Total Synthesis of Soraphen A1α

Abstract

The convergent synthesis of macrolide soraphen A 1 α is described starting from glucose (western part) and mannose (eastern part). Mannose was converted into a 2-deoxyribohexopyranoside that could be methylated and reduced stereoselectively. Chain elongation at CÐ6 was carried out by stereoselective addition of a magnesium acetylide. The two fragments (western and eastern) were assembled by a Julia olefination followed by macrolactonization. The introduction of the methyl group at CÐ2 of norsoraphen occurred stereoselectively for thermodynamic reasons.

The Julia Reaction

“…As depicted in Scheme 3.19, Giese et al had to face such a problem during the course of the total synthesis of Sopharen A 1a [75]. Deprotonation of 99 led rapidly, by competitive elimination, to vinyl sulfone 100, and no coupling between 98 and 99 was observed (reaction 3.19).…”

Myxobacterial secondary metabolites: bioactivities and modes-of-action

“…In parallel, the structure of the soraphen A was solved by X-ray crystallography, and the compound was prepared by total synthesis. 164 Comprehensive derivatization experiments were also performed in order to elucidate structure-activity relationships, as well as to evaluate whether less complicated structures might retain good bioactivity. [165][166][167][168][169] Unfortunately, even minor changes to the molecule led to a complete loss in potency.…”

Synthesis of C11-Desmethoxy Soraphen A1α: A Natural Product Analogue That Inhibits Acetyl-CoA Carboxylase

“…More recently, ACCs have become of interest to those seeking novel targeted cancer therapeutics, as several studies have established that cancer cells have an intrinsic dependence on de novo fatty acid synthesis and that inhibition of ACC, the rate-limiting step of biosynthesis, triggers apoptosis of cancer cells with little to no effect on normal cells. − While soraphen A 1α has been described as a unique tool to study altered fatty acid metabolism in cancer cells, its in vivo utility appears hampered by its poor solubility and bioavailability. , Over 30 natural product family members have been isolated from Sorangium cellulosum and numerous synthetic analogues have been prepared, yet no analogues have been discovered with activity akin to 1 . Although the natural product is readily available from fermentation (∼130 mg/L), the nature of structural changes that are easily accessible from the fully functionalized natural product are quite limited; such is often the case with natural product derivatization. − Soraphen A 1α ( 1 ) has been pursued as a target for total synthesis for ∼20 years, with two successful syntheses being reported. − Unfortunately, these accomplishments call for synthetic sequences of 25 to ≥40 steps (longest linear sequence) and define a rather substantial barrier to the use of chemical synthesis for the discovery of novel soraphen analogues that may have better properties than 1 . Here, we report a concise synthesis of C11-desmethoxy soraphen A 1α ( 2 ), a natural product analogue that was targeted in a function-oriented synthesis pursuit after analysis of the ACC2– 1 structure and an assessment of the challenges that have plagued previous syntheses of 1 .…”

“…While a cursory inspection of the structure of soraphen A 1α may lead one to suggest that the challenge associated with preparing this target may lie in the stereochemically dense C1–C7 domain, the region of soraphen A 1α that has had the most significant impact on efficiency associated with prior syntheses is C8–C12 (Figure B). While many modern chemical methods can be employed to establish this subunit, within the broader problem of completing the total synthesis of 1 , successful solutions come with significant disadvantages; i.e., they require either multistep sequences to establish the disubstituted alkene and the C11–C12 anti -diol, and/or dictate the use of coupling partners that require numerous subsequent chemical transformations to establish the functionalized macrocyclic structure. − Given these facts, we sought to define a soraphen A 1α analogue that would have similar activity versus ACC but would harbor functionality in this C8–C12 region that would simplify efforts to accomplish de novo chemical synthesis.…”