Biomedical subjects

Scott G Nelson

Publications and source records attributed to Scott G Nelson.

13 recordsLinked to original sources

PubMed2006

Strategies for expanding structural diversity available from olefin isomerization-claisen rearrangement reactions.

Boron-substituted di(allyl) ethers provide an efficient conduit for expanding the structural diversity available from olefin isomerization-Claisen rearrangement (ICR) reactions. Easily prepared allyl propargyl ethers undergo chemoselective Zr(IV)-catalyzed hydroboration to afford the boron-substituted ICR substrates. The boron-substituted allyl residue undergoes chemoselective Ir(I)-catalyzed olefin isomerization and in situ Claisen rearrangement to afford stereodefined beta-boryl aldehyde products. Functionalization of the C-B linkage by oxidation or Suzuki cross-coupling provides a route to Claisen adducts previously inaccessible from the ICR methodology.

Alkenes↗

PubMed2006

Au(I)-catalyzed annulation of enantioenriched allenes in the enantioselective total synthesis of (-)-rhazinilam.

Highly stereoselective Au(I)-catalyzed pyrrole additions to enantioenriched allenes afford a unique entry to optically active heterocycles. Asymmetric quaternary carbons can be installed with concurrent heterocycle annulation utilizing this methodology. The enantioenriched allenes are conveniently obtained by catalytic asymmetric acyl halide-aldehyde cyclocondensations and SN2' ring opening of the resulting enantioenriched beta-lactones. An enantioselective total synthesis of (-)-rhazinilam highlights the potential utility of this reaction technology in target-oriented synthesis.

Alkadienes↗

PubMed2006

Catalytic asymmetric assembly of stereodefined propionate units: an enantioselective total synthesis of (-)-pironetin.

Double diastereoselection in alkaloid-catalyzed acyl halide-aldehyde cyclocondensation (AAC) reactions provides a strategy for realizing syn- or anti-selective propionate aldol additions from a common reaction manifold. Matched AAC homologation of enantioenriched aldehydes afford cis-disubstituted beta-lactones as surrogates for syn aldols; the mismatched AAC reactions provide anti-selective aldols in the form of trans-disubstituted 2-oxetanones. The utility of this reaction technology in synthesis activities is exemplified in a catalytic asymmetric total synthesis of (-)-pironetin.

Antineoplastic Agents↗

PubMed2006

Asymmetric claisen rearrangements enabled by catalytic asymmetric Di(allyl) ether synthesis.

Merging the catalytic asymmetric synthesis of di(allyl) ethers with ensuing olefin isomerization-Claisen rearrangement (ICR) reactions provides a convenient, two-step route to asymmetric aliphatic Claisen rearrangements from easily obtained starting materials. These reactions deliver the 2,3-disubstituted 4-pentenal derivatives characteristic of aliphatic Claisen rearrangements with excellent relative and absolute stereocontrol. A catalytic enantioselective synthesis of the (+)-calopin dimethyl ether demonstrates the utility of this reaction technology in asymmetric synthesis enterprises.

Allyl Compounds↗

PubMed2006

Amphidinolide B: asymmetric synthesis of a C7-C20 synthon.

[reaction: see text] An asymmetric synthesis of a C(7)-C(20) synthon of amphidinolide B is described. The synthesis entails the construction of C(7)-C(13) and C(14)-C(20) fragments and makes extensive use of catalytic asymmetric bond constructions to establish the requisite stereochemical relationships. Fragment coupling proceeds by Suzuki cross-coupling and installs the trisubstituted diene unit that is among amphidinolide B's defining structural features.

Bridged Bicyclo Compounds, Heterocyclic↗

PubMed2005

Tandem Sakurai-aldol addition reactions as a route to structurally complex carbocycles.

Tandem intramolecular Sakurai-aldol reactions provide a concise and highly diastereoselective route to substituted cyclohexenone derivatives. The cyclization substrates are readily obtained using olefin isomerization-Claisen rearrangement (ICR) reactions to prepare the key chiral allyl silane precursors. The Claisen reaction products are elaborated to the chiral Sakurai-aldol substrates by an efficient two-step sequence involving vinyl organometallic-aldehyde addition and oxidation of the resulting alcohol. The reaction of the resulting enones with TiCl(4) elicits a highly stereoselective allyl silane conjugate addition to produce a trichlorotitanium enolate as the reaction intermediate; intermolecular trapping of the enolate with an aldehyde provides pentasubstituted cyclohexanone derivatives in which the annulation reaction establishes four stereocenters and two new C-C bonds. A fully intramolecular variant of the Sakurai-aldol reaction that creates four stereocenters, two new C-C bonds, and establishes two new carbocyclic rings is also described.

Alkenes↗

PubMed2005

Systems cell biology knowledge created from high content screening.

High content screening (HCS), the large-scale automated analysis of the temporal and spatial changes in cells and cell constituents in arrays of cells, has the potential to create enormous systems cell biology knowledge bases. HCS is being employed along with the continuum of the early drug discovery process, including lead optimization where new knowledge is being used to facilitate the decision-making process. We demonstrate methodology to build new systems cell biology knowledge using a multiplexed HCS assay, designed with the aid of knowledge-mining tools, to measure the phenotypic response of a panel of human tumor cell types to a panel of natural product-derived microtubule-targeted anticancer agents and their synthetic analogs. We show how this new systems cell biology knowledge can be used to design a lead compound optimization strategy for at least two members of the panel, (-)-laulimalide and (+)-discodermolide, that exploits cell killing activity while minimally perturbing the regulation of the cell cycle and the stability of microtubules. Furthermore, this methodology can also be applied to basic biomedical research on cells.

Antineoplastic Agents↗

PubMed2004

Cinchona alkaloid-lewis acid catalyst systems for enantioselective ketene-aldehyde cycloadditions.

Asymmetric cinchona alkaloid-catalyzed acid chloride-aldehyde cyclocondensation (AAC) reactions afford enantioenriched 4-substituted and 3,4-disubstituted beta-lactones with near perfect absolute and relative stereocontrol. These reactions are characterized by the operational simplicity derived from using commercially available or easily obtained (one-step) reaction catalysts and in situ ketene generation from acid chlorides. The range of aldehyde substrates that serve as effective AAC substrates include sterically hindered aldehydes such as cyclohexanecarboxaldehyde and pivaldehyde.

Acids↗

PubMed2004

Catalytic asymmetric acyl halide-aldehyde cyclocondensation reactions of substituted ketenes.

Catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions of alkyl-substituted ketenes with structurally diverse aldehydes provide cis-disubstituted beta-lactones with high enantioselectivity. The AAC reactions utilize a novel Al(III)-triamine catalyst in which the metal's dynamic coordination geometry leads to a highly selective catalyst complex. These AAC reactions represent a functional solution to highly enantioselective substituted ester enolate aldol additions.

Aldehydes↗

PubMed2003

Catalyzed olefin isomerization leading to highly stereoselective Claisen rearrangements of aliphatic allyl vinyl ethers.

Iridium(I)-catalyzed olefin isomerization in bis(allyl) ethers is integrated into a generally applicable strategy for affecting highly stereoselective Claisen rearrangements. Catalyzed alkene isomerization affords allyl vinyl ethers from easily prepared di(allyl) ethers; direct thermolysis of these reaction mixtures leads to highly diastereoselective [3,3] sigmatropic rearrangements affording syn-2,3-dialkyl-4-pentenal derivatives. An easily executed strategy for realizing asymmetric variants of the isomerization-Claisen rearrangement (ICR) reactions is also described.

Aldehydes↗

PubMed2002

A de novo enantioselective total synthesis of (-)-laulimalide.

An enantioselective total synthesis of the naturally occurring anticancer agent (-)-laulimalide is described. The synthesis is characterized by extensive use of new reaction methodologies based on catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions and transformations of the derived enantioenriched beta-lactones. The synthesis also incorporates a unique allenylstannane glycal acetate alkylation and chemoselective ring-closing metathesis reaction.

Animals↗

PubMed2002

S(N)2 ring opening of beta-lactones: an alternative to catalytic asymmetric conjugate additions.

Merging catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions with ensuing Grignard-mediated ring opening of the derived enantiomerically enriched beta-lactones is presented as a generally useful asymmetric synthesis of beta-disubstituted carboxylic acids. Enantiomerically enriched beta-lactones are subject to efficient S(N)2 ring opening with a variety of copper-modified alkyl Grignard reagents, including highly branched nucleophiles. Considerable structural variation in the lactone electrophile is also tolerated. Phenyl- and vinyl-derived organometallics are not efficient nucleophiles for the ring-opening reactions.

Journal Article↗

PubMed2002

Enantioenriched dihydropyrones from beta-lactone templates.

[reaction: see text] Optically active 4-substituted 2-oxetanones provide conduits for preparing 2,3-dihydro-4H-pyrone heterocycles. Enantioenriched beta-lactones are prepared by asymmetric catalytic acyl halide-aldehyde cyclocondensation reactions. Hydrazone anion-mediated beta-lactone ring opening and ensuing cyclization-dehydroamination of the derived beta-ketohydrazone afford the desired dihydropyrones (68-81%). Optimized lactone ring-opening-cyclization reaction conditions render a variety of optically active 4-substituted-2-oxetanones as effective precursors to enantioenriched 2,3-dihydro-4H-pyrones.

Cyclization↗