AMMONIUM YLIDES AS BUILDING BLOCKS FOR ALKALOID SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 445

condensation reactions with amino acids to aziridine ring openings, have been
developed. The next section contains a representative sample of azomethine ylide
cycloaddition approaches to various alkaloid natural products.

13.2.5.1. Amino Acid-Derived Ylides When N -formyl proline 121 is heated,
it undergoes an intramolecular cyclization to give ylide 122 (Scheme 13.28). Pizzorno
and Albonico used this method of ylide generation to access the pyrrolizidine ring
system by heating 121 in the presence of ethyl propiolate that gave bicyclic pyrrole
123 in 90% yield [55]. Hydrogenation of 123 over 10% palladium on carbon afforded
( )- 124 in 93% yield.

Robins and Sakdarat employed the naturally occurring 4-hydroxy- L -proline
derivative 125 under essentially the same conditions to produce 126 in 80%yield [56].
Hydrolysis of the formate ester followed by hydrogenation furnished 127 in 80%
yield. Removal of the now superfluous hydroxyl group was accomplished by reaction
of 127 with thionyl chloride followed by Raney nickel reduction that afforded
( þ )- 124 in 82% yield. Pyrrolizidine ( þ )- 124 could be converted into ( þ )-isoretro-

necanol, ( )-supinidine.

Inspired by the cephalotaxin structure, Szantay and Toke devised an approach
to azaindolic derivatives of the pentacyclic alkaloid that involves the addition of an
N -metalated imine to a nitro-olefin [57]. Application of this approach began when
indole 128 underwent dipolar cycloaddition with the azomethine ylide derived from
the reaction of glycine derivative 129 and AgOAc to produce a 3:1 mixture of
pyrrolidines (Scheme 13.29) [58]. Purification of this mixture gave 130 in 51% yield.
Acylation and Henry addition with methyl acrylate afforded 131 as a single isomer in
63% yield. Reduction of the nitro group by the action of Zn and HCl followed by a
further reduction of the carboxylate groups with LiAlH 4 provided 132 in 58%. Finally,

þ )-laburnine, and ( þ

O CO 2 Et CO 2 Et

H

CO 2 H

Ac 2 O Pd/C, H 2

EtO 2 C

O

reflux 90% N N

N N

CHO

121

123 124

122

1. SOCl 2
2. Raney Ni

82%

1. NH 3 , EtOH

CO 2 Et CO 2 Et

CO 2 H

H

2. Pd/C, H 2

EtO 2 C

HCO 2

N

HCO 2 HO

80% 80%

CHO N N

125

126 127

CH 2 OH CH 2 OH CH 2 OH

H H H

N N N

(+)-Laburnine

(+)-Isoretronecanol (+)-Supinidine

SCHEME 13.28