Ming-Phos/Gold(I)-Catalyzed Stereodivergent Synthesis of Highly Substituted Furo[3,4-d][1,2]oxazines?

Article abstract of DOI:10.1002/cjoc.202000034

A gold(I)-catalyzed asymmetric intermolecular tandem [3+3]-cyclization reaction of 2-(1-alkynyl)-2- alken-1-ones with nitrones has been developed by using Ming-Phos as a chiral ligand. This method enables access to the stereodivergent synthesis of highly substituted furo[3,4-d][1,2]oxazines in excellent efficiency and stereoselectivity (up to 99% yield, 99% ee, >20 : 1 dr).

Full text of DOI:10.1002/cjoc.202000034

Chinese Journal
of Chemistry
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Accepted Article
Title: Ming-Phos/Gold(I)-Catalyzed Stereodivergent Synthesis of Highly Substituted
Furo[3,4-d][1,2]oxazines
Authors: Lujia Zhou, Bing Xu, Danting Ji, Zhan-Ming Zhang* and Junliang Zhang*
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Ming-Phos/Gold(I)-Catalyzed Stereodivergent Synthesis of Highly
Substituted Furo[3,4-d][1,2]oxazines
Lujia Zhou,a Bing Xu,a Danting Ji,a Zhan-Ming Zhang*,b and Junliang Zhang*,a,b
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
a Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering East China Normal University,
Shanghai 200062, China
b Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438 (P. R. China)
Summary of main observation and conclusion
A Gold(I)-catalyzed asymmetric intermolecular tandem [3+3]-cyclization reaction of
2-(1-alkynyl)-2-alken-1-ones with nitrones has been developed by using Ming-Phos as a chiral ligand. This method enables access to the stereodivergent
synthesis of highly substituted Furo[3,4-d][1,2]oxazines in excellent efficiency and stereoselectivity (up to 99% yield, 99% ee, >20 : 1 dr).
modification and could be easily prepared in good yields from
Background and Originality Content
Over the past decade, a few impressive strategies in the area
of racemic 3,4-fused bicyclic furans synthesis have been
reported.[1-4] During the same time, our group has developed a
series of the metal-catalyzed intermolecular cycloaddition of
2-(1-alkynyl)-2-alken-1-ones[4] with imines,[4a] 3-styrylindoles,[4b]
1,3-diphenyl- isobenzofuran,[4c] and nitrones,[4d] which have been
extensively used for the synthesis of racemic 3,4-fused bicyclic
furans derivatives.[3,4] However, in sharp contrast to the extensive
application and the great progress recorded of racemic furan, the
synthesis of these optically active 3,4-fused bicyclic furans still
poses a considerable challenge, especially for the asymmetric
gold catalysis.[5] Therefore, the development of efficient methods
for their asymmetric synthesis from readily accessible starting
materials is highly desired.
Over the past decade, the development of homogeneous gold
catalysis has been remarkably rapid, due to yield a host of mild
and selective methods for the formation of carbon-carbon and
carbon-heteroatom by activating bonds. The “gold rush” in gold
catalysis has been accompanied with efforts to develop
asymmetric gold catalysis to further increase the synthetic utility
of these transformations.[6] However, the development of chiral
gold catalysts pose considerable challenges due to the
dicoordinated gold(I) complexes with preferred linear geometry,
which makes the active reaction site opposite to the chiral ligand
and thus limit the capability to transfer asymmetry. To address
this challenging issue, the building of an extended chiral pocket is
crucial. In this context, the introduction of bulky and extended
substituents to the chiral ligands (biaryl bisphosphines,[7]
Scheme 1 Previous results and this work on asymmetric [3+3] cycloadditions
of 2-(1-alkynyl)-2-alken-1-ones with nitrones.
monodentate phosphoramidite,[8] etc.) embracing the gold active
center and its active reaction site has been developed as one of
inexpensive commercially available chiral tert-butylsulfinamide
practical and widely accepted strategies. The major drawback for
and could be applied to address many challenging reactions. For
this steric effect strategy is bringing much extra efforts to modify
example, we reported
a
gold-catalyzed diastereo- and
and prepare the chiral ligands. Moreover, this strategy also has
been proven ineffective for a general substrate scope with regard
to the catalytic efficiency and selectivity. Therefore, the simple
and easily prepared chiral ligands with multi sites for modification
are highly desirable. Recently, our group developed a new type of
SadPhos (Ming-Phos,[9] Xiang-Phos,[10] PC-Phos,[11] Xu-Phos,[12]
WJ-Phos[13] and Xiao-Phos[14]), which have diverse sites for
enantioselective [3+3] cycloaddition of 2-(1-alkynyl)-2-alken-1-
ones with nitrones to afford an efficient synthetic route to
construct chiral highly substituted furo[3,4-d][1,2]oxazines
(Scheme 1).[5a] Unfortunately, this reaction has a large substrate
limitation and only low ee can be obtained for the aliphatic
alkyne moiety of 2-(1-alkynyl)-2-alken-1-ones. This issue was
finally addressed by the use of Ming-Phos chiral ligands and the
*E-mail:
zhangzhanming12@163.com;
jlzhang@chem.ecnu.edu.cn;
junliangzhang@fudan.edu.cn
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enantiodivergent synthesis was realized by the use of a pair of
diastereoisomeric Ming-Phos.[5f] Herein, we wish to report a
comprehensive study of this gold-catalyzed asymmetric
with electron-rich or electron-deficient aryl substituents could
deliver the corresponding optically active products 3ab–3af in
good yields with excellent enantioselectivities (Table 2, entries 7–
11: 85–91% yields, 93–99% ees). To our delight, the opitcally
active ent-3ba–3af with opposite configuration to 3ba–3af could
be also furnished in 85–99% yields with 92–98% ees with the use
of (R, Rs)-M5 as the chiral ligand (Table 2, entries 2-11).
cycloaddition
of
alkyl-
and
aryl-substituted
2-(1-alkynyl)-2-alken-1-ones with nitrones including scope,
mechanism by using Ming-Phos as the chiral ligand in excellent
diastereo- and enantioselectivity (Scheme 1). This reaction has a
broad substrate scope (28 examples), tolerates a wide range of
functional groups, and both enantiomers of the products were
obtained by the employment of the diastereoisomers of ligands.
Table 1 Optimization of the reaction conditions.a
Results and Discussion
Initially, 2-(1-alkynyl)-2-alken-1-one 1a with nitone 2a were
chosen as the model substrates to examine the performance of a
series of known and our developed chiral ligands (Figure 1), such
as (R)-2,2’-(bis(diphenylphosphino)-1,1’-binaphthyl (BINAP，L3),
(R)-2-(diphenylphosphanyl)-2’-methoxy-1,1’-binaphthyl (MOP, L4),
phosphoramidites (L5–L7) and two sets of diastereoisomeric
Ming-Phos ligands (M1–M5). It is noted that these Ming-Phos
ligands could be easily prepared on gram scale, such as the (S,
Rs)-Ming-Phos ligands could be easily obtained by using Grignard
reagent (RMgX), and the other set of (R, Rs)-Ming-Phos ligands
could be obtained from the stereoselective addition of
organolithium reagent (RLi). After the examination of known
chiral ligands, no satisfactory result was obtained (Table 1, Entries
1–7). Gratifyingly, these Ming-Phos ligands were significantly
more efficient in yield and enantioselectivity than previously
screened ligands (Table 1, entries 8–17). Several (S, Rs)-Ming-Phos
ligands were examined (entries 8–12), and to our delight, (S,
Rs)-M5 derived from naphthalen-1-ylmagnesium bromide gave
3aa in high yield with excellent ee value (entry 12, 92% yield, 94%
ee). Inspired by this result, the other set of (R, Rs)-Ming-Phos
ligands were also investigated under the same condition.
Delightfully, the other diastereoisomer M5 that was obtained by
using naphthalen-1-yllithium could also afford the ent-3aa (the
enantiomer of 3aa) in 86% yield with 96% ee.
Entry
1b
2b
3b
4
L
3aa or ent-3aa Yield(%)c
Ee(%)d
55
32
70
67
74
0
L1
3aa
3aa
77
55
72
75
70
58
68
92
94
91
90
92
89
88
87
83
86
L2
L3
3aa
L4
3aa
5
L5
3aa
6
L6
3aa
7
L7
3aa
56
89
91
73
93
94
83
80
92
95
96
8
(S,Rs)-M1
(S,Rs)-M2
(S,Rs)-M3
(S,Rs)-M4
(S,Rs)-M5
(R,Rs)-M1
(R,Rs)-M2
(R,Rs)-M3
(R,Rs)-M4
(R,Rs)-M5
3aa
9
3aa
10
11
12
13
14
15
16
17
3aa
3aa
3aa
ent-3aa
ent-3aa
ent-3aa
ent-3aa
ent-3aa
a Unless otherwise specified, the reaction was carried out using ketone 1a
(0.1 mmol), nitrone 2a (0.11 mmol), L (5.5 mol%), [Me2SAuCl] (5 mol%),
and AgNTf2 (5 mol%) in DCE at -10 oC. b 2.5 mol% L and 2.5 mol% AgNTf2
c
were used. NMR yield with CH2Br2 as an internal standard. d Determined
by chiral HPLC.
After addressing the enantioselectivity and efficiency issues
of the alkyl-substituted 2-(1-alkynyl)-2-alken-1-ones with various
nitrones, we wondered whether this pair of M5 could be
applicable to the reactions of the aryl-substituted 2-(1-alkynyl)-2-
alken-1-ones. We chose the aryl-substituted 2-(1-alkynyl)-2-
alken-1-one 1g with diphenyl nitrone 2a as the model substrates
to examine (Table 3). The (S, Rs)-M5 could deliver desired product
3ga in high yield with excellent ee (Table 3, entry 5, 93% yield, 97%
ee). Unfortunately, the ent-3ga was obtained in very low ee (9%)
by using the (R, Rs)-M5 as the chiral ligand. With a series of
Ming-Phos ligands (Figure 1) in our hand, we started to examine
their performance, again (Table 3, entries 6–10). To our delight,
the excellent ee (90%) of the ent-3ga was obtained by choosing
(R,Rs)-M3 as the chiral ligand (Table 3, entry 8). Subsequently,
choosing (S,Rs)-M5 and (R,Rs)-M3 as the ligands, we have made
extensive study on the aryl substrates 1 with various nitrones 2
Figure 1 Known and our developed chiral ligands (Ming-Phos).
Having identified a pair of diastereoisomers M5 as powerful
chiral ligands for the gold-catalyzed asymmetric [3+3]
cycloaddition of 2-(1-alkynyl)-2-alken-1-one 1a with diphenyl
nitrone 2a, we next examined the scope of aliphatic substituted
2-(1-alkynyl)-2-alken-1-ones 1 and the corresponding optically
active products 3ba–3fa were isolated as a single diastereomer in
86-99% yields with excellent enantioselectivities (94-99% ees) by
the employment of (S, Rs)-M5 derived gold complex (Table 2,
entries 2–6). Gratifyingly, substrates 1b and 1c with functional
groups such as alkyl chloride and alkyl ester were tolerated and
the reactions proceeded smoothly to deliver desired products 3ba
and 3ca in 99% yield, 99% ee and 95% yield, 99% ee, repectively
(Table 2, entries 2–3). Subsequently, the scope of nitrones was
also investigated, and the reaction of 1a with various nitrones
(Table 4). The substrates 1 bearing different aryl group (R1
=
4-BrPh, 4-NO2Ph) of the alkyne moiety were tolerable, giving the
desired products in 84–92% ees (Table 4, entries 2–3, 3ha–3ia and
ent-3ha–ent-3ia). The 1-ethynylnaphthalene derived the
2
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Chin. J. Chem.
b
compound 1j also worked well, leading to 67% yield of 3ja and
ent-3ja with 91% ee and 90% ee, repectively (Table 4, entry 4).
and AgNTf2 (5 mol%) in DCE at -10 oC. NMR yield with CH2Br2 as an
internal standard. c Determined by chiral HPLC.
Table 2 Scope of alkyl-substituted 2-(1-alkynyl)-2-alken-1-ones with
Table
4
Scope of aryl-substituted 2-(1-alkynyl)-2-alken-1-ones with
various nitrones.a
various nitrones.a
Yieldd(Ee)/[%]
Yieldd(Ee)/[%]
3b ent-3c
Entry
R1/R2/R3 (1)
R4/R5 (2)
Entry
1
R1/R2/R3 (1)
Ph/Me/Ph (1g)
R4/R5 (2)
3b
ent-3c
1
2
nBu/Me/Ph (1a)
(CH2)3Cl/Me/Ph
(1b)
Ph/Ph (2a)
3aa, 86(94) ent-3aa, 92(96)
Ph/Ph (2a)
3ga, 93(97) ent-3ga, 99(90)
3ha, 93(91) ent-3ha, 96(92)
2
3
4
5
6
7
4-BrPh/Me/Ph (1h)
4-NO2Ph/Me/Ph
(1i)
2a
2a
3ba, 99(99) ent-3ba, 99(94)
2a
2a
2a
2a
2a
2a
3ia, 83(92) ent-3ia, 47(84)
3ja, 67(91) ent-3ja, 78(90)
3ka, 88(94) ent-3ka, 89(91)
3la, 83(95) ent-3la, 87(88)
3ma, 87(95) ent-3ma, 92(88)
3na, 98(99) ent-3na, 99(98)
(CH2)2OAc/Me/Ph
(1c)
3
4
5
2a
2a
2a
3ca, 95(99) ent-3ca, 92(96)
3da, 88(97) ent-3da, 85(95)
3ea, 91(97) ent-3ea, 94(92)
1-Naph/Me/Ph (1j)
Ph/Me/4-MePh
(1k)
nPr/Me/Ph (1d)
nBu/Me/4-MePh
(1e)
nBu/Ph/4-MeOPh
(1f)
Ph/Me/4-ClPh (1l)
Ph/Me/4-BrPh
(1m)
6
7
2a
3fa, 99(97) ent-3fa, 92(97)
1a
1a
1a
1a
1a
4-MePh/Ph (2b) 3ab, 85(97) ent-3ab, 92(95)
8
9
Ph/Ph/Ph (1n)
Ph/3,4,5-(MeO)3Ph
3ac, 90(99) ent-3ac, 85(97)
(2c)
1g
4-MePh/Ph (2b) 3gb, 93(94) ent-3gb, 96(90)
8
Ph/3,4,5-(MeO)3Ph
3gc, 99(97) ent-3gc, 92(88)
(2c)
10
11
12
1g
1g
1g
9
Ph/4-MeOPh (2d) 3ad, 91(93) ent-3ad, 96(98)
3-ClPh/4-MeOPh
3ae, 88(98) ent-3ae, 87(96)
(2e)
Ph/4-MeOPh (2d) 3gd, 98(96) ent-3gd, 99(91)
10
3-ClPh/4-MeOPh
3ge, 99(94) ent-3ge, 99(91)
(2e)
11
Ph/styryl (2f)
3af, 86(95) ent-3af, 85(93)
a Unless otherwise specified, the reaction was carried out using ketone 1a
(0.4 mmol), nitrone 2a (0.44 mmol), M5 (5.5 mol%), [Me2SAuCl] (5 mol%),
and AgNTf2 (5 mol%) in DCE at -10 oC. b (S, Rs)-M5 was utilized as the chiral
13
14
15
16
17
1g
1g
1g
1g
1g
Ph/styryl (2f)
3gf, 84(96) ent-3gf, 81(90)
4-MeOPh/Ph (2g) 3gg, 77(95) ent-3gg, 67(88)
Ph/4-BrPh (2h) 3gh, 92(95) ent-3gh, 97(90)
c
ligand. (R, Rs)-M5 was utilized as the chiral ligand, leading to the
opposite enantiomer. d Isolated yield.
Ph/3-ClPh (2i)
3gi, 89(90) ent-3gi, 99(89)
Table 3 Optimization of the reaction conditions.a
Ph/1-furanyl (2j) 3gj, 76(92) ent-3gj, 76(73)
a Unless otherwise specified, the reaction was carried out using ketone 1
(0.4 mmol), nitrone 2 (0.44 mmol), M5 or M3 (5.5 mol%), [Me2SAuCl] (5
mol%), and AgNTf2 (5 mol%) in DCE at -10 oC. b (S, Rs)-M5 was utilized as
the chiral ligand. c (R, Rs)-M3 was utilized as the chiral ligand, leading to
the opposite enantiomer. d Isolated yield.
Entry
1
L
3ga or ent-3ga Yield(%)b
Ee(%)c
83
94
81
95
97
71
65
90
84
9
(S,Rs)-M1
(S,Rs)-M2
(S,Rs)-M3
(S,Rs)-M4
(S,Rs)-M5
(R,Rs)-M1
(R,Rs)-M2
(R,Rs)-M3
(R,Rs)-M4
(R,Rs)-M5
3ga
3ga
91
89
92
87
93
92
95
99
83
90
2
3
3ga
4
3ga
5
3ga
6
ent-3ga
ent-3ga
ent-3ga
ent-3ga
ent-3ga
7
8
9
Similarly, the aryl substituents (R3 = 4-MePh, 4-ClPh, 4-BrPh) of
the alkene moiety also worked well to give the corresponding
adducts in good yields and excellent enantioselectivities (Table 4,
entries 5–7, 3ka–3ma and ent-3ka–ent-3ma, 83–92% yields, 88–
10
a Unless otherwise specified, the reaction was carried out using ketone 1a
(0.1 mmol), nitrone 2a (0.11 mmol), L (5.5 mol%), [Me2SAuCl] (5 mol%),
Chin. J. Chem. 2019, 37, XXX－XXX
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3

First author et al.
Report
95% ees). The substrate 1n with all aryl substituents was also
tolerated and the reactions proceeded smoothly to deliver
desired products 3na and ent-3na in 98% yield, 99% ee and 99%
yield, 98% ee, repectively (Table 4, entry 8). Next, to our delight,
these ligands have also shown good performance on selected
nitrones 2b–2j with different electron-rich and electron-deficient
substituents, delivering the corresponding two sets of optically
active products 3gb–3gj and ent-3gb–ent-3gj (Table 4, entries 9–
17). It is not hard to find that the Ming-Phos ligands are powerful
ligands with regard to the high efficiency, excellent regio- and
enantioselectivity and general substrate scope.
3). The cycloadduct 3aa could be still furnished but with much
lower yields and enantioselectivity than those from the
corresponding precursor (S, Rs)-M5 with free N-H bond (compare
with entry 1 in Table 2). When the dosage of the chiral ligand
[Me2SAu(I)/(S,Rs)-M5/AgNTf2
= 1:2.2:1] was increased, the
reactivity and enantioselectivity were significantly decreased
(Scheme 2). Moreover, for purpose of studing the asymmetric
induction model of chiral ligands, the gold complexes [(S,
Rs)-M1•AuCl] and [(R, Rs)-M1•AuCl] have been obtained,
fortunately (Figure 2).[17] X-ray diffraction analysis revealed that
the gold atom only binds to the phosphine atom rather than to
the other heteroatoms, thus indicating that M5 serves as a
monophosphine ligand here. The gold(I) complexes preferred
linear geometry, which makes the active reaction site opposite to
the chiral ligand and thus limit the capability to transfer
asymmetry. A plausible mechanism of this transformation, the
gold(I) catalyst acts as a carbophilic π-Lewis acid to activate C–C
multiple bonds to give the furyl-Au-M1 1,3-dipole intermediate A
or A’, which be attacked by the nitrone to afford the product 3.[4d]
Based on the results studied in the proceeding sections and with
the assistance of the X-ray structure of the gold(I) complex, a
possible model for asymmetric induction is also proposed (Figure
2): the furyl-Au-M1 1,3-dipole intermediate A or A’ preferred
linear geometry, which is rapidly trapped by the oxygen atom of
the nitrone with the assistance of the H-bonding between the N-H
of the chiral ligand (Ming-Phos) and the oxygen atom of the
nitrone to give the desired product. Note, the carbon chirality of
the chiral ligand has a great influence on the enantioselectivity of
the reaction and determines the absolute configuration of the
product.
Scheme 2 Control experiments.
The gold complex of Ming-Phos ligands also performed well in
other gold mediated cycloaddition. For example, the asymmetric
[3+3] cycloaddition reaction of 2-(1-alkynl)-alk-2-en-1-one oxime
ether 4 with nitrone 2a could furnished the desired product 5 in
83% yield with 89% ee (Eq. 1).[15] The another asymmetric [4+3]
cycloaddition of 1-(1-alkynyl)cyclopropyl ketone 6 with nitrone 2a
proceeded smoothly to deliver the cycloadduct 7 in 94% yield
with 89% ee (Eq. 2).[16] Importantly, the formal [4+3] cycloaddition
is a dynamic kinetic asymmetric transformation,[16] which is
mechanistically distinct from the formal [3+3] cycloaddition of
2-(1-alkynl)-alk-2-en-1-one with nitrones.
Conclusions
In summary, the gold(I) complexes attached with the
Ming-Phos ligands showed good performance in gold-catalyzed
intermolecular [3+3] cycloaddition of 2-(1-alkynyl)-2-alken-1-ones
with nitrones, delivering synthetically useful optically active
3,4-fused bicyclic furans derivatives in good yields with high regio-
and enantioselectivities. Both enantiomers of the cycloadducts
could be obtained by the employment of either diastereomer of
the chiral ligands M5 or M3, in which the acidic N-H bond of
sulfinamide moiety play an important role in enhancement of
enantioselectivity. Further studies including synthetic application
of the present transformation and extending the application of
these Ming-Phos ligands to other transition metal catalyzed
asymmetric reactions are underway and will be reported in due
course.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement (optional)
We gratefully acknowledge the funding support of NSFC
(21425205, 21672067, 21801078), 973 Program (2015CB856600),
and the Program of Eastern Scholar at Shanghai Institutions of
Higher Learning and the China Postdoctoral Science Foundation
(2019M650071, 2019M661418).
Figure 2 X-ray crystal structure of [(S, Rs)-M1•AuCl] and [(R,
Rs)-M1•AuCl] and proposed asymmetric induction model.
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4
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

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[17] CCDC 1977834 [(S, Rs)-M1•AuCl] and CCDC 1977835 [(R,
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Entry for the Table of Contents
Page No.
Ming-Phos/Gold(I)-Catalyzed Stereodivergent
Synthesis
of
Highly
Substituted
Furo[3,4-d][1,2]oxazines
A highly enantioselective gold-catalyzed intermolecular [3+2] cycloaddition of 2-(1-alkynyl)-2-
alken-1-ones with nitrones was realized by the application of Ming-Phos M5 or M3 as chiral
ligands. Both enantiomers of the cycloadducts with opposite configuration could be obtained in
high yields with high regio- and enantioselectivity by the employment of either diastereomer of
the chiral ligands.
Lujia Zhou,a Bing Xu,a Danting Ji,a Zhan-Ming
Zhang*,b and Junliang Zhang*,a,b
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.
www.cjc.wiley-vch.de
7