Ag/P-Stereogenic Phosphine-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions: A Method to Optically Active Pyrrolidines

Article abstract of DOI:10.1021/acs.orglett.9b00926

A Ag/P-stereogenic phosphine-complex-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with electron-deficient olefins is reported. In this reaction, highly functionalized pyrrolines with a spiro-quaternary stereogenic center were obtained in good yields (up to 99%) with excellent levels of diastereo-(up to >20:1 dr) and enantioselectivities (up to >99% ee). The chirality of adducts was controlled predominantly by the P-stereogenic phosphines.

Full text of DOI:10.1021/acs.orglett.9b00926

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ag/P-Stereogenic Phosphine-Catalyzed Enantioselective 1,3-Dipolar
Cycloadditions: A Method to Optically Active Pyrrolidines
Mengna Zhi, Zhenjie Gan, Rong Ma, Hao Cui, Er-Qing Li,* Zheng Duan,* and Franco̧ is Mathey
College of Chemistry and Molecular Engineering, International Phosphorus Laboratory, International Joint Research Laboratory for
Functional Organophosphorus Materials of Henan Province, Zhengzhou University, Zhengzhou 450001, P. R. China
S
* Supporting Information
ABSTRACT: A Ag/P-stereogenic phosphine-complex-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with electron-
deficient olefins is reported. In this reaction, highly functionalized pyrrolines with a spiro-quaternary stereogenic center were
obtained in good yields (up to 99%) with excellent levels of diastereo- (up to >20:1 dr) and enantioselectivities (up to >99%
ee). The chirality of adducts was controlled predominantly by the P-stereogenic phosphines.
Scheme 1. [3 + 2] Cycloaddition of Azomethine Ylides with
2,6-Bis(arylmethylidene) Cyclohexanones
ptically active pyrrolines have long been considered as
Othe “privileged skeleton” in a wide array of natural
compounds and pharmaceutical research.1 In particular,
optically active pyrrolines containing spiral motifs are
important structural motifs in biologically active natural
products and pharmaceuticals.2 For example, Atiprimod
(SK&F-106615) is an effective anti-inflammatory and anti-
cancer agent;3 11β-HSD1 has been identified as a powerful and
selective inhibitor of 11β-hydroxysteroid dehydrogenase type
1;4 compound C has antimicrobial activity;5 and compound D
exhibits HIV-protease inhibitory activity.6 The development of
efficient synthetic methods for such motifs has become an
attractive objective (Figure 1).
Transition-metal-catalyzed asymmetric 1,3-dipolar cyclo-
addition of azomethineylides has doubtlessly been one of the
most ideal and powerful synthetic strategies for assembly of
structurally diverse pyrrolidines.7 Since the pioneering work by
Grigg,8 an enormous number of ligands, which are crucial in an
enantioselective bond forming process, have been developed to
achieve these reactions, including Wang’s TF-Biphamphos,9
Carretereo’s Fe-sulphos,10 Zhang’s Ming-Phos,11 Fukuzawa’s
ThioClickFerrophos,12 Xu’s Xing-Phos,13 and so on. Despite
these impressive advances, the design and synthesis of
structurally novel and highly efficient P-stereogenic ligands
for enantioselective catalysis is greatly desired.
2,6-Bis(arylmethylidene) cyclohexanones are useful sub-
strates, which have been applied to the synthesis of
pharmaceuticals14 and chiral ligands.15 In 2017, Zhou and
co-workers reported on the stereoselectivity of the asymmetric
1,3-dipolar cycloaddition reactions of azomethine ylides with
2,6-bis(arylmethylidene) cyclohexanones.16 The author used
chiral catalysts prepared from Ag(I) and the known P or N
ligands; however, low stereoselectivities and diastereoselectiv-
Figure 1. Biologically active spiro natural products containing
pyrroline motifs.
Received: March 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00926
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of 2,6-Bis(arylmethylidene)
Cyclohexanone 1
Scheme 3. Substrate Scope of α-Methyl Iminoesters 2
a
a
1 (0.1 mmol), 2a (0.2 mmol), Ag(I) (0.005 mmol), ligand (0.01
mmol), K2CO3 (0.4 mmol), and CH2Cl2 (2.0 mL), −78 °C, 24 h in a
b
c
sealed tube. Isolated yield. The ee values were determined by chiral
d
HPLC analysis. Diastereoisomers were isolated by column
chromatography and total yield of mixtures of the diastereomers.
a
1 (0.1 mmol), 2 (0.2 mmol), Ag(I) (0.005 mmol), ligand (0.01
mmol), K2CO3 (0.4 mmol), and CH2Cl2 (2.0 mL), −78 °C, 48 h in a
b
c
sealed tube. Isolated yield. The ee values were determined by chiral
d
HPLC analysis. Diastereoisomers were isolated by column
ities were obtained in most cases. Thus, the design of novel
chiral ligands may be the optimal way to address this issue. On
the basis of our preliminary work,17 our group has developed a
novel class of P-stereogenic ligands. The two diastereoisomeric
P-stereogenic phosphines could be obtained easily in good
yields from inexpensive, commercially available phosphole and
chiral tert-butyl-sulfinamide in 4 steps (see the Supporting
Information for details).11 Given its potentiality in pharma-
cochemistry, we would like to describe the application of the
Ag(I)/P-stereogenic complex as catalyst for the asymmetric
1,3-dipolar cycloaddition reaction of azomethine ylides with
2,6-bis(arylmethylidene) cyclohexanones in high diastereose-
lectivities and stereoselectivities (Scheme 1).
chromatography and total yield of mixtures of the diastereomers.
Scheme 4. Reactions with Linear Olefin
Scheme 5. Gram-Scale Synthesis and Application
With the novel Ag(I)/P-stereogenic complex in hand, we
initiated the study by using 2,6-bis(arylmethylidene) cyclo-
hexanone 1a and benzaldehyde Schiff base derivative 2a as
model substrates. To our delight, the reaction proceeded
smoothly with a AgOTf/L1 catalyst, and the desired adduct
3aa was isolated in 91% yield with 60% ee (Table S1, entry 1).
Encouraged by this result, different P-stereogenic ligands (ZD-
Phos) were screened, and we found the chirality of adducts
could be tuned by the P-stereogenic phosphines (Table S1,
entries 1−8). To improve the enantioselectivity, various Ag(I)
catalysts were checked, and AgNTf2 was chosen for further
optimizations (Table S1, entries 9 and 12−19). The best result
was obtained with 5 mol % AgNTf2, 10 mol % L3′, and K2CO3
(4 equiv) as base (Table S1, entry 19). The structures and
stereochemistries of 3 were characterized by NMR, HPLC,
HRMS, and the single-crystal X-ray analysis (3aa) (see SI).
Under the optimized reaction conditions (Table S1, entry
19), we carried out the 1,3-dipolar cycloaddition reactions of
various 2,6-bis(arylmethylidene) cyclohexanones 1 with 2a
(Scheme 2). Both electron-rich and -deficient aryl-substituted
1 reacted with 2a smoothly, giving the desired products 3 with
B
DOI: 10.1021/acs.orglett.9b00926
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we synthesized novel air-stable P-stereogenic
chiral phosphines from the cheap and readily available
materials through a simple procedure. Importantly, the chiral
pure ligands can be synthesized and isolated in gram scale
without using any resolving reagents. The ligands were used in
the Ag (I)-catalyzed enantioselective [3 + 2] annulations of
azomethine ylides. This method provides a highly enantiose-
lective (up to >99% ee) method for the synthesis of optically
pure pyrrolidine derivatives with multiple stereogenic centers.
Further synthetic applications of these P-stereogenic chiral
phosphines are underway in our group.
Scheme 6. Plausible Reaction Mechanism
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.9b00926.
1
Spectroscopic data for all new compounds including H
and 13C NMR spectra (PDF)
Accession Codes
CCDC 1848206 and 1852946 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.
up to >20:1 diastereoselectivities and excellent enantioselec-
tivities (up to >99% ee) in 73−99% yields (Scheme 2, 3aa−
3qa). However, lower enantioselectivities were obtained in the
case of more sterically hindered substrate (Scheme 2, 3ma vs
3la). 1-Naphthyl-substituted 1 was also well tolerated (Scheme
2, 3oa). We also found that the 2-thienyl derivative showed
higher diastereoselectivity and enantioselectivity than the 3-
thienyl one (Scheme 2, 3pa vs 3qa).
We then turned our attention to check the substrate scope of
α-substituted imino esters 2. It was observed that α-methyl
imino esters derived from various aryl and heteroaryl aldehydes
could provide corresponding pyrrolidines 3ab−3dl in 84−98%
yields, with up to >20:1 dr and 80−99% ee. In most cases, o-
substituent 2 resulted in higher enantioselectivities (Scheme 3,
3de vs 3dc, 3dd, 3dh vs 3dj and 3dk vs 3di, 3dj). To our
delight, 2-thienyl α-methyl imino ester 2l furnished the desired
pyrrolidine 3dl as the only product in 97% yield and >20:1 dr
with 83% ee (Scheme 3, 3dl).
The reaction proceeded smoothly with a linear olefin 4
(Scheme 4) and produced the corresponding pyrrolidine 5 in
95% yield and 77:23 dr with 86% ee.
A gram-scale synthesis of 3da was carried out, and 3da was
converted into 6 via oxidation with 1.1 equiv of m-CPBA
without loss of chirality (Scheme 5). The absolute config-
uration (6) was specified by single-crystal X-ray diffraction
analysis (see SI).
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: lierqing@zzu.edu.cn.
*E-mail: duanzheng@zzu.edu.cn.
ORCID
Er-Qing Li: 0000-0003-1286-6832
Zheng Duan: 0000-0002-0173-663X
Franco̧ is Mathey: 0000-0002-1637-5259
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (No. 21702189, 21672193, 21272218), China Post-
doctoral Science Foundation (No. 2017M610458,
2018T110737), Postdoctoral Research Grant in Henan
Province (No. 001701006), and Zhengzhou University of
China for financial support of this research. The authors thank
Prof. Shuyu Zhang (Shanghai Jiao Tong University) and Dr.
Bingxin Yuan (ZZU) for helpful discussions and comments.
On the basis of the above results and previous reports,18 we
propose the reaction pathway (Scheme 6). The in situ formed
azomethine ylide coordinates to the active Ag(I) complex,
leading to the tetracoordinated species (A). Conjugate
addition of the enolate to 2,6-bis(phenylmethylidene) cyclo-
hexanones gives the enolate intermediate B. The following
intramolecular cyclization yields the intermediate C. Finally,
protonation provides the product 3 and regenerates the
catalyst. In the five-membered annular transition state, the P-
stereogenic phosphine on the metallo-azomethine ylide is
placed at the equatorial position throughout the intramolecular
cyclization step, delivering the cycloadduct 3 with excellent
stereoselectivity.
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Org. Lett. XXXX, XXX, XXX−XXX