The Reaction of Hyperforin with Hydride Reducing Agents

Abstract

As part of a study aimed at generating analogues of hyperforin (1), the reaction of this prenylated phloroglucinol with various hydride reducing agents was investigated. Hyperforin contains two β‐dicarbonyl systems, one of which is non‐enolizable, and it was interesting to assess the relative reactivity of these structural elements in the highly compact framework of the natural product. Depending on the reducing agent employed, a surprising range of compounds could be obtained, sometimes in synthetically useful yields. The stereochemistry of the LiAlH4‐reduced product was secured by X‐ray analysis and served as a base for elucidating the configuration of a series of reduced and deoxygenated analogues obtained with other reducing agents. The chemoselectivity observed in these reactions is apparently the result of a combination of metal‐chelation and hydrogen‐bonding effects. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Assessable Consequences of Through‐Bond Donor–Acceptor Interactions in β‐Aminoketones

“…3 b ),11 and related monoketones12 have provided among the more compelling illustrations of the Cieplak hyperconjugative transition‐state model 9a. Unexpected reactivity emerges from treatment of 6 ( 8 and 9 ) with LiAlH 4 , Red‐Al, and DIBAL‐H under various conditions—in studies that parallel (in design) those recently performed on a related phloroglucinol‐derived natural product13—and these results will be reported separately. Of relevance to the current discussion, treatment of 6 with one equivalent of Red‐Al provides a modest (33 %) yield of the exo ‐mono‐reduction product 7 (Scheme ), in addition to more polar di‐ and trireduced compounds.…”

Tetrahydrohyperforin and Octahydrohyperforin Are Two New Potent Inhibitors of Angiogenesis

“…The role of the four carbonyl groups, functionalities that could be involved in hydrogen bondings with enzymes active sites, was also investigated. The reaction of hyperforin with different reducing agents produced compounds ( 4 ) to ( 8 ) [25] . Compounds ( 4 ) to ( 7 ) are formally 7-deoxohyperforins, where the C1-C10 non enolizable β-diketone moiety survived to reduction, like in compound ( 4 ), or was partially reduced to a 10-oxymethine (compounds 5 and 6 ) or totally reduced to the 1,10 diol (compound 7 ).…”

“…This is due to the formation of a strong intramolecular hydrogen bond between the donor 9-OH group and the acceptor hydroxyl at 10 position, which also draws the stereochemical control of the reaction, only producing the 10 S stereoisomer. Apparently, compound ( 8 ) is particularly stable if compared to hyperforin and this can be attributed to the strong intramolecular hydrogen bonding that produces orthorombic crystals [25] .…”

“…Compounds 2 to 9 were synthesized as previously described [25]. Stock solutions (10 mg/mL) were prepared in dimethyl sulfoxide (DMSO) and stored in aliquots at −20°C.…”

Oxidation and Reduction

“…Its two dicarbonyl systems are amenable to reduction or deoxygenation upon treatment with alane reducing agents and pave the way to new and interesting modifications of the natural product. 301 A series of new chiral lithium aluminum hydrides (BIFAl-Hs) based on biphenyl-2,2 -bisfenchol and various alkyl alcohols has been synthesized and used to reduce aryl alkyl ketones with up to 62% ee. The observed enantioselectivities are explained on ee the basis of computational transition structure analyses.…”