The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.
The synthesis of a series of 3-hydroxyproline benzyl esters from alpha-alkyl and alpha-alkoxy N-protected aminoaldehydes with benzyl diazoacetate is described. Aldehydes with alpha-alkyl substituents afforded prolines as a single diastereomer with a trans-cis relative configuration in 14-77%. An alpha-tert-butyldimethylsilyloxy aminoaldehyde afforded a proline as a single diastereomer with a trans-trans relative configuration in 37% yield.
A new approach to the synthesis of indolizidine and pyrrolizidine skeletons is reported. (-)-Lentiginosine and (1R,2R,7aR)-dihydroxypyrrolizidine have both been synthesized in 13 steps from di-O-isopropylidene-d-mannitol. The common key intermediate is (-)-dihydroxyproline benzyl ester 10.
The reaction of a series of beta-(triethylsilyloxy)aldehydes with several allylsilanes and crotyldimethylphenylsilane is described. Aldehydes possessing an alpha-stereocenter afforded tetrahydropyrans as mixtures of two diastereomers with allylsilane, but only a single diastereomer was observed in the case of crotylsilanes. The reaction time for crotylsilanes was longer than that for allylsilanes likely due to the increased steric hindrance. Allylsilanes afforded tetrahydropyrans in 34-67% yields, and crotylsilanes provided products in 0-62% yields.
Stereoselective Synthesis of 3-Hydroxyproline Benzyl Esters from N-Protectedβ-Aminoaldehydes and Benzyl Diazoacetate. -Lewis acid mediated treatment of N-protected β-aminoaldehydes with the diazoacetate (VII) offers a new, efficient, and stereoselective approach to 3-hydroxyprolines. In this connection, a new synthetic route is presented for the unstable substrate (VI) which is directly used for the preparation of target compound (VIII).The nature of the N-protecting group and the α-substituents play an important role in the title process. In some cases, a second product is formed [cf. β-ketoesters (XIII)]. -(ANGLE*, S. R.; BELANGER, D. S.; J. Org.
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