Total Syntheses of (+)-Australine and (−)-7-Epialexine

• Published in: Journal of organic chemistry Vol. 65; no. 18; pp. 5785 - 5793
• Main Authors: Pearson, William H, Hines, Jennifer V
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.09.2000; Amer Chemical Soc
• Subjects: Azides - chemistry; Chemistry; Chemistry, Organic; Oxidation-Reduction; Physical Sciences; Pyrrolizidine Alkaloids - chemical synthesis; Science & Technology; Spectrum Analysis; Stereoisomerism; ROUTE; CASTANOSPERMUM-AUSTRALE; SWAINSONINE; INDOLIZIDINES; (+)-CASTANOSPERMINE; (1R,2R,3R,7S,8S)-3-HYDROXYMETHYL-1,2,7-TRIHYDROXYPYRROLIZIDINE; PYRROLIZIDINES; CYCLIZATION; RAY CRYSTAL-STRUCTURE; ALKALOIDS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo000689q

Three approaches were examined for the synthesis of 3-(hydroxymethyl)pyrrolizidines, a class of compounds that includes the polyhydroxylated pyrrolizidine alkaloids alexine (1), australine (2), and various stereoisomers of thereof. In the first approach, the intramolecular cycloaddition of an azide onto an electron-rich 1,3-diene bearing a terminal alkoxymethyl substituent (i.e., 21) afforded the dehydropyrrolizidines 22a and 22b, with 22a predominating. A rationale for this stereoselectivity was proposed. Transformation of the major diastereomer 22a into a natural 3-(hydroxymethyl)pyrrolizidine was not possible due to difficulties encountered in transforming the phenyl vinyl sulfide functionality into other useful functional groups. A second approach was examined, wherein the intramolecular cycloaddition of an azide with an optically pure S-t-Bu-substituted diene (i.e., 30) was found to produce the pyrrolizidine 31. In this case, the alkoxymethyl substituent was incorporated into the tether between the azide and the diene, rather than on the diene itself. A key transformation in the synthesis of the diene 30 was the use of the allylic borane R2BCH2CHC(TMS)(StBu) for the stereoselective conversion of the d-arabinose-derived azido aldehyde 28 to the E-isomer of 30. The cyclization of 30 to 31 also produced the bicyclic triazene 32, the result of 1,3-dipolar cycloaddition of the azide onto the distal double bond of the diene. Again, difficulties in transformation of the vinyl sulfide functionality of 31 into useful oxygen functionality limited this approach to naturally occurring 3-(hydroxymethyl)pyrrolizidines. A third approach to these compounds was successful. The transformation of l-xylose into the azido epoxy tosylate 46 was accomplished using two Wittig reactions and an epoxidation, in addition to other standard functional group manipulations. Reductive double-cyclization of 46 afforded the pyrrolizidines 47a and 47b, which were debenzylated to afford (+)-australine 2 and (−)-7-epialexine 4, respectively. In the preliminary report of this work, erroneous spectroscopic data in the original literature on the structural assignment of australine led to the conclusion that the synthetic material obtained herein was actually (+)-7-epiaustraline. Recently corrected spectroscopic data have appeared which verify that (+)-australine 2 was indeed synthesized for the first time.