AMMONIUM YLIDES AS BUILDING BLOCKS FOR ALKALOID SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 470

O

CO 2 R OEt

O

RO 2 C

N

Rh 2 (OAc) 4
PhMe, reflux

RO 2 C O

O O

RO 2 C

N

OEt

N

N 2

352a (R = Me)
352b (R = Bn)

353a (R = Me)
353b (R = Bn)

354a (R = Me; 80% ee)
354b (R = Bn; 84% ee)

O O

O

Bn Bn

Bn

N N

N

Rh 2 (OAc) 4
PhMe, reflux

CO 2 Et

CO 2 Et

N N CHO 2 Et

CO 2 Et

O O

65%

CO 2 Et

N

OEt O

N 2

O

355 356 357

SCHEME 13.66

Saba and coworkers used proline-derived diazo compounds for the enantio-
selective synthesis of the indolizidine skeleton, notably creating a quaternary center
adjacent to nitrogen [115]. In this report, diazo keto ester 352a was reacted with
Rh 2 (OAc) 4 in refluxing toluene to give a 60:40 mixture of indolizidine 354a and
the trans -stereoisomer in 84% combined yield, and 354a was determined to have an
80% ee (Scheme 13.66). Subjecting benzyl ester 352b to the same reaction conditions
produced a mixture in which 354b was the major diastereomer, though the diastereo-
selectivity increased to 72:28 and 354b was isolated with 84%ee. In both cases, the use
of Cu(acac) 2 led to slightly higher yields (90% in each case) but with a significant
erosion in diastereoselectivity. Of particular interest, the ammonium ylides 353a and
353b were isolable, and each was heated to produce 354a and 354b with complete
selectivity and 95% ee. This provides further evidence of the stereoselective nature of
the [1,2]-shift.
Saba and coworkers used this Stevens rearrangement to access pyrrolo[1,2- a ]
benzodiazepine systems [116]. The Rh 2 (OAc) 4 -mediated decomposition of diazo
keto ester 355 produced spirocyclic ammonium ylide 356 , though this intermediate
could not be isolated. A stereospecific [1,2]-shift afforded 357 exclusively as
the trans -isomer in 65% yield. The stereoselectivity suggests that the intermediate
ammonium ylide is formed by approach of the carbenoid to the less crowded face of
the relatively planar quinazolinone ring.
Padwa and Beall deployed the [1,2]-Stevens rearrangement for the synthesis of
the benzazepine and tetrahydroisoquinoline ring systems, specifically targeting the
5,7-fused benzazepine skeleton of the alkaloids cephalotaxine and lennoxa-
mine [117]. For example, the Cu(acac) 2 -catalyzed decomposition of compounds
358a - 358c in boiling toluene produced 360a - 360c in 68-77% yield (Scheme 13.67).
In the case of 358b , the intermediate ammonium ylide 359b was isolable, and further
heating was shown to produce 360b . When the benzylic carbon bore a substituent, as
in 358c , the benzazepine 360c was obtained as a 1:1 mixture of diastereomers.
In all the examples presented here, an amine nitrogen reacts with the metallo-
carbenoid to give the requisite ammonium ylide. The Padwa group has also reported