12 research outputs found
Cobalt-catalyzed multi-substituted alkene synthesis from 1,3-dithiolanes and Grignard reagents
The cobalt-catalyzed reaction between 1,3-dithiolanes and Grignard reagents, for the efficient synthesis of multi-substituted alkene products, is described. The method was applicable to a variety of benzylic dithiolane substrates, affording di-, tri-, and tetra-substituted 1,1-diaryl alkene products in good to excellent yields. The use of benzylic Grignard reagents with aryl aldehyde-derived 1,3-dithiolanes enabled access to natural product-derived stilbene architectures with exquisite E selectivity. The operational simplicity, low catalyst loadings, and scalability demonstrate the general utility of the method
Cobalt‐catalyzed enantio‐ and regioselective C(sp3)−H alkenylation of thioamides
An enantioselective cobalt-catalyzed C(sp3)−H alkenylation of thioamides with but-2-ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction
Selective lability of ruthenium(II) arene amino acid complexes.
A series of organometallic complexes of the form [(PhH)Ru(amino acid)](+) have been synthesized using amino acids able to act as tridentate ligands. The straightforward syntheses gave enantiomerically pure complexes with two stereogenic centers due to the enantiopurity of the chelating ligands. Complexes were characterized in the solid-state and/or solution-state where the stability of the complex allowed. The propensity toward labilization of the coordinatively saturated complexes was investigated. The links between complex stability and structural features are very subtle. Nonetheless, H/D exchange rates of coordinated amino groups reveal more significant differences in reactivity linked to metallocycle ring size resulting in decreasing stability of the metallocycle as the amino acid side-chain length increases. The behavior of these systems in acid is unusual, apparently labilizing the carboxylate residue of the amino acid. This acid-catalyzed hemilability in an organometallic is relevant to the use of Ru(II) arenes in medicinal contexts due to the relatively low pH of cancerous cells.TGS and MO thank the EPSRC for Studentships EP/P505445/1 and EP/K503/009/1, respectively.This is the final version of the article. It was first published by ACS at http://pubs.acs.org/doi/abs/10.1021/ic502051
Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters
Molecules that contain a stereogenic phosphorus atom are crucial to medicine, agrochemistry and catalysis. While methods are available for the selective construction of various chiral organophosphorus compounds, catalytic enantioselective approaches for their synthesis are far less common. Given the vastness of possible substituent combinations around a phosphorus atom, protocols for their preparation should also be divergent, providing facile access not only to one but to many classes of phosphorus compounds. Here we introduce a catalytic and enantioselective strategy for the preparation of an enantioenriched phosphorus(V) centre that can be diversified enantiospecifically to a wide range of biologically relevant phosphorus(V) compounds. The process, which involves an enantioselective nucleophilic substitution catalysed by a superbasic bifunctional iminophosphorane catalyst, can accommodate a wide range of carbon substituents at phosphorus. The resulting stable, yet versatile, synthetic intermediates can be combined with a multitude of medicinally relevant O-, N- and S-based nucleophiles
Total synthesis of (â)-himalensine A and development of novel C(sp3)-H functionalisation reactions
This thesis describes the 22-step enantioselective total synthesis of (-)-himalensine A, and the Cp*RhIII catalysed amidation of unactivated C(sp3)-H bonds utilising dithianes or imines as directing groups.
Chapter 1 introduces the calyciphylline A-type Daphniphyllum alkaloids, their biosynthetic origin and himalensine A as one family member. Current published syntheses of these alkaloids are also highlighted as well as previous work conducted on this project.
Chapter 2 focuses on the route development towards the ABCD tetracyclic core. Optimisation of the key enantioselective organocatalytic IMDAF cascade enabled the synthesis of large quantities of the tricyclic core. After elaboration to a key cycloisomerisation precursor, a reductive radical cascade was developed to close the B ring. Finally, a highly diastereoselective low-pressure hydrogenation delivered the completed tetracyclic core.
Chapter 3 describes the route from the tetracyclic core through the end-game to access himalensine A. A pyridine and molecular oxygen mediated elimination/C-H oxidation was developed to access an enedione intermediate with the correct oxidation level and chemical handle required to complete the final ring. The E ring was furnished via a Stetter cyclisation and final chemoselective lactam reduction delivered the natural product.
Chapter 4 summarises C-H functionalisation within the context of C-N bond forming reactions. A focus is placed on rhodium, itâs ability for directed C-H amination/amidation chemistry and previous work in the field. The challenge of RhIII catalysed C(sp3)-H functionalisation is introduced.
Chapter 5 features the development of a novel Cp*RhIII catalysed dithiane-directed amidation of unactivated C(sp3)-H bonds utilising dioxazolone amidating reagents. With the optimised method, a wide range of dioxazolone reagents as well as dithiane partners are well-tolerated. Downstream derivatisation of the amidated products is also demonstrated, including the Corey-Seebach umpolung reaction.
Chapter 6 highlights use of a transient imine directing group strategy for metal catalysed C-H functionalisation, and development of this strategy for a Cp*RhIII-catalysed transient imine-directed amidation of unactivated C(sp3)-H bonds using dioxazolone reagents. Completed optimisation studies enable amidation of a sterically hindered aldehyde in good yield, delivering a synthetically useful 1,3 amidoaldehyde derivative. </p
BAF Complex in Embryonic Stem Cells and Early Embryonic Development
Embryonic stem cells (ESCs) can self-renew indefinitely and maintain their pluripotency status. The pluripotency gene regulatory network is critical in controlling these properties and particularly chromatin remodeling complexes. In this review, we summarize the research progresses of the functional and mechanistic studies of BAF complex in mouse ESCs and early embryonic development. A discussion of the mechanistic bases underlying the distinct phenotypes upon the deletion of different BAF subunits in ESCs and embryos will be highlighted
Catalytic Enantioselective Nucleophilic Desymmetrisation of Phosphonate Esters
Compounds containing one or more stereogenic phosphorous atoms in the P(V) oxidation
state are important to chemistry, biology and medicine. These include marketed
antiviral drugs such as Tenofovir alafenamide and Remdesivir, an effective treatment
for Ebola which has also recently been approved for use against SARS-CoV-2 in the US.
Existing approaches for the stereoselective synthesis of P-stereogenic centers, while
elegant, remain mostly diastereoselective, with catalytic enantioselective approaches
being limited in application. Accordingly, conceptually novel, broad-scope, catalytic
strategies for the efficient stereoselective synthesis of diverse stereogenic P(V) containing
compounds remain essential.
To this end, we describe a novel enantioselective two-stage strategy, exploiting a catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the first stereocontrolled, sequential nucleophilic substitution of enantiotopic leaving groups from readily accessible pro-chiral P(V) precursors, a bifunctional iminophosphorane (BIMP) superbase catalyst was found to be essential in delivering reactive desymmetrised intermediates capable of downstream enantiospecific substitution. This uniquely modular, catalytic platform allows broad-scope, stereoselective access to a diverse library of chiral P(V) compounds including those with O, N and S-linkages
Total Synthesis of (−)-Himalensine A
The
first enantioselective synthesis of (−)-himalensine
A has been achieved in 22 steps. The synthesis was enabled by a novel
catalytic, enantioselective prototropic shift/furan Diels–Alder
(IMDAF) cascade to construct the ACD tricyclic core. A reductive radical
cyclization cascade was utilized to build the B ring, and end-game
manipulations featuring a molecular oxygen mediated γ-CH oxidation,
a Stetter cyclization to access the pendant cyclopentenone, and a
highly chemoselective lactam reduction delivered the natural product
target
Total Synthesis of (−)-Himalensine A
The
first enantioselective synthesis of (−)-himalensine
A has been achieved in 22 steps. The synthesis was enabled by a novel
catalytic, enantioselective prototropic shift/furan Diels–Alder
(IMDAF) cascade to construct the ACD tricyclic core. A reductive radical
cyclization cascade was utilized to build the B ring, and end-game
manipulations featuring a molecular oxygen mediated γ-CH oxidation,
a Stetter cyclization to access the pendant cyclopentenone, and a
highly chemoselective lactam reduction delivered the natural product
target
Total Synthesis of (−)-Himalensine A
The
first enantioselective synthesis of (−)-himalensine
A has been achieved in 22 steps. The synthesis was enabled by a novel
catalytic, enantioselective prototropic shift/furan Diels–Alder
(IMDAF) cascade to construct the ACD tricyclic core. A reductive radical
cyclization cascade was utilized to build the B ring, and end-game
manipulations featuring a molecular oxygen mediated γ-CH oxidation,
a Stetter cyclization to access the pendant cyclopentenone, and a
highly chemoselective lactam reduction delivered the natural product
target