Chemistry and Biology of the Polycyclic Polyprenylated Acylphloroglucinol Hyperforin

Abstract

(+)‐Hyperforin (1) is a polyprenylated acylphloroglucinol (PPAP) natural product isolated in 1971 from Hypericum perforatum. Also known as St. John's wort, Hypericum perforatum is a popular medicinal plant because of its antidepressant properties. (+)‐Hyperforin (1) is the main component of the plant and has attracted the interest of the scientific community since it was identified as the agent responsible for the antidepressant activity. The subsequent discovery that it also displayed a wide range of biological activities triggered the interest of synthetic chemists because of its appealing, compact molecular structure. This microreview presents an overview of the synthetic studies reported so far for the racemic and enantioselective syntheses of (+)‐hyperforin (1) and analogues, and attempts to shed light on the intriguing structure–activity relationships (SARs) of the natural product.

Total Syntheses of Hyperforin and Papuaforins A–C, and Formal Synthesis of Nemorosone through a Gold(I)‐Catalyzed Carbocyclization

“…In the past two decades, more than 150 PPAPs have been isolated and they display a wide range of biological activities. Notably, hyperforin ( 1 ),3 isolated from St. John’s wort, displays antidepressant, antimalarial, and human histone deacetylase inhibitory activities to name but a few 4. Other PPAPs, such as papuaforin A ( 2 ),5 nemorosone ( 3 ),6 and garsubellin A ( 4 ),7 showed antibacterial, antitumor, and antineurodegenerative activities, respectively.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…74) [318]; (7) a tris(norbornenecarboxylate) connected to a carbon nanotube [319]; (8) bis(norbornenecarboxylate ester)s (e.g. 73) [320]; (9) 5-ethylidenenorbornene (68) [321], including its use as a part of a self-healing system [322]; (10) vinylnorbornene [323]; (11) tetracyclododecene (69) [324]; (12) norbornadienes connected to various hydrophobic groups, including a steroid system [325]; (13) dicyclopentadiene [326,327,328,329,330,331,332,333,334,335,336], including polymerizations performed in the presence zinc oxide nanoparticles [337], urea formaldehyde microcapsules [338],mildly oxidized graphene oxide [339], barium titanate [340], and high internal phase emulsions [341,342]; (14) the norbornadiene-anthracene Diels-Alder adduct (76) [343,344]; (15) norbornenedicarboxylate esters connected to cyanobiphenyl groups [345], to anthracene groups [346], and to nitroxide groups (e.g. 79) [347]; (16) the three stereoisomeric dimethyl norbornenedicarboxylates (determination of the relative rates of ROMP) [348]; …”

“…Specific compounds or compound classes represented include: (1) tetrahydropyrans [53]; (2) cyclopentenones [54]; (3) 3,4,5-trisubstituted isoxazolines [55]; (4) carbocyclic nucleosides [56]; (5) lycopodium alkaloids [57,58]; (6) cyclic hydrazines and azo compounds [59]; (7) tropone and tropolone natural products [60]; (8) seven-membered ring natural products [61]; [62]; (9) tetrahydroisoquinoline-3-carboxylic acid derivatives [63]; (10) chalcones and their heterocyclic derivatives [64]; (11) marine-derived cyclic ethers [65]; (12) pericosine and related marinederived carbasugar natural products [66]; (13) carbohydrate derived macrocyclic compounds [67]; (14) neurotrophic natural products [68]; (15) isodon diterpenes [69]; (16) non-isoprenoid polyene natural products [70]; (17) heterophosphacyclanes [71]; (18) chlorosulfolipids [72]; (19) seven-membered ring sulfur heterocycles; (20) organic cage compounds [73]; (21) presilphiperfolanols [74]; (22) pleuromutilin [75]; (23) hyperforin [76]; (24)…”

Domino Michael-aldol annulations for the stereocontrolled synthesis of bicyclo[3.3.1]nonane and bicyclo[3.2.1]octane derivatives

“…[1,2] (Figure 1a), especially in the placement of substituents with stereocontrol, and are become increasingly important in medicinal chemistry. [2,5] In particular, several bicyclo Seeking to develop a domino annulation, we had regard to the putative biosynthesis of hyperforin [7,10] and related natural products involving the annulation of a substituted phloroglucinol (Scheme 1, eq. I) by alkylative dearomatisation with a prenyl unit, then a second electrophilic attack completing the annulation.…”