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Scheme 3.21 Intermolecular Diels-Alder reaction of 111f.
Cbz
MeO 2C
N
111f
O
O
N Ph
toluene, reflux, 2hr
83%
Cbz
N
H
MeO 2C
O
N
Ph
143
O
O
O
N Ph
Cbz
N
H
MeO 2C
O
N
Ph
O
H
O
N
O
Ph
144
5 : 2 :1 mixture of diastereomers
(major diastereomer shown)
X-ray of 144
The relative stereochemistry of the major diastereomer from this mixture was assigned by X-ray
crystallography, and results from endo selectivity in the first cycloaddition occuring from the
same face of the methyl group, while the second dienophile adds from the less hindered convex
face of the newly formed diene in endo mode (Appendix A). Attempts to obtain the cycloadduct
143, by reaction of 111f with equimolar amount of dienophile resulted in formation of 144 and
recovered triene. This result is attributed to the higher reactivity of the second diene of 143
because it is locked in an s-cis conformation. Other dienophiles (maleic anhydride and 4-phenyl-
[1,2,4]-triazole-3,5-dione) also reacted with 111f to give mixtures of diastereomeric products
similar to 144. Although the cycloaddition reaction of 111f illustrated in Scheme 3.21 affords a
complex molecular scaffold in a rapid manner, obtaining the product as a mixture of
diastereomers discouraged applying this reaction to library synthesis. Biological testing of
mixtures of multiple compounds may complicate the interpretation of the results. Although
separation of the diastereomers by HPLC was feasible it may prove costly and time consuming
when preparing a larger scale library. Therefore, controlling the chemo- and diastereoselectivity
of the Diels-Alder reaction of the triene was important, and a new strategy for tandem
intermolecular cycloaddition was considered.
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