StePHOX, a new family of optically active, tunable phosphine-oxazoline ligands: syntheses and applications

Article abstract of DOI:10.1016/j.tet.2006.05.043

A new class of optically active phosphine-oxazoline ligands has been synthesized wherein backbone chirality of these new ligands is installed by a Sharpless asymmetric dihydroxylation. Different backbone protecting groups as well as different substitution patterns on the oxazoline ring were studied. These ligands were tested in allylic substitution (with ee's up to 97%) and asymmetric Tsuji allylation.

Full text of DOI:10.1016/j.tet.2006.05.043

Tetrahedron 62 (2006) 11470–11476
StePHOX, a new family of optically active, tunable
phosphine–oxazoline ligands: syntheses and applications
*
´
Stephane Trudeau and James P. Morken
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA
Received 27 February 2006; revised 16 May 2006; accepted 18 May 2006
Available online 15 June 2006
Dedicated in honor of Professor David W. MacMillan in recognition of his receipt of the Tetrahedron Young Investigator Award
Abstract—A new class of optically active phosphine–oxazoline ligands has been synthesized wherein backbone chirality of these new ligands
is installed by a Sharpless asymmetric dihydroxylation. Different backbone protecting groups as well as different substitution patterns on the
oxazoline ring were studied. These ligands were tested in allylic substitution (with ee’s up to 97%) and asymmetric Tsuji allylation.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
connecting elements are rendered chiral, new opportunities
arise for ligand tuning and representative examples are
depicted in Figure 1.6
The phosphine–oxazoline (PHOX, Fig. 1) ligands comprise
a versatile class of heterobidentate structures, which have
a remarkably broad range of applications in asymmetric
catalysis.1 Several features of the PHOX ligands originally
introduced by Pfaltz,2 Helmchen,3 and Williams,4 are impor-
tant. From an electronic perspective, the coordinating hetero-
atoms are sufficiently distinct that they render the reactivity
of neighboring coordination sites, in a transition metal com-
plex, nonequivalent. By altering the substitution of the aro-
matic backbone,5 the electronic properties of the ligand can
be fine tuned thereby leading to enhanced reactivity and
selectivity for a reaction of interest. Similarly, the steric envi-
ronment imposed by the ligand may be modified by altering
the substituents on the oxazoline ring and on the phosphorus
atom. In addition to these perturbations to the parent struc-
ture, several groups have examined alternate linkages that
connect the phosphine and oxazoline groups. When these
To expand the tunability of the phosphine–oxazoline li-
gands, we have designed a new ligand class, coined Ste-
PHOX, which is depicted in Figure 2. The added control
element is a dioxolane backbone, which connects the phos-
phine and oxazoline motifs. It was anticipated that chirality
associated with the dioxolane linkage would impose itself
on the ligand conformation such that the chirality on the
oxazoline may not be required for asymmetric induction.
Furthermore, the dioxolane offers an additional tuning ele-
ment to those which are already present in the PHOX
ligands. In this report, we describe an efficient synthetic
route that provides members of the StePHOX ligand family.
Also described, are structural studies on StePHOX–metal
complexes and preliminary observations on enantioselective
catalysis.
Cp*Fe
PPh2
Ph
O
O
O
O
O
N
O
Ph2P
N
N
Ph2P
N
Ph2P
N
Ph2P
N
Ph2P
R
R
R
R
PHOX
Pfaltz
Helmchem
Williams
1993
Bolm, 2002
Helmchen, 2005
Hayashi, 1998
Gilbertson, 1997 Helmchen, 2006
Figure 1.
* Corresponding author. Tel.: +1 919 962 8229; fax: +1 919 962 2388; e-mail: morken@unc.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.043

S. Trudeau, J. P. Morken / Tetrahedron 62 (2006) 11470–11476
11471
Me Me
prepared diol 11, two different protecting groups were intro-
duced (Scheme 2). First, acetal 15 was prepared in 96% yield
by heating diol 11 with 3-pentanone in benzene with cata-
lytic TsOH. Alternatively, methylene acetal 16 was isolated
in 85% yield after treating diol 11 with paraformaldehyde at
80 ꢀC. Subsequently, compounds 15 and 16 were converted
to 2 and 3 using a route, which is similar to that followed for
the parent StePHOX ligand.
O
O
O
O
Ph2P
N
N
PPh2
StePHOX-1
R
PHOX
Et Et
H
H
Me Me
Me Me
O
O
O
O
O
O
O
O
R
R
O
O
O
O
O
Ph2POH
O
O
OH
N
N
N
N
3-pentanone
or (CH2O)n
22% Pd(OAc)2
22% dppp, i-Pr2NEt
PPh2
2
PPh2
3
PPh2
PPh2
OH
i-Pr
i-Pr
CO2Et
4
5
CO2Et
p-TsOH
DMSO, 120 °C
OTf
OTf
benzene, 80 °C
Me Me
Me Me
Me Me
Me Me
11
15, R = Et (96%)
16, R = H (85%)
O
O
O
O
O
O
O
O
O
O
O
R
R
R
R
R R
N
N
N
N
NH2
1.
PPh2
PPh2
PPh2
PPh2
O
O
O
O
O
O
Me
Ph
t-Bu
Me
Ph
OH
(EtO)3SiH
O
O
Ti(Oi-Pr)4
120 °C
ent-6
7
8
9
CO2Et
N
N
2. MsCl
benzene
80 °C
Figure 2.
PPh2
O
PPh2
O
PPh2
DMAP, Et3N
CH2Cl2, 40 °C
2. Results and discussion
17, R = Et (97%)
18, R = H (99%)
19, R = Et (88%)
20, R = H (88%)
2, R = Et (49%)
3, R = H (51%)
A straightforward inexpensive route to the StePHOX family
of ligands is described in Scheme 1. In this approach, in-
expensive coumarin was treated with sodium ethoxide in
refluxing ethanol7 and the resulting trans-enoate was then
converted to the derived triflate (10). Sharpless asymmetric
dihydroxylation was then performed with AD-mix-b and
methanesulfonamide to afford, in excellent enantiopurity,
diol 11.8 After conversion of the diol to the corresponding
ketal (12), catalytic phosphination yielded phosphine oxide
13.9 The ester was then condensed with ethanolamine at
120 ꢀC in a sealed vial for 2 h to afford a hydroxyamide,
which was immediately treated with MsCl, Et3N, and cata-
lytic DMAP to provide the oxazoline 14 in 97% yield.
Finally, deoxygenation of phosphine oxide with triethoxy-
silane and titanium(IV) isopropoxide in refluxing benzene
gave the parent ligand structure 1 in 55% yield.10
Scheme 2.
A secondset of ligand structures was prepared, which possess
substitution on the oxazoline ring. Accordingly, phosphine
oxide 13 was condensed with an appropriate aminoalcohol
at 120 ꢀC for 2 h and the resulting hydroxyamide was then
treated with MsCl, Et3N, and catalytic DMAP to afford
phosphine oxides 21–26 in good to excellent yields (Table
1). Deoxygenation was then performed as usual with
Table 1. Synthesis of ligands 4–9
Me Me
Me Me
Me Me
R
NH2
OH
1.
O
O
O
O
O
O
(EtO)3SiH
120 °C
O
O
Ti(Oi-Pr)4
CO2Et
N
N
2. MsCl
benzene
80 °C
PPh2
O
PPh2
O
PPh2
OH
DMAP, Et3N
CH2Cl2, 40 °C
R
R
AD-Mix-β
1. NaOEt
OH
CO2Et
MsNH2
EtOH, 78 °C
13
21-26
ligands 4-9
Yield (%)
CO2Et
t-BuOH, H2O
79%
2. Tf2O
2,6-lutidine
CH2Cl2
OTf
O
O
OTf
Aminoalcohol
Intermediate
Yield (%)
92
Ligand
98% ee
11
10
75% (2 steps)
i-Pr
NH2
21
4
45
54
27
50
Me Me
Me Me
OH
Ph2POH
O
O
O
O
22% Pd(OAc)2
-Pr
i
(MeO)2CMe2
22% dppp, i-Pr2NEt
NH2
OH
p -TsOH
CO2Et
22
91
84
66
5
CO2Et
acetone
99%
DMSO, 120 °C
99%
PPh2
OTf
12
O
-Bu
t
13
NH2
ent-23
24
ent-6
OH
Me Me
Me Me
NH2
1.
O
O
O
O
Me
Me
(EtO)3SiH
OH
NH2
OH
7
O
O
Ti(Oi-Pr)4
120 °C
N
N
2. MsCl
DMAP, Et3N
CH2Cl2, 40 °C
97%
benzene, 80 °C
55%
PPh2
PPh2
O
NH2
OH
25
26
84
57
8
9
45
65
1
14
Scheme 1.
Ph
Ph
NH2
OH
With this robust ligand synthesis in hand, several variants
of the ligand structure were prepared. Using previously

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S. Trudeau, J. P. Morken / Tetrahedron 62 (2006) 11470–11476
triethoxysilane and titanium(IV) isopropoxide in refluxing
benzene to yield target ligands 4–9. tert-Butyl substituted
ligand ent-6 was prepared starting from (S)-tert-leucinol,
but employed ent-13 as starting material.
The effectiveness of the StePHOX class of ligands was first
assessed by employing them in an enantioselective Pd-cata-
lyzed allylic alkylation reaction.11,12 The parent StePHOX
ligand 1 was examined first, using acetate 27 and dimethyl
malonate (Table 2). This ligand, which possesses chirality
solely on the backbone of the structure, provided the product
28 in 62% enantiomeric excess and favored the (S)-enantio-
mer. As can be seen in Table 1, replacement of the backbone
dioxolane methyl groups, with either hydrogen atoms or
ethyl groups (ligand 2 and 3), leads to a slight decrease in
enantioselection. In contrast to backbone modification, mod-
ification of the oxazoline group leads to much larger changes
in selectivity. While attachment of an a-configured substitu-
ent (ligand 4) leads to a only minor diminution in selectivity
(62/48% ee), when the ligand bears a b-substituent (ligand
5), a significant enhancement in enantioselection results
(62/97% ee). This enhancement appears to be maximal
with a b-isopropyl group, the corresponding ligand with
a tert-butyl substituent exhibits diminished selectivity. Since
ligand 5 exhibits significantly improved enantioselection,
whereas epimeric ligand 4 exhibits only a moderate diminu-
tion in selectivity relative to 1, it seemed reasonable to expect
enhanced selectivity with geminally substituted ligands.
Ligands 7–9 are all accessible from commercially available
inexpensive aminoalcohols and the selectivity rivals were
achieved with valinol derived 5.
Figure 3. X-ray structure of 1$PdCl2.
significant downfield shifting of the hydrogen atom relative
to the uncomplexed ligand structure in the H NMR spec-
1
trum (6.03/9.42 ppm, vide infra).14 The geminal methyl
groups on the dioxolane ring are directed underneath the pal-
ladium square plane suggesting that, while tuning these ele-
ments did not substantially alter the selectivity in the allylic
substitution reaction, they may have a significant impact on
stereoselection in other catalytic transformations. In a similar
fashion, elements attached to the oxazoline backbone and
phosphorus atom, appear well positioned to impact reaction
outcome.
On the basis of the X-ray analysis of 1$PdCl2 and the known
requirements for selectivity in allylic substitution with
PHOX complexes, it is not too surprising that ligand 1 does
not provide high selectivity. Seminal studies by Helmchen15
and Brown16 suggest that electronic differentiation of the
allylic termini in Pd–allyl complexes derived from P,N li-
gands, favors addition of nucleophiles to the carbon, which
is trans to phosphorus.17 Effective ligands are generally those
that perturb the ratio of endo/exo p-allyl palladium com-
plexes in favor of the exo isomer, and this ratio often deter-
mines the product enantioselection. In a symmetric allyl
fragment, such as the one used here, the ratio of exo/endo
isomer should dictate the ultimate ratio of product enantio-
mers.18 Since the pseudo equatorial phenyl group on phos-
phorus in ligand 1 nearly bisects the palladium square
plane, one would expect little bias in the conformer ratio
and therefore, little selectivity. It is more surprising that
ligand 4 does not lead to a selective reaction and clearly
more detailed structural studies are required to understand
these phenomena.
Table 2. StePHOX used in allylic substitution with compound 27
R3 R3
1.6% [(allyl)PdCl]2
4% ligand, KOAc
BSA, CH2Cl2
O
O
MeO2C
Ph
CO2Me
Ph
O
OAc
Ph
N
Ph
O
O
PPh2
R2
R1
ligand
27
28
MeO
OMe
Ligand
R1
R2
R3
Yield (%)
ee 28 (%)
1
2
3
4
H
H
H
H
i-Pr
H
H
H
i-Pr
H
Me
Et
H
Me
Me
Me
Me
Me
Me
64
71
58
61
88
71
80
86
79
62
48
58
46
5
ent-6
7
8
9
97
ꢁ79
t-Bu
Me
CH2CH2CH2CH2
Ph Ph
H
Me
89
95
75
To learn about the structure of the StePHOX ligands bound
to a transition metal center, parent structure StePHOX 1
was treated with (CH3CN)2PdCl2 and the resulting complex
was crystallized from CH2Cl2. As can be observed in X-ray
analysis depicted in Figure 3, the phosphine and oxazoline
occupy cis coordination sites on the palladium center with
the oxazoline ring oriented orthogonal to the palladium
square plane and roughly parallel to a pseudo axial phenyl
group on phosphorus.13 Notably, the benzylic hydrogen on
The significant enhancement in enantioselection that results
from a b-configured substituent versus an a-substituent
appears to arise from a difference in ligand conformation.
As mentioned above, when StePHOX 1 is coordinated to
PdCl2, the benzylic hydrogen is shifted downfield as a result
of an agostic interaction. This same agostic interaction is
present in the Pd complex of ligand 4, as determined by 1H
NMR analysis (Fig. 4). In contrast, when ligand 5 is treated
with PdCl2, a much smaller perturbation in the benzylic
hydrogen resonance is observed (6.13/7.67 ppm) thereby
˚
the ligand backbone resides 2.315 A from the palla-
dium atom. This example of preagostic bonding results in

S. Trudeau, J. P. Morken / Tetrahedron 62 (2006) 11470–11476
11473
(entries 3 and 4) and it is relatively inconsequential on the
a-face (entry 2). gem-Dialkyl substituted ligands 7 and 8
did not provide similarly high levels of selectivity as in the
allylic substitution described above.
H
Me
Me
P
P
N
N
Pd
O
H
O
H
Pd
Ha
Cl
Cl
Cl
Cl
Ha
O
O
O
O
Me
Me
Me
Me
3. Conclusion
4 PdCl
Ha 1H δ: 9.74 ppm
1 PdCl
•
•
2
2
Ha 1H δ: 9.42 ppm
In summary, we have designed and synthesized a new highly
tunable family of phosphine–oxazoline ligands that shows
good to excellent enantioselectivities (ee’s up to 97%) in
the Pd-catalyzed allylic substitution and good enantioselec-
tivities (ee’s up to 59%) in the asymmetric Tsuji allylation.
Current experiments are aiming to further improve the enan-
tioselectivity and to develop new applications of this class of
ligands.
Me
Me
H
O
P
N
P
N
O
H
Pd
Ha
Pd
Ha
Cl
Cl
Cl
Cl
H
O
O
O
O
Me
Me
Me
Me
5•PdCl2
Ha 1H δ: 7.67 ppm
8 PdCl
•
2
4. Experimental
Ha 1H δ: 9.38 ppm
Figure 4.
4.1. Synthesis of 10
Finely cut pieces of sodium (3.93 g, 0.17 mol) were added to
a cooled (0 ꢀC) solution of absolute EtOH (90 mL). The so-
lution was stirred and allowed to warm to room temperature.
A solution of coumarin (5.0 g in 47 mL, 34.2 mmol) was then
added. The resulting yellow mixture was stirred at reflux for
16 h, cooled to room temperature, and the mixture was then
concentrated under reduced pressure. A saturated aqueous
solution of NH4Cl (200 mL) was added to the crude reaction
mixture and it was extracted with EtOAc (3ꢂ100 mL). The
combined organic phase was dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was dissolved in 1/1 hexane/EtOAc (100 mL) and filtered
through a pad of silica gel and the filtrate was then concen-
trated under reduced pressure to give the desired product
(5.57 g) as an off-white solid. This material (4.15 g,
21.6 mmol) was dissolved in CH2Cl2 (70 mL) and 2,6-luti-
dine (3.8 mL, 32.4 mmol) was added. The solution was
cooled to ꢁ78 ꢀC and a solution of trifluoromethanesulfonic
anhydride (4.5 mL, 27.0 mmol) in CH2Cl2 (38 mL) was
added via canula. The reaction mixture was stirred for 0.5 h
at ꢁ78 ꢀC, 0.5 h at 0 ꢀC, and 2 h at room temperature. Satu-
rated aqueous NH4Cl (100 mL) was then added and the mix-
ture was extracted with CH2Cl2 (3ꢂ100 mL). The organic
layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (1/0 to 9/1 hexane/EtOAc) to give triflate 10
(8.28 g, 75% over two steps) as a yellow oil. IR (thin film,
suggesting that this hydrogen atom is in a different environ-
ment than in the corresponding complex of 1 and 4. On the
basis of the X-ray structure in Figure 3, one might expect
that with a b-configured isopropyl group, steric interactions
between the isopropyl group and the pseudo axial aryl ring
are likely too severe (see 5$PdCl2 representation, Fig. 4)
for the ligand to adopt the same conformation as StePHOX
1 or 4. Contrary to our expectations, ligand 8 exhibits agostic
bonding that is similar to 1 and 4 when coordinated to palla-
dium, yet exhibits selectivity comparable to ligand 5. It is
tenable that conformational similarities between 5 and 8 arise
in the context of a palladium allyl, but not in a palladium
dichloride complex.
To further examine the usefulness of the StePHOX ligand
class, the asymmetric Tsuji allylation was performed on
compound 29 (Table 3).19,20 The reactions were performed
by premixing the appropriate ligand with tris(dibenzylidene-
acetone)dipalladium and then adding compound 29. Com-
pound 30 was isolated in good to excellent yield. Although
the results with respect to enantioselectivity were less im-
pressive than the previous example, the ligands showed en-
couraging levels of asymmetric induction. Again, it appears
that substitution on the b-face of the ligand is important
Table 3. StePHOX used in Tsuji allylation with compound 29
1
n cmꢁ1): 2987, 1717, 1642, 1424, 1214, 1140. H NMR:
O
d 7.85 (1H, d, J¼16.0 Hz), 7.68 (1H, dd, J¼7.8, 1.7 Hz),
7.47–7.33 (3H, m), 6.48 (1H, d, J¼16.0 Hz), 4.26 (2H, q,
J¼7.1 Hz), 1.32 (3H, t, J¼7.1 Hz). 13C NMR: d 165.8,
147.6, 135.7, 131.5, 128.6, 128.2, 128.0, 122.6, 122.2, 117.0,
60.8, 14.1. MS (ESI) (M+H)+: 325.1. HRMS (ESI) (M+Na)+
calcd for C12H11F3O5SNa: 347.0171. Found: 347.0178.
O
O
Me
O
Me
2.5% Pd2(dba)3
8% ligand
THF
29
30
Entry
Ligand
Yield 30 (%)
ee 30 (%)
4.2. Synthesis of 11
1
2
3
4
5
6
1
4
95
97
94
86
98
80
5
22
To a stirred solution of triflate 10 (8.11 g, 25.0 mmol) in
t-BuOH (125 mL) and H2O (125 mL) were added methane-
sulfonamide (2.38 g, 25.0 mmol) and AD-mix-b (35 g).
The mixture was stirred at room temperature for 48 h and
5
ent-6
7
8
59
ꢁ58
29
30

11474
S. Trudeau, J. P. Morken / Tetrahedron 62 (2006) 11470–11476
then sodium sulfite (7.57 g, 60.0 mmol) was added. The
resulting mixture was stirred for 0.5 h and then H2O
(200 mL) was added. The mixture was extracted with
CH2Cl2 (3ꢂ150 mL). The combined organic phase was dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was recrystallized from hexane
(100 mL) to give the first crop of white needles (2.51 g).
The mother liquor was purified by flash chromatography
(9/1 to 0/1 hexane/EtOAc) to give the desired product
(5.8 g), which was recrystallized in hexane to give the second
crop of white needles (2.42 g). Mother liquor was recrystal-
lized a third time to give another crop of pure diol 11 (2.13 g,
total¼7.06 g, 79%). [a]D25 ꢁ10.5 (c 1.25, CHCl3). IR (thin
99%) as a yellow foam. [a]2D5 +33.7 (c 0.76, CHCl3). IR (thin
film, n cmꢁ1): 2989, 1756, 1437, 1194, 1104. 1H NMR: d 7.81
(1H, dd, J¼7.6, 3.9 Hz), 7.68–7.57 (5H, m), 7.54–7.39 (6H,
m), 7.28–7.24 (1H, m), 7.05 (1H, dd, J¼13.9, 7.7 Hz), 6.06
(1H, d, J¼7.3 Hz), 4.43 (1H, d, J¼7.7 Hz), 4.26–4.12 (2H,
m), 1.51 (3H, s), 1.26 (3H, s), 1.19 (3H, t, J¼7.1 Hz). 13C
NMR: d 169.0, 142.2 (d, JPC¼6.7 Hz), 133.3 (d, JPC
102.9 Hz), 132.8 (d, JPC¼12.4 Hz), 132.4 (d, JPC
¼
¼
104.5 Hz), 132.1 (d, JPC¼2.5 Hz), 131.9 (d, JPC¼9.6 Hz),
131.8 (d, JPC¼102.2 Hz), 131.5 (d, JPC¼2.7 Hz), 131.4 (d,
JPC¼9.8 Hz), 131.3 (d, JPC¼4.7 Hz), 128.8 (d, JPC¼9.5 Hz),
128.1 (d, JPC¼12.2 Hz), 127.5 (d, JPC¼12.4 Hz), 111.0, 81.7,
76.6 (d, JPC¼5.4 Hz), 60.9, 26.7, 25.1, 13.6. 31P NMR: d 32.9.
MS (ESI) (M+H)+: 451.0. HRMS (ESI) (M+H)+ calcd for
C26H28O5P: 451.1669. Found: 451.1672. (M+Na)+ calcd
for C26H27O5PNa: 473.1488. Found: 473.1491.
1
film, n cmꢁ1): 3398, 2989, 1740, 1424, 1214, 1140. H
NMR: d 7.71–7.69 (1H, m), 7.44–7.37 (2H, m), 7.31–7.28
(1H, m), 5.37 (1H, dd, J¼7.5, 2.4 Hz), 4.34 (1H, dd, J¼5.6,
2.5 Hz), 4.29 (2H, q, J¼7.2 Hz), 3.29 (1H, d, J¼5.6 Hz),
2.92 (1H, d, J¼7.5 Hz), 1.29 (3H, t, J¼7.2 Hz). 13C NMR:
d 172.2, 146.1, 133.0, 129.8, 129.3, 128.5, 121.1, 119.0,
73.1, 68.5, 62.6, 13.9. MS (ESI) (M+H)+: 359.1; (M+Na)+:
381.2. HRMS (ESI) (M+Na)+ calcd for C12H13F3O7SNa:
381.0226. Found: 381.0232. Chiral HPLC analysis per-
formed on Chiralcel OD-H, Daicel, 5% i-PrOH in hexane,
1.0 mL minꢁ1, wavelength: 220 nm.
4.5. Synthesis of 14
In a vial were added phosphine oxide 13 (1.95 g, 4.32 mmol)
and ethanolamine (1.31 mL, 21.6 mmol). Thevial was sealed
with a screw cap and heated in an oil bath at 120 ꢀC for 2 h.
The resulting orange solution was diluted with brine and ex-
tracted with EtOAc (2ꢂ10 mL) and then with CH2Cl2
(2ꢂ10 mL). The combined organic phase was dried over
MgSO4, filtered, and concentrated under reduced pressure.
The crude hydroxyamide (1.94 g, 97%) obtained was used
in the next step without further purification. To the hydroxy-
amide(1.91 g, 4.10 mmol)wereaddedCH2Cl2 (53 mL), Et3N
(1.14 mL, 8.21 mmol), and DMAP (5 mg, 0.04 mmol). The
solution was cooled to 0 ꢀC and methanesulfonyl chloride
(0.64 mL, 8.21 mmol) was then added dropwise. The result-
ing solution was stirred for 1 h at 0 ꢀC where TLC showed
complete disappearance of the starting material. Another
portion of Et3N (5.15 mL, 36.9 mmol) was then added and
the solution was stirred under reflux for 16 h. After cooling
the solution, saturated aqueous NH4Cl was added and the
mixture was extracted with CH2Cl2 (3ꢂ50 mL). The organic
phase was dried over MgSO4, filtered, and concentrated un-
der reduced pressure. The crude product was purified by flash
chromatography (1/1 to 0/1 hexane/EtOAc) to give oxazoline
14 (1.78 g, 97%) as a white foam. [a]2D5 +31.6 (c 0.34,
CHCl3). IR (thin film, n cmꢁ1): 3421, 3058, 2987, 2937,
1669, 1437, 1372, 1250, 1194. 1H NMR: d 7.79 (1H, dd, J¼
7.9, 4.0 Hz), 7.63–7.54 (5H, m), 7.52–7.46 (2H, m), 7.45–
7.38 (4H, m), 7.25–7.20 (1H, m), 7.00 (1H, ddd, J¼8.8,
8.2, 1.0 Hz), 6.07 (1H, d, J¼8.2 Hz), 4.55 (1H, d, J¼
8.2 Hz), 4.24–4.17 (2H, m), 3.78–3.63 (2H, m), 1.49 (3H,
s), 1.26 (3H, s). 13C NMR: d 164.1, 142.1 (d, JPC¼5.0 Hz),
133.0 (d, JPC¼94.3 Hz), 132.9 (d, JPC¼98.0 Hz), 132.4 (d,
4.3. Synthesis of 12
To a stirred solution of diol 11 (0.99 g, 2.76 mmol) in acetone
(5.3 mL) were added 2,2-dimethoxypropane (2.1 mL) and
p-toluenesulfonicacid (26 mg, 0.14 mmol). Thesolutionwas
stirred at room temperature for 16 h and then Et3N was added
to neutralize the acid and the solvent was then removed. The
crude product was extracted with Et2O (3ꢂ10 mL) and satu-
rated with aqueous NaHCO3. The combined organic phase
was dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (9/1 hexane/EtOAc) to give acetonide 12
(1.00 g, 91%) as a colorless oil. [a]2D5 ꢁ4.7 (c 1.35, CHCl3).
IR (thin film, n cmꢁ1): 2993, 2943, 1760, 1424, 1216,
1
1142. H NMR: d 7.68–7.65 (1H, m), 7.46–7.39 (2H, m),
7.32–7.30 (1H, m), 5.44 (1H, d, J¼7.6 Hz), 4.30 (1H, d,
J¼7.6 Hz), 4.20 (2H, tt, J¼14.3, 7.2 Hz), 1.60 (3H, s), 1.55
(3H, s), 1.22 (3H, t, J¼7.2 Hz). 13C NMR: d 169.3, 147.5,
130.3, 128.9, 128.8, 121.2, 120.1, 117.0, 112.2, 81.0, 74.5,
61.8, 26.8, 25.6, 13.8. MS (ESI) (M+H)+: 399.1. HRMS
(ESI) (M+Na)+ calcd for C15H17F3O7SNa: 421.0539. Found:
421.0548.
4.4. Synthesis of 13
To a stirred solution of acetonide 12 (1.32 g, 3.31 mmol)
in DMSO (66 mL) were added diphenylphosphine oxide
(1.43 g, 7.06 mmol), palladium(II) acetate (164 mg,
0.73 mmol), 1,3-bis(diphenylphosphino)propane (0.30 g,
0.73 mmol), and N,N-diisopropylethylamine (1.15 mL,
6.63 mmol). The orange solution was stirred at 120 ꢀC for
3 h. The resulting dark red mixture was then cooled to
room temperature and 5% aqueous HCl (400 mL) was added.
The mixture was extracted with CH2Cl2 (3ꢂ100 mL). The
combined organic phase was washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography
(1/1 hexane/EtOAc) to give phosphine oxide 13 (1.48 g,
JPC¼4.9 Hz), 132.2 (d, JPC¼100.2 Hz), 132.2 (d, JPC¼
9.6 Hz), 131.7 (d, JPC¼9.7 Hz), 131.6 (d, JPC¼3.2 Hz),
131.6 (d, JPC¼4.9 Hz), 129.3 (d, JPC¼9.6 Hz), 128.4 (d,
JPC¼5.1 Hz), 128.3 (d, JPC¼5.0 Hz), 127.8 (d, JPC
¼
12.6 Hz), 110.9, 78.9, 76.7, 67.9, 54.4, 26.9, 25.6. 31P NMR:
d 33.3. MS (ESI) (M+H)+: 448.0. HRMS (ESI) (M+H)+ calcd
for C26H27NO4P: 448.1672. Found: 448.1677. (M+Na)+
calcd for C26H26NO4PNa: 470.1492. Found: 470.1503.
4.6. Synthesis of 1
To a stirred solution of oxazoline 14 (0.56 g, 1.25 mmol)
in benzene (63 mL) were added triethoxysilane (1.25 mL,

S. Trudeau, J. P. Morken / Tetrahedron 62 (2006) 11470–11476
11475
7. Shawali, A. S.; Elanadouli, B. E.; Albar, H. A. Tetrahedron
1985, 41, 1877.
8. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
6.76 mmol) and titanium(IV) isopropoxide (0.20 mL,
0.69 mmol). The solution was stirred under reflux for 4 h.
More triethoxysilane (0.23 mL, 1.25 mmol) and titanium(IV)
isopropoxide (0.20 mL, 0.31 mmol) were added and the
black solution was stirred under reflux for 1 h. After cooling
to room temperature, the solvent was removed under reduced
pressure. The crude product was purified by flash chromato-
graphy (8/2 to 1/1 hexane/EtOAc) to give P,N-ligand 1
(0.26 g, 49%) as a white foam. The product was recrystal-
lized in hexane/Et2O to give white cubic crystals (0.18 g,
32%). [a]2D5 ꢁ39.0 (c 0.65, CHCl3). IR (thin film, n cmꢁ1):
ꢀ
ꢀ
ˇ
9. Vyskocil, S.; Smrcina, M.; Hanus, V.; Polasek, M.; Kocovsky,
´ˇ
ꢀ
P. J. Org. Chem. 1998, 63, 7738.
10. (a) Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1992, 57, 3751;
(b) Coumbe, T.; Lawrence, N. J.; Muhammad, F. Tetrahedron
Lett. 1994, 35, 625.
11. For reviews, see: (a) Trost, B. M.; Crawley, M. L. Chem. Rev.
2003, 103, 2921; (b) Pfaltz, A.; Lautens, M. Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, Chapter
24; (c) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996,
96, 395.
12. For recent examples of Pd-catalyzed allylic substitution, see:
(a) Lussem, B. J.; Gais, H.-J. J. Am. Chem. Soc. 2003, 125,
6066; (b) Hou, X.-L.; Sun, N. Org. Lett. 2004, 6, 4399; (c)
Lyle, M. P. A.; Narine, A. A.; Wilson, P. D. J. Org. Chem.
2004, 69, 5060; (d) Mancheno, O. G.; Priego, J.; Cabrera, S.;
Arrayas, R. G.; Llamas, T.; Carretero, J. C. J. Org. Chem.
2003, 68, 3679; (e) Zhao, D.; Ding, K. Org. Lett. 2003, 5,
1
3056, 2987, 1669, 1436, 1245, 1216, 1077. H NMR: d
7.68 (1H, dd, J¼6.9, 3.1 Hz), 7.41 (1H, td, J¼7.9, 1.2 Hz),
7.31–7.28 (6H, m), 7.26–7.15 (5H, m), 6.94 (1H, ddd,
J¼7.7, 4.1, 1.3 Hz), 6.15 (1H, t, J¼7.9 Hz), 4.52 (1H, d,
J¼8.3 Hz), 4.07–4.00 (1H, m), 3.94–3.87 (1H, m), 3.64–
3.55 (1H, m), 3.39–3.31 (1H, m), 1.59 (3H, s), 1.53 (3H, s).
13C NMR: d 164.0, 141.7 (d, JPC¼24.0 Hz), 137.2 (d, JPC
¼
11.3 Hz), 136.9 (d, JPC¼11.8 Hz), 136.0 (d, JPC¼17.1 Hz),
134.7 (d, JPC¼1.1 Hz), 133.6 (d, JPC¼17.6 Hz), 133.4 (d,
JPC¼16.7 Hz), 129.9, 128.8, 128.7, 128.5 (d, JPC¼7.1 Hz),
128.4, 128.3, 127.1 (d, JPC¼6.0 Hz), 111.0, 77.9 (d,
JPC¼148.1 Hz), 77.9 (d, JPC¼29.6 Hz), 67.9, 54.3, 27.1,
26.2. 31P NMR: d ꢁ17.7. MS (ESI) (M+H)+: 432.1. HRMS
(ESI) (M+H)+ calcd for C26H27NO3P: 432.1723. Found:
432.1726.
`
1349; (f) Pamies, O.; Montserrat, D.; Claver, C. J. Am.
Chem. Soc. 2005, 127, 3646.
13. Crystallographic data has been deposited in the Cambridge
Crystallographic Data Centre under deposition number
CCDC 292585.
14. As opposed to agostic interactions, which exhibit upfield shifts
in the 1H NMR (Brookhart, M.; Green, M. L. H. Prog. Inorg.
Chem. 1988, 36, 1), preagostic interactions can be character-
ized by a downfield shift. See: (a) Roe, D. M.; Bailey, P. M.;
Moseley, K.; Maitlis, P. M. J. Chem. Soc., Chem. Commun.
1972, 1273; (b) Albinati, A.; Anklin, C. G.; Ganazzoli, F.;
Ruegg, H.; Pregosin, P. S. Inorg. Chem. 1987, 26, 503; (c)
Albinati, A.; Arz, C.; Pregosin, P. S. Inorg. Chem. 1987, 26,
508; (d) Ablinati, A.; Pregosin, P. S.; Wombacher, F. Inorg.
Chem. 1990, 29, 1812; (e) Yao, W.; Eisenstein, O.; Crabtree,
R. H. Inorg. Chim. Acta 1997, 254, 105; For an excellent dis-
cussion of agostic, preagostic, and M–H hydrogen bonding,
see: Lewis, J. C.; Wu, J.; Bergman, R. G.; Ellman, J. A.
Organometallics 2005, 24, 5737.
Acknowledgements
This work was supported by the NIH (GM 64451). J.P.M. is
a fellow of the Alfred P. Sloan foundation. The authors thank
Dr. Peter White of the UNC X-ray analysis facility for assis-
tance with crystallography.
Supplementary data
The supplementary data associated with this article can
be found in the online version, at doi:10.1016/j.tet.2006.
05.043.
15. (a) Sprinz, J.; Kiefer, M.; Helmchen, G.; Huttner, G.; Walter,
O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523; (b)
Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew. Chem.,
Int. Ed. 1997, 36, 2108; (c) Kollmar, M.; Goldfuss, B.;
Reggelin, M.; Rominger, F.; Helmchen, G. Chem.—Eur. J.
2001, 7, 4913; (d) Kollmar, M.; Steinhagen, H.; Janssen,
References and notes
1. For a review of catalytic asymmetric reactions using PHOX
ligands, see: Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000,
33, 336.
´
J. P.; Goldfuss, B.; Malinovskaya, S. A.; Vazquez, J.;
Rominger, F.; Helmchen, G. Chem.—Eur. J. 2002, 8, 3103.
16. Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Tetrahedron 1994, 50,
4493.
17. Electronic differentiation of the allyl carbons was originally
observed by Faller in the context of Mo complexes: Faller,
J. K.; Chao, K. H.; Murray, H. H. Organometallics 1984, 3,
1231; For related studies with P,N ligands, see: Togni, A.;
Burckhardt, U.; Gramlich, V.; Pregosin, P. S.; Salzmann, R.
2. von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32,
566.
3. Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769.
4. Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J.
Tetrahedron Lett. 1993, 34, 3149.
5. Constantine, R. N.; Kim, N.; Bunt, R. C. Org. Lett. 2003, 5,
2279.
6. (a) Bolm, C.; Wenz, K.; Raabe, G. J. Organomet. Chem. 2002,
J. Am. Chem. Soc. 1996, 118, 1031; Blochl, P. E.; Togni, A.
662, 23; (b) Wiese, B.; Knuhl, G.; Flubacher, D.; Prieß, J. W.;
¨
¨
¨
Ulriksen, B.; Brodner, K.; Helmchen, G. Eur. J. Org. Chem.
Organometallics 1996, 15, 4125; For the effect of electroni-
cally unsymmetric diphosphines on the structure of allyl
complexes, see: Breutel, C.; Pregosin, P. S.; Salzmann, R.;
Togni, A. J. Am. Chem. Soc. 1994, 116, 4067.
2005, 3246; (c) Ogasawara, M.; Yoshida, K.; Kamei, H.;
Kato, K.; Uozumi, Y.; Hayashi, T. Tetrahedron: Asymmetry
1998, 9, 1779; (d) Gilbertson, S. R.; Chang, C.-W. T. Chem.
Commun. 1997, 975; (e) Geiser, F. M.; Helmchen, G. J. Org.
Chem. 2006, 71, 2486.
18. For a general discussion, see: (a) Helmchen, G.; Kudis, S.;
Sennhenn, P.; Steinhagen, H. Pure Appl. Chem. 1997, 69,

11476
S. Trudeau, J. P. Morken / Tetrahedron 62 (2006) 11470–11476
513; (b) Helmchen, G. J. Organomet. Chem. 1999, 576, 203;
´ ˆ
(c) Pretot, R.; Lloyd-Jones, G. C.; Pfaltz, A. Pure Appl.
Chem. 1998, 70, 1035.
Lett. 1983, 1325; (d) Shimizu, I.; Takahashi, K.; Minami, I.;
Tsuji, J. Tetrahedron Lett. 1984, 25, 1797.
20. For asymmetric Tsuji allylation, see: (a) Behanna, D. C.;
Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044; (b) Trost,
B. M.; Xu, J. J. Am. Chem. Soc. 2005, 12, 2846; (c) Trost,
B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 17180.
19. (a) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24,
1793; (b) Shimizu, I.; Minami, I.; Tsuji, J. Tetrahedron Lett.
1983, 24, 1797; (c) Tsuji, J.; Minami, I.; Shimizu, I. Chem.