Biomedical Engineering Reference
In-Depth Information
O
SO
2
Ph
OMOM
O
5 steps
52%
6 steps
54%
TBDPSO
OMe
O
OTBDPS
H
HO
131
132
OMOM
OMOM
TBDPSO
TBDPSO
LiAlH
4
(5 equiv)
LiI (10 equiv)
12
12
L
-Selectride
I
I
5 steps
29%
5 steps
38%
O
O
(12
S
)-
133
(12
R
)-
134
1. Zn/Cu couple
TMSCl/Tol/DMA
rt then 50°C
1. Zn/Cu couple
TMSCl/Tol/DMA
rt then 50°C
2. Pd
2
dba
3
(3 mol%)
P(2-Furyl)
3
(6 mol%)
135
, toluene, rt
Cl
O
64%
137:138
= 3:2
40-50%
2. Pd
2
dba
3
(3 mol%)
P(2-Furyl)
3
(6 mol%)
, toluene, rt
O
O
135
OMOM
OMOM
OMOM
TBDPSO
TBDPSO
TBDPSO
6 steps
Amphidinolide T1
127
(19%)
or
Amphidinolide T4
129
(29%)
O
O
+
O
O
O
O
O
O
O
O
Epimerization
O
O
136
Amphidinolide T5
130
138
(dr = 8:3)
137
5 steps
21%
Amphidinolide T3
128
SCHEME 2.36
Synthetic pathway to amphidolidines T.
The acyl-Negishi coupling between (12
S
)-
133
and acyl chloride
135
afforded
the desired ketone
136
in a satisfying yield (40-50%), together with dehalogenated
(12
S
)-
(20-30%). Any attempt to carry out the reaction using other nucleophiles
instead of zinc reagents, other Pd(0) catalyst/ligand combinations, the use of CoBr
2
or
(PPh
3
)Rh(CO)Cl as the catalysts instead of Pd(0), or even activating the coupling
by transmetalation of the organozinc reagent with copper (CuCN
133
2LiCl, PhSCuLi,
CuBr
2LiCl) were unsuccessful, showing
that the reaction was one of the most advanced examples of the acyl-Negishi coupling.
Ketone
Me
2
S) or manganese salts (MnI
2
or MnCl
2
136
was used as a common intermediate to construct both
amphidinolines T1
127
and T4
129
, while amphidinoline T5
130
was obtained by
epimerization at C14 of amphidinoline T4
[71] (Scheme 2.36).
Surprisingly, the acyl-Negishi reaction starting from the iodinated alcohol
(12
R
)-
129
was sensitive to the inversion of the configuration of the remote stereogenic
center C12 and led to the formation of the desired ketone
134
137
, together with its
isomeric rearranged by-product
138
in 64%yield (
137
/
138¼
3:2), along with a minor
amount of the dehalogenated (12
R
)-
134
. The plausible mechanism [66] for the
synthesis of compound
138
evokes two competitive pathways, starting from a
common radical ion
issued from a single electron transfer (SET) process mediated
by the zinc/copper couple. If iodide is expelled before the second SET takes place, the
primary carbon radical
A
C
formed is in close vicinity with the anomeric hydrogen atom
of the tetrahydrofuran ring and can abstract it generating intermediate
D
via a 1,6-H
shift process. The 5-
exo
-trig cyclization delivers a radical species
E
that can react in a
new SET process to afford the organozinc reagent
G
that undergoes the acyl-Negishi
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