Highly diastereoselective approach to novel tetrahydrofuran-fused indolizidinols: a one-step formation of three contiguous stereocenters

A concise and very efficient route to enantiopure tetrahydrofuran-fused indolizidinols, which could be considered as protected new indolizidindiols, is described in two-steps sequence starting from the known furoindolizidindiones. The key-step of these transformations was the formation, in one operation, of THF indolizidinols containing a lactam function by simultaneous highly diastereoselective catalytic hydrogenation of the carbonyl function and the furan ring. During these investigations, numerous catalysts in different combinations were tested and the impact of substrates on the reduction profile is discussed.

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(3aR,4S,4aS,9aR)-4-Hydroxyoctahydrofuro[2,3-f]-indolizin-7(2H)-oneC10H15NO3[α]D = −0.6 (c 1.0, EtOH)Absolute configuration: (3aR,4S,4aS,9aR)Source of chirality: (S)-glutamic acid

(3aR,4R,4aS,9aR)-4-Hydroxyoctahydrofuro[2,3-f]indolizin-7(2H)-oneC10H15NO3[α]D = −44.8 (c 1.0, EtOH)Absolute configuration: (3aR,4R,4aS,9aR)Source of chirality: (S)-glutamic acid

(3aS,8aS,9R,9aS)-9-Hydroxyoctahydrofuro[3,2-f]indolizin-6(2H)-oneC10H15NO3[α]D = −31.8 (c 1.0, EtOH)Absolute configuration: (3aS,8aS,9R,9aS)Source of chirality: (S)-glutamic acid

(3aS,8aS,9S,9aS)-9-Hydroxyoctahydro[3,2-f]-indolizin-6(2H)-oneC10H15NO3[α]D = −35.6 (c 1.0, EtOH)Absolute configuration: (3aS,8aS,9S,9aS)Source of chirality: (S)-glutamic acid

(3aR,8aS,9S,9aR)-9-Hydroxyoctahydro[3,2-f]-indolizin-6(2H)-oneC10H15NO3[α]D = −17.8 (c 1.0, EtOH)Absolute configuration: (3aR,8aS,9S,9aR)Source of chirality: (S)-glutamic acid

(3aR,4S,4aS,9aR)-4-Hydroxyoctahydrofuro[2,3-f]-indolizineC10H17NO2[α]D = +181 (c 1.0, MeOH)Absolute configuration: (3aR,4S,4aS,9aR)Source of chirality: (S)-glutamic acid

(3aS,8aS,9R,9aS)-9-Hydroxyoctahydrofuro[2,3-f]-indolizineC10H17NO2[α]D = +34.0 (c 1.0, EtOH)Absolute configuration: (3aS,8aS,9R,9aS)Source of chirality: (S)-glutamic acid