Efficient Stereoselective Total Synthesis of Denticulatins A and B

Abstract

Five of the eight stereocenters of the denticulatin 1 were formed by stereoselective aldehyde allylboration. This approach allows an efficient synthesis of even complex molecules. Naturally occurring denticulatin is produced by Siphonaria, which are native to the tidal zones of the Indian Ocean and the Caribbean.

Marine polypropionates

“…70 Hoffmann and co-workers intuitively predicted that the protected denticulatin precursor 114, synthesised from two key components 115 and 111, would spontaneously isomerise to give the more thermodynamically favoured denticulatins upon deprotection. 71,72 The former aldehyde component was prepared in three stereoselective consecutive steps using chiral allyl boronates while the latter ketone was obtained via a kinetic Sharpless resolution of the allylic alcohol, (3R)-2-methylpent-1-en-3-ol, followed by an Ireland-Claisen rearrangement. Unfortunately, while deprotection of 114 resulted in the anticipated isomerisation, unwanted epimerization at C-10 also occurred to give a mixture of the denticulatins.…”

“…Likewise, the denticulatins are likely to be the preferred cyclisation products of the acyclic precursor 152 (Scheme 4); three of the four total syntheses of the denticulatins in the literature utilise the thermodynamic cyclisation of deprotected open chain precursors such as 112, 116 or 117, 70,[73][74][75][76] while a fourth relies on spontaneous isomerisation of an alternative hemiacetal ring system 114 to a more stable ring system. 71,72 Natural products containing a 4-pyrone ring are likely to derive spontaneously from an acyclic triketone which may easily undergo ring closure during isolation and chromatography on silica, hence the siphonarins, the baconipyrones, caloundrin, vallartanones, maurenones, cyercenes, illikonapyrone, the peroniatriols and other pyrone-based marine metabolites are unlikely to be genuine natural products. Once formed, the cyclic polypropionates also undergo some non-enzymatic reactions which are characteristic of -dicarbonyl and related systems, and which thereby confuse the structural nature of the biosynthetic products.…”

“…Once formed, the cyclic polypropionates also undergo some non-enzymatic reactions which are characteristic of -dicarbonyl and related systems, and which thereby confuse the structural nature of the biosynthetic products. Hemiacetal-containing polypropionates dehydrate to dihydropyrones under acidic, basic or buffered conditions, 16,[70][71][72]74,80 hence the status of products such as the membrenones and maurenone is also suspect. Retrohemiketalisation via a -diketone enolate occurs on brief treatment of polypropionates such as the denticulatins with mild base and provides epimeric mixtures.…”

Stereochemistry of the Allylation and Crotylation Reactions of α-Methyl-β-hydroxy Aldehydes with Allyl- and Crotyltrifluorosilanes. Synthesis ofanti,anti-Dipropionate Stereotriads and Stereodivergent Pathways for the Reactions with 2,3-anti-and 2,3-syn-α-Methyl-β-hydroxy Aldehydes

“…9:1 mixture favoring the undesired diastereomer 17. 20 The highly enantioselective enol borane and crotylboronate reagents developed by Masamune 21,22 and Hoffmann 3, 23,24 have been used successfully in challenging examples of mismatched double asymmetric reactions leading to the anti,anti-dipropionate stereotriad. However, the complex, multistep sequences required for synthesis of these reagents have restricted their widespread use in organic synthesis.…”