-Qiang Han, Xu Yang, Ke-Xin Kong, Yao-Ting Deng, Le-
Song Wu, Yi Ding, and Bing-Feng Shi
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Zitierweise: Angew. Chem. Int. Ed. 10.1002/anie.202008952
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10.1002/ange.202008952
Angewandte Chemie
COMMUNICATION
Synthesis of Acyclic Aliphatic Amides with Contiguous
Stereogenic Centers via Pd-Catalyzed Enantio-, Chemo- and
Diastereoselective Methylene C(sp3)H arylation
Ye-Qiang Han[a], Xu Yang[b], Ke-Xin Kong[a], Yao-Ting Deng[a], Le-Song Wu[a], Yi Ding[a] and Bing-Feng
Shi*[a]
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry, CAS
[a]
Y.-Q. Han, K.-X. Kong, Y.-T. Deng, L.-S. Wu, Y. Ding, Prof. Dr. B.-F. Shi
Department of Chemistry
Zhejiang University
Hangzhou 310027 (China)
E-mail: bfshi@zju.edu.cn
[b]
X. Yang
School of Biotechnology and Health Sciences
Wuyi University
Jiangmen 529020 (China)
Supporting information for this article is given via a link at the end of the document.
Abstract: The enantioselective desymmetrizing C–H activation of α-
gem-dialkyl acyclic amides remains challenging because the
availability of four chemically identical unbiased methylene C(sp3)H
bonds and increased rotational freedoms of the acyclic systems add
tremendous difficulties for chemo- and stereocontrol. Herein, we
develop the synthesis of acyclic aliphatic amides with α,β-contiguous
stereogenic centers via Pd(II)-catalyzed asymmetric arylation of
unbiased methylene C(sp3)–H in good yields and with high levels of
enantio-, chemo- and diastereoselectivity (up to >99% ee and >20:1
dr). Successive application of this protocol enables the sequential
arylation of the gem-dialkyl groups with two different aryl iodides,
giving a range of β-Ar1-β’-Ar2-aliphatic acyclic amides containing three
contiguous stereogenic centers with excellent diastereoselectivity.
were noted as outlined in Scheme 1b. First, four chemically
identical and equally accessible unbiased methylene C(sp3)-H
bonds within reach of the directing group (DG) raised significant
a) Classic Approaches
O
O
OH
RX
NH2
Conjugate
Addition[4]
FG
O
Chiral Pool[3]
alkyl
XR
O
Me
alkyl
X = N, O
R
DG
O
R
O
Reductive Claisen
Asymmetric
C-H Activation
Rearrangement [5]
b) Challenges
chemo-, diastereo-, and enantioselectivity
Aliphatic acyclic amides containing α,β-contiguous stereogenic
centers are a structural element widely found in natural products
and biologically important compounds. For example,
valnoctamide (2-ethyl-3-methyl valeramide, VCD, Nirvanil®) and
its analogues featuring this framework have a board spectrum
antiepieptic activity which are used for the treatment of
neuropathic pain.[1] Although catalytic stereodivergent process
has been well developed for the enantio- and diastereoselective
creation of multiple stereocenters in a single-pot operation,[2] the
construction of those chiral α,β-contiguous frameworks remains
challenging. Current strategies rely on the multiple
transformations from chiral pool precursors (e.g. amino acids),[3]
asymmetric conjugate addition,[4] and reductive Claisen
rearrangement[5] (Scheme 1a). To supplement these conventional
methods, we sought to develop an enantio-, diastereo- and
chemoselective methylene C(sp3)-H functionalization of aliphatic
carboxylic amides, a type of prevalent feedstocks in nature, as
shown in Scheme 1a. The success of this strategy could provide
a straightforward approach to these chiral architectures in a more
atom- and step-economical manner. However, we were aware of
the dearth of methods for enantioselective desymmetrizing C-H
activation of α-gem-dialkyl acyclic amides.[6] Several challenges
O
O
O
H
H
H
DG
DG
Pd
*
R
DG
vs
( )n
Pd
H
H
L
H
n=1,2,3
L
H
R
H
L
L
cyclic system
increased rotational freedoms
Ar
acyclic system

= identical C H bonds
-branched acyclic system
Ar
O
O
Ar
O
DG
N
NHArF
NHArF
vs
H
DG = ArF, m:d = 3:1; dr = 4:1[7a]
DG = Q, m:d = 3.6:1; dr = 3:2[7b]
65%, 3:1 dr
ee unchecked[9]
94% ee, 95:5 dr
c) This work
F
H
H
O
Ar
R
O
cat. Pd(II)
PIP
PIP
L2
cat. (S)-
OH
OH
N
R
N
R
H
Ar-I
H
N
R
High enantioselectivity (up to > 99% ee)
High diastereoselectivity (dr > 18:1)
Good chemoselectivity (m:d > 12:1)
F
(S)-L2
Scheme 1. Synthesis of α-branched acyclic amides containing α,β-contiguous
stereogenic centers via enantioselective desymmetrizing C–H activation.
1
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10.1002/ange.202008952
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COMMUNICATION
difficulties in controlling chemo- and stereocontrol. As a matter of
fact, previous studies of the arylation of α-gem-diethyl acyclic
amide led to poor mono-selectivity and diastereoselectivity
iodide substituted on the para-position of the aryl iodide was also
tolerated (68%, 16:1 dr, 91% ee, 3i). It was worth mentioning that
aryl iodides bearing free hydroxyl (75%, >20:1 dr, >99% ee, 3o)
and phosphonic acid diesters groups (68%, 18:1 dr, 86% ee, 3p)
were also survived, affording the products in good stereocontrol.
Next, a series of aliphatic amides with other branched chains were
examined. gem-Dipropyl aliphatic amides gave the corresponding
products in good yield and stereoselectivity (83%, >20:1 dr, 94%
ee, 3q). Amides with sterically hinder groups at -position (2-
naphthyl, phenyl) were also compatible, giving good results (3r-
3t, 62%-87% yield, >20:1 dr, 90%-92% ee). This protocol also
showed synthetic potential for kinetic resolution, giving arylation
product 3u in high diastereo- and enantioselectivity (>20:1 dr, 90%
ee), albeit with low conversion (20% yield). It’s worth mentioning
that all the reaction gave the corresponding mono-arylation
products and only trace of di-arylation products could be observed
(Scheme
1b,
e.g.
2-ethyl-butyramide).[7]
Second,
desymmetrization of -gem-dialkyl acyclic amides via asymmetric
methylene CH activation is fundamentally more challenging than
the cyclic version and α-unbranched ones. The acyclic system
has increased rotational freedoms, leading to the difficulty of
stereocontrol. Therefore, although the enantioselective CH
functionalization of cycloalkane-type substrates have been well
studied,[8-10] the adoption to the α-branched acyclic system
generally gave unsatisfactory results.[9] For example, the Gooßen
and Yu group achieved the Pd-catalyzed β-C-H arylation of
methylene groups in cycloalkanes with high enantio- and
diastereoinduction. However, when the procedure was applied to
α-gem-dialkyl acyclic systems, the enantioselectivity and
diastereoselectivity eroded drastically (Scheme 1b, cyclohexyl, 94% on 1H NMR analysis of the crude products. The absolute
ee, 95:5 dr; α-diethyl, 3:1 dr, ee unchecked).[9,10] The flexibility of
acyclic systems necessitates the judicious choice of proper chiral
ligand and DG to enable the efficient stereoinduction and tune the
reactivity. Herein, we describe our solution to this challenge by
the combination of bidentate 2-pyridinyisopropyl (PIP) auxiliary
and 3,3’-F2-BINOL. This protocol enables the successful
synthesis of acyclic aliphatic amides with α,β-contiguous
stereogenic centers by desymmetric C-H arylation of gem-dialkyl
C(sp3)H bonds in high enantio-, diastereo- and chemoselectivity
(Scheme 1c).
configuration of arylation product 3a was determined by X-ray
crystallographic analysis.[17]
Table 1. Scope with respect to aryl iodides and aliphatic amides[a]
PdI2 (10 mol%)
L2 (20 mol%)
PIP
Ar
O
O
K2CO3 (2.5 equiv)
PIP
R1
N
R1
N
+
Ar-I
H
H
t-BuOH (0.30 mL)
95 oC, 16 h, air
N
R2
R2
1a
2
3
3a, R = H, 75% yield, >20:1 dr, 98% ee
3b, R = OMe, 68% yield, >20:1 dr, 92% ee
3c, R = Et, 80% yield, >20:1 dr, 93% ee
3d, R = Me, 81% yield, >20:1 dr, 96% ee
R
We initiated the investigations with the reaction of PIP-derived
2-ethylbutanoic amide (1a)[11,12] and iodobenzene (2a) in the
presence of (S)-CPA,[13] a type of chiral ligand applied in
desymmetrization of methylene C-H bonds,[13f] but very low
chemo- and enantioselectivity was detected (m:d = 1.7:1, 2% ee,
Table S1, entry 1). t-Bu-N-Boc-Leu, a privileged ligand widely
used in asymmetric C-H activation,[14] was then tested. Even
worse result was obtained (m:d = 0.9:1, 2% ee, entry 2). To our
delight, when 3,3’-F2-BINOL (S)-L2 was used as ligand, high ee
was obtained, albeit with moderate ratio of mono:di selectivity
(Figure S1a, 90% ee, m:d = 3.8:1).[15,16] Various other 3,3’-
disubstituted BINOLs (L3-L9) were also investigated and (S)-L2
was found to be the optimal one (Figure S1a). Finally, high levels
of enantio- and chemoselectivity was achieved by reducing the
reaction temperature to 95 oC (3a, 75%, m:d = 12.5:1, 98% ee).
We then evaluated the ligand effect on controlling
chemoselectivity under the optimized reaction conditions (Figure
S1b). Compared to the racemic reaction using (BnO)2PO2H L11
as ligand, the use of (S)-L2 could significantly enhance the
catalytic activity and improve the chemoselectivity [(S)-L2: 3a,
75%; 3aa, 6% vs L11: 3a, 39%; 3aa, 24%]. Further kinetic studies
indicated (S)-L2 could also significantly accelerate the reaction
rate. The reaction of rac-3f with aryl iodide 2f using (S)-L2 as
ligand led to the recovery of (2S, 3S)-3f in 58% yield with 48% ee.
Therefore, we rationalized that the origin of good chemoselectivity
might be partly due to the major enantiomer of the monoarylated
product is difficult to undergo the diarylation while the minor
enantiomer transforms into the diarylated product more easily,
which also partly account for better enantioselectivity (Figure S1c).
With the optimized reaction conditions in hand, we then
examined the scope of various aryl iodides (Table 1). In general,
O
3e R = Ph
,
, 78% yield, 20:1 dr, 96% ee
[b]
PIP
3f R = Ac
,
, 71% yield, >20:1 dr, 98% ee
N
H
3g R = CF
,
3, 74% yield, >20:1 dr, 98% ee
3h, R = Cl, 87% yield, >20:1 dr, 93% ee
3i, R= I, 68% yield, 16:1 dr, 91% ee
3a
CCDC 2010220
OMe
O
Me
O
CHO
Ac
O
O
PIP
PIP
PIP
PIP
N
H
N
N
N
H
H
H
3m, 64% yield,
>20:1 dr, 96% ee[b]
3j, 74% yield
>20:1 dr, 95% ee
3k, 88% yield
>20:1 dr, 96% ee
3l, 58% yield
>20:1 dr, 92% ee[b]
OEt
Me
EtO
P
OH
O
O
O
O
O
PIP
PIP
O
N
H
N
H
PIP
N
H
PIP
N
H
3n, 73% yield
>20:1 dr, 92% ee
3o, 75% yield
>20:1 dr, >99% ee
3p, 68% yield
18:1 dr, 86% ee[b]
3q, 83% yield
>20:1 dr, 94% ee
Me
Me
kinetic resolution
Ac
Me
O
O
O
PIP
PIP
O
N
H
Ph
N
PIP
2-naphthyl
2-naphthyl
N
H
PIP
H
N
H
F
Ph
F
3r
3s
3t
3u 20% yield
>20:1 dr, 91% ee[c]
, 75% yield
>20:1 dr, 92% ee
, 62% yield
>20:1 dr, 90% ee
, 93% yield
>20:1 dr, 91% ee
[a] Conditions A: 1a (0.10 mmol), 2 (3.5 equiv), PdI2 (10 mol%), K2CO3 (2.5
equiv), (S)-L2 (20 mol%), t-BuOH (0.3 mL), 16 h, 95 oC under air. The dr value
was determined by 1H NMR. Ee was determined by chiral HPLC. [b] Conditions
B: 2 (2.0 equiv), t-BuOH (1.0 mL), 110 oC. [c] (S)-L9 as ligand, 2f (2.0 equiv).
The efficiency and practicality of this protocol was further
proved by the compatibility with aryl iodides derived from complex
organic molecules, such as natural products and drug molecules.
The drug molecule, vinpocetine, was successfully incorporated at
the proper position (4a, 64% yield, >20:1 dr, 96% ee). A series of
a
range of electron-withdrawing and electron-donating
substituents were tolerated well with high levels of diastereo- and
enantioselectivity (>20:1 dr, 91% to 96% ee, 3a-3o). Notably,
2
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10.1002/ange.202008952
Angewandte Chemie
COMMUNICATION
aryl iodides derived from natural products could also be effectively
myriad of aliphatic amides with three contiguous stereogenic
utilized and gave satisfactory results (4a-4d, >20:1 dr, 90% to 93% centers (Table 2, 5a-5h, 49%-80% yield, > 20:1 dr). The
ee). A ferrocene moiety could also be introduced and well
tolerated (4e, 64%, >20:1 dr, 92% ee).
stereochemistry of 5a-5h was assigned based on the formation of
a sterically more favored trans-palladacycle Int-A.[18]
Finally, the PIP directing group could be easily removed by
[19]
treating with NOBF4 and followed by the formation of benzyl
O
ester without erosion of enantiopurity (Scheme 3b, 6a, 69%, 95%
ee, >20:1 dr). Another unbiased -methylene could be
transformed through a highly diastereoselective Pd-catalyzed C-
H alkenylation followed by an aza-Wacker cyclization sequence
to form chiral -lactams 6b, which could be further elaborated.[15c]
O
O
N
O
O
N
O
O
Me
O
O
PIP
N
PIP
PIP
H
N
N
H
H
Me
4a, 64% yield
>20:1 dr. 96% de
4b, 66% yield
>20:1 dr, 90% de
4c, 75% yield
>20:1 dr. 93% de
Me
Me
Pd(OAc)2
K2CO3
(BnO2)PO2H
i) NOBF4, Py
ii) BnBr, Acetone
O
Fe
O
O
O
t-BuOH
PIP
N
O
PIP
PIP
125 o
C
N
N
OBn
H
O
H
O
I
p-Tol
p-Tol
6b
80% yield, >20:1 d.r.
O
O
O
6a, 69% yield
>20:1 dr, 95% ee
3d
PIP
>20:1 dr, 96% ee
N
H
Scheme 3 Synthetic transformations.
4d
4e
, 47% yield,
>20:1 dr. 92% de
, 64% yield,
>20:1 dr. 92% ee
In summary, we reported the synthesis of acyclic aliphatic
amides with contiguous stereogenic centers via Pd(II)-catalyzed
asymmetric methylene C(sp3)H arylation in good yields and with
high level of enantio-, chemo- and diastereoselectivity for the first
time. The readily available 3,3’-F2-BINOL ligand plays a crucial
role in distinguishing four chemically identical β-methylene
C(sp3)-H and enhancing mono-selectivity. The protocol is
scalable and applicable to a wide range of aryl iodides. The rapid
preparation of chiral aliphatic amides bearing two or three
contiguous centers provide a versatile platform for constructing
,-chiral centers in asymmetric synthesis.
Scheme 2 Aryl iodides containing complex organic molecules.
Table 2 Subsequent arylation of the remaining unbiased methylene group[a]
Ac
Ac
Ar1
O
O
O
1a
4.3 mmol
1.01 g
Conditions C
Conditions B
N
PIP
PIP
Ar2
I
N
Ar1 I (
2f
)
PdII
N
N
H
H
H
L
Ar2
H
Int-A
3f, 61% (0.92 g)
5
96% ee, >20:1 d.r.
Ac
Ac
Ac
Ac
O
O
O
O
PIP
PIP
PIP
PIP
N
N
N
N
H
H
H
H
Acknowledgements
Me
I
Ph
5c
t-Bu
5d
5a
5b
, 56%, >20:1 d.r.
, 80%, >20:1 d.r.
, 66%, >20:1 d.r.
, 70%, >20:1 d.r.
Financial support from the NSFC (21925109, 21772170), Out-
standing Young Talents of Zhejiang Province High-level
Personnel of Special Support (ZJWR0108) and the Fundamental
Research Funds for the Central Universities (2018XZZX001-02)
is gratefully acknowledged.
Ac
Ac
Ac
Ac
O
O
O
O
PIP
PIP
PIP
N
H
N
H
N
H
PIP
N
H
NO2
5g
, 56%, >20:1 d.r.
Me
Ac
Keywords: palladium • CH activation • enantioselectivity •
diastereoselectivity • chemoselectivity • contiguous stereogenic
centers
5e
5f
5h
, 77%, >20:1 d.r.
, 55%, >20:1 d.r.
, 49%, >20:1 d.r.
[a] Conditions C: 3f (0.10 mmol), 2 (2.0 equiv), Pd(OAc)2. (10 mol%), K2CO3
(2.5 equiv), (BnO)2PO2H (20 mol%), t-BuOH (1.0 mL), 16 h, 125 oC under air.
The dr value was determined by 1H NMR.
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In our initial investigation, we observed that diarylation product
3aa was obtained in 24% yield in the presence of (BnO)2PO2H for
the racemic condition (Figure S1b). We envisioned that the
sequential arylation could enable the successful introduction of
two distinct aryl groups, providing an efficient approach to prepare
chiral aliphatic amides bearing three contiguous stereogenic
centers. Thus, a gram-scale synthesis of monoarylated product 3f
was conducted first, affording 0.92 g 3f with high stereocontrol
(Table 2, 61%, 96% ee, >20:1 dr). After the asymmetric mono-
arylation, subsequent diastereoselective -methylene arylation
with various different aryl iodides were performed, affording a
[2]
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Angewandte Chemie
COMMUNICATION
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10.1002/ange.202008952
Angewandte Chemie
COMMUNICATION
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The enantioselective synthesis of acyclic aliphatic amides with contiguous stereogenic centers via Pd(II)-catalyzed asymmetric
methylene C(sp3)H arylation in good yields and with high levels of enantio-, chemo- and diastereoselectivity. The readily available
3,3’-F2-BINOL ligand plays a crucial role in distinguishing four chemically identical β-methylene C(sp3)-H and enhancing mono-
selectivity.
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