## 3 Chemistry and Biological Activities of Selected Meroterpenoids
These natural products have exhibited promising BACE1 inhibitory activities in cell-based assays, with IC\({}_{50}\) values of 60-80 nM. This is more active than LY2811376 (IC\({}_{50}\) of 260 nM), a potent clinical BACE1 inhibitor produced by Eli Lilly. Additional in vivo studies of one of these natural products showed significant decrease of BACE1 activity and Ab42 levels in 3 xTg AD mice, similar to LY2811376 [74]. Therefore, the synthesis of these compounds has clinical relevance, and more potent derivatives could be generated once a streamlined synthetic endeavor has been established. An impressive biomimetic synthesis towards these natural products was recently reported as shown in Scheme 23 [88]. The synthesis began with the coupling reaction of 3,5-dimethylorsellinic acid **291** with (2\(E\),6_E_)-10,11-epoxyfranesyl mesylate **292** as the electrophile under basic condition, followed by in situ methyl esterification to generate (2\(E\),6_E_)-10,11-epoxyfranesyl-5-dimethylorsellinic acid methyl ester **293**. Then, a dearomatization-driven polycylization reaction was mediated by treatment with alkyl aluminum-pair as a Lewis acid system to promote the intramolecular polyene cyclization cascade reaction to afford asperterpene scaffold **177** and related meroterpenoid **149** via intermediate **297** in a 1 to 3 ratio favoring compound **294**. Alternatively, compound **291** was coupled with electrophile (2\(Z\),6_E_)-10,11-epoxyfranesyl mesylate **295** (the stereoisomer of **292**) using base treatment, followed by in situ methyl esterification to generate compound **296**. The resultant product was treated with alkyl aluminum Lewis acid system to mediate the intramolecular polyene cyclization cascade reaction, which afforded meroterpenoid scaffolds **150**, **151**, and **178**. In addition, it was found that compound **149** could be treated with formic acid to provide natural product **178** in good yields. While the chemical yields are modest, this synthetic approach is remarkable as several centers are established in a single step, generating high complexity rapidly. **Scheme 23. Biomimetic synthesis of asperterpene A derivative and related meroterpenoids. **Dysiherbols A-C are a set of sesquiterpene hydroquinone meroterpenoids first isolated and characterized from _Dysidea_ sp., a species of marine sponge found in the South China Sea first isolated by [PERSON] and co-workers [89]. These natural products are structurally unified by a sterically compact 6/6/5/6 pentacyclic skeleton embracing an impressive oxabicyclo[3.3.1] ring system. There are 5\(-\)6 contiguous stereogenic centers in their molecular scaffold, four of which are quaternary centers. These natural products as extract mixtures were identified to inhibit NF-kB [89]. Isolation and purification of these compounds demonstrated that the pure compounds had potent inhibitory values in the low micromolar range against NF-kB, finding IC\({}_{50}\) values of 0.49 to 6 \(\upmu\)M for dysiherbols A, B, and C respectively. Additionally, these compounds were tested against a human myeloma cancer cell line, NCI H-929, and showed antiproliferation effects in the low micromolar range, with dysiherbols A being the most active with an EC\({}_{50}\) in the 500 nanomolar range. Recent divergent total syntheses of the revised structures of these sesquiterpene hydroquinone meroterpenoids (+)-dysiherbols A-E (**179**-**183**, Figure 5) was reported as shown in Schemes 24 and 25 [90]. The modular synthetic strategy began with compound **299** which had been reported to arise from the readily available dimethyl predysiherbol. Compound **299** was treated with gold to catalyze the tandem intramolecular cyclization reactions providing known Schmalz's intermediate **300**. Hydroboration/oxidative hydroxylation and subsequent Dess Martin Periodinane (DMP) oxidation reaction of compound **300** was converted to ketone **301**.