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3.3.2 Intermolecular Diels-Alder Approach-Second Generation Triene
It was reasoned that tying back the appending ester in a ring would increase the reactivity
of the diene in the first Diels-Alder reaction by reducing the steric bulk. Moreover, this
constraint leads to a sterically biased triene, in which one face is blocked by the R 1 group.
Finally, introducing an electron withdrawing carbonyl group at the C6 position would slow the
second Diels-Alder reaction. The novel imidazo-pyridinone triene 147 addresses all of these
issues (Scheme 3.22).
Scheme 3.22 Novel fused bicyclic Diels-Alder precursor 147.
control of facial
selectivity
chemoselectivity over the rate of
the second cycloaddition
N
R 1
O
6
O
R 2
improved reactivity of the diene
due to reduced steric hinderance at C2
5
2 4
3
HN
O
MeO 2C R 1
•
145
R 2
Rh(I)
HN
R1 MeO2C O R 2
146
O
R N 3
O
N
R 1
O R 2
Putting the synthesis of 147 into practice required examination of the Rh(I)-catalyzed
cycloisomerization of amide-tethered allenyne 145 to form δ-lactam triene 146. Traditionally,
lactams are synthesized via carbon-nitrogen bond formation. For example, lactams are formed
via dehydration of amino-acids, 93 by cyclization of an amide onto an alkene, 94 alkyne 95 or an
allene, 96 and intramolecular vinylation of amides. 97 Alternatively, lactams can be synthesized
from ketones by Schmidt or Beckmann rearrangement. 98 There are very few examples of lactam
syntheses via transition metal catalyzed carbon-carbon bond formation, and most involve a ring-
closing metathesis. 99 Synthesis of lactams via cycloisomerization reaction appears particularly
50
147