Abstract
Herein, we report the stereoselective and convergent synthesis of resolvin E4, a newly identified specialized pro-resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV–Vis and LC–MS/MS) data of synthetic resolvin E4 matched those obtained from biologically produced material.
Highlights
Inflammation is a consequence of the immune system responding to injurious stimuli and constitutes an essential, protective strategy with the aim of restoring cellular homeostasis
The need for absolute configuration assignments and materials of high chemical purity for further biological investigations and targeted lipidomic analyses has spurred great interest in the synthesis of the E-series resolvins.9a,10,11 we report the total synthesis of resolvin E4 (RvE4) (1) together with results from LC−MS/MS matching experiments that established its structure as (5S,6E,8Z,11Z,13E,15S,17Z)-5,15dihydroxyicosa-6,8,11,13,17-pentaenoic acid
The Carreira alkynylation was chosen as the key transformation for furnishing fragment 5, with the intent of later transforming the acetylene moiety into the corresponding E-vinyl halide functionality needed for the planned palladium cross-coupling chemistry
Summary
Inflammation is a consequence of the immune system responding to injurious stimuli and constitutes an essential, protective strategy with the aim of restoring cellular homeostasis. Recent efforts concerning the mechanisms involved in the resolution of acute inflammation have provided evidence for a new superfamily of endogenous lipid mediators named specialized pro-resolving mediators (SPMs).[1] These oxygenated polyunsaturated fatty acids are biosynthesized in the presence of lipoxygenase and cyclooxygenase enzymes.[2] SPMs are chemically labile molecules formed in nano- to picogram amounts in vivo[3] and exhibit anti-inflammatory and proresolving bioactions, often in the low nano- to picomolar range.[2,3] SPMs are important in the process of clearing bacterial infections and participate in host defense, organ protection, pain reduction and play a role in tissue remodeling.[3] The E-series resolvins, derived from eicosapentaenoic acid (EPA), were among the first SPMs to be reported (Figure 1).[4]. The need for absolute configuration assignments and materials of high chemical purity for further biological investigations and targeted lipidomic analyses has spurred great interest in the synthesis of the E-series resolvins.9a,10,11 we report the total synthesis of RvE4 (1) together with results from LC−MS/MS matching experiments that established its structure as (5S,6E,8Z,11Z,13E,15S,17Z)-5,15dihydroxyicosa-6,8,11,13,17-pentaenoic acid
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