Asymmetric catalytic [4+3] cycloaddition ofortho-quinone methides with oxiranes

Article abstract of DOI:10.1039/d1cc00262g

Catalytic enantioselective [4+3] cycloaddition reaction betweeno-quinone methides and oxiranes was achieved by using a chiralN,N′-dioxide/Tb^IIIcomplex as the catalyst, affording medium-sized hydrodioxepine derivatives in high yields (up to 99%)

Full text of DOI:10.1039/d1cc00262g

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Asymmetric catalytic [4+3] cycloaddition of
ortho-quinone methides with oxiranes†
Cite this: Chem. Commun., 2021,
57, 3018
Qingfa Tan,
Han Yu,
Yao Luo,
Fenzhen Chang,
*
Xiaohua Liu,
*
Received 15th January 2021,
Accepted 8th February 2021
Yuqiao Zhou * and Xiaoming Feng
DOI: 10.1039/d1cc00262g
rsc.li/chemcomm
Catalytic enantioselective [4+3] cycloaddition reaction between synthesize medium-sized heterocycles has yet to be explored.
o-quinone methides and oxiranes was achieved by using a chiral One alternative example is the use of 1-alkynyl oxiranyl ketones
N,N0-dioxide/TbIII complex as the catalyst, affording medium- as the four-components in the presence of a gold(I) catalyst, to
sized hydrodioxepine derivatives in high yields (up to 99%) with prepare furo[d]dioxepine derivatives (Scheme 1b).9 In connection
good to excellent diastereo-(up to 94: 6 dr) and enantioselectivities with the synthetic value of functionalized stereogenic benzo[b]
(up to 97% ee). The topographic steric maps and distribution of the oxepines and O,O-acetal moieties,10 we expect to explore new
buried volume (% VBur) of the catalysts via Cavallo’s SambVca 2 tool asymmetric catalytic [4+3] cycloaddition using o-QMs as the
were collected to effectively represent the chiral pocket of metal four-species, and epoxides with electron-withdrawing substituents
complexes of chiral N,N0-dioxides.
as the carbonyl ylide species (Scheme 1c). Herein, we reported
the ring-opening/[4+3] cycloaddition reaction towards 4,5-dihy-
Asymmetric catalytic [4+3] annulation provides a direct and drobenzo[d][1,3]dioxepine derivatives through a chiral rare earth
efficient strategy for the construction of seven-membered metal complex catalyst. For this, the topographic steric maps11 to
carbo- and hetero-rings.1 A number of processes have been characterize the catalytic pocket of chiral metal complexes of Feng
discovered using either cyclic or acyclic dienes with different N,N0-dioxides12 bearing different metal ions or subunits of the
three-atom synthons to yield such medium-sized cycles or ligands were used. It provides a straightforward comparison of the
bridged cycles.2 Oxygen-based seven-membered cycles, such ability of activation and enantiocontrol of the chiral Lewis acids
as benzo[b]oxepines, and e-lactones, are present in several upon the variation of catalyst moieties.
biologically important natural products or synthetic
In the initial investigation, o-QM 1a and epoxide 2a were
compounds.3 ortho-Quinone methides (o-QMs) have emerged chosen as the model reaction substrates to optimize the
as a type of useful oxa-diene synthon to deliver various chiro-
mane or benzo[b]oxepine derivatives.4 Nevertheless, the related
enantioselective [4+3] cycloadditions of o-QMs are limited
(Scheme 1a), and the representative examples included the annu-
lations with enals catalyzed by N-heterocyclic carbene,5 with cyclic
azomethine imines or 2-indolylmethanols by Brønsted acid
catalysts,6 with isomu¨nchnones generated from diazoimides.7
Oxiranes are a special reactant that could generate a transient
carbonyl ylide via C–C bond cleavage by undergoing cycloaddi-
tions; in addition to this, a number of asymmetric [3+2] annula-
tions to generate five-membered furan or dioxolane derivatives
have been realized,8 but the related [4+3] cycloaddition to
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, China.
E-mail: liuxh@scu.edu.cn, yqzhou@scu.edu.cn, xmfeng@scu.edu.cn
† Electronic supplementary information (ESI) available: 1H, 13C{1H} and 19F{1H}
NMR, HPLC spectra, CD spectra (PDF). X-Ray crystallographic data for 3aa and 5a
(CIF). CCDC 1997724 and 2026588. For ESI and crystallographic data in CIF or
Scheme 1 Representative examples of [4+3] cycloadditions about o-QMs.
other electronic format see DOI: 10.1039/d1cc00262g
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Table 1 Optimization of the reaction conditionsa
20 dr and 92% ee in the presence of 20 mol% of NaBArF4 as the
additive (entry 13). Finally, reducing the temperature from 35 1C to
20 1C resulted in the full formation of the desired product in 92 : 8
dr and 96% ee (entry 14).
Having established the acceptable reaction conditions,
we evaluated the generality of this reaction. Firstly, dimethyl
3-phenyloxirane-2,2-dicarboxylates with alkyl substitution at
different positions of the phenyl group were tolerable, delivering
the products (3ab–3ad) with high enantioselectivities and good
diastereoselectivities. And 1-naphthyl or 2-naphthyl substituted
oxiranes afforded the corresponding products 3ae and 3af with
better enantioselectivities. Nevertheless, when the substituent
was changed into the electron-withdrawing group, the desired
product 3ag was obtained in reduced yield (67%) with moderate
enantioselectivity (74% ee). The substrate generality was next
surveyed using ethyl diester-containing 3-aryloxiranes. Both
electron-withdrawing and -donating substituents on the aryl group
of oxiranes were tolerable, yielding the products (3ah–3au) in
acceptable yields (18–92%) with good diastereoselectivities (78 :
22–94 : 6) and moderate to high enantioselectivities (44–97% ee).
However, when the ortho-chloro-substituted oxirane substrate 2r
was used, the reactivity and enantioselectivity decreased sharply
(3ar, 44% ee after 168 h). Disubstituted oxirane reacted well,
affording the corresponding product 3as in 67% yield with 90%
Entry
Metal salt
Ligand
Yieldb (%)
drc
eec (%)
1
2
3
4
5
6
7
8
Ni(OTf)2
Sc(OTf)3
Y(OTf)3
L3-RaPr2
L3-RaPr2
L3-RaPr2
L3-RaPr2
L3-RaPr2
L3-RaPr2
L3-PrPr2
L3-PrPr3
L3-PiPr2
L3-PiPr3
L3-PiPr3
L3-PiPr3
L3-PiPr3
L3-PiPr3
n.r.
n.r.
18
30
38
30
96
99
65
62
95
99
99
99
—
—
—
—
7
0
15
3
37
28
36
66
72
87
92
96
70 : 30
80 : 20
80 : 20
73 : 27
90 : 10
85 : 15
87 : 13
88 : 12
88 : 12
83 : 17
80 : 20
92 : 8
Nd(OTf)3
Tb(OTf)3
Yb(OTf)3
Tb(OTf)3
Tb(OTf)3
Tb(OTf)3
Tb(OTf)3
Tb(OTf)3
Tb(OTf)3
Tb(OTf)3
Tb(OTf)3
9
10
11d
12e
13f
14fg
a
Unless otherwise noted, all reactions were carried out with ligand/metal
salt (1: 1, 10 mol%), 1a (0.12 mmol), 2a (0.10 mmol) and 4 Å MS (60 mg)
in CH2Cl2 (1.0 mL) at 35 1C under N2 atmosphere for 24 h. Isolated
b
c
yield. Determined by HPLC analysis on a chiral stationary phase. ee and good diastereoselectivity (94 : 6 dr). Electron-donating meta-
d
e
f
With LiNTf2 (10 mol%). With NaBArF4 (10 mol%). With NaBArF4
alkyloxy substituents had no obvious effect on the stereoselectivity
(3at and 3au), but the reactivity dropped if a phenoxy substituent
was installed, which might be due to the steric hindrance. And
g
(20 mol%). At 20 1C.
reaction conditions (Table 1). At first, various metal salts were 4-phenyl substituted oxiranes afforded the corresponding product
investigated by coordinating with chiral N,N0-dioxide L3-RaPr2 3av with good enantioselectivity. No reaction occurred if bisphenyl-
(Table 1, entries 1–6). When Ni(OTf)2 or Sc(OTf)3 was used as methanones substituted oxirane was subjected to the standard
the metal salt, no reaction occurred (entries 1–2). Lanthanide reaction conditions, but the desired [4+3] adduct 3aw could be
metal salts from Nd(OTf)3 to Yb(OTf)3, and Y(OTf)3, whose ionic isolated in 43% yield and 93% ee with 91 : 9 dr by the use of the
radii ranged from 0.87–0.98 Å, could promote the reaction with Ni(NTf2)2/L3-RaPr2 complex catalyst instead. Also, heteroaromatic
promising isolated yield, but other metal salts with longer or ring-substituted 2x can achieve the desired product 3ax with good
shorter ionic radii were sluggish in this reaction (see Table S1 results. ortho-QM 1b underwent the reaction to yield the product 3ba
in ESI,† for details). In the presence of Tb(OTf)3, the desired with comparable results. Unfortunately, if the diene was extended to
product 3aa was isolated in 38% yield with 80 : 20 dr, 15% ee 2-aminobenzyl alcohol precursor, only a trace amount of the seven-
(entry 5). Subsequently, further investigation of the ligands membered benzo[d][1,3]oxazepane 3ca was detected. When salicyla-
showed that the L-proline-derived L3-PrPr2 and L-pipecolic dimine 1d was used as the substrate, only moderate yield and
acid-derived L3-PiPr2 could give better results than the L-ramipril- enantioselectivity (43% yield, 51% ee and 94 : 6 dr) could be obtained
derived L3-RaPr2 (entries 5, 7, and 9). Steric hindrance of the amide by the use of the Tm(OTf)3/L3-PrPr2 complex catalyst.
substituents on the ligand had a significant effect on the outcomes
To test the synthetic potential of this reaction, a gram-scale
of the reaction. Increasing the steric hindrance of the amide synthesis of 3aa was carried out. As shown in Scheme 2, o-QM
moiety, such as L3-PiPr3 can get better enantioselectivity (entry 1a reacted smoothly with the substrate 2a, yielding the corres-
10). Nevertheless, the ligand L3-PrPr3 bearing the same amide ponding [4+3] cycloaddition product 3aa in 99% yield with
subunit and L-proline backbone led to high reactivity but poor slightly lower 88 : 12 dr and 96% ee (Scheme 3a). Upon treating
enantioselectivity (99% yield with 85 : 15 dr and 28% ee; entry 8). the product with LiCl (2.1 equiv.) and H2O (1.1 equiv.) in DMSO
The reaction performed well in chlorinated solvents, whereas, the at 130 1C, decarboxylated derivative 4a could be obtained in
reactions in other commonly used solvents were inert. The addition moderate diastereoselectivity (65 : 35 dr) with maintained enan-
of molecular sieves was necessary (see Tables S3 and S4 in the ESI,† tioselectivity (Scheme 3b). AlCl3 promoted acetal cleavage/
for more details). The additives might accelerate the ring-opening C-alkylation rearrangement of 3aa, affording the spirocyclic
of oxirane, readily generating the carbonyl ylide to be captured by product (3S,4S,5R)-5a in moderated yield and slight loss of
the chiral catalyst. Using an additive such as LiNTf2 or NaBArF4 was enantioselectivity, but nearly only one diastereoisomer bearing
beneficial to both the yield and enantioselectivity (entries 11–13), three vicinal stereogenic centers was obtained within a short
and the desired product could be obtained in 99% yield with 80: reaction time (Scheme 3c).
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topographical steric maps (Fig. 1 and 2). Percent buried
volumes (% VBur) of the catalysts discussed in Table 1 were
collected, highlighting a difference in steric bulkiness arising
from the metal centers (Fig. 1) and the subunits of the chiral
ligands (Fig. 2). Complexes of metal ions, such as Sc(III) (map a)
and Ni(II) (map b) possessing smaller ion radii, display more
compact space around the coordination sphere in comparison
with the rare-earth metal-based ones (map c–f). In view of the
steric hindrance of o-QM and the epoxide reactants, as well as
the seven-membered product, we proposed that the signifi-
cantly more crowded space might be accounted for by the
negative reactivity of the Sc(III) complex and Ni(II) complex in
this case, which makes the reactants less accessible to the Lewis
acid center. The excessive open-space in the complex, such as
the Nd(III) catalyst (map d), is disadvantageous to the
enantioselectivity.
The maps illustrate that different catalytic pockets could be
fine-tuned by either the metal ion or the subunits of the chiral
ligands (Fig. 1 and 2). In comparison with map g and h, there is
an obviously occupied area in the southwest of the steric map e
of the L3-RaPr2/Tb(III) catalyst, contributed by the amide sub-
stituent and amino acid backbone on the left side (Fig. 3),
which seems to be less favorable in the enantiocontrol of
the standard reaction. In contrast, as shown in map i of thew
L3-PiPr3-based catalyst versus map h of the L3-PiPr2-based
catalyst, the bulges in the northwest position hosted by the
isopropyl substituent seem important in the improvement of
the stereocontrol.
Based on the general coordination manner of chiral
N,N0-dioxide–metal complexes,14 for the absolute configuration of
the product,15 we proposed a possible transition state for the
generation of an optically active hydrodioxepine derivative. As
shown in Fig. 3, chiral N,N0-dioxide serves as a tetradentate ligand
to coordinate with Tb(III) with four oxygen atoms, and the chiral
catalyst adapts a square-antiprism geometry with a coordination
number of eight. Two solvent molecules were substituted by the
carbonyl ylide species of DA oxirane upon the coordination with the
two ester groups. The aryl group of the ylide prefers to orientate
northeast to avoid the steric hindrance from the right amide.
Meanwhile, ortho-quinone methide locates nearside, and the oxy-
gen attacks the Re-face of the ylide. The open space in the
Scheme 2 Substrate scope of the asymmetric [4+3] cycloaddition reac-
tion.a a All reactions were carried out with Tb(OTf)3/L3-PiPr3 (1 : 1, 10 mol%),
1 (0.12 mmol), 2 (0.10 mmol), 4 Å MS (60 mg) and NaBArF4 (20 mol%) in
DCM (1.0 mL) at 20 1C. Isolated yield, ee value was determined by chiral
HPLC analysis, and dr value was determined by 1H NMR. b At 35 1C.
c At 30 1C. d With 10 mol% Ni(NTf2)2 and L3-RaPr2.
Scheme 3 Scale-up synthesis of 3aa and further transformations of 3aa.
In order to understand steric effects on the reactivity and
enantioselectivity in the chiral N,N0-dioxide–metal catalyzed
reaction, we choose Cavallo’s SambVca 2 Web tool13 to generate Fig. 1 Steric map of metal complexes of chiral ligand L3-RaPr2.
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Notes and references
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Fig. 2 Steric map of Tb(III) complexes of various chiral ligands.
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Fig. 3 Possible transition state.
southwest area allows the ylide nucleophilic approach to the Si-face
of methide. [4+3] cycloaddition occurs enantioselectively to yield
the final (S,S)-configured dihydrobenzo[d][1,3]dioxepine as the
major product.
In summary, we have successfully developed a highly efficient
asymmetric [4+3] cycloaddition reaction between o-QMs and
oxiranes by using a chiral N,N0-dioxide/TbIII complex. Besides,
the further transformation of products enabled the generation of
spirocyclic products bearing three vicinal stereogenic centers. We
utilized Web application SambVca 2 to generate the topographic
steric map characterizing the chiral pocket of the N,N0-dioxide
ligand around the metal ions. A possible transition state was
proposed to elucidate the reaction process and chiral induction.
We appreciate the National Natural Science Foundation of
China (21890723, and 21625205) for financial support. The
authors give thanks to Dr Luigi Cavallo (KAUST) and Dr
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https://www.molnac.unisa.it/OMtools/sambvca2.0/.
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¨
Emanuel Hupf (Freie Universitat Berlin) for the help in the
application of the SambVca 2 suite.
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15 CCDC 1997724 (3aa) and 2026588 (5a) contain the supplementary
crystallographic data†.
Conflicts of interest
There are no conflicts to declare.
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