抄録
One-pot processes, the sequential conjugation of plural bond forming reactions, are powerful tools in organic synthesis. Conjugate addition of lithium amide 4 to enoate 5 forms an N-C bond and generates lithium enolate 6, which is further applicable as a carbonucleophile2b) reacting in an SN2 manner with electrophile 8 (Scheme 1). We have recently succeeded in the application of this tandem conjugate lithioamination-alkylation to the asymmetric total synthesis of (-)-aspidospermidine. When an electrophile has two reaction sites like dihalide 12, the initially introduced nitrogen atom in 13 undergoes an intramolecular S_N2 reaction to form piperidine 11 (Scheme 2). We describe herein an asymmetric one-pot piperidine formation using our asymmetric conjugate lithioamination of a lithium amide with an enoate as the central machinery, and the total synthesis of (-)-kopsinine 11) (Fig. 1). An asymmetric conjugate addition of 4 was performed with 14 using chiral diether ent-3 in toluene at -78℃ for 1.5h and then at -40℃ for 2h to afford, after quenching with HC1 in Me0H, 3-aminoester 16 with 95% ee in 75% yield (Scheme 3). Then, alkylation of enolate 13 as the second step was examined. After lithioamination, alkylation was performed by the addition of 12a in THF/HMPA to give, after treatment with tetrabutylammonium fluoride to remove the TBS group, 17 as a sole diastereomer in 70% yield with disappointingly poorer 86% ee (entry 1). DMPU was found to be a good additive, and 17 was obtained with excellent enantio- and diastereoselectivity (entry 2). Finally, conducting the conjugate addition step at -65℃ for 15 h, 17 was produced in 89% yield with 98% ee (entry 3). A one-pot piperidine formation was realized by sequential asymmetric conjugate lithioamination, stereoselective alkylation with 1-chloro-3-iodopropane 12b in the presence of DMPU, giving cis-11 with 98% ee in 85% yield. N-Hydroxyethylpiperidine methyl ester 19 was obtained in 85% three-step yield from cis-10 by hydrogenolysis, N-hydroxyethylation, and simultaneous de-Boc and methyl esterification by heating in refluxing methanol with sulfuric acid (Scheme 4). Claisen condensation of 19 with lithium enolate 21b gave ketoester 23 in 72% yield (Scheme 6). Mesylation of 23 and subsequent treatment with potassium tert-butoxide gave pentacyclic 10, a known synthetic intermediate of (-)-kopsinine (1), in 61% two-step yield. (-)-kopsinine (1) was synthesized by reported sequences from 15, whose absolute configuration was then undoubtedly confirmed (Scheme 7).
