Synthesis of 6‐Azaspiro[4.3]alkanes: Innovative Scaffolds for Drug Discovery

Abstract

New scaffolds for drug discovery, 6‐azaspiro[4.3]alkanes, have been synthesized in two steps from four‐membered‐ring ketones: cyclobutanone, thienone, N‐Boc‐azetidinone (Boc = tert‐butoxycarbonyl), etc. The key transformation was the reaction between electron‐deficient exocyclic alkenes and an in‐situ generated N‐benzylazomethine ylide.

Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

“…Quite recently, we showed that alkene 2 (easily obtained by Horner–Wadsworth–Emmons reaction of cyclobutanone) reacts smoothly with N ‐Bn azomethine ylide to give the spirocyclic pyrrolidine 2 a in 85 % yield . To generate the azomethine ylide, we treated reagent 1 with catalytic LiF in acetonitrile under heating (Scheme ) .…”

[3+2] Cycloaddition of an Azomethyne Ylide and Vinyl Sulfonyl Fluorides ― an Approach to Pyrrolidine‐3‐sulfonyl Fluorides

“…TFA (trifluoroacetic acid), room temp. }, which was originally developed by Achiwa and coworkers, and has been widely used by us and others in recent years, could be used for a reaction with the parent commercially available vinyl sulfonyl fluoride 1a (Scheme , R 1 = R 2 = H). We found that under these typical conditions, the target adduct 3a was obtained in 75 % yield (Table ).…”

Recent synthesis of thietanes

“…Compound 11 was converted into 3-(tert-butoxycarbonyl)-1,1bis(hydroxymethyl)aminocyclobutane (25) in 6 steps. After the treatment of 25 with methanesulfonyl chloride, the obtained dimethanesulfonate 26 was reacted with sodium sulfide giving rise to 6-(tert-butoxycarbonyl)amino-2-thiaspiro [3.3]heptane (27), which was further transformed into the desired 6-amino-2thiaspiro [3,3]heptane (28) hydrogen chloride salt after the acidic deprotection [37] (Scheme 5).…”

“…This review covers the methods outlined in Figure 2 and also some miscellaneous methods for the synthesis of various thietane derivatives. A special focus is on the construction of the thietane ring, excluding methods for the simple modifications of the thietane rings and their side chains [26][27][28][29][30][31].…”