General Synthesis of the Nitropyrrolin Family of Natural Products via Regioselective CO₂-Mediated Alkyne Hydration

Abstract

The total synthesis of the 2-nitropyrrole natural products nitropyrrolins A and B and the formal synthesis of nitropyrrolin D are reported. The key 2-nitro-4-alkylpyrrole core was efficiently assembled by Sonogashira cross-coupling, with complete control of regioselectivity. An unusual carboxylative cyclization, sulfonylcarbamate formation, and base-promoted cleavage sequence enabled access to the key hydroxy ketone without affecting the protected 2-nitropyrrole unit. The total synthesis provides a general approach for preparation of the bioactive nitropyrrolin family of natural products.

A Noble‐Metal‐Free Metal–Organic Framework (MOF) Catalyst for the Highly Efficient Conversion of CO2 with Propargylic Alcohols

“…[1] As ar esult, much effort has been devoted to developing effective methods to chemical fixation of CO 2 ,m ainly including the cycloaddition of epoxides or aziridines with CO 2 , [2] and carboxylation of terminal alkyne molecules with CO 2 . [3] Recently,the cyclization of propargylic alcohols with CO 2 has also aroused intense interest, [4] because the resultant products a-alkylidene cyclic carbonates are ac lass of important heterocyclic compounds in nature products synthesis,p harmaceutical chemistry,a nd polymers, such as b-ketocarboxylic acids, [5] nitropyrrolins A-E, [6] 2cyclopentenones, [7] poly(urethane)s and poly(carbonate)s. [8] However,o wing to the thermodynamic stability of C = O bond (bond enthalpy + 805 kJ mol À1 )a nd stable electronic structure of p 4 3 in CO 2 ,highly active catalysts are often needed in promoting this cyclization reaction, like Ag nanoparticles, [9] Ag salts, [10] and Ag-MOF or nanoparticle Ag@MOFs, [11] and it should be noted that most of these catalysts are associated with noble metal Ag. Therefore,t or educe the cost, the explorations on efficient catalysts with free noble metals are still highly desirable but ag reat challenge.…”

Highly Diastereoselective Synthesis of Syn‐1,3‐Dihydroxyketone Motifs from Propargylic Alcohols via Spiroepoxide Intermediates

“…Ther eaction sequence involves initial regioselective functionalisation of propargylic alcohols (4)w ith readily available triketones to afford enol dioxolanes (5), followed by substrate-controlled diastereoselective epoxidation to provide previously unreported spiroepoxides (6). Stereoretentive hydrolysis or acetolysis of the spiroepoxides then affords either the free syn dihydroxyketones (7)orthe mono-acetate derivatives (8), respectively.Remarkably,the entire sequence can be efficiently carried out as an operationally simple onepot process to deliver either the spiroepoxides or syn dihydroxyketones in good yields. Propargylic alcohols are well established as versatile substrates for regio-and stereoselective functionalisation.…”

“…Propargylic alcohols are well established as versatile substrates for regio-and stereoselective functionalisation. [5] We hypothesized that if an effective general method for carboxylative cyclisation could be identified, epoxidation of the resulting enol and subsequent hydrolysis could provide ag eneral route to the dihydroxyacetone motif.B ased on precedent for carboxylative cyclisation of propargylic alcohols (Scheme 2A,B) [6] or derivatives, [7] and our own previous work in this area, [8] we initiated preliminary investigations into effective methods for carboxylative cyclisation of secondary propargylic alcohols,b ut disappointingly these proved unproductive.…”

“…Ther eaction sequence involves regioselective cyclisation of propargylic alcohols (4)w ith incorporation of triketone K4 to give enol dioxolanes (5)t hat then undergo highly diastereoselective epoxidation to give spiroepoxides (6). Hydrolysis then cleanly affords syn dihydroxyketones (7) essentially as single diastereomers.Alternatively,acetolysis of the spiroepoxides delivers monoacetylated syn dihydroxyketones (8). Ther eaction sequence is operationally simple,o f wide substrate scope,a nd can be effectively carried out as ao ne-pot process with no loss of overall yield or diastereoselectivity,w ith potential for wide application to the stereoselective synthesis of complex molecular architectures.…”

Highly Diastereoselective Synthesis of Syn‐1,3‐Dihydroxyketone Motifs from Propargylic Alcohols via Spiroepoxide Intermediates

“…Stereoretentive hydrolysis or acetolysis of the spiroepoxides then affords either the free syn dihydroxyketones (7)orthe mono-acetate derivatives (8), respectively.Remarkably,the entire sequence can be efficiently carried out as an operationally simple onepot process to deliver either the spiroepoxides or syn dihydroxyketones in good yields. [5] We hypothesized that if an effective general method for carboxylative cyclisation could be identified, epoxidation of the resulting enol and subsequent hydrolysis could provide ag eneral route to the dihydroxyacetone motif.B ased on precedent for carboxylative cyclisation of propargylic alcohols (Scheme 2A,B) [6] or derivatives, [7] and our own previous work in this area, [8] we initiated preliminary investigations into effective methods for carboxylative cyclisation of secondary propargylic alcohols,b ut disappointingly these proved unproductive. [5] We hypothesized that if an effective general method for carboxylative cyclisation could be identified, epoxidation of the resulting enol and subsequent hydrolysis could provide ag eneral route to the dihydroxyacetone motif.B ased on precedent for carboxylative cyclisation of propargylic alcohols (Scheme 2A,B) [6] or derivatives, [7] and our own previous work in this area, [8] we initiated preliminary investigations into effective methods for carboxylative cyclisation of secondary propargylic alcohols,b ut disappointingly these proved unproductive.…”