Ligand-Controlled Inversion of Diastereo- and Enantioselectivity in Silver-Catalyzed Azomethine Ylide-Imine Cycloaddition of Glycine Aldimino Esters with Imines

Article abstract of DOI:10.1021/acs.orglett.8b00702

A highly diastereo- and enantioselective silver-catalyzed azomethine ylide-imine (AYI) cycloaddition reaction of glycine aldimino esters with imines was developed in which the Xing-Phos-controlled syn-selective or DTBM-Segphos-induced anti-selective AYI cycloaddition reaction could be applied to the synthesis of a variety of stereodivergent 1-alkyl-2,5-substituted imidazolidines with high yields and excellent enantioselectivities (up to 99% ee) as well as good diastereoselectivities (up to 99:1 dr) under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.8b00702

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Ligand-Controlled Inversion of Diastereo- and Enantioselectivity in
Silver-Catalyzed Azomethine Ylide−Imine Cycloaddition of Glycine
Aldimino Esters with Imines
Bo Yu, Ke-Fang Yang, Xing-Feng Bai, Jian Cao,† Zhan-Jiang Zheng, Yu-Ming Cui, Zheng Xu,
†
†
†,‡
†
†
†
†
,†,‡
Li Li, and Li-Wen Xu*
†Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University,
Hangzhou 311121, P. R. China
‡
Suzhou Research Institute and State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical
Physics, Chinese Academy of Sciences, Suzhou, Jiangsu 215123, P. R. China
*
S Supporting Information
ABSTRACT: A highly diastereo- and enantioselective silver-catalyzed azomethine ylide−imine (AYI) cycloaddition reaction of
glycine aldimino esters with imines was developed in which the Xing-Phos-controlled syn-selective or DTBM-Segphos-induced
anti-selective AYI cycloaddition reaction could be applied to the synthesis of a variety of stereodivergent 1-alkyl-2,5-substituted
imidazolidines with high yields and excellent enantioselectivities (up to 99% ee) as well as good diastereoselectivities (up to 99:1
dr) under mild reaction conditions.
he silver-catalyzed 1,3-dipolar cycloaddition of glycine
aldimino esters with structurally diverse electrophiles is a
powerful strategy for the construction of N-heterocycles, and in
Scheme 1. Synthesis of Chiral Imidazolidines from Various
Starting Materials and Our Strategy Based on the Potential
Stereoselectivity of P-Ligands for the 1,3-Dipolar
Cycloaddition with General Imines
T
the past decade, it has drawn considerable attention from
1
synthetic chemists. In this context, the design and synthesis of
novel chiral P-ligands is crucial for the enantioselective 1,3-
dipolar cycloaddition and becomes an important topic in
developing enantioselective silver-catalyzed cycloaddition re-
actions, which makes the construction of numerous five-
membered N-heterocyclic core-containing natural products and
molecular scaffolds by catalytic 1,3-dipolar cycloaddition of
glycine iminoesters with activated alkenes more and more
1
−3
simple.
Meanwhile, although continuous efforts toward
atom-economic [3 + 2] cycloaddition enable the catalytic
synthesis of imidazolidines in a minimal number of synthetic
steps with the aid of organocatalysis, transition-metal catalysis,
4
visible-light irradiation, Lewis acid, or high temperature, there
are few reports on the enantioselective azomethine ylide−imine
(AYI) cycloaddition of glycine-derived azomethine ylides with
imines that could be applied to the synthesis of chiral
5
5a,c,e
imidazolidines. In this regard, chiral Brønsted acid
and
5b
CuBF /(S,R )-PPFOMe as well as palladium catalyst with a
chiral ammonium−phosphine hybrid ligand were proven to
be effective catalysts in the cycloaddition reaction of highly
activated imines (Scheme 1) such as 2-aminomalonate- or
isatin-derived imines, fluorinated imines, and N-sulfonyl
4
p
5d
5a,c
Received: March 1, 2018
5e
5b
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00702
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
5
d
6a
6b
imines. Very recently, Guo and our group independently
reported dimerization-type homo-1,3-dipolar [3 + 2] cyclo-
addition reaction that provided good to excellent enantiose-
lectivity in the one-pot construction of chiral imidazolidines
and its polymeric derivatives, respectively. However, the
catalytic asymmetric AYI cycloaddition of azomethine ylides
Table 1. Optimization for the AYI Cycloaddition of Glycine
Aldimino Ester 1a with imine 2a
a
6
with general alkyl/aryl imines has been less investigated, and
to the best of our knowledge, there is no report describing the
asymmetric synthesis of chiral 1-alkyl-2,5-substituted imidazo-
lidines via AYI cycloaddition of glycine iminoesters with a range
of readily available simple imines, but not self-dimerization.
Herein, we report the first example of highly enantioselective
and diastereoselective AYI cycloaddition enabled by two
different P-ligands (Figure 1), wherein both syn- and anti-
b
d
yield
dr
ee
c
entry variation from the conditions A
(%)
(anti/syn)
(%)
1
2
no
70
79
25/75
99/1
93
99
DTBM-Segphos instead of Xing-
Phos
3
4
5
6
7
8
9
toluene instead of EtOAc
THF instead of EtOAc
64
55
33
42
34
61
51
26/74
21/79
28/72
20/80
21/79
30/70
2/98
91
90
89
71
69
88
50
Et O instead of EtOAc
2
e
Figure 1. X-ray structures of chiral products 3ag and 3aj.
Cu(OAc) instead of AgOAc
2
e
AgOTf instead of AgOAc
e
no base
diastereomeric isomers of chiral 1-alkyl-2,5-substituted imida-
zolidines could be obtained, respectively, with good to excellent
stereoselectivities and yields by ligand-controlled silver catalysis.
e
Et N instead of K CO
3
3
2
a
Reaction conditions and more experimental results: see Tables S1−
S6 and Scheme S1. Isolated and total yield of 3aa. Determined by
H NMR. The ee value of the major isomer is determined by chiral
HPLC. The solvent is toluene.
b
c
As our syn-(R,R )-Xing-Phos is a very good P-ligand in the [3
s
1
d
+
2] cycloaddition of glycine aldimino esters and activated
e
7
alkenes with completely stereochemistry, we envisioned that
the intermolecular cycloaddition of glycine aldimino ester 1a
with imine 2a could be promoted smoothly by a silver catalyst
and Xing-Phos under mild reactions conditions. Gratifyingly, a
series of investigation on chiral ligands, transition-metal salts,
basic additives, and solvents (see Scheme S1 and Table S1)
revealed that the AYI cycloaddition proceeds smoothly in the
presence of a AgOAc/Xing-Phos catalyst system. The choice of
metal catalyst, silver salt, and chiral ligand is crucial for this
transformation and stereoselectivity. Moreover, other reaction
parameters were also non-negligible (entries 3−9). As shown in
Table 1, we confirmed that the presence of 10 mol % of K CO
Scheme 2. Substrates of AYI Cycloaddition Reactions in
This Work
2
3
was necessary to obtain the desired imidazolidine 3aa with
good yield (70%), high diastereoselectivity (anti/syn = 75:25),
and excellent ee value (93% ee) in EtOAc and at −20 °C
imidazolidines 3 were isolated with moderate to good yields
and diastereoselectivities (up to 98:2 dr) as well as good to
excellent enantioselectivities (for major isomer, syn-3 products,
with up to 99% ee). The procedure was also applied to aliphatic
imines 2b−d with promising diastereocontrol and good yields
(corresponding imidazolidine products syn-3ab, syn-3ac, and
syn-3ad, in 50−70% yields, dr from 81:19 to 89:11), albeit with
varied enantiocontrol from 58 to 97% ee’s. In particular for
aliphatic imine 2c with a branched i-Pr group, higher yield
(70%) and better enantioselectivity (97% ee) than that for
linear aliphatic imines were observed. This result supported the
magic effect of the multiple stereogenic substituents on syn-(R,
(
Table 1, entry 1). Unexpectedly, in this model reaction, the
results with (R)-DTBM-Segphos were far superior to those
with syn-(R,R )-Xing-Phos, a significant reverse of diastereose-
s
lectivity (anti/syn = 99:1), and excellent enantioselectvity (99%
ee) was achieved (see entry 2). These results indicate that there
is an obvious match/mismatch scenario between Ag/L catalyst
and substrate and reinforce the point that it is a ligand-
controlled inversion of diastereo- and enantioselectivity in this
reaction. We also examined various metal sources and additives
as well as solvents in the presence of DTBM-Segphos (Tables
S4−S6) and identified the Na CO as the best basic additive in
2
3
7
,8
EtOAc.
Rs)-Xing-Phos
in the silver-mediated AYI cycloaddition
Under the optimized reaction conditions summarized in
Table 1, various glycine aldimino esters 1a−k with general
imines 2a−k (Scheme 2) were surveyed in the two versions of
this AYI cycloaddition reactions for stereoselective construction
of two diastereomeric isomers with high ee values. As shown in
Scheme 3, the AYI cycloaddition tolerates a broad of
substitutions at the aromatic ring of glycine aldimino esters
or aromatic imines. In most cases, the corresponding
reactions under conditions A. Notably, the stereochemical
and configuration assignment of syn-3ag was determined by X-
ray analysis (Figure 1) in which the structure of syn-products 3
was further confirmed with good syn-selectivity in this Xing-
Phos-controlled AYI cycloaddition reaction.
To further study the scope of AYI cycloaddition reactions
that were controlled by an Ag/(R)-DTBM-Segphos catalyst
system, the effect of the substituents at two types of imines on
B
DOI: 10.1021/acs.orglett.8b00702
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of the Catalytic Asymmetric AYI
Cycloaddition Reactions: Syn-Selectivity Controlled by Ag/
Xing-Phos Catalyst System
Scheme 4. Scope of the Catalytic Asymmetric AYI
Cycloaddition Reactions: Anti-Selectivity Controlled by Ag/
(R)-DTBM-Segphos Catalyst System
reactivity and stereoselectivity was also investigated in detail. As
shown in Scheme 4, a series of simple and representative
glycine aldimino esters 1a−j derived from aromatic or
heterocyclic aldehydes bearing electron-rich, -neutral, or
-
deficient groups on the aromatic ring reacted smoothly with
general imines 2a−j to afford the desired imidazolidines 3 in
good yields, almost complete diastereoselectivity (up to 99:1
dr), and excellent enanatioselectivities (93−99% ee). It appears
that the linear aliphatic imines were well tolerated in the Ag/
(
R)-DTBM-Segphos-controlled AYI cycloaddition reactions
(
Scheme 5). Because of the large differences in chemical
that proceeded with excellent diastereoselectivity (98:2 dr)
providing high yields and enantioselectivity (for anti-3ab and
anti-3ac, 95% ee and 99% ee, respectively). Similarly, the long-
chain aliphatic imine 2e is also a suitable substrate in this
reaction because a high level of diastereoselectivity and
enantioselectivity was reserved under conditions B (anti-3ae,
structure for such two P-ligands, syn-(R,R )-Xing-Phos and (R)-
DTBM-Segphos, the syn-selective approach of cycloaddition
controlled by the silver/ syn-(R,R )-Xing-Phos catalyst system,
and the anti-selectivity dominated by Ag/(R)-DTBM-Segphos
s
s
Scheme 5. Proposed Pathway Showing the Stereoselective
and Facial Coordination of the Silver Atom with the
Substrates
9
8:2 dr and 96% ee). It should be noted that hetereoatom-
substituted glycine aldimino ester or general imine was also a
type of exceptional substrate, leading to the corresponding
imidazolidines exclusively in good yields and excellent
diastereoselectivity (99:1 dr for anti-3ja and anti-3aj) as well
as excellent enantioselectivities (anti-3ja, 99% ee and anti-3aj,
9
4% ee, respectively). In addition, The X-ray crystal structures
of anti-3aj confirmed that the stereochemistry of the
corresponding imidazolidines 3 was different from that of the
Ag/Xing-Phos catalyst system (Figure 1). These results
demonstrate the feasibility of chiral P-ligand-controlled the
syn- or anti- selective construction of imidazolidines, allowing
stereochemical diverse one-pot C−C and C−N bond
installations during the course of the AYI cycloaddition
reaction.
On the basis of the experimental results, we proposed the
catalytic cycle of chiral ligand-controlled silver-catalyzed AYI
cycloaddition of glycine aldimino ester with general imines
C
DOI: 10.1021/acs.orglett.8b00702
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
system might be aroused predominately from steric repulsion
(2) (a) Naj
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era, C.; Sansano, J. M. Chem. Rec. 2016, 16, 2430. (b) Liu,
H. C.; Tao, H. Y.; Cong, H. J.; Wang, C. J. J. Org. Chem. 2016, 81,
(
DTBM-Segphos) or possibly weak hydrogen-bonding inter-
3
752. (c) Ponce, A.; Alonso, I.; Adrio, J.; Carretero, J. C. Chem. - Eur. J.
actions (Xing-Phos) between the P-ligand and in situ formed
azomethine ylide that is coordinated to the silver center
2
016, 22, 4952. (d) Cheng, H. G.; Zhang, R. M.; Yang, S. W.; Wang,
M.; Zeng, X. F.; Xie, L. J.; Xie, C. S.; Wu, J.; Zhong, G. F. Adv. Synth.
Catal. 2016, 358, 970 and references cited therein.
(
Scheme 5), in which the tetracoordinated transition state I-a
or II-a favored the formation of the corresponding intermediate
I-b or II-b, respectively, followed by intramolecular N-addition
(3) For recent examples on the use of glycine imino esters as a family
9
of building blocks in the enantioselective synthesis of functionalized
heterocycles, see: (a) Sugita, S.; Takeda, N.; Tohnai, N.; Miyata, M.;
Miyata, O.; Ueda, M. Angew. Chem., Int. Ed. 2017, 56, 2469. (b) Chen,
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only reported in 2002; see: Longmire, J. M.; Wang, B.; Zhang, X. M. J.
Am. Chem. Soc. 2002, 124, 13400.
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to imine to give the desired syn- or anti-imidazolidines 3.
In summary, we have described the first example of P-ligand-
controlled diastereoselective AYI cycloaddition of glycine
aldimino esters with general imines. It was found that both
Xing-Phos and DTBM-Segphos were critically effective P-
ligands in the silver-catalyzed AYI cycloaddition reaction, in
which a variety of chiral imidazolidines displayed high levels of
enantio- and diastereoselectivity. More interestingly, the
discovery of this two-ligand-varied catalyst system by tuning
the steric repulsion and electronic effect that give controllable
access to both diastereomeric products of a catalytic
enantioselective transformation from a common starting
material provided a synthetic strategy with switchable stereo-
selectivity.
(
́
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.8b00702.
Sansano-Gil, J. M. ChemPlusChem 2012, 77, 770. (f) Saima, Y.;
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Spectra for all new compounds 3, detailed experimental
procedures, and crystallographic data (PDF)
(
(
Accession Codes
(
CCDC 1590229 and 1816519 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing 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.
6
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AUTHOR INFORMATION
Corresponding Author
■
3
(
W. Angew. Chem., Int. Ed. 2015, 54, 5255. (b) Bai, X. F.; Xu, Z.; Xia, C.
G.; Zheng, Z. J.; Xu, L. W. ACS Catal. 2015, 5, 6016.
*E-mail: liwenxu@hznu.edu.cn.
ORCID
(8) (a) Bai, X. F.; Zhang, J.; Xia, C. G.; Xu, J. X.; Xu, L. W.
Jian Cao: 0000-0002-7782-0299
Li-Wen Xu: 0000-0001-5705-0015
Notes
Tetrahedron 2016, 72, 2690. (b) Bai, X. F.; Li, L.; Xu, Z.; Zheng, Z. J.;
Xia, C. G.; Cui, Y. M.; Xu, L. W. Chem. - Eur. J. 2016, 22, 10399.
(c) Zhao, Q.; Vuong, M. H.; Bai, X. F.; Pannecoucke, X.; Xu, L. W.;
Bouillon, J. P.; Jubault, P. Chem. - Eur. J. 2018, DOI: 10.1002/
The authors declare no competing financial interest.
chem.201706167.
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C.; de Gracia Retamosa, M.; Sansano, J. M.; Cozar, A. D.; Cossío, F. P.
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, R. G.; Martín-Matute, B.; Cossío, F. P.;
ACKNOWLEDGMENTS
■
́
This project was supported by the National Natural Science
Foundation of China (Nos. 21472031, 21703051, 21702211,
and 21773051) and the Zhejiang Provincial Natural Science
Foundation of China (LZ18B020001, LY16E030009,
LY17B030005, and LY17E030003). We also thank Dr. Z. R.
Qu, Dr. K. Z. Jiang, Dr. C. Q. Sheng, and Dr. Q. H. Pan (all at
HZNU) for their technical and analytical support.
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Tetrahedron: Asymmetry 2008, 19, 2913. (d) Kim, H. Y.; Shih, H.-J.;
Knabe, W. E.; Oh, K. Angew. Chem., Int. Ed. 2009, 48, 7420.
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DOI: 10.1021/acs.orglett.8b00702
Org. Lett. XXXX, XXX, XXX−XXX