Chemistry Reference
In-Depth Information
Initial experiments were carried out with symmetric substrates (R
1
= R
2
) to avoid
problems with the regioselectivity. (
S
,
S
)
- BnCH
2
- PYBOX
(
L42a
) was used as chiral
ligand, which gave better selectivities compared with the commercially available
i
- Pr -
PYBOX
(
L42b
). Good yields and enantioselectivities were observed with a wide range
of allylic substrates and zinc nucleophiles (entries 1-5). In general, it was observed, that
the ee decreased with increase of the steric demand of the substituent. Thus, good ees
were obtained with linear, unbranched substituents, while a signifi cant drop in yield and
selectivity was observed for the diisopropyl derivative (entry 4). By far, the best selectiv-
ity was obtained with a 1,2,3-trisubstituted substrate (entry 5). This protocol can also be
applied to unsymmetrical substrates. Not surprising, the regioselectivity is only modest
for allylic substrates having two very similar alkyl substituents, but good regioselectivi-
ties (
20:1) were obtained where the substituents differ either sterically (entries 6 and
7) or electronically (entries 8-10).
Nucleophilic attack occurs preferentially at the sterically least hindered position and/
or the double bond that remains in conjugation to the electron-withdrawing group. This
new asymmetric cross-coupling approach was applied twice in the synthesis of fl uviruci-
nine A2 (Scheme 8B.48 ).
>
O
Cl
ZnBr
O
NiCl
2
•glyme
(5 mol %),
L42a
(5.5 mol %), NaCl,
DMA/DMF (1:1),
O
CO
2
Et
EtO
2
C
O
96% ee (93%)
−
10°C
1) H
2
, Pd/C
2) LiAlH
4
3) PPh
3
PBr
2
Et
CO
2
Et
O
Zn, I
2
Cl
O
NiCl
2
•glyme (5 mol %),
L42a
(5.5 mol %), NaCl,
DMA/DMF (1:1),
O
Br
O
−
10°C
CO
2
Et
>98% ee (93%)
89%
OH
O
NH
Fluvirucinine A
1
58%
Scheme 8B.48.
Synthesis of fl uvirucinine A
2
via enantioselective Negishi coupling.
