Desymmetrization of meso-dicarbonatecyclohexene with β-Hydrazino carboxylic esters via a Pd-catalyzed allylic substitution cascade

Article abstract of DOI:10.1021/acs.orglett.0c03211

The desymmetrization of meso-dicarbonatecyclohexene with β-hydrazino carboxylic esters has been achieved via a RuPHOX/Pd-catalyzed allylic substitution cascade for the construction of chiral hexahydrocinnoline derivatives with high performance. Mechanistic studies reveal that the reaction exploits a pathway different from that of our previous work and that the first nitrogen nucleophilic process is the rate-determining step. The protocol could be conducted on a gram scale without any loss of catalytic behavior, and the corresponding chiral hexahydrocinnolines can undergo diverse transformations.

Full text of DOI:10.1021/acs.orglett.0c03211

pubs.acs.org/OrgLett
Letter
Desymmetrization of meso-Dicarbonatecyclohexene with
β‑Hydrazino Carboxylic Esters via a Pd-Catalyzed Allylic Substitution
Cascade
Kai Xu, Yan Zheng, Yong Ye, Delong Liu,* and Wanbin Zhang
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03211
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The desymmetrization of meso-dicarbonatecyclohexene with β-hydrazino carboxylic esters has been achieved via a
RuPHOX/Pd-catalyzed allylic substitution cascade for the construction of chiral hexahydrocinnoline derivatives with high
performance. Mechanistic studies reveal that the reaction exploits a pathway different from that of our previous work and that the
first nitrogen nucleophilic process is the rate-determining step. The protocol could be conducted on a gram scale without any loss of
catalytic behavior, and the corresponding chiral hexahydrocinnolines can undergo diverse transformations.
hiral cinnolines and hydrocinnolines are significant
structural motifs found in numerous medicinally
The Pd-catalyzed asymmetric allylic substitution cascade
reaction is a powerful method for the synthesis of chiral
heterocycles, owing to the ability to form successive multiple
bonds.4 Our laboratory has had a long-standing interest in the
exploration of novel Pd-catalyzed asymmetric allylic sub-
stitutions.5 Recently, we have focused on the catalytic
enantioselective desymmetrization of meso-allyl substrates and
established several straightforward protocols for accessing
chiral oxygen- and nitrogen-containing [4,3,0] fused hetero-
cycles.6 The efficient catalytic system prompted us to explore
the construction of chiral hydrocinnolines, six-membered
[4,4,0] fused azabicycles, which has not been reported so far.
β-Hydrazino carboxylic esters are useful synthons in a
variety of transition-metal-catalyzed reactions.7 In particular,
they show versatile reactivity for the construction of
heterocyclic compounds8 and can also serve as efficient 1,4-
bis-nucleophiles for the construction of diazaheterocycles.9
Recently, Hui and co-workers realized an efficient NHC-
catalyzed asymmetric [3+4] annulation of β-hydrazino
carboxylic esters with 2-bromoenals to synthesize chiral
seven-membered diazaheterocycless bearing two consecutive
stereocenters in good yields with excellent stereoselectivities
C
important compounds, such as cinoxacin, cinnopentazone,
analgesics, etc. (Figure 1).1 For this reason, much effort has
Figure 1. Chiral cinnolines and hydrocinnolines.
been devoted to their preparation, and a series of useful
methodologies have been developed and applied generally in
the organic and medicinal chemistry fields.2 Compared with
cinnolines, hydrocinnolines remain relatively unfamiliar in
modern-day organic chemistry, and their construction has been
considerably less exploited. Furthermore, most of the existing
synthetic methods are racemic.1,3 Therefore, the development
of synthetic approaches for the efficient construction of novel
chiral hydrocinnoline derivatives is greatly important.
Received: September 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03211
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
(Scheme 1, top).9a By treatment with propargylic acetates via a
copper-catalyzed [3+2] cycloaddition, Hu et al. realized the
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Asymmetric Synthesis of Chiral
Hexahydrocinnolines
b
c
d
entry
base
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DIPEA
Na2CO3
K2CO3
Cs2CO3
−
solvent
yield (%)
dr
ee
1
2
3
4
5
6
7
8
DCE
47
90
54
31
82
30
53
32
43
78
91
80
65
2:1
5:1
5:1
1:1
2:1
4:1
3:1
9:1
2:1
2:1
9:1
4:1
2:1
80/56
77/70
71/60
97/88
92/90
90/84
94/87
90/90
96/91
96/87
94/94
93/93
99/93
CH2Cl2
MeCN
toluene
dioxane
DME
MTBE
THF
THF
THF
THF
THF
9
10
11
12
13
THF
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [Pd(η3-
C3H5)Cl]2 (2.5 mol %), RuPHOX (3.0 mol %), and base (2.0 equiv)
b
in a solvent (2 mL) at 35 °C for 36 h. Isolated yield related to
c
combined diastereoisomers. Determined by 1H NMR integration.
d
Determined by HPLC analysis using an IE column.
synthesis of nonchiral five-membered diazaheterocycles
(Scheme 1, top).9b To the best of our knowledge, no example
concerning the construction of six-membered skeletons has
been reported. Herein, we describe an efficient Pd-catalyzed
asymmetric allylic substitution cascade of β-hydrazino
carboxylic esters with meso-dicarbonatecycloalkene via an
enantioselective desymmetrization, providing hexahydrocinno-
lines bearing three consecutive chiral centers (Scheme 1,
bottom).
Initially, we began our investigation by choosing meso-
dicarbonatecycloalkene (1a) and β-hydrazino carboxylic ester
(2a) as the model substrates in the presence of 2.5 mol %
[Pd(η3-C3H5)Cl]2 and DBU (2.0 equiv). The effects of
different ligands on the reaction were first examined in THF
at 35 °C, and RuPHOX (developed in our lab10) was found to
be the best choice.11 Subsequently, several solvents were tested
with RuPHOX as the ligand (Table 1, entries 1−8). Excellent
diastereomeric ratios (dr) and enantiomeric excesses (ee) were
obtained when THF was used (entry 8, 9:1 dr, 90% ee).
Further screening of the base revealed that K2CO3 gave the
best results (entries 9−13, 91% yield, 9:1 dr, 94% ee). The
optimized conditions were identified as follows: [Pd(η3-
C3H5)Cl]2 (2.5 mol %), RuPHOX (3.0 mol %), and K2CO3
(2.0 equiv) in THF at 35 °C (entry 11).
With the optimized reaction conditions in hand, we then
studied the substrate scope of the cascade reaction (Scheme
2). Thus, the reactions of various β-hydrazino carboxylic esters
(2a−ae) with 1a were carried out. A variety of substituents on
the phenyl ring of 2 consisting of either electron-donating or
electron-withdrawing groups were well tolerated, affording the
desired chiral hexahydrocinnoline products with high perform-
ance. Substrates decorated with a methyl group at each
position of the phenyl ring were converted to their desired
products with good results (3b−d, 66−90% yields, 4:1−10:1
dr, 90−94% ee). The absolute configuration of (R,R,R)-3c was
determined by X-ray crystallographic analysis.12 Substrate 2,
bearing an electron-donating group (4-tBu or 4-OMe) at the
para positions of the phenyl ring, gave the desired products 3e
in 87% yield (4:1 dr, 91% ee) and 3f in 94% yield (2:1 dr, 96%
ee). Substrates with electron-withdrawing groups (F, Cl, Br,
CO2Me, CN, CF3, and CF3O) on the phenyl rings of 2 also
gave the corresponding 3g−r in good to excellent yields (73−
95%) and enantioselectivities (78−94% ee). A substrate with a
phenyl group on the β-hydrazino carboxylic ester bearing an o-
fluorine substituent afforded the corresponding products with
better diastereoselectivity than those bearing m- and p-fluorine
groups (3g−i). Notably, chloride and bromide groups were
also tolerated (3j−n). Substrate 2p with a cyano substituent
showed good catalytic behavior, albeit with somewhat low
diastereoselectivity (2:1 dr). Compound 2 bearing an electron-
withdrawing substituent (CF3) at the para position led to a
decrease in enantioselectivity and only moderate yield and
diastereoselectivity (3q). Substrates with disubstituted phenyl
rings gave their corresponding products with excellent yields
and good to excellent enantioselectivities (3s−u). To our
delight, 2-naphthyl-, 2-furyl-, and 3-thienyl-derived β-hydrazi-
no carboxylic esters 2v−x also proved to be suitable substrates
for this reaction (3v−x, 65−84% yields, 3:1−5:1 dr, 90−95%
ee). Reaction of a β-hydrazino carboxylic ester with a linear
alkyl group (n-Pr) group gave the corresponding chiral
hexahydrocinnoline product in comparatively lower yield
(3y). A substrate bearing a benzyl group in place of the n-Pr
group afforded its corresponding product in moderate yield
and ee (3z). Finally, substrates 2aa−ae with different N-
protecting groups and esters were examined, with the desired
products 3aa−ae being obtained in good yields and excellent
enantioselectivities.
To confirm the scalability of this method, a gram-scale
synthesis of (R,R,R)-3a was carried out under the standard
reaction conditions. The asymmetric desymmetrization of 1a
(2.5 mmol) with 2a (3.8 mmol) proceeded smoothly to afford
3a in 87% yield, 9:1 dr, and 94% ee (Scheme 3, top).
B
https://dx.doi.org/10.1021/acs.orglett.0c03211
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a,b
Scheme 2. Substrate Scope
Scheme 3. Gram-Scale Synthesis and Transformation of 3a
94% ee. When 3a was treated with Br2 in the presence of i-
Pr2NEt, dibromination product 7 was formed in 62% yield and
96% ee. The CC bond could also be oxidized by m-CPBA to
give the corresponding epoxidation product 8 in 70% yield
without any loss of stereoselectivity.13
On the basis of the experimental results and our previous
studies, we initially proposed a catalytic cycle for the formation
of chiral hexahydrocinnolines (Scheme 4, pathway a). First, the
RuPHOX/Pd complex coordinates with the CC bond from
the back of the two OCO2Me groups of cis-1a. The allyl Pd
complex A intermediate is formed because of the enantiose-
lective desymmetrization.14 Next, intermediate A reacts with β-
hydrazino carboxylic ester 2a, producing B′ via a carbon
nucleophilic substitution. Finally, the terminal chiral hexahy-
drocinnoline product (9) is obtained via a cascade intra-
molecular nitrogen nucleophilic substitution. However, the
position of the CC bond in the terminal product is not
identical to that of desired product 3a. This means that the
sequence of the carbon and nitrogen nucleophilic substitution
may proceed through a different pathway compared with our
previously reported reaction.6 That is, after the formation of
intermediate A, the cascade process involves nitrogen
nucleophilic substitution prior to carbon nucleophilic sub-
stitution via intermediates B and C (pathway b). The strong
acidity of the NH in 2a, most likely resulting from a carbonyl
functional group, must be responsible for the reversed
nucleophilic pathway.
We attempted to obtain the nucleophilic nitrogen
intermediate by either decreasing the reaction temperature or
shortening the reaction time. However, only desired product
3a was obtained with starting materials 1a and 2a being
recycled. This suggests that the second intramolecular carbon
nucleophilic substitution is much faster than the first
intermolecular nitrogen nucleophilic substitution. That is, the
first nitrogen nucleophilic process is the rate-determining step
in the cascade reaction process. In addition, the asymmetric
catalytic reaction of 1a and 2a was also quenched at different
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [Pd(η3-
C3H5)Cl]2 (2.5 mol %), RuPHOX (3.0 mol %), and K2CO3 (2.0
equiv) in THF (2 mL) at 35 °C for 36 h. Isolated yields related to
combined diastereomers and the major diastereomers were isolated
via preparative HPLC. Ee values were determined by chiral HPLC
b
analysis of 3 using an IE, OX, or IC-3 column. The absolute
configuration of minor diastereomer 3x was determined by single-
crystal analysis and is shown in the Supporting Information.12.
To test the utility of these methodologies, several trans-
formations of the chiral hexahydrocinnoline product were
performed (Scheme 3, bottom). After screening a series of
deprotecting methods, we found that LiAlH4 could remove the
Ts group efficiently and reduce the ester group to the alcohol.
Subsequent protection with an allyl group in situ afforded
product 4 in 51% yield and 95% ee. Treatment of 3a with
LiOH in a MeOH/H2O/THF mixed solvent system at rt
resulted in a decarboxylation to give 5 in 47% yield with 83%
ee. Hydrogenation of the CC bond of 3a with H2 catalyzed
by Pd/C in aqueous MeOH afforded 6 in 90 yield, 9:1 dr, and
C
https://dx.doi.org/10.1021/acs.orglett.0c03211
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 4. Proposed Reaction Mechanism
AUTHOR INFORMATION
Corresponding Author
■
Delong Liu − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Pharmacy, Shanghai
Jiao Tong University, Shanghai 200240, P. R. China;
orcid.org/0000-0003-2190-1644; Email: dlliu@
sjtu.edu.cn
Authors
Kai Xu − Shanghai Key Laboratory for Molecular Engineering
of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong
University, Shanghai 200240, P. R. China
Yan Zheng − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Pharmacy, Shanghai
Jiao Tong University, Shanghai 200240, P. R. China
Yong Ye − Green Catalysis Center, College of Chemistry,
Zhengzhou University, Zhengzhou 450001, P. R. China
Wanbin Zhang − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Pharmacy, Shanghai
Jiao Tong University, Shanghai 200240, P. R. China; Green
Catalysis Center, College of Chemistry, Zhengzhou
University, Zhengzhou 450001, P. R. China; orcid.org/
0000-0002-4788-4195
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03211
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21672142, 21971162, 21831005, and
21620102003) and the Shanghai Municipal Education
Commission (201701070002E00030). The authors also
thank the Instrumental Analysis Center of Shanghai Jiao
Tong University for characterization.
reaction times and epimerization was observed at the chiral
center bearing the ester under the basic reaction conditions.11
In conclusion, we have developed a RuPHOX/Pd-catalyzed
allylic substitution cascade involving a desymmetrization of
meso-dicarbonatecyclohexene with β-hydrazino carboxylic
esters, providing chiral hexahydrocinnoline derivatives in up
to 95% yield, >20:1 dr, and 96% ee. The protocol could be
scaled to gram quantities without any loss of reaction activity
and enantioselectivity. Furthermore, the corresponding chiral
hexahydrocinnolines can undergo several transformations.
Mechanistic studies reveal that the reaction proceeds via a
different pathway compared with our previous work and the
nitrogen nucleophilic substitution is the rate-determining step.
REFERENCES
■
(1) (a) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Wagatsuma, N.;
Kusama, O.; Uryu, T. Studies on the Syntheses of Analgesics. XLI.
Optical Resolution of ( )-N-Cyclopropylmethyl-3-hydroxy-9-aza-
morphinan (Studies on the Syntheses of Heterocyclic Compounds.
Part DCLXIX). Chem. Pharm. Bull. 1976, 24, 2563. (b) Kametani, T.;
Kigasawa, K.; Hiiragi, M.; Ishimaru, H.; Wagatsuma, N.; Kohagisawa,
T.; Nakamura, T. Novel Type of Analgesic-Synthesis and Analgesic
Activity. Heterocycles 1980, 14, 449. (c) Rahier, A.; Taton, M. Sterol
Biosynthesis: Strong Inhibition of Maize Δ5,7-Sterol Δ7-Reductase by
Novel 6-aza-β-Homosteroids and Other Analogs of a Presumptive
Carbocationic Intermediate of the Reduction Reaction. Biochemistry
1996, 35, 7069. (d) Combs, D.; Piscataway, N. 1-(Arylsulfonyl)-, 1-
(Arylcarbonyl)-, and 1-(Arylphosphonyl)-3-phenyl-1,4,5,6-tetrahydro-
pyridazines. US5684151A, 1997. (e) Lei, X.; Zaarur, N.; Sherman, M.
Y.; Porco, J. A. Stereocontrolled Synthesis of a Complex Library via
Elaboration of Angular Epoxyquinol Scaffolds. J. Org. Chem. 2005, 70,
6474. (f) Han, Y. T.; Jung, J.-W.; Kim, N.-J. Recent Advances in the
Synthesis of Biologically Active Cinnoline, Phthalazine and Quinoxa-
line Derivatives. Curr. Org. Chem. 2017, 21, 1265. (g) Guo, Q.; Si, X.;
Shi, Y.; Yang, H.; Liu, X.; Liang, H.; Tu, P.; Zhang, Q.
Glucoconjugated Monoterpene Indole Alkaloids from Uncaria
rhynchophylla. J. Nat. Prod. 2019, 82, 3288. (h) Tonk, R. K.; Bawa,
S.; Kumar, D. Therapeutic Potential of Cinnoline Core: A
Comprehensive Review. Mini-Rev. Med. Chem. 2020, 20, 196.
(i) Ghosh, A. K.; Brindisi, M. Urea Derivatives in Modern Drug
Discovery and Medicinal Chemistry. J. Med. Chem. 2020, 63, 2751.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03211.
Experimental procedures and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 2007663 and 2040737 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.
D
https://dx.doi.org/10.1021/acs.orglett.0c03211
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(j) Hu, Y.-J.; Li, L.-X.; Han, J.-C.; Min, L.; Li, C.-C. Recent Advances
in the Total Synthesis of Natural Products Containing Eight-
Membered Carbocycles (2009−2019). Chem. Rev. 2020, 120, 5910.
(k) Habel, D.; Nair, D. S.; Kallingathodi, Z.; Mohan, C.; Pillai, S. M.;
Nair, R. R.; Thomas, G.; Haleema, S.; Gopinath, C.; Abdul, R. V.;
Fritz, M.; Puente, A. R.; Johnson, J. L.; Polavarapu, P. L.; Ibnusaud, I.
Natural Product-Derived Chiral Pyrrolidine-2,5-diones, Their Molec-
ular Structures and Conversion to Pharmacologically Important
Skeletons. J. Nat. Prod. 2020, 83, 2178.
(2) For selected reviews, see: (a) Vinogradova, O. V.; Balova, I. A.
Methods for the Synthesis of Cinnolines. Chem. Heterocycl. Compd.
2008, 44, 501. (b) Sadek, K. U.; Mekheimer, R. A.; Abd-Elmonem, M.
Recent Developments in the Synthesis of Cinnoline Derivatives. Mini-
Rev. Org. Chem. 2019, 16, 578. (c) Su, L.; Hou, W. Progress in the
Synthesis of Cinnoline Derivatives. Youji Huaxue 2019, 39, 363.
(d) Plieva, A. T. Methods for the Synthesis of Pyrrolo[1,2-
b]pyridazine and Pyrrolo[1,2-b]cinnoline Derivatives. Chem. Hetero-
cycl. Compd. 2019, 55, 199. For selected recent papers, see: (e) Yao,
B.; Miao, T.; Wei, W.; Li, P.; Wang, L. Copper-Catalyzed Cascade
Cyclization of Arylsulfonylhydrazones Derived from ortho-Alkynyl
Arylketones: Regioselective Synthesis of Functionalized Cinnolines.
Org. Lett. 2019, 21, 9291. (f) Liu, C.-F.; Liu, M.; Dong, L.
Iridium(III)-Catalyzed Tandem Annulation Synthesis of Pyrazolo-
[1,2-α]cinnolines from Pyrazolones and Sulfoxonium Ylides. J. Org.
Chem. 2019, 84, 409.
(3) Zhong, X.; Lv, J.; Luo, S. [4 + 2] Cycloaddition of in Situ
Generated 1,2-Diaza-1,3-dienes with Simple Olefins: Facile Ap-
proaches to Tetrahydropyridazines. Org. Lett. 2015, 17, 1561.
(4) For selected reviews, see: (a) Trost, B. M.; Van Vranken, D. L.
Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chem.
Rev. 1996, 96, 395. (b) Helmchen, G.; Pfaltz, A. Phosphinooxazo-
lines-A New Class of Versatile, Modular P,N-Ligands for Asymmetric
Catalysis. Acc. Chem. Res. 2000, 33, 336. (c) Trost, B. M.; Crawley, M.
L. Asymmetric Transition-Metal-Catalyzed Allylic Alkylations:
Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921.
(d) Lu, Z.; Ma, S. Metal-Catalyzed Enantioselective Allylation in
Asymmetric Synthesis. Angew. Chem., Int. Ed. 2008, 47, 258.
(e) Trost, B. M.; Zhang, T.; Sieber, J. D. Catalytic Asymmetric
Allylic Alkylation Employing Heteroatom Nucleophiles: A Powerful
Method for C−X Bond Formation. Chem. Sci. 2010, 1, 427. (f) Trost,
B. M. Pd- and Mo-Catalyzed Asymmetric Allylic Alkylation. Org.
Process Res. Dev. 2012, 16, 185. (g) Lumbroso, A.; Cooke, M. L.;
Breit, B. Catalytic Asymmetric Synthesis of Allylic Alcohols and
Derivatives and Their Applications in Organic Synthesis. Angew.
Chem., Int. Ed. 2013, 52, 1890. (h) Butt, N.; Zhang, W. Transition
Metal-Catalyzed Allylic Substitution Reactions with Unactivated
Allylic Substrates. Chem. Soc. Rev. 2015, 44, 7929. (i) Butt, N.;
Yang, G.; Zhang, W. Allylic Alkylations with Enamine Nucleophiles.
Chem. Rec. 2016, 16, 2687. (j) Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu,
J.-P.; Helmchen, G.; You, S.-L. Iridium-Catalyzed Asymmetric Allylic
Substitution Reactions. Chem. Rev. 2019, 119, 1855. (k) Trost, B. M.;
Kalnmals, C. A. Annulative Allylic Alkylation Reactions between Dual
Electrophiles and Dual Nucleophiles: Applications in Complex
Molecule Synthesis. Chem. - Eur. J. 2020, 26, 1906. For selected
papers, see: (l) Shintani, R.; Park, S.; Shirozu, F.; Murakami, M.;
Hayashi, T. Palladium-Catalyzed Asymmetric Decarboxylative
Lactamization of γ-Methylidene-δ-Valerolactones with Isocyanates:
Conversion of Racemic Lactones to Enantioenriched Lactams. J. Am.
Chem. Soc. 2008, 130, 16174. (m) Rong, Z.-Q.; Yang, L.-C.; Liu, S.;
Yu, Z.; Wang, Y.-N.; Tan, Z. Y.; Huang, R.-Z.; Lan, Y.; Zhao, Y. Nine-
Membered Benzofuran-Fused Heterocycles: Enantioselective Syn-
thesis by Pd-Catalysis and Rearrangement via Transannular Bond
Formation. J. Am. Chem. Soc. 2017, 139, 15304. (n) Xu, S.-M.; Wei,
L.; Shen, C.; Xiao, L.; Tao, H.-Y.; Wang, C.-J. Stereodivergent
Assembly of Tetrahydro-γ-Carbolines via Synergistic Catalytic
Asymmetric Cascade Reaction. Nat. Commun. 2019, 10, 5553.
(o) Zhang, Q.-L.; Xiong, Q.; Li, M.-M.; Xiong, W.; Shi, B.; Lan, Y.;
Lu, L.-Q.; Xiao, W. J. Palladium-Catalyzed Asymmetric [8 + 2]
Dipolar Cycloadditions of Vinyl Carbamates and Photogenerated
Ketenes. Angew. Chem., Int. Ed. 2020, 59, 14096.
(5) For selected papers, see: (a) Zhao, X.; Liu, D.; Guo, H.; Liu, Y.;
Zhang, W. C-N. Bond Cleavage of Allylic Amines via Hydrogen Bond
Activation with Alcohol Solvents in Pd-Catalyzed Allylic Alkylation of
Carbonyl Compounds. J. Am. Chem. Soc. 2011, 133, 19354. (b) Huo,
X.; Yang, G.; Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W. Palladium-
Catalyzed Allylic Alkylation of Simple Ketones with Allylic Alcohols
and Its Mechanistic Study. Angew. Chem., Int. Ed. 2014, 53, 6776.
(c) Wei, X.; Liu, D.; An, Q.; Zhang, W. Hydrogen-Bond Directed
Regioselective Pd-Catalyzed Asymmetric Allylic Alkylation: The
Construction of Chiral α-Amino Acids with Vicinal Tertiary and
Quaternary Stereocenters. Org. Lett. 2015, 17, 5768. (d) Huo, X.; He,
R.; Zhang, X.; Zhang, W. An Ir/Zn Dual Catalysis for Enantio- and
Diastereodivergent α-Allylation of α-Hydroxyketones. J. Am. Chem.
Soc. 2016, 138, 11093. (e) Huo, X.; He, R.; Fu, J.; Zhang, J.; Yang, G.;
Zhang, W. Stereoselective and Site-Specific Allylic Alkylation of
Amino Acids and Small Peptides via a Pd/Cu Dual Catalysis. J. Am.
Chem. Soc. 2017, 139, 9819. (f) Huo, X.; Zhang, J.; Fu, J.; He, R.;
Zhang, W. Ir/Cu Dual Catalysis: Enantio- and Diastereodivergent
Access to α,α-Disubstituted α-Amino Acids Bearing Vicinal Stereo-
centers. J. Am. Chem. Soc. 2018, 140, 2080. (g) Yao, K.; Yuan, Q.; Qu,
X.; Liu, Y.; Liu, D.; Zhang, W. Pd-Catalyzed Asymmetric Allylic
Substitution Cascade Using α-(Pyrdin-1-yl)-acetamides Formed in
situ as Nucleophiles. Chem. Sci. 2019, 10, 1767. (h) Yao, K.; Liu, H.;
Yuan, Q.; Liu, Y.; Liu, D.; Zhang, W. Pd-Catalyzed Three-Component
Chemospecific Allylic Substitution Cascade for the Synthesis of N-
Carbonylmethylene-2-Pyridones. Huaxue Xuebao 2019, 77, 993.
(i) Liu, H.; Sun, Z.; Xu, K.; Zheng, Y.; Liu, D.; Zhang, W. Pd-
Catalyzed Asymmetric Allylic Substitution Cascade of But-2-ene-1,4-
diyl Dimethyl Dicarbonate for the Synthesis of Chiral 2,3-
Dihydrofurans. Org. Lett. 2020, 22, 4680.
(6) (a) An, Q.; Liu, D.; Shen, J.; Liu, Y.; Zhang, W. The
Construction of Chiral Fused Azabicycles Using a Pd-Catalyzed
Allylic Substitution Cascade and Asymmetric Desymmetrization
Strategy. Org. Lett. 2017, 19, 238. (b) Xu, K.; Liu, H.; Hou, Y.;
Shen, J.; Liu, D.; Zhang, W. Pd-Catalyzed Asymmetric Allylic
Substitution Cascade via An Asymmetric Desymmetrization for the
Synthesis of Bicyclic Dihydrofurans. Chem. Commun. 2019, 55, 13295.
(c) Xu, K.; Ye, J.; Liu, H.; Shen, J.; Liu, D.; Zhang, W. Pd-Catalyzed
Asymmetric Allylic Substitution Annulation Using Enolizable
Ketimines as Nucleophiles: An Alternative Approach to Chiral
Tetrahydroindoles. Adv. Synth. Catal. 2020, 362, 2059.
́
(7) For selected reviews, see: (a) Barluenga, J.; Valdes, C.
Tosylhydrazones: New Uses for Classic Reagents in Palladium-
Catalyzed Cross Coupling and Metal-Free Reactions. Angew. Chem.,
Int. Ed. 2011, 50, 7486. (b) Shao, Z.; Zhang, H. N-Tosylhydrazones:
Versatile Reagents for Metal-Catalyzed and Metal-Free Cross-
Coupling Reactions. Chem. Soc. Rev. 2012, 41, 560. (c) Xiao, Q.;
Zhang, Y.; Wang, J. Diazo Compounds and N-Tosylhydrazones:
Novel Cross-Coupling Partners in Transition-Metal Catalyzed
Reactions. Acc. Chem. Res. 2013, 46, 236. (d) Xia, Y.; Qiu, D.;
Wang, J. Transition-Metal-Catalyzed Cross Couplings through
Carbene Migratory Insertion. Chem. Rev. 2017, 117, 13810.
(e) Lou, J.; Wang, Q.; Wu, P.; Wang, H.; Zhou, Y.-G.; Yu, Z.
Transition-Metal Mediated Carbon-Sulfur Bond Activation and
Transformations: An Update. Chem. Soc. Rev. 2020, 49, 4307.
(8) Xia, Y.; Wang, J. N-Tosylhydrazones: Versatile Synthons in the
Construction of Cyclic Compounds. Chem. Soc. Rev. 2017, 46, 2306.
(9) (a) Zhu, S.-Y.; Zhang, Y.; Wang, W.; Hui, X.-P. Stereoselective
Synthesis of Functionalized Tetrahydro-1H-1,2-diazepines by N-
Heterocyclic Carbene-Catalyzed [3 + 4] Annulation. Org. Lett.
2017, 19, 5380. (b) Han, J.; Xu, Y.-W.; Wang, X.-M.; Zhang, L.; Hu,
X.-P. Copper-Catalyzed Formal Propargylic [3 + 2] Cycloaddition for
Stereoselective Construction of (E)-β-Pyrazolylacrylates. Tetrahedron
Lett. 2020, 61, 151409.
(10) Liu, D.; Xie, F.; Zhang, W. Palladium-Catalyzed Asymmetric
Allylic Alkylation with an Enamine as the Nucleophilic Reagent.
Tetrahedron Lett. 2007, 48, 7591.
E
https://dx.doi.org/10.1021/acs.orglett.0c03211
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(11) See details in the Supporting Information.
(12) CCDC 2007663 (3c) and CCDC 2040737 (3x-minor) contain
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(13) Li, J.; Lu, Y.; Zhu, Y.; Nie, Y.; Shen, J.; Liu, Y.; Liu, D.; Zhang,
W. Selective Asymmetric Hydrogenation of Four-membered exo-α,β-
Unsaturated Cyclobutanones Using RuPHOX-Ru as a Catalyst. Org.
Lett. 2019, 21, 4331.
(14) For reviews of enantioselective desymmetrization reactions,
see: (a) Trost, B. M.; Patterson, D. E. cis-5-Amino-6-hydroxycyclo-
hexadiene as a Chiral Building Block: An Asymmetric Synthesis of
(−)-Swainsonine. Chem. - Eur. J. 1999, 5, 3279. (b) Lim, C. W.; Lee,
S.-G. C2-Symmetric Bisphosphine Ligands Derived from 1,1′-
Binaphthyldiamines and Diphenylphosphinobenzoic Acid for Palla-
dium Catalyzed Desymmetrizations. Tetrahedron 2000, 56, 5131.
(c) García-Urdiales, E.; Alfonso, I.; Gotor, V. Enantioselective
Enzymatic Desymmetrizations in Organic Synthesis. Chem. Rev.
2005, 105, 313. (d) Chapsal, B. D.; Ojima, I. Total Synthesis of
Enantiopure (+)-γ-Lycorane Using Highly Efficient Pd-Catalyzed
Asymmetric Allylic Alkylation. Org. Lett. 2006, 8, 1395. (e) Trost, B.
M.; Richardson, R.; Yong, K. Palladium-Catalyzed Chemo- and
Enantioselective Oxidation of Allylic Esters and Carbonates. J. Am.
Chem. Soc. 2006, 128, 2540. (f) Rovis, T. Recent Advances in
Catalytic Asymmetric Desymmetrization Reactions. In New Frontiers
in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; John Wiley &
́
Sons: Hoboken, NJ, 2007; p 275. (g) Díaz de Villegas, M. D.; Galvez,
́
J. A.; Etayo, P.; Badorrey, R.; Lopez-Ram-de-Víu, P. Recent Advances
in Enantioselective Organocatalyzed Anhydride Desymmetrization
and Its Application to the Synthesis of Valuable Enantiopure
Compounds. Chem. Soc. Rev. 2011, 40, 5564. (h) Zeng, X.-P.; Cao,
Z.-Y.; Wang, Y.-H.; Zhou, F.; Zhou, J. Catalytic Enantioselective
Desymmetrization Reactions to All-Carbon Quaternary Stereocenters.
Chem. Rev. 2016, 116, 7330. (i) Goh, S. S.; Guduguntla, S.; Kikuchi,
T.; Lutz, M.; Otten, E.; Fujita, M.; Feringa, B. L. Desymmetrization of
meso-Dibromocycloalkenes through Copper(I)-Catalyzed Asymmetric
Allylic Substitution with Organolithium Reagents. J. Am. Chem. Soc.
2018, 140, 7052. (j) Li, X.; Zhao, Z.-B.; Chen, M.-W.; Wu, B.; Wang,
H.; Yu, C.-B.; Zhou, Y.-G. Palladium-Catalyzed Asymmetric Hydro-
genation of 2-Aryl Cyclic Ketones for the Synthesis of trans-
Cycloalkanols through Dynamic Kinetic Resolution under Acidic
Conditions. Chem. Commun. 2020, 56, 5815. (k) Wang, H.; Zhao, Y.;
Ding, Y.-X.; Yu, C.-B.; Zhou, Y.-G. Synthesis of cis β-Hydroxy
Ketones by Desymmetrization of 1,3-Cyclopentanediones through
Ruthenium-Catalyzed Hydrogen Transfer. Asian J. Org. Chem. 2020,
9, 753.
F
https://dx.doi.org/10.1021/acs.orglett.0c03211
Org. Lett. XXXX, XXX, XXX−XXX