Asymmetric Allylation by Chiral Organocatalyst-Promoted Formal Hetero-Ene Reactions of Alkylgold Intermediates

Article abstract of DOI:10.1002/anie.202012678

An unprecedented catalytic asymmetric allylation of isatins and isatin-derived ketimines is reported enabled by a gold and chiral organocatalyst cooperative catalysis strategy. This method offers expeditious access to chiral 2,5-disubsituted alkylideneoxazolines containing vicinal stereogenic centers, mainly in optically pure form, and which are otherwise impossible to access. Mechanistic evidence reveals the presence of an alkylgold intermediate, and an X-ray crystal structure of the allylgold species illuminates its unique stability and reactivity. An asymmetric formal hetero-ene reaction of this gold intermediate, involving a dearomatization process, is enabled with assistance of a quinine-derived squaramide catalyst. This novel discovery extends the synthetic applications of gold complexes and the versatility of gold catalysis.

Full text of DOI:10.1002/anie.202012678

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Accepted Article
Title: Asymmetric Allylation by Chiral Organocatalyst Promoted Formal
Hetero-Ene Reactions of Alkylgold Intermediates
Authors: Xinfang Xu, Guizhi Dong, Ming Bao, Xiongda Xie, Shikun Jia,
and Wenhao Hu
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10.1002/anie.202012678
Angewandte Chemie International Edition
RESEARCH ARTICLE
Asymmetric Allylation by Chiral Organocatalyst Promoted Formal
Hetero-Ene Reactions of Alkylgold Intermediates
Guizhi Dong†, Ming Bao†, Xiongda Xie, Shikun Jia, Wenhao Hu,* and Xinfang Xu*
Dedication ((optional))
[*]
M. Sc. G. Dong,[†] Dr. M. Bao,[†] M. Sc. X. Xie, Dr. S. Jia, Prof. Dr. W. Hu, Prof. Dr. X. Xu
Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences
Sun Yat-sen University
Guangzhou 510006 (P. R. China)
E-mail: huwh9@mail.sysu.edu.cn (W.H.) and xuxinfang@mail.sysu.edu.cn (X.X.)
G.D. and M.B. contributed equally to this work.
[†]
Supporting information for this article is given via a link at the end of the document. ((Please delete this text if not appropriate))
Abstract: An unprecedented catalytic asymmetric allylation of
isatins and isatin-derived ketimines enabled by gold and chiral
organocatalyst cooperative catalysis strategy is reported. This
method offers expeditious access to chiral 2,5-disubsituted
alkylideneoxazolines containing vicinal stereogenic centers, mainly
in optically pure form and otherwise impossible to access.
Mechanistic evidence revealing the alkylgold intermediate, especially
its X-ray crystal structure, illuminates its unique stability and
reactivity as an allylgold species. An asymmetric formal hetero-ene
reaction of this gold intermediate involving
a dearomatization
process is enabled with assistance of quinine-derived squaramide
catalyst. This novel discovery extends the synthetic application of
gold-complex and versatility of gold catalysis.
Introduction
Oxazoles and their derivatives are regarded as privileged
scaffolds in numerous natural and synthetic bioactive molecules
that display versatile biological activities,[1] and highly efficient
and practical methodologies have been developed for their
construction.[2] Among these methods, the catalytic cyclization of
N-propargylamides 1, which are readily available materials, has
been recognized as general and atom-economical.[3-11] The initial
conversion, promoted by acid, was reported in 1962,[4] followed
by the base catalyzed version via an allene intermediate in
1989.[5] In the recent two decades, significant progress has been
made in this area with a variety of transition metal catalysts,
including those of Au,[6] Ag,[7] Pd,[8] Cu,[9] Zn,[10] and others.[11] In
these expanding studies, gold-catalyzed transformations have
attracted the most attention in terms of the mechanism studies
and synthetic applications (Scheme 1a).[6,12]
Scheme 1. Gold-catalyzed transformations of N-propargylamides.
Gold complexes have proven to be one of the most effective
catalysts for the activation of alkynes.[13] The most general
reactivity pattern is the addition of carbon, oxygen, and nitrogen
nucleophiles to alkyne-gold π-complexes, and vinylgold
complexes are key intermediates in most of these
transformations.[14] In this context, Hashmi et al. reported that
the gold-catalyzed cyclization of terminal N-propargylamides via
an anti-oxyauration process delivers alkylideneoxazoline through
key (E)-vinylgold intermediates (Scheme 1a).[6,15] The vinyl-
AuIPr and vinyl-Au(III) complexes have been isolated and
characterized by X-ray crystallography analysis in subsequent
studies independently by Hashmi, Shi, and Ahn.[12] One of the
general reaction pathways of these vinylgold intermediates is
protodeauration, followed by aromatization to form 5-methyl
oxazoles (Scheme 1a, path a).[6] Recently, efforts have been
made by various research groups to explore new reactivities of
vinylgold complexes, including halogenation (path b),[16]
oxidation (path c),[12b,12c,17] coupling (path d),[18] and others.[19]
These advances have provided an expeditious entry to a range
1
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10.1002/anie.202012678
Angewandte Chemie International Edition
RESEARCH ARTICLE
of available oxazoles containing various functional groups on the
5-position via different types of manipulations over the exocyclic
C=C bond. However, challenges and limitations remain in this
area: the asymmetric transformation of vinylgold intermediates
has not been disclosed so far, although elegant enantioselective
Alder-ene reaction[20] and allylic aromatization reaction of
alkylideneoxazolines, which are demetallated derivatives of
vinylgold species, have been reported by Feng,[21a-21c]
Hashmi,[21d] and You[21e] with corresponding chiral metal
complexes (Scheme 1a, path e). On the other hand, all of the
oxazoles/oxazolines that were formed as the final products did
not contain any functionality on the 4-position, which means that
novel reactivity on this position has not been realized so far
(Scheme 1a, path f).
Table 1: Condition Optimization.[a]
Recently our group has reported an enantioselective
Mannizch-type reaction of in situ generated gold enolate
intermediate and imine with the assistance of chiral phosphoric
acid CPA (Scheme 1b).[22,23] As a continuation of our research
program on multicomponent reactions via trapping reactive
ylide/zwitterionic intermediates,[24,25] we envisioned that novel
interception transformation on the inert 4-position might be
enabled through the alkylgold intermediate II, which could be
generated via an aromatization drived H-shift process of
vinylgold species I with the assistance of appropriate alkalic
cocatalyst, instead of direct protodeauration. Herein, we report a
Yield [%][b]
4aa/5aa
Entry
Cat. (5.0 mol %)/3 (10 mol%)
dr[c]
ee [%][d]
1
Me4tBuXPhosAuNTf2/quinine
Me4tBuXPhosAuNTf2/3a
Me4tBuXPhosAuNTf2/3b
Me4tBuXPhosAuNTf2/3c
Me4tBuXPhosAuNTf2/3d
(-)/3c
43/22
61/27
93/<5
92/<5
86/13
NR
>20:1
>20:1
2:1
9
2
85
98(49)
>99
>98
-
3
4
>20:1
>20:1
-
gold/quinine-derived
squaramide
(QN-SQA)
cooperative
5
catalysis as an effective strategy to realize the asymmetric
allylation of isatins and their ketimine derivatives via an
asymmetric formal hetero-ene reaction of alkylgold intermediate
II, which shows unique reactivity as an allylgold species
(Scheme 1c).[21a-d,26] In catalytic allylations,[27,28] the reactions
typically utilize activated allylic substrates that usually containing
a leaving group,[29-33] thus generating stoichiometric quantities of
waste material. This direct asymmetric allylation method, which
is the first example of formal hetero-ene reaction of alkylgold
intermediate that involves a dearomatization process, is an
atom- and step-economic advance in this area.[34]
6
7
Me4tBuXPhosAuNTf2/(-)
PPh3AuNTf2/3c
17/75
19/56
27/67
7/92
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
-
8
94
99
-
9
BrettPhosAuNTf2/3c
IPrAuCl + AgNTf2/3c
JohnphosAuNTf2/3c
tBuXPhosAuNTf2/3c
Me3(OMe)tBuXPhosAuNTf2/3c
10
11
12
13
20/68
32/60
93/<5
93
>98
>99
Results and Discussion
[a] The reaction was carried out on a 0.1 mmol scale: to the solution of 2a
(33.6 mg, 0.1 mmol), catalyst (5.0 mol%) and additive in DCE (1.5 mL), was
added 1a (19.1 mg, 0.12 mmol) in DCE (0.5 mL) under argon atmosphere at
30 oC in 15 min, and the reaction was running overnight. [b] Determined by 1H
NMR of the crude reaction mixture with 1,3,5-trimethoxybenzene as internal
reference. [c] The dr ratios were determined by 1H NMR of the crude reaction
mixture. [d] The ee values were determined by chiral HPLC analysis. NR = no
reaction.
The readily accessible N-propargylamide 1a and ketimine
2a were used as model substrates in the presence of
Me4tBuXPhosAuNTf2 in 1,2-dichloroethane (DCE) at 30 oC
(Table 1). Initially, a variety of quinine derived organocatalysts
were investigated in an effort to delay the protodeauration of
vinylgold intermediate and facilitate the designed process via
forming the alkylgold species (for the details of the discovery of
this reaction, see Table S1 in SI). Commercially available
quinine and its sulfamide derivative 3a promoted the
transformation smoothly, producing the allylation product 4aa in
moderate to good yields with 9% and 85% ee, respectively
(entries 1 and 2). To improve the selectivity of the reaction, dual-
functional quinine-derived squaramide catalysts 3b-3d were
examined (entries 3-5),[35] and these catalysts showed much
higher reactivity and selectivity. The phenyl substituted catalyst
3c gave the best results with 92% yield, >20:1 dr and >99% ee
(entry 4). Control experiments in the absence of either the gold
catalyst or the organocatalyst resulted in either no reaction or
formation of 5aa as the major product, respectively (entries 6
and 7). These results confirmed the importance of cooperative
catalysis in enabling this unprecedented transformation. With the
identified optimal organocatalyst 3c, various gold catalysts were
further screened (entries 8-13). All these catalysts showed high
reactivity, and the only comparable excellent selectivity was
obtained with Me3(OMe)tBuXPhosAuNTf2 (entry 13, 93% yield,
>20:1 dr, and >99% ee). Considering the cost of the catalysts,
Me4tBuXPhosAuNTf2 and 3c were chosen as the optimal
combination for the subsequent asymmetric allylation reaction
(entry 4). The absolute configuration of this product was
confirmed by single-crystal X-ray diffraction analysis of its
chloro-derivative 4ah,[36] and other products were tentatively
assigned by analogy.
2
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10.1002/anie.202012678
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RESEARCH ARTICLE
With the optimized conditions in hand, various N-
and heteroaromatic substrates also worked well, delivering the
propargylamides 1 were prepared to evaluate the reaction scope. optically pure 4ma-4oa in 58%-93% yields. Aliphatic substituted
The results are summarized in Table 2. Good substrate
propargyl amides, including styryl, tert-butyl, pentyl, benzyl, and
alkyl tethered with amide and ester, all performed well, yielding
the optically pure products in good to excellent yields (4pa-4ua).
To further evaluate the generality of this method, bioactive
molecules isoxepac and natural amino acid L-tryptophan derived
amides were used, and the desired oxazolines 4va and 4wa
were isolated in good yields with >99% ee and >20:1 dr,
respectively.
Table 2: Scope of N-propargylamides.[a]
The scope of the transformation with respect to ketimines
bearing diverse substituents on the aryl ring was then examined
(Table 3). The current method turned out to be highly efficient,
Table 3: Scope of ketimines.[a]
[a] Reaction conditions:
1 (0.24 mmol), 2a (67.2 mg, 0.2 mmol),
[a] Reaction conditions: 1a (38.2 mg, 0.24 mmol),
2
(0.2 mmol),
Me4tBuXPhosAuNTf2 (10.0 mg, 5.0 mol%), and organocatalyst 3c (10.0 mg,
10 mol%) in DCE (4.0 mL) under argon atmosphere at 30 ℃ overnight, and
the yields are given in isolated yields, all the dr values were >20:1.
Me4tBuXPhosAuNTf2 (10.0 mg, 5.0 mol%), and organocatalyst 3c (10.0 mg,
10 mol%) in DCE (4.0 mL) under argon atmosphere at 30 ℃ overnight. The
yields are given in isolated yields. Unless otherwise noted, the dr values were
>20:1. [b] The reaction was conducted in the presence of 3M (10 mol%)
instead of 3c.
compatibility was observed with this cooperative catalysis
system, and only one diastereomer was observed in all of the
tested propargylamides (>20:1 dr). Substrates with EDGs and
EWGs on different position of aryl ring all furnished the allylation
products in good to excellent yields with each as a single
enantiomer (4aa-4la, >99% ee). Relatively low yields were
observed in the cases of substrates with EWGs, which may due
to the lower nucleophilicity of the carbonyl species that is
detrimental for the intramolecular cyclization.[15] The 2-naphthyl
with all of the tested ketimines showing good to excellent
reactivity and selectivity. Except for the nitro substituted ketimine,
which formed the corresponding product 4ag with a 10:1 dr, all
other allylation products were generated with excellent
stereoselectivity (4ab-4af and 4ah-4ak, >20:1 dr, >98% ee).
Notably, the N-unprotected ketimine was also compatible for this
reaction, yielding 4al in 88% yield with 99% ee. Ketimines with
3
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10.1002/anie.202012678
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RESEARCH ARTICLE
glyoxylate-derived ketimine, no allylation reaction occurred
under current conditions. Further optimization for the reaction
with diphenyl imine in the presence of various chiral phosphonic
acids was conducted (Scheme S1 in SI for details), leading to
4ap as a mixture of two diastereosiomers (total 65% yield with
2:1 dr) in up to 60% and 44% ee, respectively (Table 3 note b),
which implied the potential for achieving highly asymmetric
versions in this direction.
Table 4: Scope of isatins.[a]
Encouraged by the above results, we directed our attention
into the evaluation of asymmetric allylation of isatins. After
optimization of conditions and substrate modification, the
quinine-derived sulfamide catalyst 3d in tert-butyl methyl ether
(TBME) showed higher stereoselectivity in allylation of the
carbonyl compound (see Table S2-S3 in SI for detail). The N-
protection groups on isatins play a key role in the selectivity
control, o-methylbenzyl and triphenylmethyl have been identified
as optimal choices in terms of the reactivity and stereoselectivity
(see Table S4 in SI for detail). As shown in Table 4, the
organocatalyst 3d promoted asymmetric allylation of isatins
showed good substrate generality. Various electron-neutral,
electron-rich, and election-deficient substitutions on the aryl
rings of propargylamides and isatins were suitable for this
reaction, producing the allylation products in good to high yields
with >10:1 dr in 91%-99% ee (7a-7p). The 1-thienyl, 2-naphthyl,
and various alkyl groups were also tolerated under optimal
conditions, furnishing corresponding products 7q-7u in >91%
yields with >20:1 dr and 93%-98% ee. Substrates with internal
alkynes, inducing N-(3-phenylpropargyl)benzamide and N-(but-
2-ynyl)benzamide, did not work under current conditions with
most of starting material recovered, which is consistent with
previous reports.[12,37]
To gain insight into the reaction mechanism of this new
process, several control experiments were performed. Model
reactions in the absence of the gold catalyst (Table 1, entry 6) or
the organocatalyst (Table 1, entry 7) revealed no reaction or
formation of alkylideneoxazoline 5aa as the major product,
respectively. These results indicated that the gold catalyst
responsible for the catalytic cyclization of N-propargylamide,
while the organocatalyst is essential in enabling the allylation
step. To explore whether this transformation went through a
gold/organo cooperative[38] or relay[39] catalysis manner,
alkylideneoxazoline 5aa and 2a were applied to the standard
conditions with or without the gold catalyst, majority of the
materials remained intact and no 4aa was observed by the
proton NMR spectrum of the reaction mixture (Scheme 2a, and
see Figures S1 and S2 in SI for details). Moreover, when this
reaction was conducted under thermal conditions, the ene
reaction product 8aa was isolated in 35% yield,[20,21]
contaminated with aromatized oxazole 9aa in 31% yield
(Scheme 2b). These results ruled out the possibility of a
stepwise catalytic relay via alkylideneoxazoline 5aa. Further
effort focused on exploration of the identity of the key
intermediate that might be generated in situ via gold catalyzed
cyclization. Equal amounts of N-propargylamide 1a and the gold
catalyst Me4tBuXPhosAuNTf2 were dissolved in a mixed solvent
(DCM/hexane) in the presence of triethylamine, and the gold-
complex 10 was formed and crystallized in 95% yield via slow
volatilization of the solvent under an argon atmosphere. The
structure of this complex was confirmed by X-ray crystallography
(Scheme 2c, and see SI for detail).[36] The red bond length of
intermediate 10 is 1.351 Å, which is shorter than the single bond
[a] Reaction conditions:
1
(0.24 mmol), isatins
6
(0.2 mmol),
Me4tBuXPhosAuNTf2 (10.0 mg, 5.0 mol%), and organocatalyst 3d (11.2 mg,
10 mol%) in TBME (4.0 mL) under argon atmosphere at 30 ℃ for 40 h, and
the yields are given by isolated yields.
other protecting groups, including methyl, acetyl, and allyl, were
all tolerated well and produced the desired products 4am-4ao in
57%-80% yields with 98%-99% ee. Beyond the isatin-derived
ketimines, non-cyclic imines also reacted smoothly to give the
corresponding products 4ap and 4aq in high yields, however,
there is no enantioselectivity in these cases. In the case with
4
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10.1002/anie.202012678
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RESEARCH ARTICLE
suggested that the alkylgold 10 is the key reactive reaction
intermediate in this reaction. To rule out the possibility that
product 4aa resulted from an allene species 10’, control
experiments under standard conditions in the presence of D2O
were conducted. No product with deuterium on the allylic
position was detected either in the formation of 5aa or in the
model reaction (Scheme 2f and 2g).[5] These results not only
confirmed that the formation of 5aa via direct protodeauration of
vinylgold species, but also indicated a one-way transformation
from vinylgold to alkylgold via H-shift driving by aromatization,
and the later could not lead to the alkylideneoxazoline 5aa
anymore under current conditions.[41]
Based on the above results and the reported literature,[6,12]
rationalized mechanism is proposed in Scheme 3. The reaction
a
Scheme 3. Proposed reaction mechanism.
is initiated via the formation of a π-complex A with the gold
catalyst and N-propargylamide 1a. Then a 5-endo-dig cyclization
of complex A via anti-oxyauration process delivers the key (E)-
vinylgold intermediate B.[12] Protodeauration of B would lead to
the alkylideneoxazoline 5aa, followed by aromatization to form
the 5-methyl oxazole 9aa. In this reaction, H-shift driving by the
aromatization is enabled with the assistance of alkalic co-
catalyst, leading to the key alkylgold species C. The final
asymmetric allylation process through a formal hetero-ene
reaction is realized by the dual functional chiral organocatalyst,
producing the product 4aa and regenerating the catalysts.
Although other types of SE2' addition of allylgold species with
imine-like electrophiles have some precedent,[42] the current
work is the first example of asymmetric catalytic version in this
area.
According to the X-ray crystal structure of the catalyst, as
well as the absolute configuration of the product,[36] a possible
transition state is proposed (Scheme 3, in dashed box) to
elucidate the source of stereoselectivity of this reaction. The
squaramide hydrogens of the bifunctional catalyst activates the
ketimine via double hydrogen bonding;[35] whereas, the N-atom
on the quinoline part of the organocatalyst might interact with the
gold catalyst.[43] And all these interactions enable the
intermolecular reaction via a formal intramolecular model. The
Scheme 2. Control experiments.
reported by Ahn (1.502 Å)[12c] and is closer to the data of C-C
double bond. Based on these observations, an alkylgold
structure 10 with allylgold reactivity, rather than the vinylgold
species, is assigned in this reaction. The vinylgold species is the
only intermediate that has been proposed and characterized in
gold-catalyzed cyclization of N-propargylamides (Scheme 1a).[12]
This is the first example of observation of alkylgold intermediate
in this area, which has been characterized by X-ray crystal
analysis.[40] Combined with 3c, this gold-complex could catalyze
the model reaction, producing the allylation product 4aa with
comparable high yield and excellent enantioselectivity (Scheme
2d, 87% yield and >99% ee vs model reaction 89% yield and
>99% ee). Moreover, the quantitive reaction between 10 and 2a
in the presence of 3c also smoothly led to 4aa in 80% yield with
63% ee, and the low ee may due to the background reaction
between the materials without the assistance of the
organocatalyst 3c (Scheme 2e). These results strongly
5
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10.1002/anie.202012678
Angewandte Chemie International Edition
RESEARCH ARTICLE
nucleophilic addition occurs on the Re-face of ketimine, affording
the (R, S)-enantiomer. In this case, the steric hinderance
between the bulky gold catalyst and the approaching
electrophile could be avoided since the gold species toward
outside the aryl ring of the ketimine.
To show the synthetic utility of this cooperative catalysis
strategy, the asymmetric allylation reaction of N-propargylamide
1a with ketimine 2a was expanded to a 1.0 mmol scale in a
reduced catalyst loading, and 4aa was isolated in 88% yield with
Support for this research from the National Natural Science
Foundation of China (21971262, 81973176), National
Postdoctoral Program for Innovative Talents (BX20190399),
Guangdong Provincial Key Laboratory of Chiral Molecule and
Drug Discovery (2019B030301005), National Mega-project for
Innovative Drugs (2019ZX09721001-006-001) and The Program
for Guangdong Introducing Innovative and Entrepreneurial
Teams (No. 2016ZT06Y337) is greatly acknowledged. We also
thank Prof. Michael P. Doyle from UTSA for discussion and
suggestions during the preparation of the manuscript.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric allylation• alkylgold • gold/organo
cooperative catalysis • heter-ene reaction • N-propargylamide
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Scheme 4. Synthetic utility.
>20:1 dr and >99% ee (Scheme 4). The free amino derivative 11
and cyclopropane product 12 could be obtained via TFA
mediated deprotection and Rh-catalyzed cyclopropanation
reaction in 92% and 65% yields, respectively. Furthermore, 4aa,
which is a bicyclic framework containing an enocyclic enol ether
motif, could be converted to the spiro structure in the presence
of NBS, forming 13 in 85% yield. In all these tested
transformations, the stereochemistry is well maintained and the
products, 11-13, are obtained in nearly optically pure form. The
structure of 13 was confirmed by X-ray diffraction analysis.[36]
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In summary, we have reported an unprecedented
asymmetric allylation reaction of isatins and isatin-derived
ketimines with N-propargylamides. This atom-economic
transformation is enabled by gold/organo cooperative catalysis,
which offers expeditious access to chiral 2,5-disubsituted
alkylideneoxazolines mainly in an optically pure form.
Mechanistic studies indicate that the alkylgold species, which
has been characterized by X-ray crystallographic analysis for the
first time, is the key intermediate and possesses allylgold
reactivity. The asymmetric formal hetero-ene reaction of this
intermediate is achieved with the assistance of a bifunctional
quinine-derived squaramide catalyst. The novel reactivity
disclosed here should in principle be transferable to many other
asymmetric reactions involving analogous gold-complexes and
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Entry for the Table of Contents
An asymmetric allylation reaction of isatins/ketimines with N-propargylamide is reported, which offers expeditious access to
alkylideneoxazolines mainly in optically pure form. The key alkylgold intermediate, which possesses allylgold reactivity, has been
confirmed by X-ray crystallographic analysis for the first time. The asymmetric formal hetero-ene reaction of this species involving a
dearomatization process is enabled with the assistance of a quinine-derived squaramide catalyst.
9
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