Synthesis of Enantiopure alpha-Chlorocyclobutanones and Cyclobutanols as Scaffolds for the Diverted Synthesis of Serine Protease Inhibitors
(2009) European Journal of Organic Chemistry — n° 11, p. 1738-1748 (2009)
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- Abstract
- Synthetic paths towards highly functionalized alpha-chlorocyclobutanone scaffolds susceptible to lead to serine proteases inhibitors were explored. The syntheses started from bicyclic alpha-chlorocyclobutanones 3, which are readily available from Seebach's oxazolines. It was found that the carbonyl group of the bicyclic alpha-chlorocyclobutanones was highly electrophilic and readily reacted with a hydroxy group to give, for example, cyclized compound 4. Also, the presence of this reactive carbonyl group did not allow the regeneration of the protected amine and hydroxy groups. Thus, the functional manipulation of these bicyclic alpha-chlorocyclobutanones required prior reduction of the carbonyl group to the corresponding cyclobutanol. Accordingly, enantiopure cyclobutanone 3d was stereoselectively reduced to exo-cyclobutanol 15. Allylation of the alcohol followed by TEMPO-catalyzed oxidation of the primary alcohol of the side chain and benzylation of the resulting carboxylic acid yielded compound 19. Cleavage of the oxazolidine ring occurred smoothly to yield densely functionalized cyclobutanol scaffold 20. A similar route allowed the efficient preparation of cyclobutanol scaffolds 14 and 25a-d in 25-27% yields. TEMPO-catalyzed oxidation of the cyclobutanol gave an excellent yield of corresponding cyclobutanones 26a,b ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
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Yang, G., & Ghosez, L. (2009). Synthesis of Enantiopure alpha-Chlorocyclobutanones and Cyclobutanols as Scaffolds for the Diverted Synthesis of Serine Protease Inhibitors. European Journal of Organic Chemistry, 11, 1738-1748. https://doi.org/10.1002/ejoc.200900083 (Original work published 2009)