Access to Chiral HWE Reagents by Rhodium-Catalyzed Asymmetric Arylation of γ,δ-Unsaturated β-Ketophosphonates

Article abstract of DOI:10.1021/acs.joc.8b00952

Asymmetric arylation of ?,?-unsaturated β-ketophosphonates with arylboronic acids is reported. By using the (R)-diene? ligated rhodium(I) chloride complex as a catalyst under none basic conditions, the corresponding β-ketophosphonates bearing a ?-chiral center were obtained in high yields (up to 99%) with good to excellent enantioselectivities (up to >99% ee). The enantioenriched products can be readily converted to diverse chiral β′-aryl enones by the Horner-Wadsworth-Emmons reaction.

Full text of DOI:10.1021/acs.joc.8b00952

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Note
Access to Chiral HWE Reagents by Rhodium-Catalyzed
Asymmetric Arylation of #,#-Unsaturated #-Ketophosphonates
Long Yin, Dewei Zhang, Junhao Xing, Yuhan Wang, Changhui
Wu, Tao Lu, Yadong Chen, Tamio Hayashi, and Xiaowei Dou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00952 • Publication Date (Web): 01 May 2018
Downloaded from http://pubs.acs.org on May 1, 2018
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Access to Chiral HWE Reagents by Rhodium-Catalyzed Asymmetric
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Arylation of ,-Unsaturated -Ketophosphonates
§
,†
§,‡
†
†
†
†,#
,‡
Long Yin, Dewei Zhang, Junhao Xing, Yuhan Wang, Changhui Wu, Tao Lu, Yadong Chen,*
,¶
,†
Tamio Hayashi,* and Xiaowei Dou*
†
‡
Department of Organic Chemistry and Laboratory of Molecular Design and Drug Discovery, School of Science, China
Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
#State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
¶Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, 21 Nanyang Link, Singapore 637371, Singapore
ABSTRACT: Asymmetric arylation of ,-unsaturated -ketophosphonates with arylboronic acids is reported. By using (R)-diene*
ligated rhodium(I) chloride complex as catalyst under none basic conditions, the corresponding -ketophosphonates bearing a -
chiral center were obtained in high yields (up to 99%) with good to excellent enantioselectivities (up to >99% ee). The enantioen-
riched products can be readily converted to diverse chiral ’-aryl enones by the HWE reaction.
The Horner–Wadsworth–Emmons (HWE) reaction is one of
the most useful methods for the preparation of olefins, and the
Scheme 2. Rhodium-Catalyzed Arylation of ,-
Unsaturated Carbonyl Compounds
1
HWE reagents (for example -carbonyl phosphonates) are
versatile synthons and widely used in the synthesis of various
2
building blocks, natural products, as well as pharmaceuticals.
Despite the great successes achieved in the development of the
HWE reaction, examples on the asymmetric synthesis of chiral
HWE reagents are rare. Asymmetric conjugate addition to ,-
unsaturated -ketophosphonates represents a convenient ap-
proach to those molecules:3 Kim and co-workers developed a
Zn(II)-catalyzed asymmetric radical conjugate addition of ,-
unsaturated -ketophosphonates, and alkyl groups could be
3
a
introduced to the -position with high enantioselectivities;
besides, the asymmetric Friedel–Crafts reaction of indoles
3
b,3c
with ,-unsaturated -ketophosphonates was also studied.
However, the available chiral HWE reagents accessed by this
route are still greatly limited, as a general method to introduce
the aryl groups remains unknown. To address this challenge,
we report herein a general asymmetric conjugate arylation of
,-unsaturated -ketophosphonates (Scheme 1).
Scheme 1. Asymmetric Conjugate Addition to ,-
Unsaturated -Ketophosphonates
The rhodium-catalyzed conjugate arylation reactions of ac-
tivated olefins with arylboronic acids have progressed remark-
4
ably since the seminal reports, and have now become one of
the most reliable methods to generate benzylic chiral centers.5
Despite the numerous reports on the rhodium-catalyzed aryla-
5,6
tion reactions of ,-unsaturated carbonyl compounds, ary-
lation of ,-unsaturated ketones bearing an ’-electron-
withdrawing group has not been studied. Such a transfor-
mation may be hampered by several challenges. First, the ad-
jacent electron-withdrawing group helps stabilize the enol
form of the ketone, thus may result in low reactivity of the
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substrate towards conjugate arylation reaction. Moreover, it is
rhodium-catalyzed asymmetric arylation reactions,8 and we
then tested the effects of those privileged ligands. Although
the (R,R)-Ph-bod ligand did not give a satisfactory ee value
proved that the catalytically active hydroxorhodium catalyst
can be immediately converted to the acetylacetonate rhodium
complex in the presence of acetylacetone, resulting in a much
less catalytically active rhodium species;7 similarly, ,-
unsaturated ketones bearing an ’-electron-withdrawing group
may also deactivate the rhodium catalyst in the same manner
9
(entry 3, 54% ee), gratifyingly, the easily accessible (R)-
10
diene*-ligated rhodium catalyst produced the product in
good yield with excellent enantioselectivity (entry 4, 95% ee).
Further screening of solvents showed that toluene was the best
to give the product in 95% yield with the maintained ee value
(entries 4–6). When the catalyst loading was reduced, the re-
(Scheme 2). Nevertheless, with an aim to address the afore-
0
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mentioned issue in the synthesis of chiral HWE reagents, as
well as to study the rhodium-catalyzed arylation of ,-
unsaturated ketones bearing an ’-electron-withdrawing group,
we embarked on a project to investigate the rhodium-catalyzed
asymmetric arylation of ,-unsaturated -ketophosphonates.
1
1
cently developed base-free condition was found to be slightly
superior to the traditional condition (entries 7 & 8). Finally,
the catalyst loading could be further reduced to 1 mol % Rh
without erosion of the yield and enantioselectivity (entry 9).
With the optimal reaction conditions, the scope of the reac-
tion was then examined. As summarized in Table 2, diverse
aryl boronic acids could be employed in this reaction system,
and generally high yields and excellent enantioselectivities
were attainable. Aryl boronic acids bearing electron-donating
groups (entries 1‒5), halogen substitutions (entries 6‒8), as
well as electron-withdrawing groups (entries 9‒10) at different
positions were all well-tolerated. Other aryl boronic acids such
as naphthyl boronic acids and 3-thienyl boronic acid worked
equally well under optimal reaction conditions, and perfect ee
value was obtained when 1-naphthyl boronic acid was em-
ployed (entries 11‒13). In addition,,-unsaturated -
ketophosphonates bearing different -substitutions were also
verified. For instance, reactions employing substrates 1 bear-
ing diversely substituted -aryl groups proceeded smoothly to
yield the desired products with good results (entries 14‒18);
those substrates bearing -alkyl substitutions were also suita-
ble to afford the corresponding arylation products in high
yields with good to excellent enantioselectivities (entries
19‒23). Notably, 3-thienyl boronic acid worked well for both
the -aryl and -alkyl substrates, producing the products in
high yield with excellent enantiocontrol (entries 13 & 22).
Other heteroaryl boronic acid like the 2-furyl one also pro-
duced the product with high ee value, but the yield was only
moderate due to the fast protodeboronation under reaction
conditions (entry 23).
Table 1. Rhodium-Catalyzed Asymmetric Conjugate Ary-
a
lation of ,-Unsaturated -Ketophosphonate 1a
entry
Rh catalyst
solvent
yield
ee
b
(%)c
(
%)
95
92
91
88
83
95
90
95
95
1
2
3
4
5
6
[Rh(OH)((R)-binap)] d
2
dioxane
dioxane
dioxane
dioxane
DCE
76
74
54
95
95
95
95
95
95
[Rh(OH)((R)-segphos)] d
2
[RhCl((R,R)-Ph-bod)] e
2
[RhCl((R)-diene*)] e
[RhCl((R)-diene*)] e
[RhCl((R)-diene*)] e
[RhCl((R)-diene*)] e
2
2
2
toluene
toluene
toluene
toluene
7f
2
Table 2. Substrate Scope for the Conjugate Arylation of
8f,g
a
[RhCl((R)-diene*)]
2
,-Unsaturated -Ketophosphonates
9g,h
[RhCl((R)-diene*)]
2
aReactions were performed with 1a (0.15 mmol), 2a (1.5 equiv to
1
6
a), and Rh catalyst (5 mol % Rh) in solvent/H
0 C for 5 h. Yield of the isolated 3a. The ee value was deter-
2
O (1.0/0.1 mL) at
o
b
c
yield (%)b
ee (%)c
entry
3 (R, Ar)
mined by HPLC analysis on a chiral stationary phase column.
d
Generated in situ from [Rh(OH)(cod)
2
]
2
(5 mol % Rh) and ligand
1
2
3
4
5
6
7
3a (C H , 3-OMe-C H )
95
99
98
91
94
91
97
95
99
93
93
93
96
95
6
5
6
4
e
f
(
6 mol %). KOH (10 mol %) was added. [RhCl((R)-diene*)]
2
(2
O was added, and the reaction
time was 14 h. [RhCl((R)-diene*)] (1 mol % Rh) was used.
g
d
mol % Rh) was used. 0.5 mL H
2
6 5 6 4
3b (C H , 2-Me-C H )
h
2
3c (C
6
H
5
, 3-Me-C
, 4-Me-C
, 4-OMe-C
6 4
H )
We commenced our investigation with the model reaction
between,-unsaturated -ketophosphonate 1a and 3-
methoxyphenylboronic acid 2a, and the results are summa-
rized in Table 1. In the first set of the experiments, chiral
bisphosphine ligands (R)-binap and (R)-segphos-coordinated
rhodium catalysts were found to catalyze the reaction effi-
ciently, furnishing the conjugate addition product 3a in high
yield, but the enantioselectivities were only moderate (entries
3d (C
6
H
5
6
H
4
)
3e (C
H
6 5
6
H
4
)
)d
3f (C
6
H
5
6 4
, 3-Cl-C H
3g (C
H
6 5
, 3-Br-C
6
4
H )
1
& 2). Chiral diene ligands have proved to be powerful in the
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3h (C
3i (C
3j (C
3k (C
3l (C
3m (C
3n (2-Cl-C
3o (3-F-C
3p (4-Cl-C
3q (3,4-Cl
3r (3,4-OCH
3s (Me, C
3t (Et, C
3u (Me, 4-Me-C
6
H
5
, 4-Br-C
6
H
4
)d
)d
99
96
97
96
>99
95
98
95
94
95
92
92
92
96
92
97
95
Scheme 3. Gram-Scale Synthesis and Derivatization of the
Product
6
H
5
, 4-Ac-C
6
H
4
88
98
84
95
88
90
82
85
94
90
91
93
92
92
49
1
0
6
H
5
, 4-CO
, 1-naphthyl)d
, 2-naphthyl)d
, 3-thienyl)e
2
Me-C
6
H
4
)d
11
6 5
H
1
1
2
3
6 5
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
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5
5
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0
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5
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0
1
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0
6 5
H
14
6
H
4
, C
, C
, C
6
H
5
)
1
1
1
1
1
2
2
5
6
7
8
9
0
1
6
H
4
6
H
5
)
6
H
4
6
H
5
)
2
-C
H
6 3
, C
6 5
H )
2
O-C
6
H
4
, C
6
H
5
)
6 5
H )
6
5
H )
In summary, we have developed the first asymmetric conju-
gate arylation reaction of ,-unsaturated -ketophosphonates.
The strategy developed here features broad substrate scope,
low catalyst loading, high yield, and good to excellent enanti-
ocontrol, which provides a practical method for preparing the
useful enantioenriched HWE reagents. We hope current meth-
od will find broad applications in organic synthesis.
6 4
H )
3v (Et, 3-thienyl)e
3w (Et, 2-furyl)e
22
2
3
aReactions were performed with 1 (0.15 mmol), 2 (1.5 equiv to 1),
and [RhCl((R)-diene*)] (1 mol % Rh) in toluene/H O (1.0/0.5
mL) at 60 C for 14 h. Yield of the isolated product 3. The ee
value was determined by HPLC analysis on a chiral stationary
phase column. 0.30 mmol of 2 (2 equiv to 1) was used. 0.45
mmol of 2 (3 equiv to 1) was used.
EXPERIMENTAL SECTION
2
2
o
b
c
General Information. All air-sensitive manipulations were
carried out with standard Schlenk techniques under nitrogen or
argon. NMR spectra were recorded on Bruker AVANCE AV-
d
e
1
13
500 spectrometer (500 MHz for H, 125 MHz for C) or
1
Bruker AVANCE AV-300 spectrometer (300 MHz for H, 75
MHz for C). Chemical shifts were reported in δ (ppm) refer-
To demonstrate the practicality of this transformation, a
gram-scale synthesis was carried out. As shown in Scheme
3(A), when the reaction was scaled up to 3.0 mmol, the prod-
uct 3e could be obtained with almost no change in chemical
yield and stereoselectivity. The asymmetric arylation products
13
enced to the residual solvent peak of CDCl3 (δ 7.26) for 1H
NMR and CDCl3 (δ 77.0) for 13C NMR. Coupling constants
were reported in Hertz (Hz). Optical rotations were measured
on a RUDOLPH AUTOPOL IV automatic polarimeter. High
resolution mass spectra (HRMS) were obtained on Thermo
Scientific LTQ Orbitrap XL (ESI). For thin layer chromatog-
raphy (TLC), Yantai pre-coated TLC plates (HSGF 254) were
used, and compounds were visualized with a UV light at 254
nm. Further visualization was achieved by staining with
KMnO4 followed by heating. Column chromatography sepa-
rations were performed on silica gel (300–400 mesh). Enanti-
omeric excesses (ee) were determined by HPLC analysis on
SHIMADZU HPLC system with Daicel chiral columns.
3
obtained here with high % ee are readily converted in-
to enones bearing a ’-chiral center by the HWE reaction. For
instance, 3e was allowed to react with aryl and alkyl aldehydes
under mild conditions to produce the corresponding chiral ’-
aryl enones in high yields with the maintained ee value
(
Scheme 3(B)). The enantioenriched ’-aryl enones are versa-
tile building blocks in organic synthesis, and their asymmetric
synthesis has been a continuous research interest.12 Our proto-
col provides an alternative approach to that reported by Wil-
12a
lis. The arylation product also reacted with ketones to give
the ’-aryl-,-disubstituted enones. For example, (S)-ar-
turmerone 5 was synthesized from the arylation product 3u
and acetone (Scheme 3(C)), which represents one of the most
General Procedure for the Synthesis of 3. [RhCl((R)-
diene*)] (0.8 mg, 0.75 μmol, 1 mol % Rh) and arylboronic
2
acid 2 (0.225 mmol or 0.3 mmol) were placed in an oven-dried
Schlenk tube under nitrogen. Toluene (0.4 mL), substrate 1
13
efficient asymmetric synthesis routes to this sesquiterpene.
The absolute configurations of 4a and 5 were determined by
comparison of their specific rotation with that reported, and
the absolute configurations of products 3e and 3u were ac-
(0.15 mmol), H
2
O (0.5 mL) and another portion of toluene
(0.6 mL) were added successively, and the mixture was stirred
14
at 60 ℃ for 14 h. Upon completion, the reaction mixture was
passed through a short column of silica gel with EtOAc as
eluent. The solvent was removed on a rotary evaporator, and
the crude product was subjected to silica gel chromatography
cordingly assigned.
with CH
2
Cl /EA (3:2) as the eluent to afford product 3.
2
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4
4
4
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4
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5
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5
5
5
5
6
2
5
1
Gram-Scale Synthesis of 3e. [RhCl((R)-diene*)]
15 μmol, 1 mol % Rh) and 2e (683.8 mg, 4.5 mmol) were
placed in an oven-dried Schlenk tube under nitrogen. Toluene
2
(15.1 mg,
[]
CDCl
D
–2.0 (c 0.5, CHCl
3
3
) for 93% ee (R). H NMR (300 MHz,
) δ 2.22 (s, 3H), 2.93 (d, JP-H = 22.7 Hz, 2H), 3.32 (dd, J
= 7.5 Hz, 1.7 Hz, 2H), 3.60 (dt, JP-H = 11.3 Hz, 2.1 Hz, 6H),
4.47 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 6.94–6.98
(m, 2H), 7.08 (t, J = 7.5 Hz, 2H), 7.15–7.22 (m, 4H); P NMR
(
10 mL), substrate 1a (762.7 mg, 3.0 mmol), H O (10 mL) and
2
31
another portion of toluene (10 mL) were added successively,
and the mixture was stirred at 60 ℃ for 20 h. Upon comple-
tion, the reaction mixture was passed through a short column
of silica gel with EtOAc as eluent. The solvent was removed
on a rotary evaporator, and the crude product was subjected to
1
3
(CDCl
3
, 121 MHz) δ 22.2; C NMR (125 MHz, CDCl ) δ
3
21.4, 41.4, 42.4, 45.7, 50.0, 52.9, 53.0, 124.7, 126.4, 127.3,
127.8, 128.4, 128.5, 128.6, 138.1, 143.5, 143.7, 199.8, 199.9.
HRMS (ESI) calcd for C19
347.1404.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
H
24
O P [M+H] 347.1407, found
4
silica gel chromatography with CH
2
Cl /EA (3:2) as the eluent
2
to afford product 3e (1.01 g, 93% yield, 93% ee).
Dimethyl (R)-(2-oxo-4-phenyl-4-(p-tolyl)butyl)phosphonate
(3d). (91% yield, 93% ee (R)). Pale yellow oil, 47.2 mg at 0.15
mmol scale. The ee of 3d was determined by HPLC analysis:
(Chiralcel IC column, 1.0 mL/min, hexane/2-propanol =
40.0/60.0, 254 nm, tmajor = 12.8 min (R), tminor = 11.5 min (S));
Procedure for the Synthesis of 4. To a solution of 3e (54.4
mg, 0.15 mmol) in EtOH (2 mL) were added K
2
CO
3
(41.5 mg,
0
.3 mmol) and the corresponding aldehyde (0.3 mmol), and
the mixture was stirred at room temperature. After completion
of the reaction as indicated by TLC analysis, the mixture was
2
5
1
[] –1.6 (c 0.4, CHCl ) for 93% ee (R). H NMR (300 MHz,
D
3
extracted with CH
2
Cl
2
, washed with H
2
O, dried over MgSO4,
CDCl ) δ 2.31 (s, 3H), 3.03 (dd, J = 22.8 Hz, 1.5 Hz, 2H),
3
P-H
filtered, and concentrated under reduced pressure. The residue
was subjected to silica gel chromatography with PE/EA (10/1)
as the eluent to afford product 4.
3.41 (d, J = 7.6 Hz, 2H), 3.71 (dt, JP-H = 11.3 Hz, 2.0 Hz, 6H),
4.58 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 7.9 Hz, 2H), 7.13–7.22
(m, 3H), 7.23–7.33 (m, 4H); P NMR (CDCl , 121 MHz) δ
22.3; C NMR (125 MHz, CDCl ) δ 20.9, 41.4, 42.4, 45.4,
50.0, 52.9, 53.0, 126.4, 127.6, 127.7, 128.5, 129.3, 136.0,
140.5, 143.8, 199.86, 199.91. HRMS (ESI) calcd for
31
3
1
3
Procedure for the Synthesis of 5. To a solution of 3e (54.4
3
mg, 0.15 mmol) in EtOH (2 mL) were added K
2
CO (41.5 mg,
3
0
.3 mmol) and acetone (3.0 mmol), and the mixture was
+
+
o
C
19
H
24
O
4
P [M+H] 347.1407, found 347.1404.
stirred at 50 C for 12 h. After completion, the mixture was
extracted with CH Cl , washed with H O, dried over MgSO4,
2
2
2
Dimethyl (R)-(4-(4-methoxyphenyl)-2-oxo-4-phenylbutyl)-
filtered, and concentrated under reduced pressure. The residue
was subjected to silica gel chromatography with PE/EA (50/1)
as the eluent to afford product 5.
phosphonate (3e). (94% yield, 93% ee (R)). Pale yellow oil,
51.1 mg at 0.15 mmol scale. The ee of 3e was determined by
HPLC analysis: (Chiralcel IB column, 1.0 mL/min, hexane/2-
propanol = 60.0/40.0, 254 nm, tmajor
16.9 min (S)); []
NMR (300 MHz, CDCl
(d, J = 7.6 Hz, 2H), 3.68 (dd, JP-H = 11.1 Hz, 1.7 Hz, 6H), 3.75
(s, 3H), 4.54 (t, J = 7.4 Hz, 1H), 6.76–6.85 (m, 2H), 7.11–7.30
(m, 7H); P NMR (CDCl
MHz, CDCl ) δ 41.4, 42.4, 45.0, 50.1, 52.9, 53.0, 55.2, 114.0,
26.4, 127.7, 128.5, 128.7, 135.7, 143.9, 158.2, 199.88,
Characterization of the Products. Dimethyl (R)-(4-(3-
methoxyphenyl)-2-oxo-4-phenylbutyl)phosphonate (3a). (95%
yield, 95% ee (R)). Pale yellow oil, 51.8 mg at 0.15 mmol
scale. The ee of 3a was determined by HPLC analysis: (Chi-
ralcel IA column, 1.0 mL/min, hexane/2-propanol = 70.0/30.0,
= 15.3 min (R), tminor =
) for 93% ee (R). H
) δ 3.00 (d, JP-H = 22.6 Hz, 2H), 3.37
25
1
D
–2.3 (c 0.4, CHCl
3
3
2
5
31
13
254 nm, tmajor = 7.4 min (R), tminor = 8.5 min (S)); []
D
–2.3 (c
0.3, CHCl3) for 95% ee (R). H NMR (300 MHz, CDCl ) δ
.04 (d, JP-H = 22.6 Hz, 2H), 3.41 (d, J = 7.6 Hz, 2H), 3.71 (dt,
P-H = 11.3 Hz, 2.0 Hz, 6H), 3.78 (d, J = 1.4 Hz, 3H), 4.58 (t, J
7.4 Hz, 1H), 6.73 (dd, J = 8.3 Hz, 2.2 Hz, 1H), 6.80 (d, J =
3
, 121 MHz) δ 22.1; C NMR (125
1
3
3
1
1
3
J
=
2
+
+
99.93. HRMS (ESI) calcd for C19
found 363.1352.
H
24
O
5
P [M+H] 363.1356,
3
1
.2 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 7.13–7.35 (m, 6H);
P
Dimethyl
(R)-(4-(3-chlorophenyl)-2-oxo-4-phenylbutyl)-
13
NMR (CDCl
3
, 121 MHz) δ 22.2; C NMR (125 MHz, CDCl
3
)
phosphonate (3f). (91% yield, 96% ee (R)). Pale yellow oil,
50.0 mg at 0.15 mmol scale. The ee of 3f was determined by
HPLC analysis: (Chiralcel IC column, 1.0 mL/min, hexane/2-
δ 41.4, 42.4, 45.8, 49.9, 52.9, 53.0, 55.2, 111.6, 114.0, 120.1,
1
26.5, 127.7, 128.6, 129.5, 143.4, 145.1, 159.8, 199.69,
+
+
199.74. HRMS (ESI) calcd for C19
H
24
O
5
P [M+H] 363.1356,
propanol = 40.0/60.0, 254 nm, t
= 15.9 min (R), t
) for 96% ee (R). H NMR
) δ 3.04 (d, JP-H = 22.9 Hz, 2H), 3.40 (m,
=12.3
major
minor
1
found 363.1352.
25
min (S)); []
(300 MHz, CDCl
2H), 3.69 (dd, JP-H = 11.3 Hz, 4.5 Hz, 6H), 4.57 (t, J = 7.4 Hz,
D
–12 (c 0.3, CHCl
3
Dimethyl (R)-(2-oxo-4-phenyl-4-(o-tolyl)butyl)phosphonate
(3b). (99% yield, 99% ee (R)). Pale yellow oil, 51.5 mg at
3
31
0
.15 mmol scale. The ee of 3b was determined by HPLC anal-
ysis: (Chiralcel IC column, 1.0 mL/min, hexane/2-propanol =
0.0/60.0, 254 nm, tmajor = 13.4 min (R), tminor = 11.1 min (S));
1H), 7.10–7.34 (m, 9H); P NMR (CDCl
3
, 121 MHz) δ 21.9;
) δ 41.4, 42.4, 45.3, 49.6, 53.0,
126.1, 126.7, 126.8, 127.7, 127.9, 128.7, 129.8, 134.3, 142.8,
13
C NMR (125 MHz, CDCl
3
4
[
2
5
1
+
]
CDCl
7.6 Hz, 2H), 3.64–3.77 (m, 6H), 4.81 (t, J = 7.4 Hz, 1H),
D
–47 (c 0.3, CHCl
3
3
) for 99% ee (R). H NMR (300 MHz,
145.7, 199.2, 199.3. HRMS (ESI) calcd for C18
[M+H] 3
H
21ClO P
4
+
) δ 2.33 (s, 3H), 3.03 (d, JP-H = 22.8 Hz, 2H), 3.40 (d, J
67.0860, found 367.0858.
=
7
Dimethyl (R)-(4-(3-bromophenyl)-2-oxo-4-phenylbutyl)-
.13–7.31 (m, 9H); 31P NMR (CDCl
, 121 MHz) δ 22.3;
13
C
3
phosphonate (3g). (97% yield, 95% ee (R)). Pale yellow oil,
59.9 mg at 0.15 mmol scale. The ee of 3g was determined by
HPLC analysis: (Chiralcel IC column, 1.0 mL/min, hexane/2-
NMR (125 MHz, CDCl
3
) δ 19.8, 41.4, 41.6, 42.4, 50.3, 52.9,
53.0, 126.1, 126.3, 126.4, 126.5, 128.1, 128.5, 130.8, 136.4,
+
1
[
41.2, 143.2, 199.8, 199.9. HRMS (ESI) calcd for C19
H
24
O
4
P
propanol = 60.0/40.0, 254 nm, t
= 22.2 min (R), tminor
=
major
+
M+H] 347.1407, found 347.1404.
Dimethyl (R)-(2-oxo-4-phenyl-4-(m-tolyl)butyl)phosphor-
nate (3c). (98% yield, 93% ee (R)). Pale yellow oil, 50.9 mg at
.15 mmol scale. The ee of 3c was determined by HPLC anal-
ysis: (Chiralcel IC column, 1.0 mL/min, hexane/2-propanol =
0.0/40.0, 254 nm, tmajor =19.7 min (R), tminor = 15.4 min (S));
25
1
16.1 min (S)); []
NMR (300 MHz, CDCl
(m, 2H), 3.69 (dd, JP-H = 11.3 Hz, 5.0 Hz, 6H), 4.56 (t, J = 7.5
Hz, 1H), 7.09–7.33 (m, 8H), 7.39 (d, J = 1.9 Hz, 1H);
NMR (CDCl
D
–9.6 (c 0.4, CHCl
3
) for 95% ee (R). H
) δ 3.03 (d, JP-H = 22.9 Hz, 2H), 3.39
3
31
0
P
13
3
, 121 MHz) δ 21.9; C NMR (125 MHz, CDCl
3
)
6
δ 41.4, 42.4, 45.2, 49.6, 53.0, 53.1, 122.6, 126.6, 126.8, 127.7,
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7
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128.7, 129.6, 130.1, 130.8, 142.8, 146.0, 199.20, 199.24.
Dimethyl
(R)-(4-(naphthalen-2-yl)-2-oxo-4-phenylbutyl)-
7
9
+
+
HRMS (ESI) calcd for C18
found 411.0351; calcd for C18
found 413.0333.
H
H
21 BrO
21 BrO
4
P
[M+H] 411.0355,
phosphonate (3l). (95% yield, 95% ee (R)). Pale yellow oil,
54.7 mg at 0.15 mmol scale. The ee of 3l was determined by
HPLC analysis: (Chiralcel IC column, 1.0 mL/min, hexane/2-
8
1
+
+
4
P [M+H] 413.0335,
propanol = 60.0/40.0, 254 nm, tmajor = 22.9 min (R), tminor
=
Dimethyl
(R)-(4-(4-bromophenyl)-2-oxo-4-phenylbutyl)-
25
1
2
1.1 min (S)); []
NMR (300 MHz, CDCl
.62 (m, 2H), 3.69 (dd, JP-H = 11.2 Hz, 4.2 Hz, 6H), 4.80 (t, J
7.4 Hz, 1H), 7.17–7.25 (m, 1H), 7.28–7.32 (m, 4H), 7.36 (dd,
J = 8.5 Hz, 1.9 Hz, 1H), 7.40–7.51 (m, 2H), 7.69–7.86 (m, 4H);
D
–27 (c 0.5, CHCl
3
) for 95% ee (R). H
phosphonate (3h). (99% yield, 96% ee (R)). Pale yellow oil,
3
) δ 3.05 (d, JP-H = 22.8 Hz, 2H), 3.45–
61.2 mg at 0.15 mmol scale. The ee of 3h was determined by
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
=
HPLC analysis: (Chiralcel IC column, 1.0 mL/min, hexane/2-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
propanol = 40.0/60.0, 254 nm, tmajor = 17.1 min (R), tminor
=
25
1
1
4.0 min (S)); []
NMR (300 MHz, CDCl
(m, 2H), 3.68 (dd, JP-H = 11.2 Hz, 1.5 Hz, 6H), 4.56 (t, J = 7.4
D
–7.3 (c 0.3, CHCl
3
) for 96% ee (R). H
31
13
P NMR (CDCl
3
, 121 MHz) δ 22.2; C NMR (125 MHz,
3
) δ 3.03 (d, JP-H = 22.9 Hz, 2H), 3.39
CDCl ) δ 41.4, 42.5, 45.8, 49.8, 52.96, 53.02, 125.6, 125.8,
3
3
1
126.1, 126.6, 126.7, 127.6, 127.8, 128.0, 128.3, 128.6, 132.3,
133.5, 140.9, 143.4, 199.7, 199.8. HRMS (ESI) calcd for
Hz, 1H), 7.09–7.31 (m, 7H), 7.35–7.42 (m, 2H); P NMR
1
3
(
CDCl
3
, 121 MHz) δ 22.0; C NMR (125 MHz, CDCl
1.4, 42.4, 45.0, 49.7, 52.98, 53.03, 120.3, 126.7, 127.7, 128.7,
29.6, 131.6, 142.6, 143.0, 199.3. HRMS (ESI) calcd for
3
) δ
+
+
C
22
H
24
O
4
P [M+H] 383.1407, found 383.1402.
4
1
C
C
Dimethyl (R)-(2-oxo-4-phenyl-4-(thiophen-3-yl)butyl)-
7
9
+
+
18
H
H
21 BrO
4
P [M+H] 411.0355, found 411.0351; calcd for
phosphonate (3m). (88% yield, 98% ee (R)). Colorless oil,
44.7 mg at 0.15 mmol scale. The ee of 3m was determined by
HPLC analysis: (Chiralcel IB column, 1.0 mL/min, hexane/2-
propanol = 80.0/20.0, 210 nm, tmajor = 29.6 min (R), tminor
17.6 min (S)); []
NMR (500 MHz, CDCl
2H), 3.36 (dd, J = 17.5 Hz, 7.3 Hz, 1H), 3.46 (dd, J = 17.4 Hz,
7.4 Hz, 1H), 3.73 (dd, JP-H = 11.2 Hz, 10.4 Hz, 6H), 4.69 (t, J
7.3 Hz, 1H), 6.93 (dd, J = 5.0 Hz, 1.3 Hz, 1H), 7.03–7.08 (m,
H), 7.19–7.30 (m, 4H), 7.30–7.34 (m, 2H); P NMR (CDCl ,
21 MHz) δ 22.1; C NMR (125 MHz, CDCl ) δ 41.3, 41.5,
81
+
+
18
21 BrO
4
P [M+H] 413.0335, found 413.0333.
Dimethyl
(R)-(4-(4-acetylphenyl)-2-oxo-4-phenylbutyl)-
=
phosphonate (3i). (88% yield, 97% ee (R)). Pale yellow oil,
9.4 mg at 0.15 mmol scale. The ee of 3i was determined by
HPLC analysis: (Chiralcel IF column, 1.0 mL/min, hexane/2-
propanol = 80.0/20.0, 254 nm, tmajor = 57.4 min (R), tminor
25
1
D
–29 (c 0.3, CHCl
3
) for 98% ee (R). H
4
3
) δ 3.04 (dd, JP-H = 22.9 Hz, 1.2 Hz,
=
2
5
1
54.6 min (S)); []
NMR (300 MHz, CDCl
P-H = 23.4 Hz, 2H), 3.47 (m, 2H), 3.70 (dd, JP-H = 11.3 Hz, 1.4
Hz, 6H), 4.67 (t, J = 7.4 Hz, 1H), 7.16–7.33 (m, 5H), 7.34–
D
–15 (c 0.3, CHCl
3
3
) for 97% ee (R). H
=
1
1
) δ 2.56 (d, J = 1.5 Hz, 3H), 3.06 (d,
3
1
3
J
13
3
3
1
42.3, 50.4, 52.9, 53.0, 120.6, 125.7, 126.6, 127.6, 127.8, 128.6,
143.3, 144.3, 199.66, 199.70. HRMS (ESI) calcd for
7
.40 (m, 2H), 7.88 (dd, J = 8.3 Hz, 1.5 Hz, 2H); P NMR
1
3
(
CDCl
3
, 121 MHz) δ 22.0; C NMR (125 MHz, CDCl ) δ
3
+
+
C
16
H
20
O
4
PS [M+H] 339.0814, found 339.0811.
2
1
6.5, 41.3, 42.4, 45.5, 49.5, 52.96, 53.02, 126.8, 127.7, 128.0,
28.6, 128.7, 135.5, 142.7, 149.0, 197.5, 199.2, 199.3. HRMS
Dimethyl (S)-(4-(2-chlorophenyl)-2-oxo-4-phenylbutyl)-
+
+
(ESI) calcd for C20
H
24
O
5
P [M+H] 375.1356, found 375.1354.
phosphonate (3n). (90% yield, 95% ee (S)). Colorless oil, 49.3
mg at 0.15 mmol scale. The ee of 3n was determined by
HPLC analysis: (Chiralcel IB column, 1.0 mL/min, hexane/2-
propanol = 70.0/30.0, 254 nm, tmajor = 18.7 min (S), tminor
9.8 min (R)); []
NMR (300 MHz, CDCl
3.54 (m, 2H), 3.72 (dd, JP-H = 11.2 Hz, 5.6 Hz, 6H), 5.11 (t, J
= 7.5 Hz, 1H), 7.15 (td, J = 7.9 Hz, 2.1 Hz, 1H), 7.19–7.22 (m,
H), 7.24 (dd, J = 7.1 Hz, 1.4 Hz, 1H), 7.26–7.33 (m, 5H),
Dimethyl
(R)-4-(4-(dimethoxyphosphoryl)-3-oxo-1-
phenylbutyl)benzoate (3j). (98% yield, 96% ee (R)). Pale yel-
low oil, 57.6 mg at 0.15 mmol scale. The ee of 3j was deter-
mined by HPLC analysis: (Chiralcel IB column, 1.0 mL/min,
hexane/2-propanol = 70.0/30.0, 254 nm, tmajor =32.4 min (R),
=
25
1
3
D
+2.1 (c 0.4, CHCl
3
) for 95% ee (S). H
3
) δ 3.07 (d, JP-H = 22.9 Hz, 2H), 3.31–
2
5
t
minor = 30.2 min (S)); []
D
–12 (c 0.4, CHCl
) δ 3.04 (d, JP-H = 22.9 Hz, 2H),
.44 (m, 2H), 3.68 (d, JP-H = 11.2 Hz, 6H), 3.87 (s, 3H), 4.66 (t,
3
) for 96% ee (R).
1
H NMR (300 MHz, CDCl
3
1
3
3
1
7.36 (dd, J = 7.8 Hz, 1.5 Hz, 1H); P NMR (CDCl
3
, 121 MHz)
) δ 41.0, 41.9, 42.0, 49.2,
52.3, 126.6, 126.9, 127.7, 128.1, 128.4, 128.5, 129.9, 134.0,
J = 7.4 Hz, 1H), 7.14–7.24 (m, 3H), 7.28 (d, J = 1.6 Hz, 2H),
13
31
δ 22.1; C NMR (125 MHz, CDCl
3
7
1
.33 (d, J = 8.1 Hz, 2H), 7.90–7.99 (m, 2H); P NMR (CDCl ,
3
1
3
21 MHz) δ 21.9; C NMR (125 MHz, CDCl ) δ 41.4, 42.4,
3
1
C
40.7, 141.9, 199.0, 199.1. HRMS (ESI) calcd for
45.6, 49.5, 52.0, 53.98, 53.03, 126.8, 127.8, 127.9, 128.5,
128.7, 130.0, 142.8, 148.8, 166.8, 199.25, 199.30. HRMS (ESI)
+
+
18
H
21ClO
4
P [M+H] 367.0860, found 367.0858.
+
+
calcd for C20
H
24
O
6
P [M+H] 391.1305, found 391.1303.
Dimethyl
(S)-(4-(3-fluorophenyl)-2-oxo-4-phenylbutyl)-
phosphonate (3o). (82% yield, 94% ee (S)). Pale yellow oil,
2.8 mg at 0.15 mmol scale. The ee of 3o was determined by
HPLC analysis: (Chiralcel IC column, 1.0 mL/min, hexane/2-
propanol = 70.0/30.0, 254 nm, tmajor = 21.0 min (S), tminor
4.2 min (R)); []
NMR (300 MHz, CDCl ) δ 3.04 (d, JP-H = 22.9 Hz, 2H), 3.33–
3.50 (m, 2H), 3.71 (dd, JP-H = 11.3 Hz, 3.1 Hz, 6H), 4.62 (t, J
= 7.4 Hz, 1H), 6.88 (tdd, J = 8.4 Hz, 2.6 Hz, 1.0 Hz, 1H), 6.96
dt, J = 10.2 Hz, 2.1 Hz, 1H), 7.01–7.08 (m, 1H), 7.16–7.22
Dimethyl
(R)-(4-(naphthalen-1-yl)-2-oxo-4-phenylbutyl)-
4
phosphonate (3k). (84% yield, >99% ee (R)). Pale yellow oil,
8.3 mg at 0.15 mmol scale. The ee of 3k was determined by
4
=
HPLC analysis: (Chiralcel IA column, 1.0 mL/min, hexane/2-
25
1
2
D
+11 (c 0.3, CHCl
3
) for 94% ee (S). H
propanol = 70.0/30.0, 254 nm, tmajor = 7.1 min (R), tminor = 10.2
25
1
3
min (S)); []
(
(
D
–14 (c 0.3, CHCl
300 MHz, CDCl ) δ 3.02 (d, JP-H = 22.9 Hz, 2H), 3.43–3.61
m, 2H), 3.68 (dd, JP-H = 11.2 Hz, 8.9 Hz, 6H), 5.43 (t, J = 7.3
3
) for >99% ee (R). H NMR
3
(
(
Hz, 1H), 7.08–7.19 (m, 1H), 7.20–7.26 (m, 2H), 7.27–7.32 (m,
31
m, 1H), 7.22–7.26 (m, 3H), 7.26–7.33 (m, 2H); P NMR
2H), 7.35–7.52 (m, 4H), 7.73 (dd, J = 7.1, 2.3 Hz, 1H), 7.80–
1
3
3
1
(CDCl
3
, 121 MHz) δ 22.2; C NMR (125 MHz, CDCl ) δ
3
7
.84 (m, 1H), 8.08–8.19 (m, 1H); P NMR (CDCl
3
, 121 MHz)
) δ 41.2, 41.3, 42.3, 50.5,
2.9, 53.98, 53.04, 123.7, 124.5, 125.2, 125.5, 126.2, 126.5,
27.4, 128.0, 128.5, 128.8, 131.5, 134.1, 138.9, 143.4, 199.7,
1
3
41.8, 42.4, 45.3, 49.7, 53.0, 113.3 (d, JC-F = 21.1 Hz), 114.7 (d,
C-F = 21.8 Hz), 123.5, 123.5, 126.7, 127.7, 128.7, 129.9,
30.0, 142.9, 146.2, 146.2, 162.9 (d, JC-F = 245.8 Hz), 199.30,
199.34. HRMS (ESI) calcd for C18
found 351.1157.
δ 22.2; C NMR (125 MHz, CDCl
3
J
1
5
1
1
+
+
+
+
H
21FO P [M+H] 351.1156,
4
99.8. HRMS (ESI) calcd for C22
H
24
O P [M+H] 383.1407,
4
found 383.1402.
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Dimethyl
phosphonate (3p). (85% yield, 95% ee (S)). Pale yellow oil,
6.7 mg at 0.15 mmol scale. The ee of 3p was determined by
HPLC analysis: (Chiralcel IC column, 1.0 mL/min, hexane/2-
propanol = 60.0/40.0, 254 nm, tmajor = 17.1 min (S), tminor
(S)-(4-(4-chlorophenyl)-2-oxo-4-phenylbutyl)-
3.02–3.12 (m, 1H), 3.71 (dd, JP-H = 17.5 Hz, 11.2 Hz, 6H),
3
1
7.15–7.23 (m, 3H), 7.26–7.33 (m, 2H); P NMR (CDCl
3
, 121
) δ 12.0, 29.2, 41.0,
42.6, 42.7, 50.80, 50.82, 52.9, 52.97, 53.00, 53.1, 126.4, 127.6,
1
3
4
MHz) δ 22.5; C NMR (75 MHz, CDCl
3
+
=
128.4, 143.9, 200.9, 201.0. HRMS (ESI) calcd for C14
[M+H] 285.1250, found 285.1248.
H
22
4
O P
2
5
1
+
2
2.1 min (R)); []
NMR (300 MHz, CDCl
dd, J = 7.4 Hz, 1.9 Hz, 2H), 3.70 (dd, JP-H = 11.3 Hz, 0.4 Hz,
H), 4.59 (t, J = 7.4 Hz, 1H), 7.16–7.21 (m, 3H), 7.21–7.28 (m,
D
+8.0 (c 0.5, CHCl
3
) for 95% ee (S). H
3
) δ 3.04 (d, JP-H = 22.9 Hz, 2H), 3.41
Dimethyl (S)-(2-oxo-4-(p-tolyl)pentyl)phosphonate (3u). (92%
yield, 92% ee (S)). Pale yellow oil, 39.3 mg at 0.15 mmol
scale. The ee of 3u was determined by HPLC analysis: (Chi-
(
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
31
5H), 7.30 (dt, J = 6.9 Hz, 1.2 Hz, 1H); P NMR (CDCl
MHz) δ 22.0; C NMR (125 MHz, CDCl
4
1
3
, 121
) δ 41.3, 42.3, 44.9,
9.7, 52.9, 52.3, 126.6, 127.6, 128.58, 128.61, 129.1, 132.2,
42.1, 143.0, 199.31, 199.35. HRMS (ESI) calcd for
ralcel IB column, 1.0 mL/min, hexane/2-propanol = 70.0/30.0,
1
3
3
25
2
54 nm, tmajor = 11.8 min (S), tminor = 13.1 min (R)); []
D
+20
) δ
1.18 (d, JP-H = 6.9 Hz, 3H), 2.24 (s, 3H), 2.70–2.97 (m, 4H),
.13–3.31 (m, 1H), 3.66 (t, JP-H = 11.3 Hz, 6H), 7.00–7.07 (m,
1
(c 0.2, CHCl
3
) for 92% ee (S). H NMR (300 MHz, CDCl
3
+
+
C
18
H
21ClO
4
P [M+H] 367.0860, found 367.0858.
3
3
1
13
Dimethyl (S)-(4-(3,4-dichlorophenyl)-2-oxo-4-phenylbutyl)-
4H); P NMR (CDCl
CDCl ) δ 20.9, 22.0, 34.8, 41.3, 42.3, 52.3, 52.9, 52.9, 53.0,
126.7, 129.2, 135.8, 142.8, 200.7, 200.8. HRMS (ESI) calcd
3
, 121 MHz) δ 22.6; C NMR (125 MHz,
phosphonate (3q). (94% yield, 92% ee (S)). Colorless oil, 56.6
mg at 0.15 mmol scale. The ee of 3q was determined by
HPLC analysis: (Chiralcel IB column, 1.0 mL/min, hexane/2-
3
+
+
for C14
H
22
O
4
P [M+H] 285.1250, found 285.1249.
propanol = 85.0/15.0, 210 nm, tmajor = 44.6 min (S), tminor
=
Dimethyl
(S)-(2-oxo-4-(thiophen-3-yl)hexyl)phosphonate
25
1
6
5.9 min (R)); []
D
+16 (c 0.5, CHCl
) δ 3.01–3.13 (m, 2H), 3.42 (qd, J =
3
) for 92% ee (S). H
(
3v). (92% yield, 97% ee (S)). Colorless oil, 40.1 mg at 0.15
mmol scale. The ee of 3v was determined by HPLC analysis:
Chiralcel IB column, 1.0 mL/min, hexane/2-propanol =
NMR (500 MHz, CDCl
3
18.0 Hz, 7.4 Hz, 2H), 3.73 (dd, J P-H = 11.3 Hz, 6.0 Hz, 6H),
4.59 (t, J = 7.3 Hz, 1H), 7.12 (dd, J = 8.4 Hz, 2.1 Hz, 1H),
(
8
0.0/20.0, 210 nm, tmajor = 10.3 min (S), tminor = 9.5 min (R));
3
1
7
.20–7.27 (m, 3H), 7.28–7.41 (m, 4H); P NMR (CDCl
3
, 121
) δ 41.0, 42.7, 44.6,
9.5, 53.1, 53.2, 126.9, 127.4, 127.7, 128.8, 129.7, 130.4,
32.4, 142.4, 143.9, 199.1, 199.2. HRMS (ESI) calcd for
25
1
[]
D
+25 (c 0.3, CHCl
) δ 0.84 (t, J = 7.3 Hz, 3H), 1.54–1.74 (m, 2H), 2.86–
.95 (m, 2H), 2.95–3.05 (m, 2H), 3.20–3.28 (m, 1H), 3.74 (dd,
P-H = 22.0 Hz, 11.2 Hz, 6H), 6.97 (dd, J = 4.9 Hz, 1.4 Hz, 1H),
.00 (dd, J = 3.0 Hz, 1.3 Hz, 1H), 7.27 (dd, J = 5.0 Hz, 3.0 Hz,
3
) for 97% ee (S). H NMR (500 MHz,
1
3
MHz) δ 21.9; C NMR (75 MHz, CDCl
3
CDCl
3
4
1
C
2
J
7
+
+
18
H
20Cl
2
O
4
P [M+H] 401.0471, found 401.0470.
3
1
13
Dimethyl
(S)-(4-(benzo[d][1,3]dioxol-5-yl)-2-oxo-4-
1H); P NMR (CDCl
CDCl ) δ 11.7, 28.9, 37.8, 41.2, 42.2, 50.4, 52.87, 52.93, 120.4,
125.4, 126.7, 144.7, 200.7, 200.8. HRMS (ESI) calcd for
3
, 121 MHz) δ 22.4; C NMR (125 MHz,
phenylbutyl)phosphonate (3r). (90% yield, 92% ee (S)). Color-
less oil, 50.8 mg at 0.15 mmol scale. The ee of 3r was deter-
mined by HPLC analysis: (Chiralcel IA column, 1.0 mL/min,
hexane/2-propanol = 85.0/15.0, 254 nm, tmajor = 18.0 min (S),
3
+
+
C
12
H
20
O
4
PS [M+H] 291.0814, found 291.0812.
Dimethyl (S)-(4-(furan-2-yl)-2-oxohexyl)phosphonate (3w).
49% yield, 95% ee (S)). Colorless oil, 20.2 mg at 0.15 mmol
2
5
t
(
minor = 16.5 min (R)); []
D
+4.0 (c 0.3, CHCl
3
3
) for 92% ee
(
1
S). H NMR (500 MHz, CDCl ) δ 3.04 (d, JP-H = 22.8 Hz, 2H),
scale. The ee of 3w was determined by HPLC analysis: (Chi-
3
4
7
.38 (d, J = 7.5 Hz, 2H), 3.74 (dd, JP-H = 11.2 Hz, 7.2 Hz, 6H),
.55 (t, J = 7.4 Hz, 1H), 5.92 (s, 2H), 6.71–6.78 (m, 3H),
ralcel IC column, 1.0 mL/min, hexane/2-propanol = 80.0/20.0,
25
2
10 nm, tmajor = 26.1 min (S), tminor = 29.5 min (R)); []
D
+6.2
) δ
31
.18–7.23 (m, 1H), 7.24–7.34 (m, 4H); P NMR (CDCl
3
, 121
) δ 41.0, 42.7, 45.4,
0.0, 53.0, 53.1, 100.9, 108.2, 108.3, 120.6, 126.5, 127.6,
128.6, 137.5, 143.6, 146.1, 147.8, 199.76, 199.84. HRMS (ESI)
1
(c 0.2, CHCl
3
) for 95% ee (S). H NMR (500 MHz, CDCl
3
13
MHz) δ 22.3; C NMR (75 MHz, CDCl
5
3
0
7
.88 (t, J = 7.4 Hz, 3H), 1.66 (d, J = 7.4 Hz, 1H), 1.70 (dd, J =
.5 Hz, 1.6 Hz, 1H), 2.89 (dd, J = 17.2 Hz, 6.4 Hz, 1H), 3.01
(
dd, J = 17.2 Hz, 7.5 Hz, 1H), 3.05 (d, JP-H = 22.7 Hz, 2H),
.26 (p, J = 7.0 Hz, 1H), 3.80 (dd, JP-H = 11.3 Hz, 8.3 Hz, 6H),
6.06 (d, J = 3.1 Hz, 1H), 6.30 (dd, J = 3.2, 1.9 Hz, 1H), 7.31–
+
+
calcd for C19
H
22
6
O P [M+H] 377.1149, found 377.1150.
3
Dimethyl (S)-(2-oxo-4-phenylpentyl)phosphonate (3s). (91%
yield, 92% ee (S)). Pale yellow oil, 36.8 mg at 0.15 mmol
scale. The ee of 3s was determined by HPLC analysis: (Chi-
ralcel IB column, 1.0 mL/min, hexane/2-propanol = 70.0/30.0,
3
1
13
7.35 (m, 1H); P NMR (CDCl
(125 MHz, CDCl ) δ 11.5, 26.8, 35.7, 41.1, 42.1, 47.9, 52.96,
53.01, 105.4, 110.0, 141.0, 200.3, 200.4. HRMS (ESI) calcd
3
, 121 MHz) δ 22.5; C NMR
3
2
5
+
+
2
54 nm, tmajor = 13.2 min (S), tminor = 14.9 min (R)); []
D
+20
3
for C12
H
20
O
5
P [M+H] 275.1043, found 275.1045.
1
(c 0.1, CHCl
3
) for 92% ee (S). H NMR (300 MHz, CDCl ) δ
(
R,E)-5-(4-Methoxyphenyl)-1,5-diphenylpent-1-en-3-one
1
1
7
.30 (d, JP-H = 7.0 Hz, 3H), 2.82–3.06 (m, 4H), 3.25–3.44 (m,
H), 3.74 (dd, JP-H = 12.8 Hz, 11.2 Hz, 6H), 7.16–7.27 (m, 3H),
12a
(
4a). A known compound. (97% yield, 93% ee (R)). White
solid, m.p. 123–125 C, 50.0 mg at 0.15 mmol scale. The ee of
o
31
.27–7.29 (m, 1H), 7.32 (dt, J = 6.8, 1.2 Hz, 1H); P NMR
4
1
9
a was determined by HPLC analysis: (Chiralcel IA column,
13
(
CDCl
3
, 121 MHz) δ 22.4; C NMR (75 MHz, CDCl
3
) δ 21.9,
.0 mL/min, hexane/2-propanol = 80.0/20.0, 254 nm, tmajor
=
35.1, 40.9, 42.6, 52.2, 53.0, 126.4, 126.9, 128.5, 145.8, 200.7,
25
.4 min (R), tminor = 10.3 min (S)); []
D
–7.1 (c 0.4, CHCl
) δ 3.37 (d, J = 7.5
3
)
+
+
200.8. HRMS (ESI) calcd for C13
found 271.1093.
H
20
O
4
P [M+H] 271.1094,
1
for 93% ee (R). H NMR (300 MHz, CDCl
3
Hz, 2H), 3.73 (s, 3H), 4.67 (t, J = 7.5 Hz, 1H), 6.68 (d, J =
Dimethyl (S)-(2-oxo-4-phenylhexyl)phosphonate (3t). (93%
yield, 96% ee (S)). Pale yellow oil, 40.0 mg at 0.15 mmol
scale. The ee of 3t was determined by HPLC analysis: (Chi-
ralcel IC column, 1.0 mL/min, hexane/2-propanol = 80.0/20.0,
16.2 Hz, 1H), 6.76–6.84 (m, 2H), 7.12–7.19 (m, 3H), 7.21–
7.28 (m, 4H), 7.33–7.39 (m, 3H), 7.45–7.53 (m, 3H); 13
C
NMR (75 MHz, CDCl ) δ 45.5, 47.3, 55.2, 114.0, 126.3, 126.3,
3
127.8, 128.3, 128.5, 128.8, 128.9, 130.4, 134.5, 136.2, 142.7,
144.5, 158.2, 198.1.
2
5
2
54 nm, tmajor = 25.2 min (S), tminor = 28.7 min (R)); []
D
+22
) for 96% ee (S). H NMR (300 MHz, CDCl ) δ
.79 (t, J = 7.4 Hz, 3H), 1.48–1.80 (m, 2H), 2.90–3.02 (m, 4H),
1
(c 0.4, CHCl
3
3
(R,E)-1-(4-Methoxyphenyl)-1-phenyloct-4-en-3-one
(4b).
0
(91% yield, 93% ee (R)). Yellowish oil, 42.2 mg at 0.15 mmol
ACS Paragon Plus Environment

Page 7 of 8
The Journal of Organic Chemistry
1
2
3
4
5
scale. The ee of 4b was determined by HPLC analysis: (Chi-
fications Involving Phosphoryl Stabilized Carbanions. Stereochemis-
try, Mechanism, and Selected Synthetic Aspects. Chem. Rev. 1989, 89,
863–927.
ralcel IA column, 1.0 mL/min, hexane/2-propanol = 98.0/2.0,
25
254 nm, tmajor = 15.8 min (R), tminor = 16.9 min (S)); []
D
–3.0
) for 93% ee (R). H NMR (300 MHz, CDCl ) δ
.82 (t, J = 7.4 Hz, 3H), 1.30–1.44 (m, 2H), 2.06 (qd, J = 7.3
(2) For selected examples, see: (a) Nicolaou, K. C.; Rhoades, D.;
1
(
c 0.2, CHCl
3
3
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Wang, Y.; Bai, R.; Hamel, E.; Aujay, M.; Sandoval, J.; Gavrilyuk, J.
12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubsti-
tuted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phos-
phonates and Design, Synthesis, and Biological Evaluation of Potent
Antitumor Agents. J. Am. Chem. Soc. 2017, 139, 7318–7334. (b)
Reddy, G. M.; Rao, B. U. M.; Sridhar, P R. Stereoselective Synthesis
of 2-(-C-Glycosyl)glycals: Access to Unusual -C-Glycosides from
3-Deoxyglycals. J. Org. Chem. 2016, 81, 2782–2793. (c) Pan, S.; Gao,
B.; Hu, J.; Xuan, J.; Xie, H.; Ding, H. Enantioselective Total Synthe-
sis of (+)-Steenkrotin A and Determination of Its Absolute Configura-
tion. Chem. Eur. J. 2016, 22, 959–970. (d) Dakarapu, U. S.; Bokka,
A.; Asgari, P.; Trog, G.; Hua, Y.; Nguyen, H. H.; Rahman, N.; Jeon, J.
Lewis Base Activation of Silyl Acetals: Iridium-Catalyzed Reductive
Horner–Wadsworth–Emmons Olefination. Org. Lett. 2015, 17, 5792–
5795. (e) Umezawa, T.; Seino, T.; Matsuda, F. Novel One-pot Three-
component Coupling Reaction with Trimethylsilylmethylphosphonate,
Acyl Fluoride, and Aldehyde through the Horner–Wadsworth–
Emmons Reaction. Org. Lett. 2012, 14, 4206–4209. (f) Markiewicz, J.
T.; Schauer, D. J.; Löfstedt, J.; Corden, S. J.; Wiest, O.; Helquist, P.
0
Hz, 1.5 Hz, 2H), 3.16 (d, J = 7.5 Hz, 2H), 3.67 (s, 3H), 4.53 (t,
J = 7.5 Hz, 1H), 5.97 (dt, J = 15.8 Hz, 1.5 Hz, 1H), 6.64–6.76
13
(
m, 3H), 7.01–7.21 (m, 7H); C NMR (75 MHz, CDCl
3
) δ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
3.6, 21.3, 34.4, 45.4, 46.4, 55.2, 113.9, 126.2, 127.7, 128.5,
28.8, 130.6, 136.3, 147.5, 158.1, 198.4. HRMS (ESI) calcd
+
+
for C21
H
24NaO
2
[M+Na] 331.1669, found 331.1668.
(S)-2-methyl-6-(p-tolyl)hept-2-en-4-one (5). A known com-
1
3
pound. (89% yield, 91% ee (S)). Yellowish oil, 28.8 mg at
.15 mmol scale. The ee of 5 was determined by HPLC analy-
sis: (Chiralcel IA column, 1.0 mL/min, hexane/2-propanol =
9.6/0.4, 254 nm, tmajor = 5.8 min (S), tminor = 6.4 min (R));
0
9
2
5
1
[]
D
+46 (c 0.4, CHCl
) δ 1.17 (d, J = 7.0 Hz, 3H), 1.78 (d, J = 1.2 Hz, 3H),
.03 (d, J = 1.3 Hz, 3H), 2.23 (s, 3H), 2.58 (qd, J = 15.7 Hz,
.2 Hz, 2H), 3.12–3.28 (m, 1H), 5.91–5.99 (m, 1H), 6.96–7.09
3
) for 91% ee (S). H NMR (300 MHz,
CDCl
3
2
7
1
3
(m, 4H); C NMR (75 MHz, CDCl ) δ 20.7, 20.9, 22.0, 27.5,
3
Synthesis of 4-Methyldienoates Using
a Vinylogous Horner–
35.3, 52.7, 124.1, 126.6, 129.1, 143.7, 154.8, 199.8.
Wadsworth–Emmons Reagent. Application to the Synthesis of Tri-
chostatic Acid. J. Org. Chem. 2010, 75, 2061–2064.
ASSOCIATED CONTENT
Supporting Information
(3) (a) Lee, S.; Kim, S. Enantioselective Radical Conjugate Addi-
tion to ’-Phosphoric Enones. Org. Lett. 2008, 10, 4255–4258. (b)
Yang, H.; Hong, Y.-T.; Kim, S. Catalytic Enantioselective Friedel-
Crafts Alkylations of Indoles with ’-Phosphoric Enones. Org. Lett.
2007, 9, 2281–2284. (c) Kang, Y. K.; Kwon, B. K.; Mang, J. Y.; Kim,
D. Y. Chiral Pd-Catalyzed Enantioselective Friedel–Crafts Reaction
of Indoles with ,-Unsaturated -Keto Phosphonates. Tetrahedron
Lett. 2011, 52, 3247–3249.
(4) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Rhodium-Catalyzed
Conjugate Addition of Aryl- or 1-Alkenylboronic Acids to Enones.
Organometallics 1997, 16, 4229–4231. (b) Takaya, Y.; Ogasawara,
M.; Hayashi, T.; Sakai, M.; Miyaura, N. Rhodium-Catalyzed Asym-
metric 1,4-Addition of Aryl- and Alkenylboronic Acids to Enones. J.
Am. Chem. Soc. 1998, 120, 5579–5580.
The Supporting Information is available free of charge on the
ACS Publications website.
Copies of 1H, 13C, 31P NMR spectra and HPLC charts (PDF)
AUTHOR INFORMATION
Corresponding Author
*
*
*
E-mail: ydchen@cpu.edu.cn (Y.C.)
E-mail: hayashi@ntu.edu.sg (T.H.)
E-mail: dxw@cpu.edu.cn (X.D.)
(5) For reviews, see: (a) Jia, T.; Cao, P.; Liao, J. Enantioselective
ORCID
Synthesis of gem-Diarylalkanes by Transition Metal-Catalyzed
Asymmetric Arylations (TMCAAr). Chem. Sci. 2018, 9, 546–559. (b)
Heravi, M. M.; Dehghani, M.; Zadsirjan, V. Rh-Catalyzed Asymmet-
ric 1,4-Addition Reactions to ,-Unsaturated Carbonyl and Related
Compounds: an Update. Tetrahedron: Asymmetry 2016, 27, 513–588.
(c) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Enantioselective
and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling
Reactions of Organometallic Reagents to Construct C–C bonds. Chem.
Rev. 2015, 115, 9587–9652. (d) Tian, P.; Dong, H.-Q.; Lin, G.-Q.
Rhodium-Catalyzed Asymmetric Arylation. ACS Catal. 2012, 2, 95–
Xiaowei Dou: 0000-0002-0748-1279
Tamio Hayashi: 0000-0001-9187-3664
Author Contributions
§
These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
X.D. thanks the financial support from the National Natural Sci-
ence Foundation of China (21602253), the Natural Science Foun-
dation of Jiangsu Province (BK20160749), and the Six Talent
Peaks Plan of Jiangsu Province. C.W. is supported by the College
Students Innovation Project for the R&D of Novel Drugs
119.
(6) For selected examples, see: (a) Sakuma, S.; Miyaura, N. Rhodi-
um(I)-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acids to
,-Unsaturated Amides. J. Org. Chem. 2001, 66, 8944–8946. (b)
Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M.
Asymmetric Synthesis of 3,3-Diarylpropanals with Chiral Diene-
Rhodium Catalysts. J. Am. Chem. Soc. 2005, 127, 10850–10851. (c)
Shintani, R.; Duan, W.-L.; Hayashi, T. Rhodium-Catalyzed Asym-
metric Construction of Quaternary Carbon Stereocenters: Ligand-
Dependent Regiocontrol in the 1,4-Addition to Substituted Malei-
mides. J. Am. Chem. Soc. 2006, 128, 5628–5629. (d) Shao, C.; Yu,
H.-J.; Wu, N.-Y.; Tian, P.; Wang, R.; Feng, C.-G.; Lin, G.-Q. Asym-
metric Synthesis of -Substituted -Lactams via Rhodium/Diene-
Catalyzed 1,4-Additions: Application to the Synthesis of (R)-Baclofen
and (R)-Rolipram. Org. Lett. 2011, 13, 788–791. (e) Wang, J.; Wang,
M.; Cao, P.; Jiang, L.; Chen, G.; Liao, J. Rhodium-Catalyzed Asym-
metric Arylation of ,-Unsaturated -Ketoamides for the Construc-
tion of Nonracemic ,-Diarylcarbonyl Compounds. Angew. Chem.,
Int. Ed. 2014, 53, 6673–6677.
(J1310032). T.H. thanks the Ministry of Education (MOE) of
Singapore (MOE2017-T2-1-064) for generous financial support.
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2
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0
1
2
3
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9
0
1
2
3
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5
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7
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9
0
1
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9
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(14) 4a: []
= –7.0 (c = 1.0, CHCl
D
= –7.1 (c = 0.4, CHCl
3
) for 93% ee; (Ref.12a) []
D
2
0
3
) for 97% ee (R). 5: []
D
= +46 (c = 0.4,
2
0
CHCl ) for 91% ee; (Ref.13a) [] = +50 (c = 1.0, CHCl ) for 92%
3
D
3
1
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