Novel Routes to Chiral 2-Alkoxy-5-/6- methoxycarbonylmethylidenepyrrolidines/-piperidines

Abstract

We report the results of a study aimed at the diastereoselective synthesis of chiral 2-alkoxy-5-/6-methoxycarbonylmethylidenepyrrolidines/-piperidines by condensation of chiral amines onto omega-oxo alkynoates and omega-oxo beta-keto esters.

Stereoselective Synthesis of New Chiral N-Tertiary Tetrasubstituted β-Enamino Ester Piperidines through an Ammonia-Catalyzed Process

“…The stereochemistry of the double bond was assigned as ( Z ) on the basis of NOE experiments that showed interactions between the methyl group on the double bond (δ 1.74) and the C-3‘ (δ 2.19) hydrogens. This result was unexpected since N -substituted pyrrolidine and piperidine β-enamino esters bearing an exocyclic double bond had been previously obtained generally as the ( E )-isomer, with at worst the ( Z )-isomer as a minor product. 2a,, …”

“…Therefore, we moved to the second strategy based on the intramolecular cyclization of α-substituted ω-amino β-keto esters 6 (Scheme , route b). Preparation of compound 6a (R 2 = Me) was carried out starting from methyl 7-chloro-3-oxoheptanoate 2c. The latter was treated with methyl iodide in the presence of potassium carbonate to cleanly afford compound 9a in 96% yield (Scheme ).…”

“…Considering the outstanding interest of heterocyclic β-enamino esters as intermediates in the total syntheses of alkaloids, we have developed a program aimed at preparing various chiral pyrrolidine and piperidine β-enamino esters . In particular, β-enamino esters 1 and 2 featuring both an exocyclic tetrasubstituted double bond (R 2 ≠ H) and a chiral auxiliary on the nitrogen atom (R 1 ≠ H) have attracted our attention (Figure ) as a way to access chiral pyrrolidines and piperidines following the stereocontrolled reduction of the double bond, which would simultaneously create two stereogenic centers.…”

New access to chiral pyrrolidine and piperidine β-enamino ketones. Application to the enantioselective synthesis of (–)-hygroline

“…Column chromatography readily afforded the isolation of the two diastereomers in respectively 48% and 18% yields. The configuration at C-7a of the major isomer of 5a was assigned to (R), by analogy with analogous pyrrolidine β-enaminoester 1 8 (Scheme 1), based on the comparison of their chemical shifts in 13 C NMR. In particular, similar chemical shifts for C-2 and C-3 were observed for the major isomer of 5a and for (7aR)-1.…”

“…3a,3b,5 Alternative procedures have been developed to synthesize morpholinone, 6 pyrrolidine 7 and piperidine 4a,7 derivatives. More recently, we described the preparation of chiral bicyclic pyrrolidine and piperidine β-enamino esters (7aR)-1 and (8aR)-2, by condensation of (S)-phenylglycinol with ω-oxo alkynoates 3 and 4 (R = OMe) 8 (Scheme 1). During the course of this work, we realized that our strategy could be extended towards the obtention of oxazolidine β-enamino ketone analogues 5 and 6 (Scheme 1).…”