Chiral, non-racemic diols, and α-amino acid-derived β-amino alcohols as templates for chiral catalysts in the Tsuji-Trost reaction

Article abstract of DOI:10.1016/j.tetasy.2009.12.011

A commercially available collection of β-amino alcohols have been converted to their corresponding β-(o-diphenylphosphino) benzoyloxy(o-diphenylphosphino) benzamides and have been employed in the Tsuji-Trost asymmetric alkylation reaction with 1,3-diphenylpropenyl acetate. The best ligand was derived from l-tert-leucinol and when applied to the asymmetric allylic alkylation reaction, yielded the product in an enantiomeric ratio of 99.5:0.5 favoring the (S)-enantiomer.

Full text of DOI:10.1016/j.tetasy.2009.12.011

Tetrahedron: Asymmetry 21 (2010) 33–38
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral, non-racemic diols, and
a-amino acid-derived b-amino alcohols
as templates for chiral catalysts in the Tsuji–Trost reaction
*
Geetanjali S. Mahadik, 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:
A commercially available collection of b-amino alcohols have been converted to their corresponding b-(o-
diphenylphosphino) benzoyloxy(o-diphenylphosphino) benzamides and have been employed in the
Tsuji–Trost asymmetric alkylation reaction with 1,3-diphenylpropenyl acetate. The best ligand was
Received 27 October 2009
Accepted 21 December 2009
Available online 3 February 2010
derived from
product in an enantiomeric ratio of 99.5:0.5 favoring the (S)-enantiomer.
Ó 2009 Elsevier Ltd. All rights reserved.
L-tert-leucinol and when applied to the asymmetric allylic alkylation reaction, yielded the
1. Introduction
ate phosphine ligands for the asymmetric alkylation reaction.7 The
success of this work prompted us to study further this catalytic
process with a different family of ligands. Herein we report the
use of chiral, non-racemic diols, and a-amino acid-derived b-ami-
no alcohols as templates for the chiral phosphine ligands, and we
The development of palladium-catalyzed asymmetric reactions
in organic synthesis has experienced much growth over the last
two decades.1 In this context, palladium-catalyzed asymmetric
allylic alkylation reactions have proven to be very successful.2
The pioneering efforts of Tsuji3 and the refinements led by Trost4
have given rise to a powerful method for the enantioselective pro-
cess of carbon–carbon bond formation. Many researchers2,5 have
contributed to this field and there is a continuing effort to create
effective chiral, non-racemic ligands for the palladium-catalyzed
alkylation reaction. In connection with our ongoing research pro-
gram concerning the synthesis and application of chiral ligands
for asymmetric reactions, we have recently become interested in
the development of effective chiral ligands for the alkylation pro-
cess. Our initial efforts in this field involved a series of norephe-
drine and pseudonorephedrine-based mono(phosphines) and
bis(phosphines) (Fig. 1).6
report on the results of these efforts.
2. Results and discussion
A series of chiral diols 2a–d were coupled with either one or
2 equiv of o-(diphenylphosphino)benzoic acid and the requisite
amount of EDC and catalytic DMAP to afford b-hydroxy and
b-(o-diphenylphosphino) benzyloxy (o-diphenylphosphino) ben-
zoates 3–8 in yields ranging from 43% to 98% (Scheme 1). With
these compounds in hand, the asymmetric allylic alkylation reac-
tion was pursued with a catalytic amount of allylpalladium chlo-
ride dimer, 1,3-diphenylpropenyl acetate and dimethyl malonate.
Potassium acetate and N,O-bis(trimethylsilyl) acetamide (BSA)
were also employed to facilitate the deprotonation of dimethyl
malonate. The collected results of this work are shown in Table 1.
The bisphosphine ligands 4 and 6 were used in the catalytic
asymmetric alkylation reaction with the palladium pre-catalyst
R
N
Ph
O
O
O
H
{[(g-C3H5)2PdCl]2}, THF, and the associated reagents to form the
PPh2 Ph2P
target homoallylic malonate 10a in 77%ee. This was expected as
Trost et al.4 had previously prepared 4 and demonstrated its suc-
cess in the allylic alkylation process. In contrast, the monophos-
phines b-hydroxy benzoates 3, 5, 7, and 8 did not serve as
suitable ligands for the palladium pre-catalyst system under the
reaction conditions and no observable product was detected. This
was surprising as the related b-hydroxybenzamides prepared by
our group were reactive. The rationale for this lack of reactivity
is unclear at this time although the absence of the amido group
was speculated to contribute to the deactivation of the palladium
catalyst.
1a: R = -CH3 (norephedrine)6
1b:
R = -Ph (1-amino-1,2-diphenylethanol)7
Figure 1. o-(Diphenylphosphino)benzoyloxy o-(diphenylphosphino) benzamides.
This work was followed by a broader study concerning a variety
of b-amino alcohols, both cyclic and acyclic, that were used to cre-
* 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.2009.12.011

34
G. S. Mahadik, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 33–38
PPh2
PPh2
O
O
OR
Ph
OR
HO
Ph
OH
Ph
HO
OH
O
O
1 or 2 equivalents
Ph
1-C10H7
1-C10H7
PPh2
1-C10H7
1-C10H7
3: R = -H (43%)
5: R = -H (88%)
6: R = -o-Ph2PC6H4CO (93%)
CO2H
2a
2c
2b
2d
4:
R = -o-Ph2PC6H4CO (56%)
EDC, DMAP, CH2Cl2
HO
Ph
OH
Ph
HO
OH
Ph
PPh2
PPh2
Ph
O
O
OH
Ph
OH
Ph
O
O
Ph
Ph
7
8
(98%)
(91%)
Scheme 1. Synthesis of mono- and bisphosphines 3–8.
the palladium pre-catalyst in such a way as to yield catalytically
inactive species.8
Table 1
Palladium-catalyzed asymmetric alkylation
The collected results from the use of diols 2a–d as chiral tem-
plates served as the inspiration for pursuing an alternate template
family. The previously used b-amino alcohol template from our
earlier work7 proved to be quite successful when converted into
bisphosphines. Over the course of this earlier work, it was noted
that the two most successful ligands, 12 and 13, afforded the same
absolute stereochemistry of the product of catalysis, even though
the two ligands possessed different structural features (Fig. 2).
PPh2
O
OR5
R4
R3
O
R1
R2
3-8
OAc
Ph
MeO2C
CO2Me
Ph
CH2(CO2Me)2, KOAc, BSA
[(h-C3H5)2PdCl]2, THF
Ph
Ph
9
(R)-10a
Entry
Ligand
Time (h)
9:ligand:Pd
Yielda (%)
er, R:S (ee)b,c
1
2
3
5
6
7
8
9
3
3
4
5
6
6
7
8
24
48
6
24
24
48
24
24
25:1:2
25:1:2
25:1:1
25:1:2
25:1:1
25:1:1
25:1:2
25:1:2
ndd
nd
86
nd
nd
80
nd
nd
nd
nd
Not critical in the transference
of asymmetry to the substrate.
O
P
Ph
Ph
88.3:11.7 (77)
nd
nd
88.7:11.3 (77)
nd
nd
R2
R1
O
Pd
H
Ph
N
P
O
Determines stereochemical
outcome by projection of chirality
a
b
c
Isolated yield after flash chromatography.
Enantiomeric ratios determined by CSP HPLC (Chiralcel AD column).
The identity of the enantiomer was based on elution from the CSP HPLC column.
Not determined.
d
12: R1 = -H; R2 = -Ph (syn-configuration)
13: R1 = -Ph; R2 = -H (anti-configuration)
The failure of the b-hydroxybenzoates to serve as catalysts for
the asymmetric alkylation reaction prompted an investigation.
The b-hydroxy component was considered to be a potential agent
for deactivation of the catalyst. Thus, monophosphine 3 was acyl-
ated with acetic anhydride to generate b-acetoxybenzoate 11
(Scheme 2). Using the reaction conditions illustrated in Table 1,
it was determined that 11 also did not afford the desired product,
suggesting that another factor, other than the presence of a free
alcohol was contributing to the failure of the reaction. There is
the possibility that ligands 3, 5, 7, 8, and 11 are coordinating with
Figure 2. Proposed asymmetric induction.
When the template possessed an anti-configuration along the
backbone (12: R1 = Ph; R2 = –H), the observed level of enantioselec-
tion in the asymmetric alkylation reaction with dimethyl malonate
was 91%ee. When the syn-configuration of the b-amino alcohol
backbone (13: R1 = H; R2 = –Ph) was employed, the observed enan-
tiomeric excess was ꢀ96%ee. The collected results suggest that the
stereochemical substitution at the carbon bearing the benzoyloxy
group does not significantly contribute to the observed asymmetric
induction. Indeed, the Lloyd–Jones–Norrby model9 would suggest
that it is the amido group that represents the pocket of reactivity
where the transfer of asymmetry is effected. Following this
PPh2
PPh2
Ac2O, DMAP, TEA
CH2Cl2
hypothesis, we pursued the synthesis of a series of a-amino acid-
O
O
OAc
Ph
OH
Ph
derived b-amino alcohol catalysts. These systems would not have
substitution at the position bearing the ester group and would
serve as investigative tools to test the nature of the transfer of
chirality.
O
O
Ph
Ph
3
11
To this end, we employed
L-tert-leucinol, L-phenylglycinol, and
Scheme 2. Acetylation of b-hydroxyester 3.
L-valinol as templates. These compounds were acylated with

G. S. Mahadik, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 33–38
35
2 equiv of (o-diphenylphosphino)benzoic acid with EDC and DMAP
ence of asymmetry. Indeed, ligand system 14c derived from tert-L-
to afford the b-(o-diphenylphosphino)benzoyl (o-diphenylphos-
phino) benzamides 15a–c (Scheme 3). With these ligands in hand,
the catalytic asymmetric alkylation of 1,3-diphenylpropenyl ace-
tate was again pursued (Table 2). We were able to see that all
the ligands performed well under the reaction conditions. The
amount of ligand, the palladium precursor, the reaction solvent,
and the time duration of reaction were varied for the sake of opti-
mizing the stereochemical outcome.
leucinol provided the highest enantioselectivities, presumably due
to the steric volume of the tert-butyl group. Mechanistically, this
suggests that the amide component is directly responsible for the
observed enantioselection and that the ester component is, in ef-
fect, a ‘coordination space holder’ that allows the palladium to
maintain an ordered cavity into which the nucleophile might enter
and undergo the alkylation process (Fig. 3).
PPh2
Supports the structrual integrity of
cavity of the reactive center.
PPh2 PPh2
CO2H
EDC, DMAP, CH2Cl2
HO
NH2
R
H
O
P
Ph
Ph
O
N
R
O
O
O
Pd
14a: R = -CH(CH3)2 (L-valinol)
14b: R = -C6H5 (L-phenylalaninol)
14c: R = -C(CH3)3 (L-tert-leucinol)
H
Nu
15a-c
M
N
P
O
Scheme 3. Synthesis of b-benzoyloxybenzamides 15a–c.
Determines stereochemical
outcome by projection of chirality
from tert-butyl group proximal to
the amide.
The
meric excesses for the product of catalysis ranging from 84% to
92%ee. The -phenylglycinol ligand 15b gave comparable results
with enantiomeric excesses ranging from 88 to 98%ee. The best re-
sults were obtained when the -tert-leucinol ligand 15c was em-
L-valinol-based ligand 15a performed well, with enantio-
L
Figure 3. Proposed stereochemical induction.
L
ployed. The observed enantioselectivity ranged from 94% to
99%ee. The use of sodium acetate as a catalytic base afforded a
slightly lower enantiomeric excess as compared to the use of
potassium acetate. Ultimately, ligands 15a–c all proved to be supe-
rior catalysts as compared to the chiral diol ligands 3–8.
The collected results from Table 2 suggest that the carbon bear-
ing the (o-diphenylphosphino)benzoyloxy component need not
possess any chirality in order for high enantiomeric excesses to
be observed. As the Lloyd–Jones–Norrby model would suggest,
the region near the amide is of central importance in the transfer-
3. Conclusion
We have developed a series of C2-symmetric ligands and b-ami-
do-esters derived from -tert-leucinol, -phenylglycinol, and
-valinol. Mono alcohols derived from C2-symmetric ligands did
not react well. The application of the b-amido-ester derived from
-tert-leucinol gave the best enantiomeric excess of 99%ee. Further
L
L
L
L
efforts are currently underway to explore the use of these ligands
in other palladium-catalyzed alkylation reactions.
Table 2
Asymmetric allylic alkylation with b-benzoyloxybenzamides 14a–c
PPh2 PPh2
H
O
N
O
O
15a-c
R
OAc
Ph
RO2C
CO2R
Ph
CH2(CO2R')2, MOAc, BSA
Ph
[(η-C3H5)2PdCl]2, THF
Ph
9
10a-b
a = -Me
b = -Et
Entry
Ligand
MOAc M =
CH2(CO2R0)2R0 =
Time (h)
9:ligand:Pd
Yielda (%)
er, R:S (ee)b
Config.c
1
2
3
4
5
6
7
8
9
14a
14a
14a
14a
14b
14b
14b
14b
14c
14c
14c
14c
K+
Me-
Me-
Me-
Et-
Me-
Me-
Me-
Et-
Me-
Me-
Me-
Et-
24
6
24
24
24
6
24
24
24
6
24
24
25:1:1
25:1:1
25:1:1
25:1:1
25:1:1
25:1:1
25:1:1
25:1:1
25:1:1
25:1:1
25:1:1
25:1:1
78
74
97
76
74
82
75
71
87
87
65
72
7.5:92.5 (85)
4.0:96.0 (92)
8.0:92.0 (84)
4.4:95.6 (91)
3.7:96.3 (93)
1.0:99.0 (98)
4.4:95.6 (91)
5.8:94.2 (88)
1.5:98.5 (97)
0.5:99.5 (99)
2.8:97.2 (94)
1.3:98.7 (97)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
K+
Na
K+
K+
K+
Na+
K+
K+
10
11
12
K+
Na+
K+
a
b
c
Isolated yield after flash chromatography.
Enantiomeric ratios determined by CSP HPLC (Chiralcel AD column).
The identity of the enantiomer was based on elution from the CSP HPLC column.

36
G. S. Mahadik, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 33–38
NMR (CDCl3): 78.1, 127.8, 128.0, 128.2, 128.3, 128.31, 128.4, 128.42,
4. Experimental section
4.1. General remarks
131.4, 132.0, 133.7, 133.8, 133.9, 134.0, 134.2, 134.4, 134.44, 135.8,
138.06, 138.1, 138.2, 140.5, 140.7, 165.5. ESI-HRMS calcd for
C52H40O4 P2 (M+H+): 791.2456. Found: 791.2444.
Methylene chloride (CH2Cl2), tetrahydrofuran (THF), and tolu-
ene were purchased as anhydrous reagents. The allylpalladium
4.4. (1R,2R)-2-Hydroxy-1,2-di(naphthalen-1-yl)ethyl 2-(diphen-
ylphosphino)benzoate 5
chloride dimer {[(g
3-C3H5)PdCl]2}, dimethyl malonate, potassium
acetate, and N,O-bis(trimethylsilyl)acetamide (BSA) were pur-
chased and used without further purification or handling.
Unless otherwise stated, all reactions were run under anhy-
drous conditions and a nitrogen atmosphere. 1H and 13C NMR spec-
tra were recorded using a 500 MHz NMR spectrometer operating at
500 MHz for the recording of 1H NMR spectra and operating at
125 MHz for the recording of 13C NMR spectra. Samples were dis-
solved in CDCl3 with trimethylsilane (TMS) as the internal stan-
dard. Chemical shifts are reported in parts per million (d scale),
and coupling constants (J values) are listed in hertz (Hz). 1H NMR
spectra were referenced to the deuterated chloroform resonance
at 7.26 ppm.
In a 250 mL nitrogen purged round-bottomed flask was added
(R,R)-1,2-di(1-naphthyl)-1,2-ethanediol (0.087 g, 0.277 mmol),
DMAP (0.007 g, 0.055 mmol), dichloromethane (5 mL), 2-(diphenyl-
phosphino)benzoic acid (0.083 g, 0.277 mmol), and EDC (0.058 g,
0.304 mmol). The reaction mixture was allowed to stir for 24 h and
then the reaction was quenched with the addition of 3 M HCl
(50 mL ꢂ 2). The organic layer was diluted with dichloromethane
(100 mL), washed with brine (50 mL), and dried with magnesium
sulfate (MgSO4). The solvents were removed via rotary evaporation
and the product was isolated by flash column chromatography (hex-
anes/EtOAc, 7:3). Viscous wax (88%), ½a D24
¼ þ121:5 (c 0.55, CHCl3).
ꢃ
IR (Nujol) (cmꢁ1): 3310, 1714, 1289, 1169, 776, 694. 1H NMR
(500 MHz, CDCl3) d (ppm): 5.30 (dd, J = 3.2, 13.1 Hz, 1H), 5.71 (d,
J = 10.6 Hz, 1H), 6.47 (d, J = 8.9 Hz, 1H), 6.89–7.61 (m, 27H), 8.05–
8.09 (m, 1H). 13C NMR (CDCl3): 74.9, 122.7, 123.6, 124.5, 124.7,
124.9, 124.94, 125.3, 125.5, 125.8, 128.0, 128.2, 128.4, 128.5,
128.7, 128.8, 129.0, 129.1, 129.15, 129.2, 129.4, 130.7, 131.1,
132.3, 132.8, 133.0, 133.5, 133.6, 133.8, 134.0, 134.3, 134.5, 135.3,
135.7, 135.9, 136.3, 136.5, 136.6, 166.7. ESI-HRMS calcd for
C41H31O3P (M+H+): 603.2089. Found: 603.208.
Infrared spectra are reported in reciprocal centimeters (cmꢁ1
)
and are measured either as a neat liquid or Nujol. Melting points
are uncorrected. Flash chromatography was conducted with an
automated single pump, fraction-collector chromatograph. Mass
spectral analyses were conducted using a quadrupole time of flight
mass spectrometer hybrid with MS/MS capability. Enantiomeric
ratios were determined using a HPLC with a chiral stationary phase
column. Optical activities were measured using at 589 nm using a
digital polarimeter purchased with NSF Grant #CHE 644950.
4.2. (1R,2R)-2-Hydroxy-1,2-diphenyl 2-
(diphenylphosphino)benzoate 3
4.5. (1R,2R)-1,2-Di(naphthalen-1-yl)ethane-1,2-diyl bis(2-
(diphenylphosphino)benzoate) 6
In a 250 mL nitrogen purged round-bottomed flask were added
(R,R)-hydrobenzoin (0.400 g, 1.87 mmol), DMAP (0.046 g,
0.373 mmol), dichloromethane (10 mL), 2-(diphenylphosphino)
benzoic acid (0.572 g, 1.87 mmol), and EDC (0.394 g, 2.05 mmol).
The reaction mixture was allowed to stir for 24 h and then the reac-
tion was quenched with the addition of 3 M HCl (50 mL ꢂ 2). The or-
ganic layer was diluted with dichloromethane (100 mL), washed
with brine (50 mL), and dried with magnesium sulfate (MgSO4).
The solvents were removed via rotary evaporation and the product
was isolated by flash column chromatography (hexanes/EtOAc,
In a 250 mL nitrogen purged round-bottomed flask were added
(R,R)-(+)-1,2-di(1-naphthyl)-1,2-ethanediol (0.250 g, 0.795 mmol),
DMAP (0.097 g, 0.795 mmol), dichloromethane (10 mL), 2-(diphen-
ylphosphino)benzoic acid (0.487 g, 1.59 mmol), and EDC (0.305 g,
1.59 mmol). The reaction mixture was allowed to stir for 48 h and
then the reaction was quenched with the addition of 3 M HCl
(50 mL ꢂ 2). The organic layer was diluted with dichloromethane
(100 mL), washed with brine (50 mL), and dried with magnesium
sulfate (MgSO4). The solvents were removed via rotary evaporation
and the product was isolated by flash column chromatography (hex-
6:4). Viscous wax (43%), ½a D24
¼ þ41:9 (c 0.80, CHCl3). IR (Nujol)
ꢃ
anes/EtOAc, 7:3). Viscous wax (93%), ½a D23
¼ þ276:0 (c 0.21, CHCl3).
ꢃ
(cmꢁ1): 3390, 1715, 1275, 1248, 746, 697. 13C NMR (CDCl3): 76.5,
83.0, 127.1, 127.3, 127.4, 127.6, 127.7, 128.5, 128.55, 128.6,
128.67, 128.70, 128.8, 129.1, 131.9, 132.0, 132.2, 133.1, 133.3,
134.0, 134.2, 134.8, 135.0, 135.2, 136.0, 136.1, 136.2, 136.45,
136.5, 136.6, 136.8, 138.1, 165.9. ESI-HRMS calcd for C33H27O3P
(M+H+): 503.1776. Found: 503.1765.
IR (Nujol) (cmꢁ1): 1711, 1268, 1249, 741, 694. 1H NMR (500 MHz,
CDCl3) d (ppm): 6.85 (m, 2H), 6.97–7.61 (m, 40H), 8.20–8.23 (m,
2H). 13C NMR (CDCl3): 124.6, 125.1, 125.7, 128.1, 128.2, 128.3,
128.4, 128.41, 128.9, 130.8, 131.4, 131.9, 133.2, 133.7, 133.74,
133.8, 133.9, 133.91, 134.0, 134.3, 134.4, 134.5, 137.9, 138.0,
138.1, 138.2, 140.4, 140.6, 165.9. ESI-HRMS calcd for C60H44O4P2
(M+H+): 891.2793. Found: 891.2762.
4.3. (1R,2R)-1,2-Diphenylethane-1,2-diyl bis(2-(diphenylphos-
phino)benzoate) 4
4.6. (S)-2-Hydroxy-1,2,2-triphenylethyl 2-(diphenylphosphino)-
benzoate 7
In a 250 mL nitrogen purged round-bottomed flask were added
(R,R)-hydrobenzoin (0.300 g, 1.40 mmol), DMAP (0.068 g, 0.560
mmol), dichloromethane (10 mL), 2-(diphenylphosphino)benzoic
acid (0.858 g, 2.80 mmol), and EDC (0.537 g, 2.80 mmol). The reaction
mixture was allowed to stir for 48 h and then the reaction was
quenched with the addition of 3 M HCl (50 mL ꢂ 2). The organic layer
was diluted with dichloromethane (100 mL), washed with brine
(50 mL), and dried with magnesium sulfate (MgSO4). The solvents
were removed via rotary evaporation and the product was isolated
by flash column chromatography (hexanes/EtOAc, 7:3). Viscous wax
In a 250 mL nitrogen purged round-bottomed flask were added
(S)-1,1,2-triphenyl-1,2-ethanediol (0.250 g, 0.861 mmol), DMAP
(0.021 g, 0.172 mmol), dichloromethane (5 mL), 2-(diphenylphos-
phino)benzoic acid (0.264 g, 0.861 mmol), and EDC (0.248 g,
1.29 mmol). The reaction mixture was allowed to stir for 24 h
and then the reaction was quenched with the addition of 3 M
HCl (50 mL ꢂ 2). The organic layer was diluted with dichlorometh-
ane (100 mL), washed with brine (50 mL), and dried with magne-
sium sulfate (MgSO4). The solvents were removed via rotary
evaporation and the product was isolated by flash column chroma-
(56%), ½a 2D3
ꢃ
¼ þ104:4 (c 0.10, CHCl3). IR (Nujol) (cmꢁ1): 1716, 1270,
1248, 744, 696. 1H NMR (500 MHz, CDCl3) d (ppm): 6.21 (s, 2H),
6.79 (d, J = 7.4 Hz, 1H), 6.94–7.30 (m, 36 H), 8.08–8.09 (m, 1H). 13C
tography (hexanes/EtOAc, 7:3). Viscous wax (91%), ½a D23
¼ ꢁ131:7
ꢃ
(c 0.44, CHCl3). IR (Nujol) (cmꢁ1): 3550, 1697, 1251, 891, 746. 1H

G. S. Mahadik, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 33–38
37
NMR (500 MHz, CDCl3) d (ppm): 3.52 (d, J = 3.2 Hz, 1H), 6.87–7.36
(m, 28H), 7.55–7.57 (m, 1H), 7.98–8.01 (m, 1H). 13C NMR (CDCl3):
80.1, 80.4, 126.2, 126.4, 126.7, 127.0, 127.1, 127.6, 128.2, 128.4,
128.5, 128.51, 128.6, 128.63, 128.7, 128.8, 130.0, 131.4, 131.41,
132.2, 133.5, 133.6, 133.7, 133.9, 134.2, 134.3, 134.8, 135.6,
137.0, 137.1, 137.3, 137,4, 139.0, 139.2, 142.7, 145.1, 165.6. ESI-
HRMS calcd for C39H31O3P (M+H+): 579.2089. Found: 579.2099.
HCl (50 mL ꢂ 2). The organic layer was diluted with dichlorometh-
ane (100 mL), washed with brine (50 mL), and dried with magne-
sium sulfate (MgSO4). The solvents were removed via rotary
evaporation and the product was isolated by flash column chroma-
tography (hexanes/EtOAc, 7:3). Viscous wax (56%), ½a D23
¼ ꢁ8:1 (c
ꢃ
0.20, CHCl3). IR (neat) (cmꢁ1): 1714, 1652, 1251, 746, 697. 1H
NMR (500 MHz, CDCl3) d (ppm): 0.85 (d, J = 6.8 Hz, 3H), 0.89 (d,
J = 6.8 Hz, 3H), 1.66–1.76 (m, 1H), 4.11 (dd, J = 3.6, 11.5 Hz, 1H),
4.20–4.25 (m, 1H), 4.34 (dd, J = 5.4, 11.5 Hz, 1H), 6.44 (d,
J = 9.5 Hz, 1H), 6.99–7.01 (m, 1H), 7.20–7.47 (m, 25H), 7.67–7.69
(m, 1H), 8.20–8.22 (m, 1H).13C NMR (CDCl3): 18.7, 19.2, 29.3,
53.5, 65.4, 127.9, 127.9, 128.3, 128.4, 128.41, 128.42, 128.46,
128.48, 128.5, 128.6, 128.62, 128.7, 130.0, 131.2, 132.0, 133.5,
133.6, 133.7, 133.8, 134.1, 134.2, 134.3, 134.1, 134.2, 134.3,
135.6, 135.8, 136.9, 137.0, 137.1, 137.2, 137.4, 137.5, 137.54,
137.6, 139.6, 139.8, 141.5, 141.7, 166.7, 168.7. ESI-HRMS calcd
for C43H39NO3P2 (M+H+): 680.2483. Found: 680.2487.
4.7. (R)-2-Hydroxy-2-phenylethyl 2-(diphenylphosphino)-
benzoate 8
In a 250 mL nitrogen purged round-bottomed flask were added
(R)-1-phenyl-1,2-ethanediol (0.250 g, 1.81 mmol), DMAP (0.221 g,
1.81 mmol), dichloromethane (10 mL), 2-(diphenylphosphino)ben-
zoic acid (1.11 g, 3.62 mmol), and EDC (0.694 g, 3.62 mmol). The
reaction mixture was allowed to stir for 24 h and then the reaction
was quenched with the addition of 3 M HCl (50 mL ꢂ 2). The or-
ganic layer was diluted with dichloromethane (100 mL), washed
with brine (50 mL), and dried with magnesium sulfate (MgSO4).
The solvents were removed via rotary evaporation and the product
was isolated by flash column chromatography (hexanes/EtOAc,
4.10. (S)-2-(2-(Diphenylphosphino)benzamido)-2-phenylethyl
2-(diphenylphosphino)benzo-ate 14b
7:3). Viscous wax (98%), ½a D23
¼ þ2:22 (c 1.68, CHCl3). IR (neat)
ꢃ
In a 250 mL nitrogen purged round-bottomed flask were added
(S)-phenylglycinol (0.100 g, 0.729 mmol), DMAP (0.089 g, 0.729
mmol), dichloromethane (5 mL), 2-(diphenylphosphino)benzoic
acid (0.447 g, 1.46 mmol), and EDC (0.613 g, 3.21 mmol). The reac-
tion mixture was allowed to stir for 48 h and then the reaction was
quenched with the addition of 3 M HCl (50 mL ꢂ 2). The organic
layer was diluted with dichloromethane (100 mL), washed with
brine (50 mL), and dried with magnesium sulfate (MgSO4). The sol-
vents were removed via rotary evaporation and the product was iso-
lated by flash column chromatography (hexanes/EtOAc, 6:4).
(cmꢁ1): 3056, 1715, 1217, 745, 668. 1H NMR (500 MHz, CDCl3) d
(ppm): 4.31 (dd, J = 3.6, 12.0 Hz, 1H), 4.46 (dd, J = 8.6, 12.0 Hz,
1H), 6.26 (dd, J = 3.6, 8.6 Hz, 1H), 6.91–6.93 (m, 1H), 7.14–7.36
(m, 17H), 8.07–8.14 (m, 1H). 13C NMR (CDCl3): 66.6, 74.1, 126.7,
128.1, 128.2, 128.22, 128.24, 128.26, 128.3, 128.33, 128.35, 128.4,
128.44, 130.9, 131.0, 131.9, 131.94, 133.4, 133.5, 133.6, 133.62,
133.7, 133.73, 133.8, 133.82, 133.9, 134.1, 134.3, 134.4, 136.0,
137.7, 137.74, 137.8, 137.83, 137.9, 139.9, 140.2, 140.8, 141.0,
165.7, 165.8. ESI-HRMS calcd for C27H23O3P (M+H+): 425.1307.
Found: 425.1310.
Viscous wax (71%), ½a D23
ꢃ
¼ ꢁ6:3 (c 0.35, CHCl3). IR (Nujol) (cmꢁ1):
1716, 1654, 1217, 751, 697. 1H NMR (500 MHz, CDCl3) d (ppm):
4.24 (dd, J = 5.6, 14.3 Hz, 1H), 4.46 (dd, J = 8.0, 14.3 Hz, 1H), 5.46–
5.50 (m, 1H), 6.90–6.93 (m, 2H), 7.11–7.37 (m, 30H), 7.64–7.67 (m,
1H), 8.02–8.06 (m, 1H). 13C NMR (CDCl3): 52.4, 67.1, 126.8, 127.7,
128.3, 128.32, 128.4, 128.41, 128.45, 128.5, 128.6, 128.64, 128.7,
128.8, 130.2, 131.2, 132.1, 133.6, 133.7, 133.74, 133.9, 133.94,
134.2, 134.3, 135.7, 136.0, 136.7, 136.8, 137.0, 137.1, 137.5,
137.52, 137.6, 137.63, 138.0, 140.1, 140.4, 140.9, 141.2, 166.5,
168.3. ESI-HRMS calcd for C46H37NO3P2 (M+H+): 714.2327. Found:
714.2335.
4.8. (1R,2R)-2-Acetoxy-1,2-diphenylethyl 2-(diphenylphosphino)
benzoate 11
In a 250 mL nitrogen purged round-bottomed flask were added
(1R,2R)-2-hydroxy-1,2-diphenyl 2-(diphenylphosphino)benzoate
(0.266 g, 0.530 mmol), acetic anhydride (0.1 mL, 0.636 mmol),
dichloromethane (15 mL), DMAP (0.013 g, 0.106 mmol), and tri-
ethyl amine (0.1 mL, 0.795 mmol). The reaction mixture was al-
lowed to stir for 24 h and then the reaction was quenched with
the addition of 1 M HCl (50 mL ꢂ 2). The organic layer was diluted
with dichloromethane (100 mL), washed with brine (50 mL), and
dried with magnesium sulfate (MgSO4). The solvents were re-
moved via rotary evaporation and the product was isolated by flash
column chromatography (hexanes/EtOAc, 7:3). Viscous wax (64%),
4.11. (S)-2-(2-(Diphenylphosphino)benzamido)-3,3-dimethylbutyl
2-(diphenylphosphino) benzoate 14c
a 2D3
ꢃ
¼ þ19:6 (c 0.58, CHCl3). IR (Nujol) (cmꢁ1): 3068, 1731, 1251,
In a 250 mL nitrogen purged round-bottomed flask were added
(S)-2-amino-3,3-dimethyl-1-butanol (0.100 g, 0.853 mmol), DMAP
(0.104 g, 0.853 mmol), dichloromethane (5 mL), 2-(diphenylphos-
phino)benzoic acid (0.523 g, 1.71 mmol), and EDC (0.359 g,
1.88 mmol). The reaction mixture was allowed to stir for 48 h
and then the reaction was quenched with the addition of 3 M
HCl (50 mL ꢂ 2). The organic layer was diluted with dichlorometh-
ane (100 mL), washed with brine (50 mL), and dried with magne-
sium sulfate (MgSO4). The solvents were removed via rotary
evaporation and the product was isolated by flash column chroma-
½
757, 667. 1H NMR (500 MHz, CDCl3) d (ppm): 2.02 (s, 3H), 6.11
(d, J = 8.8 Hz, 1H), 6.28 (d, J = 8.8 Hz, 1H), 6.92–7.44 (m, 23H),
8.14–8.16 (m, 1H). 13C NMR (CDCl3): 21.2, 77.4, 77.8, 127.7,
127.72, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.33, 128.35,
128.4, 128.44, 128.5, 130.9, 130.91, 132.1, 133.8, 133.9, 133.91,
134.0, 134.2, 134.6, 135.7, 136.0, 137.8, 137.9, 138.0, 138.1,
140.5, 140.7, 165.2, 170.0. ESI-HRMS calcd for C35H29O4P (M+H+):
545.1882. Found: 545.1871.
tography (hexanes/EtOAc, 7:3). Viscous wax (66%), ½a D23
¼ ꢁ3:2 (c
ꢃ
4.9. (S)-2-(2-(Diphenylphosphino)benzamido)-3-methylbutyl
2-(diphenylphosphino)benzo- ate 14a
0.40, CHCl3). IR (Nujol) (cmꢁ1): 1714, 1651, 1269, 743, 696. 1H
NMR (500 MHz, CDCl3) d (ppm): 0.86 (s, 9H), 4.16–4.17 (m, 1H),
4.32–4.41 (m, 1H), 6.10 (d, J = 9.9 Hz, 1H), 6.93–7.00 (m, 1H),
7.08–7.43 (m, 26H), 7.63–7.65 (m, 1H), 8.28–8.31 (m, 1H). 13C
NMR (CDCl3): 26.6, 33.7, 56.1, 64.6, 128.1, 128.15, 128.19, 128.2,
128.3, 128.4, 128.43, 128.5, 128.6, 128.63, 128.7, 128.8, 130.0,
131.6, 131.8, 132.0, 133.6, 133.61, 133.7, 133.8, 133.9, 133.91,
134.1, 134.3, 134.8, 135.0, 136.7, 136.8, 136.9, 137.0, 137.8,
In a 250 mL nitrogen purged round-bottomed flask were added
(S)-2-amino-3-methyl-1-butanol (0.100 g, 0.969 mmol), DMAP
(0.118 g, 0.969 mmol), dichloromethane (5 mL), 2-(diphenylphos-
phino)benzoic acid (0.594 g, 1.94 mmol), and EDC (0.408 g,
2.13 mmol). The reaction mixture was allowed to stir for 48 h
and then the reaction was quenched with the addition of 3 M

38
G. S. Mahadik, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 33–38
137.9, 137.91, 138.0, 140.6, 140.8, 142.0, 142.2, 166.5, 169.1. ESI-
HRMS calcd for C44H41NO3P2 (M+H+): 694.2640. Found: 694.2652.
column. 1H NMR (500 MHz, CDCl3) d (ppm): 1.00 (t, J = 8.8 Hz, 3H),
1.20 (t, J = 8.8 Hz, 3H), 3.92 (d, J = 13.7 Hz, 2H), 3.97 (q, J = 8.8 Hz,
2H), 4.17 (q, J = 8.8 Hz, 2H), 4.26 (dd, J = 10.8, 13.7 Hz, 1H), 6.34 (dd,
J = 10.8, 19.7, 1H), 6.5 (d, J = 19.7 Hz, 1H), 7.17–7.30 (m, 10H). 13C
NMR (CDCl3): 13.7, 14.1, 49.2, 57.7, 61.3, 61.5, 126.3, 127.0, 127.5,
128.0, 128.4, 128.6, 129.3, 131.6, 136.8, 140.3, 167.4, 167.8.
4.12. (S)-Dimethyl 2-(1,3-diphenylallyl)malonate (Table 2, entry
10) 10a
In a 50 mL nitrogen purged round-bottomed flask were added li-
gand (0.048 g, 0.069 mmol), [(
g
3-C3H5)PdCl]2 (0.026 g, 0.070 mmol),
Acknowledgments
KOAc (0.007 g, 0.070 mmol), THF (4 mL), BSA (1.3 mL, 5.3 mmol), 1,3-
diphenylpropenyl acetate (0.464 g, 1.73 mmol), and CH2(CO2Me)2
(0.6 mL, 5.3 mmol). The reaction mixture was allowed to stir for 6 h
at 25 °C and then the reaction was quenched with the addition of
1 M HCl (50 mL) and ammonium chloride (50 mL). The organic layer
was diluted 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 (hexanes/
EtOAc,9:1).TheproductswereanalyzedbyHPLCusinganADcolumn.
1H NMR (500 MHz, CDCl3) d (ppm): 3.44 (s, 3H), 3.62 (s, 3H), 3.88 (d,
J = 10.9 Hz, 1H), 4.19 (dd, J = 8.8, 10.8 Hz, 1H), 6.26 (dd, J = 8.60,
15.8 Hz, 1H), 6.40 (d, J = 15.8 Hz, 1H), 7.10–7.25 (m, 10 H). 13C NMR
(CDCl3): 49.2, 52.4, 52.6, 57.6, 126.4, 127.1, 127.5, 127.9, 128.5,
128.7, 129.1, 131.8, 136.8, 140.2, 167.7, 168.2.
The authors gratefully acknowledge financial support from the
National Science Foundation (Grant CHE-644950). The 500 MHz
NMR spectroscopic data collected in this work are based upon
work supported by the National Science Foundation under Grant
CHE-0722385.
References
1. (a) Chen, X.; Engle, K. M.; Wang, D.; Yu, J. Angew. Chem., Int. Ed. 2009, 48, 5094–
5115; (b) Helmchen, G.; Christmann, M.; Braese, S. Asymmetry Synth. 2007, 95–
99; (c) You, S.; Dai, L. Angew. Chem., Int. Ed. 2006, 45, 5246–5248.
2. (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395; (b) Trost, B. M. Acc.
Chem. Res. 1980, 13, 385.
3. (a) Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic Synthesis;
Wiley: Chichester, UK, 1997; (b) Tsuji, J. Tetrahedron 1986, 42, 4361.
4. (a) Trost, B. M. J. Org. Chem. 2004, 69, 5813; (b) Trost, B. M.; Crawley, M. L. Chem.
Rev. 2003, 103, 2921; (c) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem.
Soc. 1992, 114, 9327.
5. (a) Lu, Z.; Ma, S. Angew. Chem. Int. Ed. 2008, 47, 258; (b) Trost, B. M.; Machacek,
M. R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747; (c) Trost, B. M.; Breit, B.; Organ,
M. G. Tetrahedron Lett. 1994, 35, 5817.
6. Mahadik, G. S.; Knott, S. L.; Szczepura, L. F.; Hitchcock, S. R. Tetrahedron:
Asymmetry 2009, 20, 1132–1137.
4.13. (S)-Diethyl 2-(1,3-diphenylallyl)malonate (Table 2, entry
11) 10b
In a 50 mL nitrogen purged round-bottomed flask were added li-
gand (0.049 g, 0.071 mmol), [(g
3-C3H5)PdCl]2 (0.026 g, 0.072 mmol),
KOAc (0.007 g, 0.072 mmol), THF (4 mL), BSA (1.3 mL, 5.4 mmol), 1,3-
diphenylpropenyl acetate (0.476 g, 1.78 mmol), and CH2(CO2Et)2
(0.8 mL, 5.4 mmol). The reaction mixture was allowed to stir for
24 h at 25 °C and then the reaction was quenched with the addition
of 1 M HCl (50 mL) and ammonium chloride (50 mL). The organic
layer was diluted with ether (50 mL), washed with brine (50 mL),
and dried (MgSO4). The solventswere removedviarotaryevaporation
and the product was isolated by flash column chromatography (hex-
anes/EtOAc, 9:1). The products were analyzed by HPLC using an AD
7. Mahadik, G. S.; Knott, S. L.; Szczepura, L. F.; Steven, J. P.; Standard, J. M.;
Hitchcock, S. R. J. Org. Chem. 2009. doi:10.1021/jo9016474.
8. The origin of the failure of the ligands 3, 5, 7, 8, and 11 is currently unclear but
will be the subject of a future study.
9. (a) Butts, C. P.; Filali, E.; Lloyd-Jones, G. C.; Norrby, P.; Sale, D. A.; Schramm, Y. J.
Am. Chem. Soc. 2009, 131, 9945–9957; (b) Lloyd-Jones, G. C.; Stephen, S. C.;
Fairlamb, I. J.; Martorell, A.; Dominguez, B.; Tomlin, P. M.; Murray, M.;
Fernandez, J. M.; Jeffrey, J. C.; Riis-Johannessen, T.; Guerziz, T. Pure Appl. Chem.
2004, 76, 589–601; (c) Fairlamb, I. J.; Lloyd-Jones, G. C. Chem. Commun. 2000,
2447; (d) Butts, C. P.; Crosby, J.; Lloyd-Jones, G. C.; Stephen, S. C. Chem. Commun.
1999, 1707.