Highly Diastereoselective Synthesis of Syn‐1,3‐Dihydroxyketone Motifs from Propargylic Alcohols via Spiroepoxide Intermediates

Abstract

Syn dihydroxyketone motifs are embedded in awide range of biologically active natural products,h owever the development of stereoselective synthetic methods to assemble these structures has proven ac hallenging task. We report ah ighly diastereoselective method for the synthesis of syn dihydroxyketones from propargylic alcohols,w ith wide scope for application in natural product synthesis.T he reaction sequence involves regioselective cyclisation of propargylic alcohols with incorporation of at riketone to give enol dioxolanes that are then diastereoselectively epoxidised to form unusual spiroepoxide intermediates.H ydrolysis affords syn dihydroxyketones as essentially single diastereisomers.The reaction sequence is operationally simple,o fw ide substrate scope,and remarkably can be efficiently carried out as ao nepot process with no loss of overall yield or diastereoselectivity.Scheme 4. Reaction scope for spiroexpoxide hydrolysis to syn dihydroxyacetones 7a-j.Scheme 5. High diastereoselectivity restored by simple reversal of substituents (6k vs. 6l)i nthe preparation of syn dihydroxyacetone 7k. Scheme 6. One-pot process for direct preparationo fsyn dihydroxyketones from (homochiral)p ropargylic alcohols.

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

“…In 2019, we reported our development of a highly stereoselective synthesis of syn-dihydroxyketone motifs 110 from readily available propargylic alcohols 111 (Scheme 18). 59 The reaction sequence involved regioselective cyclization of propargylic alcohols 111 with incorporation of triketone 112 to give enol dioxolanes 113 that then underwent highly diastereoselective epoxidation to give spiroepoxide intermediates 114. Hydrolysis or acetolysis of the spiroepoxides 114 then cleanly afforded syn-dihydroxyketones 110 or the corresponding monoacetylated dihydroxyketones 115 as single diastereomers.…”

“…Scheme 18Diastereoselective synthesis of syn-1,3-dihydroxyketone motifs 110 by Furkert and Brimble et al59 …”

Development of a synthetic equivalent of α,α-dicationic acetic acid leading to unnatural amino acid derivatives via tetrafunctionalized methanes

“…When reagents possess nucleophilic and electrophilic sites, the formed hemiacetal attacks the electrophilic site of the nucleophile via dipolar cycloaddition (path d ). 7 Conversely, dehydration of the hemiacetal forms an electron-deficient double bond (path e ), 8–10 which subsequently accepts the addition of less nucleophilic reagents, such as pyrrole. 10…”

Dynamic kinetic resolution of transient hemiketals: a strategy for the desymmetrisation of prochiral oxetanols

“…Recent extensions regarding the alkene-electrophile 4 as well as applications in the synthesis of natural products 5 have renewed the interest in hemiacetals as a platform for reaction development. However, nucleophilic attack of a transient hemiacetal to other groups than activated alkenes are rare, 6 even though this would allow a much broader range of polyolic targets to be accessed.…”