Lactones in the Synthesis of Prostaglandins and Prostaglandin Analogs

Abstract

In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF2α and 1,15-PGF2α lactones, many 1,15-lactones of E2, E3, F2, F3, A2, and A3 were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9β-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9β-PG analogs and future applications, are also discussed.

Ag(I)/Lewis Acid Cooperatively Promoted Three-Component Coupling for Carbo-Heterofunctionalization of Alkenes

“…Our investigation started with screenings of reaction conditions using the reaction of 4-vinyl-1,1′-biphenyl ( 1a ), methyl Meldrum’s acid ( 2a ), and H 2 O ( 3a ) as the model (Table ). To our delight, the designed reaction occurred to afford the γ-lactone products that are the versatile precursors to a variety of bioactive compounds (the initially formed carboxylic acid product ( 4a′ ) was treated with trimethylsilyldiazomethane, a methylating agent, during the work-up step to give the corresponding esters ( 4a ) as the final products because esters are easy to isolate, see the Supporting Information for experimental details). Notably, previous methods for the construction of γ-lactones via radical pathways require the use of α-halocarbonyl compounds .…”

Inter-Species Redox Coupling by Flavin Reductases and FMN-Dependent Two-Component Monooxygenases Undertaking Nucleophilic Baeyer–Villiger Biooxygenations

“…The particular outcomes of the biooxygenations catalysed by LuxAB luciferase are interesting in another respect. Because the (−)-( 1S , 5R )-2-oxa-lactone formed is an acknowledged synthon for the chemoenzymatic synthesis of various potentially useful prostaglandin analogues [ 50 ], it is significant that the calculated enantiomeric purities [ 45 ] of the (−)-2-oxa-lactone recorded with this monooxygenase in combination with each of the tested purified FRs are all higher than those reported previously for equivalent biotransformations undertaken by the Type 1 BVMOs 2-oxo-Δ 3 -4,5,5-trimethylcyclopentenylacetyl-CoA monooxygenase sourced from P. putida ATCC 17453 [ 4 , 45 , 51 ], and cyclohexanone monooxygenase sourced from either Acinetobacter TD63 [ 52 ], or Acinetobacter calcoaceticus NCIMB 9871 [ 53 , 54 ].…”

FP receptor structures reveal the selectivity mechanism of prostaglandin

“…Previous drug development of prostaglandin analogs generally focused on modifications on the α-chain or the ω-chain to improve pharmacokinetics properties or drug selectivity, such as acylation to α-carboxyl on the α-chain, introducing 15-methyl or 16-methyl or aromatic ring to the ω-chain 21,27,32,33 . Our structures as well as the mutagenesis studies suggest the sub-pocket interacting with the F-ring plays a key role in ligand selectivity.…”