REARRANGEMENTS IN NATURAL PRODUCT SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 246

rearrange to d -ene imines at rather elevated temperatures, analogous protonated
substrates, Lewis acid-coordinated or quaternarized molecules rearrange under milder
conditions [33]. Thus, the aza-Cope rearrangement has been applied to the synthesis of
chain-extended amino sugars derived from N -glycosyl homoallylamines [34], to the
synthesis of 2,3-dihydro-1 H -2-benzazepine-3-carboxylic acid derivatives, which
are conformationally constrained peptide analogues [35], or to the synthesis of
5,6,7-trisubstituted 4-aminopyrido[2,3- d ]pyrimidines, which are novel inhibitors of
adenosine kinase [36]. An interesting example of a 3-aza-Cope rearrangement of a
quaternary N -allyl enammonium salt has recently been reported featuring a stereo-
specific 1,3-allyl migration from nitrogen to carbon [37].
( )-Kainic acid is a marine natural product isolated from the Japanese algae

Digenea simplex used as a neurotransmitter to study epilepsy and Alzheimer's
disease. This neuroexcitotoxic and epileptogenic agent has recently been synthesized
using a planar chiral amide as a chiral building block [28]. Hence, starting from
racemic 5-methyl-1-tosyl-3,4-dihydro-1 H -azepin-2(7 H )-one, the ( S )- and ( R )-
amides were obtained in four steps and separated by preparative chiral HPLC. It
is worth noting that these chiral amides are configurationally stable and do not
interconvert at room temperature. Next, A Cope rearrangement of the ( S )-amide was
then carried out in the presence of a catalytic amount of palladium(II) to afford the key
intermediate in good yield with excellent diastereo- and enantioselectivities. From
this compound, a series of routine reactions afforded ( )-kainic acid in enantio-

merically pure form (Scheme 8.5). A similar protocol was also reported to give
(

)-kainic acid from enantiomerically pure ( R )-amide [28].
An interesting variant of the aza-Cope is the aza-Cope-Mannich [30], a
powerful method for assembling nitrogen heterocycles based on the acid-promoted
condensation of an acyclic homoallylic amine containing an allylic hydroxy (or
alkoxy) group with an aldehyde or ketone.
(

þ

)-Actinophyllic acid, an indole alkaloid obtained from the leaves of the tree
Alstonia actinophylla , is an inhibitor of carboxypeptidase U (CPU), which has been
synthesized by Overman and coworkers [38] using an aza-Cope-Mannich
approach [30]. Acid hydrolysis on the key tertiary alcohol to selectively remove the
Boc group, followed by reaction with paraformaldehyde in the presence of a catalytic
amount of camphorsulfonic acid (CSA) at 70 C, mediated the aza-Cope-Mannich
reorganization to give a crude mixture that was treated with trifluoroacetic acid (TFA)
to afford the next intermediate in 76% yield. Two additional steps finally provided the
target natural product (Scheme 8.6).
Fumonisin B 1 (Scheme 8.7) is a primary mycotoxin produced by the fungus
Fusarium verticillioides . It was synthesized following a synthetic sequence featuring
a stereospecific allyl transfer that occurred during the course of a trimethylsilyl
triflate-mediated aldol reaction and provided a key intermediate bearing the correct
stereochemistry at C14 along with the trans alkene, as expected in a 2-oxonia Cope
rearrangement (Scheme 8.7) [39].
The oxaza Cope rearrangement has been developed in the context of a program
aimed at preparing bicyclic oxazines from esters [32] and as such applied to the
synthesis of racemic trichodermamide B, amodified dipeptide isolated fromamarine-
derived fungus Trichoderma virens , which showed significant in vitro activity against