Discovery of Unusual Sesterterpenoids from Colquhounia coccinea var. mollis and Their Metabolic Implications.

Three unusual sesterterpenoids featuring unprecedented rearranged colquhounane (C25) and tetranorcolquhounane (C21) frameworks, colquhounoids E (1) and F (3) and norcolquhounoid F (2), were isolated from a Lamiaceae medicinal plant Colquhounia coccinea var. mollis. Their structures were elucidated by spectroscopic analysis and quantum chemical calculations. A biomimetic inspired regioselective cyclopropane cleavage was achieved under acidic conditions. The immunosuppressive activities of these new sesterterpenoids were also evaluated.

A Unified Strategy for the Enantiospecific Total Synthesis of Delavatine A and Formal Synthesis of Incarviatone A.

We describe a symmetry-inspired synthetic approach that has enabled a short synthesis of delavatine A and a formal synthesis of incarviatone A, which are two likely biosynthetically related natural products. The indane core of these natural products was constructed through a cascade sequence involving five transformations that occur in a single pot. Leveraging symmetry has allowed us to trace both natural products back to a versatile building block, 3,5-dibromo-2-pyrone, and studies related to site-selective cross-coupling of this polyhalogenated heterocycle are described. In addition, our strategy gave access to a putative biogenetic precursor, from which the syntheses of both natural products were attempted.

Calyciphylline B-Type Alkaloids: Total Syntheses of (-)-Daphlongamine H and (-)-Isodaphlongamine H.

The first total synthesis of the complex hexacylic Daphniphyllum alkaloid (-)-daphlongamine H has been accomplished. Key to the success of the strategy are a complexity-building Mannich reaction, efficient cyclizations, and a highly diastereoselective hydrogenation to assemble multigram quantities of the tricyclic core bearing four contiguous stereocenters. Following construction of the hydro-indene substructure by means of a Pauson-Khand reaction, endgame redox manipulations delivered the natural product. Importantly, the synthetic studies have also given access to (-)-isodaphlongamine H and led to a revision of the reported structure of deoxyisocalyciphylline B.

A Short Synthesis of Delavatine A Unveils New Insights into Site-Selective Cross-Coupling of 3,5-Dibromo-2-pyrone.

The recognition of latent symmetry in delavatine A has enabled a short synthesis of the natural product starting from 3,5-dibromo-2-pyrone. The concise synthetic route features a cascade process involving a 6π electrocyclization to construct the indane core of delavatine A. In addition, we have conducted detailed experimental and computational studies to gain an in-depth understanding of the mechanism of the observed site-selective cross-coupling of 3,5-dibromo-2-pyrone. This insight may provide new avenues to achieve the selective cross-coupling of multiply halogenated heteroarenes.

Calyciphylline B-type Alkaloids: Evolution of a Synthetic Strategy to (-)-Daphlongamine H.

We provide a full account of our synthetic studies targeting the hexacyclic calyciphylline B-type alkaloids, a subfamily of the Daphniphyllum natural products. Following an initial set of synthetic strategies focused on constructing the piperidine core of the calyciphylline B-type framework via a 6π-azaelectrocyclization, as well as exploiting the reactivity of underexplored oxazaborinine heterocycles, we ultimately designed a highly functionalized acyclic precursor which underwent carefully orchestrated and efficient cyclizations to forge the architecturally complex natural product scaffold. Our efforts have culminated in the development of the first total synthesis of (-)-daphlongamine H, provided access to its C5-epimer, (-)-isodaphlongamine H, and led to structural revision of deoxyisocalyciphylline B.

Dyotropic rearrangements in natural product total synthesis and biosynthesis.

Covering: up to January 2017This highlight article presents some recent examples of dyotropic rearrangements, which were applied in natural product total synthesis or proposed to occur in biosyntheses. The implementation of dyotropic reactions in the preparation of complex natural products has resulted in the development of elegant synthetic routes, and thereby highlights the utility of these powerful, yet relatively underrepresented, transformations.

A Bioinspired Cyclization Sequence Enables the Asymmetric Total Synthesis of Dictyoxetane.

We have developed the first synthesis of the unique oxetane containing diterpene (+)-dictyoxetane. Our retrosynthetic planning was guided by the putative biosynthesis of the unprecedented 2,7-dioxatricyclo[4.2.1.0(3,8)]nonane ring system. A bioinspired 4-exo-tet, 5-exo-trig cyclization sequence enabled the construction of the synthetically challenging dioxatricyclic framework. The overall synthesis proceeds in 15 linear steps from a known and readily available trans-hydrindane fragment. In addition, we were able to realize the first dyotropic rearrangement of an epoxide-oxetane substrate.

A Divergent Approach to the Marine Diterpenoids (+)-Dictyoxetane and (+)-Dolabellane†V.

We present a full account of the development of a strategy that culminated in the first total syntheses of the unique oxetane-containing natural product (+)-dictyoxetane and the macrocyclic diterpene (+)-dolabellane V. Our retrosynthetic planning was guided by both classical and nonconventional strategies to construct the oxetane, which is embedded in an unprecedented 2,7-dioxatricyclo[4.2.1.03,8 ]nonane ring system. Highlights of the successful approach include highly diastereoselective carbonyl addition reactions to assemble the full carbon skeleton, a Grob fragmentation to construct the 11-membered macrocycle of (+)-dolabellane V, and a bioinspired 4-exo-tet, 5-exo-trig cyclization sequence to form the complex dioxatricyclic framework of (+)-dictyoxetane. Furthermore, an unprecedented strain-releasing type I dyotropic rearrangement of an epoxide-oxetane substrate was developed.

Bioinspired total syntheses of terpenoids.

Nature's highly efficient routes for constructing natural products have inspired chemists to mimic these processes in a laboratory setting. This Perspective presents some recent examples of conceptually different bioinspired total syntheses of complex terpenoids and thereby aims to highlight the vast benefits offered by bioinspired strategies.

Total synthesis of the leucosceptroid family of natural products.

A highly efficient strategy enabled the asymmetric total synthesis of 15 antifeedant leucosceptroid natural products. The advanced tricyclic core, available in gram quantity, served as the pivotal intermediate for the preparation of norleucosceptroids B, C, F, and G and leucosceptroids A, B, G, I, J, L, and M. Additionally, the bioinspired oxidative transformation of leucosceptroid A to leucosceptroids C, K, O, and P using singlet oxygen supports the hypothesis that leucosceptroids A and B are most likely the biogenetic precursors of all other members of this natural product family.

A general entry to antifeedant sesterterpenoids: total synthesis of (+)-norleucosceptroid A, (-)-norleucosceptroid B, and (-)-leucosceptroid K.

The first asymmetric total synthesis of the antifeedant terpenoids (+)-norleucosceptroid A, (-)-norleucosceptroid B, and (-)-leucosceptroid K has been accomplished. This highly concise synthetic route was guided by our efforts to develop a platform for the collective synthesis of a whole family of antifeedant natural products. The synthesis features a Hauser-Kraus-type annulation followed by an unprecedented, highly efficient intramolecular dilactol aldol-type condensation reaction to produce the 5,6,5 skeleton. The developed synthetic route proceeds for norleucosceptroid A and B in 16 steps (longest linear sequence) from known compounds.

In vivo bioluminescence imaging of labile iron in xenograft models and liver using FeAL-1, an iron-activatable form of D-luciferin.

Dysregulated iron homeostasis underlies diverse pathologies, from ischemia-reperfusion injury to epithelial-mesenchymal transition and drug-tolerant "persister" cancer cell states. Here, we introduce ferrous iron-activatable luciferin-1 (FeAL-1), a small-molecule probe for bioluminescent imaging of the labile iron pool (LIP) in luciferase-expressing cells and animals. We find that FeAL-1 detects LIP fluctuations in cells after iron supplementation, depletion, or treatment with hepcidin, the master regulator of systemic iron in mammalian physiology. Utilizing FeAL-1 and a dual-luciferase reporter system, we quantify LIP in mouse liver and three different orthotopic pancreatic ductal adenocarcinoma tumors. We observed up to a 10-fold increase in FeAL-1 bioluminescent signal in xenograft tumors as compared to healthy liver, the major organ of iron storage in mammals. Treating mice with hepcidin further elevated hepatic LIP, as predicted. These studies reveal a therapeutic index between tumoral and hepatic LIP and suggest an approach to sensitize tumors toward LIP-activated therapeutics.

Scalable Preparation of 4,4-Disubstituted Six-Membered Cyclic Sulfones.

We provide an account of synthetic strategies aimed at the efficient preparation of 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (3), an important cyclic sulfone building block for medicinal chemistry. A practical and scalable protocol has been developed that readily gives access to the title compound from commercially available and inexpensive starting materials. In addition, this novel approach has enabled the synthesis of various related 4,4-disubstituted cyclic sulfone derivatives that serve as valuable structural motifs for drug discovery.

Oxazaborinines from Vinylogous N-Allylic Amides: Reactivities of Underexplored Heterocyclic Building Blocks.

Access to a new class of oxazaborinines using an efficient transition-metal-catalyzed rearrangement is demonstrated. The method overcomes the synthetic challenge of achieving an aza-Claisen rearrangement of vinylogous N-allylic amide substrates, giving rise to a variety of highly modifiable oxazaborinine products. An investigation of the unique reactivity of these boron-based heterocycles has unveiled their underexplored potential as valuable building blocks and intermediates for organic synthesis.

Unraveling the metabolic pathway in Leucosceptrum canum by isolation of new defensive leucosceptroid degradation products and biomimetic model synthesis.

Seven new leucosceptroid degradation products possessing a C20, C21, or C25 framework, norleucosceptroids D-H (1-5), leucosceptroids P (6), and Q (7), have been isolated from Leucosceptrum canum. Their structures were determined by comprehensive NMR, MS, and single-crystal X-ray diffraction analyses. Discovery of these key intermediates, together with the biomimetic oxidation of a model system, supports the hypothesis that two biosynthetic pathways are operative. Antifeedant activity was observed for compounds 1-3.

Synthesis of quaternary α-methyl α-amino acids by asymmetric alkylation of pseudoephenamine alaninamide pivaldimine.

The utility of pseudoephenamine as a chiral auxiliary for the alkylative construction of quaternary α-methyl α-amino acids is demonstrated. The method is notable for the high diastereoselectivities of the alkylation reactions, for its versatility with respect to electrophilic substrate partners, and for its mild hydrolysis conditions, which provide α-amino acids without salt contaminants. Alternatively, α-amino esters can be obtained by direct alcoholysis.