Hyacinthacine

Reductive coupling of the corresponding nitrones with alkyl acrylate is the key step in the short synthetic route of the selective and irreversible GABA inhibitor of amino transferase (S)-vigabatine (534) and of polyhydroxy pyrrolizidine alkaloid (+ )-hyacinthacine A2 (535). 

Highly selective 1,3-dipolar cycloaddition reactions of nitrone (154) with acrylates have been used in the total syntheses of pyrrolizidine alkaloids, 7-deoxy-casuarine (572) and hyacinthacine A2 (573) (Scheme 2.263) (772). 

Dipolarophiles D14. The 1,3-dipolar cycloaddition of nitrones to dimethyl maleate and dimethyl fumarate is widely used in the synthesis of polyhydroxy alkaloid derivatives of dihydroindolizidinone (81), pyrrolizidine (119), (—)-codonopsinine, and (+ )-hyacinthacines Ai and A2 (312). In cases of unstable nitrones, syntheses of cycloadducts are performed in situ (81). 

The unnatural enantiomers (—)-hyacinthacine A2 (natural enantiomer is (+)-hyacinthacine A2), 7-deoxy-2-ep -alexine (enantiomer of 3-ep -hyacinthacine A2), enf-7-deoxyalexine (enantiomer of 7-deoxy-alexine) and 2-epi-hyacinthacine A2 were synthesised [150]. Interestingly, (—)-hyacinthacine A2 exhibited an a-D-glucosidase inhibitory effect which was not observed for the naturally occurring (+) enantiomer. This fact clearly indicates the urgent need for additional syntheses of non-natural enantiomers in the natural products field. 

For the described approach, it is important to note that aldolases of different origin were tested and that, in contrast to L-rhamnulose-1-phosphate aldolase (RhuA), the D-fructose-1,6-biphosphate aldolase from rabbit muscle and L-fucu-lose-1-phosphate aldolase from E. coli were not active for DHAP/(R)-N- and (S)-iV-Cbz-prolinal condensation. Since RhuA accepts both, (S)-N- and (R)-N-Cbz prolinals, the chemo-enzymatic synthesis of both, hyacinthacines A and A2 isomers could be achieved. In conclusion, the origin and the particular enzyme itself... 

Py used a nitrone-alkene coupling in a short, asymmetric synthesis of (+ )-hyacinthacine A2 (Scheme 5.43).74 The key carbon-carbon bond-forming step in their approach involved the highly diastereoselective reductive coupling of the L-xylose-derived cyclic nitrone 66 to ethyl acrylate.74... 

Several examples have been reported also this year, and among them there are the total syntheses of the natural products (-i-)-hyacinthacine A2 (73) <03TL2315> (for an analogous approach to 73 see <03SL35>), (-)-monatin 77 <03CC2678>, and (-i-)-heliotridine 81 <03EJO4373>. In all these cases, the reductive opening of the N-0 bond of cycloadducts 75, 79, and 83 was followed by a spontaneous cyclization to afford y-lactam 74, y-lactone 78, and pyrrolizidine 82, respectively. 

IS, 2R, 3R, 7a/if)-l,2-dihydroxy-3-hydroxymethylpyrrolizidine (Hyacinthacine Ai) Muscari armeniacum (Hyacinthaceae) bulbs ... 

IS, 2R, 3R, 5R, 7aR)-h2-dihydroxy-3,5-dihydroxy-meAylpyrrolizidine (Hyacinthacine Bt) Hyacinthoides non-scripta (Hyacinthaceae) fruits/stalks Scilla campanulata (Hyacinthaceae) bulb ... 

Hyacinthacine Aj Potent inhibitor of lactase, moderate inhibitor of amyloglucosidase and a-fucosidase and a poor inhibitor of a- and P-glucosidases and P-mannosidase ... 

Hyacinthacine A3 good inhibitor of amyloglucosidase and moderate inhibitor of lactase ... 

Hyacinthacine Bi Moderate to poor inhibitor of 3-glucosidases and P-galactosidases ... 

Hyacinthacine B3 good inhibitor of lactase and amyloglucosidase and poor inhibitor of a-fucosidase ... 

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