REARRANGEMENTS IN NATURAL PRODUCT SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 251

CO 2 Me
CO 2 Me

CO 2 Me
CO 2 Me

1. DEA, reflux, 10 min
2. K 2 CO 3 , MeI
48%

30% aq. KOH/MeOH
reflux, 3 h
68%

O

H

OMe

H

CO 2 Me CO 2 Me

K 2 CO 3 , MeI
Acetone

DBU, MeI
76%

72%

OH OMe

H H

Clausine F Clausamine D

CO 2 H

HO

HO

OH

N
H

O O

O O

K 2 CO 3 , MeI
Acetone
77%

1. m- CPBA, CH 2 Cl 2 , 0 C to rt
2. aq. NaHCO 3

OH OMe

60% H N

H

Clausevatine D Clausamine C

SCHEME 8.15 Synthesis of clausamines C and D, clausine F, and clausevatine D.

Scheme 8.15. Hence, when the O -prenyl carbazole was refluxed in N , N -diethylaniline
(DEA) for 10min, the para -Claisen rearrangement took place to afford the corre-
sponding phenol that was subsequently converted to its methyl ether in 48% overall
yield. After demethoxycarbonylation, the key acid was esterified in the presence of
DBU and MeI to afford clausine F in 76% yield. The latter was then converted to
clausamine D by reaction with K 2 CO 3 and MeI. Clausevatine D, on the other hand,
was serendipitously obtained in 60% yield when the key acid derivative was treated
with m -CPBA, followed by a NaHCO 3 workup. Finally, methylation (K 2 CO 3 /MeI) of
clausevatine D led to clausamine C in 77% yield (Scheme 8.15).
The Eschenmoser-Claisen amide acetal rearrangement [83] has been used for
the synthesis of natural products such as ( )-ambrox [84], morphine [85], panicu-

lide [86], gelsemine [87] and aplysin, a halogenated sesquiterpene isolated from the
sea hare Aplysia kurodai , showing antifeedant properties to defend the host molluscs
from raptorial advances (Scheme 8.16) [88].
The Johnson orthoester Claisen rearrangement [89] has been used as a key step
in a number of synthetic sequences leading to various natural products, such as
( )- b -necrodol [90], the glycoprotein processing enzyme swainsonine [91], ( )-tubi-

foline [92], alkaloids geissoschizine and isositsirikine [93], ( þ )-arenarol [94],

( )-mesembranol [95], galanthamine (Scheme 8.17) [96,97], and velloziolide, a

diterpene isolated from the Brazilian plant Vellozia candida Mikan, showing an
unusual 9,11- seco -rosane skeleton whose biological activity remains to be explored
(Scheme 8.17) [98].
The Ireland-Claisen rearrangement is a [3,3]-sigmatropic rearrangement of a
O -trialkylsilylketene acetal to the corresponding g , d -unsaturated carboxylic acid [99].
Silylketene acetals are readily prepared by reacting a trimethylsilyl halide with a
lithium enolate generated from an allylic ester. The mild reaction conditions of the
Ireland-Claisen rearrangement compared to the normal Claisen rearrangement can