Biomedical Engineering Reference
In-Depth Information
SCHEME 3.22
Intramolecular nitrile oxide cycloaddition reactions.
Pauson-Khand reaction, and 1,3-dipolar cycloaddition. Isoxazole 67 and isoxazo-
lines 68a and 68b were synthesized through 1,3-dipolar cycloaddition of the derived
nitrile oxides with the alkynyl and alkenyl substituents on the dicarbonyl compounds
(Scheme 3.22).
Marcaurelle et al. reported a stereocontrolled [3
2] azomethine ylide-alkene
cycloaddition that generated highly functionalized pyrrolidine templates 69 . Subse-
quent pyridone cyclization provided tricyclic and bridged bicyclic scaffolds ( 70 and
71 ) that, once loaded on lanterns, generated a library of 15,000 small molecules
(Scheme 3.23) [42]. The reaction of glycine-derived azomethine ylides with
+
-
unsaturated esters was promoted by AgOAc/DBU and provided cycloadducts in high
yield and with excellent diastereoselectivity.
Brawn et al. developed a three-component reaction of enantioenriched allenyl-
silanes 72 , aldehydes, and silyl ethers, focusing on enantioenriched allenylsilanes
as chiral carbon nucleophiles, which generated homopropargylic alcohols 75 and
76 . When an azide was embedded within the aldehyde components ( 73 ), a [3
α
,
β
2]
cycloaddition of the newly generated alkyne with the pendant azide occurred, yielding
tricyclic compounds with 1,2,3-triazoles (Scheme 3.24) [43]. The dipolar cyclization
reaction resulted in the formation of triazole 77 as a single regioisomer. Electron-
withdrawing and electron-donating groups on the aromatic ring were well tolerated.
In addition, aliphatic acetals with embedded azides ( 74 ) proved to be successful
in this reaction sequence,
+
thus demonstrating the versatility of this methodo-
logy ( 78 ).
In their continued efforts at the Broad Institute to design and build a small-
molecule screening collection, Marcaurelle et al. reported a synthetic pathway to
access medium-sized and large ring systems [44]. Macrocycles are of interest in drug
discovery both because their rigid structure often leads to high affinity and selectivity
for protein targets and because they are present extensively in biologically relevant
natural products. A build/couple/pair strategy was used successfully and a variety of
 
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