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Asymmetric Total Synthesis of (–)‐Azaspirene by Utilizing Ti‐Claisen Condensation and Ti‐Direct Aldol Reaction
Author(s) -
Sugi Mikiko,
Nagase Ryohei,
Misaki Tomonori,
Nakatsuji Hidefumi,
Tanabe Yoo
Publication year - 2016
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201600766
Subject(s) - chemistry , aldol reaction , lithium diisopropylamide , synthon , aldol condensation , total synthesis , claisen rearrangement , trimethylsilyl , enantioselective synthesis , adduct , organic chemistry , medicinal chemistry , stereochemistry , catalysis , ion , deprotonation
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 TiCl 4 /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 %).