Biomedical Engineering Reference
In-Depth Information
R
2
R
1
R
2
N
CHO
H
CO
2
H
R
1
N
Ts
Et
3
N, DMF, reflux
N
Ts
218a
(R
1
= H)
218b
(R
1
= Br)
219a
(R
1
= H; R
2
= Bn; 75%)
219b
(R
1
= H; R
2
= PMB; 88%)
219c
(R
1
= Br; R
2
= Bn; 81%)
219d
(R
1
= Br; R
2
= PMB; 83%)
Pd(OAc)
2
PPh
3
, MeOH
CO, NaOAc
DMF
R
2
HN
N
MeO
2
C
Pd(OH)
2
, H
2
MeO
2
C
MeOH/HCl
N
Ts
N
Ts
78-80%
221
220a
(R
2
= Bn; 95%)
220b
(R
2
= PMB; 97%)
SCHEME 13.44
hexamethyldisilazane (HMDS) afforded cycloadduct
217
in 25% yield but as a
single diastereomer. Hydrogenolysis of the benzyl group followed by Pictet-Spengler
ring closure furnished
-lycorane in 40% yield from
217
.
Snider
et al.
[80] and Lovely
et al.
[81,82] simultaneously published similar
approaches tomartinellic acid using a [3
a
2]-cycloaddition as the key step. In Lovely's
early experiments, it was discovered that
218a
reacted with several
N
-alkyl glycine
derivatives to give the pyrroloquinoline structures
219a
and
219b
in 75% and 88%
yields, respectively, and as single diastereomers (Scheme 13.44). Encouraged by these
results,
218b
was examined and found to give
219c
and
219d
in 81% and 83% yields,
respectively, again as single diastereomers. Bromides
219c
and
219d
were then
subjected to a palladium-mediated carbonylation to furnish
220a
and
220b
in 95%
and 97% yields, respectively. Finally, hydrogenolysis of the nitrogen protecting group
in
220a
or
220b
using Pearlman's catalyst gave
221
in 86% and 78% yields.
The nature of the protecting group on the glycine reaction partner does not
appear to affect the yield or selectivity of the cycloaddition. The arrangement of
substituents on the aniline nitrogen, however, was found to have a profound
influence. For example, when
222a
was reacted with the same glycine derivatives,
no cycloadduct was obtained; rather, conjugate addition predominated
(Scheme 13.45) [83]. Aldehyde
222b
, however, reacted with
N
-benzyl glycine to
give a mixture containing elimination product
223
in 16% yield and cycloadduct
224
in 7% yield, as well as the desired cycloadduct
225
in 51% yield. Elaboration of the
piperidine ring, installation of a carbomethoxy group on the aromatic ring, and
removal of protecting groups gave
226
. As tricyclic amine
226
had previously been
transformed into both martinelline
227a
and martinellic acid
227b
, this constitutes a
formal total synthesis of these two alkaloids.
รพ
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