One-Pot Multicomponent Synthesis of Diversely Substituted 2-Aminopyrroles. A Short General Synthesis of Rigidins A, B, C, and D

Abstract

Privileged medicinal scaffolds based on the structures of tetra-and penta-substituted 2-aminopyrroles were prepared via one-pot multicomponent reactions of structurally diverse aldehydes and N-(aryl-, hetaryl-, alkyl-sulfonamido)-acetophenones with activated methylene compounds. This methodology was used in a four-step synthesis of alkaloids rigidins A, B, C and D in overall yields 61%, 58%, 60% and 53%, respectively. Of these, rigidins B, C and D were synthesized for the first time.Polysubstituted pyrroles are an important class of heterocycles that display diverse pharmacological activities. 1 Furthermore, they are useful building blocks in the synthesis of natural products and heterocyclic chemistry. Although a large number of new pyrrole syntheses, 2 including multicomponent reactions (MCRs), 3 have been reported in recent years, relatively few examples are known for the preparation of polysubstituted 2-aminopyrroles. 4 Aminopyrroles are not readily available through general pyrrole ringformation methods. At the same time the 2-aminopyrrole fragment is part of many different bioactive compounds and it is recognized as a privileged medicinal structure. Known bioactivities for this class of compounds include anti-inflammatory, 5 anticancer, 6 antiviral, 7 antifungal, 8 pesticidal, 9 radioprotective, 10 MEK inhibitory, 11 MK2 inhibitory, 12 FAK, KDR and Tie2 inhibitory, 13 PDE inhibitory, 14 anti-interleukin-6, 15 TNF-α production inhibitory, 16 and afferent pelvic nerve activity inhibitory. 17 Moreover, 2-aminopyrroles are precursors for the synthesis of purine analogs -pyrrolopyrimidines, pyrrolotriazines and pyrrolopyridines. [18][19][20][21][22][23][24] Previously, we described a novel method for the synthesis of multisubstituted pyrrolines using a multicomponent reaction of various N-(aryl-and alkylsulfonamido)-acetophenones with aldehydes and malononitrile (see Table 1 graphic). 27 While the reaction is regioselective, it is not stereoselective and gives mixtures of cis and trans 2-pyrrolines, which are not easily separable. Utilizing this methodology as a starting point, we developed a new muticomponent one-pot method for the synthesis of tetra-and penta-diversely substituted 2-aminopyrroles. In addition, we utilized the new method for a short total synthesis of alkaloids rigidins A, B, C and D.Penta-substituted 2-aminopyrroles A 1-17 were prepared by a multicomponent reaction of N-(aryl-, hetaryl-and alkylsulfonamido)-acetophenones, aldehydes and cyanoacetic acid derivatives in acetonitrile, followed by oxidation with DDQ in one pot (Table 1). This threecomponent process works well for any tested combination of aliphatic, aromatic (including sterically hindered or heteroaromatic) aldehydes and malononitrile, cyanoacetamide or ethyl cyanoacetate. Because of the lower reactivity of the intermediate Knoevenagel products of cyanoacetamide or ethyl cyanoacetate, the reactions were sluggish in acetonitrile (A 16 and A 17 ). In these cases the pyrrolines were obtained in ethanol, the solvent was the...

Synthetic and Biological Studies of Tubulin Targeting C2‐Substituted 7‐Deazahypoxanthines Derived from Marine Alkaloid Rigidins

“…To develop synthetic access to the C2-substituted 7-deazahypoxanthines D , a previously discovered 13 multicomponent reaction (MCR) of sulfonamidoacetophenones with aldehydes and cyanoacetamide was utilized to prepare pyrrole 1 (Table 1). This was followed by the pyrimidine ring closure using the reaction of 1 with a variety of aromatic and aliphatic esters catalyzed by sodium ethoxide in ethanol that was reported for a related purine system.…”

“…To a stirred solution of N- methylsulfonamidoacetophenone 13 (0.084 g, 0.4 mmol), benzaldehyde (0.055 g, 0.52 mmol) and cyanoacetamide (0.044 g, 0.52 mmol) in EtOH (3 mL) was added anhydrous granulated K 2 CO 3 (0.028 g, 0.2 mmol). The mixture was then refluxed for 14 h. After this time the reaction mixture was cooled to room temperature and concentrated.…”

“…rigida found near Okinawa and New Guinea and has remained scantly explored despite initial reports of promising biological activities. 10-12 The first general total synthesis of rigidins A, B, C and D, which involved only four steps from commercially available materials, was reported by the authors in 2011 13 and allowed for a thorough investigation of their biological properties. However, despite the earlier reports of promising antiproliferative activity against murine leukemia L1210 cells, 11 the rigidins were found to have very little, if any, activity against cultured human cancer cells.…”

Multicomponent reactions in alkaloid-based drug discovery

“…Thus, we showed that pentasubstituted pyrroles 11 can be prepared by reacting various sulfonamidoacetophenones 10 with aldehydes and active methylene compounds with the subsequent oxidation of the intermediate pyrrolines with DDQ [7]. In addition, if the mixture of these three components is treated with ethanolic K 2 CO 3 , the reaction proceeds via sulfonyl elimination and provides tetrasubstituted pyrroles 12 .…”

“…We utilized the latter MCR in the synthesis of marine alkaloids rigidins A, B, C, and D, isolated from tunicates obtained near Okinawa and New Guinea [7]. To this end, commercially available aminoacetophenones 13 are converted to the corresponding sulfonamides, which are then condensed with the requisite aldehydes and cyanoacetamide in the presence of K 2 CO 3 to give tetrasubstituted pyrroles 14 .…”