Heterocyclic templates for assembling α-hydroxy-β-amino acids, sphingosines and indolizidines

Abstract

L-Aspartic acid is converted into (3S)-3-(tosylamino)butano-4-lactone (7). Electrophilic hydroxylation and methylation of 7 give, after opening with ethanolic trimethylsilyl iodide, the syn-disposed 2-hydroxy- and 2-methyl-3-tosylamino-4-iodobutyric ethyl esters (9 and 13). Nucleophilic phenylation of 9 with subsequent saponification and deprotection gives a component of bestatin. Similarly, methylation of 13 gives (2S,3R)-3-amino-2-methylpentanoic acid. The enantiomer of 9 on reaction with morpholine affords an ester which by reduction to the aldehyde and Wittig olefination gives the 1-(N-morpholine) derivative of D-threo-Z-sphingosine. Condensation of diethyl L-glutamate hydrochloride and 2,5-dimethoxytetrahydrofuran gives the pyrrole derivative 31, which is cyclized to(5S)-5,6-dihydro-5-ethoxycarbonyl-8(7H)-indolizinone (32). Hydrogenation of 32, depending on the catalyst (Pd/C or Rh/Al2O3), gives predominantly (5S,9R)-5-ethoxycarbonylindolizidine (33) or the corresponding (8S)-8-hydroxy derivative (34) respectively. By functional group conversions, 33 is transformed into piclavine A and indolizidine 209D. Indolizidine 209B is similarly obtained from 34, whereas 31 after butyrylation at C2 provides for the synthesis of (-)-monomorine through an analogous sequence.