Methyl, alcohol pyrrolidine

The Step 2 product (0.43 mmol) dissolved in 2 ml DMF was treated with sodium hydride (0.95 mmol), then stirred 30 minutes at ambient temperature. The solution was further treated with l-(2-chloroethyl)pyrrolidine HCl (0.48 mmol), then stirred 30 minutes at ambient temperature and 24 hours at 100°C. The solution was concentrated and the residue was washed with 30 ml 10% Na2C03 solution and then extracted with 20 ml EtOAc. The extract was then filtered and reconcentrated. The residue was purified by flash chromatography with CHCl3/methyl alcohol, 19 1, and the product was isolated in 72% yield as a viscous yellow oil. 

In another example, the aiylation of ketone enolates was achieved indirectly via an intermolecular Heck reaction. In this case, the diastereoselectivity is induced by chelation of a metal-coordinating auxiliary. The inexpensive and commercially available amino alcohol (6()-l-methyl-2-pyrrolidine-methanol was selected as a suitable chiral auxiliary (Scheme 13.47). The prolinol vinyl ether 182 was... 

Reduction of l-methyl-2-alkyl-.d -pyrroline and l-methyl-2-alkyl-.d -piperideine perchlorates with complex hydrides prepared in situ by partial decomposition of lithium aluminum hydride with the optically active alcohols (—)-menthol and (—)-borneol affords partially optically active l-methyl-2-alkyl pyrrolidines (153, n = 1) and 1-methy 1-2-alkyl piperideines (153, n = 2), respectively (241,242). 

Optically active alkynyl alcohols can, however, be conveniently prepared by the addition of dialkylzinc reagents of alkynyl aldehydes catalyzed by the chiral ligand (S)-l-methyl-a,a-diphenyl-2-pyrrolidine methanol33-34. 

Nicotine Nicotine, l-methyl-2-(3-piridyl)pirrolidine (13.1.27), is an alkaloid that is isolated from the plant Nicotiana (Nicotiana tabacum, Nicotiam rustica, and others) and can be synthesized in varions ways [33-36]. In particular, it is proposed to proceed from nicotinic acid ethyl ester, which is condensed with iV-methylpyrrolidone, giving l-methyl-2-nicotinoyl pyrrolidone-2 (13.1.23). Acidic hydrolysis of this compound leads to an opening of the pyrrolidine ring giving the intermediate (13.1.24), which under the reaction conditions is decarboxylated to the /-aminoketone (13.1.25). The carbonyl group is reduced to an alcohol and the resnlting prodnct (13.1.26) undergoes dehydration to nicotine (13.1.27). 

The above azomethine ylide cycloadditions have been extended to an enantioselective version involving amino alcohols both as chiral ligands and amine bases. Thus, reactions of the N-metalated azomethine yhdes derived from achiral methyl 2-(arylmethyleneamino)acetates, cobalt(II) chloride [or manganese(II) bromide], and chiral amino alcohols, 1 and 2 equiv each, with methyl acrylate as solvent have been performed to provide the enantiomer-enriched pyrrolidine-2,4-dicarboxylates with the enantioselectivities of up to 96% enantiomeric excess (ee) (128,129). However, a large excess of the metal ions and the chiral source (ligand and base) have to be employed. 

In a closely related reaction, asymmetric reduction of 3-(2V-benzyl-7V-methylamino)propiophenone using H2, [Rh(COD)Cl]2 and the chiral phosphine (2S,4S-(l-(A-methyl-carbamoyl)-4-(dicyclohexylphosphino)-2-[diphenylphosphino)methyl]-pyrrolidine ((2S,4S)-MCCPM), followed by debenzylation and addition of the alcohol to l-chloro-4-(trifluoromethyl)benzene gave (R)-fluoxetine (4-(/ )). ... 

Asymmetric reduction of ketonesLithium aluminium hydride in conjunction with this chiral ligand reduces prochiral aromatic ketones to (S)-secondary alcohols in 90-95% optical yields. Optical yields are lower (10-40% ee) in the case of alkyl aryl ketones. It is superior to (S)-2-(anilinomethyl)pyrrolidine for this reduction. Evidently the two methyl groups enhance the enantioselectivity. 

The iV-aminopyrrole - benzene ring methodology has been applied to a synthesis of the 9,10-dihydrophenanthrene juncusol (218) (81TL1775). Condensation of the tetralone (213) with pyrrolidine and reaction of the enamine with ethyl 3-methoxycarbonylazo-2-butenoate gave pyrrole (214). Diels-Alder reaction of (214) with methyl propiolate produced a 3 1 mixture of (215) and its isomer in 70% yield. Pure (215) was reduced selectively with DIBAL to the alcohol, reoxidized to aldehyde, and then treated with MCPBA to generate formate (216). Saponification to the phenol followed by O-methylation and lithium aluminum hydride reduction of the hindered ester afforded (217), an intermediate which had been converted previously to juncusol (Scheme 46). 

The (R)-enantiomer of (242) has also been prepared and used as a chiral auxiliary in an enantioselective aldol synthesis of (+)-(S )-gingerol (79CB3703). (R )-Glutamic acid (246) was thus converted into (i )-pyroglutamic acid by simply heating in water. Conversion of (247) to its methyl ester and LAH reduction delivered alcohol (248). Ethyl nitrite treatment of (248) gave nitrosoamine (249), which was methylated to furnish (250). Exposure of (250) to LAH completed the synthesis of the required chiral auxiliary RAMP [(R)- l-amino-2-(methoxymethyl)pyrrolidine]. The hydrazone (252), derived from RAMP and acetone, was... 

Reduction of 2,2-dimethyl-cyclohexane-1,3-dione (50) with Baker s yeast gave alcohol (ee 98.3%) whose tetrahydropyranyl derivative on methoxycarbonylation produced (51) quantitatively. Michael addition of (51) with methyl vinyl ketone followed by heating the adduct under reflux with pyrrolidine in benzene yielded (52) in 85% yield as stereoisomeric mixture whose separation presented problems. In order to eliminate the complexity due to a chiral center in tetrahydropyranyl protective group, deprotection of (52) was achieved by treatment with p-toluenesulphonic acid in methanol. The product obtained was a mixture of the lactone (53) and hydroxy ester (54). Probably the stereoisomer of... 

In 1987, Corey and co-workers proved that highly enantioselective reduction of ketones could be achieved by using stoichiometric borane in the presence of catalytic amounts of the oxazaborolidine 28a11 (Scheme 4.3j). Compound 28a, synthesized by heating (S)-(-)-2-(diphenylhydroxymethyl)pyrrolidine at reflux in THF with 3 equivalents of BH3 THF, shows excellent catalytic activity for the asymmetric reduction of acetophenone and other ketones. The B -methylated analog 28b was later synthesized to improve the air and moisture sensitivity associated with 28a. The third analog, 28c, with a 2-naphthyl substituent on the oxazaborolidine ring, has proven to be the best to afford the alcohol 29 with superb levels of enantioselectivity. 

Enantioselective Addition of Alkyllithium Reagents to Aldehydes. (25, 2 5)-2-Hydroxymethyl-l-[(l-methylpyr-rolidin-2-yl)methyl]pyrrolidine (1) is a chiral amino alcohol which binds well to alkyllithium reagents. Enantioselective addition of n-Butyllithium to benzaldehyde in the presence of (1) in a mixed solvent of Mc20 and dimethoxymethane (DMM) (1 1) at —123 °C affords (5)-l-phenylpentan-l-ol with 95% ee in 77% yield. In the addition to 3-methylbutanal, the corresponding (5)-alcohol is obtained in 80% ee (eq 1). 

While caoutchouc was first obtained by polymerizing isoprene it has been found that other hydrocarbons containing the buta i-ydi-ene group will likewise yield caoutchouc. Such hydrocarbons have been obtained from several sources, e.g., turpentiney petroleuniy coaly acetylene. Also compounds related to succinic acid, e.g., pyrotartaric acid (methyl succinic acid) are possible of transformation into isoprene. Levulinic acid, which is aceto propionic acid, CHa—CO—CH2—CH2—COOH, yields a cyclic sulphur compound, methyl-thiophen (p. 853), which, like methyl pyrrolidine, yields isoprene. Ethyl alcohol by conversion into acetone and then by aldol condensation with ethane yields 2-methyl buta 2-ene, CHa—C = CH—CHa which may be transformed... 

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