Au(I)/(R)-BINOL-Ti(IV) concerted catalyzed asymmetric cascade cycloaddition reaction of arylalkynols

Article abstract of DOI:10.1021/acs.orglett.1c00976

An efficient catalytic asymmetric cascade cycloaddition reaction of arylalkynols with dioxopyrrolidines was developed. This reaction was achieved using Au(I) and (R)-BINOL-Ti(IV) bimetallic catalysts and exclusively delivered a series of chiral oxo-bridged bicyclic benzooxacine compounds in up to 86% yield with 96% ee as well as >33:1 dr. Meanwhile, three new σ bonds and three new stereogenic centers were formed in a one-pot process.

Full text of DOI:10.1021/acs.orglett.1c00976

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Letter
Au(I)/(R)‑BINOL−Ti(IV) Concerted Catalyzed Asymmetric Cascade
Cycloaddition Reaction of Arylalkynols
Hongkai Wang, Tianlong Zeng, Weixing Chang, Lingyan Liu,* and Jing Li*
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ABSTRACT: An efficient catalytic asymmetric cascade cycloaddition
reaction of arylalkynols with dioxopyrrolidines was developed. This reaction
was achieved using Au(I) and (R)-BINOL−Ti(IV) bimetallic catalysts and
exclusively delivered a series of chiral oxo-bridged bicyclic benzooxacine
compounds in up to 86% yield with 96% ee as well as >33:1 dr. Meanwhile,
three new σ bonds and three new stereogenic centers were formed in a one-
pot process.
symmetric synthesis has been widely used in many fields
of chemistry. Among them, asymmetric catalysis is the
Scheme 1. Synthesis of Chiral Oxo-Bridged Bicyclic
Benzooxacines
A
most fashionable method, and it is devoted to the development
of chiral catalysts to convert prochiral and racemic substrates
into valuable chiral synthesis blocks. Thus, plenty of chiral
catalysts have been exploited and synthesized to date. For
example, chiral diols are among the most privileged scaffolds in
asymmetric catalysis, especially for the derivatives of the chiral
1,1′-bi-2-naphthol (BINOL) skeleton.1 Of course, it is highly
desirable to directly use commercially available or easily
synthesized chiral catalysts, as they will provide potential
application in industry.
On the other hand, oxo-bridged heterocyclic skeletons are
ubiquitous in natural products and bioactive molecules.2
Therefore, the development of new and efficient methods for
the construction of oxo-bridged heterocyclic compounds has
attracted increasing attention, especially the development of
intermolecular reactions, which are more appealing because of
their flexible substrate candidates.3 However, to the best of our
knowledge, there are scarce reports on examples of the
asymmetric synthesis of oxo-bridged bicyclic compounds.
Recently, bimetallic relay catalysis has shown unique potential
in modern asymmetric synthesis.4 With the combination of a
chiral catalytic system and a metal catalyst to activate two
different substrates, highly efficient asymmetric chemical
transformations can be achieved to afford complex chiral
molecules in high yields with high enantio- and diastereose-
lectivities from simple starting materials. For example, Feng’s
research group developed an efficient asymmetric synthesis of
oxo-bridged oxazocines through a RhII/ZnII relay catalytic [4 +
3] cycloaddition reaction of diazoimides and β,γ-unsaturated
α-keto esters (Scheme 1a).5a In their work, a relatively
Received: March 22, 2021
Published: April 22, 2021
https://doi.org/10.1021/acs.orglett.1c00976
Org. Lett. 2021, 23, 3573−3577
© 2021 American Chemical Society
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complicated chiral N−O ligand was used. Schneider and co-
workers described a rhodium- and chiral phosphoric acid-
cocatalyzed [4 + 3] cycloaddition of o-quinone methides and
carbonyl ylides to furnish functionalized oxo-bridged diben-
zooxacines in excellent yields and stereoselectivities in a single
synthetic step (Scheme 1b).5b The authors employed a highly
substituted chiral phosphoric acid as a chiral catalyst. These
two reactions utilized diazoimides as substrates and proceeded
through a [4 + 3] cycloaddition mode. In view of this and as a
continuation of work by our research group,6 here we
developed a simple and highly efficient bimetallic relay
catalytic asymmetric cascade cycloaddition reaction of
arylalkynols 17 and dioxopyrrolidines 28 via a formal [4 + 4]
cycloaddition reaction (Scheme 1c). The chiral oxo-bridged
bicyclic compounds 3 were exclusively obtained with excellent
diastereoselectivity and high enantioselectivity, and no
dominant competitive spirocyclic compounds 4 were observed.
More importantly, the commercially available chiral (R)-
BINOL−Ti(OiPr)4 complex and XPhosAuCl are directly used
as bimetallic catalysts, which provides a great potential
application in future synthesis of natural products and
pharmaceutical intermediates. To the best of our knowledge,
the use of arylalkynols as 4C synthons to carry out a formal
asymmetric [4 + 4] cycloaddition reaction is unprecedented.
2-(Ethynylphenyl)methanol (1a) and (E)-1-benzyl-4-benzy-
lidenepyrrolidine-2,3-dione (2a) were initially chosen as the
model substrates (Table 1). In the presence of achiral
Ph3PAuCl, which aimed at catalyzing the intramolecular 5-
exo-dig hydroalkoxylative cyclization−isomerization of 1a to
give the reactive 4C synthon intermediate, various chiral
catalytic systems were used to activate 2a and thus
enantioselectively induce the subsequent formal [4 + 4]
cycloaddition. As shown in Table 1, the two combinations of
Zn(OTf)2/tBu-Box (L1) and Y(OTf)3/Ph-PyBox (L2) gave
only undesired cascade [2 + 4] product 4aa in excellent yields
with 60% ee (entry 1) and 23% ee (entry 2), respectively. Using
the (R)-BINOL−Ti(OiPr)4 complex, the oxo-bridged bicyclic
benzooxacine 3aa could be obtained in 74% yield with 60% ee
and >20:1 dr, and no 4aa was observed by 1H NMR analysis of
the crude product (Table 1, entry 3). Intrigued by this result,
we conducted further screening of complexes of chiral BINOL
derivatives and Ti(OiPr)4. To our surprise, using 3,3′-
disubstituted (R)-BINOLS, regardless of the substituent (Ph,
3,5-(CF3)2C6H3, or 2-naphthyl), only a trace amount of the
desired product 3aa was generated, with a great amount of the
starting materials remaining untouched (entries 4−6). Next,
we changed the ligand species from (R)-BINOL to (R)-
octahydro-binaphthol (L7), (R)-SPINOL (L8), or diol ligand
L9 derived from L-tartaric acid, and no reaction occurred
(entries 7−9). The (R)-phosphoric acid (CPA) catalyst was
also investigated to activate dicarbonyl substrate 2a through
hydrogen-bonding interactions. Consequently, this reaction
afforded a 75% yield of the corresponding product 3aa as a
racemate (entry 10). Therefore, (R)-BINOL−Ti(OiPr)4 was
determined to be the best chiral metal complex candidate. A
variety of Au(I) species were then examined in the presence of
20 mol % (R)-BINOL−Ti(OiPr)4 (entries 11−21). It was
found that 5 mol % XPhosAuCl gave the best result, affording
3aa in 83% yield with 81% ee (entry 20). Other additives, such
as molecular sieve (MS) types, were also examined with the
XPhosAuCl/(R)-BINOL−Ti(OiPr)4 bimetallic catalyst sys-
tem, and a surprising phenomenon was observed (entries
22−25). In the absence of 4 Å MS, the reaction gave as the
Table 1. Screening of Chiral Catalytic Systems in the
Cascade Reaction
a
b
c
entry
Cat*
Zn(OTf)2−L1
additive
yield (%)
ee (%)
d
1
2
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
−
96
98
78
trace
trace
trace
−
60
23
65
−
−
−
−
−
−
0
81
80
70
67
40
42
−7
18
33
81
79
−29
−
d
Y(OTf)3−L2
Ti(OiPr)4−L3
Ti(OiPr)4−L4
Ti(OiPr)4−L5
Ti(OiPr)4−L6
Ti(OiPr)4−L7
Ti(OiPr)4−L8
Ti(OiPr)4−L9
(R)-CPA
3
4
5
6
7
8
9
−
−
10
11
12
13
14
15
16
17
18
19
20
75
64
58
68
76
70
75
18
67
78
83
75
48
−
IPrAuCl
(2,4-(t-Bu)2C6H3O)3PAuCl
(CF3Ph)3PAuCl
(2-MePh)3PAuCl
Bu3PAuCl
(PhO)3AuCl
IPrAuNTf2
(Me2S)AuCl
JohnPhosAuCl
XPhosAuCl
XPhosAuCl
XPhosAuCl
XPhosAuCl
XPhosAuCl
e
21
22
23
24
25
3 Å MS
5 Å MS
MgSO4
4 Å MS
70
68
78
0
0
84
XPhosAuCl
XPhosAuCl
f
26
a
Unless otherwise noted, all of the reactions were carried out with 1a
(40 mg, 0.3 mmol), 2a (55 mg, 0.2 mmol), 4 Å MS (20 mg), Au(I)
catalyst (0.01 mmol, 5 mol %), and catalyst (20 mol %) in toluene (2
mL) under N2. All of the reactions gave the product 3aa except for
entries 1 and 2. Abbreviations: (R)-CPA = (R)-(−)-1,1′-binaphthyl-
2,2′-diyl hydrogen phosphate; JohnPhosAuCl = 2-(di-tert-butylphos-
phino)-1,1′-biphenyl gold chloride; IPrAuNTf2 = [1,3-bis(2,6-
diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene][bis-
(trifluoromethylsulfonyl)azanylidene]gold; XPhosAuCl = 2-dicyclo-
hexylphosphino-2′,4′,6′-triisopropylbiphenyl gold chloride. In entries
1−10, Ph3PAuCl was used as a catalyst. In entries 11−26, (R)-
b
BINOL−Ti(OiPr)4 was used as a chiral catalyst. Yields of the
c
isolated products. In all cases, the dr was >20:1. Determined by
d
e
HPLC analysis. 4aa was obtained. 2.5 mol % Au catalyst was used.
f
(2-Ethynyl-4-methoxyphenyl)methanol (1b) was used.
major product the opposite enantiomer as with 4 Å MS (entry
22). Also, racemic 3aa was obtained with 5 Å MS or MgSO4
(entries 24 and 25), and no reaction occurred in the presence
of 3 Å MS (entry 23). More details were investigated about the
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MS (Table S1). All of these results indicated that 4 Å MS may
have the appropriate aperture size and water absorption as well
as the proper interactions with the substrate and BINOL−
Ti(IV). The detailed reason remains unclear at present.
Notably, when (2-ethynyl-4-methoxyphenyl)methanol (1b)
was used as the substrate, 3ab was generated with slightly
enhanced enantioselectivity under the standard reaction
conditions (entry 26).
The reaction system concentration, the amount of (R)-
BINOL−Ti(OiPr)4, the solvent, and temperature as well as the
ratio of the two substrates were then examined in detail
(Tables S2−S5). Overall, the optimized conditions were finally
established as follows: arylalkynol 1 (0.3 mmol, 1.5 equiv) and
dioxopyrrolidine 2 (0.2 mmol, 1.0 equiv) along with
XPhosAuCl (5 mol %) and the (R)-BINOL−Ti(OiPr)4
complex (20 mol %) as dual catalysts in the presence of 4 Å
MS in toluene (2 mL) at 25 °C under N2.
enantioselectivity (ee 96%), and 3-bromophenyl-substituted
dioxopyrrolidine 2i also gave the corresponding product 3bi
with high enantioselectivity (92% ee) and diastereoselectivity.
Unfortunately, cyclohexyl-substituted dioxopyrrolidine 2k
failed to give the target compound 3bk, which might be
ascribed to the low reactivity of 2k. In the case of 1a, the
reactions with 2a, 2h, and 2i also afforded 3aa, 3ah, and 3ai,
respectively, in good yields (up to 83%, 3aa) with high
enantioselectivities (up to 92% ee, 3ah). However, the reaction
of 1a and 2j generated the product 3aj in moderate yield with
low ee with part of the starting material left over, even with a
prolonged reaction time. Similarly, the 2-thienyl-substituted
heteroaromatic 2l also rendered a moderate yield and ee of the
desired product 3al with some starting material remaining.
Also, it was observed that all of the arylalkynols 1, regardless of
whether they had an electron-withdrawing or electron-
donating substituent at the para or meta position of the
aromatic ring of the arylalkynol, reacted with 2d and 2e to
deliver the corresponding products 3ad−fd and 3ae−fe in
good yields (66−85%) with high enantioselectivities (up to
92% ee). The absolute configuration of the major enantiomer
of 3ed was unambiguously determined to be (5S,10R,11S) by
single-crystal X-ray diffraction analysis (Figure S1).9 However,
no reaction occurred in the case of internal arylalkynol 1g.
When the nucleophilic O in substrate 1 (X = O) was changed
to N (X = NTs (1h); X = NBn (1i)), no desired aza-bridged
bicyclic compound (3hd or 3id) was generated under the
standard reaction conditions. These results implied that alkynyl
alcohols have high reactivity in this formal [4 + 4]
cycloaddition while alkynyl amides or alkynyl amines have
low reactivity under the current reaction conditions. Notably, a
scaled-up reaction of 1c (3.0 mmol) and 2d (2.0 mmol) was
carried out and afforded 725.1 mg of 3cd in 72% yield with
88% ee.
With the optimal reaction conditions in hand, the substrate
scope with respect to arylalkynols 1 and dioxopyrrolidines 2
was then investigated. As shown in Scheme 2, dioxopyrroli-
Scheme 2. Substrate scope of Arylalkynols 1 and
a
Dioxopyrrolidines 2
The corresponding oxo-bridged bicyclic benzooxacines 3
could be further transformed (Scheme S1). For example, an
elegant Suzuki coupling reaction between 3cd and p-
tolylboronic acid was conducted and gave the desired product
5cd in 76% yield with a nearly unchanged ee value (87% ee)
with the oxo-bridged bicyclic benzooxacine structure unbroken
(Scheme S1, eq 1). This result indicated that this structure was
relatively stable and tolerant to the base, Pd catalyst, and high
temperature. Interestingly, an unexpected ring-opened product
6cd was obtained in 58% yield with 50:1 dr and 89% ee, in
which the C−O bond was cleaved but the CC double bond
was unaffected when H2/Pd/C reduction was used (Scheme
S1, eq 2). Moreover, the Br atom on the aromatic ring was also
reduced under these reaction conditions. This reaction
demonstrated that the ketal structure of the oxo-bridged
benzooxacine could be cleaved under certain reaction
conditions. In addition, in the presence of the Lewis acid
BF3·OEt2 and the nucleophile TMSCN, a similar ring-opened
product 7ae was generated in 75% yield with retention of the
ee (Scheme S1, eq 3).
Several control experiments were carried out to investigate
the synergism of the Au(I) and (R)-BINOL−Ti(IV) bimetallic
catalysts, and it was concluded that both Au(I) and BINOL/
Ti(IV) were necessary to achieve this asymmetric cascade
cycloaddition reactionneither of them was dispensable
(Scheme S2). Besides, a good linear relationship was observed
between the ee of the chiral (R)-BINOL ligand and the ee of
the product 3ad, which indicated that one Ti(IV) center was
coordinated by one BINOL (Scheme S3). On the basis of
a
Yields refer to the isolated products, and ee values were determined
by HPLC analysis. N. R. = no reaction.
dines either with an electron-withdrawing substituent (F, Cl,
Br, or CF3; 2b−e) or an electron-donating substituent (OMe
or Me; 2f and 2g) at the para position of the aromatic ring
delivered the corresponding chiral products 3ba−bg in up to
79% yield with up to 92% ee. Interestingly, when R2 on the
dioxopyrrolidine was 3-cyanophenyl (2h), the reaction
afforded the oxo-bridged benzooxacine 3bh with the highest
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these results and the absolute configuration of 3ed, we propose
a possible transition state model (Figure 1). The dioxopyrro-
AUTHOR INFORMATION
Corresponding Authors
■
Lingyan Liu − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, P. R. China; orcid.org/0000-
0001-5268-5986; Email: liulingyan@nankai.edu.cn
Jing Li − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, P. R. China; Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, P. R. China; Email: lijing@nankai.edu.cn
Authors
Hongkai Wang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, P. R. China
Tianlong Zeng − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, P. R. China
Weixing Chang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, P. R. China
Figure 1. Proposed transition state model.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00976
lidine is activated by coordination with the (R)-BINOL−Ti
complex, and then the 4C intermediate formed in situ prefers
to approach the Re face of the dioxopyrrolidine but not the
sterically hindered Si face. The final product is formed with the
(5R,10S,11R) configuration.
Notes
The authors declare no competing financial interest.
In summary, a highly efficient asymmetric catalytic cascade
reaction of arylalkynols and dioxopyrrolidines was developed.
In this bimetallic cooperative catalysis, a simple and
commercially available Au(I) catalyst and a chiral BINOL−
Ti(IV) complex gave the corresponding fused oxo-bridged
bicyclic benzooxacines in moderate to good yields with high
enantioselectivities (up to 96% ee) under mild reaction
conditions with the formation of three new σ bonds and
three new chiral stereogenic centers in a one-pot process.
Control experiments indicated that XPhosAuCl, (R)-BINOL,
and Ti(OiPr)4 are all mutually reinforcing and indispensable.
Furthermore, a plausible transition state model was proposed
to explain the origin of the high stereoselectivity. Further
applications of this catalytic strategy to other reactions are in
progress in our group.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Key
Research and Development Program of China
(2017YFD0201404) and the National Natural Science
Foundation of China (21873051). We also acknowledge
support from the Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin).
DEDICATION
■
This work is dedicated to the 100th anniversary of chemistry at
Nankai University.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00976.
Screenings of reaction conditions, reaction mechanism,
product transformation, crystallographic data, synthesis
of substrates, experimental procedures, characterization
and analytical data of products, NMR spectra, and
HPLC traces (PDF)
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(9) Crystal data for 3ed: C27H21BrClNO3, MW = 522.81;
monoclinic, P21; final R indices [I > 2σ(I)], R1 = 0.0481, wR2 =
0.0858; R indices (all data), R1 = 0.0842, wR2 = 0.0774; a = 10.951(2)
Å, b = 6.5509(13) Å, c = 15.865(3) Å, V = 1128.6(4) Å3, Z = 2; T =
113 K; 13739/5377 collected/unique reflections (Rint = 0.079); 3232
observations [I > 2σ(I)]; 299 parameters; goodness of fit on F2 =
0.97. Supplementary crystallographic data have been deposited at the
Cambridge Crystallographic Data Center (CCDC 1974108).
3577
https://doi.org/10.1021/acs.orglett.1c00976
Org. Lett. 2021, 23, 3573−3577