Asymmetric Total Synthesis of (–)‐Azaspirene by Utilizing Ti‐Claisen Condensation and Ti‐Direct Aldol Reaction

Abstract

A successful asymmetric total synthesis of (–)‐azaspirene has been accomplished by utilizing (3R)‐6‐cinnamyl‐3‐methyl‐3‐phenyl‐1,4‐dioxane‐2,5‐dione, a readily accessible chiral template. The present method involves two distinctive TiCl4/amine‐mediated reactions: (i) an asymmetric Ti‐crossed‐Claisen condensation of the chiral template with propanoyl chloride followed by methanolysis to afford methyl (2R)‐(4E)‐2‐hydroxy‐5‐phenyl‐2‐propanoylpent‐4‐enoate, the key chiral synthon and (ii) a robust Ti‐direct aldol addition reaction, instead of the reported lithium diisopropylamide/hexamethylphosphorictriamide (LDA/HMPA) or potassium hexamethyldisilazide (KHMDS)‐mediated reaction, by using the trimethylsilyl (TMS) ether of α‐acyl‐γ‐lactam to successfully furnish the new aldol adduct. Final oxidation, cyclization, and tert‐butyldimethylsilyl (TBS) removal produced (–)‐azaspirene from the key template in 23 steps (total yield 1.7 %).

Asymmetric Total Syntheses of Two 3-Acyl-5,6- dihydro-2H-pyrones: (R)-Podoblastin-S and (R)- Lachnelluloic Acid with Verification of the Absolute Configuration of (−)-Lachnelluloic Acid

“…Our asymmetric total synthesis of 1 involves asymmetric Ti-Claisen condensation as a crucial step for the synthesis of elaborated left side chain [ 6 ]. In addition, very recently, we performed relevant asymmetric total synthesis of azaspirene, a unique hetero-spirocylic γ-lactam-type antibiotic, utilizing Ti-Claisen condensation and Ti-mediated direct aldol addition [ 7 ].…”

Total Synthesis of (−)-FD-838 and (−)-Cephalimysin A

“…More recently, Švenda and co-workers published an enantioselective total synthesis of cephalimysins B (12 longest linear steps) and C (12 longest linear steps) via a Ni­(II)-diamine-catalyzed conjugate addition of a furanone moiety . Besides these representative examples, Rovis (diastereomers of cephalimysin A, 12 longest linear steps), Tadano ((−)-pseurotin A ( 1 ), 37 longest linear steps), and Tanabe/Misaki ((−)-azaspirene ( 4 ), 29 longest linear steps) have also made notable contributions in this field.…”

Straightforward Synthesis of 2(5H)-Furanones as Promising Cross-Coupling Partners: Direct Furanone Annulation Utilizing Ti-Mediated Aldol Addition

“…In addition, a furan derivative prepared from a 2(5H)-furanone by DIBAL reduction underwent smoothly Suzuki-Miyaura cross-coupling to give the biphenyl analogue. The utility of the Ti-Claisen and the crossed Ti-direct aldol reactions is also demonstrated in recent asymmetric total syntheses of alternaric acid [11] and azaspirene [26].…”