Biomedical Engineering Reference
In-Depth Information
key step in the three-component reaction is the 1,3-dipolar cycloaddition reaction of an
electron-deficient alkene with the azomethine ylide generated in situ upon treatment
of the imine with Ag(I). Oppolzer's chiral glicyl sultam, used as the amine component,
played an important role in this reaction, as this chiral auxiliary controlled the absolute
stereochemistry and facilitated the reaction cascade by reducing the nucleophilicity
of the amine, thereby preventing Michael addition, and by increasing the
-acidity
of the intermediate imine, thus facilitating the formation of azomethine ylides. In
addition, it was useful as a chemical handle for further synthetic transformations.
The reaction exhibited high endo selectivity, tolerated several aldehydes, including
sterically hindered, heteroalkyl-substituted, and chiral aldehydes, and showed high
regioselectivity when monoactivated alkenes were used.
The presence of tetrahydro-1,2-oxazines in biologically relevant natural products
and the lack of this heterocycle in common chemical libraries make them particularly
interesting scaffolds. Young and Kerr reported a facile and versatile synthesis of
highly functionalized tetrahydro-1,2-oxazines
58
through intermolecular 1,3-dipolar
cycloaddition reaction of freshly prepared nitrones and cyclopropane diesters in the
presence of Yb(OTf)
3
(Scheme 3.19) [34]. The cis product was the sole diastere-
omer produced in most cases. Among the new 26 isoxazines, skeletal congeners of
FR900482 [35], an antitumor and antibiotic natural product, were synthesized.
Using rhodium(II)-catalyzed consecutive cyclization-cycloaddition reactions
developed by Padwa's group [36], Oguri and Schreiber developed a folding path-
way to generate indole alkaloid-like skeletons [37]. Rh(II)-catalyzed cyclization of
rhodium carbenoid, generated from
α
-diazoketocarbonyl, with adjacent carbonyl
oxygen yielded a carbonyl ylide, which underwent a 1,3-dipolar cycloaddition with
the double bond at the 2- and 3-positions of the neighboring indole. Using the
same reaction conditions, six different modes of intramolecular reaction were pos-
sible, based on all combinations of indole and
α
-diazo ketocarbonyl groups (Fig-
ure 3.1). Three different modes were reported, and in all cases the tandem cyclization-
cycloaddition proceeded with excellent yield and complete diastereoselectivity (
59
to
61
) (Scheme 3.20).
Several studies propose that macrocycles, with their restricted conformation,
seem to perform uniquely in biological assays [38]. To test this hypothesis, Looper
et al. developed an elegant macrocycloaddition strategy that combines a 1,3-dipolar
α
SCHEME 3.19
Intermolecular 1,3-dipolar cycloaddition reaction of nitrones and cyclo-
propane diesters in the presence of Yb(OTf)
3
to yield highly functionalized tetrahydro-1,2-
oxazines.
