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M. Raghunath, X. Zhang / Tetrahedron Letters 46 (2005) 8213–8216
transformations.5 The sp2–sp2 rotation in these chiral
biaryl ligands causes only a small energy change within
a wide range of bite angles with transition metals. While
these ligands have been proven effective, sometimes they
are not efficient for certain substrates due to lack of
ligand rigidity. To overcome this drawback, prior work
in our group focused on introducing a bridge with
variable length tolink the diaryl groups, such that the
new ligands are rigid with tunable bite angles. The
resulting family of Cn-TunePhos was produced with
n = 1–6 ligands.6 The dihedral angle of the series was
calculated with CAChe7 MM2 calculations and is listed
(Fig. 1). Based on its structural features, it was postu-
lated that the Cn-TunePhos ligands would be less flexible
than BINAP as their sp2–sp2 bond rotation is restricted.
The ligands were put to test for the well-known Ru-cat-
alyzed asymmetric hydrogenation of b-ketoesters. The
results demonstrated the influence of ligand dihedral
angle upon % ee, with the maximum enantioselectivity
obtained with C4-TunePhos.6 The current work is an
extension toward studying the influence of ligand dihe-
dral angle on C–C bond formation reactions, such as
Pd-catalyzed asymmetric allylic alkylations (AAA)8
and asymmetric cycloadditions.9
chiral pocket-type ligands described by Trost, the
concept of ꢀbuttressing effectꢁ of ligands is invoked to
explain the trend in enantioselectivity.
Our next goal was to extend the scope of Cn-TunePhos
ligands tomroe challenging substrates. Butadiene
monoepoxide 4 is an inexpensive four-carbon building
block and has been extensively used toward several
natural product syntheses.12 We were interested in the
reaction of 4 with phthalimide 5 under the catalysis of
Pd/Cn-TunePhos. Under the conditions mentioned by
Trost et al.,13 catalyst formed in situ from 1 mol % of
[(p-allyl)PdCl]2 and 2.2 mol % chiral ligand in CH2Cl2
with Na2CO3 as base afforded the product 6 in 67–
90% yields and low % eeꢁs (Table 2, entries 2–7). Switch-
ing toTHF as reaction solvent significantly improved
the % ee with a maximum of 82% for C4-TunePhos
(Table 2, entries 9–14).
Further optimization with varying reaction temperature
was done with C4-TunePhos, which gave higher enantio-
selectivity at the cost of lower yields (Table 3, entry 3 vs
entry 4). The reaction yields and % eeꢁs could not be
improved significantly by altering other reaction para-
meters such as base or Pd(0)-precursors or additives.
Mechanistically, the Pd-catalyzed AAA is one of the
best studied asymmetric C–C bond forming reactions.10
We first chose the reaction of 1,3-diphenylpropenyl ace-
tate 1 with dimethyl malonate 2, the standard test reac-
tion for asymmetric allylation chemistry (Table 1).
Under the standard conditions: catalyst formed in situ
from 2 mol % of [(p-allyl)PdCl]2 and 5 mol % chiral
ligand; a mixture of N,O-bis(trimethylsilyl)acetamide
(BSA) and catalytic amounts of KOAc (5%), the prod-
uct 3 was afforded in high yields. THF solvent and
BSA/KOAc was discovered as the optimum reaction
condition and all the Cn-TunePhos ligands were
screened. As observed from the results, C6-TunePhos
gave the best result (Table 1, entry 6). This result showed
an alignment of the enantioselectivity with the increas-
ing ligand dihedral angle. Further optimization studies
were not included due to the simplicity of this substrate
and it sufficed to demonstrate the effectiveness of Cn-
TunePhos ligands for AAA reaction. It is to be noted
that our results of dihedral angle correlation sharply
contrast the results obtained by Trost et al.11 For the
Having achieved a modest success with Pd-catalyzed
AAA reaction of butadiene monoepoxide 4, we wished
to explore this substrate for asymmetric cycloadditions
with heterocumulenes viz. phenyl isocyanate 7 and
diphenyl carbodiimide 8. Both these reactions have been
well studied by Alper et al.9 and once again, our goal
was toevaluate the C -TunePhos ligandsꢁ performance
n
(Table 4). In the case of cycloadditions of heterocumu-
lenes, Pd2(dba)3ÆCHCl3 precursor and THF solvent were
better choices. It was found that the enantioselectivities
were highly substrate dependent. The C4-TunePhos
worked best for phenyl isocyanate, while C1-TunePhos
worked the best for carbodiimide 8 substrate. As
evidenced in Table 4, for most parts, the Cn-TunePhos
seem to give good yields and enantioselectivities.
In bisphosphine ligands like those developed by Trost
et al.,14 the depth of such pockets correlates with the
(P–Pd–P) bite angle. Larger the bite angle, deeper the
pocket, better is the enantioselectivity of product. In
Table 1. Cn-TunePhos ligands for AAA of the standard substrate 1
MeO C
CO Me
2
2
OAc
Ph
2.5 mol% [Pd (allyl) Cl ] ; 5 mol% ligand
2
MeO C
CO Me
2
2
+
Ph
Ph
Ph
BSA; KOAc; CH Cl ; RT; 12 hrs
2
2
2
3
1
Entry
Ligand
% Yielda
% eeb
1
2
3
4
5
6
C1-TunePhos
C2-TunePhos
C3-TunePhos
C4-TunePhos
C5-TunePhos
C6-TunePhos
89
86
90
91
91
90
77
82
84
87
92
95
a Isolated yields.
b Determined by chiral HPLC.
Raghunath, Malati
