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We were motivated to first examine the formation of pyrroles D for three reasons: (1)
multicomponent processes involving a Stetter/Paal-Knorr reaction sequence have been utilized
previously for the synthesis of functionalized pyrroles; 204 (2) an additional diversification site
could be easily introduced by the preparation of pyrrole by using a variety of amines (R 3 -NH2);
and (3) a plethora of biologically interesting compounds from natural and synthetic origin
possess pyrroles as part of their substructure thus it is presumed that these compounds will be
useful as potential biological probes. 205
To this end, the conversion of 287a and 287b to 1,4-diketones was explored using a
Stetter reaction protocol reported by Tius. 206 Diversifications were performed only with
phenylalanine derived α-methylene cyclopentenones 287a and 287b since the major
diastereomers 287d and 287e (from the alanine and leucine derived substrates, respectively)
isomerize under basic conditions needed for the Stetter reaction. v Treatment of 287a to
butyraldehyde, Et3N and thiazolium salt 292 in 1,4-dioxane for 6h at 70 °C resulted in the Stetter
product 293 in 73% yield as a 4 : 1 mixture of diastereomers.
Scheme 4.40 Stetter reaction of 287a and 287b with butyraldehyde.
BzN
R
O
O
H C3H7 , Et3N BzN
MeO2C Bn
H
20 mol % 292
1,4-dioxane, 6h, 70 °C
MeO2C Bn
H
287a, R=Me
287b, R=H
N
+ Cl- S
HO 292
Ph
R
O
O
C 3H 7
293, R=Me, 73%, dr 293a : 293b = 4 : 1
294, R=H, 66%, dr 294a : 294b = 4 : 1
BzN
MeO2C Bn
H
The major diastereomer 293a selectively precipitates from an EtOAc/hexanes solution of the
v Treatment of 287d and 287e to the Stetter reaction conditions resulted mainly in decomposition and very low
yields of 1,4-diketone.
113
293a
O
O
C 3H 7