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.  more » « less
Award ID(s):
1800511
NSF-PAR ID:
10146309
Author(s) / Creator(s):
;
Date Published:
Journal Name:
Chemical Science
Volume:
10
Issue:
45
ISSN:
2041-6520
Page Range / eLocation ID:
10562 to 10565
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. null (Ed.)
    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 marine 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). 
    more » « less
  2. Abstract

    The biosynthetic origins of the structurally related racemic isoxazolidinePapaveraceaealkaloids Setigerumine I, Dactylicapnosinine and Dactylicapnosine have remained elusive since their original isolation over two decades ago. Herein we report the first biosynthetic hypothesis for their formation and, inspired by it, the first synthesis of (±)‐Setigerumine I with accompanying computational rationale. Based on the results, these isoxazolidine alkaloids arise from racemizing oxidative rearrangements of prominent isoquinoline alkaloids Noscapine and Hydrastine. The key steps featured in this synthesis are a room temperature Cope elimination and a domino oxidation/inverse‐electron demand 1,3‐dipolar cycloaddition of an axially chiral, yet configurationally unstable, intermediate. The work opens this previously inaccessible family of natural products for biological studies.

     
    more » « less
  3. Abstract

    The biosynthetic origins of the structurally related racemic isoxazolidinePapaveraceaealkaloids Setigerumine I, Dactylicapnosinine and Dactylicapnosine have remained elusive since their original isolation over two decades ago. Herein we report the first biosynthetic hypothesis for their formation and, inspired by it, the first synthesis of (±)‐Setigerumine I with accompanying computational rationale. Based on the results, these isoxazolidine alkaloids arise from racemizing oxidative rearrangements of prominent isoquinoline alkaloids Noscapine and Hydrastine. The key steps featured in this synthesis are a room temperature Cope elimination and a domino oxidation/inverse‐electron demand 1,3‐dipolar cycloaddition of an axially chiral, yet configurationally unstable, intermediate. The work opens this previously inaccessible family of natural products for biological studies.

     
    more » « less
  4. 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 the 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. 
    more » « less
  5. Abstract

    Quaternary carbons are useful motifs in chemical synthesis but can be challenging to prepare using many chemical methods. Here, we report a stereoselective synthesis ofβ‐quaternary lactams using flavin‐dependent ‘ene’‐reductases via a 5‐exo‐trig radical cyclization. The products are formed in moderate to good levels of enantioselectivity using an ‘ene’‐reductase variant fromZymomonas mobilis. This method highlights the opportunity for biocatalysis to form quaternary centers using non‐natural reactions.

     
    more » « less