Site‐Isolated Base‐ and Acid‐Mediated Michael‐Initiated Cyclization Cascades

Abstract

Cascade reactions are attractive in modern synthetic strategies as they enable several bond-forming events to occur in the same reaction vessel without the necessary drain of resources associated with one-reaction, one-pot approaches. [1] This allows rapid and efficient syntheses of complex molecules from relatively simple starting materials whilst minimizing cost and waste, and thus, the impact of the chemistry on the environment. Many examples involving cascade sequences catalyzed by a single chemical entity have been reported.[1] However, those involving more than one mutually compatible catalyst are much less common.[2] Furthermore, the use of site-isolated catalysts that would otherwise be mutually destructive and thus ineffective in solution phase to facilitate reaction cascades is in its infancy. [3] Although pioneered around 30 years ago by Cohen et al., [4] recent papers reporting new ways of preventing mutual deactivation of reagents have brought site isolation to the forefront again. [5,6] Reported sequences have included acid-and base-catalyzed condensation of carbonyl compounds with active methylene compounds to form electrondeficient alkenes, which are subsequently attacked by a nucleophilic reagent or reduced by using hydrogen over a palladium catalyst. However, to date the concept has not been exploited to generate complex molecular structures and accordingly, we believed the true synthetic power of cascades catalyzed by both basic and acidic reagents in one pot was still to be realized.By combining a base-catalyzed intermolecular Michael addition reaction of an a,b-unsaturated carbonyl compound 1 and a suitable amide pronucleophile 2 with an acid-catalyzed intramolecular N-acyl iminium ion cyclization [7] of the resulting adduct 3, we believed site isolated base and acid (SIBA) catalysis could be exploited to form structurally complex multiring heterocyclic molecules 4 in one pot and under mild conditions (Scheme 1). With five points of diversity present in the reaction products, this procedure could be a powerful tool for both library generation and target synthesis. Herein we present our findings.Proof-of-principle studies were required to determine the necessity and feasibility of the SIBA catalysis cascade. b-Keto amide 5 containing an acidic methine group and pendant nucleophilic pyrrole substituent was chosen as a test substrate. When a dichloromethane solution of 5 and methyl vinyl ketone 6 (1.1 equiv) at room temperature was treated with PS-BEMP [8] (10 %), Michael adduct 7 was formed as the sole reaction product in an excellent yield.[9] When the reaction was repeated by using Amberlyst A15 (200 %) in the presence or absence of liquid BEMP (10 %), the only observed reaction product was substituted pyrrole 8 in 68 % yield; 7 was not present in the reaction mixture. However, when the reaction was repeated by using a combination of PS-BEMP (10 %) and Amberlyst A15 (200 %), the sole reaction product was the desired tetracyclic product 9 produced in 83 % yield as a 1:1 mixture of diastereoiso...

Asymmetric Alkaloid Synthesis: A One‐Pot Organocatalytic Reaction to Quinolizidine Derivatives

“…[4,5] The development of new stereoselective, efficient, and short routes to this class of compound would therefore open up new opportunities for natural product synthesis and medicinal chemistry. [6] To devise such a method a retrosynthetic analysis of indolo [2,3a]quinolizidine skeleton was carried out, taking in account the selective formation of the three stereocenters indicated (C2, C3, and C12 b; Scheme 1). It was anticipated that the stereocenter at C2 could be introduced in the first step through an enantioselective, organocatalytic conjugate addition.…”

Asymmetric Synthesis of Octahydroindoles via a Domino Robinson Annulation/5-Endo Intramolecular Aza-Michael Reaction

“…We also evaluated the use of PS-BEMP with Amberlyst-15 (B and C, Table 1) under the concept of siteisolated reactivity using the conditions reported by Dixon. 21 However, only traces of the Michael product were observed (entry 4). Increasing the amount of PS-BEMP to 1 equiv gave a good yield, but significant quantities of the transesterification products were also isolated, presumably catalyzed by the acid resin (entry 5).…”

Stereoselective Multiple Bond‐Forming Transformations (MBFTs): The Power of 1,2‐ and 1,3‐Dicarbonyl Compounds

“…Exploiting the dual C,N nucleophilicity of simple β‐ketoamides in domino MCRs first developed by our group in 2005 (vide infra, Scheme ),9, 33 Dixon’s group proposed a two‐component cyclization cascade with functionalized acyclic ketoamides. The sequence, initiated by an intermolecular Michael addition, evolved through the in situ formation of acyl iminiums ions 34. The overall transformation is promoted by site‐isolated base and acid (SIBA) heterogeneous catalysts namely, polymer‐supported phosphazene PS‐BEMP35 and Amberlyst A15, leading to complex spiropolyheterocyclic systems with relatively modest diastereoselectivities (Scheme ).…”