Biomedical Engineering Reference
In-Depth Information
Toluene
Sealed tube
190°C, 3.5 h
CN
BnO
N
BnO
CN
N
- PhCH=CH
2
O
O
Ph
306
305
80%
steps
BnO
N
H
HO
N
CN
O
H
H
(-)-Histrionicotoxin
308
307
SCHEME 9.53
Synthesis of histrionicotoxin (
308
) by Holmes and coworkers.
Boger and coworkers developed a domino Diels-Alder/retro/normal-[3
þ
2]-
dipolar cycloaddition reaction of
314
in their asymmetric synthesis of vindoline (
318
),
vindorosine
)
was isolated as the major alkaloid from
Catharanthus roseus
and constitutes the
lower half of vinblastine. Vinblastine and the structurally related vincristine are very
important anticancer agents, especially vincristine that allows the treatment of acute
leukemia of children with a success rate of over 60%. It can be assumed that
compounds
319
, and key vinblastine analogues (Scheme 9.55) [122]. Vindoline (
318
are intermediates in this domino process in which four
C-C bonds, three rings, and six new stereogenic centers are formed (Scheme 9.55).
The chiral substituent on the dienophile tether effectively controls the facial selectivity
of
315
and
316
þ
2]-cycloaddition reaction, preferring that the protected
hydroxymethyl group at C7 and the C5 ethyl group reside
trans
to one another on
the newly formed five-membered ring. This orientation avoids a steric interaction
on the more congested concave face in the transition state, leading to the initial
the initiating [4
Ph
O
OR
O
N
O
310
O
Si
NO
2
H
Si
O
i
-Pr
i
-Pr
i
-Pr
i
-Pr
309
311
OH
O
OR
O
N
steps
N
HO
H
Si
O
H
i
-Pr
HO
OH
i
-Pr
(+)-1-
epi
-Australine
313
312
SCHEME 9.54
Synthesis of 1-
epi
-australine
313
by Denmark and coworkers.
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