Enantiomerically divergent pathways in Tsuji-Trost reactions: exploiting the structural differences between β-acyloxy-o-(diphenylphosphino)benzamides and β-amido-o-(diphenylphosphino)benzoates

Article abstract of DOI:10.1016/j.tetasy.2016.08.012

Using a single chiral scaffold, (1R,2S)-norephedrine, a series of monophosphine ligands have been prepared. The ligands prepared, β-acyloxy-(o-diphenylphosphino)amides and β-amido-(o-diphenylphosphino)esters, give rise to enantiomerically divergent produc

Full text of DOI:10.1016/j.tetasy.2016.08.012

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiomerically divergent pathways in Tsuji-Trost reactions:
exploiting the structural differences between b-acyloxy-o-
(diphenylphosphino)benzamides and b-amido-o-
(diphenylphosphino)benzoates
Brandon M. Nelson, Mihir K. Chavda, Jonathan Oliphant, Jalisa M. King, Lisa F. Szczepura,
⇑
Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Using a single chiral scaffold, (1R,2S)-norephedrine, a series of monophosphine ligands have been
prepared. The ligands prepared, b-acyloxy-(o-diphenylphosphino)amides and b-amido-(o-diphenylphos-
phino)esters, give rise to enantiomerically divergent products in the Tsuji-Trost asymmetric allylic
reaction. The phosphinoamides afforded the best enantioselectivities and favored the (S)-enantiomer
of the product. In contrast the phosphinoesters afforded lower enantioselectivities and favored the (R)-
enantiomer. A mechanistic rationale for this observation is proposed.
Received 5 July 2016
Accepted 19 August 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
ety present as an amide, b-acyloxy-o-diphenylphosphinobenza-
mide 5, or as an ester, b-amido-o-diphenylphosphino benzoate 6
The Tsuji-Trost asymmetric allylic alkylation reaction has
attracted much attention due to its efficiency in the enantioselec-
tive synthesis of allylic substrates.1 Trost ligand 1 has been shown
to be highly effective in the allylic alkylation reaction and has rep-
resented a high standard in terms of ligand design.2 In this context,
related ligands have been synthesized in the hope of creating
ligands of comparable efficacy as chiral ligands for phosphines in
the Tsuji-Trost reaction.3 Since the Trost ligand is derived from a
C2-symmetric chiral diamine, our interest was in exploiting b-
aminoalcohols due to the broader diversity and commercial avail-
ability of these compounds. Thus, our research group developed a
series of bis(phosphine) ligands based on (1R,2S)-norephedrine 2a,
(1S,2S)-pseudonorephedrine 2b,4 and b-aminoalcohols 3a–c5
(Fig. 1). Herein, we report on the synthesis of these two ligand fam-
ilies and their application in the Tsuji-Trost reaction. A rationale is
proposed for the observed stereoselectivities for the two classes of
phosphine ligands.
2. Results and discussion
This investigation began with the synthesis of the b-acyloxy-(o-
diphenylphosphino)amide ligands 5a–d. (1R,2S)-Norephedrine
was coupled with o-(diphenylphosphino)benzoic acid in the pres-
ence of EDC and a catalytic amount of DMAP. The amide was then
reacted with a variety of acyl chlorides to form the target amide
ligands 5a–d (Table 1).
The second group of ligands synthesized employed the same
(1R,2S)-norephedrine template. Norephedrine was reacted with
an acyl chloride that had been used in the synthesis of the prior
group of ligands. This process yielded four amides, which were
then esterified by the addition of o-(diphenylphosphino)benzoic
acid in the presence of EDC and a catalytic amount of DMAP. This
yielded the desired b-amido-(o-diphenylphosphino)esters 9a–d.
All of the phosphine ligands 5a–d and 9a–d were fully charac-
terized and evaluated by 31P NMR spectroscopy. The 31P NMR sig-
nal for the o-diphenylphosphinobenzamido ligands 5a–d appeared
between ꢀ8.0 and ꢀ11 ppm in CDCl3. The 31P NMR signal for the
derived from a-amino acids (Fig. 1). These ligand systems proved
to be successful in terms of promoting the enantioselective alkyla-
tion of rac-1,3-diphenyl-1-propenyl acetate with diethylmalonate
with enantioselectivities as high as 96% ee. Beyond this success,
we were interested in exploring further the chemistry of these
compounds as monophosphines. The synthesis of such compounds
would allow for a study of the stereochemical consequences of
having the key diphenylphosphinobenzoyl (o-Ph2PC6H4CO–) moi-
⇑
Corresponding author. Tel.: +1 309 438 7854; fax: +1 309 438 5538.
E-mail address: Hitchcock@illinoisState.edu (S.R. Hitchcock).
http://dx.doi.org/10.1016/j.tetasy.2016.08.012
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nelson, B. M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.012

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B. M. Nelson et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
R2
R1
H3C
N
R
N
O
O
O
O
O
O
N
N
O
O
H
H
H
H
PPh2
Ph2P
PPh2
PPh2
Ph2P
Ph2P
R1 = -Ph, R2 = -H
R
Trost ligand 1
3a: R = -CH(CH3)2
2a:
2b:
3b:
R = -CH2Ph
1 = -H, R2 = -Ph
3c: R = -C6H5
H3C
H3C
N
Ph
Ph
O
O
R
O
O
R
O
H3C
H2N
Ph
O
N
H
H
OH
PPh2
Ph2P
4
β
5
β
6
-amido-o-diphenylphosphinobenzoate
-acyloxy-o-diphenylphosphinobenzamide
Figure 1. Bis(phosphine) ligands 1–3 and proposed monophosphines 5 and 6.
Table 1
Synthesis of the b-acyloxy-(o-diphenylphosphino)amides 5a–d
CO2H
H3C
N
Ph
H3C
N
Ph
O
O
O
O
R
H3C
H2N
Ph
PPh2
OH
R
Cl
O
H
PPh2
H
PPh2
EDC, DMAP, CH2Cl2
DMAP,TEA CH2Cl2
OH
reference 10
4
7
5a:
R = -C6H5
5b: R = -p-C6H4NO2
5c:
5d:
R = -C6H2(CH3)3
R = -C(CH3)3
Entry
R=
Phosphine
Yielda (%)
1
2
3
4
–C6H5
5a
5b
5c
5d
88
56
49
61
–p-C6H4NO2
–C6H2(CH3)3
–C(CH3)3
a
Isolated yield after purification.
o-diphenylphosphinobenzoate ligands 9a–d appeared between
ꢀ4.0 and ꢀ6.0 ppm in CDCl3. Collectively, these signals appear in
nearly the same region as the signal for triphenylphosphine which
appears as a singlet at ꢀ4.72 ppm in CDCl3. It is worthwhile noting
that all but a few of the compounds showed a small singlet (<5%)
near 30–37 ppm in the 31P spectrum. We propose that this signal
represents the oxidized phosphine of the phosphine being ana-
lyzed. An independent sample of triphenylphosphine oxide was
analyzed and found to contain a singlet in the same region at
29.7 ppm. The putative phosphine oxides may have originated
from the handling of these compounds in the presence of air
(Table 2).
The collected ligands 5a–d and 9a–d were then treated with a
catalytic amount of the palladium allyl chloride dimer, catalytic
potassium acetate, N,O-bis(trimethylsilyl)acetamide, rac-1,3-
diphenyl-1-propenyl acetate rac-10, and diethylmalonate. The
observed enantioselectivities from the catalysis indicated that the
o-diphenylphosphinobenzamide ligands 5a–d afforded high
enantioselectivities ranging from 87% to 90% ee while favoring
the (S)-enantiomer of the product. In contrast, the o-diphenylphos-
phinobenzoate ligands 9a–d afforded low enantioselectivities
ranging from 5% to 58% ee while favoring the (R)-enantiomer of
the product (Table 3).
the mechanistic model developed by Burke et al.,6 it is proposed
that the key complexation event that leads to the enantioselective
product formation can be represented by complex-12A and com-
plex-12B. These complexes illustrate a favored pathway for the
binding of the palladium with the phosphine and the carbonyl oxy-
gen. In the case of complex-12A, the amide component of complex
serves as a rigid template and is most likely responsible for ensur-
ing that the enantioselection is high (87.2% to 90% ee through
phosphines 5a–d). In this model, the identity of ester component
is not critical as it projects away from the point of the introduction
of chirality. Thus, the presence of an electron withdrawing nitro
group ligand 5b, the steric volume of the trimethylphenyl group
5c, and the steric volume of the tert-butyl group 5d did not signif-
icantly affect the overall catalysis (Fig. 2).
In contrast, the (o-diphenylphosphino)benzoate based com-
plex-12B provides a rationale for the lower enantioselectivities
that were observed for ligands 9a–d. The mechanistic model that
was developed by Burke et al. is invoked again. The conformation
that is adopted by the ligand is similar to that in complex-12A;
however, the positions of the amide and the ester are switched.
The stereochemical arrangement of the ligand causes the enantios-
election to be reversed compared to complex-12A. The compro-
mised enantioselectivity in ligands 9a–d can be attributed to the
conformational flexibility of the ester linkage. The ester ligands
containing the benzamido group 9a and the p-nitrobenzamido
group afforded enantioselectivities of 25.6% ee and 19.3% ee,
The enantiodivergence that was observed for these palladium
catalyzed reactions can be attributed to the ligand structures and
the overall complexing events that occur during the reaction. Using
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B. M. Nelson et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 2
Synthesis of the b-amido-(o-diphenylphosphino)esters 9a–d
CO2H
H3C
N
Ph
O
O
H3C
N
Ph
O
R
O
PPh2
R
Cl
O
R
4
OH
DMAP,TEA CH2Cl2
H
EDC, DMAP, CH2Cl2
H
Ph2P
8a:
9a:
R = -C6H5
R = -C6H5
8b: R = -p-C6H4NO2
8c: R = -C6H2(CH3)3
9b: R = -p-C6H4NO2
9c: R = -C6H2(CH3)3
8d:
9d:
R = -C(CH3)3
R = -C(CH3)3
Entry
Amide
Yielda (%)
Phosphine
Yielda (%)
1
2
3
4
8a
8b
8c
8d
47
94
83
51
9a
9b
9c
9d
71
62
43
20
a
Isolated chemical yield after purification.
Table 3
Asymmetric catalysis with ligands 5a–d and 9a–d
ligand
MeO2C
CO2Me
Ph
MeO2C
H
CO2Me
OAc
η3
[( -C3H5)PdCl]2, CH2(CO2Me)2
H
Ph
Ph
( )
R
cat. KOAc, BSA
solvent
Ph
Ph
(S) Ph
11
10
rac-
11
(R)-
(S)-
Entry
Phosphine
Yielda (%)
R:S
e.e.b (%)
Configuration
1
2
3
4
5
6
7
8
5a
9a
5b
9b
5c
9c
5d
9d
64
69
79
91
83
67
40
58
5.6:94.4
62.8:37.2
5.6:94.4
59.7:40.4
5.0:95.0
54.2:45.8
6.4:93.6
84.2:15.8
88.8
25.6
88.8
19.3
90.0
8.4
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
87.2
68.4
a
Isolated chemical yield after purification.
The enantioselectivity of the catalytic reactions was determined by CSP HPLC using a OD-H column, 95:5, hexanes:isopropyl alcohol.
b
H
H3C
O
N
O
O
O
H
O
OCH3
O
OCH3
K
CH3
K
N
O
O
O
O
Pd
Ph
Pd
Ph
OCH3
OCH3
P
P
from bottom face
from top face
Ph
Ph
complex-12A
complex-12B
MeO2C
Ph
CO2Me
Ph
MeO2C
Ph
CO2Me
Ph
(S)-11
(R)-11
Figure 2. Proposed mechanistic complexation.
respectively. The lower enantioselectivity associated with ligand
9b versus that of 9a might be caused by the nitro group causing
the carbonyl to be less Lewis basic, resulting in a weaker interac-
tion with the binding phosphine.
The application of the ligand containing the 2,4,6-trimethylben-
zamido group 9c caused the enantioselection to be at its lowest
value for this family of ligands with a value of 8.4% ee. This low
value is attributed to the steric volume of the benzamido group.
This very large volume may distort the complex-12B template
and may well give rise to alternate conformations that cause the
enantioselection to converge to only slightly favor the (R)-enan-
tiomer. Finally, the ligand containing the tert-butyl ligand 9d gave
the highest level of enantioselectivity. It is proposed that this
ligand possesses the optimal balance of an electronic effect and
the steric volume of the amido ligand. These features allow for
the o-diphenylphosphinobenzoate ligand 9d to have a level of cat-
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B. M. Nelson et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
alytic stereoselectivity comparable to the o-diphenylphosphi-
nobenzamide ligand 5d.
(1.59 g, 5.20 mmol) were added and the solution was allowed to
stir at room temperature overnight. Methylene chloride (50 mL)
was added and the solution was transferred to a separatory funnel
and washed with 1 M HCl (50 mL), NH4Cl (50 mL) and with brine
(50 mL). The organic extract was dried over anhydrous MgSO4
and the solvent was removed via rotary evaporation.
3. Conclusion
In conclusion, we have prepared a series of mono(phosphines)
in the class of the o-diphenylphosphinobenzamide ligands 5a–d
and the o-diphenylphosphinobenzoate ligands 9a–d. These ligands
were employed in the asymmetric allylic alkylation reaction with
palladium allyl chloride dimer, rac-1,3-diphenyl-1-propenyl
acetate, and diethyl malonate. Ligands 5a–d afforded the highest
enantioselectivities due to the rigidity of the diphenylphosphi-
nobenzamide component. Ligands 9a–d gave lower enantioselec-
tivities due to the conformational flexibility of the ester linkage
of the o-diphenylphosphinobenzoate component. Ligands 5d and
9d gave the most comparable enantioselection.
4.2.3. Representative reaction for the palladium catalyzed Tsuji-
Trost asymmetric allylic alkylation using prepared ligands
To a flame dried 100 mL round bottom flask under nitrogen
were added 5b (0.059 g, 0.11 mmol) and [(g
3-C3H5)PdCl]2
(0.019 g, 0.054 mmol) and dissolved in THF (4 mL). This solution
was allowed to stir for 20 min. Following the induction period,
potassium acetate (0.015 g, 0.16 mmol), N,O-bis(trimethylsilyl)ac-
etamide (2.00 ml, 8.10 mmol) and 1,3-diphenylpropenylacetate
(0.733 g, 2.73 mmol) were added. Dimethyl malonate (0.93 mL,
8.1 mmol) was added last and the reaction was allowed to stir at
room temperature for 18 hours. The reaction was extracted with
diethyl ether (50 mL) and washed with 1 M HCl (50 mL), NH4Cl
(50 mL), and brine (50 mL). The organic extract was collected and
dried over MgSO4 and the solvent was removed via rotary
evaporation.
4. Experimental
4.1. General
Reaction solvents (dichloromethane, tetrahydrofuran) were
purchased as an anhydrous reagents and used without further
purification. All reactions were run under a nitrogen atmosphere.
All 1H and 13C NMR were recorded on a Bruker Avance III
500 MHz NMR spectrometer operating at 500 MHz and 125 MHz,
respectively. 1H NMR spectra were referenced to the deuterated
chloroform resonance at 7.26 ppm; 13C NMR spectra were refer-
enced to the deuterated chloroform resonance signal centered at
77.00 ppm. All 31P{1H} NMR spectroscopic data were collected on
4.3. Ligand syntheses
4.3.1. (1R,2S)-2-(2-(Diphenylphosphinyl)benzamido)-1-phenyl-
propyl benzoate 5a
a
Bruker Avance III 400 MHz instrument operating at
400.13 MHz. 31P NMR spectra were externally referenced to 85%
H3PO4 (0.00 ppm). All spectra were collected at room temperature.
Chemical shifts are reported in parts per million (d scale), and cou-
pling constants (J values) are listed in Hertz (Hz). Infrared spectra
are reported in reciprocal centimeters (cmꢀ1) and are measured
either as a Nujol mull, a neat liquid, or in CHCl3. Melting points
were recorded on a Mel-Temp apparatus and are uncorrected.
Optical activities were measured using at 589 nm using a digital
polarimeter.
H
O
N
PPh2
O
O
Ph
CH3
The product was purified by flash column chromatography
(80:20, hexanes:EtOAc) to yield 0.382 g (88%) of product as a white
solid. [a]
23 = +31.0 (c 1.11, CHCl3). Mp = 178–179 °C. 1H NMR
D
(500 MHz, CDCl3): d 1.05 (d, J = 7.0 Hz, 3H), 4.59–4.66 (m, 1H),
6.09 (d, J = 3.9 Hz, 1H), 6.19 (d, J = 8.2, 1H), 6.89–6.93 (m, 1H),
7.17–7.37 (m, 18H), 7.45–7.49 (m, 2H), 7.51–7.54 (m, 1H), 7.57–
7.61 (m, 1H), 8.10 (dd, J = 8.2, 1.3 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d 14.70, 49.64, 78.13, 126.26, 127.96, 128.01, 128.06,
128.51, 128.56, 128.62, 128.65, 128.72, 128.83, 128.88, 128.93,
129.87, 130.07, 130.19, 133.29, 133.74, 133.86, 133.93, 134.06,
134.08, 135.51, 135.72, 136.68, 136.79, 136.99, 137.10, 137.42,
141.32, 141.57, 165.58, 168.28. 31P NMR (162 MHz, CDCl3): d
ꢀ10.10. IR (Nujol): 1714, 1647, 1274, 745, 711, 702 cmꢀ1. ESI
HRMS for C35H30NO3P: calcd (M+H) 544.2042; found 544.2036.
4.2. General procedures
4.2.1. Representative reaction for acyl chloride acylation
To a flame-dried, 100 mL round bottom flask under nitrogen
were added (1R,2S)-norephedrine (0.600 g, 3.97 mmol) and
4-(dimethylamino)pyridine (0.121 g, 0.993 mmol). Methylene
chloride (12 mL) was added and the mixture was allowed to stir
until fully dissolved. Triethylamine (0.76 mL, 6.0 mmol) was then
added followed by 2,4,6-trimethylbenzoyl chloride (0.72 mL,
4.4 mmol). The reaction was allowed to stir at room temperature
overnight. Methylene chloride (50 mL) was added and the solution
was transferred to a separatory funnel and washed with 1 M HCl
(50 mL), NH4Cl (50 mL) and with brine (50 mL). The organic extract
was dried over anhydrous MgSO4 and the solvent was removed via
rotary evaporation.
4.3.2. (1R,2S)-2-(2-(Diphenylphosphinyl)benzamido)-1-phenyl-
propyl 4-nitrobenzoate 5b
O2N
4.2.2. Representative reaction for amino acid coupling
H
To a flame dried, 100 mL round bottom flask under nitrogen
were added (1R,2S)-norephedrine (0.750 g, 4.96 mmol) and
4-(dimethylamino)pyridine (0.120 g, 0.990 mmol). The mixture
was dissolved in methylene chloride (15 mL). To this solution,
N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide hydrochloride
(1.07 g, 5.20 mmol) and 2-(diphenylphosphino)benzoic acid
O
N
PPh2
O
O
Ph
CH3
Purified by recrystallization in CH3Cl/hexanes to yield 0.116 g
(56%) of product as a white solid. [
a]
23 = ꢀ25.4 (c 0.290, CHCl3).
D
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B. M. Nelson et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Mp = 177–180 °C. 1H NMR (500 MHz, CDCl3): d 0.87 (d, J = 6.9 Hz,
4.3.5. (1R,2S)-2-Benzamido-1-phenylpropyl 2-(diphenylphos-
phinyl)benzoate 9a
3H), 4.54–4.60 (m, 1H), 6.21(d, J = 2.8 Hz, 1H), 6.98–7.00 (m, 1H),
7.12–7.15 (m, 4H), 7.24–7.30 (m, 11H), 7.34–7.43 (m, 3H), 7.90
(d, J = 8.8 Hz, 2H), 7.97–8.00 (m, 1H), 8.11 (d, J = 8.8 Hz, 2H). 13C
NMR (100 MHz, CDCl3): d 15.35, 49.01, 79.17, 123.62, 126.53,
127.85, 127.90, 128.43, 128.57, 128.59, 128.63, 128.65, 128.73,
128.87, 128.97, 130.35, 130.99, 133.56, 133.71, 133.76, 133.90,
134.32, 135.38, 135.49, 135.58, 136.24, 136.54, 136.64, 136.71,
136.82, 141.27, 141.53, 150.60, 163.78, 168.40. 31P NMR
(162 MHz, CDCl3): d ꢀ10.32. IR v (cmꢀ1, Nujol mull): 1721, 1644,
1529, 1351, 1276, 862, 745, 720, 700 cmꢀ1. ESI HRMS for C35H29N2-
O5P: calcd (M+H+) 589.1892; found 589.1884.
H
Ph2P
O
N
O
O
Ph
CH3
Purified by recrystallization in CH2Cl2/hexanes to yield 0.702 g
(71%) of product as a white solid. [
a
]
23 = ꢀ5.9 (c 1.04, CHCl3).
D
Mp = 77–81 °C. 1H NMR (400 MHz, CDCl3): d 0.93 (d, J = 7.0 Hz,
3H), 4.64–4.71 (m, 1H), 6.22 (d, J = 2.9 Hz, 1H), 7.03–7.05 (m,
1H), 7.07 (dd, J = 8.8, 2.5 Hz, 1H), 7.20–7.49 (m, 20H), 7.83 (d,
J = 8.3 Hz, 2H), 8.08 (m, 1H). 13C NMR (100 MHz, CDCl3): d 14.45,
49.63, 79.55, 126.20, 127.28, 127.30, 127.99, 128.48, 128.50,
128.59, 128.66, 128.74, 128.93, 129.00, 130.92, 130.96, 131.38,
132.26, 133.34, 133.53, 133.97, 134.17, 134.63, 134.96, 135.44,
135.67, 137.02, 137.11, 137.15, 137.25, 137.39, 138.57, 138.80,
4.3.3. (1R,2S)-2-(2-(Diphenylphosphinyl)benzamido)-1-phenyl-
propyl 2,4,6-trimethyl benzoate 5c
H
166.77, 167.03. 31P NMR (162 MHz, CDCl3): d ꢀ5.64. IR v (cmꢀ1
,
O
N
PPh2
Nujol mull): 1722, 1627, 1247, 753, 695. ESI HRMS for C35H30NO3P:
calcd (M+H) 544.2042; found 544.2042.
O
O
Ph
CH3
4.3.6. (1R,2S)-2-(4-Nitrobenzamido)-1-phenylpropyl 2-(diphenyl-
phosphinyl)benzoate 9b
The product was purified by flash column chromatography
(80/20, hexanes/EtOAc) followed by recrystallization (EtOAc/hex-
23
anes) to yield 0.229 g (49%) of product as a white solid. [
a]
=
D
+4.4 (c 0.602, CHCl3). Mp = 169–170 °C. 1H NMR (500 MHz, CDCl3):
d 0.99 (d, J = 6.7 Hz, 3H), 2.11 (s, 6H), 2.20 (s, 3H), 4.44–4.51 (m,
1H), 6.02 (d, J = 8.2 Hz, 1H), 6.77 (s, 1H), 6.83–6.87 (m, 1H), 7.13–
7.30 (m, 19H), 7.38–7.42 (m, 1H). 13C NMR (100 MHz, CDCl3): d
15.17, 20.12, 21.18, 49.54, 78.37, 126.93, 127.72, 127.77, 128.21,
128.46, 128.53, 128.55, 128.62, 128.69, 128.76, 128.80, 128.82,
128.98, 130.18, 130.76, 133.77, 133.89, 133.97, 134.05, 134.09,
135.23, 135.68, 135.89, 136.77, 136.89, 137.13, 137.20, 137.24,
139.49, 141.22, 141.48, 168.26, 169.44. 31P NMR (162 MHz, CDCl3):
d ꢀ9.86. IR v (cmꢀ1, Nujol mull): 1715, 1645, 1269, 850, 754, 745,
700. ESI HRMS for C38H36NO3P: calcd (M+H) 586.2511, found
586.2485.
NO2
H
Ph2P
O
N
O
O
Ph
CH3
Purified by flash column chromatography (50/50, hexanes/
EtOAc) to yield 0.300 g (43%) of product as
a yellow oil.
[
a
]
D
23 = ꢀ18.9 (c, 1.04 CHCl3). 1H NMR (500 MHz, CDCl3): d 0.94
(d, J = 7.0 Hz, 3H), 4.61–4.68 (m, 1H), 6.29 (d, J = 2.8 Hz, 1H),
7.06–7.09 (m, 1H), 7.19–7.23 (m, 4H), 7.30–7.38 (m, 11H), 7.43–
7.50 (m, 3 H), 7.99 (d, J = 8.8 Hz, 2 H), 8.05–8.08 (m, 1H), 8.18 (d,
J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): d 13.95, 50.41, 79.33,
123.66, 126.10, 128.13, 128.49, 128.52, 128.59, 128.68, 128.75,
128.89, 129.08, 129.17, 130.78, 130.82, 132.42, 133.28, 133.46,
133.76, 133.96, 134.10, 135.11, 135.43, 135.66, 136.75, 136.81,
136.90, 137.15, 138.26, 138.48, 140.25, 149.43, 164.88, 167.33.
31P NMR (162 MHz, CDCl3): d ꢀ5.39. IR v (cmꢀ1, neat): 3068,
2982, 1717, 1660, 1524, 1346, 1250, 729, 698. ESI HRMS for
4.3.4. (1R,2S)-2-(2-(Diphenylphosphinyl)benzamido)-1-phenyl-
propyl pivalate 5d
H
O
N
PPh2
O
O
C
35H29N2O5P: calcd (M+H) 589.1892, found 589.1901.
Ph
CH3
4.3.7. (1R,2S)-1-Phenyl-2-(2,4,6-trimethylbenzamido)propyl
2-(diphenylphosphinyl)benzoate 9c
With 0.600 gram of starting material, the product was purified
by flash column chromatography (100% hexanes followed by
95/5, hexanes/EtOAc) to yield 0.450 g (61%) of product as a white
solid. MP = 195–197 °C. [
a]
23 = ꢀ12.5 (c 1.03, CHCl3). 1H NMR
D
(500 MHz, CDCl3): d 0.94 (d, J = 7.0 Hz, 3H), 1.12 (s, 9 H), 4.47–
4.53 (m, 1H), 5.83 (d, J = 4.1 Hz, 1H), 6.40 (s, 1H), 6.97–7.00 (m,
1H), 7.27–7.38 (m, 14H), 7.43 (td, J = 7.5, 1.2 Hz, 1H), 7.63–7.66
(m, 1H). 13C NMR (100 MHz, CDCl3): d = 15.98, 26.98, 38.66,
58.14, 78.20, 128.17, 128.24, 128.34, 128.38, 128.41, 128.47,
128.56, 129.93, 129.97, 131.29, 133.15, 133.34, 133.67, 133.85,
135.64, 135.66, 137.45, 137.54, 138.31, 138.41, 140.96, 141.19,
H
Ph2P
O
N
O
O
Ph
CH3
171.04, 176.80. 13P NMR (162 MHz, CDCl3) d = ꢀ9.74. IR v (cmꢀ1
,
Purified by flash column chromatography (80/20, hexanes/
23
EtOAc) to yield 0.481 g (61%) of product as a yellow oil. [
a
]
=
Nujol mull): 1735, 1648, 1376, 1365, 1148, 751, 720, 702. ESI
HRMS for C33H34NO3P: calcd (M+Na) 524.2355, found 524.2355.
D
+11.7 (c 0.977, CHCl3). 1H NMR (500 MHz, CDCl3): d 0.89 (d,
Please cite this article in press as: Nelson, B. M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.012

6
B. M. Nelson et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
J = 7.2 Hz, 3H), 2.10 (s, 6H), 2.17 (s, 3H), 4.61–4.68 (m, 1H), 6.05
(m 1H), 6.11 (d, J = 4.0 Hz, 1H), 6.19 (d, J = 4.0 Hz, 1H), 6.20
(m, 1H), 6.71 (s, 2H), 6.90–6.94 (m, 1H), 6.98–7.06 (m, 4H), 7.11–
7.27 (m, 8 H), 7.30–7.38 (m, 3H), 7.97–8.00 (m, 1H). 13C NMR
(100 MHz, CDCl3): d 15.08, 19.01, 21.07, 48.44, 79.16, 125.85,
126.39, 127.97, 128.09, 128.38, 128.45, 128.47, 128.50, 128.57,
128.61, 128.77, 128.85, 130.77, 130.81, 132.09, 133.36, 133.56,
133.85, 134.06, 134.12, 134.70, 135.01, 135.41, 135.64, 136.93,
137.04, 137.41, 138.15, 138.47, 138.71, 165.50, 169.92. 31P NMR
(162 MHz, CDCl3): d ꢀ5.67. IR v (cmꢀ1, neat): 3056, 2978, 1719,
1636, 1378, 1249, 849, 744, 696. ESI HRMS for C38H36NO3P: calcd
(M+H) 586.2511, found 586.2502.
Acknowledgements
We thank Cassie A. Goodman for her technical assistance. We
acknowledge support from the Department of Chemistry at Illinois
State University.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.08.
012.
References
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Purified by flash column chromatography (80/20, hexanes/
EtOAc) to yield 0.256 g (20%) of product as
a yellow oil.
[a
]
23 = ꢀ12.7 (c 0.694, CHCl3). 1H NMR (500 MHz, CDCl3): d 0.86
D
(d, J = 6.9 Hz, 3H), 1.04 (s, 9H), 4.35–4.41 (m, 1H), 6.00 (s, 1H),
6.02 (d, J = 3.7 Hz, 1H), 6.90–6.93 (m,1H), 7.14–7.26 (m, 16H),
7.31–7.39 (m, 3H), 8.04–8.07 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 14.75, 27.58, 38.67, 49.00, 79.18, 126.62, 127.92, 128.38, 128.57,
128.63, 128.68, 128.73, 128.87, 130.90, 130.94, 132.31, 133.47,
133.66, 133.81, 133.96, 134.17, 134.79, 134.89, 135.00, 137.48,
137.58, 137.69, 139.58, 139.84, 166.33, 177.80. 31P NMR
(162 MHz, CDCl3): d ꢀ5.24. IR v (Nujol): 1717, 1652, 1398, 1378,
1251, 746, 697 cmꢀ1. ESI HRMS for C33H34NO3P: calcd (M+H+)
524.2355; found 524.2353.
Please cite this article in press as: Nelson, B. M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.08.012