Synthesis of Annulated and Spirocyclic Butenolide Derivatives by Condensation of Malonates with Cyclic α-Hydroxy β-Dicarbonyl Compounds

Abstract

Cyclocondensation of alicyclic and heterocyclic α-hydroxy β-dicarbonyl compounds with dimethyl malonate gives bicyclic butenolide derivatives. The reaction sequence is catalyzed by 4-(N,N-dimethylamino)pyridine and consists of two processes: Knoevenagel condensation followed by transesterification. Depending on the chemical nature of the β-dicarbonyl moiety (oxoester, diketone or α-acetyl lactone or lactam), products with either annulated or spirocyclic constitution are obtained.The 2,5-dihydrofuran-2-one ring (butenolide) is a common structural motif in heterocyclic chemistry, 1 and several biologically active compounds hold a substituted butenolide ring. The structural formulae of the natural products Strigol (1) and Carlactone (2) are given as examples in Scheme 1. 1 These compounds are important factors for cell signaling and gene regulation and, thus, for controlling growth and development of plants. The structure of natural product 1 actually holds two α,β-unsaturated lactone rings, one being annulated with a cyclopentane ring. Several methods for butyrolactone formation have been reported in the recent years. 2,3 The obvious retrosynthetic approach to butenolide 3 is the cyclization of an α,β-unsaturated carboxylic acid derivative bearing a hydroxyl group in the γ-position. Such a structural motif could be accessible by vinylogization of an α-hydroxy ketone 5 (acyloin) by aldol (or Knoevenagel if R 1 is an electron-withdrawing group) condensation with an enolate derived from carboxylic acid derivative 4. 4 Since we had recently discovered a simple access to acyloins by cerium-catalyzed, aerobic α-hydroxylation of β-oxoesters, 5 we considered these products to be perfect 1,2-dioxy-functionalized building blocks for the construction of butenolide derivative rings by cyclocondensation with malonates.Scheme 1 Strigol (1) and Carlactone (2), two naturally occurring strigolactones, and a retrosynthetic approach to butenolides 3We started our investigations with the conversion of α-hydroxy-β-oxoester 6a with dimethyl malonate. From the plethora of conditions reported for the Knoevenagel condensation, 6 we decided to use EDDA, 7 NH 4 OAc, and β-alanine; 8 however, we were never able to identify the target compound 7a (by GC-MS and NMR analyses) in the reaction mixtures, which were always very complex. We attributed this finding to the strained nature of a putative product 7a with two annulated five-membered rings; therefore, we turned to the conversion of cycloheptanone derivative 6c as starting material. Indeed, when using NH 4 OAc (1 equiv) and AcOH (4 equiv) in toluene (reflux, Dean Stark trap) and an excess of dimethyl malonate (3 equiv), we were able to detect lactone 7c in the reaction mixture and isolate it in 10% yield. Since lactone formation after Knoevenagel condensation would require a transesterification, we added DMAP (5 Me Me OH O O O O Me O 1 2

Strategies and methodologies for the construction of spiro-γ-lactams: an update

“…Christoffers and co-workers reported an efficient synthesis of spiro-γ-lactams starting from the appropriate lactam-containing precursors. 109 This synthetic methodology relies on a DMAPcatalyzed Knoevenagel condensation of α-hydroxy-α-acetyl-lactams 312 with dimethyl malonate followed by lactonization to afford spirocyclic γ-, δ-, or ε-lactams 313 in high yields (77-89%) (Scheme 78). Scheme 78.…”