Chemistry Reference
In-Depth Information
which led to the reduction of the complex rather than alkylation. Addition of HMPA
completely suppressed the reduction and gave rise to the alkylation product, although
not the expected one. Instead of the standard alkylation product, a
- unsaturated ester,
a cyclopropyl derivative was obtained, resulting from an attack of the enolate at the
central position of the
γ
,
δ
-allyl complex (cf. Scheme 8B.1). The mechanism of this unusual
reaction was investigated by Hoffmann et al. [161]. They were able to isolate and char-
acterize an intermediate palladacycle [162].
The reaction of silyl ketene acetals with allylic acetates was investigated by Musco,
Santi, and others [163]. They used chelating phosphine ligands and obtained mainly the
π
-allylation product. Attack at the central position was also observed. In both cases,
nucleophilic attack occurred from the face opposite to the palladium. Malacria et al.
reported on ester enolate alkylations with vinyl epoxides [164]. In these cases, nucleo-
philic attack occurred at the sterically less hindered position, and
E
/
Z
mixtures of sub-
stitution products were generally obtained.
An early application of chiral ligands to control the allylation of zinc enolates was
described by Moorlag et al. in 1992 [165]. The dioxolane derivative of racemic mandelic
acid was deprotonated with LHMDS and the lithium enolate transmetallated to the zinc
enolate. Allylic alkylation in the presence of
CHIRAPHOS
(
L34
) gave the product with
33% ee (Scheme 8B.38). Other ligands and protecting groups gave even less satisfactory
results.
α
Ph
Ph
O
O
Ph
OZnCl
H
3
C
CH
3
OAc
OO
LHMDS
ZnCl
2
OO
OO
Ph
2
P
PPh
2
Pd(dba)
2
,
(
R
,
R
)-
CHIRAPHOS
(
L34
)
(
R
,
R
)-
L34
33% ee (67%)
Scheme 8B.38.
Asymmetric allylic alkylation of zinc enolates.
A breakthrough was the introduction of chelated amino acid ester enolates (cf.
Scheme 8B.39) by Kazmaier and Zumpe in 1999 [166]. Chelation not only results in an
enhancement of the thermal stability of these enolates, it also diminishes the tendency
of the enolate to coordinate to the palladium. The allylation already takes place under
very mild conditions at −78°C as a result of the high reactivity of these metal enolates.
Under these conditions, isomerization processes such as π - σ - π isomerizations can be
suppressed completely [27,167]. Asymmetric allylations have been carried out by using
substrate control with chiral allylic substrates [168] or by incorporating the chelate
enolate into a chiral peptide chain [169].
In 2002, Helmchen et al. reported the fi rst asymmetric allylation of these enolates in
the presence of chiral ligands [170]. As ligands phosphinoxazoline
L14a
, which is particu-
larly suited for acyclic substrates, as well as the cymantrene derivative
L14c
, which
proved superior for cyclic substrates, were used (Fig. 8B.16). High levels of selectivity
were achieved with 1,3-diphenylacetate as substrate, and recrystallization of the crude
product provided the enantio- and diastereomerically pure amino acid derivative. Allylic
alkylations of cyclic substrates such as cyclohexenyl acetate gave a nearly 1:1 mixture of
diastereomers with ees around 80% (Scheme 8B.39).
