Synthesis of diverse heterocyclic scaffolds via tandem additions to imine derivatives and ring-forming reactions

Abstract

A novel strategy has been developed for the efficient syntheses of diverse arrays of heterocyclic compounds. The key elements of the approach comprise a Mannich-type, multicomponent coupling reaction in which functionalized amines, aromatic aldehydes, acylating agents, and π-and organometallic nucleophiles are combined to generate intermediates that are then further transformed into diverse heterocyclic scaffolds via a variety of cyclization manifolds. Significantly, many of these scaffolds bear functionality that may be exploited by further manipulation to create diverse collections of compounds having substructures found in biologically active natural products and clinically useful drugs. The practical utility of this strategy was exemplified by its application to the first, and extraordinarily concise synthesis of the isopavine alkaloid roelactamine.

Evolution of a strategy for preparing bioactive small molecules by sequential multicomponent assembly processes, cyclizations, and diversification

“…In our early work 31,32 we applied the Huisgen [3+2]-dipolar cycloaddition 33 to the synthesis of 1,2,3-triazolo-1,4-benzodiazepines, 34 and building upon these findings, we developed an MCAP/cyclization sequence to prepare several series of novel members of this structural class. In one version of this approach, cyanide ion was employed as the nucleophilic partner in a MCAP involving propargylamine and a 2-azidobenzaldehyde, such as 29 , to produce the α -aminonitrile 30 (Scheme 4), 35,36 which underwent a Huisgen dipolar cycloaddition when heated in toluene to afford the 1,4-benzodiazepine 31 .…”

“…31,32 A straightforward modification of this methodology using dihalo aldehydes 88 and 89 83 as inputs together with allylamine, benzyl chloroformate, and allylzinc bromide afforded the dienes 90 and 91 , respectively (Scheme 13). 84,85 Cyclizations of these compounds via RCM to give the corresponding tetrahydropyridines 92 and 93 were induced using Grubbs II catalyst.…”

Combinatorial Chemistry Online

“…Alternatively, the pyrrole could be acylated on nitrogen with an isocyanate to give a urea, and subsequent cyclisation and oxidative elimination gave 1,3-dioxo-2,3,5,7a-tetrahydro-1H-pyrrolo [1,2-c]imidazoles (8). Finally, in a third option, acylation of the pyrrole nitrogen with chloroacetyl chloride, and cyclisation with an amine, gave, after oxidative elimination, 1,4-dioxo-1,2,3,4,6,8a-hexahydropyrrolo[1,2-a]pyrazines (9).…”

Diversity oriented synthesis: concise entry to novel derivatives of Yohimbine and Corynanthe alkaloids

“…These adducts can be subjected to various cyclization reactions that are enabled by selective functional group pairing to construct substituted heterocyclic ring systems. 7 We have demonstrated the utility of this general approach to diversity oriented synthesis (DOS) by applying it to preparation of small libraries of substituted benzodiazepines, 8 norbenzomorphans, 9 aryl piperidines, 10 tetrahydroisoquinolines, 11 as well as several conformationally-constrained benzoxazocines and benzazocines. 12 We now report the extension of this useful methodology to the facile preparation of compounds derived from the yohimbine and corynanthe scaffolds.…”

“…7 Toward this end, treatment of 6 with crotonyl chloride and tert -butyldimethyl(vinyloxy)silane in CH 2 Cl 2 afforded the amide 8 in 85% yield. Heating 8 with N -methylhydroxylamine hydrochloride and triethylamine in refluxing toluene then provided an intermediate nitrone that underwent a spontaneous [3+2] dipolar cycloaddition to give 9 as a single diastereoisomer.…”