Total Synthesis of (−)‐Histrionicotoxin through a Stereoselective Radical Translocation–Cyclization Reaction

Abstract

Stereoselective total syntheses of (-)-histrionicotoxin and (-)-histrionicotoxin 235A are described. The 1-azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation-cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (-)-histrionicotoxin 235A through a one-pot partial-reduction-allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3-amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (-)-histrionicotoxin.

Dehydration reactions in polyfunctional natural products

“…79,80 Scheme Elimination reactions from primary alcohols are the most common application of the Grieco dehydration and benchmark examples may be found in the literature. [81][82][83][84][85] As the oxaphosphonium ions, such as (54), of secondary or tertiary alcohol are sterically less accessible, these intermediates may complicate construction of the alkyl aryl selenide. In studies geared towards the synthesis of the chartelline C core, elimination of the secondary hydroxyl in (62), was problematic, as all sampled conditions favored substitution over elimination (see Scheme 11A).…”

Rapid, two-pot procedure for the synthesis of dihydropyridinones; total synthesis of aza-goniothalamin

“…It was reasoned that adaptation of the Veenstra protocol would allow us to introduce a second alkene unit during the same process, thus generating a ring-closing metathesis precursor in a single step. This general strategy towards nitrogen heterocycles has been utilized in several reports [20][21][22][23], including asymmetric variants [24,25], but in these cases the ring-closing metathesis precursor was always generated in multiple steps.…”

Cyclic Sulfamidite as Simultaneous Protecting Group for Amino Alcohols: Development of a Mild Deprotection Protocol Using Thiophenol

“…We unexpectedly found that cyclic sulfamidite was useful for the simultaneous protection of 1,3-amino alcohol during our synthetic studies on (−)-histrionicotoxin (5, HTX). [25][26][27] Previous synthetic studies conducted by Stork and Zhao 28) as well as our own investigation into the endgame sequence, 29) demonstrated that the highly congested 1,3-amino alcohol of (−)-HTX 235A (1) completely resists protection as its acetonide or carbamate form. However, the protection of the 1,3-amino alcohol was unavoidable in elongating two terminal alkenes to enynes to complete the total synthesis (Chart 2).…”