Enantioselective Synthesis of Multisubstituted Allenes by Cooperative Cu/Pd-Catalyzed 1,4-Arylboration of 1,3-Enynes

Article abstract of DOI:10.1002/anie.201912703

A cooperative Cu/Pd-catalyzed enantioselective synthesis of multisubstituted allenes is established. By employing chiral sulfoxide phosphine (SOP)/Cu and PdCl₂(dppf) complexes as catalysts, the 1,4-arylboration of 1,3-enynes provides an efficient approach to trisubstituted chiral allenes with up to 92 % yield and 97:3 er. Furthermore, by using 2-substituted 1,3-enynes as substrates, the tetrasubstituted chiral allenes were successfully generated using this strategy. Finally, theoretical calculations indicate that the transmetallation of the allenylcopper species is the rate-limiting step of this transformation.

Full text of DOI:10.1002/anie.201912703

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201912703
German Edition: DOI: 10.1002/ange.201912703
Synthetic Methods
Enantioselective Synthesis of Multisubstituted Allenes by Cooperative
Cu/Pd-Catalyzed 1,4-Arylboration of 1,3-Enynes
Yang Liao, Xuemei Yin, Xihong Wang, Wangzhi Yu, Dongmei Fang, Lianrui Hu,* Min Wang,*
and Jian Liao*
Abstract: A cooperative Cu/Pd-catalyzed enantioselective
synthesis of multisubstituted allenes is established. By employ-
ing chiral sulfoxide phosphine (SOP)/Cu and PdCl2(dppf)
complexes as catalysts, the 1,4-arylboration of 1,3-enynes
provides an efficient approach to trisubstituted chiral allenes
with up to 92% yield and 97:3 er. Furthermore, by using 2-
substituted 1,3-enynes as substrates, the tetrasubstituted chiral
allenes were successfully generated using this strategy. Finally,
theoretical calculations indicate that the transmetallation of the
allenylcopper species is the rate-limiting step of this trans-
formation.
Hoveyda and co-workers[6a] first developed Cu-catalyzed 1,4-
hydroboration of 1,3-enynes for the synthesis of trisubstituted
allenyl-B(pin) compounds with excellent results. Shortly
thereafter, the groups of Ge[6b] and Engle[6c] independently
disclosed the same protocols (Scheme 1b). Recently, by
G
iven their unique structural characteristics (cumulated
diene and axial chirality), related biological activities, and
physical and chemical properties, chiral allene scaffolds are
not only widely present in natural products, pharmaceuticals,
and materials, but also frequently employed as an important
class of synthetic intermediates in various organic trans-
formations.[1] Allene chemistry has stimulated the interest of
organic and medicinal chemists for decades. However, gen-
eral and efficient enantioselective synthetic method to access
axially chiral allenes from prochiral precursors is a long-
standing challenge. Many classical methods predominantly
rely on central-to-axial chirality transfer[2] or resolution of
racemic allenes.[3] Until recently, increasing attention has
focused on developing catalytic asymmetric approaches for
the synthesis of chiral allenes.[1f,h]
Scheme 1. Cu-catalyzed enantioselective 1,2- and 1,4-functionalization
of 1,3-enynes.
Since the pioneering work of the group of Hayashi,[4] 1,3-
enynes have been gradually considered ideal achiral precur-
sors for the construction of highly valuable chiral allenes, and
several metal- or organocatalyzed approaches were estab-
lished in the past few years.[5–7] Among these, enantioselective
Cu-catalyzed 1,4-hydrofunctionalization of 1,3-enynes was
proven to be an elegant strategy to access nonracemic allenes.
employing a proton and quinolone as electrophiles, the
groups of Buchwald and Ge reported 1,4-hydroprotonation
and 1,4-hydro(hetero)arylation, respectively, of 1,3-enynes.
And the corresponding 1,3-disubstituted and quinolinyl-
substituted chiral allenes were successfully afforded (Sche-
me 1b).[7] The key point of these protocols was the trapping of
the chiral allenylcopper species with suitable electrophiles
(HBpin, proton, and quinolone), otherwise, for example,
when using ketone as an electrophile, the propargylic
products were generated exclusively (Scheme 1a).[8]
Similarly, the addition of chiral Cu-Bpin species to 1,3-
enynes also enables the generation of chiral allenylcopper
intermediates, which were readily captured by aldehydes and
ketones to afford the corresponding propargylic products
with excellent selectivities (Scheme 1c).[9] However, the
synthesis of chiral allenes by this allenylcopper intermediate
still remains challenging. The difficulty can be attributed to
the readily racemied allenylcopper species, which could cause
low stereoselectivity if an unsuitable electrophile was employ-
ed.[1f,6a] Another challenge, as shown in Scheme 1, is access to
tetrasubstituted chiral allenes, and this has not been realized
via Cu-catalyzed 1,4-bifunctionalization of 2-substituted 1,3-
[*] Y. Liao, X. Yin, X. Wang, W. Yu, D. Fang, Dr. M. Wang, Prof. Dr. J. Liao
Chengdu Institute of Biology, Chinese Academy of Sciences
Chengdu 610041 (China)
and
University of Chinese Academy of Sciences
Beijing 100049 (China)
E-mail: wangmin@cib.ac.cn
jliao@cib.ac.cn
Dr. L. Hu
School of Science and Research Center for Advanced Computation,
Xihua University, Chengdu 610039 (China)
E-mail: hulianrui@iccas.ac.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201912703.
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enynes (R2 ¼ H). In fact, to date, asymmetric catalytic
methods to access tetrasubstituted chiral allenes have rarely
been exploited.[10]
spectroscopy and moderate enantioselectivity (90%, 78:22
er; entry 1) under the following reaction conditions: 10 mol%
CuCl/sulfoxide phosphine (SOP, L1),[11,13] 5 mol% PdCl2-
(dppf) as catalysts, and 2.5 equivalents NaOMe as base in
THF, stirring at 208C for 3 hours. There are two possible
reasons for the unsatisfactory stereoselectivity, one originates
from the weak stereocontrol of chiral ligand, and another
comes from ineffective Cu-to-Pd stereospecific transfer. We
guessed the latter might be caused by a mismatch in the speed
of formation between allenylcopper and arylpalladium spe-
cies.[11b,14] To confirm this hypothesis, the ratio of the Cu and
Pd catalyst was carefully tuned (entries 2–6). Encouragingly,
an increased er value (93:7) with a satisfactory 86% yield
(NMR) was detected when 5 mol% of the Cu catalyst and
15 mol% of the Pd catalyst were used (entry 5). Replacement
of CuCl with CuBr can slightly increase the er value (entry 7).
Chiral ligand screening showed that the SOPs L1–L4 were the
preferred ligands in terms of enantioselectivity, whereas poor
er values were achieved when employing commercially
available chiral ligands (L5–L8; entries 8–14). The use of
10 mol% tri(2-furyl)phosphine (TFP) as an additive and
replacing NaOMe with NaOEt could further improve the
er value slightly (entries 15 and 16). Finally, the best result
[94% yield (NMR), 88% yield (isolated) and 96:4 er] was
achieved by using a mixed solvent [2:1 THF/2-MeTHF (v/v);
entry 17]. It is notable that a 1,2-addition product was not
observed in this catalysis, and it could be attributed to the
efficient Cu-to-Pd allenylmetal transfer and reductive elim-
ination of allenylpalladium.
Cooperative Cu/Pd catalysis is an efficient strategy for the
enantioselective carbonboration of alkenes.[11,12] We envi-
sioned that a bimetal catalytic system might enable the
allenylcopper intermediate to be efficiently trapped by
a C electrophile with high stereoselectivity. As a result,
nonracemic, multisubstituted allenes could be prepared. The
challenge of this strategy is to maintain the highly stereospe-
cific metal-to-metal transfer (allenylcopper to allenylpalla-
dium). Herein, we report the first cooperative Cu/Pd-
catalyzed enantioselective synthesis of axially chiral tri- and
tetra-substituted (R2 = H, Ar) allenes through 1,4-arylbora-
tion of 1,3-enynes (Scheme 1d).
We commenced our study by using the arylsubstituted
enyne 1a as a model substrate, iodobenzene (2a) as a C el-
ectrophile, and bis(pinacolato)diboron (B2(pin)2) as a boron
source (Table 1). To our delight, the desired product 3aa was
achieved with an excellent yield as determined by NMR
Table 1: Optimization of reaction conditions.[a]
Entry
CuCl
(x mol%)
PdCl2(dppf)
(y mol%)
Ligand
Yield
[%][b]
er[c]
With optimal reaction conditions in hand, we then turned
our attention to explore the scope with respect to the aryl
iodides for the cooperative Cu/Pd-catalyzed enantioselective
1,4-arylboration of 1,3-enynes (Table 2). We found that
various aryl iodides worked well in this reaction. The ortho-,
meta-, and para-substituted, as well as disubstituted arylio-
dides were converted smoothly into the corresponding
trisubstituted axially chiral allenes with satisfactory yields
and er values (3ab–ar). Substrates with different functional
groups like alkyl (Me, tBu, CF3), halogens (F, Cl, Br), ether
(OMe, OEt, OCF3), aryl (Ph), and cyanide on the phenyl ring
were tolerated in this transformation. It was notable that
heteroaromatic iodides (thiophene, quinoline, and pyridine)
also worked well and the desired products (3as–au) were
prepared with good yields and excellent enantioselectivities.
Next, we evaluated the scope with respect to the 1,3-
enynes. Delightfully, both aromatic and aliphatic substituted
1,3-enynes serve as competent substrates in this process
(Table 3). The aromatic 1,3-enynes bearing either electron-
donating or electron-withdrawing groups at the ortho-, meta-,
or para-positions in the phenyl rings, including alkyl, alkoxy,
phenyl, and halogen, were compatible with the reaction
conditions, and the corresponding products were afforded in
78–92% yields with 93:7–96.5:3.5 er values (3bg–jg). In
addition, 2-naphthyl (3kg) and heteroaromatic 1,3-enynes
(3lg and 3mg) did not adversely affect the efficiency and
enantioselectivity. Aliphatic 1,3-enynes with different chain
lengths and functional groups (phenyl ring and chlorine atom)
covert readily into the desired products with moderate yields
and good enantioselectivities (3ng–rg).
1
2
3
4
10
10
10
10
5
2.5
5
5
5
5
5
5
5
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L1
L1
L1
90
91
86
70
86
72
88
90
89
76
65
72
80
81
90
95
78:22
88:12
91:9
90:10
93:7
10
15
20
15
15
15
15
15
15
15
15
15
15
15
15
15
5
6
93:7
7[d]
93.5:6.5
90:10
93:7
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
14[d]
15[d,e]
16[d,e,f]
17[d,e,f,g]
92:8
55:45
52:48
54:46
54:46
94.5:5.5
95.5:4.5
96:4
5
5
5
5
5
94(88)
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), B2(pin)2
(0.4 mmol), CuCl (x mol%), PdCl2(dppf) (y mol%), and NaOMe
(0.5 mmol) in THF (2.0 mL) at 208C for 3 h. [b] Determined by 1H NMR
spectroscopy with dimethyl terephthalate as an internal standard. Yield
of the isolated product given within parentheses. [c] Determined by
chiral-phase HPLC analysis. [d] CuBr instead of CuCl. [e] 10 mol% TFP
was added as additive. [f] NaOEt instead of NaOMe. [g] Mixed solvents:
2.0 mL THF and 1.0 mL 2-MeTHF. THF=tetrahydrofuran.
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Table 2: Scope with respect to the aryl iodides.[a,b,c]
Table 3: Scope with respect to the 1,3-enynes.[a,b,c]
[a] Reaction conditions: enynes (0.2 mmol, 1.0 equiv), aryl iodides
(0.4 mmol, 2.0 equiv), B2(pin)2 (0.4 mmol, 2.0 equiv), 5 mol% CuBr/
SOP L1, 15 mol% PdCl2(dppf), NaOEt (0.5 mmol, 2.5 equiv), and
10 mol% TFP in 2:1 THF/2-MeTHF (v/v) at 208C for 3 h. [b] Yield of
isolated products. [c] The er value was determined by chiral-phase HPLC
analysis. [d] 3 mol% CuBr/SOP, 3.0 mL 2-MeTHF, 08C, overnight.
[a] Reaction conditions: enynes (0.2 mmol, 1.0 equiv), aryl iodides
(0.4 mmol, 2.0 equiv), B2(pin)2 (0.4 mmol, 2.0 equiv), 5 mol% CuBr/
SOP L1, 15 mol% PdCl2(dppf), NaOEt (0.5 mmol, 2.5 equiv), and
10 mol% TFP in 2:1 THF/2-MeTHF (v/v) at 208C for 3 h. [b] Yield of
isolated product. [c] The er value was determined by chiral-phase HPLC
analysis.
Table 4: Synthesis of tetrasubstituted allenes.[a,b,c]
Elegant protocols of transition metal catalyzed 1,4-
difunctionalization of 2-substituted 1,3-enynes to afford
racemic tetrasubstituted allenes were established recently.[15]
To access nonracemic tetrasubstituted allenes with our
catalysis, 2-arylsubstituted 1,3-enynes were employed as
substrates (Table 4). Under the slightly modified reaction
conditions, we were pleased to find that the desired tetrasub-
stituted chiral allenes were successfully obtained with sat-
isfactory yields and enantioselectivities. In addition, 1,1,3-
triaryl tetrasubstituted allene (4n) can be prepared with
modest yield (48%) and good enantioselectivity (86.5:13.5
er), and the lower er value probably results from a more easily
racemization of this conjugated a,g-diaryl-substituted alle-
nylmetal intermediate.
To demonstrate the synthetic utility of this asymmetric
catalysis (Scheme 2), we treated the chiral allene product 3ag
[a] Reaction conditions: enynes (0.2 mmol, 1.0 equiv), aryl iodides
(0.4 mmol, 2.0 equiv), B2(pin)2 (0.4 mmol, 2.0 equiv), 3 mol% CuBr/
SOP L1, 15 mol% PdCl2(dppf), NaOMe (0.5 mmol, 2.5 equiv), and
5 mol% TFP in 3.0 mL 2-MeTHF at 108C overnight. [b] Yield of isolated
product. [c] The er value was determined by chiral-phase HPLC analysis.
with N-iodosuccinimide (NIS) in acetone, and the chiral 2,5-
dihydrofuran 5 (a class of important structural motifs
presented in various bioactive natural products[16]) bearing
a quaternary center was obtained with 65% yield with
Scheme 2. Transformations of products.
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94.5:5.5 er.[17] In addition, a methylene insertion into the C B
bond can be readily realized without loss of enantioselectivity
using the standard procedure.[6c,18]
Keywords: allenes · copper · palladium · enantioselectivity ·
synthetic methods
ꢀ
A plausible catalytic pathway is shown in Figure 1. In the
copper cycle, (SOP)CuBr reacts with B2(pin)2 in the presence
of NaOEt to produce the chiral Cu-Bpin species A. The 1,2-
addition of A to 1,3-enynes generates the propargylic copper
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Figure 1. Proposed catalytic pathway.
B, which underwent a stereospecific isomerization to an
axially chiral allenylcopper (C). The stereospecific metal
transformation of C with the arylpalladium specie E formed
the allenylpalladium F, which finally afforded the desired
axially chiral allene product G by reductive elimination. The
unstable product G was readily oxidized to afford the final
product.
In summary, we have developed an efficient approach for
the synthesis of multisubstituted chiral allenes with excellent
enantioselectivities by cooperative Cu/Pd-catalyzed 1,4-aryl-
boration of 1,3-enynes. By employing this protocol, the
prochiral aryl-, alkyl-, and 2-substituted 1,3-enynes were
smoothly converted into the corresponding tri- and tetrasub-
stituted allenes. Theoretical calculations disclosed that the
transmetallation of allenylcopper species was the rate-limit-
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had a much lower energy barrier than both racemization
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We thank the National Nature Science Foundation of China
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Conflict of interest
The authors declare no conflict of interest.
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Manuscript received: October 5, 2019
Version of record online: && &&, &&&&
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Communications
Synthetic Methods
Y. Liao, X. Yin, X. Wang, W. Yu, D. Fang,
L. Hu,* M. Wang,*
J. Liao*
&&&& — &&&&
Enantioselective Synthesis of
A cooperative Cu/Pd-catalyzed enantio-
selective 1,4-arylboration of 1,3-enynes
was developed with excellent yields and
enantioselectivities, and broad substrate
scope. By employing this method, tri- and
tetrasubstituted axially chiral allenes were
prepared. Theoretical calculations indi-
cate that the transmetallation of the
allenylcopper species is the rate-limiting
step of this transformation.
Multisubstituted Allenes by Cooperative
Cu/Pd-Catalyzed 1,4-Arylboration of 1,3-
Enynes
6
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Angew. Chem. Int. Ed. 2019, 58, 1 – 6
These are not the final page numbers!