Biomedical Engineering Reference
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as complexity-generating reactions (simple
complex), contributing to the achieve-
ment of structural diversity in the first case and of structural complexity in the second.
In addition, with their ability to generate new stereocenters, cycloaddition reactions
also contribute to the development of stereo structure-activity relationships during
screening campaigns. Following a chronological order, in this review we present
an overview of Diels-Alder and inverse electron-demand Diels-Alder reactions,
and 1,3-dipolar cycloaddition reactions, including Huisgen [3
2] cycloadditions,
nitrone and nitrile oxide cycloadditions, and azomethine ylide cycloadditions. In
the final section, miscellaneous cyloaddition reactions, such as [2
+
+
2
+
2], [2
+
2],
formal [4
+
3], and [3
+
3], are presented.
3.2
[4
2] CYCLOADDITION REACTIONS
+
[4
2] Cycloadditions represent one of the most important reactions in the area, as
is evident from the large number of papers, reviews, and topic chapters in the field.
Due to the fact that [4
+
2] cycloaddition reactions usually furnish a high degree
of chemo-, regio-, and stereoselectivities, and generate up to four stereocenters in a
single step, these reactions have long been adopted for DOS.
+
3.2.1 Diels-Alder Reaction
One of the first examples of a Diels-Alder reaction in DOS was reported by
Schreiber's group in 2000 (Scheme 3.1) [5]. Aiming to generate structural complex-
ity, the authors reported an example of the pairwise use of complexity-generating
reactions involving the Ugi four-component, intramolecular Diels-Alder, and ring-
opening/ring-closing olefin metathesis reactions. Fundamental to the success of this
pathway is the introduction of a diene and dienophile in two of the four components
in the Ugi reaction [6]. The intramolecular Diels-Alder product 1 was synthesized
as a single stereoisomer with good yield.
Using a one bead-one stock solution technology platform [7], Schreiber et al.
reported an efficient synthesis of 29,400 polycyclic compounds [8] based on the
methodology developed by Fallis's group for the use of consecutive Diels-Alder
reactions (Scheme 3.2) [9]. Fallis-type trienes were loaded on macrobeads, followed
by the Diels-Alder reaction. Double cycloaddition occurred when disubstituted cyclic
dienophiles were utilized ( 3 ), whereas monocycloaddition was found with tri- or
tetrasubstituted cyclic dienophiles ( 2 ). Monocyclic dienes 2 were then reacted with
a second dienophile to yield tetracycles, generated from two different dienophiles
( 4 ). Single and double cycloaddition both proceeded stereoselectively, and bi- and
tetracyclic compounds with up to six stereocenters were synthesized.
The discovery byWinterfeldt's group [10] of a Diels-Alder and transannular retro-
Diels-Alder reaction sequence of a steroidal diene enabled Kumar et al. to develop a
new DOS pathway generating fused bicyclic compounds containing a five-membered
ring and a 14-membered ring paracyclophane (Scheme 3.3) [11]. The Diels-Alder
reaction between the stereoidal dienes 5 and ynones is catalyzed by the Lewis acid
Et 2 AlCl, which accelerates the Diels-Alder reaction ahead of the retro-Diels-Alder
reaction. This allowed for the formation and isolation of intermediate Diels-Alder
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