Total Synthesis of (−)-Strictosidine and Interception of Aryne Natural Product Derivatives “Strictosidyne” and “Strictosamidyne”

Abstract

Monoterpene indole alkaloids are a large class of natural products derived from a single biosynthetic precursor, strictosidine. We describe a synthetic approach to strictosidine that relies on a key facially selective Diels–Alder reaction between a glucosyl-modified alkene and an enal to set the C15–C20–C21 stereotriad. DFT calculations were used to examine the origin of stereoselectivity in this key step, wherein two of 16 possible isomers are predominantly formed. These calculations suggest the presence of a glucosyl unit, also inherent in the strictosidine structure, guides diastereoselectivity, with the reactive conformation of the vinyl glycoside dienophile being controlled by an exo-anomeric effect. (−)-Strictosidine was subsequently accessed using late-stage synthetic manipulations and an enzymatic Pictet–Spengler reaction. Several new natural product analogs were also accessed, including precursors to two unusual aryne natural product derivatives termed “strictosidyne” and “strictosamidyne”. These studies provide a strategy for accessing glycosylic natural products and a new platform to access monoterpene indole alkaloids and their derivatives.

Leveraging Fleeting Strained Intermediates to Access Complex Scaffolds

“… 121 Additionally, our laboratory has performed late-stage intermolecular aryne cycloadditions to access derivatives of strictosidine, the last common biosynthetic precursor to all monoterpene indole alkaloids. 122 More commonly, natural products have been accessed through diastereoselective intramolecular aryne trappings of enantioenriched substrates. Early on, our laboratory used an “indolyne” cyclization to build the complex bridged bicyclic core of coveted welwitindolinone natural products.…”

“…The synthesis of natural products and their derivatives also provides an opportunity to use arynes in complex settings, as has been well demonstrated in the literature. ,,, With regard to several recent efforts, the Hoye group has used arynes generated from hexadehydro-Diels–Alder reactions with readily abundant natural products to access complex derivatives . Additionally, our laboratory has performed late-stage intermolecular aryne cycloadditions to access derivatives of strictosidine, the last common biosynthetic precursor to all monoterpene indole alkaloids . More commonly, natural products have been accessed through diastereoselective intramolecular aryne trappings of enantioenriched substrates.…”

“…Although our initial strategies proved unsuccessful in the laboratory, they helped us appreciate the challenge of establishing quaternary stereocenters in complex frameworks using arynes. Prior studies had largely focused on the use of arynes to access tertiary stereocenters. ,− With regard to setting quaternary centers of natural products and drug candidates using arynes, notable precedent was available in the synthesis of crinine ( 72 ) and ibutamoren mesylate ( 73 ) (Figure ). There were no such examples where scaffolds bearing vicinal quaternary stereocenters, like those seen in the tubingensin alkaloids, were accessed using aryne cyclizations.…”

Superseding Substrate Control with Catalyst Control to Improve Regioselectivity in Aryne Annulations

“…29,30 Other studies have further corroborated this electronic influence on aryne regioselectivity (Figure 1b). [31][32][33][34][35][36][37] This effect has been leveraged in the synthesis of substituted 3,4-pyridines. Addition of functional groups in both positions ortho to the triple bond allowed for both enhanced and reversed selectivity compared to the parent unsubstituted 3,4pyridyne.…”

Synthesis of a Seco iso-Secologanin Aglycone Analogue of Interest toward Secoiridoids and Monoterpene Indole Alkaloids

“…In 2019, Ishikawa achieved the first enantioselective total synthesis of secologanin itself via the key organocatalyzed anti -1,4-addition of an aldehyde onto a Michael acceptor . Very recently, Garg also reported the asymmetric total synthesis of secologanin via a hetero Diels–Alder cycloaddition …”