REARRANGEMENTS IN NATURAL PRODUCT SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 250

eventually gave the corresponding bromidewhichwas converted to the corresponding
selenide derivative under standard conditions. The next steps involved the conden-
sation of this selenide with an enantiomerically pure b -hydroxy acid to afford the
dioxanone, as well as a Petasis-Ferrier rearrangement [7] to provide the desired
tetrahydropyranone in 42-46% yield for three steps. The end of the synthesis
proceeded via various key intermediates, in particular the methyl ester and the allylic
chloride shown in Scheme 8.13.

8.3. THE CLAISEN REARRANGEMENT

The Claisen rearrangement is a thermal [3,3]-sigmatropic rearrangement of an allyl
vinyl ether to the corresponding g , d -unsaturated carbonyl product (Scheme 8.14) [4].
From a mechanistic point of view, the Claisen rearrangement is a suprafacial
concerted [3,3]-sigmatropic rearrangement with activation parameters that suggest
a very constrained transition state [55] in which the stereochemical information in
the precursor is transferred from the double bond to the newly formed s -bond
implementing an early six-membered chair-like transition state [56].
The Claisen rearrangement of allyl vinyl ethers has been used in the total
synthesis of a number of natural products including acetoxycrenulide [57],
sesquiterpene þ

ceratopicanol [58], ( )-cassiol [59], cytotoxic diterpenoid

( )-sclerophytin [60], sesquiterpene cyclomyltaylane-5 a -ol [61], pancratistatin [62],

both enantiomers of labdane-derived diterpene saudin [63], nerylgeraniol-18-oic
acid [64], and alkaloid mesembrine [65].
The original Claisen rearrangement has also been extended to a number of
substrates bearing a variety of substituents on their basic framework, leading to the
emergence of the aromatic Claisen rearrangement, the Eschenmoser-Claisen
amide acetal rearrangement, the Johnson orthoester Claisen rearrangement, or the
Ireland-Claisen rearrangement. The aromatic Claisen rearrangement of allyl phenyl
ethers is a simple and efficient entry to ortho -allylphenols [66] (Scheme 8.14). It was
actually used in the synthesis of salfredin B 11 [67], nebivolol [68], subelliptenone
F [69], neurotrophic illicinones [70], potent phytoestrogens 8-prenylnaringenin and
6-(1,1-dimethylallyl)naringenin [71], ( )-debromoaplysin [72],

coumarin trachypleuranin-A [73], prenylated flavonoid lupiwighteone [74], alkaloid
(

)-aplysin and (

)-pseudophrynaminol [75], carpanone [76], suberosin and toddaculin [77,78],
neolignans usiderin K and J [79], hongconin [80], and deliquinone [81].
Carbazole alkaloids such as clausamines C and D, clausine F, and clausevatine D
belong to a well-known class of secondary metabolites of plant origin showing
interesting activities against different cancer cell lines. These compounds have recently
been synthesized [82] using an ester-driven para -Claisen rearrangement as shown in

Heat
or
Lewis acid
[3,3]

O OH

heat
[3,3]

O O

Allyl phenyl ether ortho -allylphenol

SCHEME 8.14 Claisen rearrangement.