Synthesis of indolizidines from optically pure α‐amino acids via stereocontrolled rhodium‐catalyzed hydroformylation of N‐allylpyrroles

Abstract

Indolizidine alkaloids have attracted considerable attention because of their vast array of structural diversity and varied biological activity. This article relates the results that we obtained in the field of the total synthesis of indolizidines from α-amino acids, based on the rhodium-catalyzed hydroformylation of N-allylpyrroles intermediates. The formed pyrrolylbutanals undergo an intramolecular cyclodehydration to 5,6-dihydroindolizines, which are fully hydrogenated to indolizidines. All reaction sequences are stereocontrolled: indeed, the chiral center in the starting amino acid is transferred into 5,6-dihydroindolizine moiety with complete stereochemical integrity and the new stereogenic center at C9 carbon atom in the final indolizidines is generated in only one configuration.

Domino Reactions Triggered by Hydroformylation

“…Compound 101 can be used as the starting material for the synthesis of (S)-coniceine 102 where a tandem process involving HF is essential (Scheme 18 [b]). CHC also proved to be helpful in the total synthesis of many natural products like coniine 104, anabasine 105 [26], crispine A [41] (Scheme 19), and many other indolizidine alkaloids (for a review on the use of domino HF protocols in natural products synthesis see [42]). …”

Studies toward the First Stereoselective Total Synthesis of (±)-Quinolizidine 195C and Other Transformations

“…Using a procedure similar to that for the preparation of compound 8, compound 7 (39.1 mg, 0.13 mmol) gave product 9 (20.3 mg, 80%). Yellow oil; (10). To a solution of compound 8 (17.1 mg, 0.09 mmol) in THF (1 mL) under nitrogen was added dropwise LiAlH 4 (2.4 M in THF, 0.16 mL, 0.38 mmol) at 0 °C.…”

“…Among the piperidine natural products are the bicyclic indolizidines and quinolizidines [5][6][7][8][9][10][11][12][13][14][15][16]. Imino-Diels-Alder reactions are very useful for the synthesis of tetrahydropyridines [17][18][19].…”

Synthesis of Aminoindolizidines through the Chemoselective and Diastereoselective Catalytic Hydrogenation of Indolizines

“…Different synthetic strategies have been developed to construct the indolizidine skeleton according to the substitution pattern pursued, including (a) by using pyrroles as building blocks, (b) from α-amino acids via stereocontrolled rhodium-catalyzed hydroformylation of N -allylpyrroles, (c) based on organosulfur and selenium chemistry (i.e., conjugate addition of nitrogen nucleophiles containing ester or chloroalkyl substituents to acetylenic sulfones, followed by base-mediated intramolecular alkylation or acylation), (d) by stereocontrolled cyclic nitrone cycloaddition, (e) by addition of allylsilanes to N -acyliminium ions, (f) by stereoselective conjugate addition reactions, (g) through radical azidation reactions, and (h) through chiral oxazolopiperidone lactams . However, although the synthesis of indolizidines by the reduction of indolizines seems to be a direct approach, it has been barely documented and limited to some isolated examples .…”