Asymmetric Total Synthesis of (–)‐Azaspirene by Utilizing Ti‐Claisen Condensation and Ti‐Direct Aldol Reaction. Issue 28 (6th October 2016)

• Record Type: Journal Article
• Authors: Sugi, Mikiko; Nagase, Ryohei; Misaki, Tomonori; Nakatsuji, Hidefumi; Tanabe, Yoo
• Is Part Of: European journal of organic chemistry. Issue 28(2016)
• Page Start: 4834
• Page End: 4841
• Publication Date: 2016-10-06
• Subjects: Total synthesis -- Asymmetric synthesis -- Claisen condensation -- Aldol reactions -- Titanium; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201600766
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract : A successful asymmetric total synthesis of (–)‐azaspirene has been accomplished by utilizing (3 R )‐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 (2 R )‐(4 E )‐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 %). Abstract : A successful asymmetric total synthesis of (–)‐azaspirene has been accomplished in 23 steps from 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 and (ii) a robust Ti‐direct aldol addition reaction.