Iterative Synthetic Strategy for Azaphenalene Alkaloids. Total Synthesis of (−)-9aepi-Hippocasine

Abstract

A new strategy for the stereoselective synthesis of alkaloids with perhydro-9b-azaphenalene skeleton has been developed. The starting material is the substituted glutarimide derivative 1, readily available in either enantiomeric form through the palladium-catalyzed asymmetric allylic alkylation of glutarimide. The strategy relies on an iterative methodology encompassing two nucleophilic allylations and two ring closing metathesis processes. The approach has been used in the first synthesis of (−)-9a-epi-hippocasine.

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications

“…Bayoń, Figueredo, and co-workers used enantiopure 122 to develop a new strategy for the stereoselective synthesis of perhydro-9b-azaphenalene alkaloids. 508 The starting material in this approach (122) is available in high yield and enantiomeric purity by Pd-catalyzed asymmetric allylic amination of butadiene monoepoxide (119) with glutarimide, 509 and the authors successfully developed the first synthesis of (−)-9a-epi-hippocasine by forging the additional stereocenters in the molecule in an iterative manner from the chiral information contained in 122 (Scheme 190).…”

Novel semicarbazone-based α-amidoalkylating reagents: general synthesis and reactions with <em>H</em>-, <em>O</em>-, <em>S</em>-, <em>N</em>-, and <em>P</em>-nucleophiles

“…Thus, the major isomers of 1h,i have (E)-and minor isomers have (Z)configuration. The additional evidence of (E)-configuration in the major isomers of compounds 1h,i is a long-range coupling 4 J between the NH and CH protons (0.6-0.7 Hz), which was also observed for (E)-1j (0.7 Hz), while the spectra of the minor isomers of semicarbazones 1h,i did not show this coupling.…”

“…Chemical shifts of the CH=N proton in the major isomers of 4h-j (7.14-7.18 ppm) are close to those of (E)-1h-j (7.08-7.16 ppm) and in minor isomers of 4h-j (6.33-6.48 ppm) are close to those of (Z)-1h,i (6.34-6.37 ppm). A long-range coupling 4 J between the NH and CH protons was observed in the spectra of the major isomers of 4hj (0.6-0.7 Hz) and (E)-1h-j (0.6-0.7 Hz), while the spectra of the minor isomers of 4h-j and (Z)-1h,i did not show this coupling. Close values of carbon chemical shifts of the α-CH2 group were observed for (E)-1h,i (25.0 and 33.6 ppm) and the major isomer of 4h,i (25.0 and 33.5 ppm), and for (Z)-1h,i (20.1 and 28.5 ppm) and the minor isomer of 4h,i (20.3 and 28.6 ppm).…”

“…The distinguishing features of amidoalkylating reagents are higher electrophilicity and wider structural diversity compared with those of reagents involved in aminoalkylation reactions (the Mannich reaction, the Pictet-Spengler reaction, etc.). Therefore, amidoalkylation has been extensively applied in the synthesis of various nitrogencontaining acyclic and heterocyclic compounds including bioactive natural products (e.g., alkaloids [4][5][6][7], antibiotics [8][9][10][11], toxins [12][13][14], vitamins [15,16]) and pharmaceuticals [17][18][19][20]. Recently, some enantioselective variants of this reaction employing catalytic amounts of chiral auxiliaries has also been described [21][22][23].…”

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…Figueredo, Bayón, and co‐workers delineated the first stereoselective synthesis of defensive coccinellid compound (−)‐ 9a ‐epi‐hippocasine 212 (Scheme 16), [195] an alkaloid with perhydro‐ 9b ‐azaphenalene framework. In this wonderful synthetic strategy, total 11 steps were inloved, and the RCM was one of the key steps utilized twice: firstly in the initial steps to forge bicyclic amide 209 and secondly in the late‐stage to construct tricyclic core.…”