AMMONIUM YLIDES AS BUILDING BLOCKS FOR ALKALOID SYNTHESIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 472

MeI
Acetone, reflux

t- BuOK
1,4-Dioxane
80%

I

N

N

N

R R

R

Me

Me

367 368 369

N

N R

Me

Me

R

370a 370b

t- BuOK

Cl

11

5

5

1,4-Dioxane
80°C

N
Cl

N N

12

11

12

371 372 373

SCHEME 13.69

rearrangment (ionic or diradical). The A 1,2 strain encountered in 370b disfavors this
fragmentation pathway. Under the thermodynamic conditions of ylide formation, only
products from the fragmentation involving 370a are observed. Alternatively, a
fragmentation pathway similar to 370b is favored when a ring changes the stereo-
electronics of the system as in compound 371 . Isopavine 373 , for example, was formed
when 371 was reacted with t -BuOK. Isopavine 367 showed an IC 50 value of 60-66 nM
against human

m -opioid receptor (compared to morphine, IC 50 ¼ 0.6-1 nM) and was

highly selective (IC 50 ¼ receptors, respectively,

whereas morphine shows values of 169 and 146 nM, respectively).

6113 and 8226 nM against the k and q

13.3.2. [2,3]-Rearrangements
Generally, [2,3]-sigmatropic rearrangements of ammonium ylides occur faster than
[1,2]-Stevens rearrangements [120] and several groups have exploited this method for
alkaloid synthesis. Clark and coworkers demonstrated the diversity of structures that
can be generated using this method [121]. Decomposition of -diazoketone 374 by

exposure to Cu(acac) 2 at elevated temperatures gave 376 as a single diastereomer
in 65% yield (Scheme 13.70). The intermediate ylide

a

375 derived by treating

a -diazoketone 374 with Cu(acac) 2 underwent a concerted [2,3]-sigmatropic

rearrangement to provide 376 . Aziridine 377 afforded 379 , though only in 24% yield,
when subjected to the same conditions. The reaction of proline-derived 380 with
Cu(acac) 2 in benzene at reflux gave 382 in 56% yield and with 98% ee.

Shortly after Clark and coworkers reported this work, Rowlands and Barnes
published an account that focused more closely on the aziridinium ylide rearrange-
ment [122]. The intermolecular reaction of simple vinyl aziridines, such as 383 , failed

H