7 research outputs found
Nickel-Catalyzed Enantioselective Reductive Cross-Coupling Reactions
Nickel-catalyzed reductive cross-coupling reactions have emerged as powerful methods to join two electrophiles. These reactions have proven particularly useful for the coupling of sec-alkyl electrophiles to form stereogenic centers; however, the development of enantioselective variants remains challenging. In this Perspective, we summarize the progress that has been made toward Ni-catalyzed enantioselective reductive cross-coupling reactions
SeOâ-Mediated Oxidative Transposition of PausonâKhand Products
Oxidative transpositions of bicyclic cyclopentenones mediated by selenium dioxide (SeOâ) are disclosed. Treatment of PausonâKhand reaction (PKR) products with SeOâ in the presence or absence of water furnishes di- and trioxidized cyclopentenones, respectively. Mechanistic investigations reveal multiple competing oxidation pathways that depend on substrate identity and water concentration. Functionalization of the oxidized products via cross-coupling methods demonstrates their synthetic utility. These transformations allow rapid access to oxidatively transposed cyclopentenones from simple PKR products
Nickel-Catalyzed Asymmetric Reductive Cross-Coupling of a-Chloroesters with (Hetero)Aryl Iodides
An asymmetric reductive cross-coupling of alpha-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording alpha-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the alpha-chloroester substrate and ligand on enantioselectivity
Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis
Conspectus: With complex molecular architectures, intriguing oxidation patterns, and wide-ranging biological activities, diterpene natural products have greatly impacted research in organic chemistry and drug discovery. Our laboratory has completed total syntheses of several highly oxidized diterpenes, including the ent-kauranoids maoecrystal Z, trichorabdal A, and longikaurin E; the antibiotic pleuromutilin; and the insecticides ryanodol, ryanodine, and perseanol. In this Account, we show how analysis of oxidation patterns and inherent functional group relationships can inform key CâC bond disconnections that greatly simplify the complexity of polycyclic structures and streamline their total syntheses. In articulating these concepts, we draw heavily from the approaches to synthetic strategy that were codified by Evans, Corey, Seebach, and others, based on the formalism that heteroatoms impose an alternating acceptor and donor reactivity pattern upon a carbon skeleton. We find these ideas particularly useful when considering oxidized diterpenes as synthetic targets.
In the first part of the Account, we describe the use of reductive cyclizations as strategic tactics for building polycyclic systems with Îł-hydroxyketone motifs. We have leveraged Sm-ketyl radical cyclizations as âreactivity umpolungsâ to generate Îł-hydroxyketones in our total syntheses of the Isodonent-kauranoid diterpenes (â)-maoecrystal Z, (â)-longikaurin E, and (â)-trichorabdal A. Following this work, we identified the same Îł-hydroxyketone pattern in the diterpene antibiotic (+)-pleuromutilin, which again inspired the use of a SmIâ-mediated reductive cyclization, this time to construct a bridging eight-membered ring. This collection of four total syntheses highlights how reductive cyclizations are particularly effective umpolung tactics when used to simultaneously form rings and introduce 1,4-dioxygenation patterns.
In the second part of the Account, we detail the syntheses of the complex and highly oxidized ryanodane and isoryanodane diterpenes and present the oxidation pattern analysis that guided our synthetic designs. We first discuss our 15-step total synthesis of (+)-ryanodol, which incorporated five of the eight oxygen atoms in just two transformations: a dihydroxylation of (S)-pulegone and a SeOâ-mediated trioxidation of the A-ring cyclopentenone. This latter transformation gave rise to an independent investigation of SeOâ-mediated peroxidations of simple bicyclic cyclopent-2-en-1-ones. The syntheses of (+)-ryanodine and (+)-20-deoxyspiganthine are also presented, which required modified end-game strategies to selectively incorporate the key pyrrole-2-carboxylate ester. Finally, we describe our fragment coupling approach to prepare the isoryanodane diterpene (+)-perseanol. Using a similar oxidation pattern analysis to that developed in the synthesis of ryanodol, we again identified a two-stage strategy to install the five hydroxyl groups. This strategy was enabled by a Pd-mediated carbopalladation/carbonylation cascade and leveraged unexpected, emergent reactivity to sequence a series of late-stage oxidations.
While each of the diterpene natural products discussed in this Account present unique synthetic questions, we hope that through their collective discussion, we provide a conceptual framework that condenses and summarizes the chemical knowledge we have learned and inspires future discourse and innovations in strategy design and methodology development
Unified Approach to Substituted Allenoates via Pd-Catalyzed βâHydride Elimination of (<i>E</i>)âEnol Triflates
A robust
synthesis of allenoates via a Pd-catalyzed β-hydride
elimination of (<i>E</i>)-enol triflates is presented. Salient
features of this method include low catalyst loadings, mild reaction
conditions, and the ability to access all four patterns of substituted
allenoates from a single substrate class
Surveillance of Cancer Stem Cell Plasticity Using an Isoform-Selective Fluorescent Probe for Aldehyde Dehydrogenase 1A1
Cancer stem cells
(CSCs) are progenitor cells that contribute to
treatment-resistant phenotypes during relapse. CSCs exist in specific
tissue microenvironments that cell cultures and more complex models
cannot mimic. Therefore, the development of new approaches that can
detect CSCs and report on specific properties (e.g., stem cell plasticity)
in their native environment have profound implications for studying
CSC biology. Herein, we present AlDeSense, a turn-on fluorescent probe
for aldehyde dehydrogenase 1A1 (ALDH1A1) and Ctrl-AlDeSense, a matching
nonresponsive reagent. Although ALDH1A1 contributes to the detoxification
of reactive aldehydes, it is also associated with stemness and is
highly elevated in CSCs. AlDeSense exhibits a 20-fold fluorescent
enhancement when treated with ALDH1A1. Moreover, we established that
AlDeSense is selective against a panel of common ALDH isoforms and
exhibits exquisite chemostability against a collection of biologically
relevant species. Through the application of surface marker antibody
staining, tumorsphere assays, and assessment of tumorigenicity, we
demonstrate that cells exhibiting high AlDeSense signal intensity
have properties of CSCs. Using these probes in tandem, we have identified
CSCs at the cellular level via flow cytometry and confocal imaging,
as well as monitored their states in animal models