Improved Synthesis of the C16–C20 Segment of Resolvin E1 Using Enantioselective Ketone Reduction and Lipase-Catalyzed Resolution

Abstract

A practical synthesis targeting the C16−C20 segment of the endogenous metabolite Resolvin E1 (RvE1) is described. The original route was revised to avoid the use of source-constrained raw materials and chemistries that were problematic on larger scale. The revised route utilizes commercially available (E)-1-chloropent-1-en-3-one as the key raw material to replace (S)-glycidol. The (E)-vinyl iodide functionality was installed by an addition/elimination sequence to prepare the segment required for a subsequent Sonogashira coupling. The chiral secondary hydroxyl group at C18 was established by Corey− Bakshi−Shibata (CBS) reduction followed by lipase-catalyzed acetylation to achieve chiral purity in excess of 98% ee. The revised route offered a viable multikilogram process to support early clinical production of this pro-resolution therapeutic agent.

Total synthesis of the endogenous inflammation resolving lipid resolvin D2 using a common lynchpin

“…The total synthesis of resolvin D1 has also been reported [ 10 ] along with resolvins D3 [ 11 ], D5 [ 12 ], D6 [ 13 ] and resolvins E1 [ 4 , 14 – 15 ], E2 [ 16 – 17 ] and E3 [ 18 ] with full experimental details included for resolvins D3 [ 11 ], E2 [ 16 ] and E3 [ 18 ]. An improved synthesis of the C16–C20 fragment of resolvin E1 has also been reported [ 19 ]. We were interested in accessing amounts of RvD2 ( 1 ) for biological evaluation but without detailed synthetic sequence to follow and given the very high cost [ 20 ] of commercial 1 we elected to develop an alternative route to provide this important compound and analogues for further biological evaluation.…”

Effect of Solvent Polarity on Enantioselectivity in Candida Antarctica Lipase B Catalyzed Kinetic Resolution of Primary and Secondary Alcohols

“…Enzymatic kinetic resolution is a method widely employed in the drug industry, as well as in the laboratory, to optically resolve a racemic compound by an enzyme-catalyzed reaction, taking advantage of the difference in reaction rates between the enantiomers. , Resolution reactions have often been conducted using enzymes suspended in organic solvents in order to resolve water-insoluble compounds, suppress undesired side reactions, and shift the thermodynamic equilibrium to products . For example, enantiopure carbocylic nucleosides, which are key intermediates for the synthesis of antiviral agents, were prepared by the pancreatin-catalyzed acetylation of their precursory alcohols .…”

A Modular, Enantioselective Synthesis of Resolvins D3, E1, and Hybrids

“…This tactic has been adopted by others for related resolvins, and has enabled the in vivo testing of the natural products. A further synthesis of resolvin E1 was disclosed in which the ( Z )-configured double bonds were introduced from a ( Z )-alkenyl bromide via Suzuki coupling, and from a Wittig reaction …”