Synthesis of natural butenolides and analogs

Abstract

Butenolides represent a large family of -lactones, having a common furan-2(5H)-one subunit that is highly diversified in natural products. These lactones are found in several naturally-occurring sources and are associated with a wide range of biological activities, including, antibiotic, anti-inflammatory, anticancer, phytotoxic, insecticidal, among other properties. In addition to this, these compounds are employed as models for synthetic materials displaying pharmacological and industrial potential. Rubrolides are a butenolide sub-family of natural products occurring in marine species. These compounds are constituted by a polysubstituited 4-aryl-5-benzylidenefuran-2(5H)-one structure. Numerous total synthesis and biological activity studies have been described in literature, including cytotoxic, bactericidal, and photosynthesis inhibition reports. The first part of this work presents aconcise and efficient synthesis of two of these natural products, rubrolides B and K. The main steps include: (i) synthesis of 4-arylfuran-2(5H)-one via selective Suzuki-Miyaura cross-coupling; (ii) vinylogous aldol condensation between silyloxyfuran derivatives and aldehydes; and (iii) regioselective bromination/demethylation, leading to the functionalization of the aromatic rings. The methodology developed allowed the total synthesis of rubrolides B and K in three to four steps with 41% and 37% global yield, respectively. Additionally, another type of butenolide, known as tetronamides, has attracted much synthetic interest. Its structure is characterized by a 4-aminofuran-2(5H)-one moiety and was used as a model in the development of agrochemicalsand wide-range antibacterials. Basidalin is the first and only natural tetronamide reported, this compound of fungal origin is a derivate of (Z)-4-amino-5-(formylmethylene)furan-2(5H)-one and has antibiotic and antitumor activities. Its structure is simple, but richly functionalized, leading to various synthetic approaches, but so far with littlesuccessful synthesis. Therefore, the second part of this work describes the first successful total synthesis of basidalin. The main steps of synthesis include: (i) regio and stereocontrolled vinylogous aldol condensation forming key intermediate (Z)-4-bromo-5-((1,3-dithiane-2-yl)methylene)butenolide startingwith 2-formyl-1,3-dithiane and 4-bromo-2-triisopropylsilyloxyfuran, (ii) addition of the 4-amino group using an Aza-Michael addition/elimination reaction, and (iii) thioacetal removal as the last step. Basidalin synthesis was completed in five steps with 39% global yield. Enhygrolides are a class of novel, highly substituted antibiotic butenolides found in the obligate marine myxobacterium, Enhygromyxa salina, their structureis related to the biologically-active compounds, nostoclides and cadiolides; whose synthesis were amply described in literature. The third chapter of the present work will describe the first synthesis of scarce enhygrolide A. The key steps include (i) addition of [alfa]-benzyl group through organocatalytic reductive alkylation, (ii) introduction of ß-alkyl substituent by efficient and green ironcatalyzed sp2-sp3 cross-coupling with Grignard reagents, and (iii) typical stereoselective vinylogous aldol condensation reaction to stablish characteristic (Z)-y-benzylidenefuran-2(5H)-one scaffold. Aside from its brevity and reliance on environmentally sustainable processes, the synthesis demonstrates the serviceability of butenolide pivalates in cross-coupling reactions. This process was achieved in five steps and 54% overall yield.Natural and synthetic rubrolides and tetronamides are a relevant class ofhighly biologically-active butenolides, giving rise to the development of diverse derivatives with important properties ranging from herbicidal to anticancer. In the last chapter of this work, the procedures involved in the synthesis and study of herbicide and cyanobactericide activities of ß-azarubrolide analogs or y-alkylidenetetronamides, are described. The main steps of the synthesis include: (i) syn diastereospecific aldol condensation protocol yielding aldolic addition tetronamide products, starting from N-arylbutenolides and aromatic aldehydes and (ii) optimized dehydration reaction to get the y-alkylidene derivatives.However only three y-benzylidene derivatives with no substituted and with simple aromatic substituents as 2-Cl and 3-NO2 yielded satisfactory result. Nevertheless, cyanobacterial and photosynthesis inhibition assays of all precursors and the final unsaturated derivatives were developed. y-Alkylidene molecules did not render good results giving IC50 >180 µ M and >150 M, respectively. On the contrary, itsprecursors showed more promising results, mainly when possess biphenyl group, showed a moderate IC50 = 58.4 µM for herbicidal activity and an important cyanobatericidal activity, with IC50 = 2.8 M. In this manner, a total of 20 4-amino-5-(hydroxy(aryl)methyl)furan-2(5H)-one analogs were produced in 51%-100% yield and dr(syn:anti) from 56:44 to >99:1. Later, on these compounds for the same activities were tested. Herbicide activity were moderate, differently to the cyanobactericide, where 5 biphenyl analogs gave the best activity with IC50 = 1.3- 5.1 µM. Since aldolic addition products are obtained as racemic mixture, an enantioselective synthetic approach for these tetronamides was described. This was done by means of two steps: (i) oxidation of addition aldolic products and (ii) optimized asymmetric hydrogen transfer protocol with Ru tethered catalyst (Ruteth-cat). Initial N-aryltetronamide analog tested for the oxidation showed to be an instable product. Then, more robust -pyrrolidinebutenolides were employed. This, in turn, rendered excellent yields for the production of specific tetronamide syn-enantiomers with yield of 96% and ee = 87% using (R,R)-Ru-teth-cat and yield of 89% and ee = 80% using (S,S)-Ru-teth-cat for the dextrorotatory and levorotatory species, respectively.