Total Synthesis of (+)-Hyacinthacine A₁ Using a Chemoselective Cross-Benzoin Reaction and a Furan Photooxygenation–Amine Cyclization Strategy

Abstract

We report the shortest synthesis of glycosidase inhibitor (+)-hyacinthacine A 1 using a highly chemoselective N-heterocyclic carbene-catalyzed crossbenzoin reaction as well as a furan photooxygenation−amine cyclization strategy. This is the first such cyclization on a furylic alcohol, an unprecedented reaction due to the notorious instability of the formed intermediates. The photooxygenation strategy was eventually incorporated into a three-step one-pot process that formed the requisite pyrrolizidine framework of (+)-hyacinthacine A 1 .(+)-Hyacinthacine A 1 [7 (Figure 1)] is a member of a large class of polyhydroxylated pyrrolizidine and indolizidine structures that act as glycosidase inhibitors. 1 These belong to the broader class of amino sugars, a group of compounds that have found significant use in glycobiology as tools and as frameworks for potential pharmaceuticals. 1,2 Important amino sugars include the various deoxynojirimycin derivatives, 3 Celgosivir, 4 and other neuraminidase inhibitors such as zanamivir. 5 (+)-Hyacinthacine A 1 ( 7) is especially interesting due to its low micromolar range inhibition, making it an important target for further study. 6 It is also one of the more challenging hyacinthacine derivatives to access, highlighting the need to develop more efficient methods for its preparation. 6,7 Previously, in attempting to solve the chemoselectivity issues that plagued cross-benzoin reactions, 8 our group discovered that two aldehydes could be coupled catalytically with Nheterocyclic carbenes (NHCs) when one of the reactants was a protected amino aldehyde. 9,10 The reaction generates an αhydroxy-β-aminoketone [3 (Figure 1)] with good yields and diastereoselectivities. We believed that incorporating a furan ring into this structure would make it more amenable to useful transformations, 11 thereby allowing us to target a variety of natural products. 12−15 The high availability and versatility of furans from biomass emphasize the importance of furthering our understanding of these transformations. 16

Recent Advances in NHC‐Catalyzed Chemoselective Activation of Carbonyl Compounds

“…The key step involved the reaction chemoselectivity could be determined by the substitutes on the amino group, and then the framework of (+)-hyacinthacine A 1 was constructed through a three-step, one-pot photooxygenation strategy (Scheme 3). [13] In 2018, Connon and Delanny designed a novel pre-NHC catalyst B, enabling high chemoselectivity in reactions between two aromatic aldehydes (Scheme 4a). [14] By comparing non-ortho-substituted aldehydes with ortho-substituted aldehydes, the broad applicability of substrate scope in this reaction was observed.…”

Remote Electronic Effect of Chiral N‐Heterocyclic Carbene Catalyst on an Asymmetric Benzoin Reaction

“…Typically, the reaction is a simple dimerization of aldehyde to give α‐hydroxy ketones, and thus, has been utilized as a benchmark test for a newly developed chiral NHC catalyst, [11–20] due to the simple operation as well as the ready availability of various aldehydes. In addition, the reaction, especially an intramolecular version, is useful as a synthetic method to give versatile synthetic intermediates, α‐hydroxy ketones, and its application to natural product synthesis has been reported [21–28] …”

“…In addition, the reaction, especially an intramolecular version, is useful as a synthetic method to give versatile synthetic intermediates, α-hydroxy ketones, and its application to natural product synthesis has been reported. [21][22][23][24][25][26][27][28] During our research on organocatalyzed reactions, [29][30][31][32][33][34][35][36][37][38][39][40][41] we developed the electronic tuning of an aminoindanol-derived chiral NHC [42] by installing a remote electron-withdrawing substituent. [43][44][45] A common strategy to tune the electron density on NHC is substitution of the N-aryl group of NHCs.…”

Enantiospecific Total Synthesis of (−)‐Hyacinthacine A1 and (+)‐Hyacinthacine A1 and Their Homologues Using Nitrogen Substituted Donor–Acceptor Cyclopropane

“…Chandrasekhar and co‐workers reported the synthesis of (+)‐hyacinthacine A 1 from L‐(+)‐diethyl tartrate (DET) via the introduction of an azido group then pyrrolizidine construction in a one pot process (Scheme 1b) [8b] . Gravel and his group recently disclosed the synthesis of (+)‐hyacinthacine A 1 using a N ‐heterocyclic carbene‐catalysed cross‐benzoin reaction as well as a furan photooxygenation‐amine cyclization (Scheme 1c) [8c] . Through the utilization of a dichloroketene‐chiral enol ether cycloaddition approach, Delair et al .…”