Doctor of Philosophy
University of Wollongong. School of Chemistry
Au, Christopher Wai Gee, Synthesis of 1,2-anti amino alcohols and their applications in the asymmetric synthesis of polyhydroxylated indolizidine and pyrrolizidine alkaloids, Doctor of Philosophy thesis, University of Wollongong. School of Chemistry, University of Wollongong, 2010. http://ro.uow.edu.au/theses/3162
POLYHYDROXYLATED ALKALOIDS—NATURAL HETEROCYCLES THAT CONTAIN ONE OR MORE BASIC NITROGEN ATOMS AND VARIOUS NUMBERS OF HYDROXY SUBSTITUENTS—ARE A CLASS OF ORGANIC COMPOUNDS THAT HAS ATTRACTED MUCH ATTENTION DUE TO THEIR INHIBITORY ACTIVITIES AGAINST GLYCOSIDASE ENZYMES. THE 1,2,8-TRIHYDROXY-INDOLIZIDINE ALKALOID (-)-SWAINSONINE 1 WAS FIRST ISOLATED IN 1973 FROM THE FUNGUS RHIZOCTONIA LEGUMINICOLA AND EXHIBITED HIGH INHIBITORY ACTIVITIES (IC50 = 0.2 μM) TOWARDS BOTH GOLGI MANNOSIDASE II AND LYSOSOMAL α-d-MANNOSIDASE. THE POLYHYDROXYLATED PYRROLIZIDINE ALKALOID HYACINTHACINE B3 104 WAS ISOLATED FROM FRESH BULBS OF THE HYACINTHACEAE PLANT MUSCARI ARMENIACUM AND WAS FOUND TO BE A MODERATE INHIBITOR OF β-GALACTOSIDASE (IC50 = 18 μM) AND WAS A WEAK AMYLOGLUCOSIDASE INHIBITOR (IC50 = 51 μM). HYACINTHACINE B7 112, REPORTED TO BE THE C-7 EPIMER OF 104, WAS ISOLATED FROM THE BULBS OF SCILLA SOCIALIS AND EXHIBITED WEAK INHIBITORY ACTIVITY TOWARDS AN AMYLOGLUCOSIDASE ENZYME.
The main focus of this study was to examine the utility of 1,2-anti amino alcohols in the development of a general strategy towards synthesizing polyhdroxylated indolizildine and pyrrolizidine alkaloids. Chiral α-hydroxy aldehydes generated in situ by the Sharpless asymmetric dihydroxylation (ADH) reaction of vinyl sulfones underwent a borono-Mannich reaction with β-styrenyl boronic acid and primary amines to give 1,2-anti amino alcohols in high enantiomeric purities (83-95% ee). The anti amino alcohol 353, synthesized via the Sharpless-Petasis sequence from 4-penten-1-ol, was converted into indolizidine 22 in an additional four synthetic steps. This represented a formal synthesis of (-)-1 in ten-steps and 7.7% overall yield from commercially available starting material.
The utility 1,2-anti amino alcohols in alkaloid synthesis was further exemplified in the total syntheses of hyacinthacine B3 104 and the purported structure of hyacinthacine B7 112. Starting from (S)-4-penten-2-ol, the anti amino alcohol 382 was synthesized via the Sharpless-Petasis sequence and was converted to 104 in a total 13 steps and 5.6% overall yield. This total synthesis confirms the structure of hyacinthacine B3. In an analogous fashion, the reported structure of hyacinthacine B7 112 was synthesized in 13 synthetic steps from (R)¬4-penten-2-ol (397) and 3.4% overall yield. However, the NMR data of our synthetic 112 did not agree with those of not agree with those of the natural product. Further spectroscopic studies have confirmed the structure and stereochemical configuration of our synthetic 112 and concluded that the reported structure of hyacinthacine B7 was incorrect.
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