Biomedical Engineering Reference
In-Depth Information
O
TfO
O
TBS
steps
OTf
O
1
O
2
TMSCH
2
ZnBr
Pd(PPh
3
)
4
23°C, 18 h
92%
H
O
OH
TMS
1. MeAlCl
2
, CH
2
Cl
2
-94°C, 15 min
2. TBAF, 1 h
TMS
63%
HO
H
O
(+)-Onocerin
4
3
SCHEME 9.1
Synthesis of (
þ
)-onocerin
(4)
by Corey and coworkers.
of this [6,6,6,6,6]-membered ring systemwas part of a total synthesis of the antitumor
marine natural product (
[5]. Hence, treating the enantiopure
aldehyde
5
with a specific concentration of methanesulfonic acid facilitated a
cyclization through the acyliminium ion
)-cribrostatin 4
(11)
6
that in turn formed the intermediate
enamine
7
. A second higher conjugated acyliminium ion
8
was then produced from
compound
-elimination. Following the formation of this aforementioned
intermediate, an intramolecular cyclization through either of the two available
aromatic C-H positions on the benzyl tether provided a 3.4:1 mixture of the two
regioisomers
7
through
b
. Interestingly, the concentration
of MeSO
3
H was vital to the observed selectivity. Compound
9
and
10
in favor of the desired isomer
9
9
was eventually taken
through to the target cribrostatin 4
11
, the overall yield of the total synthesis being
4.3% after 21 steps (Scheme 9.2).
In 2009, Nicolaou and coworkers devised a domino epoxide ring-opening/Diels-
Alder reaction in the total synthesis of hirsutellone B
[6]. This target natural product
isolated from a pathogenic fungus
Hirsutella nivea
BCC 2594 has exceptional activity
in
Mycobacterium tuberculosis
inhibitory assays. In the formation of [6,5,6]-fused
tricyclic core of hirsutellone B, the enantiopure epoxide
16
generated through
a Jørgensen asymmetric epoxidation [7] was activated to further nucleophilic
substitution upon treatment with the Lewis acid Et
2
AlCl. In this series of reactions
(Scheme 9.3), the resulting tetraene
12
14
was appropriately set up for an intramolecular
15
12
Diels-Alder reaction to give
(50% yield from
). This enantiopure tricyclic ring
(16)
system was then taken through to hirsutellone B
following the formation of a
14-membered macrocyclic sulfone and a Ramberg-Backlund-based ring contraction
to afford the desired 13-membered macrocycle (Scheme 9.3).
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