AMMONIUM YLIDES AS BUILDING BLOCKS FOR ALKALOID SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 433

O

CO 2 Et

O

O

HO
EtO 2 C

H

N 2

N

N

Rh(II) BF 3 •OEt 2

91%

CO 2 Et

O O N

H

OMe

OMe

OMe

OMe

OMe

OMe

39 40 41

SCHEME 13.9

the least hindered side, as has already been established by Mondon and coworkers
[12-14]. Cationic cyclizations of this type are known to be governed by steric
control [17]. In the case of cycloadduct 34 , the bridgehead proton does not exist, and
thus deprotonation can occur only in one direction. Apparently, the initially formed
iminium ion derived from 33 undergoes fast p -cyclization prior to proton loss. In this
case, the deprotonation step is significantly slower than that in the 6/5 system due
to the larger dihedral angle (113 ) between the bridgehead proton and the

-system
of the N -acyliminium ion. The stereochemical outcome in 36 is the result of a
stereoelectronic preference for axial attack by the aromatic ring of the N -acyliminium
ion from the least hindered side.
Thus, by incorporating an internal

p

p -nucleophile on the tether, annulation of the

original isom unchnone cycloadduct allows the construction of a more complex

nitrogen heterocyclic system, particularly B-ring homologues of the erythrinane
family of alkaloids [18]. This reaction sequence represents the first example where
a[3

€

2]-cycloaddition and a N -acyliminium ion cyclization have been coupled in a
one-pot sequence. The novelty of the process lies in the method of N -acyliminium ion
generation, which was unprecedented at the time that the research was carried out.
N -Acyliminium ions are traditionally generated from the N -acylation of imines,
N -protonation and oxidation of amides, electrophilic additions to enamides, and the
heterolysis of amides bearing a leaving group adjacent to nitrogen [19]. These reactive
intermediates readily react with a wide assortment of nucleophiles to effect an overall
a

þ

-amido alkylation.
A number of approaches to complex alkaloids have been reported in which the
intramolecular cycloaddition reactions of a transient isomunchnone dipole feature as
the pivotal step for assembling the polycyclic frameworks. Intramolecular reactions
of isomunchnone dipoles generated from a series of alkenyl- and alkynyl-substituted
diazoimides have been exploited to develop an approach to the quinoline ring system
(rings C and D) of the ergot alkaloids (e.g., lysergic acid, 45 ). In one example,
the Rh 2 (OAc) 4 -mediated tandem cyclization/cycloaddition sequence from the
diazoimide 42 led to the cycloadduct 43 in very good yield (Scheme 13.10) [20].
The polycyclic adduct 43 was readily elaborated to 44 en route to ergot alkaloids via
BF 3 OEt 2 -mediated ether bridge cleavage and a Barton-McCombie deoxygenation

sequence. Further attempts toward lysergic acid were, however, thwarted due to the
inability to isomerize the trisubstituted double bond in 44 .