Rational Design of New Dihydrobenzooxophosphole-Based Lewis Base Organocatalysts

Article abstract of DOI:10.1055/s-0039-1690851

A series of new dihydrobenzooxophosphole-based Lewis base organocatalysts were designed and synthesized. They are shown to be effective in trichlorosilane-mediated stereoselective conjugate reductions of C=C bonds. DFT calculations reveal that the strong

Full text of DOI:10.1055/s-0039-1690851

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Georg Thieme Verlag Stuttgart · New York
2020, 31, 587–591
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Synlett
B. Qu et al.
Letter
Rational Design of New Dihydrobenzooxophosphole-Based Lewis
Base Organocatalysts
Bo Qu*a
0
0
0
0-
0
0
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1-7
3
4
7-0
1
0
8
Lalith P. Samankumaraa
Anjan Sahaa
Mac G. Schumerb
O
O
NH HN
O
O
O
O
P
P
tBu
tBu
O
Zhengxu S. Hana
Nizar Haddada
Carl A. Busaccaa
Nathan K. Yeea
0
0
0
0-0
0
0
1-8
3
8
6-
1
3
5
6
O
(10 mol%)
OMe
MeO
Ph
Ar
Ph
Ar
0
0
0
0-0
0
0
1-
7
0
6
8-7
8
9
7
HSiCl3 (5 equiv), acetonitrile, 0 °C
up to 90.2:9.8 er
4% yield
9
Marisa C. Kozlowskib
Jinghua J. Songa
Chris H. Senanayakea,1
0
0
0
0-0
0
0
2-4
2
2
5-7
1
2
5
Strong H-bonds enhance reactivity of the new catalyst
a
Chemical Development, Boehringer Ingelheim Pharmaceuti-
cals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
b
Published as part of the ISySyCat2019 Special Issue
Received: 22.01.2020
Accepted after revision: 20.02.2020
Published online: 12.03.2020
duction of (E)-1,3-diphenylbutenone (1a) in the presence of
trichlorosilane was selected as a model transformation to
4
DOI: 10.1055/s-0039-1690851; Art ID: st-2020-b0050-l
evaluate the effectiveness of such catalysts (Scheme 1).
However, when BIBOPO was applied in the test reaction,
only trace amount of product 2a was observed (Scheme 1a).
We rationalized that an increased coordinating angle of the
Si atom to bis P=O might be required to accommodate the
Abstract A series of new dihydrobenzooxophosphole-based Lewis
base organocatalysts were designed and synthesized. They are shown
to be effective in trichlorosilane-mediated stereoselective conjugate re-
ductions of C=C bonds. DFT calculations reveal that the strong hydro-
gen bonds between the amide linker and the chloride on silicon in the
transition state contribute to the high reactivity of the catalyst.
substrate coordination (Scheme 1b). C -Symmetric tetra-
2
dentate bisphosphine/diamine (PNNP) ligands with NH-
functionality have been reported as highly efficient catalyst
systems for asymmetric hydrogenation/transfer hydrogena-
Key words chiral Lewis base, organocatalyst, enone reduction, hydro-
gen bonds
9
10
tion of ketones and other enantioselective reactions. We
therefore decided to apply the versatile features of a di-
amine linker and prepare new P(O)NNP(O)-based organo-
catalysts. We hypothesized that such a linker would not
only increase the bite angle, but also lead to potential hy-
Chiral Lewis base catalysts have emerged as powerful
organocatalysts in the past decade for the construction of
2
C–C or C–X bonds. Among them, phosphine oxide-contain-
ing Lewis base catalysts (Figure 1) have been applied exten-
sively in a number of enantioselective transformations in-
cluding Mukaiyama aldol and double aldol reactions, tri-
drogen bonding of HSiCl with the hydrogen atoms on di-
amine.
3
3
The proposed catalysts were synthesized by coupling of
chlorosilane-mediated stereoselective reductions of C=N
the corresponding carboxylic acid11 with diamines in the
4
5
and C=C bonds, bromoaminocyclization, enantioselective
presence of propylphosphonic anhydride (T P) in acetoni-
3
6
7
allylation and epoxide ring-opening reactions.
The availability of diversified phosphine ligand libraries
has enabled successful application of metal-catalyzed reac-
tions on industrial scales. With increasing attention on de-
veloping organocatalyst-catalyzed asymmetric synthesis,
the advancement of novel efficient catalyst systems re-
mains an attractive endeavor. Recently, we reported a series
of tunable P-stereogenic dihydrobenzooxophosphole-based
bisphosphine ligands BIBOPs that are highly effective in a
O
iPrO
OPr
i
PPh2
H
N
PPh2
PPh2
O
O
O
P
Ph
O
PPh2
O
O O
N
P
Ph
Ph
N
H
H3C
(
R)-binapo
Me
Me
N
N
O
N
O
P
P
8
N
3
N
number of asymmetric transformations. We reasoned that
the corresponding bis-phosphine oxide BIBOPOs might be
applicable as Lewis base organocatalysts. The conjugate re-
N
Me Me
Me
Me
Figure 1 Selected P=O containing Lewis base organocatalysts
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 587–591
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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Synlett
B. Qu et al.
Letter
O
cat (10 mol%)
O
HSiCl3 (5 equiv)
CH2Cl2
Ph
Ph
Ph
Ph
1a
2a
O H H O
(a)
P
P
tBu O
O
tBu
OMe
MeO
BIBOPO
trace conversion to 2a
(b)
O
P
O
P
O
O
tBu OMe
MeO tBu
(c)
O
O
NH HN
i) diamine
T3P, TEA
O
O
P
O
O
O
i) LDA, –70 °C
ii) CO2, –70 °C
O
O
P
P
P
OH
CH3CN
rt, 3 h
tBu
tBu
O
O
OMe tBu
OMe tBu
OMe
MeO
Lewis base catalysts (3a–e)
entry
catalyst
Conversion (%)
er
82.5:17.5
1
2
3
4
5
6
3a
90
100
49
3aa
3ba
3ca
3da
3ea
89.6:10.4
67.8:32.2
69.0:31.0
87.5:12.5
73.8:26.2
10
100
100
(
R)(R)
(S)(S)
O
O
O
O
NH HN
NH HN
O
O
O
O
O
O
O
O
P
P
P
P
tBu
tBu
tBu
tBu
OMe
MeO
OMe
MeO
3a
3b
Ph
Ph
O
O
O
O
O
O
NH HN
NH HN
NH HN
O
O
O
O
O
O
O
O
O
O
O
O
P
P
P
P
P
P
tBu
tBu
tBu
tBu
tBu
tBu
OMe
MeO
OMe
MeO
OMe
MeO
Scheme 1 Conjugate reduction of 1a with P(O)NNP(O) Lewis base catalysts. Reagents and conditions: 1a (0.27 mmol), HSiCl (1.35 mmol), catalyst
3
(
0.027 mmol) in CH Cl at 0 °C for 20 h unless specified otherwise. Conversion of 1a into 2a, and enantioselectivity were analyzed on SFC at 220 nm UV
2 2
wavelength with a chiral stationary phase. (a) Application of BIBOPO catalyst; (b) rational design of new catalysts; (c) synthesis and evaluation of the
a
new catalysts. Reaction was run in acetonitrile.
trile (Scheme 1c).12 In each case, only one diastereomer
product was obtained under the coupling conditions, with-
out any racemization. We first synthesized the bis-amide
catalyst 3a, featuring a (R,R)-diaminocyclohexane linker.
the corresponding diastereomeric (S,S)-diaminocyclohexyl-
containing catalyst 3b provided incomplete conversion and
67.8:32.2 er, indicating that the conformation of the bis-
amide linker is integral to both turnover and selectivity.
When the rigidity of the catalyst backbone linker was in-
creased with phenyl diamine, however, low reactivity and
selectivity were observed for catalyst 3c. On the other hand,
the (R,R)-1,2-dicyclohexyl ethylene diamine-containing
catalyst 3d provided the product 2a with 100% conversion
13
Pleasingly, (S)-1,3-diphenylbutan-1-one (2a) was fur-
nished in 90% conversion and an 82.5:17.5 enantiomeric ra-
tio in CH Cl (entry 1). Several environmentally friendly
2
2
solvents were tested, and acetonitrile was found to provide
the highest selectivity (89.6:10.4 er; entry 2). Interestingly,
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 587–591

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Letter
O
3a (10 mol%)
O
Ph
Ar
HSiCl3 (5 equiv)
MeCN, 0 °C
Ph
Ar
O
O
1
a–d
2a–d
NH HN
Cl Cl
O
O
O
O
P
O
Si
O
P
O
O
OMe
tBu
tBu
O
O
Ph
Ph
Ph
Ph
Ph
H
OMe
O
NH HN
Cl Cl
MeO
CF3
Cl
O
P
O
2.2
2a
100% conversion (90%) 100% conversion (92%)
9.2:10.8 er 89.4:10.6 er
2b
2c
2d
[0.6]
100% conversion (94%) 100% conversion (89%)
O
Si
O P
tBu
8
90.2:9.8 er
88.1:11.9 er
tBu Cl
Cl
Scheme 2 Conjugate 1,4-enone reduction using organocatalyst 3a.
OMe
MeO
O
O
Reagents and conditions: enone 1 (0.27 mmol), HSiCl (1.35 mmol), cat-
3
NH HN
Cl Cl
alyst 3a (0.027 mmol) in acetonitrile at 0 °C for 20 h; the yields in paren-
thesis are isolated yields after silica gel purification.
O
O
P
O
Si O P
Blue = productive catalyst (3a)
Red = unproductive catalyst (3b)
tBu
tBu
H
O
OMe
MeO
tive to the enone, and the geometry of the enone (since it
can undergo isomerization under the reaction conditions).
Detailed conformational analyses of these transition states
were undertaken to identify the relevant lowest energy
transition states for the different catalysts.
Amongst the catalysts screened, there was a notable dif-
ference in behavior of the diastereomeric compounds ob-
tained from the two enantiomers of cyclohexane diamine
(matched 3a, mismatched 3b). To assess the reactivity of
these diastereomeric catalysts, the activation energies for
hydride transfer in the respective systems were analyzed.
Calculations showed that a higher activation energy is re-
quired for the reduction of the enone using the (S,S)-isomer
of the catalyst 3b by 2.2 kcal/mol, which is consistent with
the observed reactivity (Figure 2).
As projected, both catalysts form hydrogen bonds be-
tween the amide linker and the chlorine ligands of the sili-
con in the transition state. The productive catalyst 3a forms
stronger hydrogen bonds than the unproductive catalyst 3b,
as determined by bond lengths (Figure 3). These hydrogen
bonds would be expected to enhance the Lewis acidity of
the silicon center and thereby enhance reactivity. It thus
appears that the mismatched catalyst, 3b, must engage in
greater deformation (i.e., is more strained) to achieve such
Figure 2 Relative activation energies of the reduction of the simplified
enone by both diastereomeric catalysts 3a (blue) and 3b (red). Com-
puted at B3LYP/6-31G(d) level. Free energy values are reported in
kcal/mol, and enthalpies are given in brackets. Acrolein was used as a
model for the enone.
and 87.5:12.5 er. When the bis-cyclohexyl group was re-
placed with a bis-phenyl group in catalyst 3f, the same re-
activity of 100% conversion was achieved, but diminished
enantioselectivity of 74:26 er was observed.
14
We initiated a DFT study with Gaussian 16 at the
15
B3LYP/6-31G(d) level to understand the origin of the cata-
lyst reactivity in these reductions. According to the pro-
posed mechanism,1 the stereodetermining step involves a
6
1,4-addition of a silicon hydride to the enone via a six-
membered transition state. In this transition state, the cat-
ionic silicon coordinates to the carbonyl oxygen, geometri-
cally placing the silicon hydride near the -carbon of the
enone. Upon reduction, the enolate remains coordinated to
the cationic silicon. Possible transition states differ in the
position of the hydride on the catalyst, the position of the
enone on the catalyst, the orientation of the hydride rela-
Figure 3 CYL view of the transition-state structures with productive (3a, left) and unproductive (3b, right) diastereomeric catalysts. Hydrogen bonds
between the amide linker and chlorine atoms are indicated with dashed lines, distances are given in Angstroms.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 587–591

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B. Qu et al.
Letter
hydrogen bonds, which are also weaker, causing less activa-
tion. Together, these factors account for the much lower re-
activity of 3b (49% conversion) relative to 3a (100% conver-
sion).
(8) (a) Chong, E.; Qu, B.; Zhang, Y.; Cannone, Z. P.; Leung, J. C.;
Tcyrulnikov, S.; Nguyen, K. D.; Haddad, N.; Biswas, S.; Hou, X.;
Kaczanowska, K.; Chwalba, M.; Tracz, A.; Czarnocki, S.; Song, J.
J.; Kozlowski, M. C.; Senanayake, C. H. Chem. Sci. 2019, 10, 4339.
(b) Tang, W.; Qu, B.; Capacci, A. G.; Rodriguez, S.; Wei, X.;
The conjugate reduction conditions with catalyst 3a are
compatible with (E)-1,3-diphenylbutenones bearing both
electron-rich and electron-poor functional groups and give
similar enantioselectivity (2a–d) in acetonitrile (Scheme 2).
In conclusion, we have developed new Lewis base or-
ganocatalysts derived from a P-stereogenic dihydrobenzo-
oxophosphole core structure by coupling with (R,R)-dicyclo-
hexyl ethylene diamine, which provides a conformational
match for the enantioselective reduction of enone deriva-
Haddad, N.; Narayanan, B.; Ma, S.; Grinberg, N.; Yee, N. K.;
Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2010, 12, 176.
(9) (a) Sui-Seng, C.; Freutel, F.; Lough, A. J.; Morris, R. H. Angew.
Chem. Int. Ed. 2008, 47, 940. (b) Gao, J. X.; Ikariya, T.; Noyori, R.
Organometallics 1996, 15, 1087.
(
10) (a) Li, Y.-Y.; Yu, S.-L.; Shen, W.-Y.; Gao, J.-X. Acc. Chem. Res. 2015,
48, 2587. (b) Trost, B. M. Tetrahedron 2015, 71, 5708. (c) Trost, B.
M.; Van Vranken, D. L. Angew. Chem. Int. Ed. 1992, 21, 228.
11) Qu, B.; Samankumara, L. P.; Ma, S.; Fandrick, K. R.; Desrosiers, J.-
N.; Rodriguez, S.; Li, Z.; Haddad, N.; Han, Z. S.; McKellop, K.;
Pennino, S.; Grinberg, N.; Connella, N. C.; Song, J. J.; Senanayake,
C. H. Angew. Chem. Int. Ed. 2014, 53, 14428.
12) General procedure for catalyst preparation: To a solution of
carboxylic acid phosphine oxide (5.0 g, 17.6 mmol, 2.2 equiv),
diamine (8.0 mmol, 1 equiv) and triethylamine (32.0 mmol, 4
equiv) in acetonitrile at room temperature was added propyl-
(
tives mediated with HSiCl . The asymmetric transformation
3
is effected by the P-stereogenic center and the selectivity is
tunable by the substituents on the catalyst. This class of cat-
alysts has potential as tunable Lewis base catalysts in terms
of reactivity and selectivity. Further work to identify cata-
lysts that are more efficient is ongoing, and such tuning will
be reported in due course.
(
phosphonic anhydride (T P) solution in DMF (16.0 mmol, 2
3
equiv) in portions over 3 h. The reaction was stopped after com-
plete consumption of the carboxylic acid. The mixture was then
treated with 50% aqueous NaOH (10 mL) and stirred at 35 °C for
Funding Information
3
h. The suspension was diluted with water and the resulting
clear solution was extracted three times with EtOAc. The com-
bined organic layer was washed with brine, dried with MgSO4
and concentrated, and the crude mixture was purified by chro-
matography on silica (100% EtOAc to 10% MeOH/EtOAc) to
obtain a white solid after drying.
M. C. K. thanks the NIH (GM087605) and Boehringer Ingelheim Phar-
maceuticals for financial support.
N
ati
o
n
a
l Institute of
H
e
a
l
th (G
M
0
8
7
6
0
5)
Acknowledgment
(2R,2′R,3S,3′S)-N,N′-((1R,2R)-cyclohexane-1,2-diyl)bis(3-
(
tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-
Computational support was provided by XSEDE (TG-CHE120052). The
authors also thank Mr. Scott Pennino for HRMS analysis.
1
carboxamide 3-oxide) (3a): Yield: 3.67 g (71%). H NMR (500
MHz, CDCl ):  = 7.46 (t, J = 8.23 Hz, 2 H), 6.80 (br d, J = 6.70 Hz,
3
2
4
2
4
H), 6.71 (dd, J = 8.3, 2.8 Hz, 2 H), 6.54 (dd, J = 8.2, 4.4 Hz, 2 H),
.93 (s, 2 H), 3.88 (s, 6 H), 3.80 (br s, 2 H), 2.11 (br d, J = 7.3 Hz,
H), 1.65 (br s, 2 H), 1.37 (d, J = 17.0 Hz, 18 H), 1.25–1.23 (m,
Supporting Information
13
H). C NMR (125 MHz, CDCl ):  = 165.2 (d, J = 2.7 Hz), 164.5
Supporting information for this article is available online at
3
(
(
(
d, J = 14.2 Hz), 161.1 (d, J = 2.4 Hz), 136.9 (d, J = 0.87 Hz), 106.6
d, J = 5.3 Hz), 104.1 (d, J = 5.7 Hz), 102.70 (d, J = 90.8 Hz), 75.4
d, J = 48.4 Hz), 55.6, 53.7, 34.07 (d, J = 74.5 Hz), 32.4, 25.1 (d, J =
https://doi.org/10.1055/s-0039-1690851.
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31
References
0.96 Hz), 24.5. P NMR (202 MHz, CDCl
3
):  = 62.83. HRMS
+
(ESI): m/z [M + H] calcd for C32H45O N P : 647.26457; found:
8
2 2
(
(
(
1) Current address: TCG Lifesciences Private Limited, 737 North
th Street, Richmond, Virginia 23219, US.
2) (a) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.
b) Guizzetti, S.; Benaglia, M. Eur. J. Org. Chem. 2010, 5529.
647.26495.
5
(2R,2′R,3S,3′S)-N,N′-((1S,2S)-cyclohexane-1,2-diyl)bis(3-(tert-
butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carbox-
amide 3-oxide) (3b): Yield: 3.36 g (65%). H NMR (400 MHz,
1
(
3) (a) Shimoda, Y.; Kubo, T.; Sugiura, M.; Kotani, S.; Nakajima, M.
Angew. Chem. Int. Ed. 2013, 52, 3461. (b) Aoki, S.; Kotani, S.;
Sugiura, M.; Nakajima, M. Chem. Commun. 2012, 48, 5524.
4) (a) Han, Z. S.; Zhang, L.; Xu, Y.; Sieber, J. D.; Marsini, M. A.; Li, Z.;
Reeves, J. T.; Kandrick, K. R.; Patel, N. D.; Desrosiers, J.-N.; Qu, B.;
Chen, A.; Rudzinski, D. M.; Samankumara, L. P.; Ma, S.; Grinberg,
N.; Roschangar, F.; Yee, N. K.; Wang, G.; Song, J. J.; Senanayake,
C. H. Angew. Chem. Int. Ed. 2015, 54, 5474. (b) Sugiura, M.; Sato,
N.; Kotani, S.; Nakajima, M. Chem. Commun. 2008, 4309.
5) Li, Z.; Shi, Y. Org. Lett. 2015, 17, 5752.
CDCl ):  = 7.43 (t, J = 8.2 Hz, 2 H), 6.86 (br d, J = 6.0 Hz, 2 H),
3
6.62 (dd, J = 8.2, 3.0 Hz, 2 H), 6.50 (dd, J = 8.1, 4.4 Hz, 2 H), 5.22
(s, 2 H), 3.80 (s, 6 H), 3.73 (br s, 2 H), 2.12 (br d, J = 6.6 Hz, 2 H),
1.69 (br s, 2 H), 1.31–1.26 (overlapping d, J = 17.0 Hz, and m,
(
13
22 H). C NMR (100 MHz, CDCl ):  = 165.7 (d, J = 2.0 Hz), 165.3
3
(d, J = 15.3 Hz), 161.3 (d, J = 2.1 Hz), 136.8, 106.4 (d, J = 5.4 Hz),
103.8 (d, J = 5.8 Hz), 101.6 (d, J = 91.6 Hz), 74.6 (d, J = 48.3 Hz),
55.6, 53.5, 34.3 (d, J = 74.0 Hz), 32.2, 24.6, 24.5. P NMR (162
31
+
MHz, CDCl ):  = 62.36. HRMS (ESI): m/z [M + H] calcd for
3
(
(
C32H45O N P : 647.26457; found: 647.26433.
8
2 2
6) Ogasawara, M.; Kotani, S.; Nakajima, H.; Furusho, H.; Miyasaka,
M.; Shimoda, Y.; Wu, W.-Y.; Sugiura, M.; Takahashi, T.;
Nakajima, M. Angew. Chem. Int. Ed. 2013, 52, 13798.
(2R,2′R,3S,3′S)-N,N′-(1,2-phenylene)bis(3-(tert-butyl)-4-
methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide
3-oxide) (3c): Yield: 3.07 g (60%); H NMR (400 MHz, CDCl ): 
1
3
(
7) Kotani, S.; Hashimoto, S.; Nakajima, M. Tetrahedron 2007, 63,
= 8.65 (s, 2 H), 7.54 (m, 2 H), 7.44 (t, J = 8.2 Hz, 2 H), 7.16 (m,
2 H), 6.68 (dd, J = 8.3, 2.8 Hz, 2 H), 6.54 (dd, J = 8.2, 4.4 Hz, 2 H),
3122.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 587–591

5
91
Synlett
B. Qu et al.
Letter
5
(
.33 (s, 2 H), 3.86 (s, 6 H), 1.34 (d, J = 17.1 Hz, 18 H); 13C NMR
100 MHz, CDCl ):  = 165.2 (d, J = 14.9 Hz), 164.5 (d, J = 2.6 Hz),
t = 1.69 (major), 1.91 (minor) min. NMR data match those
R
18 1
reported in the literature. H NMR (400 MHz, CDCl ):  = 7.97–
3
3
1
5
4
61.3 (d,J = 2.2 Hz), 137.0, 129.9, 126.7, 126.2, 106.5 (d, J =
7.92 (m, 2 H), 7.60–7.56 (m, 3 H), 7.50–7.45 (m, 2 H), 7.41 (d, J =
8.3 Hz, 2 H), 3.69 (sextet, J = 6.9 Hz, 1 H), 3.35 (dd, J = 16.8,
.4 Hz), 104.1 (d, J = 5.8 Hz), 102.0 (d, J = 91.6 Hz), 75.5 (d, J =
31
7.5 Hz), 55.7, 34.4 (d, J = 73.8 Hz), 24.7. P NMR (202 MHz,
6.4 Hz), 3.25 (dd, J = 16.9, 7.5 Hz, 1 H), 1.39 (d, J = 7.0 Hz, 3 H).
+
13
CDCl ):

=
63.9. HRMS (ESI): m/z [M
+
H] calcd for
C NMR (100 MHz, CDCl ):  = 198.4, 150.6, 137.0, 133.2, 128.6,
3
3
C32H39O N P : 641.21762; found: 641.21767.
128.0, 127.3, 125.5 (q, J = 3.8 Hz), 46.5, 35.3, 21.9.
8
2 2
(
2R,2′R,3S,3′S)-N,N′-((1R,2R)-1,2-dicyclohexylethane-1,2-
(S)-3-(4-Chlorophenyl)-1-phenylbutan-1-one (2c): Yield:
94%; 90.2:9.8 er; SFC (ES Industries CCA column 4.6 × 100 mm,
diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphos-
phole-2-carboxamide 3-oxide) (3d): Yield: 3.03 g (50%);
1
H
3 m: 35 °C, A: CO , B: methanol; gradient: 1% B to 3% B in 3
2
NMR (400 MHz, CDCl ):  = 7.45 (t, J = 8.2 Hz, 2 H), 6.72–6.68
min, to 50% B in 5 min; 3 mL/min,  = 220 nm): t = 2.93 (major),
3
R
(
4
(
overlapping s and dd, J = 8.2, 3.0 Hz, 4 H), 6.54 (dd, J = 8.1,
.3 Hz, 2 H), 4.92 (d, J = 0.48 Hz, 2 H), 4.06–4.00 (m, 6 H), 3.88
s, 6 H), 1.74–1.67 (m, 9 H), 1.54–1.34 (overlapping d, J =
3.51 (minor) min. NMR data match those reported in the litera-
18 1
ture. H NMR (400 MHz, CDCl ):  = 7.95–7.92 (m, 2 H), 7.60–
3
7.56 (m, 1 H), 7.50–7.45 (m, 2 H), 7.30–7.27 (m, 2 H), 7.25–7.21
1
7.0 Hz, and m, 24 H), 1.22–1.02 (m, 10 H), 0.9–0.81 (m, 2 H).
(m, 2 H), 3.52 (sextet, J = 6.9 Hz, 1 H), 3.29 (dd, J = 16.7, 6.3 Hz),
3.2 (dd, J = 16.7, 7.7 Hz, 1 H), 1.35 (d, J= 7.0 Hz, 3 H). C NMR
1
3
13
C NMR (100 MHz, CDCl ):  = 165.1 (d, J = 2.3 Hz), 164.4 (d, J =
3
13.9 Hz), 161.1 (d, J = 2.1 Hz), 136.7, 106.5 (d, J = 5.2 Hz), 104.1
(100 MHz, CDCl ):  = 198.7, 145.0, 137.1, 133.1, 131.9, 128.6,
3
(d, J = 5.7 Hz), 103.1 (d, J = 90.5 Hz), 75.6 (d, J = 48.9 Hz), 55.6,
128.3, 128.0, 46.8, 35.0, 22.0.
5
2
+
4.7, 38.9, 34.1 (d, J = 74.4 Hz), 30.5, 27.3, 26.2, 26.16, 26.11,
(S)-3-(2-Methoxyphenyl)-1-phenylbutan-1-one (2d): Yield:
89%; 88.1:11.9 er; SFC (Lux Cel 1 column 4.6 × 100 mm, 3 m:
31
5.2. P NMR (162 MHz, CDCl ):  = 61.64. HRMS (ESI): m/z [M
3
+
H] calcd for C40H59O N P : 757.37412; found: 757.37417.
35 °C, A: CO , B: methanol; gradient: 1% B to 3% B in 3 min, to
8
2
2
2
(
2R,2′R,3S,3′S)-N,N′-((1R,2R)-1,2-diphenylethane-1,2-
50% B in 5 min; 3 mL/min,  = 220 nm): t = 3.94 (major), 4.27
R
19
diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphos-
phole-2-carboxamide 3-oxide) (3e): Yield: 2.98 g (50%);
(minor) min. NMR data match those reported in the literature.
1
1
H
H NMR (500 MHz, CDCl ):  = 7.90 (d, J = 7.8 Hz, 2 H), 7.45 (t, J =
3
NMR (500 MHz, CDCl ):  = 7.52 (br d, J = 2.8 Hz, 2 H), 7.43 (t, J =
7.3 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.15 (d, J = 7.3 Hz, 1 H), 7.11
(t, J = 7.7 Hz, 1 H), 6.85 (t, J = 7.4 Hz, 1 H), 6.77 (d, J = 8.1 Hz,
3
8
6
3
.2 Hz, 2 H), 7.11–7.06 (m, 10 H), 6.70 (dd, J = 8.3, 2.5 Hz, 2 H),
.50 (dd, J = 8.1, 4.3 Hz, 2 H), 5.40–5.38 (m, 2 H), 5.00 (s, 2 H),
1 H), 3.78–3.73 (m, 1 H), 3.73 (s, 3 H), 3.27 (dd, J = 15.8, 4.8 Hz,
13
13
.85 (s, 6 H), 1.35 (d, J = 16.9 Hz, 18 H). C NMR (100 MHz,
1 H), 2.97 (dd, J = 15.7, 9.2 Hz, 1 H), 1.23 (d, J = 7.0 Hz, 3 H).
C
CDCl ):  = 165.5 (d, J = 2.4 Hz), 164.5 (d, J = 14.1 Hz), 161.1 (d,
NMR (125 MHz, CDCl ):  = 199.7, 156.9, 137.3, 134.5, 132.8,
3
3
J = 2.3 Hz), 137.7, 136.8, 128.5, 127.74, 127.69, 106.5 (d, J =
128.5, 128.2, 127.2, 126.9, 120.7, 110.6, 55.3, 46.0, 29.6, 19.7.
(13) (S)-isomer was assigned by comparison to the reported data in
ref. 4b.
5.3 Hz), 104.0 (d, J = 5.8 Hz), 102.7 (d, J = 91.1 Hz), 75.3 (d,
J = 48.8 Hz), 59.1, 55.6, 34.1 (d, J = 74.5 Hz), 25.1 (d, J = 0.8 Hz).
31
+
P NMR (202 MHz, CDCl ):  = 62.13. HRMS (ESI): m/z [M + H]
(14) Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M.
A., Cheeseman J. R., Scalmani G., Barone V., Petersson G. A.,
Nakatsuji H., Li X., Caricato M., Marenich A. V., Bloino J., Janesko
B. G., Gomperts R., Mennucci B., Hratchian H. P., Ortiz J. V.
Izmaylov, A. F., Sonnenberg J. L., Williams-Young D., Ding F., Lip-
parini F., Egidi F., Goings J., Peng B., Petrone A., Henderson T.,
Ranasinghe D., Zakrzewski V. G., Gao J., Rega N., Zheng G., Liang
W., Hada M., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida
M., Nakajima T., Honda Y., Kitao O., Nakai H., Vreven T., Throssell
K., Montgomery J. A. Jr., Peralta J. E., Ogliaro F., Bearpark M. J.,
Heyd J. J., Brothers E. N., Kudin K. N., Staroverov V. N., Keith T. A.,
Kobayashi R., Normand J., Raghavachari K., Rendell A. P., Burant
J. C., Iyengar S. S., Tomasi J., Cossi M., Millam J. M., Klene M.,
Adamo C., Cammi R., Ochterski J. W., Martin R. L., Morokuma K.,
Farkas O., Foresman J. B., Fox D. J.; Gaussian 16, Revision B.01;
Gaussian, Inc., Wallingford CT, 2016
3
calcd for C40H47O N P : 745.28022; found: 745.28012.
8
2 2
General procedure for enone reduction: To a stirring solution
of 1a (60 mg, 0.27 mmol) and catalyst 3a (0.027 mmol, 10
mol%) in acetonitrile (2 mL) at 0 °C was added HSiCl3 (1.35
mmol, 5 equiv) dropwise, and the mixture was stirred at 0 °C
for 20 h. The reaction was then quenched with a solution of 5N
aqueous NaOH (2 mL), and the mixture was warmed to room
temperature then diluted with EtOAc and water. The phases
were separated, and the aqueous phase was further extracted
once with EtOAc. The combined organic layers were washed
with water followed by brine, dried with Na SO and concen-
2
4
trated. The product was purified on silica with a mixture of
hexanes/EtOAc (10:1) to obtain a colorless oil after drying.
(S)-1,3-Diphenylbutan-1-one (2a): Yield: 90%; 89.2:10.8 er;
SFC (ES Industries CCA column 4.6 × 100 mm, 3 m: 35 °C, A:
CO , B: isopropanol; gradient: 1% B to 3% B in 3 min, to 50% B in
(15) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988,
37, 785.
(16) Sugiura, M.; Ashikari, Y.; Takahashi, Y.; Yamaguchi, K.; Kotani,
S.; Nakajima, M. J. Org. Chem. 2019, 84, 11458.
(17) Kanazawa, Y.; Tshchiya, Y.; Kobayashi, K.; Shiomi, T.; Itoh, J.-I.;
Kikuchi, M.; Yamamoto, Y.; Nishiyama, H. Chem. Eur. J. 2006, 12,
63.
2
5
min; 3 mL/min,  = 220 nm): tR = 2.50 (major), 2.80 (minor)
17 1
min. NMR data match those reported in the literature. H NMR
500 MHz, CDCl ):  = 7.96 (d, J = 7.9 Hz, 2 H), 7.57 (t, J = 7.3 Hz,
(
3
1
2
H), 7.47 (t, J = 7.6 Hz, 2 H), 7.35–7.21 (m, 4 H), 7.35–7.28 (m,
H), 7.23 (t, J = 6.8 Hz, 1 H), 3.54 (sextet, J = 6.9 Hz, 1 H), 3.33
(
dd, J = 16.5, 5.7 Hz, 1 H), 3.22 (dd, J = 16.5, 8.3 Hz, 1 H), 1.37 (d,
13
J= 6.9 Hz, 3 H). C NMR (125 MHz, CDCl ):  = 199.1, 146.6,
3
1
37.2, 133.0, 128.6, 128.5, 128.1, 126.9, 126.3, 47.0, 35.6, 21.9.
(18) Miaskiewicz, S.; Reed, J. H.; Donets, P. A.; Oliveira, C. C.; Cramer,
N. Angew. Chem. Int. Ed. 2018, 57, 4039.
(19) Yamamoto, Y.; Kurihara, K.; Takahashi, Y.; Miyaura, N. Molecules
2013, 18, 14.
(
(
S)-1-Phenyl-3-(4-(trifluoromethyl)phenyl)butan-1-one
2b): Yield: 92%; 89.4:10.6 er; SFC (ES Industries CCA column
4.6 × 100 mm, 3 m: 35 °C, A: CO , B: isopropanol; gradient: 1%
2
B to 3% B in 3 min, to 50% B in 5 min; 3 mL/min,  = 220 nm):
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2020. Thieme. All rights reserved. Synlett 2020, 31, 587–591