Synthesis of Enantiopure α-Chlorocyclobutanones and Cyclobutanols as Scaffolds for the Diverted Synthesis of Serine Protease Inhibitors

• Published in: European Journal of Organic Chemistry Vol. 2009; no. 11; pp. 1738 - 1748
• Main Authors: Yang, Gaoqiang, Ghosez, Léon
• Format: Book Review Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-04-2009; WILEY‐VCH Verlag
• Subjects: Asymmetric synthesis; Heterocycles; Inhibitors; Small ring systems
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200900083

Synthetic paths towards highly functionalized α‐chlorocyclobutanone scaffolds susceptible to lead to serine proteases inhibitors were explored. The syntheses started from bicyclic α‐chlorocyclobutanones 3, which are readily available from Seebach's oxazolines. It was found that the carbonyl group of the bicyclic α‐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 α‐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(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Resistance to β‐lactam antibiotics has become a major threat to public health. We prepared scaffolds equivalent to β‐lactams for the diverted total synthesis of hydroxy‐alkylating inhibitors of penicillin‐binding proteins.