Synthesis of the stereogenic triad of the halicyclamine A core

Abstract

We describe herein our progress toward the synthesis of halicyclamine A, which possesses very interesting biological activities and has never been synthesized. For this purpose, we proposed a stereoselective Diels-Alder reaction as a key step for the establishment of the stereogenic triad of the bis(piperidinyl) core of this molecule. A series of NMR studies was then conducted to establish the correct stereochemical assignment subsequent to the Diels-Alder reaction.

Alkylidene Dihydropyridines As Synthetic Intermediates: Model Studies toward the Synthesis of the Bis(piperidine) Alkaloid Xestoproxamine C

“…Apart from these studies, only two additional reports describing approaches to functionalized bis­(piperidine) ring systems have appeared. Molander described a diastereoselective approach to the bis­(piperidine) core of halicyclamine A which envisioned using a Diels–Alder cycloaddition to establish the correct relative stereochemistry within the piperidine rings, and Banwell et al examined the feasibility of crossed-aldol condensations between substituted 4-pyridinones as a means to construct 3,4′ bis­(piperidine) derivatives …”

“…Details of 2D NMR experiments and X-ray crystallography can be found in the Supporting Information. 3-Butenylboronic acid (18). 4-Bromobut-1-ene (2.00 mL, 19.7 mmol, 1.00 equiv) was dissolved in THF (∼200 mL) and Mg turnings (0.575 g, 23.6 mmol, 1.20 equiv) were added to the reaction mixture.…”

“…17 Apart from these studies, only two additional reports describing approaches to functionalized bis(piperidine) ring systems have appeared. Molander described a diastereoselective approach to the bis(piperidine) core of halicyclamine A which envisioned using a Diels−Alder cycloaddition to establish the correct relative stereochemistry within the piperidine rings, 18 and Banwell et al examined the feasibility of crossed-aldol condensations between substituted 4-pyridinones as a means to construct 3,4′ bis(piperidine) derivatives. 19 As part of general efforts aimed at developing new synthetic methods for construction and manipulation of aza-heterocyclic ring systems, we have been examining the reactivity of pyridine and related aza-arene anhydrobases (i.e., 7, Scheme 1).…”

Click and Cut: a click chemistry approach to developing oxidative DNA damaging agents

“…N -Boc-4-ethynylaniline (7) . The compound was prepared according to literature procedures ( 43 , 44 ). To a solution of 4-ethynylaniline (5 mmol) in dry THF (20 ml), di-tert-butyl dicarbonate (15 mmol) was added dropwise.…”

Intramolecular cyclizations of alkyl pyridines & alkylidene dihydropyridines as synthetic intermediates toward synthesis of bis(piperidine) alkaloids

“…Total synthesis of (±)-haliclonacyclamine C Apart from these studies, only two additional reports describing approaches to functionalized bis(piperidine) ring systems have appeared. Molander and coworkers described a diastereoselective approach to bis(piperidine) core of halicyclamine A which envisioned using a Diels-Alder cycloaddition to establish the correct relative stereochemistry within the piperidine rings (Scheme 4.2) 165. Boc-protected propargyl amine (4.13) was converted to intermediate product 4.14 which was the substrate needed for the Diels Alder reaction.…”