scholarly journals Total synthesis reveals atypical atropisomerism in a small-molecule natural product, tryptorubin A

Science ◽  
2020 ◽  
Vol 367 (6476) ◽  
pp. 458-463 ◽  
Author(s):  
Solomon H. Reisberg ◽  
Yang Gao ◽  
Allison S. Walker ◽  
Eric J. N. Helfrich ◽  
Jon Clardy ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Small Molecules ◽  
Natural Product ◽  
Small Molecule ◽  
Molecular Shape ◽  
Molecular Graphs ◽  
Synthetic Strategy

Molecular shape defines function in both biological and material settings, and chemists have developed an ever-increasing vernacular to describe these shapes. Noncanonical atropisomers—shape-defined molecules that are formally topologically trivial but are interconvertible only by complex, nonphysical multibond torsions—form a unique subset of atropisomers that differ from both canonical atropisomers (e.g., binaphthyls) and topoisomers (i.e., molecules that have identical connectivity but nonidentical molecular graphs). Small molecules, in contrast to biomacromolecules, are not expected to exhibit such ambiguous shapes. Using total synthesis, we found that the peptidic alkaloid tryptorubin A can be one of two noncanonical atropisomers. We then devised a synthetic strategy that drives the atropospecific synthesis of a noncanonical atrop-defined small molecule.

Computationally Augmented Retrosynthesis: Total Synthesis of Paspaline A and Emindole PB

2018 ◽  
Author(s):  
Timothy Newhouse ◽  
Daria E. Kim ◽  
Joshua E. Zweig
Keyword(s):  
Chemical Synthesis ◽  
Total Synthesis ◽  
Small Molecules ◽  
First Principles ◽  
Quantum Chemical ◽  
Computational Analysis ◽  
Empirical Evaluation ◽  
Synthetic Strategy ◽  
Catalyzed Reactions ◽  
Enzyme Catalyzed Reactions

The diverse molecular architectures of terpene natural products are assembled by exquisite enzyme-catalyzed reactions. Successful recapitulation of these transformations using chemical synthesis is hard to predict from first principles and therefore challenging to execute. A means of evaluating the feasibility of such chemical reactions would greatly enable the development of concise syntheses of complex small molecules. Herein, we report the computational analysis of the energetic favorability of a key bio-inspired transformation, which we use to inform our synthetic strategy. This approach was applied to synthesize two constituents of the historically challenging indole diterpenoid class, resulting in a concise route to (–)-paspaline A in 9 steps from commercially available materials and the first pathway to and structural confirmation of emindole PB in 13 steps. This work highlights how traditional retrosynthetic design can be augmented with quantum chemical calculations to reveal energetically feasible synthetic disconnections, minimizing time-consuming and expensive empirical evaluation.

scholarly journals Synthesis of Highly Functionalised Furo[3,4-b]pyrans: Towards the Fungal Metabolite (−)-TAN-2483B

2021 ◽  
Author(s):  
◽  
R.M. Kalpani K. Somarathne
Keyword(s):  
Natural Products ◽  
Total Synthesis ◽  
Natural Product ◽  
Cyclopropane Ring ◽  
Ring Expansion ◽  
Ethyl Esters ◽  
Pyran Ring ◽  
Synthetic Strategy ◽  
Alternative Approach ◽  
Synthetic Approaches

<p>Carbohydrate-derived cyclopropanes combine both the stereochemical wealth of carbohydrates and the reactivity of cyclopropanes. A diverse variety of reaction modes for these cyclopropyl carbohydrates can be harnessed for the synthesis of natural products and other targets.  The natural products (−)-TAN-2483A and (−)-TAN-2483B are fungal secondary metabolites displaying a variety of bioactivities such as inhibition of c-src kinase action and parathyroid hormone-induced bone resorption. This thesis described several synthetic approaches to the natural product (−)-TAN-2483B and analogues of (−)-TAN-2483B employing cyclopropane ring expansion.  The synthetic route to (−)-TAN-2483B began with the readily available substrate D-mannose. The pyran ring unsaturation of the natural product was established by a cyclopropanation-ring expansion sequence. A synthetic strategy via dichlorocyclopropane-based intermediates is described in chapter 2. This being unsuccessful, an alternative approach via 2-fomyl-glycal was developed in chapter 3. The chapter 2 and 3 provided a solid background for the achievement of the analogues synthesis illustrated in chapter 4 via dibromocyclopropane. Lewis acid-mediated alkynylation followed by Pdcatalysed carbonylative lactonisation was successfully utilised in the revelation of the furo[3,4-b]pyran ring skeleton. This route afforded analogues of TAN-2483B; the Z-and E-unsaturated ethyl esters 140 and 141 and hydroxy(−)-TAN-2483B 145. The total synthesis of (−)-TAN-2483B was not achieved due to unforeseen obstacles encountered in the deoxygenation of the side arm of 335 (Chapter 4) into the E-propenyl side arm of (−)-TAN-2483B.</p>

scholarly journals Total synthesis of diptoindonesin G and its analogues as selective modulators of estrogen receptors

2016 ◽  
Vol 14 (38) ◽  
pp. 8927-8930 ◽  
Author(s):  
Ji-tian Liu ◽  
Truman J. Do ◽  
Christopher J. Simmons ◽  
John C. Lynch ◽  
Wen Gu ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Estrogen Receptors ◽  
Natural Product ◽  
Synthetic Strategy

We have developed a versatile synthetic strategy for the synthesis of the natural product diptoindonesin G and its analogues as selective modulators of estrogen receptors.

scholarly journals Development and Implementation of an HTS-Compatible Assay for the Discovery of Selective Small-Molecule Ligands for Pre-microRNAs

2017 ◽  
Vol 23 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Daniel A. Lorenz ◽  
Steve Vander Roest ◽  
Martha J. Larsen ◽  
Amanda L. Garner
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Two Dimensional ◽  
Small Molecule Ligands ◽  
Gene Regulatory ◽  
Regulatory Rnas ◽  
Target Rna

microRNAs (miRNAs) are small gene regulatory RNAs, and their expression has been found to be dysregulated in a number of human diseases. To facilitate the discovery of small molecules capable of selectively modulating the activity of a specific miRNA, we have utilized new high-throughput screening technology targeting Dicer-mediated pre-miRNA maturation. Pilot screening of ~50,000 small molecules and ~33,000 natural product extract libraries against pre-miR-21 processing indicated the potential of our assay for this goal, yielding a campaign Z′ factor of 0.52 and an average plate signal-to-background (S/B) ratio of 13. Using two-dimensional screening against a second pre-miRNA, pre-let-7d, we evaluated the selectivity of confirmed hits. The results presented demonstrate how high-throughput screening can be used to identify selective small molecules for a target RNA.

First total synthesis of marine derived anti-inflammatory natural product (-)-Herdmanine-D enabled by Steglich esterification

Synlett ◽  
2021 ◽  
Author(s):  
Pankaj Sharma ◽  
Nutan Sharma ◽  
Gunjan Kashyap ◽  
Sunita Bhagat
Keyword(s):  
Carboxylic Acid ◽  
Drug Development ◽  
Total Synthesis ◽  
Natural Product ◽  
Optical Activity ◽  
Marine Natural Product ◽  
Current Strategy ◽  
Synthetic Strategy ◽  
Steglich Esterification ◽  
Anti Inflammatory

An efficient and regioselective route for the first total synthesis of anti-inflammatory marine natural product (-)-Herdmanine-D has been described with an excellent overall yield of 18%. The key feature of the synthetic strategy includes Steglich esterification of regioselectively constructed 6-bromo-5-methoxy-1H-indole-3-carboxylic acid and L-Tyrosine. L-isomer was confirmed through measurement of optical activity. The current strategy paves the way for construction of diverse analogues of the title natural product for drug development.

Doubly interpenetrated indium-tricarboxylate frameworks mediated by small molecules with enhanced porosity

CrystEngComm ◽  
2019 ◽  
Vol 21 (34) ◽  
pp. 5045-5049 ◽  
Author(s):  
Yujing Du ◽  
Li Zhong ◽  
Yue Hu ◽  
Qipeng Li ◽  
Jinjie Qian
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Coordination Polymers ◽  
Synthetic Strategy

A synthetic strategy of indium-tricarboxylate frameworks by using small molecule regulators has been proposed to obtain four types of In-based coordination polymers with doubly interpenetrated structures.

Computationally Augmented Retrosynthesis: Total Synthesis of Paspaline A and Emindole PB

2018 ◽  
Author(s):  
Timothy Newhouse ◽  
Daria E. Kim ◽  
Joshua E. Zweig
Keyword(s):  
Chemical Synthesis ◽  
Total Synthesis ◽  
Small Molecules ◽  
First Principles ◽  
Quantum Chemical ◽  
Computational Analysis ◽  
Empirical Evaluation ◽  
Synthetic Strategy ◽  
Catalyzed Reactions ◽  
Enzyme Catalyzed Reactions

The diverse molecular architectures of terpene natural products are assembled by exquisite enzyme-catalyzed reactions. Successful recapitulation of these transformations using chemical synthesis is hard to predict from first principles and therefore challenging to execute. A means of evaluating the feasibility of such chemical reactions would greatly enable the development of concise syntheses of complex small molecules. Herein, we report the computational analysis of the energetic favorability of a key bio-inspired transformation, which we use to inform our synthetic strategy. This approach was applied to synthesize two constituents of the historically challenging indole diterpenoid class, resulting in a concise route to (–)-paspaline A in 9 steps from commercially available materials and the first pathway to and structural confirmation of emindole PB in 13 steps. This work highlights how traditional retrosynthetic design can be augmented with quantum chemical calculations to reveal energetically feasible synthetic disconnections, minimizing time-consuming and expensive empirical evaluation.

scholarly journals The Serendipitous Discovery of a Rose Odorant

2020 ◽  
Vol 74 (4) ◽  
pp. 247-251
Author(s):  
Nicole Hauser ◽  
Philip Kraft ◽  
Erick M. Carreira
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Small Molecule ◽  
First Generation ◽  
Scientific Research ◽  
Careful Analysis ◽  
Target Compound ◽  
Electrically Conductive ◽  
New Approaches ◽  
Expected Outcome

Serendipity has played a role in many groundbreaking scientific discoveries. Key to their identification and exploitation is the ability to recognize the unexpected and invest time trying to understand it. Like any other field of scientific research, total synthesis requires determination and perseverance. When the first-generation route towards a target compound fails, new approaches are developed based on insights gained in the initial studies. Careful analysis of data obtained in a 'failed' approach, e.g. when a reaction did not yield the desired or any expected outcome, can lead to spectacularly improved routes and discoveries that have impact beyond the synthesis of the selected target compound. Serendipity has further led to the identification of intriguing properties that materials or single molecules have, as exemplified by the discovery of electrically conductive polymers. During our total synthesis endeavors towards a complex natural product, we identified a small molecule with interesting olfactory properties, which we decided to investigate further.

scholarly journals Toward the library generation of natural product-like polycyclic derivatives by stereocontrolled diversity-oriented synthesis

2005 ◽  
Vol 77 (1) ◽  
pp. 163-178 ◽  
Author(s):  
P. Arya ◽  
S. Quevillon ◽  
R. Joseph ◽  
C.-Q. Wei ◽  
Z. Gan ◽  
...  
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Small Molecule ◽  
Protein Interactions ◽  
Protein Function ◽  
Three Dimensional ◽  
Structural Complexity ◽  
Complex Nature ◽  
Bioactive Natural Products ◽  
Small Molecule Libraries

Due to the growing interest in small molecules that could help in understanding protein–protein interactions based on signal transduction, the demand for the generation of small-molecule libraries that are inspired by bioactive natural products has grown significantly. Many of these pathways are highly complex and present tremendous challenges with the use of classical tools. A rapid access to natural product-like small molecules having structural complexity and diversity is crucial for systematically dissecting the functions of complex protein networking and understanding cell signaling pathways. The complex nature, the three-dimensional architecture, and the number of protein binding functional groups presented in three-dimensional arrays are some of the attractive features to incorporate in small-molecule chemical probes to be used as modulators of protein function.

Arenophile-Mediated Dearomative Functionalization Strategies

Synlett ◽  
2018 ◽  
Vol 29 (07) ◽  
pp. 845-855 ◽  
Author(s):  
David Sarlah ◽  
Mikiko Okumura
Keyword(s):  
Transition Metal ◽  
Small Molecules ◽  
Natural Product ◽  
Recent Work ◽  
Transition Metal Catalysis ◽  
Natural Product Synthesis ◽  
Direct Connection ◽  
Metal Catalysis ◽  
Synthetic Strategy

The dearomatization of arenes is a fundamental synthetic strategy, providing a direct connection between simple hydrocarbons and valuable, more complex intermediates. While several strategies exist, the functionalization with concurrent introduction of functionality (i.e., dearomative functionalization) is still a largely underdeveloped field. This Synpacts article provides an overview and insights from our recent work in this area using small molecules—arenophiles.1 Introduction2 Arenophiles3 Olefin-Like Dearomative Functionalizations4 Arenophiles and Transition-Metal Catalysis5 Applications in Natural Product Synthesis6 Conclusion

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