Ruthenium Catalyzed Tandem Pictet–Spengler Reaction

Abstract

We report a pyridyl-phosphine ruthenium­(II) catalyzed tandem alcohol amination/Pictet–Spengler reaction sequence to synthesize tetrahydro-β-carbolines from an alcohol and tryptamine. Our conditions use a Lewis acid cocatalyst, In­(OTf)3, that is compatible with typically base catalyzed amination and an acid catalyzed Pictet–Spengler cyclization. This method proceeds well with benzylic alcohols, heterocyclic carbinols, and aliphatic alcohols. We also show how combining this reaction with a subsequent cycloamination enables a direct synthesis of tetracyclic alkaloids like harmicine.

Synthesis of 1,4-Diazacycles by Hydrogen Borrowing

“…12 Complex 1 further facilitates a tandem alcohol amination/Pictet−Spengler reaction for the synthesis of tetrahydro-β-carbolines, owing to its unique ability to operate independently of a base, thus enabling an acid-catalyzed Pictet−Spengler reaction in situ. 13 Hypothesizing that chelation of starting diamines was the principle hurdle to a hydrogen borrowing route to diazacycles, we suspected that this same ruthenium catalyst might be tolerant of chelating diamines, thus avoiding this peril and cyclizing simple diamines and diols where other catalysts struggle. While 1 is not unique in the formation of piperazines, 14 we perceive a need to address the low yield, high catalyst loading, long reaction time, and limited substrate scope (Figure 1) and fill the void for methods for the synthesis of 1,4-diazepanes from diamines and diols.…”

“…Our lab has developed a ruthenium catalyst ( 1 ) that enables hydrogen borrowing amination on substrates such as phenols, anilines, indoles, and halides, which are challenging or incompatible with other catalysts (Figure ). Complex 1 further facilitates a tandem alcohol amination/Pictet–Spengler reaction for the synthesis of tetrahydro-β-carbolines, owing to its unique ability to operate independently of a base, thus enabling an acid-catalyzed Pictet–Spengler reaction in situ . Hypothesizing that chelation of starting diamines was the principle hurdle to a hydrogen borrowing route to diazacycles, we suspected that this same ruthenium catalyst might be tolerant of chelating diamines, thus avoiding this peril and cyclizing simple diamines and diols where other catalysts struggle.…”

“…17 Importantly, reaction of chiral diamines preserved their configuration through the reaction, which is consistent with our mechanistic studies showing the irreversibility of imine hydrogenation with catalyst 1. 13 For example, coupling of (1R,2R)-N,N′-dibenzylcyclohexane-1,2diamine (2b) with ethylene glycol (5a) afforded 6b in the trans configuration and >99% ee. Product 6b belongs to the decahydroquinoxaline class of compounds, which are potent and selective κ-opioid receptor agonists with anti-inflammatory activity.…”

Recent Advances in the Synthesis of β-Carboline Alkaloids

“…Finally, oxidation of the hydroxy group in alcohols 129-131 was achieved using MnO2 on Celite ® , and aldehydes 16, 132, 133 were isolated in good yields. The synthesis of alkaloids 17-21 was then performed from these building blocks (16,132,133), which were reacted with indoles (134)(135)(136)(137) to afford secondary alcohols and then oxidized with active MnO2 to provide the first total synthesis of trigonostemines A (17) and B (18), carried out in 7 steps. At the same time, this pathway represents a new synthetic method for the preparation of pityriacitrin (20).…”

“…By applying this procedure, (−)-(S)-harmicine ((−)-39) was synthesized from DHβC (147), using coupling agent 222, copper(II)isobutyrate and a chiral ligand to give intermediate 223, which was deprotected and transformed into (−)-39 in a titanium-catalyzed ring closure and subsequent C=N bond reduction with good yield and excellent stereoselectivity. Synthesis of (-)-harmicine ((−)-39).The one-step synthesis of racemic harmicine(39) has been recently reported by Nalikezhathu et al (Scheme 25)[136]. The new method is based on the pyridyl-phosphine ruthenium(II)-catalyzed tandem Pictet-Spengler reaction through the amination of alcohols.…”