Total Syntheses of Scabrolide A and Yonarolide.

The concise total syntheses of oxidized norcembranoid terpenoids (-)-scabrolide A and (-)-yonarolide have been accomplished in 10 and 11 steps, respectively. The carbocyclic skeleton was efficiently constructed from two chiral-pool-derived fragments, including a [5,5]-bicyclic lactone accessed through a powerful Ni-catalyzed pentannulation of functionalized cyclopentenone with methylenecyclopropane and subsequent fragmentation. Additional features included a Liebeskind-Srogl coupling, induction of a cyclization/elimination cascade by a zinc-amido base, and installation of a sensitive enedione motif by late-stage γ-oxidation.

Interrupted Nef Reaction of Cyclic Nitronates: Diastereoselective Access to Densely Substituted α-Chloronitroso Compounds.

The reaction of cyclic nitronic esters (isoxazoline- and 5,6-dihydro-4H-1,2-oxazine-N-oxides) with hydrochloric acid affords geminal chloronitroso compounds bearing a distant hydroxyl group. The reaction is usually diastereoselective, and in some cases stereodivergent formation of isomers at different temperatures is observed. The discovered process represents the first example of an interrupted Nef reaction of nitronic esters. DFT calculations support the initial formation of N,N-bis(oxy)iminium cations (key intermediates in the Nef reaction), which are intercepted by the chloride anion followed by ring opening. The synthetic utility of the resulting functionalized chloronitroso compounds in the Diels-Alder reaction with cyclopentadiene was demonstrated.

Correction: Dearomative logic in natural product total synthesis.

Correction for 'Dearomative logic in natural product total synthesis' by Christopher J. Huck et al., Nat. Prod. Rep., 2022, https://doi.org/10.1039/d2np00042c.

Dearomative logic in natural product total synthesis.

Covering: 2011 to 2022The natural world is a prolific source of some of the most interesting, rare, and complex molecules known, harnessing sophisticated biosynthetic machinery evolved over billions of years for their production. Many of these natural products represent high-value targets of total synthesis, either for their desirable biological activities or for their beautiful structures outright; yet, the high sp3-character often present in nature's molecules imparts significant topological complexity that pushes the limits of contemporary synthetic technology. Dearomatization is a foundational strategy for generating such intricacy from simple materials that has undergone considerable maturation in recent years. This review highlights the recent achievements in the field of dearomative methodology, with a focus on natural product total synthesis and retrosynthetic analysis. Disconnection guidelines and a three-phase dearomative logic are described, and a spotlight is given to nature's use of dearomatization in the biosynthesis of various classes of natural products. Synthetic studies from 2011 to 2021 are reviewed, and 425 references are cited.

Total Synthesis of Stelletins through an Unconventional Annulation Strategy.

Marine ecosystems present the largest source of biodiversity on the planet and an immense reservoir of novel chemical entities. Sessile marine organisms such as sponges produce a wide range of complex secondary metabolites, many of these with potent biological activity engineered for chemical defense. That such compounds exert dynamic effects outside of their native context is perhaps not surprising, and the realm of marine natural products has attracted considerable attention as a largely untapped repository of potential candidates for drug development. Only a handful of the more than 15 000 marine natural products that have been isolated to date have advanced to the clinic, and more are to be expected. The rich chemical information encoded in the intricate three-dimensional structures of many marine natural products facilitates highly discriminating interactions with cell signaling pathways, and especially within cancer cells such nuanced effects offer an exciting opportunity for the development of targeted therapies that lack the side effects and general toxicity of conventional chemotherapeutics. The isomalabaricanes are a rare class of marine triterpenoids that have been hailed as promising cytotoxic lead compounds for the treatment of cancer, and they have attracted a flurry of excitement from researchers because of their potent cytotoxicity in certain human cancer cell lines along with a range of other antineoplastic effects. Most notably, their inhibitory activity is highly cell-selective, characterized by large deviations from their mean GI50 concentrations across 3 orders of magnitude in the NCI-60 Human Tumor Cell Lines screen, suggesting mechanistic specificity rather than general and unbridled toxicity. Despite these auspicious preliminary reports, the isomalabaricane scaffold remains largely unexplored as a potential anticancer lead because of lack of material. This Account describes our recent efforts to develop a general, modular synthesis of the isomalabaricanes, as exemplified by the successful total syntheses of rhabdastrellic acid A, stelletin E, and stelletin A. The unorthodox trans-syn-trans configuration of their perhydrobenz[e]indene core severely circumscribes the synthetic methods available for its construction and required several generations of strategy to assemble. Ultimately, a series of unconventional transformations were identified that were capable of building this highly strained motif, and the syntheses of rhabdastrellic acid A and stelletin E were completed in racemic fashion. Subsequently, a second-generation approach to these natural products was developed, rendering the synthesis enantioselective as well as providing access to stelletin A. These synthetic efforts were greatly assisted by computational techniques such as 13C NMR prediction, which enabled structural assignments of hydrocarbon diastereomers, as well as relaxed surface scan conformational analysis, which informed a campaign for directed hydrogenation of an alkene. High-throughput experimentation methods were brought to bear during optimization of a late-stage Suzuki coupling on stelletin A. Finally, preliminary structure-activity relationship studies in glioblastoma and nonsmall cell lung cancer cell lines were conducted on stelletin A, revealing that the singular trans-syn-trans perhydrobenz[e]indene core is essential for the cytotoxic activity of the isomalabaricane triterpenoids.

Synthetic Studies on Selective, Proapoptotic Isomalabaricane Triterpenoids Aided by Computational Techniques.

The isomalabaricanes comprise a large family of marine triterpenoids with fascinating structures that have been shown to be selective and potent apoptosis inducers in certain cancer cell lines. In this article, we describe the successful total syntheses of the isomalabaricanes stelletin A, stelletin E, and rhabdastrellic acid A, as well as the development of a general strategy to access other natural products within this unique family. High-throughput experimentation and computational chemistry methods were used in this endeavor. A preliminary structure-activity relationship study of stelletin A revealed the trans-syn-trans core motif of the isomalabaricanes to be critical for their cytotoxic activity.

Total Synthesis of Isomalabaricane Triterpenoids.

The first total syntheses of (±)-rhabdastrellic acid A and (±)-stelletin E, highly cytotoxic isomalabaricane triterpenoids, have been accomplished in a linear sequence of 14 steps from commercial geranylacetone. The exceptionally strained trans-syn-trans-perhydrobenz[e]indene core characteristic of the isomalabaricanes is efficiently accessed in a selective manner through a rapid, complexity-generating sequence. This process features a reductive radical polyene cyclization, an unprecedented oxidative Rautenstrauch cycloisomerization, and umpolung α-substitution of a p-toluenesulfonylhydrazone with in situ reductive transposition. A late-stage cross-coupling in concert with a modular approach to polyunsaturated side chains renders this a general strategy for the synthesis of numerous family members of these synthetically challenging and hitherto inaccessible marine triterpenoids.

Synthesis of PDE IVb Inhibitors. 3. Synthesis of (+)-, (-)-, and (±)-7-[3-(cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one via reductive domino transformations of 3-ß-carbomethoxyethyl-substituted six-membered cyclic nitronates.

Simple three-step asymmetric and racemic syntheses of GlaxoSmithKline's highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-ß-carbomethoxyethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cycloaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed.

Synthesis of PDE IVb inhibitors. 1. Asymmetric synthesis and stereochemical assignment of (+)- and (-)-7-[3-(cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one.

Asymmetric synthesis of GlaxoSmithKline's highly potent phosphodiesterase inhibitor 1 has been accomplished in nine steps and 16% overall yield. The original strategy suggested involves as a key step the silylation of enantiopure six-membered cyclic nitronates 4 obtained by a highly stereoselective [4 + 2]-cycloaddition of an appropriate nitroalkene 5 to trans-1-phenyl-2-(vinyloxy)cyclohexane. Functionalization of the resulting 5,6-dihydro-4H-1,2-oxazine and subsequent stereoselective reduction of 1,2-oxazine ring in intermediate 2 furnished the pyrrolizidinone framework with the recovery of chiral auxiliary alcohol.