AMMONIUM YLIDES AS BUILDING BLOCKS FOR ALKALOID SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 435

OCH 3

O

O O O OCH 3

H

Rh(II)

EtO

EtO N

O

N 2 CH 2 Ph

O N

Bn

52 53

BF 3 ·2 AcOH

O

OH

EtO

steps steps

H

H H

N O N O N

H Bn

OCH 3 OCH 3

(±) Lycopodine 56

55 54

SCHEME 13.12

constitutes a formal synthesis of ( )-vallesamidine 51 , based on the successful

conversion of 50 into 51 by Heathcock and Dickman [24].
Another application of the domino cascade process toward the construction of
alkaloids involved the synthesis of (

)-lycopodine 56 (Scheme 13.12) [25]. The

isom unchnone cycloadduct 53 was formed from the Rh(II)-catalyzed reaction

of diazo imide 52 and was found to be the precursor of the key Stork intermediate
55 (via 54 ). Formation of 55 from 54 occurred by way of a Pictet-Spengler cyclization
of the N -acyliminium ion derived from 53 . Central to this strategy was the expectation
that the bicyclic iminium ion originating from 53 would exist in a chair-like
conformation [26,27]. Indeed, cyclization of the aromatic ring onto the N -acyliminium
ion center readily occurred from the axial position [12-14]. The rearranged product 54
was then converted into the key intermediate 55 previously used by Stork for the
synthesis of (

€

)-lycopodine 56 [26].
Another implementation of the cascade method involves the efficient
assembly of the indolizidine ring system by using the Rh(II)-catalyzed [3 2]-dipolar

cycloaddition of the phenylsulfonyl-substituted diazopyrrolidinone 57 with an
appropriately substituted dipolarophile (Scheme 13.13). The resultant pyridone 60
represents a very versatile synthon. As shown in Scheme 13.12, structural manipulation
of the pyridinone ring and subsequent functional group interconversions provide
access to several indolizidine alkaloids [28]. The C6 hydroxyl substituent, protected as
triflate 61 , allows an assortment of cross-coupling possibilities. The Padwa group
demonstrated the versatility of the method through the synthesis of the angiotensin-
converting enzyme inhibitor (

þ

)-A58365A 62 ,( )-ipalbidine 63 , b -carbolinone 64 ,

and a variety of other novel indolizidine-based compounds [28].
An efficient synthesis of the naturally occurring oxoindolizino quinoline
mappicine ketone 70 was carried out by Greene and coworkers [29] by making use
of pyridone 65a as a key intermediate. The synthesis of 70 beganwith the formation of
the known cycloadduct (R 1 H; R 2

65a ¼ ¼ CO 2 Me) by cycloaddition of the