β-Hydroxy and β-(o-diphosphino)benzoyloxy(o-diphosphino) benzamides as ligands for asymmetric allylic alkylation

Article abstract of DOI:10.1016/j.tetasy.2009.04.007

Diphenylphosphinobenzoic acid was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), DMAP, and with either one of two equivalents of (1R,2S)-norephedrine and (1S,2S)-pseudonorephedrine. This process yielded a series of β-hydroxy and β-(dip

Full text of DOI:10.1016/j.tetasy.2009.04.007

Tetrahedron: Asymmetry 20 (2009) 1132–1137
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
b-Hydroxy and b-(o-diphosphino)benzoyloxy(o-diphosphino) benzamides
as ligands for asymmetric allylic alkylation
*
Geetanjali S. Mahadik, Stanley A. Knott, 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:
Diphenylphosphinobenzoic acid was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
(EDC), DMAP, and with either one of two equivalents of (1R,2S)-norephedrine and (1S,2S)-pseudonor-
ephedrine. This process yielded a series of b-hydroxy and b-(diphosphino) benzoyloxy(diphosphi-
no)benzamides that were employed in the Tsuji–Trost asymmetric allylic alkylation process. It was
determined that the diastereomeric geometry of the norephedrine series was superior to that of the
pseudonorephedrine-based ligands. In addition, it was determined that the norephedrine-based b-(o-
diphosphino)benzoyloxy(o-diphosphino)benzamide afforded the best enantiomeric ratio (94:6) favoring
the (S)-enantiomer.
Received 11 February 2009
Accepted 16 April 2009
Available online 22 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Ph2P
Ph2P
O
Ph2P
O
The Tsuji–Trost asymmetric allylic alkylation process1–3 has
been quite successful and has inspired many to pursue the devel-
opment of chiral, non-racemic ligands as templates for conducting
asymmetric syntheses. Among the ligands that have been widely
studied and applied is the Trost bis(diphenylphosphinobenzamide)
1 (Fig. 1).4 The successful application of the Trost ligand has
spurred the development of new ligands with key differences that
are meant to enhance their applicability.5 Mino et al.6 developed a
O
NH
O
PPh2
NH
R
NH
Ph
N
H
OMe
OH
Trost, 1
Mino, 2
Burke
b-methoxy(diphosphino benzamide) 2 derived from L-phenylalan-
3: R = -Ph
4: R = -Bn
inol which gave very good enantioselectivities. This work was
followed by the design and application of b-hydroxy(diphos-
phinobenzamides) 3 and 4 by Burke et al.7 Burke et al. sought to
exploit the presence of the free alcohol as a coordination site for
the palladium, potentially leading to an augmented enantiomeric
ratio. The observed enantioselectivities ranged from moderate to
good. The authors speculated that the hydroxyl group served as
an additional binding site but was led to the dual problems of deac-
Figure 1. Phosphine ligands research and development.
the catalyst by the hydroxyl group in the new ligand application
was also of interest. Thus, in connection with our ongoing research
program involving the use of Ephedra alkaloids, we became inter-
ested in employing (1R,2S)-norephedrine and (1S,2S)-pseudonor-
ephedrine8 as chiral, non-racemic templates for the construction
of ligands that might be suitable for usage. In addition to using
these b-aminoalcohols in an attempt to obtain better enantioselec-
tivities, we were also interested in the idea of using the alcohol as a
tool for introducing a second coordinating phosphine ligand. Here-
in, we report on the synthesis of four ligands based on these Ephe-
dra alkaloids and their application in the Tsuji–Trost reaction.
tivation of the palladium and allylic isomerization (g3 g1 g3
? ? )
that diminish the transfer of asymmetry from the ligand to the
substrate. The source of asymmetric induction in the ligands devel-
oped independently by Mino et al. and Burke et al. was a single ste-
reogenic center bound to the nitrogen. We considered the
possibility of employing b-aminoalcohols containing two stereo-
centers that might suppress the proposed allylic isomerization
and thereby enhance the asymmetric induction of the allylic alkyl-
ation process. The potential issue of moderating the deactivation of
2. Results and discussion
(1R,2S)-Norephedrine and (1S,2S)-pseudonorephedrine were
treated with o-diphenyl phosphinobenzoic acid and 1-ethyl-3-(3-
* Corresponding author. Tel.: +1 309 438 7854; fax: +1 309 438 5538.
E-mail address: hitchcock@ilstu.edu (S.R. Hitchcock).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.04.007

G. S. Mahadik et al. / Tetrahedron: Asymmetry 20 (2009) 1132–1137
1133
dimethylaminopropyl)carbodiimide (EDC) and a catalytic amount
of DMAP to give b-hydroxy(diphenylphosphino)benzamides 7
and 8, in 71% and 54%, respectively (Scheme 1). With the Ephe-
dra-based phosphine ligands in hand, we applied these compounds
in the asymmetric allylic alkylation reaction with 1,3-diphenylp-
tance, as the conformations of these complexes place the benzylic
position closes to the reacting center. As these complexes have
opposing stereochemical features near the reactive palladium cen-
ter, it is unlikely that this conformational mode is responsible for
the observed enantioselection.
ropenyl acetate, dimethylmalonate, and [g
3-(C3H5)PdCl]2. Initial
experimentation focused on the relative amounts of the substrate,
benzamide 7, and the palladium (0) source (Table 1, entries 1–3).
Of these entries, entry 1 afforded the best combination, although
the highest enantioselectivity was a modest 56% ee. This suggested
that the addition of more of the palladium source and phosphine
ligand 7 relative to the allylic acetate substrate was detrimental
in optimizing the enantioselection of the reaction. Reducing the
temperature to 0 °C from 25 °C did not improve the enantiomeric
ratio of the product (cf. Table 1, entries 1 and 4). Furthermore,
increasing the amount of ligand to the palladium (0) source at
the lower temperature only led to diminished enantioselectivities.
In contrast, progressively increasing the amount of the palladium
(0) source from a ratio of 1:1 to 1:2 to 1:3 revealed that the optimal
ligand/Pd ratio was 1:2 with an enantiomeric ratio of 87.5:12.5
(75). We were gratified to learn that we were able to obtain a good
level of enantioselectivity, moreso than that obtained with the re-
R2
R1
CO2H
H3C
OH
OH
R2
O
NH
PPh2
NH2
CH3
R1
EDC, DMAP, CH2Cl2
PPh2
5: R1 = -Ph, R2 = H
R1 = -H, R2 = -Ph
6:
R1 = -Ph, R2 = H
8: R1 = -H, R2 = -Ph
7:
Scheme 1. Synthesis of b-hydroxybenzoyloxy(diphosphino)benzamides.
The successful application of 7 and 8 prompted the synthesis of
the bis(phosphine) ligands 11 and 12 (see Scheme 2). Thus, Ephdra
alkaloids 5 and 6 were coupled with 2 equiv of o-(diphenylphos-
phino)benzoic acid, EDC, and DMAP to afford b-(o-diphosphi-
no)benzoyloxy(o-diphosphino)benzamides 11 and 12 in 44% and
54%, respectively. These compounds were employed in the asym-
metric allylic alkylation reaction. It was determined that these li-
gands afforded enantioselectivities of 94:6 for 11 and 81.5:18.5
for 12 favoring the formation of the (S)-enantiomer of the product.
These observations were contrary to earlier findings that the
o-(diphosphino)benzamides 7 and 8 predominantly favored the
formation of the (R)-enantiomer. In addition to this, it was deter-
mined that the level of enantioselection of the alkylation reaction
using 11 did not vary when the relative amount of the palladium
pre-catalyst was changed (Table 2, cf. entries 1 and 2).
To gain a better understanding of the difference and similarity
between 7, 8, 11, and 12, 31P NMR spectra were collected (Fig. 3).
In the proton decoupled 31P NMR spectra collected for the ligands,
monophoshines 7 and 8 contain a single resonance at ꢀ10.40 and
ꢀ10.32 ppm, respectively. The bis(phosphines) ligands 11 and 12
had two resonances each appearing at ꢀ9.32 and ꢀ5.54 ppm, and
lated L-phenylalaninol and L-phenylglycinol benzamide ligands
developed by Burke et al.7 The use of dichloromethane as the reac-
tion solvent in place of THF gave comparable results with differing
ratios of ligand to the palladium pre-catalyst (see Table 1, entries 9
and 10). We became interested in the use of the (1S,2S)-pseudonor-
ephedrine-derived benzamide ligand and applied it to the asym-
metric allylic alkylation process. An enantiomeric ratio 76.5:23.5
favoring the (R)-enantiomer was obtained using this ligand. Thus,
the diastereomeric ligands 7 and 8 yielded the same absolute ste-
reochemistry in the product. It is proposed that the two ligands 7
and 8 form palladium complexes 7A, 7B, 8A, and 8B, respectively
(Fig. 2). These intermediates are similar to those proposed by Burke
et al.7 Based on the fact that the absolute stereochemistry of the
product from the asymmetric alkylation is the same when either
ligand 7 or 8 is employed, it is proposed that the dominant control
element of the asymmetric induction is the stereocenter that is
proximal to the benzamide nitrogen (i.e., conformations 7A and
8A). In contrast, complexes 7B and 8B, wherein there is coordina-
tion with the hydroxyl group would appear to be of lesser impor-
Table 1
Tsuji–Trost reaction of 9 and 10 with rac-1,3-diphenylpropenyl acetate
MeO2C
H
CO2Me
Ph
OAc
[(η3-C3H5)PdCl]2, CH2(CO2Me)2
Ph
Ph
Ph
cat. KOAc, BSA
Ephedra ligand 7 or 8
Solvent
(R)-10
rac-9
Entry
Ligand
Solvent
Temp (°C)
9:Ligand:Pd
Yielda (%)
er (|R–S|)b,c
Enant.c
1
2
3
4
5
6
7
8
9
7
7
7
7
7
7
7
7
7
7
8
THF
THF
THF
THF
THF
THF
THF
THF
25
25
25
0
50:2:1
25:2:1
16.7:2:1
50:2:1
100:4:1
25:1:1
25:1:2
25:1:3
50:2.5:1
25:1:2
25:1:2
62
87
47
49
56
62
68
43
47
42
47
78.0:22.0 (56)
74.0:26.0 (48)
68.0:32.0 (36)
76.0:24.0 (52)
68.0:32.0 (36)
81.5:18.5 (63)
87.5:12.5 (75)
75.5:24.5 (51)
85.5:14.5 (71)
86.5:13.5 (73)
76.5:23.5 (53)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
0
25
25
25
25
25
25
CH2Cl2
CH2Cl2
CH2Cl2
10
11
a
Isolated yield after flash chromatography.
Enantiomeric ratios determined by CSP HPLC (Chiralcel AD column).
The identification of the enantiomers was based on the order of elution from the CSP HPLC AD column. The correlation between the elution and the absolute stereo-
b
c
chemistry of the products has been established.12

1134
G. S. Mahadik et al. / Tetrahedron: Asymmetry 20 (2009) 1132–1137
Ph
Ph
Ph
Ph
Pd
Pd
Ph2P
MeO2C
H
CO2Me
Ph
Ph2P
O
CH3
O
CH3
OH
OH
N
H
N
H
Ph
Ph
Ph
(R)-10
(1S,2S)-8-Pd complex A
(1R,2S)-7-Pd complex A
Ph
Ph
O
Ph
Ph
O
H
H
Pd
Pd
Ph
Ph
Ph2P
O
Ph2P
O
N
H
CH3
N
H
CH3
(1R,2S)-7-Pd complex B
(1S,2S)-8-Pd complex B
Figure 2. Putative intermediates in the asymmetric allylic alkylation with 7 and 8.
R2
themselves oxidized during the course of their use in these studies.
R1
CO2H
H3C
NH
PPh2 Ph2P
Notably, no resonancesignals were observed in the positive region
of the 31P NMR spectra, indicating that the newly prepared com-
pounds were free of phosphine oxides. Ultimately, the similarity
between the chemical shifts of triphenylphosphine and the ligands
suggested that the phosphines all shared nearly the same elec-
tronic environment.
O
O
O
PPh2
5,6
EDC, DMAP, CH2Cl2
R1 = -Ph, R2 = H
12: R1 = -H, R2 = -Ph
11:
A rationale for the formation of the (S)-enantiomer as the dom-
inant enantiomer for the bis(phosphine) ligand 11 is only putative
at this time but it may be possible that bis(phosphine) 11 may be
involved in complex equilibria involving the palladium propenyl
cationic complexes 13A–D (Scheme 3). Related putative intermedi-
ates have been isolated and proposed in independent investigative
studies by Lloyd–Jones,9 Amatore,10 and Dahan (nickel allyl com-
plexes).11 Palladium complex 13A is viable but would not be the
key intermediate as the stereochemical result would be the same
as the mono(phosphine) ligands 7 and 8. Complex 13B does not
seem plausible as the dominant catalytic entity either as there is
no participation from the phosphorus bound the amide portion
of the molecule, which is in stark contrast to known activity ob-
served in 7 and 8. The bis(palladium)–bis(phosphine) complex
13C is not believed to be the dominant pathway as there would
be two stereochemical pathways opposing each other leading to
a compromised enantioselection. Based on these rationalizations,
it is believed that 13D, or some derivative thereof, is the species
most responsible for the observed enantiomeric ratios, although
there may be other catalytic species that have not been considered.
Interestingly, the (1S,2S)-pseudonorephedrine ligand 12 yielded
the opposite stereochemistry (S)-enantiomer of the product as the
dominant product. This is in contrast to the case of ligand 8 of the
same stereochemical family. Based on this result, it can be
postulated that the mode of asymmetric induction for the
mono(phosphine) ligand is significantly different from that of the
bis(phosphine) ligands.
Scheme 2. Synthesis of b-(diphosphino)benzoyloxy(diphosphino)benzamides 11
and 12.
Table 2
Asymmetric alkylation reaction of 11 and 12 with rac-1,3-diphenylpropenyl acetate
MeO2C
CO2Me
[(η3-C3H5)PdCl]2, CH2(CO2Me)2
9
cat. KOAc, BSA
Ph
Ph
Ephedra ligand 11 or 12
10
Entrya
Ligand
9:Ligand:Pd
Yieldb (%)
er (|R–S|)c
Enantiomerd
1
2
3
11
11
12
25:1:2
25:1:1
25:1:1
59
51
65
94.0:6.0 (88)
94.0:6.0 (88)
81.5:18.5 (63)
(S)
(S)
(R)
a
All reactions were conducted in THF at 25 °C.
Isolated yield after flash chromatography.
b
c
Enantiomeric ratios determined by CSP HPLC (Chiralcel AD column).
The identity of the enantiomer was based on elution from the CSP HPLC column.
d
at ꢀ9.44 and ꢀ4.69 ppm, respectively. The phosphine bound to the
aryl ester appeared at an averaged frequency of ꢀ5.12 ppm; the
phosphorus bound to the aryl amide appeared at an averaged fre-
quency of ꢀ9.38 ppm. The collected data support the fact that the
two phosphorus atoms in 11 and 12 are similar but unique. The
chemical shifts for all of the phosphorus atoms appear in the same
region as the resonance signal of triphenylphosphine (Ph3P) col-
lected under similar conditions (singlet at ꢀ4.72 ppm). For the sake
of comparison, data were also collected on triphenylphosphine
oxide (singlet at 29.68 ppm) to ensure that the ligands were not
3. Conclusion
A series of Epedra-based b-hydroxy and b-(o-diphosphino)ben-
zoyloxy(o-diphosphino) benzamides have been successfully ap-
plied in the asymmetric allylic alkylation reaction. The use of the

G. S. Mahadik et al. / Tetrahedron: Asymmetry 20 (2009) 1132–1137
1135
δ (31P) = -10.40 ppm
δ = -10.32 ppm
Ph2P
O
CH3
Ph2P
O
CH3
OH
OH
N
H
N
H
Ph
Ph
8
7
δ (31P) = -5.54, -9.32 ppm
δ (31P) = -4.69, -9.44 ppm
H3C
Ph
H3C
Ph
O
O
O
O
NH
O
NH
O
PPh2 Ph2P
PPh2 Ph2P
12
11
Figure 3. 31P NMR spectroscopic data for ligands 7, 8, 11, and 12.
four ligands have revealed interesting aspects about the catalysis
process based on the mixed phosphine ligand system employed.
Efforts are underway to investigate the further use of the norephe-
drine-based ligand and related systems (e.g., 2-amino-1,2-diphe-
nyl-1-ethanol) in asymmetric allylation reactions to further
pursue the use of dissymmetrical bis(phosphines).
referenced to the deuterated chloroform resonance at 7.26 ppm
while 31P NMR spectra were externally referenced to 85% H3PO4
(0.00 ppm). All spectra were collected at 300 K. Infrared spectra
are reported in reciprocal centimeters (cmꢀ1) and are measured
either as a neat liquid or as a KBr window. Melting points were re-
corded on a Mel-Temp apparatus and are uncorrected. Flash chro-
matography was conducted with an Analogix chromatograph.
Mass spectroscopic analyses were conducted by the mass spec-
trometry analytical laboratories of the University of Illinois at
Urbana-Champaign using a quadrapole time of flight mass spec-
trometer hybrid with MS/MS capability. Enantiomeric ratios were
determined using a Shimadzu HPLC with either Chiral Stationary
Phase Chiralcel AD column. Optical activities were measured at
589 nm using a digital polarimeter purchased with NSF grant
#CHE 644950.
4. Experimental
4.1. General remarks
Methylene chloride (CH2Cl2) was purchased as an anhydrous re-
agent. Unless otherwise stated, all reactions were run under anhy-
drous conditions and a nitrogen atmosphere. 1H and 13C NMR
spectra were recorded either on a Varian spectrometer in CDCl3
operating at 500 MHz and 125 MHz. Chemical shifts are reported
in parts per million (d scale), and coupling constants (J values)
are listed in hertz (Hz). All 1H and 31P{1H} NMR spectral data were
collected on a Bruker Avance III 500 MHz instrument operating at
500.13 MHz and 202.45 MHz, respectively. 1H NMR spectra were
4.2. o-(Diphenylphosphino)-N-(1R,2S)-1-hydroxy-1-phenyl-2-
propyl)benzamide 7
In a 250 mL nitrogen purged round-bottomed flask were added
(1R,2S)-norephedrine (0.740 g, 4.90 mmol), DMAP (0.119 g,

1136
G. S. Mahadik et al. / Tetrahedron: Asymmetry 20 (2009) 1132–1137
Ph
Ph
H3C
NH
PPh2
Ph
O
H3C
NH
Ph
Ph
Pd
PPh2
Ph
Pd
Ph2P
O
O
O
O
O
Ph2P
13A
13B
Ph
Ph
H3C
NH
Ph
O
O
H3C
NH
Ph
O
O
Ph
Pd
Ph2P
Pd
PPh2
Ph
O
O
PPh2 Ph2P
Pd
13C
Ph
Ph
13D
Scheme 3. Proposed intermediates for the asymmetric allylation reaction.
0.979 mmol), dichloromethane (13 mL), 2-(diphenylphosphino)
benzoic acid (1.50 g, 4.89 mmol), and EDC (1.03 g, 5.39 mmol). The
reaction mixture was allowed to stir for 24 h and was quenched with
the addition of 3 M HCl (50 mL ꢁ 2). The organic layer was diluted
with dichloromethane (100 mL), washed with brine (50 mL), and
dried (MgSO4). The solvents were removed via rotary evaporation
and the product was isolated by recrystallization from chloroform
128.5, 128.5, 128.7, 128.7, 130.0, 133.6, 133.6, 133.8, 133.8, 133.9,
135.3, 135.5, 136.6, 136.7, 136.8, 141.1, 141.4, 169.5 31P{1H} NMR
(CDCl3): ꢀ10.32 ppm. ESI-HRMS calcd for C28H26NO2P (M+H+):
440.1779. Found: 440.1773.
4.4. (1R,2S)-2-(o-Diphenylphosphino)benzamido)-1-phenyl-2-
propyl(o-diphenyl phosphino)benzoate 11
and hexanes (1:2). White solid (71%), ½a D23
¼ ꢀ15:6 (c 0.10, CHCl3).
ꢂ
Mp = 168–171 °C. IR (nujol) (cmꢀ1): 3373, 3325, 1623, 1581, 1008.
1H NMR (400 MHz, CDCl3) d (ppm): 0.85 (d, J = 6.6 Hz, 3H), 3.26 (s,
1H), 4.29 (pd, J = 7.3, 1H), 6.03 (d, J = 7.3, 1H), 6.95–6.98 (m, 1H),
7.32–7.34 (m, 17H), 7.59–7.62 (m, 1H). 13C NMR (CDCl3, extra peaks
In a 250-mL nitrogen purged round-bottomed flask were added
(1R,2S)-norephedrine (0.420 g, 2.78 mmol), DMAP (0.271 g, 2.22 mmol),
dichloromethane (15 mL), o-(diphenylphosphino)benzoic acid
(1.70 g, 5.55 mmol), and EDC (1.06 g, 5.55 mmol). The reaction mix-
ture was allowed to stir for 24 h and was quenched with the addition
of 3 M HCl (50 mL ꢁ 2). The organic layer was diluted with dichloro-
methane (100 mL), washed with brine (50 mL), and dried over
MgSO4. The solvents were removed via rotary evaporation and the
product was isolated by flash column chromatography (hexanes/
were observed due to the coupling interaction between 13C and 31
P
nuclei): 13.3, 51.8, 75.2, 126.1, 127.2, 128.1, 128.6, 128.6, 128.71,
128.7, 128.8, 128.94, 128.9, 129.0, 130.2, 133.8, 133.8, 133.9,
133.9, 134.0, 135.0, 135.2, 136.3, 136.4, 136.5, 136.6, 140.8, 141.5,
141.7, 169.3. 31P{1H} NMR (CDCl3): ꢀ10.40 ppm. ESI-HRMS calcd
for C28H26NO2P (M+H+): 440.1779. Found: 440.1774.
EtOAc, 75:25). Yellow oil (44%), ½a D23
¼ þ7:8 (c 0.10, CHCl3). IR (NaCl)
ꢂ
(cmꢀ1): 3303, 1716, 1652, 1586, 1250. 1H NMR (400 MHz, CDCl3) d
(ppm): 0.81 (d, J = 6.9 Hz, 3H), 4.50–4.55 (m, 1H), 6.07(d, J = 3.4 Hz,
1H), 6.70 (d, J = 8.3 Hz, 1H), 6.92–6.94 (m, 1H), 7.00–7.03 (m, 1H),
7.11–7.31 (m, 1H), 7.39–7.47 (m, 1H), 7.54–7.57 (m, 1H), 8.10–
8.13 (m,1H). 13C NMR (CDCl3, extra peaks were observed due to
the coupling interaction between 13C and 31P nuclei): 14.3, 49.1,
78.9, 126.0, 127.7, 127.7, 127.7, 128.2, 128.3, 128.4, 128.4, 128.5,
128.5, 128.6, 128.7, 128.7, 129.8, 130.8, 130.8, 131.9, 133.3, 133.4,
133.6, 133.8, 133.8, 133.8, 133.9, 134.6, 135.2, 135.4, 136.1, 136.3,
137.0, 137.1, 137.1, 137.2, 137.2, 137.3, 138.7, 138.9, 141.1, 141.3,
166.3, 167.9. 31P{1H} NMR (CDCl3): ꢀ5.54, ꢀ9.32 ppm. ESI-HRMS
calcd for C47H40NO3P2 (M+H+): 728.2483. Found: 728.2466.
4.3. o-(Diphenylphosphino)-N-(1S,2S)-1-hydroxy-1-hydroxy-
1-phenyl-2-propyl)benzamide 8
In a 250-mL nitrogen purged round-bottomed flask were added
(1S,2S)-norephedrine (0.494 g, 3.27 mmol), DMAP (0.079 g,
0.653 mmol), dichloromethane (13 mL), o-(diphenylphosphino)
benzoic acid (1.000 g, 3.265 mmol), and EDC (0.689 g, 3.592 mmol).
The reaction mixture was allowed to stir for 24 h and then quenched
with the addition of 3 M HCl (50 mL ꢁ 2). The organic layer was di-
luted with dichloromethane (100 mL), washed with brine (50 mL),
and dried with MgSO4. The solvents were removed via rotary evap-
oration and the product was isolated by flash column chromatogra-
phy (hexanes/EtOAc, 1:1). Viscous wax (54%), ½a D24
ꢂ
¼ þ11:3 (c 0.10,
4.5. (1S,2S)-2-(o-Diphenylphosphino)benzamido)-1-phenyl-2-
propyl(o-diphenylphosphino) benzoate 12
CHCl3). IR (NaCl) (cmꢀ1): 3372, 3325, 1626, 1522, 1006. 1H NMR
(500 MHz, CDCl3) d (ppm): 0.90 (d, J = 6.8 Hz, 3H), 3.67 (s, 1H), 4.20
(sextet, J = 6.8 Hz), 4.45–4.47 (m, 1H), 6.05 (d, J = 8.0 Hz), 6.94–
6.97(m, 1H), 7.25–7.35(m, 17H), 7.50–7.53 (m, 1H). 13C NMR(CDCl3,
extra peaks were observed due to the coupling interaction between
13C and 31P nuclei) 16.9, 52.1, 77.2, 126.5, 127.5, 127.7, 127.7, 128.1,
In a 250-mL nitrogen purged round-bottomed flask were added
(1S,2S)-norephedrine (0.420 g, 2.78 mmol), DMAP (0.271 g,
2.22 mmol), dichloromethane (15 mL), o-(diphenylphosphino)ben-
zoic acid (1.70 g, 5.55 mmol), and EDC (1.06 g, 5.55 mmol). The reac-

G. S. Mahadik et al. / Tetrahedron: Asymmetry 20 (2009) 1132–1137
1137
tion mixture was allowed to stir for 24 h and then quenched with the
Acknowledgments
addition of 3 M HCl (50 mL ꢁ 2). The organic layer was diluted with
dichloromethane (100 mL), washed with brine (50 mL), and dried
over MgSO4. The solvents were removed via rotary evaporation
and the product was isolated by flash column chromatography (hex-
The authors gratefully acknowledge support for this work by
the National Science Foundation (NSF grant # CHE-644950). The
Bruker Avance III 500 MHz NMR spectroscopic data collected in
this work are based upon work supported by the National Science
Foundation under CHE-0722385.
anes/EtOAc, 75:25). Yellow oil (54%). ½a D23
¼ ꢀ16:9 (c 0.10, CHCl3). IR
ꢂ
(NaCl) (cmꢀ1): 3350, 1714, 1652, 1585, 1251. 1H NMR (400 MHz,
CDCl3) d (ppm): 0.88 (d, J = 6.7, 3H), 4.59–4.65 (m, 1H), 5.89
(d, J = 7.3, 1H), 6.36 (d, J = 8.8, 1H), 6.89–6.94 (m,1H), 7.11–7.17
(m, 1H), 7.21–7.29 (m, 28H), 7.36–7.49 (m, 1H), 8.20–8.23 (m, 1H).
13C NMR (CDCl3), extra peaks were observed due to the coupling
interaction between 13C and 31P nuclei): 17.4, 49.6, 78.9, 127.2,
127.6, 128.2, 128.3, 128.4, 128.4, 128.5, 128.5, 128.5, 128.6, 129.9,
131.4, 131.4, 132.2, 133.5, 133.6, 133.6, 133.7, 133.7, 133.8, 133.8,
133.9, 133.9, 133.9, 134.1, 134.5, 135.9, 136.1, 137.0, 137.2, 137.4,
137.5, 137.6, 137.6, 137.6, 137.7, 139.9, 140.1, 141.2, 141.4, 166.1,
168.3. 31P{1H} NMR (CDCl3): ꢀ4.69, ꢀ9.44 ppm. ESI-HRMS calcd
for C47H40NO3P2 (M + H+): 728.2483. Found: 728.2466.
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4.6. General procedure for the catalytic asymmetric allylic
alkylation reactions (Table 1, entry 1)
In a 50-mL nitrogen purged round-bottomed flask were added
ligand (0.048 g, 0.109 mmol), [(g
3-C3H5)PdCl]2 (0.019 g, 0.054 mmol),
KOAc (0.005 g, 0.054 mmol), THF (4 ml), BSA (1.65 g, 8.10 mmol),
1,3-diphenylpropenyl acetate (0.733 g, 2.73 mmol), CH2(CO2Me)2
(1.07 g, 8.10 mmol). The reaction mixture was allowed to stir for
24 h at 25 °C and was quenched with the addition of 1 M HCl
(50 mL) and ammonium chloride (50 mL). The organic layer was di-
luted with ether (50 mL), washed with brine (50 mL), and dried
(MgSO4). The solvents were removed via rotary evaporation and
the product was isolated by flash column chromatography (hex-
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