Biomedical Engineering Reference
In-Depth Information
9.4. RADICAL DOMINO REACTIONS
The endoperoxide moiety of the antimalarial natural product yingzhaosu A (
) was
prepared by Bachi and coworkers via a domino-based approach [100]. In their total
synthesis, an early preparation of the 2,3-dioxabicyclo[3.3.1]nonane system was
achieved through the treatment of the chiral pool starting material (
S
)-limonene (
259
)
with oxygen, thiophenol, and AIBN (Scheme 9.43) [101]. In this process, the
proposed main reaction sequence involves initial reaction with thiophenol radical
to the intermediate
252
253
, which is in turn trapped with molecular oxygen to afford
peroxy radical
. This intermediate then undergoes a 6-
exo
-intramolecular addition
to form the endoperoxide and then a tertiary carbon-centred radical that reacts with a
second equivalent of oxygen to provide radical
254
. The reaction is then quenched
in situ
by treatment with the thiophenol present in the reaction mixture to afford
256
257
as two diastereomers in a 55:45 ratio. Reduction of the hydroperoxide moiety with
triphenyl phosphane led to compound
. The yield for this process, in which five
new bonds are created, is 50%. The major diastereomer
258
258
is then taken through to
the yingzhaosu A (
) with an overall yield of 7.3%; the synthesis can also be carried
out on a larger scale (Scheme 9.43).
The natural product (
259
264
) is an anticancer agent
currently in clinical use. This drug isolated from some
Podophyllum
genus of
plant is thought to elicit its activity through tubulin-binding and antimitotic
activities. Sherburn and coworkers first prepared the aryl tetrahydronaphthalene
lactone skeleton through a radical/radical cyclization approach by treating thio-
carbonate
)-podophyllotoxin (
with tris(trimethylsilyl)silane and AIBN (Scheme 9.44) [102]. The
intermediate radical
260
initially formed then undergoes two sequential cyclizations
and C-C bond forming steps to the second radical intermediate
261
262
, which upon
PhSH, O
2
AIBN, hv
CH
3
CN
O
PhS
PhS
O
PhS
O
O
252
253
254
255
O
OH
OH
O
O
PPh
3
PhSH
50% (2 steps)
O
O
O
PhS
PhS
PhS
O
O
O
258
256
257
(dr = 55:45)
HO
O
O
Yingzhaosu A
259
SCHEME 9.43
Synthesis of yingzhaosu A
259
by Bachi and coworkers.
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