Steric vs hydrogen-bonding control of atropisomerization: preparation of either diastereomer of configurationally stable allocolchicinoids.
Steric vs hydrogen-bonding atropisomerization control of configurationally stable analogues of the biaryl natural product allocolchicine is described. Intramolecular hydrogen bonding between the C8 hydroxy group and the C7 oxygen functionality in (aR,7R)-diastereomer II of 2 and 4 leads to its thermodynamic stabilization relative to the opposite diastereomer (aR,7S)-I, which is manifested by the strong preference toward II under thermal equilibration conditions (>94% de). Protection of C8-OH removes the H-bonding and results in repulsive interaction between C7 and C8 functionalities, which destabilizes II. Steric tuning of the C8 protecting group in 7-12 allows for almost complete inversion of the axial configuration in 2 under thermal equilibration conditions (>96% de toward I). Previously unavailable phenolic allocolchicinoids (aR,7S)-2,I are subsequently released by deprotection.
Vorogushin
Andrei V
AV
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, USA.
Wulff
William D
WD
Hansen
Hans-Jürgen
HJ
D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D003078:Colchicine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D006860:Hydrogen Bonding; D006873:Hydroquinones / Q000737:chemistry; D010636:Phenols / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000970:Antineoplastic Agents; D006873:Hydroquinones; D010636:Phenols; C032782:allocolchicine; D003078:Colchicine; C031927:hydroquinone