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Total Synthesis of α‐Tocopherol through Enantioselective Iridium‐Catalyzed Fragmentation of a Spiro‐Cyclobutanol Intermediate
Author(s) -
Ratsch Friederike,
Schlundt Waldemar,
Albat Dominik,
Zimmer Anne,
Neudörfl JörgMartin,
Netscher Thomas,
Schmalz HansGünther
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201900564
Subject(s) - enantioselective synthesis , metathesis , iridium , alkene , chemistry , catalysis , medicinal chemistry , stereochemistry , organic chemistry , polymerization , polymer
A conceptionally new strategy for the asymmetric (2 R ‐selective) synthesis of α‐tocopherol (vitamin E) was developed. In the stereocontrolled key step, a prochiral spiro[chromane‐2,3′‐cyclobutanol] unit is effectively desymmetrized under C−C bond activation in an unprecedented iridium‐catalyzed transformation using ( S )‐DTBM‐SegPhos as a chiral ligand (e.r. 97:3). To complete the synthesis, the side chain was attached through Ru‐catalyzed cross‐metathesis employing an alkene derived from ( R , R )‐hexahydrofarnesol. To suppress epimerization during the final hydrogenation, PtO 2 had to be used as a catalyst instead of Pd/C. In an alternative approach (employing a propargyl‐substituted spiro‐cyclobutanol), the side chain was constructed prior to the Ir‐catalyzed ring fragmentation (>99:1 d.r.) through enyne cross‐metathesis (using an alkene derived from ( R )‐dihydrocitronellal) followed by Cr‐catalyzed 1,4‐hydrogenation and (diastereoselective) Pfaltz hydrogenation of the resulting triple‐substituted olefin. The work demonstrates the potential of iridium catalysis for enantioselective C−C bond activation.