Chemoenzymatic Synthesis and Inhibitory Activities of Hyacinthacines A₁ and A₂ Stereoisomers

Abstract

A novel straightforward chemoenzymatic procedure for the synthesis of hyacinthacine stereoisomers based on the aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-prolinal under catalysis by l-rhamnulose 1-phosphate aldolase from E. coli is presented. The synthesis is complemented by a simple and effective purification protocol consisting of ion-exchange chromatography on CM-sepharose. As examples, (À)-hyacinthacine A 2 [the enantiomer of (+)-hyacinthacine A 2 ], 7-deoxy-2-epialexine (the enantiomer of 3-epihyacinthacine A 2 ), ent-7-deoxyalexine (the enantiomer of 7-deoxyalexine) and 2-epihyacinthacine A 2 were synthesized by these procedures and characterized for the first time. These new isomers were assayed as inhibitors of glycosidases. As a result, (À)-hyacinthacine A 2 demonstrated to be a good inhibitor of a-d-glucosidase from rice whereas the natural enantiomer, hyacinthacine A 2 , was not. Moreover, a new family of inhibitors of a-l-rhamnosidase was uncovered.

Double Asymmetric Induction in Organocatalyzed Aldol Reactions: Total Synthesis of (+)‐2‐epi‐Hyacinthacine A2and (–)‐3‐epi‐Hyacinthacine A1

“…{[ α ] D 20 = –6.8 ( c = 0.32, H 2 O), ref 12a,18. [ α ] D 20 = +3.4 ( c = 0.32, H 2 O), ref 13g. [ α ] D 20 = –1.0 ( c = 0.6, MeOH)}.…”

Synthesis of hyacinthacine B3and purported hyacinthacine B7

“…Others include a lipase resolution of a meso-2,5-disubstituted-2,5-dihydropyrrole to prepare an A-ring precursor, 4 a [2+2]-cycloaddition approach using a chiral auxiliary 6 and a chemoenzymatic synthesis using an aldolase. 7 The synthesis of epimers 8 and a racemic synthesis have also been reported. 9 A recent study has revealed that the proposed structure of hyacinthacine C 3 is incorrect.…”

Enzyme‐Catalyzed Aldol Additions

“…FucA was fully stereoselective regardless of the configuration of the aminoaldehyde, whereas RhuA gave mixtures of syn-/anti-configured aldol adducts with the (R)-N-Cbz-aminoaldehyde. Following the same strategy, glycosidase inhibitors of the hyacinthacine and alexine types have been prepared by a concise two-step aldol addition of DHAP to N-Cbz-protected prolinal, catalyzed by RhuA from E. coli, followed by a reductive amination (Scheme 8.24) [89].…”