Diversified Transformations of Tetrahydroindolizines to Construct Chiral 3-Arylindolizines and Dicarbofunctionalized 1,5-Diketones

Article abstract of DOI:10.1021/jacs.0c07066

Enantioselective diverse synthesis of a small-molecule collection with structural and functional similarities or differences in an efficient manner is an appealing but formidable challenge. Asymmetric preparation and branching transformations of tetrahydroindolizines in succession present a useful approach to the construction of N-heterocycle-containing scaffolds with functional group, and stereochemical diversity. Herein, we report a breakthrough toward this end via an initial diastereo- A nd enantioselective [3 + 2] cycloaddition between pyridinium ylides and enones, following diversified sequential transformations. Chiral N,N′-dioxide-earth metal complexes enable the generation of optically active tetrahydroindolizines in situ, across the strong background reaction for racemate-formation. In connection with deliberate sequential transformations, involving convenient rearomatic oxidation, and light-active aza-Norrish II rearrangement, the tetrahydroindolizine intermediates were converted into the final library including 3-arylindolizine derivatives and dicarbofunctionalized 1,5-dicarbonyl compounds. More importantly, the stereochemistry of four-stereogenic centered tetrahydroindolizine intermediates could be efficiently transferred into axial chirality in 3-arylindolizines and vicinal pyridyl and aryl substituted 1,5-diketones. In addition, densely functionalized cyclopropanes and bridged cyclic compounds were also discovered depending on the nature of the pyridinium ylides. Mechanism studies were involved to explain the stereochemistry during the reaction processes.

Full text of DOI:10.1021/jacs.0c07066

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Article
Diversified Transformations of Tetrahydroindolizines to Construct
Chiral 3-Arylindolizines and Dicarbofunctionalized 1,5-Diketones
Dong Zhang, Zhishan Su, Qianwen He, Zhikun Wu, Yuqiao
Zhou, Chenjing Pan, Xiaohua Liu, and Xiaoming Feng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07066 • Publication Date (Web): 20 Aug 2020
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Dong Zhang, Zhisan Su, Qianwen He, Zhikun Wu, Yuqiao Zhou, Chenjing Pan, Xiaohua Liu*,
Xiaoming Feng*
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Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China. *e-mail: liuxh@scu.edu.cn; xmfeng@scu.edu.cn;
Homepage: http://www.scu.edu.cn/chem_asl/;
KEYWORDS: asymmetric catalysis, axial chirality, photocatalysis, rearrangement, tetrahydroindolizine
ABSTRACT: Enantioselective diverse synthesis of a small-molecule collection with structural and functional similarities or
differences in an efficient manner is appealing but a formidable challenge. Asymmetric preparation and branching
transformations of tetrahydroindolizines in successions present a useful approach to the construction of N-heterocycle-
containing scaffolds with functional group, and stereochemical diversity. Herein, we report a breakthrough toward this end
via an initial diastereo- and enantioselective [3+2] cycloaddition between pyridinium ylides and enones, following
diversified sequential transformations. Chiral N,Nʹ-dioxide-earth metal complexes enables the generation of optically active
tetrahydroindolizines in situ, across the strong background reaction for racemate-formation. In connection with deliberate
sequential transformations, involving convenient rearomatic oxidation, and light-active aza-Norrish II rearrangement, the
tetrahydroindolizine intermediates were converted into the final library including 3-arylindolizine derivatives and
dicarbofunctionalized 1,5-dicarbonyl compounds. More importantly, the stereochemistry of four-stereogenic centered
tetrahydroindolizine intermediates could be efficiently transferred into axially chirality in 3-arylindolizines and vicinal
pyridyl and aryl substituted 1,5-diketones. In addition, densely functionalized cyclopropanes and bridged cyclic compound
were also discovered depended on the nature of the pyridinium ylides. Mechanism studies were involved to explain the
stereochemistry during the reaction processes.
Introduction
approved
pharmaceuticals,
especially
the
ones
Diversity-oriented synthesis to span large regions of
versatile small-molecule libraries in an efficient manner
presents new challenges in organic synthesis.1 The
utilization of a common and available synthon capable of
embellished at C2-position.5 Indolizines are also popular
heterocyclic cores which bear valuable photochemical
properties6 and involve within pharmaceutical targets for
abroad array of therapeutic indications7 (Fig. 1a).
Pyridinium ylides, a class of easily available and useful
nucleophiles, enable various reactions, such as [3+2]
cycloadditions to form tetrahydroindolizines and other
nitrogen-containing compounds beyond,8 2-pyridinyl
containing betaines,9 or cyclopropanations10 etc.. Among
them, tetrahydroindolizines, readily generated from 1,3-
dipolar cycloaddition, seem very attractive since they can
performing
different
transformations
provides
opportunities to build various chemical species. In the past
decades, great efforts have been devoted to searching
diversified synthesis, which enables to access to different
types of products with scaffold selectivities.2 However, the
catalytic asymmetric transformations from an in situ
generated enantioenriched structural motif via branching
reaction sequences remain to be rarely reported.3 There is
no doubt to be a challenging task that several key issues
should be taken into account, for instance, the
stereoselective construction of the privileged structure
motif, the competitive diversification processes in related
to its multiple reactive sites, and the tolerance of different
catalytic systems for sequential transformations without
purification of the key intermediate, the last but not the
least the chirality conversion during the transformations.
Nitrogen-containing heterocycles are one of the most
prevalent structural components of pharmaceuticals and
agrochemicals.4 In particular, pyridine is the second most
commonly used nitrogen heterocycle among FDA
serve as
a
privileged synthon for late-stage
functionalizations, e.g. oxidation into indolizine,8a,11
reduction into indolizidine,12 rearrangements into carbo-2-
pyridylation derivatives.13
As the enantioselective construction of unprecedented
N-heterocycle-bearing scaffolds is an important goal in
organic synthesis, we envision to probe diversified
sequential transformations of chiral tetrahydroindolizines,
initiated by diastereo- and enantioselective [3+2]
cycloaddition of pyridinium ylides and enones (Fig. 1b).
Although such a kind of cycloaddition process has been
extensively studied, the asymmetric version is meager and
difficult arising from the high reactivity of the ylides and
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Fig. 1 | Representative biologically active indolizines and the strategy for diversified transformations of the in-situ
generated tetrahydroindolizines.
instability of the adducts.14 As one of our long-term
objective to expand the scope of chiral N,Nʹ-dioxide-metal
complexes15 promoted asymmetric transformations, we
test their ability in asymmetric cycloaddition of pyridinium
ylides. To address the stability issue of the
tetrahydroindolizines and to expand the pluripotent
nitrogen-containing structures, diverse transformations
are designed which are capable to yield either axially chiral
3-arylindolizines or chiral 2-pyridyl-3-aryl substituted 1,5-
diketones (Fig. 1b). In connection with aromatic oxidation
of tetrahydroindolizines, the creation of the stereogenic
axis in heteroaromatic ring via central-to-axial chirality
conversion strategy16 is accomplished (Fig. 1b, sequential
Asymmetric
construction
of
3-arylindolizine
atropisomer via [3+2] cycloaddition/oxidation
sequential reaction I: The direct construction of 3-
arylindolizines with stereogenic axis upon oxidation of
tetrahydroindolizines is appealing and challenging (Table
1). There are three main difficulties needed to be
considered: firstly, tetrahydroindolizine initiated by highly
reactive [3+2] cycloaddition between α,β-unsaturated
carbonyl compound and pyridinium ylide is unstable,
bearing four stereogenic carbon centers, including the
kinetic and thermodynamic adducts.17 Secondly, central-
to-axial chirality conversion in the oxidation process
remains fuzzy, and partly dehydrogenation product might
be generated from the diastereomers of the
intermediate.17b,18 Thirdly, rotation barriers of the 3-
reaction I), which provides
a
useful route for
atroposelective synthesis. Alternatively, the ensuing
rearomatization reaction via photo-induced single electron
transfer (SET) process,13 formal carbo-2-pyridylation and
phenacylidation products are available with vicinal
stereogenic centers (Fig. 1b, sequential reaction II).
Additionally, synthesizing multi-substituted cyclopropanes
as well as bridged cyclic compound was also discovered,
depending on the nature of the employed pyridinium
ylides. Herein, we wish to disclose our achievement along
this line that an array of nitrogen-heterocyclic derivatives
was obtained under mild reaction condition via
enantioselective [3+2] cycloaddition of pyridinium ylides
with enones, followed by diversified transformations.
arylindolizine products are unknown. As
a result,
exploratory testing should be carried out to reach
enantioselective creation of tetrahydroindolizines and
indolizine atropisomers in successions. To assess our
hypothesis, we began by choosing the substrates of α,β-
unsaturated enones A with ortho-substituent at the β-aryl
ring in order to get stable atropisomer products at room
temperature. The initial tests were conducted in the
presence of 10 mol% of chiral N,Nʹ-dioxide L3-
PiMe2/Sc(OTf)3
complex
and
3-chloropyridinium
phenacylide B1 in dichloromethane at 30 C (Table 1).
K2CO3 was used as a base to generate the corresponding
pyridinium ylide in situ, and DDQ (2,3-dichloro-5,6-
dicyano-1,4-benzoquinone) was added into the catalytic
system after 12 hours as the oxidant for the sequential
Results and discussion
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Table 1 | Optimization of the reaction conditions for the construction axially chiral 3-arylindolizines.
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formation of 3-arylindolizine E. When (E)-3-(2-
fluorophenyl)-1-phenylpropenone was used, the desired
product E1 was obtained in 48% yield, but it was rotation-
free at room temperature. Further increasing the steric
hindrance of ortho-substituents (see page S8, Table S1 for
details), such as by introducing 2-nitrophenyl group or 1-
naphthyl group, led to identified atropisomer products E4
and E6. Although the enantioselectivity was poor, these
preliminary results suggest that the strategy to construct
axially chiral 3-arylindolizine is feasible. We also noticed
that the enantioselectivity of 3-naphthylindolizine E6
slowly whittled down in CH2Cl2 within 24 hours (from
60:40 to 55:45 e.r.). We concluded this racemization
phenomenon to the readily rotation of the two benzoyl
groups on 2,4-positions of indolizine, leaving wide open
for the rolling-over of the unsymmetric 3-aryl substituent.
Next, our attention was turned to raise the steric
hindrance of the electron-withdrawing substituent on the
desired product E11 in 59% yield with 65:35 e.r..
Noteworthily, the rotation energy of the product E11
seems high in view of the fact that its optical purity was
maintained after stirring in CH2Cl2 at 40 °C for 72 h. The
structures of these atropisomers were confirmed via X-ray
crystal diffraction analysis.19 Next, the chiral catalyst
species, including N,Nʹ-dioxide ligands with varied amino
acid backbones and amide units, and metal salts as well,
were examined to improve the enantioselectivity (see page
S10, Table S3-S4 for details). It was found that the product
E11 could be obtained in 33% yield and 81:19 e.r. in the
assistance of chiral ligand L3-PrEt2 and Yb(OTf)3. However,
the regioselective product E'1119 was detected along with
the major isomer E11.
In order to improve the reactivity of the pyridinium
ylides and avoid the regioselective byproduct, substituents
on the para-position of pyridine ring were investigated
(see page S11, Table S5 for details). As shown in Scheme 1,
when the 4-cyano pyridine derived pyridinium salt C4 was
tested in the reaction, the corresponding product E14
could be isolated in 90% yield with 85:15 e.r. by using the
catalyst of L3-PrEt2/Yb(OTf)3 at 30 °C, and the
enantiomeric ratio increased to 94:6 at 0 °C after longer
reaction time (see page S12, Table S6 for details).
pyridinium
salts.
When
3-chloropyridinium
1-
naphthoylide B2 was subjected into the reaction, the
related product E9 was isolated in 63% yield with low e.r.
value. To our delight, the reaction between 3-
bromopyridinium
ethyl
acetate
C1
and
8-
methoxynaphthalenyl substituted enone A8 delivered the
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Scheme 1. The sequential reaction I for the synthesis of
axially chiral 3-arylindolizine and further transformation.
Optically pure product E14 is easily available after
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8
recrystallization in ethyl acetate/petroleum ether mixture.
As a result of the important biological activity associated
with this motif (Fig 1a), upon treatment with NaBH4, the
related reduction products were isolated in a 95% total
yield with moderate diastereoselectivity, but maintained
high enantioselectivity. The absolute configuration of
optically pure atropisomer E14 and the major reduction
product F1 was determined by X-crystallography to be (aR)
and (aR,R), respectively.19
9
With the optimized reaction conditions in hand, further
substrate scope investigation of 8-methoxynaphthalenyl
substituted enones A and pyridinium acetates C was
carried out with the prospective catalyst L3-
PrEt2/Yb(OTf)3 (Table 2). Specifically, enones with
electron-donating substituents at the para- or meta-
position on the phenyl ring of the benzoyl group were
converted to the corresponding products E14~E22 in 61-
94% yield, with 90:10 to 99:1 e.r.. Enone bearing an ortho-
methyl group at benzoyl unit afforded the target product
E23 in 75% yield with a slightly lower enantioselectivity
(87:13 e.r.). Substrate bearing benzo[1,3]dioxol-5-yl unit
also performed well to provide the desired product E24 in
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Table 2 | Substrates scope of axially chiral 3-arylindolizines via oxidation sequential reaction.a
aUnless otherwise noted, the reactions were performed with enone A (0.10 mmol), pyridinium salt C (1.0 equiv), K2CO3 (1.5 equiv),
L3-PrEt2/Yb(OTf)3 (1:1, 10 mol%) in DCM (1.0 mL) at 0 °C for indicated hours. Subsequently, DDQ (2.0 equiv) was added and the
reaction mixture was stirred for 0.5 h. Isolated yield by silica gel chromatography. The e.r. value was determined by HPLC analysis
on a chiral stationary phase.
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85% yield with 93:7 e.r.. The reactions of enones with undergo visible-light-active
aza-Norrish
II
rearrangement13,21, affording formal dicarbofunctionalized
1,5-dicarbonyl compounds (Scheme 3). The difficulty of
creating the vicinal carbon centers stems from two issues:
the competition of base-promoted racemic process, and
the epimerization of the intermediate D or the product G.
Our preliminary study (see page S14, Table S9 for details)
showed that a strong background reaction is concomitant,
a 46% yield of the diketone product G1 with high
diastereoselectivity was obtained with K2CO3 in CH2Cl2.
However, performing the sequential light-induced reaction
in MeOH, the racemic product G1 was isolated in 56%
yield with a dramatically decreased diastereoselectivity
(34:66 anti:syn ratio), implying that an epimerization
process was involved. Moreover, the nucleophilicity study
about pyridinium ylides from Mayr and co-workers have
manifested that the 1,3-dipolar cycloadditions of
pyridinium ylides with acceptor substituted dipolarophiles
might proceed stepwise or in a highly unsymmetrical
concerted way.8a As a result, diastereomers of the key
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7
8
halo-substituted benzoyl group can be readily converted
into the desired 3-arylindolizines E25~E29, albeit the
yields and enantioselectivities varied with the position of
the halo-substituents (76-97% yield, and 81:19-90:10 e.r.).
Furthermore, the enantioselectivity of the reaction with
different pyridinium acetates was good in all cases
(E30~E33; 90:10-95:5 e.r.), but the yield dropped as the
hindrance of ester group increased. Remarkably, when the
2-methoxy-1-naphthyl group was replaced with 1-
naphthyl group, the corresponding product E34 was
obtained in 90% yield with moderated enantioselectivity
(77:23 e.r.). More importantly, the e.r. value dropped to
61:39 seven months later, though it was stored in the
refrigerator, indicating that the methoxy group is crucial to
the stability of the axially chiral product. On the other hand,
enones bearing cyclohexyl or isopropyl substituent were
also tested. However, the reactivities dropped dramatically
under the optimized reaction conditions, and only a
slightly enantiomeric ratio was observed (E35~E36,
52:48-54:46 e.r.).
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tetrahydroindolizine intermediates
byproducts should also be taken into consideration. In
addition, the stereo-arrangement of the
tetrahydroindolizine isomers D will also interfere with the
intersystem crossing process (ii) and 1,5-hydrogen shift
process (iii)13.
D
and other
Scheme 2. Asymmetric three-component sequential
reactions for the direct synthesis of 3-arylindolizine
atropisomers.
Scheme 3. The sequential reaction II for the synthesis of
dicarbofunctionalized 1,5-diketones.
The sequential reaction for the synthesis of 3-
arylindolizine atropisomers could further be simplified
into a three-component one-pot process of enone A, ethyl
diazoacetate and isonicotinonitrile via a bimetallic relay
catalysis14a,20 (Scheme 2). In the presence of a catalytic
amount of Fe(TPP)Cl (TPP
pyridinium ylide can be generated in-situ via the reaction
of iron-carbene species with isonicotinonitrile.
= tetraphenylporphyrin),
Subsequently, asymmetric [3+2] cycloaddition with
enones in the presence of L3-PrEt2/Lu(OTf)3 catalyst,
following oxidation reaction afforded the final products
E14~E22 in 84-99% yield with 87:13-93:7 e.r..
Comparably, this procedure enabled the formation of
axially chiral 3-arylindolizine in slightly higher yields
within shorter reaction time.
To balance the reactivity and enantiocontrol, we chose
(E)-3-(4-chlorophenyl)-1-phenylprop-2-enone A22 and N-
benzoylmethyl 3-chloropyridinium bromide B1 as the
model substrates to investigate the optimal chiral catalysts.
The initial [3+2] cycloaddition step was carried out in
CH2Cl2 in dark, and then blue LED lamps were introduced
to intrigue the rearrangement. Although the reaction
Asymmetric construction of 2,3-diaryl substituted 1,5-
diketones via [3+2] cycloaddition/light-initiated
rearrangement sequential reaction II: The chiral
tetrahydroindolizines generated from dearomative 1,3-
dipolar cycloaddition of pyridinium phenacylide might
mixture
was
complicated,
the
desired
dicarbofunctionalization product G1 could be isolated in
50% yield, >19:1 dr and 98:2 e.r. in the presence of chiral
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Table 3 | Substrates scope of the dicarbofunctionalized 1,5-diketones via photo-promoted rearrangement sequential
reaction.a
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aUnless otherwise noted, all reactions were performed with enone A (0.105 mmol), pyridinium salt B (0.10 mmol), K2CO3 (0.15
mmol), L3-PiMe2/Sc(OTf)3 (1:1, 10 mol%) in DCM (2.0 mL) at 30 °C in dark for 12 h. Subsequently, the mixture was stirred at
r.t. under blue LED lamps (4 × 20 W) for 10 h. Isolated yield by silica gel chromatography. The e.r. value was determined by
HPLC analysis on a chiral stationary phase.
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(S)-pipecolinic acid derived L3-PiMe2 ligand upon 37% yield, 5:1 dr and 98:2 e.r.. Concurrently, hydrogen
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8
coordination with Sc(OTf)3. It is worthy to note that the
base, solvent, and the reaction time in dark had obvious
influence on the outcomes (see page S13, Table S7-S9 for
details).
elimination reaction resulted the olefin product J1 in 35%
yield, > 19:1 dr and 98:2 e.r..
Other sequential reactions of pyridinium ylides:
Different behavior was observed for the ylides with varied
electronic nature. In the above-mentioned reactions,
electron-withdrawing substituents on the pyridine unit
were involved. Although reference study shows that
variation of the heterocyclic ring of N-benzoyl-based ylides
has little influence on the nucleophilicity, we found that
the major sequential pathway changed if unsubstituted or
electron-donating group substituted pyridinium ylides B
participated in. For instance, at the same reaction
The optimal conditions thus obtained were then applied
to the synthesis of other 2,3-dicarbofunctionalized 1,5-
diketones (Table 3). To examine the scope of the enone
component in this sequential reaction, we employed N-
benzoylmethyl 3-chloropyridinium bromide (B1) as the
ylide precursor. The electronic properties and steric
hindrance of substituents on the β-phenyl ring of
chalcones had no obvious effect on the enantioselectivities.
A variety of chalcones could react smoothly to give the
corresponding products G1~G10 with high level of e.r.
values (94:6 to 98:2 e.r.; 35-53% yields), except G11
(74:26 e.r. with 28% yield) which contains an ortho-
chlorine substituted phenyl ring. Notably, enones bearing a
1-naphthyl or 2-naphthyl group as well as disubstituted
phenyl group were proved to be suitable in the reaction,
affording G12~G14 in 93:7 to 97:3 e.r.. In addition to β-
aryl substituted enones, several β-alkyl substituted enones
have also been tested, however, the conversions were slow
in all cases, and only trace amount of the desired products
could be detected (see page S8 for details,).
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Scheme 4. Other cascade transformations of pyridinium
phenacylides.
Subsequently, chalcones with different substituents on
the benzyl moiety were tested, and the para-position
substituted substrates afforded G15~G17 in moderate to
good results, but the meta-methyl substituted substrate
only provided G18 in 41% yield with 78:22 e.r.. The
absolute configuration of the major enantiomer of G16
was determined to be (2R,3S) by X-ray crystallographic
analysis.22 The compatibility of this catalytic system for
chalcone derivative with benzo[3,4]dioxole substituent
was also tested, but the yield of the desired product G19
was poor albeit with good enantioselectivity. (E)-1-
(naphthalen-2-yl)-3-phenylprop-2-enone performed the
reaction well, and a 54% isolated yield with 87:13 e.r.
could be given for the product G20.22
Next, the substrate scope with respect to the pyridinium
ylides was investigated. Substituents, including fluor-,
bromo-, cyano-, and ester groups at meta- or para-position
of the pyridine ring were tolerated, affording the desired
products G21~G26 in 27-54% yields, with 70:30 to 98:2
e.r.. On the other hand, the electron properties on the N-
benzyl unit of the pyridinium salt had no apparent effect
both on the yields and enantioselectivities, giving G27 and
G28 with good results. In these cases, the
diastereoselectivity is equally high, and nearly only anti-
products G were isolated.
condition as that of sequential aza-Norrish II
rearrangement, the reaction between chalcone and other
benzoyl-based enones with unsubstituted pyridinium
phenacylide B12 yielded 2'-pyridine substituted
cyclopropane K1~K3 and 3-phenyl substituted 1,5-
diketone L1~L3 via disproportionation and rearrangement
(Scheme 4, eq. 1). The structures were confirmed by X-ray
single crystal diffraction analysis.22 Such a process is much
more complicated, and only a slightly enantiomeric ratio
was observed at present. In another case, when N-benzyl
4-methylpyridinium salt B13 was used to react with
chalcone, a [3+2] cycloaddition followed by a [4+2]
cascade reaction took place to afford diaromatic bridged 7-
The enantiomeric diversion of the product ent-G2 (55%
yield, 98:2 e.r.) and ent-G8 (33% yield, 99:1 e.r.) could be
easily obtained when ent-L-PiMe2/Sc(OTf)3 complex was
used instead, which made the structural library more
plentiful. To further investigate the utility of chiral 2,3-
diaryl substituted 1,5-diketones, reduction and cyclization
of G1 was carried out. Upon treatment with NaBH4, the
related reduction product 1,5-diol H1 was isolated as a
mixture of diastereomers in 92% yield, and further
cyclization occurred under the addition of AuBr3 via
carbocation formation23 at C-1 or C-5 position of H1,
providing the four-aryl substituted tetrahydropyran24 I1in
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Page 8 of 13
methyl-1,2,3,5,8,8a-hexahydro-5,8-ethano-indolizine
stepwise process.8a Based on the information, we proposed
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structure M1 with high diastereoselectivity (Scheme 4, eq.
2), taking advantage the high active dienamine unit in the
tetrahydroindolizines structure.
a possible reaction model as shown in Fig. 2a. The stable
anti-ylide undergoes a Michael addition onto enone giving
the enolate intermediate, following rapidly ring-close onto
the aza-cyclic ring to yield the dearomative adduct D',
where the substituents of the dipolarophile remain trans to
each other.
Mechanism consideration: The stereochemistry of both
3-arylindolizine atropisomers and dicarbofunctionalized
1,5-diketones stem from the asymmetric catalytic [3+2]
cycloaddition reaction. Nevertheless, isolation and identify
of the key chiral tetrahydroindolizine intermediate D failed
due to its poor stability. As a comparison task, we
synthesized the cycloadduct D' of isoquinolinium ylides of
C11 with enone A8 instead to assign the relative stereo-
arrangement of the major diastereomer (Fig. 2a). The
reaction readily occurred in the presence of K2CO3 alone,
providing the tetrahydropyrroloisoquinoline D' in a 40%
yield with high diastereoselectivity. The relative
configuration was determined to be rel-(1R, 2S, 3R, 4R) via
X-ray crystal analysis of this authentic sample22, that is
The energy barrier (E) associated with the
interconversion between the two isomers before and after
oxidation was roughly evaluated by a relaxed potential
energy surface scan of the dihedral angel D(C5-C1-C8-C9) in
tetrahydroindolizine D1 (IM1) and the corresponding 3-
arylindolizine E14 (IM5) (Fig 2b, and see page S17 for
details). In the view point of energy, the rotation processes
were easy to occur for D1 (IM1) due to structural
flexibility of sp3-hybridized C1, C3 and C5 atoms, with E
of 9.8~11.9 kcal/mol. However, the conjugation
interaction between the substituents (i.e., COPh and CO2Et)
and C=C double bonds in 3-arylindolizine E14 (IM5)
enhanced the rigidity, with barrier to rotation from 26.6 to
32.9 kcal/mol at 298K. It should be noted that without
MeO substituent, rotation could occur at room
temperature. The e.r. value of the related 3-arylindolizine
E34 dropped gradually (Table 2, 77:23 e.r. vs 61:39 e.r.
after 7 months), in agreement with the calculated rotation
energy (E = 24.7~ 22.7 kcal/mol at 298K, see page S18
for details). Thus, the central-to-axial chirality conversion
might be dramatically affected by the readily rotation of
the naphthyl substituent.
The chiral catalyst information was obtained from the X-
ray crystal diffraction analysis, which provides interesting
disposition information (Fig. 3a).22 It shows that the
scandium(III) complex of the chiral tetradentate N,N'-
dioxide ligand L3-PiPr2 and tow ancillary species adopts a
distorted octahedral geography, such that the complex has
two trans-related amide donors (angles ∠1 = 165.90o) and
two cis-related amine-oxide donors (angles ∠2 = 89.75o).
While the ytterbium(III) complex of this ligand and four
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four methine hydrogens are in
a trans-trans-trans
relationship, related to a thermodynamic stable structure.
ancillary solvents exhibits
a
proximate square
antiprismatic geometry version. This illustrates an
important steric factor in Yb(III) complex that such twist
(angles ∠1 = 149.48o, ∠2 = 82.49o) brings the two amide
units closer to offset its longer ionic radii in comparison
with the Sc(III) complex. The other rare earth metal salts
of chiral N,N'-dioxide ligands are regarded to adopt similar
stereo-arrangement (see page S42 for details).
Figure
3 exhibits our current proposal of the
stereochemical outcome of the formation of axially chiral
3-arylindolizine E and 1,5-dikotone G. We rationalize that
two kinds of pyridinium ylide undergoes the 1,3-dipolar
cycloadditions with enones in
a common reaction
pathway8a and stereochemical outcome. When the two
reactants were mixed with the chiral N,N'-dioxide-metal
complex catalyst, both the enone and pyridinium ylide
coordinate to metal center by releasing the ancillary
molecules in less-hindered positions. Next, the 1,5-dipole
of ylide variation nucleophilic attacks the β-Si face of
enone with its Re-face, which might be rate-determining C-
Fig.
2 Identification of tetrahydropyrroloisoquinoline
analogue and the interconversion of the rotamers.
This diastereomer is also overwhelming in the presence of
the chiral Lewis acid catalyst, however, the
enantioselectivity is hard to get due to the dramatic
background reaction. The general mechanism of formation
of tetrahydroindolizines is considered as more probable a
C
bond-forming step, generating the corresponding
betaine intermediates (Fig 3a and 3b, step 1).
Subsequently, ring-closure occurs between α-Si face of
enolate and Re-face of pyridine, affording the key (1R, 2S,
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Fig. 3 | Proposed activation mode for the [3+2] cycloaddition and sequential transformations.
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3R, 4R) tetrahedroindolizine intermediate D (Fig 3a and 3b,
step 2). This thermodynamic adduct is more stable, and its
configuration is also more compact than the corresponding
kinetic adduct (see page S23 for details).
the Csp2-Csp3 bond, and delivers the atropiomeric 3-
arylindolizine. In addition, the methoxy substituent is
critical to limit the rotation, and to direct the access route
of the oxidants. As shown in the optimized rotamers of
intermediates D1, the abstraction of H4, H3, and H2 of the
rotamer D1-IM1b is disfavorable, in which the three
oxygen-bearing groups locate at homolateral position. In
this view, the distance between H4 and ester group is
shorter, and the large aryl ring of methoxynaphthyl unit is
closer to H3, and the repulsion is stronger when the
oxidant approaches to H2 near to the methoxy group.
These factors might lead to higher barrier to be oxidated
from D1-IM1b. Therefore, the favorable oxidation from
D1-IM1 with minimum steric congestion, and restricted
rotation of the methoxynaphthyl developed in the H-
abstraction process, will result in the highly selective
formation of axially chiral (aR)-E14, reaching chirality
conversion from four carbon central to one axial.
In the first oxidative sequential reaction (Fig. 3a), H4-
proton abstraction by DDQ from beneath of the distorted
aza-cycle would give flat pyridinium cation intermediate
D1-IM2. The flat cation structure leads to up spaciou room
for H3-proton abstraction by hydrochloranil anion,
affording partly dehydrogenation product D1-IM3. Next, a
similar oxidation process occurred for H2, H1-proton
abstraction by chloranil and hydrochloranil anion,
respectively, resulting in the formation of 3-arylindolizine
E14 (IM5). Optimized geometries of the intermediates
(D1-IM2 to D1-IM4, see page S24 for details) generated in
the oxidation process indicates the two dihedral angles
reduced gradually, indicating a shrinkage of the two-
carbonyl unit towards the methoxynaphthyl unit. The
increased steric hindrance of the oxidized species, as well
as the interaction of the oxidants with the substrate, might
hamper the rotation of the methoxynaphthyl group around
On the other hand, the light-initiated aza-Norrish II
rearrangement starts from the optically active
tetrahydroindolizine D, which is generated by a similar
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pathway. As shown in Fig. 3b, the long-pair electrons of the
Page 10 of 13
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nitrogen in tetrahydroindolizine is close to the downward
N-benzoyl unit, and intramolecular single electron-transfer
occurs upon absorption of visible light and intersystem
crossing process. Then, H4 proton shifts readily at the
beneath to the oxygen of N-benzoyl group, generating
neutral biradical (Scheme 3). Next, a formal aza-Norrish II
cleavage at the N-benzoyl bond yields enol isomer, and the
stereochemistry of dicarbonfunctional groups remains.
Finally, tautomerization affords the (2R, 3S)-2-pyridinyl-3-
phenyl substituted pentane-1,5-dione G2.
Xiaohua Liu
-
Key Laboratory of Green Chemistry
&
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China. ORCID 0000-
0001-9555-0555; E-mail: liuxh@scu.edu.cn
Xiaoming Feng - Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China. ORCID 0000-
0003-4507-0478; E-mail: xmfeng@scu.edu.cn
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Conclusion
Dong Zhang - College of Chemistry, Sichuan University,
Chengdu 610064, China. ORCID 0000-0002-3020-3218;
In summary, we have discovered enantioselective
diversified transformations of tetrahydroindolinzines
based on asymmetric catalytic [3+2] cycloaddition reaction
between pyridinium ylides and enones. The key to success
is the use of suitable chiral N,N-dioxide-metal complexes
as the efficient catalysts to control the stereoselectivity in
the initial cyclization process. The combination of
rearomatic oxidation sequential reaction enables a direct
access to axially chiral 3-arylindolizines via a central-to-
axial chirality conversion in high yields with moderate to
good enantioselectivities. By introducing a light source, a
sequential aza-Norrish II rearrangement affords formal
carbo-2-pyridylation and benzylation products with vicinal
Zhisan Su - College of Chemistry, Sichuan University, Chengdu
610064, China. ORCID 0000-0001-5168-3823;
Qianwen He - College of Chemistry, Sichuan University,
Chengdu 610064, China. ORCID 0000-0001-9777-2178;
Zhikun Wu
- College of Chemistry, Sichuan University,
Chengdu 610064, China. ORCID 0000-0001-9213-7693;
Yuqiao Zhou - College of Chemistry, Sichuan University,
Chengdu 610064, China. ORCID 0000-0003-3490-4182;
Chenjing Pan - College of Chemistry, Sichuan University,
Chengdu 610064, China. ORCID 0000-0002-4810-5237.
stereogenic centers in
a
highly diastereo- and
enantiocontrolled fashion. In addition, multi-substituted
cyclopropane as well as bridged indolizine derivative via
disproportionation reaction and dearomatization reaction,
separately were also demonstrated in this protocol.
Modification of the optically active products to enlarge the
structural library, as well as mechanism study were also
involved. Further investigations of the asymmetric diverse
transformations of pyridinium ylide-based cycloadducts
are undergoing in our lab.
The authors declare no competing financial interest.
The authors acknowledgements financial support from the
National Natural Science Foundation of China (grant nos.
21890723 and 21772127).
(1) (a) Burke M. D.; Schreiber S. L. A Planning Strategy for
Diversity-Oriented Synthesis. Angew. Chem. Int. Ed. 2004, 43,
46-58. (b) Mortensen K. T.; Osberger T. J.; King T. A.; Sore H. F.;
Spring D. R. Strategies for the Diversity-Oriented Synthesis of
Macrocycles. Chem. Rev. 2019, 119, 10288-10317. (c) O'
Connor C. J.; Beckmann H. S.; Spring D. R. Diversity-Oriented
Synthesis: Producing Chemical Tools for Dissecting Biology.
Chem. Soc. Rev. 2012. 41, 4444-4456.
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website at http://pubs.acs.org.
Experimental procedures, full spectroscopic data for all new
compounds, and copies of H, 13C{1H} NMR, and HPLC spectra
(PDF)
1
(2) (a) Tan D. Diversity-Oriented Synthesis: Exploring the
Intersections between Chemistry and Biology. Nat. Chem. Biol.
2005, 1, 74-84. (b) Galloway W. R.; Isidro-Llobet A.; Spring D.
R. Diversity-Oriented Synthesis as a Tool for the Discovery of
Novel Biologically Active Small Molecules. Nat. Commun. 2010,
1, 80-92.
X-ray crystallographic data
Crystallographic data are deposited at the Cambridge
Crystallographic Date Centre (CCDC) as 1996521 (E4),
1953762 (E6), 1996927 (E9), 1961380 (E11), 1978182
(E'11), 1963783 (E12, for detail, see Table S5), 1978465
(E14), 1996542 (F1), 1954825 (G16), 1949148 (G20),
1953763 (K4), 1982957 (L3), 2002383 (D'), 1999904 [(S)-L3-
PiPr2/Yb(III)], 1957788 [(S)-L3-PiPr2/Sc(III)], 2004203 [(S)-
(3) Schreiber S. L. Target-Oriented and Diversity-Oriented
Organic Synthesis in Drug Discovery. Science 2000, 287, 1964-
1969.
(4) (a) Taylor R. D.; MacCoss M.; Lawson A. D. Rings in Drugs. J.
Med. Chem. 2014, 57, 5845-5859. (b) Vitaku E.; Smith D. T.;
Njardarson J. T. Analysis of the Structural Diversity,
Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J.
Med. Chem. 2014, 57, 10257-10274.
L3-PiPr2/Lu(III)],
2004841
[(R)-L3-PrPr2-4-Br/Lu(III)],
2006294 [(R)-L3-PrPr2-4-Br/Yb(III)] The data can be
obtained free of charge from the Cambridge Crystallographic
Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
All the data supporting the findings of this study are available
within the article and its Supporting Information, or from the
corresponding author on reasonable request.
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(5) (a) Nakao Y. Transition-Metal-Catalyzed C-H
equivalent Amount of K2Cr2O7 as an Efficient Oxidant Under
Base Free Conditions. RSC Adv. 2015, 5, 41255-41258. (b) Hu
H.; Feng J.; Zhu Y.; Gu N.; Kan Y. Copper Acetate Monohydrate:
1
2
3
4
5
6
7
8
Functionalization for the Synthesis of Substituted Pyridines.
Synthesis 2011, 2011, 3209-3219. (b) Fier P. S.; A Bifunctional
Reagent Designed for the Mild, Nucleophilic Functionalization
of Pyridines. J. Am. Chem. Soc. 2017, 139, 9499-9502. (c) Zhou
W.; Miura T.; Murakami M. Photocatalyzed ortho-Alkylation of
Pyridine N-oxides through Alkene Cleavage. Angew. Chem. Int.
Ed. 2018, 57, 5139-5142. (d) Kundu A.; Inoue M.; Nagae H.;
Tsurugi H.; Mashima K. Direct ortho-C-H Aminoalkylation of 2-
Substituted Pyridine Derivatives Catalyzed by Yttrium
Complexes with N,N'-Diarylethylenediamido Ligands. J. Am.
Chem. Soc. 2018, 140, 7332-7342. (e) Moon Y.; Lee W.; Hong,
S.; Visible-Light-Enabled Ortho-Selective Aminopyridylation of
Alkenes with N‑Aminopyridinium Ylides. J. Am. Chem. Soc.
2020, 142, 12420-12429.
A
Cheap but Efficient Oxidant for Synthesizing Multi-
substituted Indolizines from Pyridinium Ylides and Electron
Deficient Alkenes. RSC Adv. 2012, 2, 8637-8644. (c) Brioche J.;
Meyer C.; Cossy J. Synthesis of 2-Aminoindolizines by 1,3-
Dipolar Cycloaddition of Pyridinium Ylides with Electron-
Deficient Ynamides. Org. Lett. 2015, 17, 2800-2803.
(12) (a) Teodoro B. V. M.; Correia J. T. M.; Coelho F. Selective
Hydrogenation of Indolizines: An Expeditious Approach to
Derive Tetrahydroindolizines and Indolizidines from
Morita−Baylis−Hillman Adducts. J. Org. Chem. 2015, 80, 2529-
2538. (b) Ortega N.; Tang D. T. D.; Urban S.; Zhao D.; Glorius F.
Ruthenium-NHC-Catalyzed Asymmetric Hydrogenation of
Indolizines: Access to Indolizidine Alkaloids. Angew. Chem. Int.
Ed. 2013, 52, 9500-9503.
9
10
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) Kim E.; Lee Y.; Lee S.; Park S. B. Discovery, Understanding,
and Bioapplication of Organic Fluorophore: A Case Study with
an Indolizine-Based Novel Fluorophore, Seoul-Fluor. Acc.
Chem. Res. 2015, 48, 538-547.
(13) Hu R. B.; Sun S.; Su Y. Visible-Light-Induced Carbo-2-
pyridylation of Electron-Deficient Alkenes with Pyridinium
Salts. Angew. Chem. Int. Ed. 2017, 56, 10877-10880.
(7) (a) Singh G. S.; Mmatli E. E. Recent Progress in Synthesis
and Bioactivity Studies of Indolizines. Eur. J. Med. Chem. 2011,
(14) Zhang D.; Lin L. L.; Yang J.; Liu X. H.; Feng X. M.
Asymmetric Synthesis of Tetrahydroindolizines by Bimetallic
Relay Catalyzed Cycloaddition of Pyridinium Ylides. Angew.
Chem. Int. Ed. 2018, 57, 12323-12327. (b) Xu X.; Zavalij P. Y.;
Doyle M. P. Catalytic Asymmetric Syntheses of Quinolizidines
46, 5237-5257. (b) Sharma V.; Kumar V. Indolizine:
A
Biologically Active Moiety. Med. Chem. Res. 2014, 23, 3593-
3606. (c) Chen P.; Chaikuad A.; Bamborough P.; Bantscheff. M.;
Bountra C.; Chung C.; Fedorov O.; Grandi P.; Jung D.; Lesniak R.;
Lindon M.; Mü ller S.; Philpott M.; Prinjha R.; Rogers C.;
by
Dirhodium-Catalyzed
Dearomatization
of
Selenski C.; Tallant C.; Werner T.; Willson T. M.; Knapp S.;
Drewry D. H..; Discovery and Characterization of GSK2801, A
Selective Chemical Probe for the Bromodomains BAZ2A and
BAZ2B. J. Med. Chem. 2016, 59, 1410-1424.
Isoquinolinium/Pyridinium Methylides--the Role of Catalyst
and Carbene Source. J. Am. Chem. Soc. 2013, 135, 12439-
12447.
(15) (a) Liu X. H.; Lin L. L.; Feng X. M. Chiral N,N'-Dioxides:
New Ligands and Organocatalysts for Catalytic Asymmetric
Reactions. Acc. Chem. Res. 2011, 44, 574-587. (b) Liu X. H.; Lin
L. L.; Feng X. M. Chiral N,N’-Dioxide Ligands: Synthesis,
Coordination Chemistry and Asymmetric Catalysis. Org. Chem.
Front. 2014, 1, 298–302. (c) Liu X. H.; Zheng H. F.; Xia Y.; Lin L.
L.; Feng X. M. Asymmetric Cycloaddition and Cyclization
Reactions Catalyzed by Chiral N,N'‑Dioxide-Metal Complexes.
Acc. Chem. Res. 2017, 50, 2621-2631. (d) Liu X. H.; Dong S. X.;
Lin L. L.; Feng X. M. Chiral Amino Acids-Derived Catalysts and
Ligands. Chin. J. Chem. 2018, 36, 791-797.
(8) (a) Allgauer D. S.; Mayer P.; Mayr H. Nucleophilicity
Parameters of Pyridinium Ylides and Their Use in Mechanistic
Analyses. J. Am. Chem. Soc. 2013, 135, 15216-15224. (b) Li F.;
Chen J.; Hou Y.; Li Y.; Wu X. Y.; Tong X. 1,3-Dipolar
Cycloadditions of 4-Acetoxy Allenoates: Access to 2,3-
Dihydropyrazoles, 2,3-Dihydroisoxazoles, and Indolizines. Org.
Lett. 2015, 17, 5376-5379. (c) Day J.; Uroos M.; Castledine R.
A.; Lewis W.; McKeever-Abbas B.; Dowden J. Alkaloid Inspired
Spirocyclic Oxindoles from 1,3-Dipolar Cycloaddition of
Pyridinium Ylides. Org. Biomol. Chem. 2013, 11, 6502-6509. (d)
Day J.; McKeever-Abbas B.; Dowden J. Stereoselective
Synthesis of Tetrahydroindolizines through the Catalytic
Formation of Pyridinium Ylides from Diazo Compounds.
Angew. Chem. Int. Ed. 2016, 55, 5809-5813.
(16) (a) He X. L.; Zhao H. R.; Song X.; Jiang B.; Du W.; Chen Y. C.
Asymmetric Barton-Zard Reaction to Access 3‑Pyrrole-
Containing Axially Chiral Skeletons. ACS Catal. 2019, 9, 4374-
4381. (b) Hu Y. L.; Wang Z.; Yang H.; Chen J.; Wu Z. B.; Lei Y.;
Zhou L. Conversion of Two Stereocenters to One or Two Chiral
Axes: Atroposelective Synthesis of 2,3-Diarylbenzoindoles.
Chem. Sci. 2019, 10, 6777-6784. (c) Zheng S. C.; Wang Q.; Zhu J.
P. Catalytic Kinetic Resolution by Enantioselective
Aromatization: Conversion of Racemic Intermediates of the
Barton-Zard Reaction into Enantioenriched 3-Arylpyrroles.
Angew. Chem. Int. Ed. 2019, 58, 9215-9219. (d) Xia W.; An Q. J.;
Xiang S. H.; Li S. Y.; Wang Y. B.; Tan B. Chiral Phosphoric Acid
Catalyzed Atroposelective C-H Amination of Arenes. Angew.
Chem. Int. Ed. 2020, 59, 6775-6779.
(9) Allgäuer D. S.; Mayr H. One-Pot Two-Step Synthesis of 1-
(Ethoxycarbonyl)indolizines via Pyridinium Ylides. Eur. J. Org.
Chem. 2013, 28, 6379-6388.
(10) (a) Wang Q. F.; Song. X. K.; Chen J.; Yan C. G. Pyridinium
Ylide-Assisted One-Pot Two-Step Tandem Synthesis of
Polysubstituted Cyclopropanes. J. Comb. Chem. 2009, 11,
1007-1010. (b) Kanomata N.; Sakaguchi R.; Sekine K.;
Yamashita S.; Tanaka H. Enantioselective Cyclopropanation
Reactions with Planar-Chiral Pyridinium Ylides: A Substituent
Effect and a Remote Steric Effect. Adv. Synth. Catal. 2010, 352,
2966-2978. (c) Abaszadeh M.; Seifi M. Ultrasound-Assisted
1,3-Dipolar Cycloaddition and Cyclopropanation Reactions for
the Synthesis of Bis-indolizine and Bis-cyclopropane
Derivatives. Org. Biomol. Chem. 2014, 12, 7859-7863. (d)
Anand A.; Yenagi J.; Tonannavar J.; Kulkarni M. V.
Cyclopropanes in Water: A Diastereoselective Synthesis of
Substituted 2H-chromen-2-one and Quinolin-2(1H)-one
linked Cyclopropanes. Green Chem. 2016, 18, 2201-2205.
(17) (a) Katritzky A. R.; Grzeskowiak N. E.; Alvarez-Builla J.
Preparation of Tetrahydroindolizines from Pyridinium and
Isoquinolinium Ylides. J. Chem. Soc. Perkin Trans. 1981, 1,
1180-1185. (b) Tsuge O.; Kanemasa S.; Takenaka S.
Stereochemical Study on 1,3-Dipolar Cycloaddition Reactions
of Heteroaromatic N-Ylide with Symmetrically Substituted cis
and trans Olefins. Bull. Chem. Soc. Jpn. 1985, 58, 3137-3157.
(18) (a) Kakehi A.; Ito S. Preparation of Stable 2,3-
Dihydroindolizines by the Reactions of Pyridinium Methylides
(11) (a) Wang C.; Hu H.; Xu J.; Kan W. One-Pot Synthesis of
Indolizine via 1,3-Dipolar Cycloaddition Using
a Sub-
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Page 12 of 13
Various Acrylates. Bull. Chem. Soc. Jpn. 1974, 47, 938-941. (b)
1
2
3
4
Han Y.; Hou H.; Fu Q.; Yan C. G. One-Pot Two-Step Tandem
Reactions for Selective Synthesis of Pyrrolo[2,1-
a]isoquinolines and Dihydro-, Tetrahydro-derivatives.
Tetrahedron 2011, 67, 2313-2322.
(19) CCDC 1996521 (E4); CCDC 1953762 (E6); CCDC
1996927 (E9); CCDC 1961380 (E11); CCDC 1978182 (E'11)
CCDC 1978465 (E14); CCDC 1996542 (F1) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
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15
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18
19
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21
22
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24
25
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27
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32
33
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35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(20) (a) Li J.; Lin L. L.; Hu. B. W.; Zhou P. F.; Huang T. Y.; Liu X.
H.; Feng X. M. Gold(I)/Chiral N,N'-Dioxide-Nickel(II) Relay
Catalysis
for
Asymmetric
Tandem
Intermolecular
Hydroalkoxylation/Claisen Rearrangement. Angew. Chem. Int.
Ed. 2017, 56, 885-888. (b) Xu C. R.; Wang K. X.; Li D. W.; Lin L.
L.; Feng X. M. Asymmetric Synthesis of Oxa-Bridged
Oxazocines through a Catalytic Rh(II)/Zn(II) Relay [4+3]
Cycloaddition Reaction. Angew. Chem. Int. Ed. 2019, 58,
18438-18442. (c) Chen Y. S.; Liu Y.; Li Z. J.; Dong S. X.; Liu X. H.;
Feng X. M. Tandem Insertion-[1,3]-Rearrangement: Highly
Enantioselective Construction of α-Aminoketones. Angew.
Chem. Int. Ed. 2020, 59, 8052-8056. (d) Hu B. W.; Zhang X. Y.;
Mo Y. H.; Li J. Z.; Lin L. L.; Liu X. H.; Feng X. M. Catalytic
Asymmetric Tandem Cycloisomerization/[5+2] Cycloaddition
Reaction
of
N-Aryl
Nitrone
Alkynes
with
Methyleneindolinones. Org. Lett. 2020, 22, 1034-1039.
(21) (a) Wender P. A.; Rawlins D. B. Toward the Synthesis of
the Taxol C, D Ring System: Photolysis of a-Methoxy Ketones.
Tetrahedron 1992, 48, 7033-7048. (b) Mal J.; Venkateswaran
R. V. Convenient Synthesis of an A-Ring Aromatic
Trichothecene Analog. J. Org. Chem. 1998, 63, 3855-3858. (c)
Hickford P. J.; Baker J. R.; Bruce I.; Booker-Milburn K. I. Acid-
Catalyzed Rearrangement of Fused Alkylideneoxetanols. Org.
Lett. 2007, 9. 4681-4684. (d) Alvarez D. D.; Leon E. I.; Kennedy
A. R.; Riesco. F. C.; Suarez E. Sequential Norrish Type II
Photoelimination and Intramolecular Aldol Cyclization of 1,2-
Diketones in Carbohydrate Systems: Stereoselective Synthesis
of Cyclopentitols. Angew. Chem. Int. Ed. 2008, 47, 8917-8919.
(22) CCDC 1954825 (G16); CCDC 1949148 (G20); CCDC
1953763 (K4); CCDC 1982957 (L3); CCDC 2002383 (D');
CCDC 1999904 [L3-PiPr2/Yb(III)]; CCDC 1957788 [L3-
PiPr2/Sc(III)] contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
(23) (a) Shibata T.; Fujiwara R.; Ueno Y. Cationic Platinum-
Catalyzed Etherification by Intra- and Intermolecular
Dehydration of Alcohols. Synlett 2004, 2005, 152-154. (b)
Jiang X.; London E. K.; Morris D. J.; Clarkson G. J.; Wills M. Gold-
Catalysed Cyclic Ether Formation from Diols. Tetrahedron
2010, 66, 9828-9834. (c) Chithiravel R.; Rajaguru K.;
Muthusubramanian S.; Bhuvanesh N. Characterization of the
Major Isomers of Substituted Tetrahydro-2H-pyrans from
1,3,5-Triarylpentane-1,5-Diols by p-Toluenesulfonic Acid
Treatment. Journal of Molecular Structure 2018, 1156, 684-
689. (d) Jia W. Q.; Xi Q. M.; Liu T. Q.; Yang M. J.; Chen Y. H.; Yin
D. L.; Wang X. J. One-Pot Synthesis of O-Heterocycles or Aryl
Ketones Using an InCl3/Et3SiH System by Switching the
Solvent. J. Org. Chem. 2019, 84, 5141-5149.
(24) Lee A.; Betori R. C.; Crane E. A.; Scheidt K. A. An
Enantioselective Cross-Dehydrogenative Coupling Catalysis
Approach to Substituted Tetrahydropyrans. J. Am. Chem. Soc.
2018, 140, 6212-6216.
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