## 3 Chemistry and Biological Activities of Selected Meroterpenoids
The synthetic approach offers rapid access to impressively complex structures [70]. The metorterpenoids macrocarpals and pigudials isolated from _Psidium guajava_ a food crop widely abundant in tropical regions has been reported to display an array of medicinal properties [71; 72]. These compounds have displayed significant biological properties as anti-HIV and anti-bacterial agents. To further evaluate their properties, access to sufficient quantities of these compounds is required. The application of a hetero-Diels-Alder (HDA) reaction in metorterpenoid synthesis is frequently utilized due to the likely probability that a similar pathway is taking place in nature to generate these natural products [72]. A short biomimetic-inspired synthesis to guajadial **113** and compound **30** was recently reported (Scheme 4). The synthesis commenced with a Knoevenagel condensation between benzaldehyde **31** and diformylphoroglucinol **32** providing compound **33** for in situ generated \(o\)-quinone methide **34**. The HDA cycloaddition reaction between caryophyllene **30** and \(o\)-QM **34** led to guajadial **113**, psidial A **114** and cycloadduct **36**[72]. **Scheme 3. Biomimetic-inspired synthesis of caryophyllene-derived meroterpenoids (part 2). **  
**Scheme 4. Biomimetic synthesis of guajadial and psidial A. **  
Hyperorin-like structures are a large family of meroterpenes that share a challenging molecular caged motif. A recent innovative synthetic strategy based on an annulative approach of polycyclic polyprenylated acylphoroglucinol (PPAP) meroterpenoids with 3,5-dimethylorsellinic (DMOA) was reported as shown in Scheme 5[73]. The synthesis commenced with the readily available methylcyclopenenone synthon, which was sub jected to sequential 1,4-copper-mediated conjugate addition reaction, namely formation of the lithium enolate followed by alkylative enolate trapping to generate the substituted cyclopentanone **37**, which was subjected to further \(\alpha\)-alkylated to furnish the highly substituted cyclopentanone **38**. Next, cyclopentanone **38** was subjected to the key annulation reaction with \(\beta\)-lactone diketene, leading to diketone **39** as the major product, along with C-acylated product **40** and O-acylated product **41**. Diketone **39** was further methylated with trimethylsilyldiazomethane to generate the vinylogous ester isomers **42** and **43**. Compound **43** was subjected to oxidative rearrangement mediated by hypervalent iodine to provide product **45** with bicyclo[3.3.1]nonane ring system via intermediate **44**. Compound **45** was subjected to a subsequent chlorination reaction to provide halogenated compound **46**. Finally, a deprotonation/preylation alkylation, acylation reaction sequence was used to introduce the last isoprenyl group generating the most challenging quaternary center. This was followed by deprotection of the methoxy group to yield hyperforin (**103**) in modest yields. The short strategy is flexible enough to generate a potential diverse library of derivatives for future biological evaluations. A similar approach has been applied to the caged meroterpenoid garsubellin A (**104**, **Scheme 6**) [73]. The total synthesis was initiated with methylcyclopenteno, which was \(\alpha\)-prenylated to generate compound **47**, followed by 1,2 Grignard reaction to access allylic alcohol **48**. The resultant compound **48** was subjected to an anionic oxy-Cope rearrangement to provide bisprelated cyclopentanone **49**. Then, compound **49** underwent an annulation reaction with \(\beta\)-lactone diketene to produce diketone **50**, followed by Pd(OAc)\({}_{2}\)/Cu(OAc)\({}_{2}\) mediated unusual Wacker-type-intramolecular cyclization to provide tricycle system **51**. Tricyclic system **51** was treated with PhI(OAc)\({}_{2}\) under basic condition for an oxidative ring expansion leading to compound **52**, the needed bicyclo[3.3.1]nonane ring system that upon cobalt catalyzed Mukaiyama hydration reaction provided tricycle **53**.