Synthesis and Glycosidase Inhibition of Broussonetine M and Its Analogues

Abstract

Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M (3) from the d-arabinose-derived cyclic nitrone 14. By a similar strategy, ent-broussonetine M (ent-3) and six other stereoisomers have been synthesized, respectively, starting from l-arabino-nitrone (ent-14), l-lyxo-nitrone (ent-3-epi-14), and l-xylo-nitrone (2-epi-14) in five steps, in 26%–31% overall yield. The natural product broussonetine M (3) and 10’-epi-3 were potent inhibitors of β-glucosidase (IC50 = 6.3 μM and 0.8 μM, respectively) and β-galactosidase (IC50 = 2.3 μM and 0.2 μM, respectively); while their enantiomers, ent-3 and ent-10’-epi-3, were selective and potent inhibitors of rice α-glucosidase (IC50 = 1.2 μM and 1.3 μM, respectively) and rat intestinal maltase (IC50 = 0.29 μM and 18 μM, respectively). Both the configuration of the polyhydroxylated pyrrolidine ring and C-10’ hydroxyl on the alkyl side chain affect the specificity and potency of glycosidase inhibition.

Recent advances in the total synthesis of polyhydroxylated alkaloids via chiral oxazines

“…In summary, our synthetic strategy utilizing syn , syn -, syn , anti -, anti , syn -oxazines as chiral building blocks enabled the synthesis of 30 diverse polyhydroxylated alkaloids, providing enantiomerically and diastereomerically pure products in a facile, efficient, and versatile manner. Various flexible strategies employed by other researchers, utilizing such as Overman rearrangement reaction, 38–42 tandem [4 + 2]/[3 + 2] nitroalkene cycloaddition, 45–49 Birch reduction, 50–54 and metal-mediated cross-coupling, 81–83 or with the use of key starting materials like chlorosulfonyl isocyanate, 61–67 Garner's aldehyde, 71–80 protected amino aldehydes, 84,85 and sugar-derived cyclic nitrone, 55–60,86–91 have been valuable. However, our strategy stands out due to its versatility, successfully synthesizing a range of natural products and offering potential applications in other natural products and pharmaceuticals like lycoricidine and miglitol.…”

“…Yu and coworkers initiated their synthesis using xylose-derived cyclic nitrone and explored various fluorinated derivatives, along with their subsequent biological evaluation. Using this and similar routes, they successfully synthesized compounds such as radicamine B, 86 hyacinthacine A 3 , 87 DMDP, 88 homoDMDP, 88 broussonetines I, 89 J 2 , 89 M, 90 australine, 91 and 7- epi -australine. 91…”

The chemistry and biology of natural ribomimetics and related compounds

“…[44][45][46][47][48] Broussonetines have been shown to have inhibitory activity against various glycosidases. 49,50 Some other plants also produce N-ribomimetics. For example, the Asian bell flower plant Codonopsis clematidea produces codonopsinine (48), codonopsine (49), and codonopsinol (50), [51][52][53] all of which showed good glycosidase inhibitory activity.…”

“…44–48 Broussonetines have been shown to have inhibitory activity against various glycosidases. 49,50…”

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

“…Expectedly, quite a number of these five-membered acetamide derivatives were found to be potent β-HexNAcase inhibitors [16,21,25,26]. In continuation of our interests in structure-activity relationship study of iminosugars [39,[43][44][45][46], in this work, 20 stereoisomeric pyrrolidine analogues of pochonicine (1) were synthesized and systematically assayed as glycosidase inhibitors, in order to look for novel molecules with simplified structure and remained potent inhibitory activities. 2, As one of the most potent β-HexNAcase inhibitors, pochonicine (1) possesses a polyhydroxylated pyrrolizidine skeleton, in contrast to the polyhydroxylated piperidine ring present in the other two naturally occurring iminosugars, nagstatin (2) [12] and siastatin B (3) ( Figure 1) [13].…”