A general asymmetric copper-catalysed Sonogashira C(sp 3)–C(sp) coupling

Article abstract of DOI:10.1038/s41557-019-0346-2

Continued development of the Sonogashira coupling has made it a well established and versatile reaction for the straightforward formation of C–C bonds, forging the carbon skeletons of broadly useful functionalized molecules. However, asymmetric Sonogashira coupling, particularly for C(sp³)–C(sp) bond formation, has remained largely unexplored. Here we demonstrate a general stereoconvergent Sonogashira C(sp³)–C(sp) cross-coupling of a broad range of terminal alkynes and racemic alkyl halides (>120 examples) that are enabled by copper-catalysed radical-involved alkynylation using a chiral cinchona alkaloid-based P,N-ligand. Industrially relevant acetylene and propyne are successfully incorporated, laying the foundation for scalable and economic synthetic applications. The potential utility of this method is demonstrated in the facile synthesis of stereoenriched bioactive or functional molecule derivatives, medicinal compounds and natural products that feature a range of chiral C(sp³)–C(sp/sp²/sp³) bonds. This work emphasizes the importance of radical species for developing enantioconvergent transformations.

Full text of DOI:10.1038/s41557-019-0346-2

Articles
https://doi.org/10.1038/s41557-019-0346-2
A general asymmetric copper-catalysed
Sonogashira C(sp3)–C(sp) coupling
Xiao-Yang Dong1,3, Yu-Feng Zhang1,3, Can-Liang Ma1,3, Qiang-Shuai Guꢀ ꢀ2,3, Fu-Li Wang1,3,
Zhong-Liang Li2, Sheng-Peng Jiang1 and Xin-Yuan Liuꢀ ꢀ1*
Continued development of the Sonogashira coupling has made it a well established and versatile reaction for the straightfor-
ward formation of C–C bonds, forging the carbon skeletons of broadly useful functionalized molecules. However, asymmetric
Sonogashira coupling, particularly for C(sp3)–C(sp) bond formation, has remained largely unexplored. Here we demonstrate
a general stereoconvergent Sonogashira C(sp3)–C(sp) cross-coupling of a broad range of terminal alkynes and racemic alkyl
halides (>120 examples) that are enabled by copper-catalysed radical-involved alkynylation using a chiral cinchona alka-
loid-based P,N-ligand. Industrially relevant acetylene and propyne are successfully incorporated, laying the foundation for
scalable and economic synthetic applications. The potential utility of this method is demonstrated in the facile synthesis of
stereoenriched bioactive or functional molecule derivatives, medicinal compounds and natural products that feature a range of
chiral C(sp3)–C(sp/sp2/sp3) bonds. This work emphasizes the importance of radical species for developing enantioconvergent
transformations.
arbon–carbon bond formation represents one of the most presence of a chelating group11. As for C(sp3)–C(sp) Sonogashira
fundamental tasks of chemical synthesis and lies at the cross-coupling, the few relevant examples are all asymmetric
C
heart of organic chemistry1. Over the past fifty years, tran- allylic alkylation reactions between allylic electrophiles and ter-
sition metal-catalysed cross-coupling reactions have changed the minal alkynes or their derivatives to afford mostly γ-alkynylation
way organic compounds are constructed through the evolution (or seldom α-alkynylation) products12–15. The development of
of a wide variety of carbon–carbon bond-forming reactions, the complementary enantioconvergent pathways that highly selectively
importance of which has been recognized with the 2010 Nobel deliver one α-alkynylation enantiomer from a broad range of read-
Prize in Chemistry2,3. There are three types of carbon–carbon cross- ily available racemic alkyl halides16–18 thus constitutes a major chal-
coupling reactions: C–C(sp3), C–C(sp2) and C–C(sp) (Fig. 1a), and lenge. Furthermore, their difficult oxidative addition by a transition
investigations and applications of the first two (for example, the metal catalyst and the high propensity of the ensuing alkyl–metal
Heck, Suzuki–Miyaura, Negishi and Kumada couplings, as well as intermediate for β-hydride elimination compared with their aryl/
many others) have greatly outcompeted those of the last one. This is alkenyl counterparts also need to be dealt with (Fig. 1b)10,19. Aside
possibly mainly due to the higher stability and geometric versatility from these, a considerable challenge lies in the accommodation of
of sp3 and sp2 carbons, which predominate in carbon skeletons of acetylene gas—an abundant, inexpensive and widely used industrial
natural organic molecules, medicines, agrochemicals and material feedstock (Fig. 1e)—as a suitable starting material for an asymmet-
molecules. Nevertheless, the unsaturation of an sp carbon renders ric Sonogashira cross-coupling reaction in terms of cost efficiency
it innately more amenable to versatile transformations that deliver and step economy20,21. Its lack of substituents renders it distinct from
sp3 and sp2 carbons as products4 while under mild reaction condi- its homologues and often inapplicable for suitable transformations
tions. In this sense, mild and versatile C–C(sp) cross-couplings, if of the latter21. Accordingly, transition metal-catalysed asymmetric
well established, would offer substantial complementary approaches transformations that use acetylene gas have been scarce22–27 and
to C–C(sp3)/C(sp2) couplings, which typically require organometal- may suffer from decomposition and/or polymerization of acety-
lic and/or pre-functionalized reagents with potential compatibility lene as well as undesired displacement of the chiral ligand used for
and cost issues.
enantiocontrol.
Among others, the traditional Sonogashira C–C(sp) coupling
In light of the aforementioned challenges, we were intrigued to
reaction5–7 between terminal alkynes and aryl/alkenyl halides or develop an efficient catalyst system to realize catalytic enantiocon-
pseudohalides in the presence of various transition metal catalysts vergent Sonogashira C(sp3)−C(sp) cross-coupling of common alkyl
has become a popular and reliable method to forge C–C bonds electrophiles, which, if successful, would provide not only an excel-
(Fig. 1b)8. Continued interest in this reaction has recently culmi- lent complementary approach to established enantioconvergent
nated with the expansion of the electrophile scope to alkyl halides9,10
.
C(sp3)−C(sp3/sp2) cross-couplings, but also immediate access to
Despite continuous development of the Sonogashira coupling, the chiral C(sp3)−C(sp) bonds that are essential to a number of impor-
exploration of its asymmetric variants for expedited access to chiral tant natural products and drugs (Fig. 1c). Copper catalysis holds
C–C bonds has been met with limited success. Highly enantiose- high potential for economical and operational benefits thanks to its
lective C(sp2)–C(sp) Sonogashira cross-coupling for the construc- low toxicity19, ready commercial availability at low cost and com-
tion of axial or planar chirality has been only achieved once in the plementary reactivity compared with heavier late d-block metals,
1Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China. 2Academy for Advanced
Interdisciplinary Studies and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China. 3These authors contributed
equally: Xiao-Yang Dong, Yu-Feng Zhang, Can-Liang Ma, Qiang-Shuai Gu, Fu-Li Wang. *e-mail: liuxy3@sustech.edu.cn
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a
b
R
C–C(sp2)/C(sp3)
R
MnL, R'
H
C–C(sp)
M
n+2L
C
C
C
C
C
C
R
X
cross-coupling
cross-coupling
Oxidative addition
Reductive
elimination
R'
R'
C(sp2)–C(sp) coupling: facile OA; C(sp3)–C(sp) coupling: difficult OA and possible β-H elimination
O
c
H
O
N
O
O
3
HO
O
OH
OH
O
HN
OH
Cl
O
CF3
O
O
H
HO
2
HO
O
OH
(–)-Chamaecynone
Efavirenz
Dynemicin A
Alfaprostol
d
e
R3
H
OMe
Synthetic building blocks
Chemical probes
R1
CuTC (5.0 mol%)
L* (7.5 mol%)
R1
N
R1
R1
R2
Cu/L*
R1
R2
H
H
R2
X
R2
Natural products
NH
PAr2
R3
H
N
Bioactive molecules
and drugs
O
X
R2
>120 examples
with up to 99% e.e.
L* (Ar = 3,5-tBu2C6H3)
Fig. 1 | Motivation and design of catalytic enantioselective Sonogashira C(sp3)−C(sp) cross-couplings. a, The C–C(sp) cross-coupling (for example,
the Sonogashira coupling) provides not only facile access to alkyne compounds, but also excellent complementary approaches to C–C(sp2) and C–C(sp3)
cross-couplings (for example, Suzuki–Miyaura, Negishi, Kumada and Heck couplings) when allied with versatile further transformations. Nevertheless,
the development and application of C–C(sp) cross-coupling lags far behind the other two. b, Sonogashira C(sp3)−C(sp) cross-coupling is more difficult
than C(sp2)−C(sp) cross-coupling due to its more challenging oxidative addition (OA), as well as the potential for β-H elimination. c, Important chiral
alkyne natural products ((−)-chamaecynone and dynemicin A) and drugs are shown (dynemicin A, anti-cancer drug; alfaprostol, veterinary drug for
breeding control; efavirenz, antiretroviral drug for HIV/AIDS). d, This work involves a Cu(i)/cinchona alkaloid-based P,N-ligand catalyst for catalytic,
enantioconvergent Sonogashira cross-couplings of racemic alkyl electrophiles via a radical intermediate. e, The current methodology well accommodates
the industrial feedstock acetylene gas and the resulting chiral terminal alkynes are amenable to versatile applications in various areas.
Table 1 | the effect of different ligands in the model reaction and the optimal results
Ph
H
CuI (10 mol%), L* (15 mol%), Cs2CO3 (2.0 equiv.)
+
+
Ph
Ph
Ph
Br
CH3CN, rt, 24 h
Ph
Phenylacetylene
Ph
Racemic
1
1'
1-phenylethyl bromide
O
O
N
PPh2
O
MeO
MeO
PAr2
PAr2
P
N
O
N
N
O
PPh2
Ph
Ph
L*1
L*2
1 trace; 1' trace
L*3
1 trace; 1' 52%
L*4
1 trace; 1' 34%
L*5 (Ar = 3,5-tBu2-4-MeO-C6H2)
1 trace; 1' trace
1 trace; 1' 22%
OMe
OMe
OMe
L*8, Ar = Ph, 1, 81%, 50% e.e. (89%, 82% e.e.a)
L*9, Ar = 4-MeOC6H4, 1, 83%, 85% e.e.a
L*10, Ar = 2,4,6-Me3C6H2, 1, 50%, 89% e.e.a
L*11, Ar = 2-Naphthyl, 1, 82%, 80% e.e.a
L*12, Ar = 3,5-(CF3)2C6H3, 1, 75%, 75% e.e.a
N
N
N
N
NH
S
NH
NH
PAr2
NH
PPh2
O
O
N
N
N
N
N
L*13, Ar = 3,5-tBu2C6H3, 1, 90%, 94% e.e.a (82%, 94% e.e.b)
O
O
O
L*6
1 trace; 1' 42%
L*7
L*14
1 trace; 1' trace
Standard reaction conditions: racemic 1-phenylethyl bromide (0.050ꢀmmol, 1.0 equiv.), phenylacetylene (1.5 equiv.), CuI (10ꢀmol%), ligand (15ꢀmol%) and Cs2CO3 (2.0 equiv.) in CH3CN (0.50ꢀml) at room
temperature (rt) for 24ꢀh. aCuTC (10ꢀmol%) and Et2O (1.0ꢀml) were used. bCuTC (5.0ꢀmol%), ligand (7.5ꢀmol%) and Et2O (1.0ꢀml) were used.
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Table 2 | the substrate scope of the alkynes
Ph
Et
H
Ph
CuTC (5.0 mol%), L*13 (7.5 mol%), Cs2CO3 (2.0 equiv.)
Et2O, rt
+
R
Br
Et
R
Alkyne
Racemic alkyl bromide
2–53, 55, 56
Aryl alkynes (R)
MeO
F
MeO
OMe
Me
H2N
F
F
2, 82%, 97% e.e.
3, 66%, 95% e.e.
4, 94%, 96% e.e.
5, 84%, 97% e.e.
6, 78%, 97% e.e.
7, 87%, 97% e.e.
8, 83%, 96% e.e.
9, 98%, 96% e.e. 10, 94%, 97% e.e.
Cl
Br
Cl
Br
F3C
NC
OHC
CHO
11, 81%, 97% e.e.
12, 98%, 94% e.e.
13, 96%, 97% e.e.
14, 96%, 94% e.e.
15, 84%, 97% e.e.
16, 97%, 96% e.e.
17, 97%, 96% e.e.
18, 79%, 91% e.e.
O
Fe
O
MeO2C
O2N
Bpin
MeO
24, 93%, 97% e.e.
19, 92%, 96% e.e.
20, 94%, 98% e.e.a
21, 94%, 96% e.e.
22, 77%, 96% e.e.
23, 65%, 96% e.e.
25, 75%, 98% e.e.
26, 88%, 98% e.e.
Heteroaryl alkynes (R)
N
O
S
N
N
N
N
N
N
N
N
S
N
N
N
27, 86%, 95% e.e.
28, 88%, 97% e.e.
29, 99%, 96% e.e.
30, 99%, 94% e.e.
31, 97%, 97% e.e.
32, 91%, 96% e.e.
33, 99%, 96% e.e.
34, 91%, 97% e.e.
Other alkynes (R)
PMPHN
2
Cz
Ph
Cy
Cl
3
PhthN
O
35, 92%, 96% e.e.
36, 88%, 98% e.e.b
37, 74%, 97% e.e.
38, 81%, 97% e.e.
39, 88%, 97% e.e.
40, 78%, 97% e.e.
41, 96%, 97% e.e.
42, 98%, 98% e.e.
iBu
S
TMS
CN
Ph
EtO
OEt
AcO
PhO
HO
Ph
tBu
Me
43, 99%, 96% e.e.
44, 91%, 96% e.e.
45, 90%, 98% e.e.
46, 98%, 97% e.e.
47, 98%, 96% e.e.
CN
48, 95%, 97% e.e.
49, 99%, 95% e.e.c
Acetylene- and propyne-participated transformations
Ph
Me
3
Ac
Et
H
H
H
Me
50, 88%, 97% e.e.d
51, 96%, 96% e.e.e
52, 77%, 95% e.e.e
53, 71%, 93% e.e.e
Ac
Ac
Ac
N
S
N
TsN
H
Et
Et
54, 81%, 95% e.e.f
55, 68%, 95% e.e.g
56, 49%, 95% e.e.g
Standard reaction conditions: alkyne (0.20ꢀmmol), racemic alkyl bromide (1.5 equiv.), CuTC (5.0ꢀmol%), L*13 (7.5ꢀmol%) and Cs2CO3 (2.0 equiv.) in Et2O (4.0ꢀml) under argon at room temperature. The yields
are isolated yields. aThe reaction was at −10ꢀ°C. bAlkyne (1.5 equiv.), racemic alkyl bromide (0.20ꢀmmol) and KOtBu (2.0 equiv.) were used. cThe e.e. was determined after desilylation and the yield given
is the crude yield. dPropyne (2.5 equiv.) and racemic 1-phenyl-1-propyl bromide (0.20ꢀmmol) were used. eAn acetylene balloon and racemic alkyl bromide (0.20ꢀmmol) were used. fCrude 51 (~0.20ꢀmmol),
CuTC (5.0ꢀmol%) and TsN3 (1.0 equiv.) in toluene (2.0ꢀml) were used at room temperature (r.t.) under argon. gCrude 51 (~0.20ꢀmmol), racemic alkyl bromide (1.5 equiv.), CuTC (5.0ꢀmol%), L*13 (7.5ꢀmol%)
and Cs2CO3 (2.0 equiv.) in Et2O (4.0ꢀml) were used under argon. The diastereomeric ratio (d.r.) was roughly estimated by HPLC to be larger than 20:1. Pin, pinacolato; PMP, para-methoxyphenyl; Phth,
phthalyl; Cz, 9-carbazolyl; TMS, trimethylsilyl; Ac, acetyl; Ts, para-toluenesulfonyl.
especially palladium28,29. Furthermore, copper acetylide could be feedstock acetylene gas to provide valuable chiral terminal alkyne
readily formed from terminal alkyne and copper salt in the presence synthons with high monosubstitution selectivity (Fig. 1e). Most
of mild base30. We then questioned whether a copper salt together importantly, this protocol was compatible with various core struc-
with an appropriate chiral ligand would overcome all of the chal- tures of bioactive and functional molecules (five examples) and pro-
lenges described above. Here we present a copper(i)/cinchona vides facile access to chiral C–C(sp3), C–C(sp2) and C–C(sp) bonds
alkaloid-based P,N-ligand catalyst system for enantioconvergent in enantioenriched drugs and drug leads (four examples) as well as
Sonogashira C(sp3)−C(sp) cross-coupling via a radical intermedi- natural products (formal syntheses).
ate. This reaction exhibits a broad scope (>120 examples, Fig. 1d)
across a range of both terminal alkyne and racemic alkyl halide cou- results and discussion
pling partners while under operationally simple and mild reaction Reaction development. In comparison with the considerable
conditions. Moreover, this process well accommodates industrial advances pioneered by Fu and co-workers16–18 of enantioconvergent
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Table 3 | the substrate scope of racemic secondary alkyl halides
R1
R1
CuTC (5.0 mol%), L*13 (7.5 mol%), Cs2CO3 (2.0 equiv.)
Et2O, rt
H
+
R2
Ph
Br
R2
Ph
Alkyne
Racemic alkyl bromide
1, 57–116
Phenyl-substituted alkyl bromides (R1 = Ph, R2)
Ph
Ph
Ph
1, n = 0, 75%, 94% e.e.
57, n = 2, 77%, 96% e.e.
58, n = 3, 70%, 96% e.e.
Ph
Ph
60, n = 1, 62%, 92% e.e.
61, n = 2, 71%, 94% e.e.
62, n = 3, 52%, 95% e.e.
Ph
n
63, 70%, 96% e.e.
71, n = 1, 34%, 92% e.e.
64, 81%, 98% e.e.a
Ph
65, 30%, 96% e.e.
n
59, n = 4, 65%, 96% e.e.
O
Ph
Ph
Ph
Ph
66, n = 1, 73%, 96% e.e.
CN
3
69, n = 1, 64%, 96% e.e.
70, n = 3, 75%, 96% e.e.
72, n = 2, 86%, 86% e.e.
73, n = 3, 75%, 92% e.e.
CO2Et
67, n = 2, 79%, 96% e.e.a
Ph
74, 84%, 92% e.e.
3
n
68, n = 3, 82%, 98% e.e.a
n
n
75, 83%, 94% e.e.
Ph
Ph
O
Ph
Ph
Ph
Ph
Ph
OTBDPS
OMe
3
SO2Ph
Br
Cl
SiMe3
O
Cz
2
3
2
2
2
82, 86%, 97% e.e.b
76, 74%, 94% e.e.
77, 83%, 95% e.e.
78, 83%, 95% e.e
79, 92%, 80% e.e.
80, 77%, 96% e.e.
81, 78%, 97% e.e.
Aryl-substituted alkyl bromides (R1, R2)
OMe
NHAc
OAc
CHO
83, 4-Me, 85%, 96% e.e.
84, 3-Me, 79%, 93% e.e.
85, 2-Me, 43%, 95% e.e.a
89, 4-Br, 84%, 96% e.e.
90, 3-Br, 62%, 95% e.e.
Me
Br
Br
Et
Et
Et
86, 70%, 96% e.e. 87, 90%, 90% e.e. 88, 95%, 92% e.e.
CF3
91, 38%, 95% e.e. 92, 68%, 90% e.e.
O
CN
N
COMe
CO2Me
F3C
CF3
O
N
Et
Cz
Et
Et
96, 69%, 96% e.e.
93, 95%, 93% e.e.
94, 91%, 89% e.e.
95, 88%, 84% e.e.
97, 74%, 94% e.e.
98, 84%, 90% e.e.
99, 50%, 91% e.e.
100, 80%, 96% e.e.
Heteroaryl-substituted alkyl bromides (R1, R2)
N
Br
S
Et
N
S
O
N
Br
Et
Et
N
N
S
N
N
Et
Cz
Cz
Cz
101, 77%, 97% e.e. 102, 66%, 93% e.e. 103, 77%, 87% e.e. 104, 78%, 99% e.e. 105, 87%, 92% e.e. 106, 76%, 98% e.e. 107, 64%, 90% e.e.c 108, 61%, 82% e.e. 109, 70%, 97% e.e.
Other bromides (R1, R2)
Alkyl chlorides (R1, R2)
CH2Bn
R3
CN
O
N
Ph
Ph
Ph
111, R3 = TIPS, 93%, 96% e.e.d
112, R3 = TES, 83%, 92% e.e.d
113, R3 = tBu, 84%, 91% e.e.d
Cy
Br
Cz
Cz
116, 92%, 86% e.e.g
CH2Bn
Bn
1, 70%, 94% e.e.c 110, 52%, 92% e.e.c
114, 97%, E/Z 4/1, 76% e.e.e
115, 61%, 77% e.e.f
Cz
Standard conditions: racemic alkyl halide (0.20ꢀmmol), alkyne (1.5 equiv.), CuTC (5.0ꢀmol%), L*13 (7.5ꢀmol%) and Cs2CO3 (2.0 equiv.) in Et2O (4.0ꢀml) under argon. The yields are isolated yields. aL*8
(7.5ꢀmol%). bAlkyne (0.20ꢀmmol) and racemic alkyl halide (1.5 equiv.) were used. cCuTC (10ꢀmol%) and L*13 (15ꢀmol%) were used. dAlkyne (0.20ꢀmmol), racemic alkyl halide (1.5 equiv.), CuTC (8.0ꢀmol%)
and L*13 (12ꢀmol%) in dichloromethane (4.0ꢀml) were used. e1-Bromo-4-ethynylbenzene (2.0 equiv.) and Cu(PPh3)Br (5.0ꢀmol%) in 1,4-dioxane (4.0ꢀml) were used. fAlkyne (0.20ꢀmmol) and racemic alkyl
halide (1.5 equiv.) at −40ꢀ°C. gCuTC (8.0ꢀmol%) and L*13 (12ꢀmol%) were used. TBDPS, tert-butyl-diphenylsilyl; TIPS, triisopropylsilyl; TES, triethylsilyl; Cy, cyclohexanyl.
radical-involved C–C cross-couplings of racemic alkyl electrophiles homocoupling product 1′ (Table 1). To promote the oxidative addi-
using chiral nickel catalysis, the use of a chiral copper catalyst for tion of a Cu(i) catalyst, we envisaged using an electron-rich amine
such transformations remains rare31. This deficit may be attributed ligand38 to increase the electron density on copper, and we resorted to
to its relatively difficult oxidative addition compared with a nickel multidentate ligands to depress undesired Glaser coupling39. As such,
catalyst under similar conditions19,28,32–37. An exhaustive screening we chose a series of cinchona alkaloid-derived P,N-ligands (L*6−
of various types of monodentate and bidentate ligands—including L*13) that feature a bridgehead tertiary amine for such a reaction40
monophosphine (L*1), monophosphoramidite (L*2), bis(oxazoline) (Table 1). The reaction using bidentate quinine-derived sulfonamide
(L*3), phosphinooxazoline (L*4) and biphenylphosphine (L*5)— (L*6) still suffered from the alkyne homocoupling whereas triden-
for the model coupling of racemic 1-phenylethyl bromide and phen- tate picolinamide (L*7) did not. Although both of these ligands
ylacetylene resulted in the formation of trace amounts of desired failed to deliver the desired coupling, Dixon’s tridentate ligand41 L*8,
coupling product 1, although occasionally together with the Glaser which possesses an electron-rich phosphine coordination motif,
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a
O
S
4
Ph
O
117
3
O
3
75% yield, d.r. >20:1
(L-menthol derivative)
O
HN
NH
Ph
O
N
O
CN
O
Ph
O
O
EtO2C
119
Ph
H
121
50% yield, d.r. >20:1
(sulbactam derivative)
S
120
83% yield, 96% e.e.
Ph
O
25% yield, d.r. >20:1
(biotin derivative)
H
H
118
H
O
(mesogenic compound analogue)
87% yield, d.r. >20:1
(estrone analogue)
OMe
b
CF3
CO2H
Ph
H2N
N
N
N
N
Me
N
COOH
O
H2N
123
122
(a mGluR modulator for neurological disorders)
124
(AMG 837, a GPR40 agonist for type 2 diabetes)
7 steps, 10% overall yield, 83% e.e.a
3 steps, 69% yield, 93% e.e.
(UCP1172, DHFR inhibitor for bacterial infection)
5 longest linear steps, 27% overall yield, 92% e.e.a
c
H
refs.49,50
Cu/Pd/L1, TMDSO
H2, Pd/C, then HCl
N
Et
(S)
O
128 (5 steps, 78% overall yield, 89% e.e.)a
Formal synthesis of
(+)-erogorgiaene and so on
125 (74% yield, Z/E 25/1, 98% e.e.)
R1
HO
ref.51
Cu/Pd/L1, PhSiH3
H2, Pd/C, then HCl
MeO
R2
*
R3
Et
129 (5 steps 67% overall yield, 83% e.e.)
126 (65% yield, Z /E 1/10, 96% e.e.)
Formal synthesis
of (+)-mutisianthol
H2O, Ru/L2
ref.52
RuCl3, NaIO4
OH
O
O
OH
127
130 (4 steps, 61% overall yield, 98% e.e.)a
Formal synthesis of
(+)-bisacumol and so on
((S)-ibuprofen, NSAI drug)
4 steps, 64% overall yield, 82% e.e.a
Fig. 2 | Synthetic applications of the catalytic enantioselective Sonogashira cross-coupling. a, Examples where the reaction exhibited excellent
compatibility with core structures of bioactive molecules and a mesogenic compound are shown. b, Examples where the reaction provided practical
and convenient synthetic routes towards drug leads are shown. c, The current asymmetric C(sp3)–C(sp) coupling easily delivered chiral C(sp3)–C(sp2)
and C(sp3)–C(sp3) bonds in drugs and natural products following further manipulations in one or two steps, thus constituting excellent complementary
approaches to established asymmetric C(sp3)–C(sp2) and C(sp3)–C(sp3) couplings. aThe e.e. values were determined on an immediate precursor or
derivative of the product (see the Supplementary Information for details). NSAI, non-steroidal anti-inflammatory; GPR40, G-protein-coupled receptor
40; mGluR, metabotropic glutamate receptor; DHFR, dihydrofolate reductase; Cu/Pd/L1, [1,3-bis[2,6-bis(1-methylethyl)phenyl]-2-imidazolidinylidene]
chlorocopper/palladium acetate/dicyclohexyl(2’-methoxy[1,1’-biphenyl]-2-yl)phosphine; TMDSO, 1,1,3,3-tetramethyldisiloxane; Ru/L2, cyclopentadienyltris
(acetonitrile)-ruthenium hexafluorophosphate/5,5’-bis(trifluoromethyl)-2,2’-bipyridine.
successfully provided 1 in 81% yield with 50% e.e. without the forma- in terms of cost efficiency thus involve CuTC (5.0mol%) as well as
tion of 1′. Encouraged by this finding, we systematically evaluated L*13 (7.5mol%) in Et2O (0.05M) at room temperature.
different copper salts, inorganic bases and solvents (Supplementary
Table 1) and found that the copper salt CuTC (TC=thiophene- The substrate scope. With the optimal reaction conditions estab-
2-carboxylate) and solvent Et2O performed better to give 1 in 89% lished, we next examined the generality of this enantioselective
yield with 82% e.e. Considering the substantial role that the phos- Sonogashira C(sp3)−C(sp) cross-coupling. With regards to the
phine motif might play in the reaction, we then examined several alkyne scope (Table 2), a broad series of substituted aryl alkynes—
analogues of L*8 with different steric and electronic properties including those that have monosubstituted phenyl rings with
(L*9−L*13) and observed favourable effects for electron-donating electron-donating or -withdrawing groups at different positions
and steric bulky P-substituents on enantioselectivity (Table 1). (ortho, meta or para), a disubstituted phenyl ring, a naphthalene
Accordingly, the best ligand (L*13) afforded 1 in 90% yield with ring and a ferrocene ring—can readily participate in this reac-
94% e.e. at ambient conditions, and reducing the catalyst loading tion to afford 2–26 in 65–98% yield with 91–98% e.e. Many com-
by half did not affect the enantioselectivity. The optimal conditions mon functional groups, such as methoxyl (3–5), free amino (7),
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a
b
Ph
TEMPO (1.2 equiv.)
Br
Et2O, r.t.
Ph
Br
CuTC (5.0 mol%), L*8 (7.5 mol%)
+
Cu
Ph
Et
+
H
Ph
N
Ph
Et
Copper phenylacetylide
Phenylactylene
Cs2CO3 (2.0 equiv.), Et2O, rt
Ph
Et
O
Et
Ph
Racemic
1-Phenyl-1-propyl bromide
With L*8: 2 (82%, 88% e.e.)
Without L*8: no reaction
Racemic
1-Phenyl-1-propyl bromide
131 (~10%)a
c
Ph
d
Ph
4-Cyanophenylacetylene
CuTC (5.0 mol%),
L*8 (7.5 mol%)
Br
Br
Br
CuTC (5.0 mol%), L*14 (7.5 mol%)
+
+
Ph
H
Ph
Ph
Cs2CO3 (2.0 equiv.), Et2O, rt, 2 h
3
Ph
Ph
Phenylactylene
Cs2CO3 (2.0 equiv.),
Et2O, rt
Ph
NC
(
)-132
Ph
133 (76% yield)
1-Phenylethyl bromide
(i) Racemic
134
Remaining bromide
(i) 0% e.e.
(i) 35%, 72% e.e.
(ii) 31%, 72% e.e.
(ii) 75% e.e.
(ii) 75% e.e.
X
e
L
R2
R3
CuI
R1
LCuI
R1
LCuII
R1
+
R2
R3
n
H
R1
V
II
III
IV
X
R2
HCO3
R3
H
R1
CuIL
R1
2
CO3
I
Fig. 3 | Mechanistic studies of the catalytic enantioconvergent Sonogashira cross-coupling. a, Copper phenylacetylide participated directly in the
reaction, which was greatly promoted by ligand L*8. b, The reaction was completely inhibited by the radical inhibitor TEMPO and TEMPO-trapped product
131 was formed, supporting the involvement of a benzylic radical. c, Alkene-tethered substrate 132 led to formation of 133 under standard conditions,
suggesting the generation of a benzylic radical and its subsequent 5-exo-trig cyclization and C(sp3)–C(sp) coupling. d, No changes to the enantiopurities of
the starting alkyl bromide were observed in the reactions on racemic and chiral 1-phenylethyl bromide, respectively, therefore probably excluding pathways
that involve kinetic resolution or fast racemization of alkyl bromide. Values aligned horizontally belong to one experiment. e, The reaction was proposed to
proceed via a single-electron transfer between in situ generated copper acetylide complexes ii and racemic alkyl halides to form Cu(ii) complexes iii and
alkyl radicals iV and subsequent C(sp3)–C(sp) coupling. Alkyne substrates might form polymeric Cu(i) complexes V that are catalytically inactive.
aNo desired product 2 was observed.
halo (8–14), cyano (16), formyl (17 and 18), methoxylcarbonyl alkyl bromides (Fig. 1d) to provide chiral terminal alkynes 51–53 in
(19), nitro (20) and pinacolborato (21)—as well as terminal olefin excellent yields with excellent e.e. The high monosubstitution selec-
(22) and alkyne (23)—were all compatible with the mild reaction tivity makes this reaction an ideal tool for preparing chiral termi-
conditions. As for the scope of heteroaryl alkynes, we find that nal alkyne building blocks. The crude product 51 thus participated
many alkynes that contain medicinally relevant heterocycles42— well in the following click reaction without purification, yielding
such as pyridine (27), benzo[d]oxazole (28), benzo[d]thiazole (29), cycloaddition product 54 in high yield and enantioselectivity. This
quinoline (30), pyrimidine (31), imidazo[1,2-b]pyridazine (32), crude product was also suitable for a second Sonogashira coupling
pyrazolo[1,5-a]pyrimidine (33) and thiophene (34)—were compe- to provide internal alkynes 55 and 56 in high diastereoselectivity
tent substrates, providing the desired products in excellent yields and enantioselectivity.
with excellent enantioselectivity. With respect to alkyl alkynes,
In the following study, we switched our attention to evaluate the
barely functionalized aliphatic alkynes 35 and 36 successfully scope of the other coupling partner; that is, racemic alkyl halides
underwent efficient cross-coupling. Most importantly, a wide range (Table 3). Using phenylacetylene as a model alkyne, we observed
of functional groups, such as conjugating alkene (37), cyclopro- that simple unfunctionalized linear benzyl bromides all worked well
pane (38), primary chloride (39), amide (40), imide (41), carbazole to give 1 and 57–59 with good results (Table 3, 65–77% yield and
(42), nitrile (43), acetal (44), free alcohol (45), ester (46) and ether 94–96% e.e.). As for the effect of steric hindrance around the chiral
(47)—as well as coordinating thioether (48)—were well tolerated at centre, most substituents in the alkyl branch did not greatly affect
different distances away from the reacting alkynes, providing high the reaction efficiency or enantioselectivity (60–64 and 66–68) and
chemoselectivity and excellent enantioselectivity in this cross-cou- even a tert-butyl group was moderately tolerated (65). With regards
pling process. Furthermore, silyl alkyne worked well under standard to potentially reactive functional groups, a gamut of functionalities,
conditions to provide 49 in almost quantitative yield with 95% e.e.
such as terminal olefin (69 and 70), ester (71–73), ketone (74),
The direct conversion of industrial feedstocks to medicinally nitrile (75), acetal (76), silyl ether (77), ether (78) and sulfone (79),
and agriculturally relevant chiral products is an important goal of were left unscathed under the coupling reaction conditions. Perfect
chemical research. To this end, we first tested our reaction using chemoselectivity was observed for the secondary benzylic bro-
the industrially relevant propyne—a key component of the readily mide over primary bromide and chloride (80 and 81, respectively).
available methylacetylene-propadiene propane welding gas43—as Notably, an α-bromo silane also smoothly underwent the desired
a substrate (Table 2). We obtained the desired product 50 from a coupling to afford the valuable α-chiral silane 82, which has recently
commercial solution of pure propyne in 88% yield with 97% e.e. been receiving increasing synthetic and application interest46. With
under standard conditions. We then noted that industrial-grade respect to the phenyl ring of alkyl bromides, a broad series of elec-
acetylene gas (an important industrial raw material mainly pro- tron-donating or -withdrawing substituents at different positions
duced from coal44, 500 kilotonnes were produced in 2014 at ~US$26 (ortho, meta, para, 3,4- or 3,5-), and even a naphthalene ring, were
cents per mol45) chemoselectively coupled with various secondary all well accommodated in this process to deliver 83–100 in 38–95%
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yield with 84–97% e.e. Alkyl bromides that contain different types of subsequent manipulations for forging chiral C(sp3)–C(sp2) and
of medicinally relevant heterocycles—including pyridines (101– C(sp3)–C(sp3) bonds, which would be particularly invaluable when
103), benzo[b]thiophene (104), thiophene (105), benzo[b]furan functionalities that have low compatibility with organometallics,
(106), quinoline (107), thiazole (108) and pyrimidine (109)—were such as carboxylic acid and aldehyde, are desired.
viable substrates. The less reactive alkyl chloride also underwent
the desired Sonogashira coupling reaction with slightly increased Mechanistic considerations. Our mechanistic study revealed
catalyst loading to afford 1 in comparable efficiency and enanti- that copper phenylacetylide participated in the reaction while in
oselectivity. Notably, with this protocol we were able to incorporate the presence of L*8, whereas no reaction occurred in its absence
a small cyclopropane ring (110)—a chemically and metabolically (Fig. 3a). This result confirmed the ligand-promoting effect of this
stable bioisostere for alkyl groups47—into the chiral internal alkyne reaction. Control experiments with the radical inhibitor TEMPO
product. All of these results highlight the potential of our method- ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) demonstrated complete
ology in the process of drug discovery. The scope with respect to inhibition of the desired reaction and TEMPO-trapped product 131
the electrophile is not limited to the racemic α-aryl and -heteroaryl was isolated in ~10% yield (Fig. 3b). Moreover, substrate 132 with
substituted alkyl halides. For example, various racemic propargylic a tethered alkene underwent tandem cyclization and alkynylation
bromides were found to be suitable substrates to afford the expected to provide product 133 under standard conditions (Fig. 3c). No
bis-alkynyl products 111–113 in 83–93% yield with 91–96% e.e. enantioenrichment or enantioerosion of recovered starting materi-
Furthermore, allylic and α-cyano/aminocarbonyl alkyl bromides als were observed when racemic or scalemic 1-phenylethyl bromide
all are well applicable to this transformation, delivering various were used, respectively (Fig. 3d), indicating that kinetic resolution
alkynylation products 114, 115 and 116 in good to excellent enanti- or fast racemization of alkyl bromide is unlikely. These pieces of
oselectivity, respectively. These results emphasize the high substrate evidence strongly support the formation of alkyl radical species.
diversity of the current cross-coupling reaction.
Further kinetic experiments on the reaction disclosed first-order
dependences of reaction rates on the alkyl bromide and copper
Syntheticapplications.Toillustratetheutilityofthistransformation, catalyst (Supplementary Figs. 10 and 11, respectively), indicating
we initially examined this asymmetric Sonogashira C(sp3)−C(sp) that related species are involved in the reaction step(s) until the
cross-coupling reaction using the core structures of several bioac- rate-determining step. Moreover, elemental analyses were carried
tive molecules, such as l-menthol (117), estrone (118), sulbactam out on both the copper catalyst and the crude reaction mixture, and
(119) and biotin (120), and a mesogenic compound (121) (Fig. 2a). control experiments were conducted to exclude possible catalysis by
All of the desired alkynylated products were obtained in high ste- trace metal impurities (Supplementary Tables 2–8). With regards to
reoselectivity, irrespective of existing chiral centres and complex acetylene, the reaction rate was initially increased and then slightly
molecular structures.
As for the immediate potential in medicinal chemistry (Fig. 2b), Fig. 12), highlighting the multifaceted roles it played in the reaction.
we have easily prepared chiral alkyne drug leads 122 (AMG 837 a On the basis of the above-mentioned mechanistic results, as
decreased following its concentration increase (Supplementary
G-protein coupled receptor GPR40 agonist) and 123 (a patented well as the literature53, we propose a possible reaction mechanism
mGluR modulator) in high enantiopurity through a key asym- (Fig. 3e). The reaction starts with the formation of monomeric cop-
metric Sonogashira C(sp3)–C(sp) cross-coupling (Supplementary per acetylide II from copper complex I by reacting with terminal
Figs. 1 and 2). We have also prepared the newly reported highly alkyne in presence of base. This copper complex II may transform
potent DHFR inhibitor UCP1172 (124) for drug-resistant bac- to catalytically inactive polymeric copper acetylide V in the pres-
teria treatment via a convergent synthetic route culminating in ence of excessive terminal alkyne, leading to reaction inhibition54.
an asymmetric Sonogashira coupling and subsequent hydrolysis Subsequent oxidative addition of II with alkyl halide (through either
(Supplementary Fig. 3). This convergence emphasizes the endowed inner- or outer-sphere electron transfer38) results in the formation
capacity of this newly devised coupling reaction for enabling novel of alkyl radical IV. Next, C(sp3)–C(sp) bond coupling via either a
synthetic planning, leading to the possibility of more facile con- Cu(iii) intermediate or radical addition to the acetylide triple bond
struction of a structurally diverse molecular library for further gives rise to enantioenriched product and Cu(i) complex I. Further
drug optimization.
experimental and computational studies are underway in our labo-
To demonstrate the potential for chiral C(sp3)–C(sp2) and ratory to delineate the mechanistic details.
C(sp3)–C(sp3) formation (Fig. 2c), the highly stereoselective hydro-
genation of two chiral alkyne products is shown, giving Z-alkene Conclusion
125 and E-alkene 126, respectively, by following Lalic’s recent We have established a robust strategy for the practical and versa-
protocols48. Furthermore, we have oxidatively cleaved one alkyne tile enantioconvergent Sonogashira C(sp3)–C(sp) cross-coupling—
product to carboxylic acid (S)-ibuprofen (127), which is the more via a radical intermediate—by combining a copper catalyst with
biologically active enantiomer of this common NSAID (for details a cinchona-based chiral P,N-ligand, providing a tool for the con-
on its synthesis and that of its enantiomer, see Supplementary struction of chiral C–C bonds. The successful direct incorporation
Fig. 4). Notably, the preparations of AMG 837 and (S)-ibuprofen of acetylene gas in this reaction demonstrates important potential
involved industrially relevant propyne and acetylene gas raw mate- for industrial-grade applications. We envision that this method-
rials as coupling substrates, respectively, demonstrating great poten- ology will not only open up new avenues for enantioconvergent
tial of this methodology for industrial applications in the future. C–C bond formation but also inspire the discovery of more novel
Furthermore, we have fully hydrogenated two alkyne products to catalyst systems that can handle challenging asymmetric radical
aldehyde 128 and alkene 129 following palladium catalysis and transformations.
further acidic treatments, and hydrated another alkyne product to
aldehyde 130 through ruthenium catalysis. These three compounds Data availability
are all synthetic precursors of a range of natural products, such as All of the characterization data and experimental protocols are pro-
(+)-erogorgiaene49,50, (+)-mutisianthol51, (+)-bisacumol52 and so vided in this article and its Supplementary Information. Data are
on (for details on the total synthesis or formal synthesis of several also available from the corresponding author on request.
families of natural products, see Supplementary Figs. 5–9). In sum-
mary, these diverse transformations showcase the robust capability Received: 19 February 2019; Accepted: 28 August 2019;
of our asymmetric C(sp3)–C(sp) cross-coupling allied with a variety
Published online: 21 October 2019
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Financial support for this work was provided by the National Natural Science Foundation
of China (grant nos. 21722203, 21831002 and 21801116), Shenzhen Special Funds (grant
nos. JCYJ20170412152435366 and JCYJ20170307105638498) and Shenzhen Nobel Prize
Scientists Laboratory Project (grant no. C17783101).
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Author contributions
Additional information
X.-Y.D., Y.-F.Z., C.-L.M., Q.-S.G. and F.-L.W. designed the experiments and analysed the
data. X.-Y.D., Y.-F.Z., C.-L.M., F.-L.W., Z.-L.L. and S.-P.J. performed the experiments.
All authors participated in writing the manuscript. X.-Y.L. conceived and supervised
the project.
Supplementary information is available for this paper at https://doi.org/10.1038/
s41557-019-0346-2.
Correspondence and requests for materials should be addressed to X.-Y.L.
Reprints and permissions information is available at www.nature.com/reprints.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
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Competing interests
The authors declare no competing interests.
© The Author(s), under exclusive licence to Springer Nature Limited 2019
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