Enantioselective Synthesis of 3-Substituted Cyclobutenes by Catalytic Conjugate Addition/Trapping Strategies

Article abstract of DOI:10.1002/anie.201913825

A copper-catalyzed tandem process to generate chiral cyclobutene derivatives has been developed. It is based on an enantioselective conjugate addition or reduction of a cyclobutenone and sequential trapping with a chlorophosphate in a one-pot process. These phosphates are stable under mildly acidic conditions and serve as good electrophiles in Negishi coupling reactions.

Full text of DOI:10.1002/anie.201913825

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Accepted Article
Title: Enantioselective Synthesis of 3-Substituted Cyclobutenes via
Catalytic Conjugate Addition/Trapping Strategies
Authors: Changxu Zhong, Yingchao Huang, Haocheng Zhang, Qiang
Zhou, Yu Liu, and Ping Lu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913825
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10.1002/anie.201913825
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Enantioselective Synthesis of 3-Substituted Cyclobutenes via
Catalytic Conjugate Addition/Trapping Strategies
Changxu Zhong+, Yingchao Huang+, Haocheng Zhang, Qiang Zhou, Yu Liu, and Ping Lu*
metal catalyzed conjugate reduction or addition to
Abstract: The copper-catalyzed tandem process to access chiral
cyclobutenones would afford achiral cyclobutanone, when in-situ
generated metal enol intermediate (M-1) was quenched with
protonic solvent (Scheme 1b). However, if this enol intermediate
cyclobutene derivatives has been developed, enabled by
enantioselective conjugate addition or reduction of cyclobutenones,
and sequential trapping with chlorophosphate in one pot. These
M-1 was trapped with electrophile,
a chiral cyclobutene
phosphates are stable to mild acidic conditions and serve as good
electrophiles for Negishi-coupling reactions.
intermediate with a tri- or tetrasubstituted chiral center and a
functionalized alkene could be produced, which is then
amenable for further derivatization.
Cyclobutane motifs, due to high torsion strains and unique
conformation properties, are important building blocks in organic
synthesis and medicinal chemistry.[1] Some representative drugs
or drug candidates with trisubstituted cyclobutane ring are
depicted in Figure 1.[2] Although this area has received
Honda
, stoichiometric chiral lithium amide approach
a.
A-1
n-BuLi,
(1.3 equiv)
O
TESO
TESCl, THF, 100 o
C
Ph
N
H
Ph
67% yield, 92% ee
A-1
Ph
Ph
considerable
attention,
enantioselective
synthesis
of
A-2
, TESCl
n-BuLi,
t-Bu Ph
NMe
O
TESO
THF/HMPA, 100 o
C
cyclobutanes is still an attractive yet challenging topic for
synthetic community.[3,4] Functionalization of four-membered
carbocycles continues to attract growing interests.[5]
N
N
H
68% yield, 78% ee
A-2
Ph
Ph
this work
b.
, catalytic conjugate addition/trapping approach
H
O
protonic
quench
achiral
chiral
R
R1
OM
O
TM, L*
Si-H or
R2-M
R
OFG
then FG-X
trapping
R1
R1
M-1
R = H, or R2
R
Figure 1. Selected drugs or drug candidates containing the trisubstituted
cyclobutane subunit.
R1
.
Scheme 1. Enantioselective synthesis of cyclobutene derivatives.
Enantioselective deprotonation of meso or prochiral cyclic
ketones using chiral lithium amides as the base provided a
straightforward approach to access enantiomerically enriched
enol intermediates.[6] In 1993, Honda and co-workers developed
an elegant enantioselective desymmetrization of 3-substituted
cyclobutanone to access chiral silyl enol ether in the synthesis of
lignin lactones (Scheme 1a).[7] Using stoichiometric lithium
(S,S’)-α,α’-dimethyldibenzylamide (Li-A-1) as the base at ‒100
oC, the reaction of 3-phenyl cyclobutanone provided
corresponding silyl enol ether in good yield and high
enantioselectivity (67% yield, 92% ee). However, in the case of
3,3-disubstituted cyclobutanone, the selectivity is only moderate
under optimal conditions (A-2, 78% ee). Recently,
enantioselective synthesis of cyclobutene derivatives has been
reported via [2+2]-cycloaddition approaches.[4a-c] To the best of
our knowledge, functionalization of cyclobutenones is a far less
studied strategy.[4d] In line with our continued interest in
desymmetrization of cyclobutanones,[8] we planned to access
these chiral cyclobutene derivatives with higher stability and
efficiency in a catalytic process. We proposed that the transition-
3-Substituted cyclobutenones were readily prepared using
Danheiser’s two-step procedure as depicted in Scheme 2.[9]
[2+2]-Cycloaddition of alkyne and dichloroketene, followed by
reductive dechlorination afforded desired cyclobutenone
smoothly.
1
Scheme 2. Preparation of 3-substituted cyclobutenone 1.
With these thoughts in mind, we commenced our studies with
copper-catalyzed 1,4-conjugate reduction of 3-substituted
cyclobutenones. Pioneered by Brunner and Stryker,[10] the Cu-H
catalyzed enantioselective hydrofunctionalization of carbonyl
compounds and alkenes has evolved dramatically, and a wide
array of enantiomerically enriched substrates could be
synthesized via various processes.[11,12] We postulated that
exposure of cyclobutenone 1a to a copper catalyst and silane
would afford the corresponding silyl enol ether M-2, then
[*]
C. Zhong, H, Zhang, Q, Zhou, Prof. Dr. P. Lu
Department of Research Center for Molecular Recognition and
Synthesis, Department of Chemistry, Fudan University
220 Handan Lu, Shanghai 200433, P. R. China
E-mail: plu@fudan.edu.cn
subsequent
lithium-silicon
exchange
and
diphenyl
chlorophosphate trapping would provide cyclobutenyl phosphate
2a. We reasoned that cyclobutenyl phosphate would be more
stable than the corresponding silyl enol ether under mild acidic
conditions. In addition, cyclobutenyl phosphate would serve as a
good precursor for further cross-coupling reactions. Indeed, after
screening several privileged ligands, we found that Josiphos
ligands gave better results, as summarized in Table 1. The
optimal conditions were achieved using (R, Sp)-Josiphos (L-5)
Homepage: http://rcmrs.fudan.edu.cn/Data/View/173
Y, Huang, Prof. Dr. Y. Liu
College of Chemistry and Life, Advanced Institute of Materials
Science, Changchun University of Technology, Changchun 130012,
P. R. China
Supporting information for this article is given via a link at the end of
the document.
[+]
These authors contributed equally to this work.
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10.1002/anie.201913825
Angewandte Chemie International Edition
COMMUNICATION
as ligand (59-61% yield, 93-95% ee). Lower temperature (‒20
oC) gave slightly better selectivity, and THF was chosen as
solvent for convenience.
reaction of 3-phenyl cyclobutenone (2o) performed as well when
L-4 was used (31% yield, 90% ee) albeit in a lower yield. In
addition, product 2p with alkene functional group could also be
obtained in good yield and ee (58% yield, 95% ee). However,
1,4-reduction of 2,3-dibutyl cyclobutenone did not work under
current conditions.
Table 1. Optimization of 1,4-reduction/trapping reaction of 1a.[a]
Table 3. Optimization of 1,4-addition/trapping reaction of 1b.[a]
O
OPh
OPh
P
O
MO
Cu(OTf)2, L*, Et2Zn
PhCH3, 78 o
ClP(O)(OPh)2
O
Et
THF, 78 to 0 o
C
C
Et
R
R
R
1b
, R = CH2CH2CH2Ph
M-3
3b
O
O
O
O
P
N
P
N
P N
O
O
L-7
L-8
L-9
52%, 57% ee
47%, 39% ee
51%, 50% ee
OMe
OMe
Ph
O
Ph
O
Me
Me
Me
Me
O
P
N
P
N
P N
O
O
O
Ph
Ph
[a] 1a (0.5 mmol), CuCl (5 mol%), L* (5 mol%), Ph2SiH2 (0.54 equiv) in PhCH3,
then MeLi (1.25 equiv), THF, followed by ClPO(OPh)2 (2 equiv), see SI for
more details. [b] THF was used as solvent. [c] at ‒20 oC.
L-10
52%, 95% ee
L-11
47%, 31% ee
L-12
60%, -3% ee
Guided by these optimized experiments, we investigated
substrate scope of cyclobutenone 1 (Table 2). Under standard
conditions, substrates with diverse 3-alkyl groups afforded the
corresponding cyclobutene derivatives in high yields and in the
range of 94-96% ee, including 3-aryl or cyclohexyl propyl (2b-
2e), 3-aryl or cyclohexyl ethyl (2f-2h), and linear aliphatic
substituents (2i-2j). Substrates with a variety of functional
groups, for instance, chlorobutyl (1k), methoxypropyl (1l) and
benzyloxyethyl (1m), were well tolerated, producing the
expected products in good enantioselectivity uneventfully (2k-
2m, 95-96% ee). 3-Cyclopropyl group (2n) was also compatible
when diethoxymethylsilane was used in lieu of Ph2SiH2. And the
[a] 1b (0.5 mmol), Cu(OTf)2 (2.5 mol%), L* (2.5 mol%), ZnEt2 (1.25 equiv) in
PhCH3, then ClPO(OPh)2 (2 equiv) and THF, see SI for more details.
Next, we investigated 1,4-conjugate addition to cyclobutenone
1. Asymmetric 1,4-conjugate addition is one of the most
fundamental C−C or C−heteroatom construction processes in
organic synthesis. Since the pioneering reports on copper-
catalyzed enantioselective Michael addition by Alexakis and
Feringa,[13] significant progress has been achieved with the
development of chiral ligands and organometallic reagents.[14]
However, installing chiral quaternary centers via 1,4-addition of
zinc reagents is still underdeveloped.[15,16] Here we assumed that
treatment of enol intermediate M-3 in one-pot with electrophile
Table 2. Substrate scope of 1,4-reduction/trapping reaction 1.[a]
would furnish 3,3-disubstitued cyclobutene derivative
3
containing a chiral quaternary center. We started our studies
with the reaction of 1b, choosing diethyl zinc as nucleophilic
reagent and diphenyl chlorophsphate as electrophile. Gladly,
due to high strain of cyclobutenone, conjugate addition took
place at ‒78 oC smoothly. We screened several privileged
ligands and the results are summarized in Table 3.
Phosphoramidite ligands gave better results than Josiphos
ligands (see supporting information for more details), and the
optimal results were achieved when (S,R,R)-L-10 was used as a
chiral ligand and Cu(OTf)2 as copper source (52% yield, 95%
ee). Of note, (S,S,S)-L-11 and L-12 gave poor selectivity (3-31%
ee).
We further examined the substrate scope of the above 1,4-
addition/trapping reaction of cyclobutenones, as summarized in
Table 4. Various 3-substituted cyclobutenones were compatible
under optimal conditions. 3-Alkyl substituted cyclobutenones
gave the corresponding products (3a-3d, 3f and 3h-3j) in 93-
96% ee. A variety of functional groups, for example, methoxy
and chloro, were also tolerated, and the resulting phosphates
(3k-l) were obtained in excellent enantioselectivity (95-96% ee).
3-Cyclopropyl and 3-cyclohexyl cyclobutenones (1n and 1v)
provided the corresponding products (3n and 3v) in 93-96% ee
as well. In addition, aryl substituted cyclobutenones also
provided desired products (3o and 3q-t) in 90-97% ee and high
[a] 1 (0.5 mmol) in THF. [b] Diethoxymethylsilane was used. [c] L-4 was used.
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10.1002/anie.201913825
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COMMUNICATION
o
yields. Of note, 3u with o-methylphenyl substituent were
obtained in moderate enantioselectivity (65% ee).
smoothly at room temperature or 0 C in the presence of aryl or
alkyl zinc reagents without obvious erosion of enantiomeric
purity (see SI for details). The absolute configuration could be
determined by comparison of optical rotation values for products
4a and 4e with those reported in the literature.[3c]
Dialkyl znic reagents were also tested. Methyl and n-butyl
addition products (3w and 3x) were furnished in good
enantioselectivity using commercially available dimethyl or
dibutyl zinc. However, diphenyl zinc showed low reactivity under
current conditions, and 1,4-addition of 2,3-disubstituted
cyclobutenones with diethyl znic did not work either.
At this point, hydroborationoxidation of cyclobutene using
BH3ꞏMe2S and NaBO3 was conducted (Scheme 3). The reaction
of 4c showed good diastereoselectivity (>20:1) to afford alcohol
5 in moderate yield, while the reaction of cyclobutene 4e gave
Table 4. Substrate scope of 1,4-addition/trapping reaction of 1.[a]
only poor (1.7:1) diastereoselectivity.[19]
Me
N
i. BH3.Me2S
O
OPh
OPh
L-10
Cu(OTf)2, ent-
P
THF, 0 oC to r.t.
a)
O
Ph
Ph
Cy
R'2Zn, ClP(O)(OPh)2
O
O
Cy
OH
O
ii. NaBO3.4H2O, r.t.
P
PhCH3/THF
R'
R
78 to 0 o
C
Me
1
3
43% yield, d.r. >20:1
Ar = p-OMeC6H4
Ar
R
Ar
4c
5
L-10
ent-
b)
i. BH3.Me2S
THF, 0 oC to r.t.
ii. NaBO3.4H2O, r.t.
O
OPh
O
OPh
OPh
O
OPh
OPh
P
P
Ph
P
Ph
OH
OPh
O
O
O
Et
Et
Et
Et
Et
Ph
Ph
34% yield
d.r. 1.7:1
4e
6
n-C4H9
R
R
3a
3b
3c
3d
, 46%, 96% ee
, R = Ph, 52%, 95% ee
, R = p-ClC6H4, 53%, 93% ee
, R = p-OMeC6H4, 58%, 93% ee
3f
, R = Ph, 67%, 94% ee
3h
, R = c-Hex, 63%, 96% ee
, R = n-C4H9, 59%, 95% ee
, R = CH(CH3)2, 69%, 96% ee
Scheme 3. Functionalization of cyclobutene 4.
3i
3j
O
OPh
O
OPh
OPh
O
OPh
OPh
P
P
P
OPh
In conclusion, we reported a highly enantioselective copper-
catalyzed 1,4-addition/trapping of cyclobutenones to access
cyclobutenyl phosphates. With the aid of enantioselective
hydrosilylation and 1,4-conjugate addition, cyclobutenes with
embedded chiral tertiary and quaternary carbon centers could
be conveniently prepared. Subsequent cross-coupling reactions
effectively afforded chiral cyclobutene derivatives. Development
of further tandem processes to access chiral functionalized
cyclobutane motifs from cyclobutenones is underway.
O
O
O
Et
Et
Et
Cl
R
OMe
3n,
R = c-C3H5, 61%, 96% ee
75%, 93% ee
3l
, 58%, 96% ee
3k
O
, 61% 95% ee
3v
, R = c-Hex,
O
OPh
O
OPh
OPh
OPh
P
OPh
P
P
OPh
O
O
O
Et
Ar
n-Bu
Me
Ph
, 55% yield, 99% ee
Ph
3x, 78% yield, 95% ee[b,c]
3o
3q
3r
3s
3t
, Ar = Ph, 54%, 90% ee
, Ar = m-ClC6H4, 50%, 97% ee
, Ar = p-MeC6H4, 68%, 94% ee
3w
ACKNOWLEDGMENT
, Ar = p-ClC6H4,
51%, 96% ee
63%, 96% ee[b]
47%, 65% ee[b]
, Ar = p-FC6H4,
This work was supported by National Natural Science
Foundation of China (21772024, 21921003), 1000-Youth
Talents Program and Fudan University (for the start-up
grant).
3u
, Ar = o-MeC6H4,
[a] 1 (0.5 mmol), Cu(OTf)2 (2.5 mol%), ent-L-10 (2.5 mol%), ZnR2 (1.25 equiv)
in PhCH3, then ClPO(OPh)2 (2 equiv) and THF was used, see SI for more
details. [b] Cu(OTf)2 (10 mol%), ent-L-10 (10 mol%) were used. [c] Bu2Zn (1.5
equiv) were used.
With chiral cyclobutenyl phosphates in hand, the nickel-
catalyzed Negishi coupling reaction was examined. The optimal
conditions were achieved using NiCl2(dmpe) as a catalyst (Table
5).[17] Under these conditions, 3-substituted cyclobutenes (4a-
4d) or 3,3-disubstituted cyclobutenes (4e-4f) were synthesized
Conflict of interest
The authors declare no conflict of interest.
Keywords: Cyclobutenone • 1,4-addition• hydrosilylation •
Table 5. Further transformations of cyclobutene phosphate.[a]
tandem reaction • cross-coupling
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determined by 2D NMR yet.
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10.1002/anie.201913825
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Changxu Zhong, Yingchao Huang,
Haocheng Zhang, Qiang Zhou, Yu Liu,
and Ping Lu *
Page No. – Page No.
Enantioselective Synthesis of 3-
Substituted Cyclobutene Derivatives
via Catalytic Conjugate
The first enantioselective synthesis of cyclobutenes from cyclobutenones has been
developed by conjugate addition/trapping strategies. The highly strained cyclobutenones
show unique reaction characters.
Addition/Trapping Strategies
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