Enantioselective Synthesis of Isoxazolines Enabled by Palladium-Catalyzed Carboetherification of Alkenyl Oximes

Article abstract of DOI:10.1002/anie.201912408

Reported here is a highly efficient Pd/Xiang-Phos catalyzed enantioselective carboetherification of alkenyl oximes with either aryl or alkenyl halides, delivering various chiral 3,5-disubstituted and 3,5,5-trisubstituted isoxazolines in good yields with u

Full text of DOI:10.1002/anie.201912408

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Accepted Article
Title: Enantioselective Synthesis of Isoxazolines Enabled by Palladium-
Catalyzed Carboetherification of Alkenyl Oximes
Authors: Junliang Zhang, Lei Wang, Kenan Zhang, Yuzhuo Wang,
Mingjie Chen, and Wenbo Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912408
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10.1002/anie.201912408
Angewandte Chemie International Edition
RESEARCH ARTICLE
Enantioselective Synthesis of Isoxazolines Enabled by Palladium-
Catalyzed Carboetherification of Alkenyl Oximes
Lei Wang, Kenan Zhang, Yuzhuo Wang, Wenbo Li, Mingjie Chen, Junliang Zhang*
Abstract: Herein we reported a highly efficient Pd/Xiang-Phos
catalyzed enantioselective carboetherification of alkenyl oximes with
aryl or alkenyl halides, delivering various chiral 3,5-disubstituted and
3,5,5-trisubstituted isoxazolines in good yield with up to 97% ee. The
sterically bulky and electron-rich (S, Rs)-NMe-X2 is responsible for
the excellent reactivity and enantioselectivity. The salient features of
this transformation include mild reaction conditions, general substrate
scope, well functional group tolerance, good yields, high
enantioselectivity, easy scale-up and application in late stage
modification of bioactive compounds. The obtained products can be
readily transformed into useful chiral 1, 3- aminoalcohols.
Despite significant progress in the racemic synthesis, the
development of asymmetric versions still poses considerable
challenges and only a few strategies have been explored so far.
In general, the classic method for synthesis of enantioenriched
isoxazolines are 1, 3-dipolar cycloaddition via chiral auxiliary
strategy or Lewis acid asymmetric catalysis (Scheme 1a).[5-8] In
2018, Liu[9a] and co-workers demonstrated an elegant
enantioselective radical oxytrifluoromethylation of alkenyl oximes
enabled by the use of copper/cinchona alkaloid-based
sulfonamide, leading to an α-tertiary stereocenter with CF3-
containing isoxazolines (Scheme 1b).
Introduction
Isoxazolines are key structural motifs in natural products,
pharmaceutics, materials and agrochemicals (Figure 1). [1] They
are also used as useful precursors to chiral acyclic building blocks
such as β-hydroxy ketones, and γ-aminoalcohols in organic
synthesis. [2] Therefore, the development of new methods for their
efficient synthesis has kept attracting much attention, for
examples, Loh’s group firstly reported Pd-catalyzed allylic oxime
cyclization for the dioxygenation of an alkene.[3a] Later, the groups
of Han[4a] and others reported the radical difunctionalization route
to promote cyclization of β, γ-unsaturated oximes to synthesize
isoxazolines. [4] Very recently, Shi’s group reported a gold redox
catalysis strategy for cyclization/arylation of allylic oximes to
afford the aryl-containing 3, 5-disubstituted isoxazolines.[4i]
Scheme 1. Enantioselective synthesis of isoxazolines.
Figure 1. Chemical structures of biological active isooxazoline and 1,3-
With regard to the significance of chiral isoxazolines, the
development of asymmetric methods for their synthesis is still
highly desirable. Recently, our group developed a series of chiral
sulfinamidephosphine (Sadphos) ligands, so called Ming-Phos,
Xu-Phos, and Xiang-phos.[11] Inspired by their good performance
in asymmetric transition-metal catalysis as well as Chen[3b] and
Mosher’s[3c] elegant work on the palladium-catalyzed alkenyl
oximes carboetherification[10] reactions for the synthesis of
racemic isoxaolines, we became very interested in whether the
asymmetric version of palladium-catalyzed reaction could be
realized by the employment of our developed Sadphos ligand.
However, this hypothesis will face considerable challenges: (1)
How to minimize the isomerization of β, γ-unsaturated oximes to
aminoalcohol.
[*] L. Wang, K. Zhang, Y. Wang, W. Li, M. Cheng, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China Normal
University Shanghai, 200062 (P. R. China)
E-mail: jlzhang@chem.ecnu.edu.cn
L. Wang, Prof. Dr. J. Zhang
Department of Chemistry, Fudan University, 2005 Songhu Road,
Shanghai 200438, China.
E-mail: junliangzhang@fudan.edu.cn
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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α, β-unsaturated oximes.[3b, 12] (2) How to efficiently control both
chemoselectivity and enantioselectivity. Herein, we describe an
efficient palladium/Xiang-Phos catalyzed enantioselective
alkenyl oximes carboetherification with both aryl halides (Br, Cl)
and alkenyl bromides, delivering chiral 3, 5-disubstituted and
3,5,5-trisubstituted isoxazolines in good yields with up to 98% ee
(Scheme 1c).
carboetherification (Table 1, entry 6 vs entry 5). When (S, Rs)-
NMe-Xu2 with a bulk aryl group was used, the ee was slightly
improved from 3% to 28% (Table 1, entry 7). Gratifyingly, with the
use of more bulky N-methyl Xiang-Phos (S, Rs)-NMe-X1 as
ligand, 3a was isolated in 50% yield with 89% ee (Table 1, entry
8). Further lowering the reaction temperature resulted in lower
yield and the more byproduct 1a' was detected (Table 1, entry 9).
To address this issue, we proposed that increasing the oxidative
addition rate of the arylbromide with PdLn via increasing the
electron-richness of ligand might favor the subsequent
carboetherification reaction and thus improved the reaction yield.
The (S, Rs)-NMe-X2 bearing two electron-donating methoxy
groups on the aryl backbone was then prepared and subjected to
the reaction. To our delight, the yield was indeed significantly
improved to 82% with the enantioselectivity increasing to 96% ee
(Table 1, entry 10).
Results and Discution
Optimization of Reaction Conditions. In our initial study, β,
γ-unsaturated ketoxime 1a and 4-bromotoluene 2a were selected
as the model substrates. A series of commercially available chiral
ligands were first investigated (Figure 2). Unfortunately, N, P-
ligands L1-L2 provided 3a in poor yield with low enantioselectivity.
When bisphosphine ligands such as Josiphos (L3-L4), (S)-MeO-
DTBM-Biphep (L5), (R)-BINAP (L7), (R, R)-DIPAMP (L8) as well
as (R)-QuinoxP® (L9) were further examined, the desired product
3a was also obtained in low yield with up to 48% ee. Moreover,
Binol-derived phosphoramidite(L10) was found to be inefficient
either in this reaction. In these reactions, the low yield was
attributed to the isomerization reaction of the β, γ-unsaturated
oximes to α, β-unsaturated oximes.
Table 1. Optimization of reaction conditions.[a]
Entry
Ligand
Pd sources
Base
Yield[b] (Ee[c])(
%) of 3a/1a'
1
2
(R, Rs)-M1
(S, Rs)-M1
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
PdCl2
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
K2CO3
0 (-)/85
0 (-)/73
0 (-)/75
0 (-)/77
0 (-)/78
72 (3)
3
(S, Rs)-W1
4
(S, Rs)-X1
5
(S, Rs)-Xu1
6
(S, Rs)-NMe-Xu1
(S, Rs)-NMe-Xu2
(S, Rs)- NMe-X1
(S, Rs)-NMe-X1
(S, Rs)-NMe-X2
(S, Rs)-X2
7
70 (28)
50 (89)
38 (88)
82(96)
8
9[d]
10[d]
11[d]
12[d]
13[d,e]
14[d]
15[d,e]
16[d]
17[d]
18[d]
19[d,f]
20[d,g]
21[d,h]
trace(-)/60
16 (92)
23(94)
(S, Rs)-NMe-X2
(S, Rs)-NMe-X2
(S, Rs)-NMe-X2
(S, Rs)-NMe-X2
(S, Rs)-NMe-X2
(S, Rs)-NMe-X2
(S, Rs)-NMe-X2
(S, Rs)-NMe-X2
(S, Rs)-NMe-X2
(S, Rs)-NMe-X2
Pd(OAc)2
[Pd(allyl)Cl]2
PdCl2(CH3CN)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
68 (96)
44 (55)
44 (88)
55 (92)
0(-)/80
33 (94)
47 (94)
42 (90)
Cs2CO3
Na2CO3
NaOtBu
NaOtBu
NaOtBu
Figure 2. Screened chiral ligands in this work.
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), NaOtBu (1.5 equiv), 3
mol% Pd2(dba)3, and 10 mol% ligand in 2.0 mL toluene, 100 oC under Ar for 12
h. [b] Isolated yield. [c] Ee was determined by HPLC analysis [d] 70 oC , 12 h.
[e] 5 mol % palladium catalysts. [f] THF, [g] 1,4-dioxane and [h] DCE were used
respectively as solvent.
We next turned our attention to our developed Sadphos ligands.
Unfortunately, Ming-Phos (R, Rs)-M1, (S, Rs)-M1, Wei-Phos (S,
Rs)-W1 and Xiang-Phos (S, Rs)-X1 as well as Xu-Phos (S, Rs)-
Xu1 could not deliver the desired product 3a at all and byproduct
α, β-unsaturated oxime 1a' was ontained in good yield (Table 1,
entries 1-5). In contrast, 72 % yield of 3a was obtained albeit with
only 3% ee with the use of (S, Rs)-NMe-Xu1 as the ligand,
indicating the NH moiety of Xu-Phos might inhibit the
For comparison, the use of (S, Rs)-X2 with NH moiety only give
trace amount of the product 3a (Table 1, entry 11). Other
palladium sources such as PdCl2, Pd(OAc)2, Pd(CH3CN)2Cl2 and
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10.1002/anie.201912408
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allylpalladium(II) chloride gave 3a in lower yield.(Table 1, entries
12-15). Further base and solvent screening didn’t give better
result (Table 1, entries 16-21).
well tolerant, delivering 3u-3z in 70-83% yields with 89-95% ee.
A range of the alkenyl oximes, including those disubstituted
phenyl ring, naphthyl ring and heteroaryl also reacted smoothly to
furnish 3aa-3ad in moderate to good yields with 88-94% ee.
Enantioselective Synthesis of 3, 5, 5-trisubstituted
Isoxazolines. We next examined the reaction scope of aryl
bromides with gem-disubstituted alkenes 1 (Scheme 3). Electron-
neutral, -donating and -withdrawing substituents were generally
compatible, durnishing 3, 5, 5-trisubstituted isoxazolines 4a-4m
bearing α-tertiary stereocenter in 71-97% yields with up to 97%
ee. Moreover, a range of heteroaryl bromides, in particular,
pyridinyl, thiophenyl, furanyl, indolyl, quinolinyl containing
substrates were successful to produce 4q-4w in moderate to good
yields with up to 96% ee. To demonstrate potential applications,
late-stage modification of various natural products, biologically
active molecules and pharmaceuticals were conducted. The
clofibrate derivative 4x could be obtained in 77% yield with 96%
ee. The late stage modification of racemic 4-bromo-phenylalanine
delivered 4y in 95% yield with 95% ee and a 1.2:1 dr. Particularly,
Menthol, carbohydrate, derived chiral isoxazolines 4z-4aa were
afforded
in
good
yields
and
moderate
to
high
diastereoselectivities.
Given that greater abundance of aryl chlorides and less price,
the development of conditions that allow use of aryl chlorides in
this reaction is important. Gratifyingly, various aryl chlorides
including electron rich, electron-neutral and electron-poor were
also applicable to this transformation, the corresponding
isoxazolines were obtained in 40-78% yields with 83−96% ee
(Scheme 3). Notably, the poorer yield is some cases was caused
by the more double bond isomerisation of substrate. Moreover,
both 2-chloronaphthalene and 6-chlorinequinoline could be
employed to form 4m, 4ac and 4ad in 71−81% yields with 89-91%
ee. A range of alkenyl oximes with electron-rich and electron-
deficient functional groups at the aryl and heteroaryl were well
tolerated, giving 4ag–4al in 65–95% yields with 92–95% ee. In
addition, products 4am-4an could be also obtained with excellent
enantioselectivities albeit in relatively lower yields. Moverover,
compounds 4ap-4aq were isolated in excellent yields high
enantioselectivities. Notably, an aryl-substituted alkene could also
be employed in this reaction to give 4ar in 87% yield with 62% ee,
further modification of the ligand is necessary.
Scheme 2. Substrate scope of aryl bromides. [a] Unless otherwise noted, all
reactions were carried out with 0.2 mmol of 1a, 0.4 mmol of 2, NaOtBu (1.5
equiv), 3 mol% Pd2(dba)3 and 10 mol% ligand in 2.0 mL of toluene, 65 oC under
Ar for 12 h. [b] 70 oC under Ar for 12 h. [c] The dr was determined by NMR
analysis.
Enantioselective
Synthesis
of
3,5-disubstituted
Isoxazolines. With the optimal reaction conditions in hand, we
then explored the scope of aryl bromides with alkenyl oxime 1a
(Scheme 2). Both electron-donating and electron-withdrawing
group at the para-position of aryl bromides are compatible,
delivering 3, 5-disubstituted isoxazolines 3a-3k in good yields with
90-96% ee. The absolute configuration of 3g was confirmed by X-
ray crystallography. Besides, aryl bromides bearing substitution
at meta- and ortho-substituent(s) were also applicable to give the
desired 3l-3n in moderate yields with up to 96% ee. Moreover,
polycyclic aryl and heteroaryl bromides could be employed to
afford 3o-3t in moderate yields with good enantioselectivity.
Inspired by the above results, we then turned to explore the
reaction scope via variation of the alkenyl oximes. Various para-
and meta-substituents on the aromatic ring of the oximes were
Enantioselective Synthesis of Isoxazolines with the Use of
Alkenyl Bromides. Olefin groups are one of the simplest and
most useful functional transformations in organic synthesis.
Inspired by the above good results, expanding this reaction from
aryl halides to alkenyl bromides is desirable (Scheme 4). We
firstly examined the partners with β, γ-unsaturated oxime 1a and
2-bromopropene. To our surprises, the desired product 6a was
afforded in 65% yield and 94% ee. Various aromatic ring of the
oximes bearing electron-donating and electron-withdrawing
groups, such as 4-methoxy, 4-methyl, 4-tert-butyl, 4-fluoro, 4-
chloro, 3, 4-dimethyl and 3, 5-dichloro were well tolerated, and the
desired alkenyl isozolines 6b-6h were isolated in moderate to
good yields with excellent enantioselectivities (90-96% ee).
Notably, halogens
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10.1002/anie.201912408
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Scheme 3. Enantioselective synthesis of 3, 5, 5-trisubstituted isoxazolines. [a] Unless otherwise noted, all reactions were carried out with 1 (0.2 mmol), aryl bromide
(0.4 mmol), NaOtBu (1.5 equiv), 3 mol% Pd2(dba)3 and 10 mol% of ligand in 2.0 mL of toluene, 65 oC, Ar, 8 h. [b] 0.2 mmol of 1, 0.6 mmol of aryl chloride, NaOtBu
(1.5 equiv), 3 mol% Pd2(dba)3 and 10 mol% ligand in 2.0 mL of toluene, 65 oC, Ar, 56 h. [c] 0.6 mmol of aryl chloride, 80 oC, Ar, 48 h. [d] 5 mol% allylpalladium(II)
chloride dimer and 15 mol% of ligand in 2.0 mL of toluene, 70 oC , Ar, 40 h.
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groups provide the handle for further functionalization. Moreover,
gem-disubstituted alkenes oximes exhibit excellent activities, the
corresponding α-tertiary stereocenter isoxazolines 6i-6o were
isolated in 80-95% yields and 91-95% ee. A variety of alkenyl
bromides such as 2-bromo-2-butene, 1-bromocyclohexene and 2-
bromo-1-butene furnished the products 6p-6s in 40-95% yields
with 92-96% ee. Notably, product 6t was furnished in 95% yield
with relatively low ee with the use of β-bromostyrene.
corresponding valuable chiral β-hydroxy ketones and 1, 3-
aminoalcohols. For example, the simple reduction of 3a smoothly
generated the β-hydroxyketone 7 in 73% yield with 93% ee. Chiral
isoxazole 4b was selectively transformed to 1, 3-aminoalcohols 8
as a 3: 2 mixture of diastereomers in 95% yield with 98% ee by
using the NiCl2/NaBH4 reduction system. The corresponding
product 9 by further treatment with CDI, was isolated in 54% and
36% yields without diminishing the enantioselectivity.
Furthermore, the addition of allylmagnesium bromide to 4b,
delivered 10 bearing two stereocenters with a 1:1 dr.
Scheme 5. Gram-scale synthesis and synthetic applications
Scheme 4. Enantioselective synthesis of isoxazolines with alkenyl bromides.[a]
Unless otherwise noted, all reactions were carried out with 0.2 mmol of 1, 0.5
mmol of 5, NaOtBu (1.5 equiv), 3 mol% Pd2(dba)3 and 10 mol% ligand in 2.0 mL
of toluene, 65 oC under Ar for 12 h. [b] 90 oC under Ar for 12 h.
Mechanistic
Considerations
for
the
Asymmetric
Carboetherification. Based on by Wolfe’s [13] studies as well as
our own observation, the catalytic cycle and asymmetric induction
model were proposed (Scheme 6). Oxidative addition of the aryl
bromides to a (S, Rs)-NMe-X2 Pd(0) complex would provide
Pd(II) complex II. With NaOtBu as the base, ligand exchange
between the bromide group and the substrate 1l takes place to
form the Pd complex III, which could undergo intramolecular
insertion of the alkene into the Pd-O bond to afford Pd complex
IV. Reductive elimination of complex Pd complex IV forms the
product 4a with concomitant regeneration of the Pd(0) catalyst.
Remarkably, because of the slow oxidative addition of palladium
to aryl chlorides, the side product 1l' via the isomerization was
Gram-scale Synthesis and Synthetic Applications. This
Pd/Xiang-Phos-catalyzed asymmetric carboetherification could
be applied to the enantioselective synthesis of the potent firefly
luciferase inhibitor 3ae and 88% yield with 96% ee were obtained
(Scheme 5, a). The practicability of our method was demonstrated
with the 8 mmol scale of reaction, the 1.89 g of 4b was isolated in
89% yield without loss of the enantioselectivity (Scheme 5, b). To
display the synthetic utility, several transformations of the
isoxazolines have been carried out (Scheme 5, c). The
enantioenriched isoxazolines can be transformed into the
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10.1002/anie.201912408
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RESEARCH ARTICLE
often detected and thus leading the lower yield of the desired
carboalkoxylation product.
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Conclusion
In summary, we have successfully developed a new robust
Pd/Xiang-Phos
catalytic
system
for
the asymmetric
carboetherification of β, γ-unsaturated ketoximes with aryl halides
and alkenyl bromides, which provide a rapid access to a series of
chiral isoxazolines. The new chiral monophosphorus ligand (S,
Rs)-NMe-X2 was responsible for the excellent reactivity and
enantioselectivity of these transformations. The salient features of
this reaction including mild reaction conditions, general substrate
scope, well functional group tolerance, good yields and high
enantioselectivity, readily available starting materials, easy scale-
up and application in late stage modification of bioactive
compounds make this method extremely attractive. The obtained
products can be readily transformed into useful chiral 1, 3-
aminoalcohols.
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We gratefully acknowledge the funding support of NSFC
(21425205,
21672067,
21702063),
973
Program
(2015CB856600), the Program of Eastern Scholar at Shanghai
Institutions of Higher Learning and the Innovative Research Team
of Ministry of Education.
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Conflict of interest
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The authors declare no conflict of interest.
Keywords: palladium catalyzed • xiang-Phos • alkenyl oximes •
carboetherification • chiral isoxazolines
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[14] (S, Rs)-NMe-X2 (CCDC: 1946327), 3g (CCDC:1946328) and 4c (CCDC:
2946329)
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
RESEARCH ARTICLE
Lei Wang, Kenan Zhang, Yuzhuo Wang,
Wenbo Li, Mingjie Chen, Junliang Zhang*
Page No. – Page No.
Chiral
Isoxazolines
Enabled
by
Palladium/Xiang-Phos–Catalyzed
Enantioselective Carboetherification of
Alkenyl Oximes
A new robust Pd/Xiang-Phos catalytic system for the asymmetric carboetherification of β,
γ-unsaturated ketoximes with aryl halides. The sterically bulky and electron-rich ligand (S,
Rs)-NMe-X2 is responsible for the excellent reactivity and enantioselectivity. The salient
features of this transformation include mild reaction conditions, general substrate scope,
well functional group tolerance, good yields, high enantioselectivity, easy scale-up and
application in late stage modification of bioactive compounds.
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