Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to rapid assembly of D-ring analogs

Abstract

The total syntheses of dihydrolysergic acid and dihydrolysergol are detailed based on a Pd(0)-catalyzed intramolecular Larock indole cyclization for the preparation of the embedded tricyclic indole (ABC ring system) and a subsequent powerful inverse electron demand Diels–Alder reaction of 5-carbomethoxy-1,2,3-triazine with a ketone-derived enamine for the introduction of a functionalized pyridine, serving as the precursor for a remarkably diastereoselective reduction to the N-methylpiperidine D-ring. By design, the use of the same ketone-derived enamine and a set of related complementary heterocyclic azadiene [4 + 2] cycloaddition reactions permitted the late stage divergent preparation of a series of alternative heterocyclic derivatives not readily accessible by more conventional approaches.

Direct Synthesis of β-Aminoenals through Reaction of 1,2,3-Triazine with Secondary Amines

“…12 The exploration and development of the 1,2,3-triazine cycloaddition reactions was inspired by their projected use in the total syntheses of natural products that now include dihydrolysergic acid, 13 pyrimidoblamic acid, 14 P-3A, 14 and methoxatin. 15 …”

Cycloadditions of 1,2,3-Triazines Bearing C5-Electron Donating Substituents: Robust Pyrimidine Synthesis

“…11 Recently, our efforts extended to 1,2,3-triazines, examining the synthesis and cycloaddition reaction scope of the parent 1,2,3-triazine and a series of 1,2,3-triazines that contain electron-withdrawing groups at sites where their electronic impact was both consonant and dissonant to that innate to the 1,2,3-triazine core (Figure 1). 12 In addition to defining the scope of the 1,2,3-triazine cycloaddition reactions, these studies have also found application in the total syntheses of (−)-pyrimidoblamic acid and P-3A 13 as well as the late-stage divergent total syntheses of dihydrolysergic acid, dihydrolysergol, and a series of heterocyclic derivatives 14 .…”

Crystal structure and Hirshfeld surface analysis of (E)-N-[(2-ethoxynaphthalen-1-yl)methylidene]-5,6,7,8-tetrahydronaphthalen-1-amine

“…There are no direct precedents for the structure of (I) in the crystallographic literature (CSD version 5.39, update of August 2018;Groom et al, 2016). However, there are several precedents for (E)-N-benzylidene-5,6,7,8-tetrahydronaphthalen-1-amine and (E)-N-[(2-ethoxynaphthalen-1-yl)methylene]aniline including 2-(4-isopropylphenyl)-1,3-diphenyl-2,3dihydro-1H-naphtho[1,2-e][1,3]oxazine (Borah et al, 2014), 2-(2-nitrophenyl)-3-(5,6,7,8-tetrahydronaphthalen-1-yl)-1,3thiazolidin-4-one (Drawanz et al, 2017) (Wu et al, 2013) and methyl (5aR,6aR,9R,-10aR)-4-benzoyl- 7-methyl4,5,5a,6,6a,7,8,9,10,10adecahydroindolo[4,3-fg]quinoline-9-carboxylate dihydrate (Lee et al, 2015).…”