skip to main content

Title: Enantioselective construction of the tricyclic core of curcusones A–D via a cross-electrophile coupling approach
Herein we report our recent progress toward the enantioselective total synthesis of the diterpenoid natural products curcusones A–D by means of complementary Stetter annulation or ring-closing metathesis (RCM) disconnections. Using the latter approach, we have achieved the concise construction of the 5–7–6 carbocyclic core embedded in each member of the curcusone family. Essential to this route is the use of a cross-electrophile coupling strategy, which has not previously been harnessed in the context of natural product synthesis.
Authors:
;
Award ID(s):
1800511
Publication Date:
NSF-PAR ID:
10146309
Journal Name:
Chemical Science
Volume:
10
Issue:
45
Page Range or eLocation-ID:
10562 to 10565
ISSN:
2041-6520
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract. Reconstructions of global hydroclimate during the Common Era (CE; the past ∼2000 years) are important for providing context for current and future global environmental change. Stable isotope ratios in water are quantitative indicators of hydroclimate on regional to global scales, and these signals are encoded in a wide range of natural geologic archives. Here we present the Iso2k database, a global compilation of previously published datasets from a variety of natural archives that record the stable oxygen (δ18O) or hydrogen (δ2H) isotopic compositions of environmental waters, which reflect hydroclimate changes over the CE. The Iso2k database contains 759 isotope records from the terrestrial and marinemore »realms, including glacier and ground ice (210); speleothems (68); corals, sclerosponges, and mollusks (143); wood (81); lake sediments and other terrestrial sediments (e.g., loess) (158); and marine sediments (99). Individual datasets have temporal resolutions ranging from sub-annual to centennial and include chronological data where available. A fundamental feature of the database is its comprehensive metadata, which will assist both experts and nonexperts in the interpretation of each record and in data synthesis. Key metadata fields have standardized vocabularies to facilitate comparisons across diversearchives and with climate-model-simulated fields. This is the firstglobal-scale collection of water isotope proxy records from multiple typesof geological and biological archives. It is suitable for evaluatinghydroclimate processes through time and space using large-scale synthesis,model–data intercomparison and (paleo)data assimilation. The Iso2k databaseis available for download at https://doi.org/10.25921/57j8-vs18 (Konecky and McKay, 2020) and is also accessible via the NOAA/WDS Paleo Datalanding page: https://www.ncdc.noaa.gov/paleo/study/29593 (last access: 30 July 2020).« less
  2. l-Tyrosine is an essential amino acid for protein synthesis and is also used in plants to synthesize diverse natural products. Plants primarily synthesize tyrosine via TyrA arogenate dehydrogenase (TyrAa or ADH), which are typically strongly feedback inhibited by tyrosine. However, two plant lineages, Fabaceae (legumes) and Caryophyllales, have TyrA enzymes that exhibit relaxed sensitivity to tyrosine inhibition and are associated with elevated production of tyrosine-derived compounds, such as betalain pigments uniquely produced in core Caryophyllales. Although we previously showed that a single D222N substitution is primarily responsible for the deregulation of legume TyrAs, it is unknown when and how themore »deregulated Caryophyllales TyrA emerged. Here, through phylogeny-guided TyrA structure–function analysis, we found that functionally deregulated TyrAs evolved early in the core Caryophyllales before the origin of betalains, where the E208D amino acid substitution in the active site, which is at a different and opposite location from D222N found in legume TyrAs, played a key role in the TyrA functionalization. Unlike legumes, however, additional substitutions on non-active site residues further contributed to the deregulation of TyrAs in Caryophyllales. The introduction of a mutation analogous to E208D partially deregulated tyrosine-sensitive TyrAs, such as Arabidopsis TyrA2 (AtTyrA2). Moreover, the combined introduction of D222N and E208D additively deregulated AtTyrA2, for which the expression in Nicotiana benthamiana led to highly elevated accumulation of tyrosine in planta. The present study demonstrates that phylogeny-guided characterization of key residues underlying primary metabolic innovations can provide powerful tools to boost the production of essential plant natural products.« less
  3. Aryl carboxylic acids are among the most abundant substrates in chemical synthesis and represent a perfect example of a traceless directing group that is central to many processes in the preparation of pharmaceuticals, natural products and polymers. Herein, we describe a highly selective method for the direct step-down reduction of carboxylic acids to arenes, proceeding via well-defined Pd(0)/( ii ) catalytic cycle. The method shows a remarkably broad substrate scope, enabling to direct the classical acyl reduction towards selective decarbonylation by a redox-neutral mechanism. The utility of this reaction is highlighted in the direct defunctionalization of pharmaceuticals and natural products,more »and further emphasized in a range of traceless processes using removable carboxylic acids under mild, redox-neutral conditions orthogonal to protodecarboxylation. Extensive DFT computations were conducted to demonstrate preferred selectivity for the reversible oxidative addition and indicated that a versatile hydrogen atom transfer (HAT) pathway is operable.« less
  4. Peroxidase mimics of nanoscale materials as alternatives to natural peroxidases have found widespread uses in biomedicine. Among various types of peroxidase mimics, platinum-group metal (PGM) nanocrystals have drawn considerable attention in recent years due to their superior properties. Particularly, PGM nanocrystals display high catalytic efficiencies, allow for facile surface modifications, and possess excellent stabilities. This feature article summarizes our recent work on development of PGM nanocrystals as peroxidase mimics and exploration of their applications in in vitro diagnostics. We begin with a brief introduction to controlled synthesis of PGM nanocrystals in solution phase. We then elaborate on a variety ofmore »physicochemical parameters that can be carefully tuned to optimize the peroxidase-like properties of PGM nanocrystals. Then, we highlight the applications of PGM nanocrystals in different in vitro diagnostic platforms. We conclude this article with personal perspectives on future research directions in this emerging field, where challenges and opportunities are remarked.« less
  5. Metabolic engineering seeks to reprogram microbial cells to efficiently and sustainably produce value-added compounds. Since chemical production can be at odds with the cell’s natural objectives, strategies have been developed to balance conflicting goals. For example, dynamic regulation modulates gene expression to favor biomass and metabolite accumulation at low cell densities before diverting key metabolic fluxes toward product formation. To trigger changes in gene expression in a pathway-independent manner without the need for exogenous inducers, researchers have coupled gene expression to quorum-sensing (QS) circuits, which regulate transcription based on cell density. While effective, studies thus far have been limited tomore »one control point. More challenging pathways may require layered dynamic regulation strategies, motivating the development of a generalizable tool for regulating multiple sets of genes. We have developed a QS-based regulation tool that combines components of the lux and esa QS systems to simultaneously and dynamically up- and down-regulate expression of 2 sets of genes. Characterization of the circuit revealed that varying the expression level of 2 QS components leads to predictable changes in switching dynamics and that using components from 2 QS systems allows for independent tuning capability. We applied the regulation tool to successfully address challenges in both the naringenin and salicylic acid synthesis pathways. Through these case studies, we confirmed the benefit of having multiple control points, predictable tuning capabilities, and independently tunable regulation modules.« less