Enantioselective Synthesis of 2-Oxindole Spirofused Lactones and Lactams by Heck/Carbonylative Cylization Sequences: Method Development and Applications

Article abstract of DOI:10.1002/anie.201904838

An efficient one-pot assembly of all-carbon spiro-oxindole compounds from non-oxindole-based materials has been developed through a palladium-catalyzed asymmetric Heck/carbonylative lactonization and lactamization sequence. Diversified spirooxindole γ-and

Full text of DOI:10.1002/anie.201904838

A Journal of the Gesellschaft Deutscher Chemiker
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Chemie
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Accepted Article
Title: Enantioselective Synthesis of 2-Oxindole Spiro-Fused Lactones
and Lactams by Heck/Carbonylative Cyclization: Method
Development and Applications
Authors: Qiang Zhu, Huaanzi Hu, Fan Teng, Jian Liu, Weiming Hu, and
Shuang Luo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904838
Angew. Chem. 10.1002/ange.201904838
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10.1002/anie.201904838
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COMMUNICATION
Enantioselective Synthesis of 2-Oxindole Spiro-fused Lactone
and Lactam via Heck/Carbonylative Cylization: Method
Development and Applications
Huaanzi Hu, Fan Teng, Jian Liu, Weiming Hu, Shuang Luo*, and Qiang Zhu*
Abstract: An efficient one-pot assembly of all-carbon spirooxindole
compounds from non-oxindole-based materials has been developed
through palladium-catalyzed asymmetric tandem Heck/carbonylative
lactonization and lactamization. Diversified spirooxindole γ-and δ-
lactones/lactams were accessed in high yields with good to excellent
enantioselectivity (up to 99% ee) under mild conditions. Natural
product coixspirolactam A was conveniently synthesized by applying
the current methodology, and thus its absolute configuration was
elucidated for the first time. Asymmetric synthesis of an effective
CRTH2 receptor antagonist has been demonstrated utilizing this
method as a key step.
Figure 1. Representative natural products and bioactive molecules containing
the spirooxindole lactone or lactam framework.
2-Oxindole spiro-fused with a lactone or lactam moiety is a
privileged three-dimensional framework existing across a large
family of alkaloid natural products with diverse biological
profiles.[1] For example, coixspirolactams A-C, isolated from
traditional Chinese medicine adlay bran,[2] exhibit potent anti-
proliferative effect on human lung cancer cell A549, human
colorectal carcinoma cell HT-29, and COLO 205 (Figure 1).[3]
Although their optical rotation was reported, the absolute
configuration of the spirocarbon was not elucidated.[3a] Trigolutes
A-C are extracted from the twigs of trigonostemonlutescens and
show promising activity in the treatment of hemorrhagic fever with
renal syndrome.[4] Lactam derivatives of spirooxindole are
antagonists on the mouse CRTH2 receptor, which may directly
mediate the recruitment of inflammatory cells in allergic diseases
such as asthma, allergic rhinitis, and atopic dermatitis.[5] The S-
enantiomer which is separated by chiral preparative HPLC is
about 52 times more active than the R-isomer. Therefore, highly
thiourea catalyzed [5 + 1] annulation of oxindoles with ester-linked
bisenones (a, Scheme 1).[8a] An enantioselective synthesis of
spirooxindole alkylidene-γ-lactones was successfully developed
by Quintavalla through organocatalytic Aldol reaction of C3
alkylated oxindoles with aldehydes (b).[8b] The first asymmetric
synthesis of spirooxindoles γ-lactam was accessed by an
oxoindolin-3-ylidene involving
a
four-component reaction
promoted by recyclable fluorous bifunctional cinchona
a
alkaloid/thiourea organocatalyst (c).[8c] Each of these reactions
must start from oxindoles or their derivatives to deliver a specific
skeleton in normally long reaction time (up to 8 days). Therefore,
a general and highly enantioselective approach applicable to all
of these spirooxindole γ- and δ-lactones/lactams starting from
non-oxindole-based materials under mild conditions is highly
desirable.
enantioselective
assembly
of
these
spirooxindole
lactones/lactams is of great interest in medicinal chemistry.[6]
Although stereoselective construction of the spirooxindole has
been well established,[7] asymmetric synthesis of all-carbon
spirooxindoles containing a lactone or lactam moiety has had
limited success.[8] In 2014, Liang and Xu developed a novel
approach to chiral spirooxindole δ-lactones through bifunctional
[*]
H. Hu, F. Teng, J. Liu, W. Hu, Dr. S. Luo, Prof. Dr. Q. Zhu
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of
Biomedicine and Health
Chinese Academy of Sciences
190 Kaiyuan Avenue, Guangzhou 510530, China
E-mail: luo_shuang@gibh.ac.cn; zhu_qiang@gibh.ac.cn
H. Hu, F. Teng, J. Liu, W. Hu, Dr. S. Luo, Prof. Dr. Q. Zhu
University of Chinese Academy of Science
No. 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China
H. Hu, F. Teng, W. Hu, Dr. S. Luo, Prof. Dr. Q. Zhu
Guangzhou Regenerative Medicine and Health Guangdong Laboratory
Guangzhou 510005, China
Supporting information for this article is given via a link at the end of the
document.
Scheme 1. Methods to synthesize all-carbon spirooxindole lactones or
lactams.
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10.1002/anie.201904838
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COMMUNICATION
On the other hand, palladium-catalyzed carbonylation offers
routine access to carbonyl derivatives including lactones and
lactams.[9] Chiral ligand-induced asymmetric carbonylation is
occasionally successful mainly in the area of hydroformylation of
alkenes[10] together with scattered examples of other reaction
types.[11] Meanwhile, carbopalladation initiated transformations in
which the formation of Heck products by β-elimination is
prohibited or unfavorable can provide efficient approaches to
construct all-carbon quaternary stereocenters.[12] The process
combining carbopalladation and CO insertion (also known as
Heck/carbonylation) is common. [13] However, an enantioselective
version of this process to give carbonyl compounds with a
quaternary stereocenter is surprisingly scarce.[14] Recently,
Correia reported the first successful asymmetric Heck
carbonylative Suzuki coupling and esterification reaction enabled
by a chiral N,N ligand to deliver ketone or ester substituted
quaternary carbon containing dihydrobenzofurans in up to 96%
ee.[14b] We envisaged that lactonization or lactamization would
take place following Pd-assisted CO insertion when an alkenyl
substrate with an embedded oxygen- or nitrogen-based
nucleophile is applied (d). The ring size could be modulated by
changing the distance between the nucleophilic atom and the
alkenyl moiety. Thus, a general method to build spirooxindole γ-
and δ-lactones and lactams could be expected as well as in their
enantioenriched form. Thus, this method would be expected to
find potential application in the synthesis of related natural
products and bioactive compounds enantioselectively.
8
L7
L8
L5
L5
L5
L5
DMAP
DMAP
DMAP
Cs2CO3
K2CO3
K2CO3
-
22
92
28
53
92
46
7
9
-
11
91
84
91
89
10
11
12
13
PivOH
PivOH
PivOH
-
[a] Reaction conditions: 1a (0.1 mmol), Pd2(dba)3 (entries 1-10: 4 mol%;
entries 11-13: 5 mol%), ligand (entries 2-8: 8 mol%; entries 1 and 9: 16
mol%; entry 10: 10 mol%; entries 11-13: 12 mol%), base (entries 1-11: 1.5
equiv; entry 12-13: 1.2 equiv), PivOH (entry 10: 0.75 equiv; entries 11-13:
1.0 equiv), toluene (1.0 mL), 60 oC, 5 h, CO balloon (1 atm). [b] Isolated
yield. [c] Determined by HPLC analysis. DMAP = N, N-dimethylpyridin-4-
amine.
To
test
this
hypothesis,
the
N-(2-iodophenyl)-N-
methylacrylamide derivative 1a bearing a branched homoallylic
alcohol was investigated in Pd-catalyzed carbonylation. When
PPh3 was used as a ligand in the presence of balloon pressure of
CO, intramolecular carbopalladation followed by carbonylative
lactonization occurred to give a racemic spirooxindole δ-lactone
2a in excellent yield (92%, entry1, Table1). Encouraged by this
result, a number of chiral bidentate phosphine ligands were then
screened to test their efficiency in asymmetric induction (entries
2-6). To our delight, reaction with L5 could deliver the product with
good enantioselectivity (88% ee) albeit in a low chemical yield
(17%, entry 6). Other kinds of ligands, including bisoxazoline L7
and BINOL-derived phosphoramidite L8 gave 2a in poor
enantioselectivity. When PivOH was used as an additive, both the
yield and enantioselectivity were increased slightly (entry 10). By
replacing the organic base DMAP with K2CO3, a satisfactory yield
of 92% was reached without any loss of ee (entry 12).
Table 1. Optimization of the Reaction Conditions.[a]
entry
ligand
PPh3
L1
base
additive
yield (%)[b]
ee (%)[c]
1
2
3
4
5
6
7
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
-
-
-
-
-
-
-
92
13
39
20
12
17
9
-
-3
L2
-32
2
L3
L4
52
88
-15
L5
L6
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10.1002/anie.201904838
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COMMUNICATION
(93% ee) and 88% yield (98% ee), respectively. A wide array of
substituents (t-Bu, OMe, Me, F, and CF3) at the para position of
the protecting phenyl group were tolerable to generate the
corresponding products 4c-4f and 4h in good yields with ee
ranging from 89% to 93%. However, substrate 3g containing a
CN group led to 4g in poor yield and ee probably due to the
coordination ability of CN to Pd catalyst. Products 4i-4k containing
an ortho Me, OMe and Ph were obtained in good yields with
excellent enantioselectivity (up to 99% ee), while the formation of
ortho t-butyl substituted 4l failed. Excellent result (4m) for both
isolated yield (98%) and enantioselectivity (97% ee) was
identified when applying 3,5-dimethyphenyl as a protecting group.
Subsequently, the compatibility of substituents on the
iodobenzene ring was then investigated with the optimal nitrogen
protecting group fixed. The resulting Heck/carbonylative
lactamization proceeded smoothly to deliver 4n-4s in good to
excellent yields and enantioselectivity. It was noted that 1 mmol-
scale synthesis of 4v was also highly stereoselective (99% ee),
sacrificing isolated yield to some extent (73% yield). The
stereochemistry of 4r was determined by X-ray crystallographic
analysis as R configuration similar to the analogous lactones.
Scheme 2. Scope of lactones. Reaction conditions: 1 (0.1 mmol), Pd2(dba)3
(5 mol%), L5 (12 mol%), base (1.2 equiv), PivOH (1.0 equiv), toluene (1.0
mL), 60 oC, 5 h, CO balloon (1 atm).
With the optimal reaction conditions in hand, the substrate
scope for the synthesis of spirooxindole δ-lactone was briefly
investigated (Scheme 2). When changing the substituent on
the nitrogen from methyl to benzyl or adding a methyl group
on the aromatic ring, the corresponding products 2b and 2c
were obtained in excellent yields with 93% and 91% ee,
respectively. To synthesize a five-membered spirolactone,
substrates in which the alcoholic oxygen was one carbon
closer to the alkenyl moiety were synthesized and tested.
Under the same reaction conditions, the spirooxindole γ-
lactone 2d was produced in 75% yield with 91% ee. The
formation of other substituted γ-lactones 2e-2h was also less
efficient (51-75% yield), while the enantioselectivities were
maintained or even improved (up to 96% ee for 2h).
Unfortunately, only primary alcohols were able to trap the acyl
palladium species. When more sterically hindered secondary
alcohol was used as the substrate, the reaction failed to
provide the desired product. The stereochemistry of 2e was
confirmed unambiguously as the R configuration via X-ray
crystallographic analysis (see the Supporting Information (SI)
for details). To elucidate the absolute stereochemistry of
coixspirolactam A, both enantiomers 2j and 2j’ were
synthesized conveniently through a two-step sequence with
99% and 97% ee, respectively (Scheme 3). By comparing
their optical rotations with the reported value ([α]D25 = +9.7, c
= 0.70, MeOH),[3a] the structure of coixspirolactam A was
confirmed as 2j.
Scheme 4. Scope of lactams. Reaction conditions: 3 (0.1 mmol), Pd2(dba)3
(5 mol%), L5 (12 mol%), base (1.2 equiv), PivOH (1.0 equiv), toluene (1.0
mL), 60 oC, 5 h, CO balloon (1 atm). Ts = tosyl; Bz = benzoyl.
Scheme 3. Elucidation of the absolute configuration of coixspirolactam A.
PMB
=
4-methoxybenzyl; TFA
=
trifluoroacetic acid; TfOH
=
trifluoromethanesulfonic acid.
Although all of the resulting spirooxindole γ-lactams were
aryl protected, removal of the aryl protection and further
modification on the nitrogen could be realized. For example,
the p-methoxyphenyl in 4v was deprotected in 70% yield
under oxidative conditions without any influence on the
stereogenic center (a, Scheme 5). The resulting NH free
lactam 5 could be served as a key intermediate for the
synthesis of antagonist on the human CRTH2 receptor.[5] The
following four steps of routine transformations including
benzylation, deprotection of the PMB, alkylation, and
hydrolysis afforded the antagonist 8 enantioselectively (98%
ee, a). In addition, the synthesis of enantiomerically pure
spirooxindole δ-lactam 10 was accessed by making a detour
In addition to spirooxindole γ- and δ-lactones, their lactam
analogues could also be produced starting from similar substrates
containing an intramolecular nitrogen-based nucleophile
(Scheme 4). Initially, unprotected 2-(aminomethyl)-N-(2-
iodophenyl)-N-methylacrylamide was tested under the same
reaction conditions. Unfortunately, the reaction only led to a
messy mixture without any separable product. A series of
common nitrogen protecting groups such as Bn, Boc, Ts, and Bz
were then used but none of these substrates could deliver the
desired lactams. Amazingly, phenyl and 1-naphthyl protected
substrates could react smoothly delivering 4a and 4b in 99% yield
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10.1002/anie.201904838
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and an alkyl Pd(II) species is ready for CO insertion and
nucleophilic cyclization. This favorable approach leads to
spirooxindole lactones or lactams in (R)-configuration as we
observed.
around lactone analog 2a due to the difficulty in the synthesis
of the corresponding homoallylic amino precursor (b). Thus,
all of the four oxindole-based scaffolds spiro-fused with a
lactone or lactam moiety were accessible enantioselectively.
Moreover, the new stereogenic centers introduced around the
spiro carbon were accessible (c). For instances, treatment of
4m with LDA at -78 oC and electrophiles could afford
methylated product 11 (97% yield, 6.5:1 dr) and sulfurated
derivative 12 (72% yield, 8:1 dr) diastereoselectively. When
benzaldehyde was used as an electrophilic reagent, two
additional chiral centers were generated simultaneously. Only
two diastereoisomers 13 and 13’ were isolated by column
chromatography at a ratio of 2.5 : 1.
Figure 2. Plausible model for asymmetric introduction.
In conclusion, we developed a general approach to construct
enantiomerically pure all-carbon spirooxindole γ- and δ-
lactones/lactams through palladium-catalyzed carbonylative
Heck cyclization. This is the first case of transition-metal-
catalyzed asymmetric synthesis of these valuable skeletons
starting from non-oxindole-based materials with good functional
group tolerance and excellent enantioselectivity. By utilizing the
present methodology as
coixspirolactam A as well as an effective CRTH2 receptor
antagonist have been synthesized conveniently. These
a
key step, natural product
8
spirooxindole lactones/lactams could be easily derivatized to
introduce more stereogenic cetrers around the chiral quaternary
spiro carbon in a diastereoselective manner. The proposed model
for asymmetric introduction offers hints for designing new
enantioselective Heck/carbonylation reactions.
Accession Codes
CCDC
1889073-1889074
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, U.K.; fax: +44 1223 336033.
Acknowledgements
Scheme 5. Deprotection and further transformation of 4v (a); synthesis of
spirooxindole δ-lactam 10 (b), and derivatization of 4m (c). PMB
= 4-
methoxybenzyl; CAN = ceric ammonium nitrate; TsCl = tosyl chloride; LDA =
lithium diisopropylamide.
We gratefully acknowledge the National Natural Science
Foundation of China (Nos. 21532009, 21772198, and 21871268)
and Youth Innovation Promotion Association of CAS for financial
support. We thank Prof. Honggen Wang at Sun Yat-sen University
for assistance in X-ray crystallographic analysis.
The transition state that determines the asymmetric
introduction is proposed in Figure 2. After oxidative addition, the
terminal alkene should approach the Pd(II) centre, tightly
coordinated with a bidentate phosphine ligand, at an orientation
with the side chain stretching to the open area away from ligand
(left, Figure 2). Then, migratory insertion of the alkenyl moiety to
Ar-Pd(II) forms the quaternary carbon centre stereoselectively,
Keywords: palladium catalyze • asymmetric carbonylation •
spirooxindole lactones and lactams
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10.1002/anie.201904838
Angewandte Chemie International Edition
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Huaanzi Hu, Fan Teng, Jian Liu,
Weiming Hu, Shuang Luo*, Qiang Zhu*
Page No. – Page No.
Enantioselective Synthesis of 2-
Oxindole Spiro-fused Lactone and
Lactam via Heck/Carbonylative
Cylization: Method Development and
Applications
An efficient one-pot assembly of all-carbon spirooxindole compounds from non-oxindole-based materials
has been developed through palladium-catalyzed asymmetric tandem Heck/carbonylative lactonization
and lactamization. Diversified spirooxindole γ-and δ-lactones/lactams were accessed in high yields with
good to excellent enantioselectivity (up to 99% ee) under mild conditions. Natural product
coixspirolactam A was conveniently synthesized by applying the current methodology, and thus its
absolute configuration was elucidated for the first time. The asymmetric synthesis of an effective CRTH2
receptor antagonist has been demonstrated utilizing this method as a key step.
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