Ligand-Controlled Rhodium-Catalyzed Site-Selective Asymmetric Addition of Arylboronic Acids to α,β-Unsaturated Cyclic N -Sulfonyl Ketimines

Article abstract of DOI:10.1021/acs.orglett.8b00289

A site-selective rhodium-catalyzed asymmetric 1,4-/1,2-addition of arylboronic acids to challenging α,β-unsaturated cyclic ketimines was realized through a ligand-controlled strategy. By employing different chiral olefin ligands, a ligand-controlled switc

Full text of DOI:10.1021/acs.orglett.8b00289

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ligand-Controlled Rhodium-Catalyzed Site-Selective Asymmetric
Addition of Arylboronic Acids to α,β-Unsaturated Cyclic N‑Sulfonyl
Ketimines
Chun-Yan Wu,†,‡ Yu-Fang Zhang,†,‡ and Ming-Hua Xu*,†
†State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: A site-selective rhodium-catalyzed asymmetric 1,4-/1,2-addition of arylboronic acids to challenging α,β-
unsaturated cyclic ketimines was realized through a ligand-controlled strategy. By employing different chiral olefin ligands, a
ligand-controlled switch in the reaction regioselectivity was attained for the first time. The reactions allow the synthesis of highly
valuable α,α-disubstituted chiral allylic amines and enantioenriched 1,4-adducts. Further product transformation provided easy
access to various quaternary carbon-containing chiral amines and amino acid derivatives bearing multifunctional groups.
rhodium-catalyzed sequential 1,4-/1,2-addition reactions with
arylboronic acids by employing different chiral olefin ligands,
which allowed the rapid construction of benzosulfamidates
bearing two gem-diaryl stereocenters with high enantiopurities
(Scheme 1a).4j Despite the notable success in achieving regio-
hodium-catalyzed asymmetric addition of organoboron
1,2
imines,3,4 and
Rreagents to electron-deficient olefins,
carbonyl compounds5 constitutes an important and powerful
method for the construction of carbon−carbon bonds. Among
the electron-deficient conjugated substrates, α,β-unsaturated
imines represent an intriguing class of substrates, as they might
be subjected to 1,4-addition and 1,2-addition simultaneously
under rhodium catalysis. Surprisingly, despite the fact that
many beautiful examples of asymmetric 1,2-addition of imines
have been realized,3,4 to our knowledge, the utilization of α,β-
unsaturated imines for stereoselective 1,2-addition to access
chiral allylic amines has not been reported. On the other hand,
asymmetric 1,4-addition of α,β-unsaturated imines is also rarely
explored, in sharp contrast to the achievements with α,β-
unsaturated ketones/esters/amides.1,2 Only recently has a
successful example of rhodium-catalyzed enantioselective 1,4-
addition of arylboronic acids to α,β-unsaturated imino esters
using a chiral bicyclic bridgehead phosphoramidite ligand been
disclosed, which allowed the synthesis of γ,γ-diaryl-α,β-
dehydroamino esters.6 Therefore, achieving either 1,4- or 1,2-
addition of α,β-unsaturated imines in a regio- and enantiose-
lective manner remains a particularly challenging task. It would
be ideal to develop a regiodivergent highly enantioselective
addition of α,β-unsaturated imines through ligand/catalyst
tuning.
Scheme 1. Rh-Catalyzed Asymmetric 1,4-/1,2-Addition of
α,β-Unsaturated Ketimines
and enantioselective 1,4-addition of these α,β-unsaturated
ketimines, it is exceedingly difficult to access α,α-disubstituted
chiral allylic amines via direct 1,2-addition by tuning the catalyst
system. The low reactivity of the CN may be attributed to
the double conjugation with the CC and aromatic ring in the
molecule. To address this issue, we designed an unprecedented
type of α,β-unsaturated cyclic ketimines8 and wanted to achieve
Over the past few years, our group has been interested in
rhodium-catalyzed enantioselective addition of imines using
simple chiral olefins as ligands.3c,f,g,4c,g−k,7 With challenging α,β-
unsaturated cyclic N-sulfonyl ketimines, we recently developed
a catalytic stereoselective double arylation process through
Received: January 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00289
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
both asymmetric 1,4- and 1,2-addition through direct control of
the chiral ligand. Herein, we describe the first example of
rhodium-catalyzed site-selective asymmetric addition of ar-
ylboronic acids to α,β-unsaturated cyclic ketimines (Scheme
1b). A ligand-controlled switch in the reaction regioselectivity
was attained.
Table 1. Optimization of Reaction Conditions
Our initial investigation was carried out by evaluating the
reaction of the newly designed α,β-unsaturated five-membered
cyclic N-sulfonyl imine 1a with p-methoxyphenylboronic acid
2a under conditions similar to our previously reported ones in
the presence of the optimal C1-symmetric chiral diene ligand9
and branched sulfur-olefin ligand (Scheme 2). The diene ligand
3a
4a
yield
ee
yield
bc
ee
bc
,
,
entry
L
additive
t (°C)
(%)
(%)
(%)
(%)
1
2
3
4
5
L5
L5
L5
L5
L5
L5
L5
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
K2HPO4
KOH
K3PO4
KF
rt
92
94
90
76
88
15
79
85
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
93
94
93
92
93
93
93
93
−
−
−
−
−
−
−
−
−
−
−
0
−
−
−
−
−
−
−
−
99
98
98
97
97
97
95
98
98
98
98
rt
0
rt
0
rt
0
Scheme 2. Ligand Screening
KHF2
KOH
KOH
KOH
K2HPO4
K2HPO4
K2HPO4
K2HPO4
KHF2
K3PO4
KOH
KF
rt
0
d
6
rt
0
e
7
f
rt
0
8
rt
0
9
rt
10
20
41
40
47
34
30
49
54
60
86
10
11
12
13
14
15
16
50
80
100
80
80
80
80
80
80
80
g
17
KF
gh
,
18
19
KF
gi
,
L1 exhibited truly excellent catalytic reactivity for 1,4-addition,
giving the corresponding β-gem-diaryl substituted ketimine 3a
solely with commendable enantioselectivity (86% ee). For
comparison, C2-symmetric diene ligand L3 was evaluated;
however, a much lower ee was obtained. Gratifyingly, by
examination of the substituents on the phenyl ring of chiral
[2.2.2]dienes, ligand L5 bearing a pentafluorobenzene moiety
was found to be superior to the others, giving the sole 1,4-
addition product in 92% yield and 93% ee. On the other hand,
we were very pleased to find that the sulfur-olefin ligand L6
showed exclusive 1,2-addition performance, which led to the
formation of the desired quaternary-containing 1,2-adduct 4a
with extremely high ee (99%), albeit in low yield (10%).
Inspired by these promising results, further examination on
the reaction parameters including additive, solvent, temper-
ature, catalyst loading, and reactant ratio were subsequently
carried out (Table 1). As for 1,4-addition, among the various
additives (entries 1−5), the enantioselectivity remained nearly
constant and KOH gave the best yield (94%) (entries 1−5).
Varying the solvent did not furnish better results (entries 6−7).
Lowering the catalyst loading would lead to a somewhat
diminished yield, while still maintaining the enantioselectivity
(entry 8). Notably, no 1,2-adducts formation was observed
even with an excess amount of arylboronic acid 2a. In the study
of 1,2-addition, we investigated the effect of temperature
(entries 10−14). An increase to 41% was observed at 80 °C
(entry 11); however, no further improvement was attained at
higher temperature (entry 12). The screening of additives
indicated that KF could facilitate rhodium/sulfur-olefin L6 in
exhibiting better catalytic activity, giving the 1,2-adduct 4a in
49% yield with 98% ee (entry 16). In the presence of 1.0 equiv
of aqueous KF (1.5 M), the reaction afforded 4a in a slightly
increased yield (54%, entry 17). Fortunately, increasing the
amount of p-methoxyphenylboronic acid was found to be
beneficial to the 1,2-addition yield. With 6 equiv of arylboronic
acid, the reaction proceeded with high efficiency and great
KF
a
The reaction was carried out with 0.1 mmol of α,β-unsaturated cyclic
imine 1a and 0.2 mmol of 2a in the presence of 5 mol % of [Rh]/L
with 1.0 mL of solvent. Isolated yield. Determined by chiral HPLC.
Dioxane was used. DCE was used. With 3 mol % of [Rh]/L5. 1.0
equiv of KF (1.5 M) was used. 4 equiv of 2a were used. 6 equiv of 2a
b
c
d
e
f
g
h
i
were used.
stereoselectivity, providing the corresponding 4a in good yield
(86%) and enantioselectivity (98% ee) (entry 19). Under these
conditions, the formation of only a trace amount of 1,4-addition
products was detected, suggesting the unique site-differ-
entiation ability of the catalyst. It is worth noting that this is
the first achievement of rhodium-catalyzed enantioselective 1,2-
addition of α,β-unsaturated imines.
After identifying the two optimal reaction conditions, we
proceeded to evaluate the scope of the reactions. As revealed in
Scheme 3, 1,4-addition reactions involving α,β-unsaturated
cyclic N-sulfonyl ketimine 1a with a wide range of arylboronic
acids 2 bearing diverse steric and electronic properties were all
found to be successful, affording the corresponding β-gem-
diaryl substituted ketimines without any accompanying 1,2-
products in high yields and excellent enantioselectivities (85−
99% ee). Imines bearing diverse substituents on the phenyl ring
were also tolerated in this reaction. By simply switching
acceptor and donor aryl substituents, both enantiomers of the
product could be smoothly accessed (3g vs 3g′). Of particular
note is that more challenging β-alkyl substituted substrates were
also suitable for the conjugate addition (3q−v). Having
established the highly enantioselective 1,4-addition, we turned
our attention to the generality of 1,2-addition at the ketimine
site using sulfur-olefin ligand L6 (Scheme 4). In most cases, the
reaction proceeded well and gave uniformly high enantiose-
lectivities (95−98% ee). With arylboronic acid bearing an para-
electron-donating group, the reaction of α,β-unsaturated cyclic
ketimine 1a produced the desired 1,2-adducts in moderate to
B
DOI: 10.1021/acs.orglett.8b00289
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Letter
enantioselectivity (99% ee). With the use of alkylboronic acids,
neither 1,4-addition nor 1,2-addition occurred.
Scheme 3. Rh-Catalyzed Asymmetric Enantioselective 1,4-
Addition of α,β-Unsaturated Ketimines
a b c
, ,
To demonstrate the synthetic utility, we have applied this
method for the synthesis of some structurally and biologically
interesting compounds (Scheme 5). The ring-opening reaction
Scheme 5. Synthetic Transformations of Addition Products
a
The reaction was carried out with 0.1 mmol of α,β-unsaturated cyclic
ketimine 1, 2.0 equiv of arylboronic acid 2 in the presence of 5.0 mol
% of [Rh]/L5, and KOH (1.5 M, 0.5 equiv) in 1.0 mL toluene at rt for
b
c
1−8 h. Isolated yield. Determined by chiral HPLC.
of the 1,4-adduct 3a was carried out by treatment with NaBH4
and LAH at room temperature, and followed by the N-Boc-
protection of amine, giving gem-diaryl substituted amino
alcohol diastereomers 5a and 5b without loss of enantiopurity.
Similarly, ring cleavage of the 1,2-adducts with LAH could also
occur easily, leading to highly functional α,α-disubstituted chiral
allylic amines bearing a quaternary stereocenter and β-amino
alcohol framework, which are otherwise difficult to be prepared.
Such compounds are extremely valuable synthetic building
blocks. For example, exposure of the ring-opening product 6a
with BTC smoothly provided 4,4-disubstituted 2-oxazolidinone
7 in 80% yield. Through a three-step conversion involving
Dess-Martin oxidation, Pinnick oxidation (NaClO2, NaH2PO4,
2-methyl-2-butene, tBuOH, H2O),10 and esterification from the
Boc-protected intermediate 6b, challenging α,α-disubstituted-
β,γ-unsaturated amino acid ester 8 could be readily obtained.
On the other hand, upon treatment of appropriate
nucleophiles, uniquely functionalized tetrasubstituted chiral
allylic amines such as 9 and 10 could be successfully
furnished.11,12 It should be noted that no ee erosion was
observed in all these transformations. Thus, we were able to
flexibly construct diverse chiral amines bearing different
substituent groups in a highly enantioenriched manner, which
could be useful in medicinal chemistry.
Single-crystal X-ray analysis of the 1,4-adduct 3e and
compound 6b (CCDC 1819866, 1819867) derived from the
1,2-adduct 4a allowed us to determine the absolute
configurations of the newly formed carbon stereocenters
(Figure 1). To elucidate the stereocontrol of the 1,4-addition
using the diene ligand and the 1,2-addition using sulfur-olefin
ligand, two possible transition-state models were illustrated.
Although the detailed reaction mechanism remains unclear, the
switch in the reaction regioselectivity suggests two unique
coordination modes of the rhodium and substrate in the
presence of two different ligands. In both cases, the sulfonyl
moiety of the imine substrates orients away from the
substitution group attached to the double bond of the olefin
ligands to minimize the steric interaction. Thus, the stereo-
Scheme 4. Rh-Catalyzed Asymmetric Enantioselective 1,2-
Addition of α,β-Unsaturated Ketimines
a b c
, ,
a
The reaction was carried out with 0.1 mmol of α,β-unsaturated cyclic
ketimine 1, 2.0 equiv of arylboronic acid 2 in the presence of 5.0 mol
% of [Rh], 5.0 mol % of ligand L6, and KF (1.5 M, 1.0 equiv) in 1.0
b
c
mL toluene at 80 °C for 24 h. Isolated yield. Determined by chiral
HPLC.
good yields. However, the use of arylboronic acid having an
electron-withdrawing group on the phenyl ring led to an
obvious yield drop, while the enantioselectivity still remained
excellent (4d). The meta-substituted arylboronic acids were
compatible with the 1,2-addition, and the corresponding
products (4e, 4f) could be obtained in moderate yields. The
substitution pattern and the electronic nature of the aryl group
attached to the double bond of α,β-unsaturated ketimines did
not seem to affect the enantioselectivity of the products (4g,
4h, 4i). When a less reactive β-methyl substituted substrate was
employed, the yield was low (<20%), albeit in excellent
C
DOI: 10.1021/acs.orglett.8b00289
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Organic Letters
Letter
ORCID
Ming-Hua Xu: 0000-0002-1692-2718
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation of China
(21325209, 21472205, 81521005) for financial support. We
are especially grateful to Dr. Stefan Abele in Actelion
Pharmaceuticals Ltd., Switzerland for his very generous
donation of the key intermediate (1R,4R)-5-phenylbicyclo-
[2.2.2]oct-5-en-2-one for diene preparation.
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Figure 1. X-ray crystal structures of 3e and 6b and the proposed
transition-state models.
chemical outcome of both addition reactions could be assigned
by analogy assuming the same reaction pathway.
To summarize, we have developed a site-selective rhodium-
catalyzed asymmetric 1,4-/1,2-addition of arylboronic acids to
the challenging α,β-unsaturated cyclic ketimines through a
ligand-controlled strategy. C1-symmetric chiral diene and
branched chiral sulfur-olefin were utilized to afford stereo-
specific 1,4- and 1,2-adducts, respectively. This protocol enables
efficient synthesis of various chiral β-gem-diaryl substituted
ketimines and α,α-disubstituted chiral allylic amines bearing
multifunctional groups in a highly regio- and enantioselective
manner under mild conditions. Of particular note, this method
provides the first achievement of rhodium-catalyzed regiose-
lective asymmetric 1,2-addition to α,β-unsaturated ketimines.
Owing to the synthetic importance of the obtained products
and the difficulty of their accessibility by other transformations,
we believe that this work should be of great interest to both
organic and medicinal chemists.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00289.
Experimental procedures and spectroscopic data of all
new compounds (PDF)
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Accession Codes
CCDC 1819866−1819867 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
(7) For reviews on chiral olefin ligands: (a) Defieber, C.;
*E-mail: xumh@simm.ac.cn.
Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47,
D
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Letter
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