Synthesis of optically active piperidine and pyrrolidine alkaloids from L-lysine, L-ornithine, or L-proline using anodic oxidation as key steps

Abstract

We have already exploited several convenient methods2 for introducing nucleophiles (R-) to the position a to the nitrogen atom of carbamates 1 using anodically prepared a-methoxylated carbamates 2 as the key intermediates (eq 11.3 1 2 Although this method is applicable to syntheses of a variety of alkaloid^?^ enantioselective introduction of Rat the a position remains to be investigated. Our methodology for this purpose is shown in Scheme I in which (1) chiral compounds 3 are anodically prepared from a-amino acids (step a), (2) R-is diastereoselectively introduced to the a-position through the influence of a substituent on the chiral a'-position (step b), (3) the a'-substituent is eliminated after R-is introduced (step c), and (4) formally enantioselective introduction of R-to the a-position is thus attained through these steps.Although we have already described this methodology in a preliminary note: recent publication of a report6 on the synthesis of optically active alkaloids using our methodology prompted us to report our new findings.Optically active (+)-N-methylconiine 10 was synthesized according to the route outlined in Scheme 11.The key intermediate 5 was prepared by anodic oxidation of 4 derived from L-lysine followed by treatment with acid.5 Treatment of 5 with allyltrimethylsilane followed by hydrogenation gave the cis isomer 6 exclusively. Hydrolysis of 6 followed by anodic decarboxylation7 gave 8, which was then successively reduced with NaBH, and (1) Electroorganic Chemistry, 96.(2) (a) Shono, T.; Mataumura, Y.; Tsubata, K. (3) Shono, T.; Hamaguchi, H.; Matsumwa, Y. J. Am. Chem. SOC. 1975, 97, 4264. (4) Shono, T.; Matsumura, Y.; Uchida, K.; Tsubata, K.; Makino, A. J. Org. Chem. 1984,49, 300. (5) (a) Whole process of this methodology has been presented at the 3rd Synoposium on Electroorganic Chemistry, Osaka, Japan (19829, Abstr. p 59. (b) Shono, T.; Matsumura, Y.; Inoue, K. J. Chem. SOC., Chem. Commun. 1983,1169. (c) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.; Yamane, S.; Kanazawa, T.; Aoki, T. J. Am. Chem. SOC. 1982, 104,6697. (6) Irie, K.; Aoe, K.; Tanaka, T.; Saito, S. J. Chem. SOC., Chem. Commun. 1985,633. (7) Iwasaki, T.; Horikawa, H.; Matsumoto, K.; Miyoshi, M. J. Org. Chem. 1979,44, 1552.

Anodic Selective Functionalization of Cyclic Amine Derivatives

“…Diastereoselective nucleophilic substitution of pipecolinate derivative at the 6-position smoothly proceeded to afford cis-isomer, while control of diastereoselectivity in case of prolinate derivative was difficult. 44 Recently, we found that the N-protecting group affected the diastereoselectivity. 45 That is, N-methoxycarbonylated prolinnate mainly gave cis-allylated prolinate (cis/trans = 73/27), while N-benzoylated prolinate preferentially changed into trans-allylated prolinate (cis/trans = 13/87) (Eq.…”

Convenient synthesis of an enantiomerically pure bicyclic proline and its N-oxyl derivatives

“…10 After isolation of cis-3 by chromatography, transformation of the 6-allyl group to tosyloxyethyl group was carried out by ozonolysis, then NaBH 4 reduction followed by tosylation to obtain 5 in sufficient high yield. Finally, compound 5 underwent a base catalyzed intramolecular alkylation 5d,11 to afford enantiomerically pure 6 with an 8-azabicyclo[3.2.1]octane skeleton in high yield.…”

“…Methyl N-methoxycarbonyl-L-pipecolinate (ent-1) 10 and methyl N-methoxycarbonyl-6-methoxy-L-pipecolinate (ent-2) 10 are known compounds.…”

An easy access to two epimeric N-substituted (2S)-2-(2'-hydroxypropyl)pyrrolidines

“…Dissolution of this product in dioxane (10.0 mL), followed by the addition of water (10.0 mL) and Ag 2 O (0.10 g) and stirring at 90 °C for 6h completed the reaction. Filtration over celite, solvent removal and purification by column chromatography over silica using CH 2 …”

“…There are entries for the racemic alcohols 3 and 4, 1,2 and also of enantiomerically pure 4. 3 Our interest developed knowing the fact that pyrrolidine derivatives possess biological activities.…”