The structurally unique akuammiline alkaloid (+)-scholarisine A was synthesized in 14 steps from a known enone (15 steps from commercial materials) through a route empowered by a unique C–H arylation reaction to forge its polycyclic core. Additional key steps include a pyrone Diels–Alder reaction and a radical cyclization/Keck allylation to fashion the core cage polycycle and one of the molecule’s quaternary centers, as well as the use of a carefully positioned pendant hydroxyl group to facilitate the chemoselective reduction of an extremely unreactive lactam in the presence of a readily reduced lactone.

Peyssonol A, a brominated natural product with documented anti-HIV-1 activity, was synthesized racemically along with 6 isomers and 15 truncated analogues and synthetic precursors. These compounds were screened in a cell-based assay against a recombinant HIV-1 strain to investigate structure–activity relationships. The results obtained suggest that both the aliphatic and aromatic domains of peyssonol A are responsible for its potency, while the stereochemical configuration of the substituents on the aliphatic domain, including their bromine atom, are largely irrelevant. Although none of the analogues tested were as potent as the parent natural product, several exhibited greater therapeutic indices due to reduced cytotoxicity, noting that nearly all compounds tested were measurably cytotoxic.

Herein is presented a cohesive strategy to rapidly fashion diverse members of the lauroxocane family of natural products, leading to the shortest syntheses of any member to date. These efforts include racemic formal total syntheses of laurefucin and E- and Z-pinnatifidenyne as well as a facile preparation of the oxocene core of 3E-dehydrobromolaurefucin. The key elements of the design are novel diastereoselective ring-expanding bromoetherifications of tetrahydrofurans triggered by a unique bromonium source (BDSB, Et2SBr·SbBrCl5) and strategically positioned nucleophilic traps, where altering the identity and position of these traps affords diverse functionality on the eight-membered ring backbone. Its biogenetic relevance is also discussed in light of the range of substrates that successfully undergo this key rearrangement.

The first total synthesis of the unique terpene rippertenol, a molecule with dense stereochemical complexity arrayed on a compact framework largely devoid of functional groups, is described. Key elements include orchestrated and unique applications of aldol condensations, Diels–Alder chemistry, and a ring expansion to advance a chiral starting material containing a single chiral center into the final target in a concise and diastereocontrolled manner.

A unique procedure to effect a ring-expanding bromoetherification process is described, wherein tetrahydrofurans and tetrahydropyrans are smoothly transformed into 8- and 9-membered bromoethers in a regio- and stereocontrolled manner through the use of BDSB (bromodiethylsulfonium bromopentachloroantimonate). These products resemble the cores of the Laurencia C15 acetogenins. In light of the generality and effectiveness of the approach, this work provides a unique strategy for their laboratory preparation and may implicate a possible biosynthesis pathway.

Covering: up to the end of 2010

Chemical syntheses of two stereochemically unique resveratrol dimers, caraphenols B and C, have shown that their structures are misassigned. Thoughts on their potential chemical etiology led to an alternate structural proposal that has been confirmed through synthesis, one indicating that the substituents on their respective indane systems exist in a relative trans,trans orientation rather than the originally postulated all-cis arrangement.

Although there are many reagent combinations that can initiate polyene cyclizations, simple electrophilic halogen sources have not yet proven broadly effective as promoters of such processes. Herein is described a readily prepared and stable class of reagents capable of effecting such transformations for a wide range of electron-rich and -deficient terpenes derived from geraniol, farnesol, and nerol, thereby enabling the effective synthesis of a diverse array of complex chlorine-, bromine-, and iodine-containing polycyclic frameworks. Efforts to date have led to the first racemic laboratory total synthesis and structural revision of the anti-HIV natural product peyssonol A as well as an efficient and concise inaugural total synthesis of peyssonoic acid A. They have also permitted formal racemic total syntheses of aplysin-20, loliolide, K-76, and stemodin to be achieved through routes that are typically shorter, higher-yielding, and more environmentally conscious than previous efforts. Preliminary attempts to use chiral forms of the reagent class for enantioselective alkene halogenation are also described.

This review explores the concept of using privileged scaffolds to identify biologically active compounds through building chemical libraries. We hope to accomplish three main objectives: to provide one of the most comprehensive listings of privileged scaffolds; to reveal through four selected examples the present state of the art in privileged scaffold library synthesis (in hopes of inspiring new and even more creative approaches); and also to offer some thoughts on how new privileged scaffolds might be identified and exploited.