Nickel-Catalyzed Enantioconvergent Reductive Hydroalkylation of Olefins with α-Heteroatom Phosphorus or Sulfur Alkyl Electrophiles

Article abstract of DOI:10.1021/jacs.9b09415

Substantial advances in enantioconvergent C(sp³)-C(sp³) bond formation reactions have been made in recent years through the use of transition-metal-catalyzed cross-coupling reactions of racemic secondary alkyl electrophiles with organometallic reagents. Herein, we report a general process for the asymmetric construction of alkyl-alkyl bonds adjacent to heteroatoms, namely, a nickel-catalyzed enantioconvergent reductive hydroalkylation of olefins with α-heteroatom phosphorus or sulfur alkyl electrophiles. Including the use of readily available olefins, this reaction has considerable advantages, such as mild reaction conditions, a broad substrate scope, and good functional group compatibility, making it a desirable alternative to traditional electrophile-nucleophile cross-coupling reactions.

Full text of DOI:10.1021/jacs.9b09415

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Article
Nickel-Catalyzed Enantioconvergent Reductive Hydroalkylation of
Olefins with #-Heteroatom Phosphorus or Sulfur Alkyl Electrophiles
Shi-Jiang He, Jia-Wang Wang, Yan Li, Zhe-Yuan Xu, Xiao-Xu Wang, Xi Lu, and Yao Fu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b09415 • Publication Date (Web): 15 Dec 2019
Downloaded from pubs.acs.org on December 15, 2019
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Nickel-Catalyzed Enantioconvergent Reductive Hydroalkylation of
Olefins with α-Heteroatom Phosphorus or Sulfur Alkyl Electrophiles
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Shi-Jiang He,† Jia-Wang Wang,† Yan Li,† Zhe-Yuan Xu, Xiao-Xu Wang, Xi Lu,* Yao Fu*
Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion,
Anhui Province Key Laboratory of Biomass Clean Energy, iChEM, University of Science and Technology of China, Hefei
230026, China
KEYWORDS Nickel-Catalysis; Alkyl-Alkyl Cross-Coupling; Alkyl Electrophiles; Enantioconvergent Synthesis; Reductive
Hydroalkylation
ABSTRACT: Substantial advances in enantioconvergent C(sp3)-C(sp3) bond formation reactions have been made in recent years
through the use of transition-metal-catalyzed cross-coupling reactions of
racemic secondary alkyl electrophiles with organometallic reagents.
Br
Ni cat.
R
Herein, we report a general process for the asymmetric construction of
alkyl-alkyl bonds adjacent to heteroatoms, namely, a nickel-catalyzed
enantioconvergent reductive hydroalkylation of olefins with α-heteroatom
phosphorus or sulfur alkyl electrophiles. Including the use of readily
available olefins, this reaction has considerable advantages, such as mild
reaction conditions, a broad substrate scope, and good functional group
compatibility, making it a desirable alternative to traditional electrophile–
nucleophile cross-coupling reactions.
+
R
[P/S]
R
H
[P/S]
[Si]-
R
>50 examples up to 99% e.e.
,
phosphonates, phosphine oxides,
sulfonamides, sulfones
enantioenriched
alkyl-alkyl cross-coupling and our reductive olefin
hydrocarbonation concept, enantioconvergent reductive
hydroalkylation of olefins could make extensive alternative to
traditional electrophile–nucleophile cross-coupling reactions.
1. INTRODUCTION
Carbon–carbon bond formation is
a
fundamental
transformation in organic synthesis. Over the past few decades,
a wide array of effective strategies for constructing carbon–
carbon bonds have been developed.1 Even so, the demand for
the controlled construction of bonds between sp3-hybridized
carbon atoms is continually growing, as such a method would
be a privileged reaction in retrosynthetic analysis due to the
ubiquity of alkyl-alkyl bonds.2 In recent years, progresses have
been made in transition-metal-catalyzed (especially nickel-
catalyzed) enantioconvergent substitution reactions, which
enable the cross-coupling of racemic secondary alkyl
electrophiles with organometallic reagents.3
On the other hand, stereochemical control of the formation of
C(sp3)-C(sp3) bonds adjacent to heteroatoms is an important
topic in organic synthesis. For example, Fu and co-workers
reported the enantioconvergent cross-coupling of racemic α-
haloboronates with alkylzinc reagents (Scheme 1a, top).7 Later,
Fu and Oestreich independently reported enantioselective alkyl-
alkyl bond formations using racemic α-silylated alkyl halides
and alkylzinc reagents (Scheme 1a, bottom).8 In addition, the
asymmetric construction of C(sp2)-C(sp3) bonds at the α-
positions of oxygen,9 sulfur,10 or nitrogen11 atoms have also
been realized. Considering that chiral phosphorus or sulfur-
bearing compounds are useful intermediates or target molecules
in coordination chemistry,12 materials chemistry,13 and
pharmaceutical chemistry,14 the development of effective
methods for the creation of these products is of great importance
in synthetic chemistry (Scheme 1b).15 Herein, we report the
discovery of a general process for the asymmetric construction
of alkyl-alkyl bonds adjacent to heteroatoms, specifically, a
nickel-catalyzed enantioconvergent reductive hydroalkylation
of olefins with α-phosphorus or sulfur alkyl electrophiles. In
terms of applicability and practicality, this reaction shows high
chemo-, regio-, and enantioselectivity and provides a general
and modular strategy for the preparation of enantioenriched
phosphonates, alkyldiarylphosphine oxides, sulfonamides, and
sulfones (Scheme 1c).
Simple unactivated olefins are frequently involved as
synthons in organic synthesis, also as bulk chemicals in
industry.4 The use of olefins to replace alkyl organometallic
reagents (e.g., alkylzinc reagents) would have considerable
advantages, such as milder reaction conditions, increased
availability of the starting materials, broader substrate scope,
and better functional group compatibility. In 2016, our group
reported the first example of a nickel-catalyzed intermolecular
reductive coupling between unactivated olefins with alkyl or
aryl electrophiles; however, the enantiomer mixture products
limited their further transformation.5 Most recently, Fu reported
a breakthrough in enantioselective alkyl-alkyl cross-couplings
of racemic alkyl electrophiles with olefins, and alkyl bromides
adjacent to carbonyl groups (amide, ester, or ketone) were
suitable substrates for this reaction.6 Combining with the
historical achievements in nickel-catalyzed enantioconvergent
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Br
Scheme 1. Enantioselective Alkyl-Alkyl Bond Formation
Adjacent to Heteroatoms
OEt
Ph
P
1
2
3
4
5
6
7
8
standard conditions
OEt
Me
O
L*
10% NiBr2(diglyme), 15% (S,S)-
2.5 eq. (MeO)3SiH, 2.5 eq. Cs2CO3
1
2
, 1.0 eq.
OEt
OEt
Previous Works
Alkyl-Alkyl Bond Formation Adjacent to Heteroatom B, Si
a)
Ph
P
+
glyme:DCE (2:1), 18 oC, 12 h
O
10% NiBr2(diglyme)
R2
Me
3
Ar
Ar
X
L *
13% (S,S)-
1
+
+
R2ZnBr
R2ZnBr
, 2.0 eq.
MeHN
NHMe
R1
[B]
R1
THF/DMAc, 0 o
C
[B]
Ar = 2-Me-Ph
(S,S)-L1
[B] = Bpin
X = Cl, I
O
O
N
O
N
N
N
N
N
Ph
tBu
tBu
10% NiBr2(diglyme)
L *
Ph
Ph
R2
R
OH
HO
O
O
Br
13% (S,S)-
2
N
9
R1
N
N
L3, 3% yield, N.D. e.e.
L4, 12% yield, 1% e.e.
L5, R = H, 2% yield, N.D. e.e.
6, R = Me, 4% yield, N.D. e.e.
[Si]
R1
[Si]
DMAc, r.t.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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50
51
52
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58
59
60
L
iBu
(S,S)-L2
iBu
[Si] = SiPh2Et, SiMe3 etc.
n
Me Me
Representative Compounds
b)
Alkyl Carbon Centre Adjacent to Heteroatom P
O
O
R
R
R
R
O
O
O
O
R
R
R
R
R
R
N
N
N
N
N
N
P
P
R1 = H, Me
n
Ph
Ph
OH
N
O
P
Ph
Ph
Ph
Ph
R1
R2 = H, Aryl, Alkyl
L
L
L
L
L
L
OH
7, R = H, 30% yield, 60% e.e.
8, R = Ph, 49% yield, 89% e.e.
9, n = 1, 38% yield, 45% e.e.
10, n = 3, 43% yield, 61% e.e.
11, R = H, 39% yield, 69% e.e.
12, R = Ph, 56% yield, 91% e.e.
OH
Fosmidomycin
(R1 = R2 = H)
O
R2
n = 0, 1, 2; R = Me, Et
Ar
O
Ar
O
Me Bn
Antimalarial Drugs
Asymmetric Ligands
O
O
R
R
R
R
This Work
c)
Reductive Hydroalkylation of Olefins with Alkyl Electrophiles Adjacent to P, S
N
N
N
N
Ph
Ph
Ph
Ph
Ar = 4-tBu-Ph
L
14, 49% yield, 63% e.e.
R
Ni cat.
Br
R
L
13, R = H, 52% yield, 69% e.e.
L*
+
(S,S)- , R = Ph, 87% yield, 98% e.e.
[P/S]
Enantioconvergent
R
[P/S]
R
H
[Si]-
>50 examples
up to 99% e.e.
enantioenriched
phosphonates,
phosphine oxides,
sulfonamides,
sulfones
yield
entry
deviation from the standard conditions
e.e. (%)
(%)
Novel auxiliary heteroatom for stereochemical control
Broad substrate scope and functional group compatibility
Excellent enantioselectivity and good coupling yield
Ready availability of olefins for C-C formation
87
98
1
2
none
(84b)
NiCl2(glyme), NiBr2(glyme) or
Applications in pharmaceutical chemistry and coordination chemistry
76-83
97-98
Ni(NO3)2(6H2O) instead of NiBr2(diglyme)
(EtO)3SiH instead of (MeO)3SiH
DEMS instead of (MeO)3SiH
3
4
5
6
7
8
9
77
21
98
93
Bpin = pinacol borate. Diglyme = 2-methoxyethyl ether. THF =
tetrahydrofuran. DMAc = N,N-dimethylacetamide.
MeEt2SiH instead of (MeO)3SiH
K2CO3, K3PO4 or CsF instead of Cs2CO3
KHCO3 instead of Cs2CO3
<1
N.D.
96-98
97
2. RESULTS AND DISCUSSION
64-82
19
We began our investigation with the synthesis of
phosphonate 3 through the reductive hydroalkylation of the
olefin 2 with alkylbromide 1 (Table 1). Based on our previous
work,5a careful selection of the bidentate N-ligand was critical
to the success of this reaction. Bipyridine (L3), bioxazoline (L4)
and pyridine-oxazoline (L5, L6) ligands were tested, and small
amounts of the desired products were observed. The use of
bisoxazoline ligands (L7-L14) dramatically improved the
coupling efficiency, and 5,5-diphenyl substitution on the
oxazoline ring further improved the yield and
enantioselectivity.16 (S,S)-L* provided the best results: 87% GC
yield, 84% isolated yield, and 98% enantiomeric excess. We
also screened the impact of other reaction parameters on the
efficiency of this reaction. For example, other nickel sources
(entry 2) led to slightly reduced yields. Other oxygen-bearing
silanes (entries 3-4),17 such as (EtO)3SiH and DEMS, could also
be used in this transformation, but MeEt2SiH provided no cross-
coupling product (entry 5). A moderately strong base gave
moderate to good productivity (entry 6), and a low yield was
obtained when using a weak base, such as KHCO3 (entry 7).
Finally, a number of other solvents were compared with the best
glyme/DCE mixture (entry 9); glyme gave a slightly reduced
conversion, while DCE, THF, and DMAc were inferior due to
significant hydrodebromination as a side reaction (see the
Supporting Information for more details).
glyme instead of glyme/DCE
73
96
DCE, THF or DMAc instead of glyme/DCE
44-48
95-98
a
Conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.4 mmol, 2.0 equiv),
nickel source (0.02 mmol, 10 mol%), ligand (0.03 mmol, 15
mol%), silane (0.5 mmol, 2.5 equiv), base (0.5 mmol, 2.5 equiv),
solvent (1.2 mL), 18 °C, 12 h. Triphenylmethane was used as an
internal standard. GC yield. b Isolated yield. Bn = benzyl. Glyme =
= 1,2-dichloroethane. DEMS =
diethoxymethylsilane. e.e. = enantiomeric excess. N.D. = no
detection.
1,2-dimethoxyethane. DCE
With the optimized reaction conditions in hand, we sought to
probe the substrate scope of unactivated alkenes (Scheme 2). A
variety of unactivated alkenes were successfully converted to
the desired products (3-20) in uniformly good yields (56-93%
yield) and with high enantioinduction (96-99% e.e.). For the
synthesis of phosphonate 3, when using (R,R)-L* as the ligand,
the opposite enantiomer was formed in good yield and high
enantioselectivity (86% GC yield, -96% e.e.). This reaction also
proceeded smoothly when we halved the catalyst loading (71%
GC yield, 97% e.e.), or used less alkene (68% GC yield, 98%
e.e.), and the yields were only slightly diminished. Moreover,
this cross-coupling was not overly sensitive to air (capped vial,
58% GC yield, 98% e.e.) or moisture (1.0 equivalent of water
added, 82% GC yield, 98% e.e.).
Table 1. Optimization of the Reaction Conditionsa
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The mild conditions make this reaction tolerant of a diverse
for epoxide (19) and other sensitive functional groups
demonstrated that this reaction offers considerable advantages
over longstanding methods, such as substitution reactions using
alkali metal phosphides or alkyl organometallic reagents
(organolithiums or Grignard reagents) and strong base-
promoted H-phosphinate alkylation reactions.18 Finally,
ethylene (in a balloon), the simplest alkene, was demonstrated
to be a good substrate, and it provided desired product 20 in
excellent isolated yield (93%) and 98% enantiomeric excess;
subsequent hydrolysis gave out the corresponding phosphonic
acid (21).19
1
2
3
4
5
6
7
8
array of synthetically relevant functional groups, including
relatively robust ones, such as ether (4), aryl fluoride (4),
alkylamide (5), phthalimide (6), and aryl ester moiety (7).
Several base-sensitive functional groups, such as alkyl ester (8),
cyano (9), ketone (10), and silylether groups (11), were also
well tolerated. Heterocycles such as pyran (12), furan (13),
thiophene (14), indole (15), and pyrrole (16) survived in the
reaction. The compatibility of aryl chloride (17) and aryl
bromide (18) facilitates further functionalization reactions at
the retained carbon-halogen bond. Furthermore, the tolerance
9
10
11
12
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
Scheme 2. Substrate Scope of Unactivated Alkenesa
standard conditions
10% NiBr2(diglyme), 15% (S,S)-
2.5 eq. (MeO)3SiH, 2.5 eq. Cs2CO3
Me
Bn
N
L*
R2
Br
O
O
Ph
Ph
Ph
Ph
OEt
OEt
P
R2
+
Ph
P
O
N
Ph
glyme:DCE (2:1), 18 oC, 12 h
OEt
OEt
Ph
O
Ph
L*
(S,S)-
1
2.0 eq.
, 1.0 eq.
F
Bn
N
Me
b
L*
(R,R)- : 86% yield, -96% e.e.
Me
b
OEt
5
O
L*
5% NiBr2(diglyme), 7.5% (S,S)- : 71% yield, 97% e.e.
OEt
P
O
OEt
Ph
P
O
1.5 eq. alkene: 68% yield, 98% e.e.b
F
OEt
Ph
Ph
P
O
OEt
under air, capped vial: 58% yield, 98% e.e.b
1.0 eq. H2O added: 82% yield, 98% e.e.b
OEt
O
3
4
5
, 83% yield, 98% e.e.
, 84% yield, 98% e.e.
, 79% yield, 99% e.e.
O
OMe
O
O
N
OEt
OEt
P
Me Me
O
Ph
P
Ph
P
O
COOEt
Ph
CN
OEt
O
O
OEt
OEt
OEt
OEt
O
Ph
P
OEt
O
6
7
8
9
, 77% yield, 96% e.e.
, 91% yield, 98% e.e.
, 86% yield, 98% e.e.
, 60% yield, 96% e.e.
O
O
O
Me
O
OTBS
O
O
OEt
OEt
Me Me
P
OEt
O
Ph
Ph
P
O
Ph
P
O
O
OEt
Ph
P
OEt
OEt
OEt
OEt
O
10
11
12
13
, 80% yield, 99% e.e.
, 80% yield, 98% e.e.
, 82% yield, 98% e.e.
, 56% yield, 97%/97% e.e., 1.1 : 1 d.r.
Cl
O
N
N
O
S
OEt
OEt
P
OEt
Me
P
OEt
O
Ph
P
Ph
Ph
O
Ph
P
Cl
OEt
OEt
O
OEt
OEt
17
, 70% yield, 97% e.e.
O
O
O
14
15
16
, 80% yield, 99% e.e.
, 78% yield, 99% e.e.
, 80% yield, 98% e.e.
Me
Br
O
O
Me
OEt
Me
OH
P
H
4
H
OEt
H
Ph
P
Ph
Ph
P
OEt
O
OEt
OH
H
OEt
O
O
O
Ph
P
OEt
O
18
19
ethylene balloon
20
21
, 85% yield, 96% e.e.
, 85% yield, 98% e.e.
, 70% yield, 98%/98% e.e., 1 : 1 d.r.
, 93% yield, 98% e.e.
a Standard conditions: alkyl bromide (0.2 mmol, 1.0 equiv), alkene (0.4 mmol, 2.0 equiv), NiBr2(diglyme) (0.02 mmol, 10 mol%), (S,S)-L*
(0.03 mmol, 15 mol%), (MeO)3SiH (0.5 mmol, 2.5 equiv), Cs2CO3 (0.5 mmol, 2.5 equiv), glyme/DCE (1.2 mL, v/v = 2:1), 18 °C, 12 h.
Isolated yield. b Triphenylmethane was used as an internal standard. GC yield. TBS = tert-butyldimethylsilyl. Diastereomers marked with
spherical symbol.
We next investigated the substrate scope of α-heteroatom
alkyl electrophiles (Scheme 3). This reaction tolerated a diverse
array of phosphates, including diethyl (22), dimethyl (23),
diisopropyl (24), and diisobutyl phosphonates (25). Although
these substituents result in dramatically different amounts of
steric hindrance (22-25), high coupling efficiencies (70-86%
yield) and excellent enantioselectivities (98% e.e.) were
obtained in all cases. The α-alkyl substituent of the
bromophosphate could also be altered. In general, substrates
with less bulky alkyl substituents delivered products in good
yields and high enantioselectivities (26-28), while bulkier
substrates gave moderate coupling efficiencies (29 and 30). In
the case of the α tert-butyl substituted substrate, a large amount
of the hydrodebromination side-product was formed, and the
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yield was 22% with complete loss of enantioselectivity (31).
stereochemistry of the α-position of the phosphonate was
entirely controlled by the chiral catalysts, and the
stereoselectivity at the α-position of the methyl group (1.5:1
diastereomeric ratio) was attributed to kinetic resolution during
the C-C bond formation.
1
2
3
4
Nonetheless, this reaction showed notable functional group
compatibility; internal alkene (32), phthalimide (33), and
thioether (34) were all well tolerated in the transformation.
Finally, with substrate 35, which has two chiral centres, the
5
6
Scheme 3. Substrate Scope of α-Heteroatom Alkyl Electrophilesa
7
8
9
standard conditions
10% NiBr2(diglyme), 15% (S,S)-
2.5 eq. (MeO)3SiH, 2.5 eq. Cs2CO3
Me
Bn
N
L*
R2
Br
O
O
Ph
Ph
Ph
Ph
R2
+
R1
[P/S]
R1
[P/S]
N
glyme:DCE (2:1), 18 oC, 12 h
Ph
Ph
10
11
12
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
L*
(S,S)-
1.0 eq.
2.0 eq.
Phosphonates
Ar =
OAr
OAr
OAr
O
OMe
OiPr
OiBu
OiBu
OEt
Ph
P
Ph
P
Ph
P
O
Ph
P
O
OMe
OiPr
O
O
OEt
22
23
24
25
, 86% yield, 98% e.e.
, 70% yield, 98% e.e.
, 80% yield, 98% e.e.
, 82% yield, 98% e.e.
OAr
OEt
OAr
OAr
OEt
Me
OEt
P
OEt
Me
P
O
Me
P
Me
P
OEt
OEt
O
OEt
OEt
O
O
Me
26
27
28
29
, 65% yield, 96% e.e.
, 68% yield, 97% e.e.
, 61% yield, 97% e.e.
, 43% yield, 93% e.e.
OAr
OAr
OAr
OEt
Me
OAr
O
OiPr
OEt
P
OEt
P
Me
Me
N
P
O
P
O
OiPr
OEt
O
OEt
OEt
O
Me
O
30
31
32
33
, 32% yield, 96% e.e.
, 22% yield, < 2% e.e.
, 63% yield, 96% e.e.
, 85% yield, 97% e.e.
Phosphine Oxides
OAr
OAr
OAr
OAr
Ph
OEt
P
OiPr
Ph
Me
S
P
O
Ph
P
Me
P
OEt
OiPr
Ph
Ph
O
Me
O
O
tBu
b
b
34
L*
35 with (S,S)- , 51% yield, 94%/92% e.e., 1.5:1 d.r.
with (R,R)- , 48% yield, -96%/-94% e.e., 1.44:1 d.r.
, 46% yield, 96% e.e.
,
36
37
, 83% yield, 94% e.e.
, 42% yield, 92% e.e.
L*
Sulfonamides
OAr
Me
OAr
Me
O
ArO
Me
Ph
Me
P
S
Ph
P
Me
Me
P
N
2
O
O
Ph
2
O
O
O
Me
b
b
b
38
39
43
47
40
41
, 57% yield, 91% e.e.
70% yield, 92% e.e.b
, 87% yield, 93% e.e.
, 37% yield, 90% e.e.
, 71% yield, 93% e.e.
Me
Me
O
S
O
Me
O
S
O
O
S
O
S
Me
Me
COOEt
N
Ph
N
Ph
N
O
N
O
O
O
O
Ph
Ph
, 90% yield, 84% e.e.
b
b
45
42
44
, 50% yield, 89% e.e.
, 62% yield, 92% e.e.
76% yield, 92% e.e.b
, 90% yield, 92% e.e.
Sulfones
OAr
Me
O
S
Me
OAr
O
O
S
Me
O
S
O
Me
Me
Me
S
O
O
Me
O
Me
Me
Me
b
b
b
b
46
48
49
, 83% yield, 85% e.e.
, 67% yield, 85% e.e.
, 81% yield, 80% e.e.
, 80% yield, 82% e.e.
a Standard conditions: as shown in Scheme 2, 0.2 mmol scale. Isolated yield. b Modified conditions: alkyl bromide (0.2 mmol, 1.0 equiv),
alkene (0.4 mmol, 2.0 equiv), NiBr2(diglyme) (0.02 mmol, 10 mol%), (S,S)-L* (0.03 mmol, 15 mol%), (MeO)3SiH (0.5 mmol, 2.5 equiv),
K3PO4 (0.5 mmol, 2.5 equiv), DMAc/DCE (1.2 mL, v/v = 1:1), 18 °C, 12 h. Isolated yield. iPr = isopropyl. iBu = isobutyl. tBu = tert-butyl.
Diastereomers marked with spherical symbol.
Although α-bromophosphates were the primary focus in this
study, this reaction could also be applied to α-bromo
alkyldiarylphosphine oxides with minimal reoptimization (36-
40). The aryl substituents on the diarylphosphine oxide did not
influence the enantioselectivity. However, the α-alkyl
substituent substantially affected the coupling yield, and
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hydrodebromination was the major side reaction. We were
This reaction exhibited good tolerance to diverse functional
groups and provides attractive options for the easy modification
of natural products or drug molecules (Scheme 4). For example,
derivatives of coumarin (50), glucose (51 and 52), and estrone
(53 and 54) reacted with α-bromophosphate 1 to afford the
corresponding products. Moreover, with the other enantiomer
of the ligand, diastereomers of the products were obtained,
although slightly decreased yields were obtained with the
mismatched catalyst. In the modification of the complex drug
molecules indomethacin and atorvastatin, we obtained desired
products 55, 56, and 57 using the corresponding enantiomers of
the ligand (Scheme 4a). Fosmidomycin has anti-plasmodium
falciparum activity and thus could be used as an antimalarial
1
2
3
4
5
6
7
8
pleased to find that even vastly different sulfur-containing
compounds were suitable substrates for this transformation.
Thus, good enantioselectivities and excellent isolated yields
were achieved with functionalized α-bromo sulfonamide (41-
45) and sulfone substrates (46-49). Notably, although α-sulfur
alkyl halides have been reported as good substrates in
enantioselective C(sp2)-C(sp3) formation reactions, they have
never been used for the asymmetric construction of C(sp3)-
C(sp3) bonds.10a
9
10
11
12
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
Scheme 4. Synthetic Applicationsa
a) Late-stage functionalization
drug. The α-substituent adjacent to the phosphorous atom could
Me
O
OBn
O
influence the antimalarial activity.15b,
To our delight,
20
BnO
OBn
OBn
from Coumarin
brominated fosmidomycin derivative 58 was indeed a good
substrate in our method (Scheme 4b). α-Ethylated derivative 59
was obtained in 55% isolated yield and 99% enantiomeric
excess. Moreover, this reaction efficiently coupled unnatural
amino acids to deliver products 60 and 61 in a convergent
fashion.21 Finally, we used this method as an efficient approach
to access new ligands (Scheme 4c). Product 64 was obtained
from a gram-scale reaction in 49% isolated yield and 94%
enantiomeric excess. Further nucleophilic substitution of an
alkyl tosylate and phosphine-oxygen double bond reduction
would lead to a novel chiral DPPPe analogue 65.18, 22
from Glucose
O
O
3
OEt
OEt
P
Ph
Ph
P
Ph
OEt
O
OEt
O
50
51
52
L*
L*
, 78% yield, 98% e.e.
, with (S,S)- , 84% yield, 99 : 1 d.r.
, with (R,R)- , 71% yield, 1.5: 98.5 d.r.
O
from Indomethacin
OMe
OEt
O
Me
O
P
OEt
O
3
Me
N
H
H
O
Me
S
from Estrone
O
O
O
N
H
Cl
O
53
54
L*
, with (S,S)- , 86% yield, 98 : 2 d.r.
Scheme 5. Mechanism Studya
b
L*
55
, with (R,R)- , 81% yield, 1: 99 d.r.
, 40% yield, 83% e.e.
Ph
Ar
a)
from Atorvastatin
HN
Ar =
Ph
OAr
standard
conditions
O
P
Br
OEt
Me
O
3
N
OEt
P
OEt
O
67
+
OEt
P
O
S
F
O
O
OAc OAc
OEt
, 1.0 eq.
OAr
OEt
Me
O
O
Me
2.0 eq.
N
O
66
68
69
, Not observed
, 22% yield
b
56
57
L*
, with (S,S)- , 26% yield, 90 : 10 d.r.
b
L*
, with (R,R)- , 30% yield, 7 : 93 d.r.
O
P
OEt
P
OEt
OEt
P
OEt
O
OEt
H
b) Synthesis of Fosmidomycin analogues
O
OEt
70
, 35% yield
standard
conditions
R
P
Br
OiBu
OiBu
OiBu
OiBu
Boc
b)
Boc
N
P
N
standard
conditions
Br
Me
3
O
OBn
O
OBn
OEt
+
2
OEt
Ph
c)
P
58
, 1.0 eq.
R =
reaction time = 1 h
33% conversion
59
, R = Me, 55% yield, 99% e.e.
OEt
Ph
P
O
O
2.0 eq.
OEt
b
COOMe
NHBoc
1
1
67% yield of recovered, racemic
, 1.0 eq.
b
60
61
L*
, with (S,S)- , 57% yield, 98.5 : 1.5 d.r.
L*
, with (R,R)- , 62% yield, 2.5 : 97.5 d.r.
3
, 26% yield, 97% e.e.
standard
conditions
Me
3
Ph
H
c) Synthesis of DPPPe analogue
Ph
OEt
OEt
Me
+
Si(OMe)3
1
modified
conditions
P
5
Br
P
w/o (MeO)3SiH
OEt
OEt
OTs
O
O
b
1.0 eq.
71
, 2.0 eq.
+
1
74% yield of recovered
OTs
Me
PPh2
b
Me
PPh2
b
3
, Not observed
72
, 23% yield
O
O
62
63
64
0.2 mmol, 56% yield, 94% e.e.b
, 1.0 eq.
, 2.0 eq.
a
Standard conditions: as shown in Scheme 2, 0.2 mmol scale.
Isolated yield. w/o = Without. b Triphenylmethane was used as an
internal standard. GC yield. Ar = 2-naphthyl.
b
1.12 g
5.0 mmol,
, 49% yield, 94% e.e.
i) nucleophilic substitution
ii) P=O reduction
PPh2
To examine the reaction mechanism, we conducted a radical
clock experiment using substrate 66, which contains a
(cyclopropyl)methyl group. We obtained only ring-opening
product 68 in 22% isolated yield, which revealed the
involvement of a radical ring-opening process (Scheme 5a).23
Under the standard conditions the conversion was on 33%, the
enantiomeric excess of desired product 3 was unaffected.
Recovered alkyl bromide 1 was racemic, which could rule out
the pathway of a simple kinetic resolution process (Scheme
5b).24 Nickel was previously shown to be highly active in the
hydrosilylation of unactivated alkenes.25 Thus, an in-situ
PPh2
Me
PPh2
, 61% yield, 92% e.e.
DPPPe
PPh2
65
a
Standard conditions: as shown in Scheme 2, 0.2 mmol scale.
b
Isolated yield. Modified conditions: as shown in Scheme 3, 0.2
mmol scale. Isolated yield. For nucleophilic substitution and
phosphine-oxygen double bond reduction, see the Supporting
Information for more details. Ac = acetyl. Ts = tosyl. Diastereomers
marked with spherical symbol.
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Detailed experimental procedures and spectral data for all
compounds
hydrosilylation and Hiyama-type cross-coupling might be a
1
2
3
4
5
6
possible pathway. To verify this possibility, putative alkylsilane
71 was subjected to the standard reaction conditions, but no
desired product was observed, which ruled out this pathway
(Scheme 5c). Collectively, a radical-type enantioconvergent
reaction mechanism should be a reasonable explanation. Our
current hypothesis was consistent with the proposed mechanism
depicted in Fu and Hu’s works.6a, 26, 27
AUTHOR INFORMATION
Corresponding Author
*E-mail: luxi@mail.ustc.edu.cn.
*E-mail: fuyao@ustc.edu.cn.
7
8
9
ORCID
3. CONCLUSION
Xi Lu: 0000-0002-9338-0780
Yao Fu: 0000-0003-2282-4839
In summary, we have described a general method for an
enantioconvergent alkyl–alkyl cross-coupling adjacent to
heteroatoms, namely, a nickel-catalyzed asymmetric reductive
hydroalkylation of olefins with racemic α-phosphorus or sulfur
alkyl electrophiles. This reaction proceeded under mild
conditions and exhibited good chemo-, regio-, and
enantioselectivity, providing an attractive complement to
traditional electrophile–nucleophile cross-coupling reactions
using alkyl organometallic reagents. We anticipate that this
reaction could be broadly applicable, including in the fields of
pharmaceutical chemistry and coordination chemistry.
10
11
12
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
Author Contributions
All authors have given approval to the final version of the
manuscript.
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors acknowledge the National Natural Science Foundation
of China (Grants 21732006, 21702200, 51821006, and
51961135104), the support from the National Key R&D Program
of China (Grant 2017YFA0303502), the Strategic Priority
Research Program of CAS (Grant XDB20000000), the Major
Program of Development Foundation of Hefei Centre for Physical
Science and Technology (Grant 2017FXZY001), and the Users
with Excellence Program of Hefei Science Center CAS (Grant
2019HSC-UE017).
4. EXPERIMENTAL SECTION
4.1. General Procedure (Standard Synthetic Method) for
Reductive Hydroalkylation. In the air, a 10 mL screw-cap test
tube equipped with a magnetic stirrer was charged with
NiBr2(diglyme) (7.0 mg, 0.02 mmol, 10 mol%), ligand L* (21.4
mg, 0.03 mmol, 15 mol%) and Cs2CO3 (162.9 mg, 0.5 mmol,
2.5 eq.) (if olefin or racemic electrophile is a solid, it was also
added at this time). The test tube was evacuated and backfilled
with argon for three times, then glyme (0.8 mL) and DCE (0.4
mL) were added, followed by the olefin (0.4 mmol, 2.0 eq.) and
racemic electrophile (0.2 mmol, 1.0 eq.). The resulting solution
was stirred for 10 min at 0 °C, (MeO)3SiH (64 uL, 0.5 mmol,
2.5 eq.) was added dropwise via syringe and the solution was
kept stirring for 2 min at 0 °C, then was stirred at 18 °C for 12
h. The reaction mixture was diluted with H2O followed by
extraction with EtOAc, dried with anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel to give the target product.
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Supporting Information.
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
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Journal of the American Chemical Society
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