Chemistry Reference
In-Depth Information
NHBoc
NH
2
O
I
2
, AgO
2
CCF
3
O
Boc
2
O, NaOH
O
O
9.160
9.161
HCl, Br
2
, AcOH
Ts O
NHBoc
NH
2
O
CF
3
CO
2
H
O
Bu
4
NI
9.16
4
AcO
O
O
I
X
9
1
9
1
N
N
O
O
Pd(PPh
3
)
4
TMG, <50 °C
X = Br
O
O
Br
X
L
2
Pd
9
1
9
1
AcO
Herrmann's catalyst
Bu
4
NOAc,
Δ
O
N
N
O
O
H
O
Br
9
1
6
9
1
Scheme 9.48
product
9.154
could be selectively
N
-deformylated. Hydroboration, followed by Suzuki coupling then in-
stalled the Michael acceptor. Treatment of the Suzuki product
9.155
with KO
t
-Bu at low temperature
gave the
trans
pyrrolidine
9.156
. The two side chains could then be separately extended using the Wit-
tig reaction in each case. Palladium-catalysed hydrogenation of the double Wittig product
9.158
then un-
leashed a tandem sequence of double alkene reduction,
N
-deprotection and reductive amination to give the
alkaloid
9.150
.
9.2.5 Synthesis Using Palladium Allyl Chemistry
An intramolecular allylation was employed in a synthesis of cephalotaxine
9.168
(Scheme 9.48).
63
The
benzene ring of the starting amine
9.160
was halogenated - this process requires that the nitrogen be
protected or, in the case of bromination, protonated. The halogenation was not straightforward. The substrate
would appear to be electron rich due to the oxygen substituents on the ring, but they are poor donors as
they are sp
3
-hybridized. To fully donate their lone pairs into the ring, they would have to be sp
2
-hybridized,
but the resulting 120
◦
bond angles would impose too much strain. The halogenated amine
9.163
was then
alkylated with tosylate
9.164
to install the allylic acetate moiety. Allylic alkylation only worked using the
bromide substrate
9.165
(X
I, the palladium is not selective for the
allylic acetate, leading to side products. With the less-reactive bromo compound, the palladium selectively
attacks at the allylic acetate. The resulting
=
Br). It seems likely that, with X
=
-allyl palladium complex
9.166
is then attacked by nitrogen at
the nearer (“proximal”) terminus, giving the spirocyclic amine
9.167
. The geometry of the ring formation
overcomes the usual preference for attack at the less-hindered terminus. With the second five-membered ring
