Enantioselective Mannich Reaction of Glycine Iminoesters with N-Phosphinoyl Imines: A Bifunctional Approach

Article abstract of DOI:10.1021/acs.orglett.9b03223

A bifunctional catalytic approach for the asymmetric Mannich reaction of glycine iminoesters with N-phosphinoyl imines has been developed. By the combination of metal catalysis and organocatalysis, the vicinal two stereogenic centers were efficiently constructed, affording a wide range of syn-diamino esters in high yields with excellent enantio- and diastereoselectivities (up to >99:1 dr, 99% ee).

Full text of DOI:10.1021/acs.orglett.9b03223

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Mannich Reaction of Glycine Iminoesters with
N‑Phosphinoyl Imines: A Bifunctional Approach
Changhui Zhang, Jiao Yang, Wenqiang Zhou, Qiuyuan Tan, Zhao Yang, Ling He,* and Min Zhang*
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, China
S
* Supporting Information
ABSTRACT: A bifunctional catalytic approach for the asymmetric Mannich reaction of glycine iminoesters with N-
phosphinoyl imines has been developed. By the combination of metal catalysis and organocatalysis, the vicinal two stereogenic
centers were efficiently constructed, affording a wide range of syn-diamino esters in high yields with excellent enantio- and
diastereoselectivities (up to >99:1 dr, 99% ee).
α,β-Diamino acids and their derivatives are the central
structural units in a number of bioactive natural products
and therapeutics.1 Some selected examples are shown in Figure
1. Ficellomycin is a potentially pathogen-specific antibiotic
simultaneously creating two adjacent stereocenters, represents
one of the most powerful and straightforward approaches. The
N-activating groups of the imine electrophiles are usually
crucial for the reactivity and stereoselectivity of this type of
reaction.7b,g,8b Although N-sulfonyl13 and N-Boc14 imines have
been widely used as electrophiles in enantioselective glycinate
Mannich reactions, these studies often suffer from several
drawbacks that limit their utility, such as difficulty in cleaving
the N-protecting groups of the products,9c instability of the
imine substrates, and narrow substrate scope. In this respect,
N-phosphinoyl imines may be a suitable alternative owing to
their well-known better stability and ease of cleaving the
phosphoryl group of the products,15 as well as application of
chiral N-phosphoryl diamine compounds as catalysts or ligands
in asymmetric synthesis.16 However, the glycinate Mannich
reaction of N-phosphinoyl imines remains largely undeveloped,
probably because of their relatively low reactivity. Zhao and co-
workers17 reported a biomimetic aldehyde-catalyzed Mannich
reaction of N-phosphinoyl imines with glycinates, which
delivered N-phosphoryl diamino acid esters with high levels
of anti-diastereoselectivity and enantiocontrol. Despite this
advancement, the syn-selectivity Mannich reaction between N-
phosphinoyl imines and glycine iminoesters has not been
reported.18 Therefore, development of new and efficient
catalytic systems that afford N-phosphoryl diamino esters
with complementary stereochemistry is highly desirable.
In recent years, the combination of metal catalysis and
organocatalysis has emerged as a highly efficient and powerful
strategy for implementing unprecedented transformations with
exciting results.19 Recently, our group reported an efficient
bifunctional amidophosphine−urea ligand for enantioselective
Figure 1. Representative molecules containing the α,β-diamino acid
moiety.
against Gram-positive bacteria.2 XV 459 is the active form of
roxifiban (DMP 754), which is a potent and highly selective
antagonist of the platelet glycoprotein IIb/IIIa receptor.3
Streptothricins A−F are a group of naturally occurring
antibiotic compounds that are used as agro-antibiotics to
prevent bacterial and fungal diseases in China.4 (2R,3S)-2,3-
Diamino-3-phenylpropanoic acid is an alternative side chain of
Taxol to improve its water solubility.5
The abundance and intriguing biological activities of α,β-
diamino acid derivatives have stimulated extensive effort to
access this vital class of compounds with defined stereo-
chemistry.1 Among them, the asymmetric Mannich reaction of
glycine iminoesters with imines,6−12 which is capable of
Received: September 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03223
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
1,3-dipolar cycloaddition of glycine iminoester with the inert
dipolarophile methylacrylonitrile (Scheme 1).20 The high
Table 1. Optimization of the Reaction Conditions
Scheme 1. Cu/Amidophosphine−Urea Complex as a
Bifunctional Catalyst
b
cd
,
time
(h)
yield (%) (syn/
ee
c
entry
[M]
L
anti)
(%)
1
2
3
4
5
6
7
8
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4PF4
Cu(OTf)2
L1
L2
L3
L4
L5
L4
L4
L4
L6
L7
L8
L9
L10
L11
L12
11
72
11
11
11
11
11
11
1
72
10
72
2
90 (10:1)
trace (−)
95 (9:1)
95 (16:1)
87 (7:1)
95 (14:1)
91 (15:1)
61 (7:1)
42 (1.4:1)
29 (1:1.6)
89 (4.7:1)
63 (1.6:1)
85 (1.3:1)
85 (2.4:1)
88 (1:1.9)
87
reactivity and stereoselectivity can be largely attributed to
the synergistic activation and spatial orientation of the two
reactants. Given the remarkable performance of our bifunc-
tional catalyst system for activation and stereocontrol of an
inert electrophile (i.e., methylacrylonitrile) with low intrinsic
reactivity, we wondered whether it could effectively activate N-
phosphinoyl imines, which can also serve as electrophiles to
react with glycine iminoesters.
45
93
7
92
91
72
6
13
−32
3
64
−28
49
AgClO4
9
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
10
11
12
13
14
15
We began our investigation by examining the model reaction
of glycine iminoester 2a with N-diphenylphosphinoyl (dpp)
imine 1a using 5 mol % Cu(CH3CN)4BF4 as the metal salt and
Et3N as the base, and the representative results are summarized
in Table 1. The initial results were encouraging since the
reaction was smoothly completed within 11 h with L1 as the
ligand, and the desired Mannich adduct 3a was obtained in
90% yield with a promising level of stereoselectivity after
hydrolysis of the preformed α-imino ester upon addition of
aqueous NH2OH·HCl to the crude reaction mixture (10:1 dr
and 87% ee, Table 1, entry 1). Switching the hydrogen donor
unit to thiourea completely blocked the reaction (entry 2).
Decreased enantioselectivity was observed with squaramide L3
as the ligand (entry 3), indicating that the urea segment is
crucial for this reaction. Employment of L4 with (R,R)-1,2-
diphenylethane-1,2-diamine as the chiral scaffold further
enhanced the reaction performance, affording 3a with
substantially improved diastereomeric ratio and enantiomeric
excess value (entry 4). Variation of the phosphine unit resulted
in a dramatic decrease in the stereoselectivity (entry 5). Other
copper salts provided 3a with slightly lower enantioselectivity
(entries 6 and 7), while silver salt AgClO4 gave disappointing
results (entry 8). An extensive survey of other reaction
parameters indicated that THF and Et3N were the best solvent
and base for this reaction.21 Using other known privileged
ligands under our typical conditions or the optimal conditions
reported in the literature led to lower yields or inferior
stereoselectivities (L6−L12, entries 9−15, Figure 2),21
demonstrating the uniqueness of our bifunctional catalytic
system.
2
10
a
Reaction conditions: 1a (0.10 mmol), 2a (0.15 mmol), [M] (0.005
mmol, 5 mol %), ligand (0.006 mmol, 6 mol %), Et3N (0.05 mmol), 4
Å MS (300 mg), THF (3.0 mL), −20 °C. Combined yields of two
diastereoisomers. Determined by chiral HPLC analysis. ee values of
b
c
d
syn-isomer.
Figure 2. Known chiral ligands examined in the Mannich reaction of
1a and 2a.
bearing various N-alkylidene groups (Table 2). Compared with
substrate 2a, glycinate 2b with an additional p-methyl group on
the phenyl ring led to slightly lower diastereo- and
enantioselectivity (entry 2). Glycinate 2c with an electron-
withdrawing p-nitrile group on the phenyl ring led to
significantly reduced stereoselectivity (entry 3). A similar
negative effect was observed for other electron-withdrawing
groups (e.g., −NO2, −F, −Br, and −Cl), regardless of the
substitution patterns (entries 4, 5, and 8−11). The electron-
Taking into consideration that glycinates with sterically and
electronically different N-alkylidene groups could result in
different reaction outcomes,7 and to further optimize this
reaction, we next examined a series of glycine iminoesters
B
DOI: 10.1021/acs.orglett.9b03223
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Mannich Reaction of Various Glycine Iminoesters
Table 3. Substrate Scope of the Mannich Reaction of N-
Phosphinoyl Imines
a−c
b
cd
,
time
(h)
yield (%) (syn/
ee
c
entry
2
R
anti)
(%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
11
15
72
12
16
72
12
15
12
24
16
24
12
95 (16:1)
89 (10:1)
87 (6:1)
93
91
36
81
41
90
93
80
81
64
67
90
85
p-MeC6H4
p-CNC6H4
m-BrC6H4
m-NO2C6H4
o-OMeC6H4
o-MeC6H4
o-FC6H4
95 (15:1)
89 (18:1)
76 (26:1)
95 (31:1)
89 (30:1)
95 (37:1)
79 (14:1)
84 (17:1)
90 (10:1)
95 (9:1)
9
o-BrC6H4
10
11
12
13
2j
2k
2l
2-Br-4-ClC6H3
2-Br-5-FC6H3
1-naphthyl
2-naphthyl
2m
a
Reaction conditions: 1a (0.10 mmol), 2 (0.15 mmol), Cu-
(CH3CN)4BF4 (0.005 mmol, 5 mol %), ligand (0.006 mmol, 6 mol
%), Et3N (0.05 mmol), 4 Å MS (300 mg), THF (3.0 mL), −20 °C.
b
c
Combined yields of two diastereoisomers. Determined by chiral
d
HPLC analysis. ee values of syn-isomer.
donating o-methoxy group resulted in slightly reduced
enantioselectivity (entry 6), while the o-methyl derivative 2g
gave a comparable ee value but substantially improved
diastereoselectivity (entry 7 vs entry 1). Glycine iminoesters
with fused aromatic groups gave lower stereoselectivities
(entries 12 and 13). These investigation identified that glycine
iminoester 2g is the best pronucleophile for the Mannich
reaction with N-phosphinoyl imine.
Having established the optimal reaction conditions and
identified the best glycine iminoester, we subsequently
investigated the scope of N-phosphinoyl imines (Table 3).
Generally, a broad range of N-phosphinoyl imines bearing
multifarious functional groups were well tolerated, providing
the corresponding diaminoester products in high yields with
good stereoselectivities. Benzaldehyde-derived N-dpp imine 1b
afforded 3b in 91% yield with 29:1 dr and 94% ee. N-
Phosphinoyl imines possessing both electron-withdrawing and
electron-donating groups on the phenyl ring all reacted
smoothly, furnishing the corresponding syn-products (3a,
3c−3g) with satisfactory results (85−96% yield, 9:1−31:1 dr,
89−97% ee). The substitution pattern of the phenyl ring had a
negligible effect on the reaction performance, and N-
phosphinoyl imines containing a bromide group at the para-
(1a), meta- (1i), and ortho-position (1k) of the phenyl ring
were all tolerated. It is noteworthy that ortho-substituted
substrates, which have been documented to be suboptimal
substrates in previous reports,7f,9c led to excellent enantiose-
lectivities (3j−3o, 98−99% ee). Among the ortho-substituted
substrates, 2-cyanobenzaldehyde-derivated imine with a
potential disturbing nitrile group also proved to be a viable
substrate, albeit with a relatively low yield (3l). Additionally,
the catalytic system was found to be applicable to imines with
fused aryl groups. Imines bearing 2-naphthyl and 1-naphthyl
groups efficiently reacted with 2g to produce the correspond-
ing diaminoesters 3p and 3q in good yields with high
stereoselectivities. A challenging substrate containing a
a
Reaction conditions: 1 (0.10 mmol), 2g or 2n (0.15 mmol),
Cu(CH3CN)4BF4 (0.005 mmol, 5 mol %), ligand (0.006 mmol, 6 mol
%), Et3N (0.05 mmol), 4 Å MS (300 mg), THF (3.0 mL), −20 °C.
b
c
Combined yields of two diastereoisomers. The ee value and dr
(ratio of syn/anti isomers) were determined by chiral HPLC analysis.
d
1
The dr was determined by H NMR analysis of the crude reaction
mixture.
pyridine ring gave the corresponding product 3r with excellent
enantioselectivity (99%), albeit with relatively low yield (60%)
and diastereoselectivity (2:1). Heteroaromatic substrate with a
2-furyl group worked well, and imine bearing a 2-thienyl group
also successfully afforded the corresponding product 3t with
acceptable results. Under our typical reaction conditions,
aliphatic N-dpp-imines failed to deliver the corresponding
adducts.17a Compared with methyl glycinate 2g, the con-
versation of tert-butyl glycinate 2n was sluggish, giving 3u with
reduced dr and in lower yield. The reaction using 1.0 mmol of
1a was completed after 24 h with no compromise in yield
(96%) and stereoselectivity (>20:1 dr, 92% ee).21 The
diphenylphosphinoyl group can be readily removed in the
C
DOI: 10.1021/acs.orglett.9b03223
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
presence of TMSCl in MeOH at room temperature to yield
the free-NH2 products.21
*E-mail: minzhang@cqu.edu.cn.
ORCID
The relative and absolute configurations of compound 3m
were unequivocally determined to be (2S,3R) by X-ray
crystallographic analysis, and the same configurations were
analogously assigned to other products. On the basis of the
experimental evidence together with previous theoretical
calculations,20 a plausible transition state involving synergistic
activation of both the glycine iminoester and N-phosphinoyl
imine by the Cu/L4 complex is depicted in Figure 3. The in
Min Zhang: 0000-0002-3851-7836
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Fundamental Research Funds
for the Central Universities (106112017CDJXSYY0001), the
National Natural Science Foundation of China (21672029,
21871033, and 21702023), and Chongqing Science and
Technology Commission (cstc2018jcyjAX0421). We thank
Mr Xiangnan Gong (CQU) for X-ray crystallographic analysis.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: heling2015@cqu.edu.cn.
D
DOI: 10.1021/acs.orglett.9b03223
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Organic Letters
Letter
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́
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E
DOI: 10.1021/acs.orglett.9b03223
Org. Lett. XXXX, XXX, XXX−XXX