The Renaissance of α‐Methylene‐γ‐butyrolactones: New Synthetic Approaches

Abstract

The amount of research activity concerning alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones has increased dramatically in recent years. This Review summarizes the structural types, biological activities, and biosynthesis of these compounds, concentrating on publications from the past 10 years. Traditional approaches to alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones are then reviewed together with novel approaches, including those from our own research group, reported more recently.

Diastereodivergent and Enantioselective [4+2] Annulations of γ-Butenolides with Cyclic 1-Azadienes

“…(3aS,4S,11aS)-3a-Methyl-4-(p-tolyl)-3a,4-dihydro-1H-benzo [4,5]isothiazolo [2,3-a]furo [2,3- [4,5]isothiazolo [2,3-a]furo [2,3- [4,5]isothiazolo [2,3-a]furo [2,3-e] pyridin-2(11aH)-one 10,10-dioxide (5d) was obtained in 34% yield; the enantiomeric excess was determined to be 63% by HPLC analysis on Daicel Chiralcel IA column (10% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tminor = 57.94 min, tmajor = 73.67 min. [4,5]isothiazolo [2,3-a]furo [2,3- (3aS,12R,12aS)-8-Bromo-12a-methyl-12-phenyl-3,3a,12,12a-tetrahydro-2H-benzo[e]furo [2ʹ,3ʹ:5,6] pyrido [1,2-c] [1,2,3]oxathiazin-2-one 5,5-dioxide (8b) was obtained in 45% yield; the enantiomeric excess was determined to be >99% by HPLC analysis on Daicel Chiralcel IA column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 6.28 min, tminor = 8.00 min.…”

“…isothiazolo [2,3-a]furo [2,3-e]pyridin-2(11aH)-one 10,10-dioxide (5f) was obtained in 37% yield; the enantiomeric excess was determined to be 55% by HPLC analysis on Daicel Chiralcel ID column (40% 2-propanol/n-hexane, 1 [4,5]isothiazolo [2,3-a]furo [2,3- [2',3':5,6]pyrido [1,2-c] [1,2,3]oxathiazin-2-one 5,5-dioxide (8a) was obtained in 56% yield; the enantiomeric excess was determined to be 92% by HPLC analysis on Daicel Chiralcel IA column (40% 2-propanol/n-hexane, 1 mL/min, temperature 35 °C), UV 285 nm, tmajor = 5.40 min, tminor = 8.00 min. …”

“…γ-Butenolides represent an important class of heterocycles, which widely exist in a large number of natural products and pharmaceutically useful molecules [1,2]. In addition, the γ-butenolides act as competent direct vinylogous nucleophiles in addition reactions for the construction of an array of structurally diverse architectures [3][4][5][6], even for preparing more challenging molecules with quaternary carbon centers by using γ-substituted butenolides [7][8][9][10][11][12][13].…”

Design, synthesis and anticancer activity of Michael-type thiol adducts of α-santonin analogue with exocyclic methylene

“…The lactones can form covalent adducts in vivo with proteins and other nucleophilic bio-molecules via a Michael-type addition of a free sulfhydryl or amine group. [7][8][9] A thorough review of the literature revealed similar amine adducts derived from helenalin 1, 10-12 ambrosin 2, 13 We studied α-santonin 6, a promising sesquiterpeniod lactone, isolated from Artemisia maritima. α-Santonin has been reported to possess anti-parasitic, 16 antipyretic and antiinflammatory activities.…”

Targeting NF-κB p65 with a Helenalin Inspired Bis-electrophile

“…The medicinal properties of helenalin have been known for over a century, 23 which are structurally endowed, in part, by its α-methylene-γ-butyrolactone; a moiety found in scores of bioactive natural products. 24 Exocyclic methylene butyrolactones undergo hetero-Michael addition with biological thiols to form covalent adducts. Helenalin also contains an endocyclic α,β-unsaturated ketone (cyclopentenone) that can also undergo hetero-Michael addition with thiols.…”