REARRANGEMENTS IN NATURAL PRODUCT SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 242

For each one of these selected types of rearrangements, we will briefly describe
the origin, the importance in the field, the mechanism involved, and various synthetic
applications, showing with recent examples described in the current literature how
these transformations have been used as key steps in the synthesis of relevant natural
products.

8.2. THE COPE AND OXY-COPE REARRANGEMENTS

8.2.1. The Cope Rearrangement
The Cope rearrangement [4] is a reversible, thermal [3,3]-sigmatropic rearrangement
of 1,5-dienes producing preferentially highly substituted olefins (Scheme 8.1).
A review focused on the evolution of the accepted mechanism of the Cope
sigmatropic rearrangement was reported in 1995 [11a], and a number of papers have
been published dealing with different aspects of the mechanism [11b,c]. Since the
pioneering work of Doering and Roth, the Cope rearrangement of acyclic 1,5-dienes
is generally considered to proceed via a highly ordered six-membered chair-like
transition state [12]. In spite of its potential for chirality transfer processes, the Cope
rearrangement has rarely been investigated in the context of acyclic stereoselection.
In order to gain new insights into this aspect, the Cope rearrangement of syn - and anti -
aldols present in different substituted acyclic 1,5-hexadienes has been investigated,
showing that the reaction is more stereoselective for the syn - than for the anti -
precursors [13]. The Cope rearrangement is often accelerated by the presence of
catalysts [14] such as palladium(0) [15] or various protic acids, as it was the case in the
rearrangement of 2- exo -carbomethoxytricyclo[5.2.1.0 2,6 ]deca-3,8-dien-5-one with
ethylene glycol that, in the presence of PTSA, led to 1-carbomethoxy endo -dicy-
clopenta-1,4-diene-8-one 8-ethylene acetal [16].
Various applications of the thermal Cope rearrangement to the synthesis of
natural products have been reported in the literature, such as in the hemisynthesis of
sesquiterpenes vernolepin and 8- epi -vernolepin prepared starting from saloniteno-
lide and cnicin [17]. The latter has also been used as a starting material in the
synthesis of elemane and heliangolane derivatives [18]. Other applications of the
Cope rearrangement can be found in the first synthesis of floerkein B and barbi-
lycopodin [19], in the synthesis of the racemic diterpene obtunone [20], in synthetic
approaches to D 3,8 -taxane tricarbocycles [21], or in the synthesis of the racemic
tetracyclic core of CP-225917 [22]. The enantioselective total synthesis of ( þ )- and

( )-asteriscanolide was achieved using a sequence involving an intramolecular

cyclobutadiene cycloaddition, a ring-opening metathesis, and a Cope rearrange-
ment [23]. Similarly, a compound containing the nonaromatic tricyclic ring system
present in morphine was prepared using an intramolecular Diels-Alder cycload-
dition and a Cope rearrangement [24].

R

R R

heat

heat
[3,3]

heat

R

[3,3]

R R R

R [3,3]

SCHEME 8.1 Cope rearrangement.