AMMONIUM YLIDES AS BUILDING BLOCKS FOR ALKALOID SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 440

CH 2

CH 2

N 2 +

CO 2 Et

CO 2 Et

H

O O

CO 2 Et

Rh(II)

X = O

O -

X N O

CH 3

X N O

CH 3

O

O N

CH 3

86a (X = H 2 )
86b (X = O)

87a (X = H 2 )
87b (X = O)

88

SCHEME 13.20

of mesoionic betaines. Cycloaddition of this “ push-pull ” dipole furnished tetra-
cycle 88 in good yield, provided that the tether engaged in ring formation carried a
carbonyl group (i.e., 86b ,X

¼ O) (Scheme 13.20). Without the C ¼ O functionality

(i.e., 86a ,X H), only decomposition products were observed. By performing ab

initio geometry optimizations with 86a , it was shown that a severe cross-ring 1,3-
diaxial interaction exists in the transition state for the cycloaddition. The presence
of a carbonyl group in the tether, on the other hand, helps to relieve the steric
congestion by favoring a second boat conformation in the latter ring. When the side
chain is devoid of a carbonyl group, the calculated reaction barrier is much larger,
thereby permitting competing processes to occur. Thus, the reactivity discrepancy
between

¼

-diazo amido esters 86a and 86b has been attributed to relative differ-
ences in steric effects in the respective transition states [46].
Selective modification of the starting

a

-diazo amido ester allowed an appli-
cation of this methodology for an eventual synthesis of the Aspidosperma alkaloid
family. In particular, intramolecular [3 þ 2]-cycloaddition of the push-pull dipole
across a tethered heteroaromatic

a

-diazo imides such as 89-91
proceeded smoothly and provided the novel pentacyclic compounds 92-94 in good
yield and in a stereocontrolled fashion (Scheme 13.21) [47]. In the case of the
thiophenyl-substituted

p -bond of several a

-diazo imide 91 , changing the ligand group on the rhodium
catalyst resulted in a major difference in the overall reaction pathway. Thus, treatment
of 91 with Rh(II)-pivalate afforded only cycloadduct 94 . In contrast, the only
compound isolated from the rhodium(II) perfluorobutyrate (Rh 2 (pfb) 4 ) catalyzed
reaction of 91 was lactam 95 . The formation of this compound arose from a formal
insertion of the metal carbene into the C-H bond at C5 of the lactam ring, followed by
an unusual ethoxydecarboxylation reaction. The variation in reactivity reflects the
difference in electrophilicity between the various rhodium carbenoid intermediates.
Intramolecular C-H insertion is enhanced with the more electrophilic carbene
generated using the Rh(II) perfluorobutyrate catalyst.
A related annulation sequencewas then used to prepare the required pentacyclic
skeleton of the Aspidosperma family of alkaloids. Thus, treatment of

a

-diazoimide 96
withRh 2 (OAc) 4 produced the expected push-pull dipole that subsequently underwent
cycloaddition across the tethered indole

a

-bond. The resulting cycloadduct 97 is the
consequence of endo cycloaddition with respect to the dipole and this is fully in
accord with the reaction proceeding via the lowest energy transition state. The
stereospecific nature of the internal cycloaddition reaction results in the correct
relative stereochemistry about the four chiral centers of the C-ring. Cycloadduct 97

p