Highly Stereoselectivetrans Addition of π-Type Nucleophiles to a BicyclicN-Acyliminium Ion – Application to the Synthesis of Indolizidine and Pyrrolizidine Alkaloids

Abstract

Enantiopure bicyclic 5‐ethoxytetrahydropyrrolo[1,2‐c]oxazol‐3‐one 1b was prepared in two steps from the known tosylate 4, which is readily available from (S)‐pyroglutamic acid. Trapping of the N‐acyliminium ion (I), generated in situ from 1b in the presence of Lewis acid, with various silylated π‐type nucleophiles gave rise selectively to trans adducts 2. The usefulness of this stereoselective access to trans‐2,5‐disubstituted pyrrolidines was illustrated by formal syntheses of 3,5‐disubstituted indolizidine toxins, starting from 5‐allyltetrahydropyrrolo[1,2‐c]oxazol‐3‐one 2a. Moreover, an enantiodivergent synthesis of the pyrrolizidine alkaloids (+) and (–)‐xenovenine was achieved starting from the same chiral building block 2a.

Origin of Diastereoselection in the Hydrosilylation of Chiral N‐Acyliminium Intermediates Derived from Pyroglutamic Acid

“…As predicted by the experimentally observed π‐face selectivity (Table 1, entries 5–8), syn ‐ TS‐II is 1.01 kcal mol −1 [MP2/6‐311+G(d,p)//HF/6‐31G(d,p) including ZPVE correction scaled by 0.913514] lower in energy than anti ‐ TS‐II 15. Based on AM1 calculations, Lhommet and co‐workers proposed that the syn attack is preferred owing to a relief in the steric hindrance existing between the two methoxycarbonyl groups 4d. However, our calculation shows that the dihedral angle between the two methoxycarbonyl groups in syn ‐ TS‐II is 11.3° smaller than that in anti ‐ TS‐II , indicating such steric interaction does not play a role in the diastereoface selection.…”

An expedient synthesis ofN-acceptor-substituted 2,3-dihydropyrrols from the corresponding 2-pyrrolidinones

“…If R 1 is an alkyl substituent the target compounds 1 are ideally prepared from the corresponding N,O-acetals 3 or from the lactamols 2 which may in turn be obtained either oxidatively from pyrrolidines [1,6] or reductively from pyrrolidinones [7]. The oxidative approach has been reported to be not regioselective in some instances [8]. The proton-catalyzed [1] and the uncatalyzed [7] thermal elimination procedures which have been used to transform the N-alkoxycarbonyl-pyrrolidines 2 or 3 into dihydropyrrols did not prove to be well suited for small scale work in our hands.…”

Stereodivergent routes in organic synthesis: carbohydrates, amino acids, alkaloids and terpenes

“…Enantiopure trans-2,5-disubstituted pyrrolidines are constituent units of natural pyrrolizidine and indolizidine alkaloids constituents of ant venom and frog poison. Lhommet and co-workers 72 have synthesized the pyrrolizidine alkaloids (+)-and ()xenovenine, found in ant venom (Solenopsis xenovenum), by enantiodivergent routes from the same chiral intermediate. The synthesis of (+)-xenovenine began by reduction of the tosylate with the superhydride to the trans-pyrrolidine, followed by oxidative hydroboration of the allyl substituent and final oxidation and hydrogenation 73 (Scheme 45).…”