Total synthesis of the proposed structures of hyacinthacines C2, C3, and their C5-epimers

A Convenient Synthetic Route towards 3,5‐Bis(hydroxymethyl)pyrrolizidines: Stereoselective Synthesis of Unnatural (–)‐Hyacinthacine B2

“…Hyacinthacine C 2 also exhibits a moderate inhibition of the human placenta α‐L‐fucosidase (IC 50 =17 μM), and hyacinthacine C 3 possesses weak inhibition against bovine liver β‐galactosidase (IC 50 =52 μM). The first three 1–3 were synthetically prepared and their structures were identical to those from natural sources, whereas synthesis of 4 disproved the initial structural proposal …”

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][52][53][54][55][56][57][58][59][60][61][62][63][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.…”

“…In addition to the aforementioned issues, recent synthetic studies have also revealed that the original structures proposed for hyacinthacine B 7 , C 3 and C 5 are incorrect. [58][59][60][61][62] It therefore becomes apparent that structural revision of the original isolates is necessary because as demonstrated in the earlier table, hyacinthacine alkaloid epimers determine the degree of specificity as well as the potency for the inhibition of various glycosidases.…”

“…The first synthesis of hyacinthacine C-type alkaloids was the synthesis of hyacinthacine C 2 and C 3 along with their C5epimers reported by Yoda et al in 2009. [60] This synthesis was an initial attempt to reveal information regarding structure-activity relationships between the hyacinthacine Ctype alkaloids and their inhibition against various glycosidases. Their synthetic strategy (Scheme 1) starts with the preparation of the N-Boc lactam 1 from commercially available (S)-(-)-2-pyrrolidone-5-carboxylic acid.…”

The boronic acid Mannich reaction in alkaloid synthesis

“…5). The recent syntheses of hyacinthacines C 3 by Yoda [27] and C 5 by Zhang [28] have shown that these proposed structures are also incorrect (Fig. 6).…”