Biomedical subjects

Jonathan A Ellman

Publications and source records attributed to Jonathan A Ellman.

At least 37 records · Page 2Linked to original sources

PubMed2005

N-sulfinyl metalloenamine conjugate additions: asymmetric synthesis of piperidines.

[reaction: see text] The first examples of conjugate additions of N-tert-butanesulfinyl metalloenamines are reported. Highly stereoselective conjugate additions (97:3 to 99:1 dr) were observed between metalloenamines derived from N-sulfinyl ketimines and alpha,beta-unsaturated ketones bearing either alkyl or aryl substituents. The conjugate addition products could rapidly be converted with high diastereoselectivity to 2,4,6-trisubstituted piperidines, which are difficult to access by other methods.

Journal Article↗

PubMed2005

Annulation of aromatic imines via directed C-H bond activation.

A directed C-H bond activation approach to the synthesis of indans, tetralins, dihydrofurans, dihydroindoles, and other polycyclic aromatic compounds is presented. Cyclization of aromatic ketimines and aldimines containing alkenyl groups tethered at the meta position relative to the imine directing group has been achieved using (PPh3)3RhCl (Wilkinson's catalyst). The cyclization of a range of aromatic ketimines and aldimines provides bi- and tricyclic ring systems with good regioselectivity. Different ring sizes and substitution patterns can be accessed through the coupling of monosubstituted, 1,1- or 1,2-disubstituted, and trisubstituted alkenes bearing both electron-rich and electron-deficient functionality.

Carbon↗

PubMed2005

A rapid and general method for the asymmetric synthesis of 2-substituted pyrrolidines using tert-butanesulfinamide.

A new method for the asymmetric synthesis of 2-substituted pyrrolidines in three steps from commercially available starting materials is described. Addition of the Grignard reagent prepared from 2-(2-bromoethyl)-1,3-dioxane to N-tert-butanesulfinyl aldimines proceeds in high yields and with good diastereoselectivities. The sulfinamide products are then cleanly converted into pyrrolidines in one step.

Butanes↗

PubMed2005

Catalytic enantioselective sulfinyl transfer using cinchona alkaloid catalysts.

[reaction: see text] Practical reaction conditions for the catalytic enantioselective synthesis of sulfinate esters are reported. Commercially available cinchona alkaloids were found to be superior catalysts for the sulfinyl transfer reaction of tert-butanesulfinyl chloride and a variety of benzyl alcohols. Sulfinyl transfer with 2,4,6-trichlorobenzyl alcohol and 10 mol % of the commercially available, inexpensive catalyst quinidine provided the pure sulfinate ester product in 92% isolated yield and with 90% ee.

Catalysis↗

PubMed2005

High throughput substrate specificity profiling of serine and cysteine proteases using solution-phase fluorogenic peptide microarrays.

Proteases regulate numerous biological processes with a degree of specificity often dictated by the amino acid sequence of the substrate cleavage site. To map protease/substrate interactions, a 722-member library of fluorogenic protease substrates of the general format Ac-Ala-X-X-(Arg/Lys)-coumarin was synthesized (X=all natural amino acids except cysteine) and microarrayed with fluorescent calibration standards in glycerol nanodroplets on glass slides. Specificities of 13 serine proteases (activated protein C, plasma kallikrein, factor VIIa, factor IXabeta, factor XIa and factor alpha XIIa, activated complement C1s, C1r, and D, tryptase, trypsin, subtilisin Carlsberg, and cathepsin G) and 11 papain-like cysteine proteases (cathepsin B, H, K, L, S, and V, rhodesain, papain, chymopapain, ficin, and stem bromelain) were obtained from 103,968 separate microarray fluorogenic reactions (722 substrates x 24 different proteases x 6 replicates). This is the first comprehensive study to report the substrate specificity of rhodesain, a papain-like cysteine protease expressed by Trypanasoma brucei rhodesiense, a parasitic protozoa responsible for causing sleeping sickness. Rhodesain displayed a strong P2 preference for Leu, Val, Phe, and Tyr in both the P1=Lys and Arg libraries. Solution-phase microarrays facilitate protease/substrate specificity profiling in a rapid manner with minimal peptide library or enzyme usage.

Amino Acid Sequence↗

PubMed2005

Diastereoselective and enantioselective Rh(I)-catalyzed additions of arylboronic acids to N-tert-butanesulfinyl and N-diphenylphosphinoyl aldimines.

Two new Rh(I)-catalyzed methods for the synthesis of chiral alpha-branched amines via addition of arylboronic acids to N-tert-butanesulfinyl and N-diphenylphosphinoyl imines have been developed. The syntheses are more functional group tolerant than alternative methods utilizing Grignard or organolithium reagents, and the imine activating groups used are easily removed. These methods are both high-yielding (70-97% yield) and very selective (>93:7 dr and 88-94% ee). Significantly, the N-tert-butanesulfinyl imine method works for aliphatic imines with enolizable protons. In addition, a one-pot procedure for the synthesis of N-tert-butanesulfinyl protected alpha-branched amines from aldehydes has been developed.

Aldehydes↗

PubMed2005

Potent 4-aminopiperidine based antimalarial agents.

A series of compounds with potent activity against a multi-drug-resistant strain of Plasmodium falciparum, the causative agent of the deadliest strain of malaria, is described. These compounds were also tested for cytotoxicity in human foreskin fibroblast assays, evaluated to determine their logD, and assayed for metabolism by human and murine hepatocytes. This work resulted in the development of compounds 9e and 10d, which showed good potency (IC(50)=75 nM and <60 nM, respectively, against Dd2), acceptable logD values, and reasonable metabolic stability.

Animals↗

PubMed2005

Profiling serine protease substrate specificity with solution phase fluorogenic peptide microarrays.

A novel microarray-based proteolytic profiling assay enabled the rapid determination of protease substrate specificities with minimal sample and enzyme usage. A 722-member library of fluorogenic protease substrates of the general format Ac-Ala-X-X-(Arg/Lys)-coumarin was synthesized and microarrayed, along with fluorescent calibration standards, in glycerol nanodroplets on microscope slides. The arrays were then activated by deposition of an aerosolized enzyme solution, followed by incubation and fluorometric scanning. The specificities of human blood serine proteases (human thrombin, factor Xa, plasmin, and urokinase plasminogen activator) were examined. The arrays provided complete maps of protease specificity for all of the substrates tested and allowed for detection of cooperative interactions between substrate subsites. The arrays were further utilized to explore the conservation of thrombin specificity across species by comparing the proteolytic fingerprints of human, bovine, and salmon thrombin. These enzymes share nearly identical specificity profiles despite approximately 390 million years of divergent evolution. Fluorogenic substrate microarrays provide a rapid way to determine protease substrate specificity information that can be used for the design of selective inhibitors and substrates, the study of evolutionary divergence, and potentially, for diagnostic applications.

Amino Acid Motifs↗

PubMed2004

Asymmetric alpha-alkylation of N'-tert-butanesulfinyl amidines. Application to the total synthesis of (6R,7S)-7-amino-7,8-dihydro-alpha-bisabolene.

A highly diastereoselective alpha-alkylation of N'-tert-butanesulfinyl amidines has been developed along with methods for converting the alkylation products to enantiomerically enriched amines that incorporate both alpha- and beta-stereocenters. The utility of this chemistry is further demonstrated by the first asymmetric synthesis of the antimicrobial marine natural product (6R,7S)-7-amino-7,8-dihydro-alpha-bisabolene.

Alkylation↗

PubMed2004

Intermolecular coupling of alkenes to heterocycles via C-H bond activation.

The intermolecular coupling of unactivated alkenes to a range of heterocycles using a Rh(I) catalyst was investigated. A variety of functional groups were incorporated into the alkene, including esters, nitriles, acetals, and phthalimide. Furthermore, the heterocycle tolerated substitution with both electron-rich and electron-deficient groups. The intermolecular coupling became possible after it was discovered that weak acids dramatically increase the rate of both the inter- and intramolecular reactions. An extensive optimization of additives was performed, and HCl.PCy(3) (Cy = cyclohexyl) and HCl.P-t-Bu(2)Et were in general found to be the best additives for the reaction.

Alkenes↗

PubMed2004

Self-condensation of N-tert-butanesulfinyl aldimines: application to the rapid asymmetric synthesis of biologically important amine-containing compounds.

[reaction: see text] Highly diastereoselective intra- and intermolecular self-condensation reactions of N-tert-butanesulfinyl aldimines have been developed and applied to the rapid, asymmetric synthesis of trans-2-aminocyclopentanecarboxylic acid and the drug candidate SC-53116. Key to both syntheses is a novel microwave-assisted reaction in which N-sulfinyl aldimines are cleanly converted into nitriles in high-yielding concerted elimination processes.

Amines↗

PubMed2004

Catalytic enantioselective synthesis of sulfinate esters through the dynamic resolution of tert-butanesulfinyl chloride.

Development of a new synthetic route to obtain enantiomerically enriched tert-butanesulfinate esters in excellent yields through catalytic enantioselective sulfinyl transfer is described. As little as 0.5 mol % of chiral amine catalysts was used to couple racemic tert-butanesulfinyl chloride with arylmethyl alcohols to provide sulfinate esters in near quantitative yields and with enantiomeric excesses up to 81%. The method represents the first example of the catalytic dynamic resolution of sulfinyl derivatives.

Journal Article↗

PubMed2004

Highly efficient and enantioselective cyclization of aromatic imines via directed C-H bond activation.

The first highly enantioselective catalytic reaction involving aromatic C-H bond activation is communicated. Enantioselective cyclization of aromatic ketimines containing alkenyl groups tethered at the meta position of an imine directing group has been achieved using 5 mol % [RhCl(coe)2]2 and 15 mol % of an (S)-binol-derived phosphoramidite ligand. Selectivities of up to 96% ee and up to quantitative yields were obtained. Moreover, the identified catalyst system enables the intramolecular alkylation reaction to be performed at temperatures 75 degrees C lower than our previously reported achiral system. The reaction can even be performed at room temperature for one of the optimal substrates.

Carbon↗

PubMed2004

Rhodium-catalyzed direct C-H addition of 4,4-dimethyl-2-oxazoline to alkenes.

A new method for the preparation of 2-substituted oxazolines by rhodium-catalyzed coupling of alkenes with 4,4-dimethyl-2-oxazoline is reported. The oxazoline products are obtained in good yield with excellent selectivity for the linear product. A variety of alkene substitution patterns and functional groups are tolerated. This procedure represents an attractive alternative to hydroesterification because it does not involve the manipulation of CO gas.

Alkenes↗

PubMed2004

Highly stereoselective addition of organometallic reagents to N-tert-butanesulfinyl imines derived from 3- and 4-substituted cyclohexanones.

Addition of alkyl or aryl Grignard reagents to N-sulfinyl imines derived from 3- and 4-substituted cyclohexanones proceeds with good yields and with excellent diasteroselectivity. The selectivity of the reaction is controlled by the ring substituent rather than the sulfinyl group stereochemistry, and therefore racemic tert-butanesulfinamide can be employed.

Journal Article↗

PubMed2004

Application of P,N-sulfinyl imine ligands to iridium-catalyzed asymmetric hydrogenation of olefins.

The utility of a novel class of P,N-ligands incorporating a chiral sulfinyl imine moiety is demonstrated in the iridium-catalyzed hydrogenation of both functionalized and unfunctionalized olefins, in which enantioselectivities of up to 94% are achieved. The modularity of the P,N-sulfinyl ligand class is highlighted by the facile preparation of a variety of sterically and electronically different ligands. Interesting structure-activity data for both the phosphine and sulfinamide components is provided by this expanded ligand set.

Alkenes↗

PubMed2004

Arylation of heterocycles via rhodium-catalyzed C-H bond functionalization.

[reaction: see text] A new method for the rhodium-catalyzed arylation of a variety of heterocycles has been developed. The reaction provided moderate to good yields of the arylated products. A preliminary mechanistic investigation of this reaction revealed the intermediacy of an isolable N-heterocyclic carbene complex.

Catalysis↗

PubMed2003

Stereoselective synthesis of 1,2-disubstituted beta-amino alcohols by nucleophilic addition to N-tert-butanesulfinyl alpha-alkoxyaldimines.

N-tert-Butanesulfinyl alpha-alkoxyaldimines are readily prepared from protected (S)-lactals without epimerization at the alpha-stereocenter. Addition of ethyl and phenyl Grignard reagents, as well as the titanium enolate of methyl acetate, to the N-tert-butanesulfinyl aldimines provides 1,2-disubstituted beta-amino alcohols in good yields (73-98%) and with high diastereoselectivities. Either syn- or anti-amino alcohol products can be obtained by the appropriate choice of alcohol protecting groups and/or reaction conditions. Finally, deprotection of the addition products provides straightforward access to either syn- or anti-1,2-amino alcohols.

Amino Alcohols↗