Biomedical Engineering Reference
In-Depth Information
O
OH
Negishi coupling
O
Me
Me
Me
Me
OH
Me
NH
Scyphostatin
68
O
Me
Me
Me
Me
O
OH
Me
Cl
+
O
O
OH
NH
2
Me
Me
Me
Me
Me
Me
Me
Me
BnO
OTBDPS
BnO
+
I
OTBDPS
I
69
70
71
SCHEME 2.27
Retrosynthesis of scyphostatin
68
.
3 equiv of
t-
BuLi with ZnCl
2
(1 equiv) to generate the mixed zinc reagent
72
was
successful, and the coupling with vinyliodide
70
under classical conditions with
Pd(PPh
3
)
4
(10 mol%) afforded
69
in 84% yield (Scheme 2.28).
Vinyl iodide
70
was prepared by hydrozirconation/iodination of alkyne
73
. This
as a 87:13 mixture (determined by
1
H NMR) of regioisomers that
were not separated but used as a mixture in the Negishi coupling as the more hindered
minor regioisomer did not react and was recovered unchanged after the coupling.
While in the synthesis of Katoh and coworkers [27,28] protected diol
method yielded
70
was
chosen as a key intermediate, Negishi and coworkers [29] considered the more
elaborate molecule
69
80
, where the terminal ethyl group is already present in the
structure (Scheme 2.29). Two Negishi couplings were used in the synthesis of
80
.
The first one consisted of transforming iodide
into the corresponding zinc
derivative using a
t
-BuLi/ZnCl
2
mixture (3:1 ratio). The latter was coupled to vinyl
bromide in the presence of a palladium catalyst to afford alkene
74
. A zirconium-
catalyzed asymmetric carboalumination (ZACA) [3] performed with trimethyl-
aluminum in the presence of the chiral catalyst
75
76
followed by an oxidation then
provided
, which
in turn was transformed into the corresponding organozinc species using the same
procedure as described previously, and coupled with vinyl iodide
77
as a single enantiomer. The latter was then converted to iodide
78
79
to afford
80
.
Me
Me
Me
Me
t
-BuLi, ZnCl
2
I
OTBDPS
Zn
OTBDPS
t-
Bu
Et
2
0
71
72
Me
Me
Me
Pd(PPh
3
)
4
(10 mol%)
THF
84%
1. Cp
2
ZrHCl
BnO
BnO
I
2. I
2
73
70
Me
70%
Me
Me
Me
Me
BnO
OTBDPS
69
SCHEME 2.28
Preparation of intermediate
69
.
Search WWH ::
Custom Search