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16. Stereoselective Synthesis of Alexine Stereoisomers from (S)-Pyroglutamic Acid
Nobuo Ikota and Hidehiko Nakagawa
Keywords: polyhydroxylated pyrrolizidine alkaloid, glyosidase inhibitor, (S)-pyroglutamic acid, diastereoselective allylation, chiral synthesis
Alexines1 are polyhydroxylated pyrrolizidine alkaloid with a carbon substituent at C-3 and five adjacent asymmetric carbons. They have been shown to possess interesting biological activities such as inhibitory activity toward glucosidase and antiviral activity. In a continuation of our synthetic studies to utilize optically active pyroglutamic acid derivatives for natural product synthesis, we describe here a stereocontrolled synthesis of 1-epialexine 11 and 1,7-diepialexine 12 via a non-carbohydrate based approach utilizing (S)-pyroglutamic acid derivative (Fig. 11).
An enone 3was obtained by the reaction of (3R,4R,5R)-1-(tert-butoxycarbonyl)-3,4-isopropylidenedioxy-5-trityloxymethyl-2-pyrrolidinone 2, prepared from the unsaturated lactam 1 by dihydroxylation with a catalytic amount of OsO4 in the presence of N-methylmorpholine N-oxide followed by isopropylidenation, with vinylmagnesium bromide in tetrahydrofuran (THF) at -40 to -50°C in 93% yield. Redution of 3 with NaBH4 in the presence of CeC3 in MeOH gave an allylic alcohol 4 as a mixture of diastereomers in 91% yield. Mesylation of 4 followed by cyclization with potassium tert-butoxide in THF gave the pyrrolidine 5 as an inseparable diastereomeric mixture in 68% yield, from which the diols 6 and 7 were isolated by treatment with ozone followed by NaBH4 reduction in EtOH in 60% and 25% yields, respectively.
The carbon unit required for the pyrrolizidine ring was introduced using a diastereoselective allylation of the aldehyde derived from the alcohols 6 and 7. 6 was oxidized by the method of Swern to afford the corresponding aldehyde , which was very unstable, and only a trace of aldehyde was obtained after aqueous workup. Therefore, allylmagnesium chloride in THF was directly added to the crude Swern oxidation mixture of 6 in THF at -78°C to afford allylic alcohols 8a and 9 in 52% and 25% yields after column chromatography, respectively. The hydroxy group in 8a was protected as the methoxymethyl ether (chloromethyl methyl ether, N,N-diethyl-aniline, methylene chloride), and selective transformation of the N-tert-butoxycarbonyl group in 8b into the N-benzyl group was done by treatment with tert-butyldimethylsilyltrifluoro-methane-sulfonate in the presence of 2,6-lutidine followed by successive treatments with tetrabutylammonium fluoride in THF and benzyl bromide in the presence of potassium carbonate in acetone to furnish 8c in 58% yield. Ozonolysis of 8c followed by reductive workup with NaBH4 gave the alcohol 10 in 58% yield. Mesylation of 10 gave a mesylate, which was spontaneously cyclized to give the pyrrolizidine derivative. After hydrogenation of the protected pyrrolizidine with 10% palladium on carbon in EtOH under hydrogen in the presence of hydrogen chloride to remove the N-benzyl group, acidic treatment with 10% HCl-MeOH (1:1) at 70°C to cleave the acetonide and trityl groups afforded the 1-epialexine 11 ([
]D20 +34.8° (c=0.5, H2O)), in 52% yield after purification by ion exchange chromatography (Dowex 50W-X8, H+ form). By a parallel series of reactions, the allylic alcohol 9 was converted to 1,7-diepialexine 12([]D20 +37.0° (c=0.7, H2O), in 15% yield.
Publications:
Ikota N., Nakagawa H., Ohno S., Okuyama K., Noguchi K. : Tetrahedron, 54, 8985-8998 , 1998.
