Pseurotin A, isolated in 1976, inhibits chitin synthase and also induces cell differentiation of PC12 cells, while azaspirene, isolated in 2002 by Kakeya and Osada et al., is an angiogenesis inhibitor, and attracted much attention as a lead of a drug for the treatment of cancer. As they both contain a novel, highly-substituted and oxygenated 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton with three continuous chiral centers, their total syntheses are a challenge. We have synthesized pseurotin A and azaspirene from the same key elaborated ketone intermediate. The ketone was stereoselectively synthesized by the following key reactions: a MgBr_2・OEt_2-mediated Mukaiyama aldol reaction affords the desired syn-aldol in good yield with high selectivity. A NaH-promoted, intramolecular cyclization of a non-activated alkynylamide provides (Z)-benzylidene-γ-lactam. The aldol condensation proceeds smoothly between a side chain aldehyde and the ketone containing functionalized γ-lactam moiety without protection of tert-alcohol and amide functionalities. In the synthesis of pseurotin A, introduction of the benzoyl group by the selective oxidation of a benzylidene moiety with dimethyldioxirane (DMD) was successfully performed. In the synthesis of azaspirene, we found that the order of the last two reactions is very important because the reversed reaction sequence afforded a racemic azaspirene. By this total synthesis, the absolute stereochemistry of azaspirene has been determined.