Alkoxyallene-Based Stereodivergent Syntheses of (−)-Hyacinthacine B₄ and of Putative Hyacinthacine C₅ Epimers: Proposal of Hyacinthacine C₅ Structure

Abstract

Hyacinthacines are members of the class of polyhydroxylated pyrrolizidines exhibiting outstanding biological activity as glycosidases inhibitors. Their structural complexity is embodied in the densely functionalized core, possessing a series of contiguous stereogenic centers. In this synthetic study we report a route to the more complex congeners of this class of alkaloids exploiting the diastereoselective addition of an axially chiral lithiated alkoxyallene to an enantiopure cyclic nitrone. Our stereodivergent approach enabled the installation of the targeted configuration at the ring A by minimal synthetic manipulations and at ring B by using stage dependent selective functionalizations. The versatility and robustness of this methodology were demonstrated by the syntheses of (-)-hyacinthacine B and of two epimers of (+)-hyacinthacine C, allowing a suggestion of the likely structure of the isolated natural product.

Total Synthesis of Natural Hyacinthacine C5 and Six Related Hyacinthacine C5 Epimers

“…10 does not spectroscopically match with the same structure previously reported. 22 Our enzyme inhibition studies suggest that relative to casuarine, the C5 methyl substituted derivatives prepared here were generally less potent glycosidase inhibitors. 13 C NMR signals that were absent in the standard 13 C NMR spectrum were identified using gHSQC experiments.…”

“…Table 2. Comparison of literature 13 C NMR data of (+)-5-epi-6 ((+)-10) (100 MHz, D 2 O) 22 with synthetic 10 and 10.HCl 13 These results prompted us to conduct extensive NOE experiments on compound 10, finding key correlations between H7-Me, H1-H7, H5-H6, H2-H7a, H6-H7a and Me-H3 ( Figure 5).…”

“…Table 1. Comparison of literature 1 H NMR data of (+)-5-epi-6 ((+)-10) (400 MHz, D 2 O) 22 with synthetic 10 and 10.HCl (500 MHz, D O)…”

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

“…To date, fourteen of the natural hyacinthacines, A 1 , A 2 , A 3 , A 6 , A 7 , B 1 , B 2 , B 3 , B 4 , B 5 , B 7 , C 2 , C 3 and C 5 have been synthesized, along with their related epimers and enantiomers [ 51 - 64 ]. At this point, the authors note that an increasing number of reports suggest the confirmation of hyacinthacine A 5 through methods of total synthesis [ 61 , 63 , 65 ]. To the best of our knowledge, hyacinthacine A 5 has not yet been synthesized and although epimers of the structure have been reported [ 66 ], the absolute configuration of the natural isolate is still yet to be confirmed.…”

“…A recent addition towards the synthesis of the hyacinthacine C-type alkaloids was reported in 2017 by Goti and co-workers through their synthesis of the proposed structure of (+)-hyacinthacine C 5 and its C-5 epimer 120 [ 63 ]. Their goal was to implement a straightforward and convenient synthesis of these complex iminosugar motifs.…”