Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mechanism and origins of selectivity in the enantioselective oxa-Pictet-Spengler reaction: a cooperative catalytic complex from a hydrogen bond donor and chiral phosphoric acid.

ABSTRACT: Enantioselective additions to oxocarbenium ions are high-value synthetic transformations but have proven challenging to achieve. In particular, the oxa-Pictet-Spengler reaction has only recently been rendered enantioselective. We report experimental and computational studies on the mechanism of this unusual transformation. Herein we reveal that this reaction is hypothesized to proceed through a self-assembled ternary hydrogen bonding complex involving the substrate, chiral phosphate ion, and a urea hydrogen-bond donor. The computed transition state reveals C2-symmetric grooves in the chiral phosphate that are occupied by the urea and substrate. Occupation of one of these grooves by the urea co-catalyst tunes the available reactive volume and enhances the stereoselectivity of the chiral phosphate catalyst.

SUBMITTER: Maskeri MA

PROVIDER: S-EPMC8163393 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Thiourea-catalyzed enantioselective iso-Pictet-Spengler reactions.

Project description:A one-pot condensation of isotryptamines and aldehydes that affords enantiomerically enriched 4-substituted tetrahydro-γ-carbolines is reported. The reaction is induced by a chiral thiourea/benzoic acid dual catalyst system. Purification of the N-Boc-protected products by trituration or crystallization provides the optically pure tetrahydro-γ-carboline derivatives in a scalable and highly practical procedure.

| S-EPMC3206290 | biostudies-literature

Catalytic Enantioselective Pictet-Spengler Reaction of α-Ketoamides Catalyzed by a Single H-Bond Donor Organocatalyst.

Project description:The asymmetric Pictet-Spengler reaction (PSR) with aldehydes is well known. However, PSR involving ketones as electrophilic partners is far-less developed. We report herein the first examples of catalytic enantioselective PSR of tryptamines with α-ketoamides. A new class of easily accessible prolyl-urea organocatalysts bearing a single H-bond donor function catalyzes the title reaction to afford 1,1-disubstituted tetrahydro-β-carbolines in excellent yields and enantioselectivities. The kinetic isotope effect using C2-deuterium-labelled tryptamine indicates that the rearomatization of the pentahydro-β-carbolinium ion intermediate might be the rate- and the enantioselectivity-determining step.

| S-EPMC9313548 | biostudies-literature

Enantioselective Pictet-Spengler Reactions of Isatins for the Synthesis of Spiroindolones.

Project description:The condensation cyclization between isatins and 5-methoxy tryptamine catalyzed by chiral phosphoric acids provides spirooxindole tetrahydro-?-carboline products in excellent yields (up to 99%) and enantioselectivity (up to 98:2 er). A comparison of catalysts provides insight for the substrate scope and factors responsible for efficient catalytic activity and selectivity in the spirocyclization. Chiral phosphoric acids with different 3,3'-substitution on the binaphthyl system and opposite axial chirality afford the spiroindolone product with the same absolute configuration.

| S-EPMC3307811 | biostudies-literature

Chiral Thioureas Promote Enantioselective Pictet-Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction.

Project description:An investigation of the mechanism of benzoic acid/thiourea co-catalysis in the asymmetric Pictet-Spengler reaction is reported. Kinetic, computational, and structure-activity relationship studies provide evidence that rearomatization via deprotonation of the pentahydro-?-carbolinium ion intermediate by a chiral thiourea·carboxylate complex is both rate- and enantioselectivity-determining. The thiourea catalyst induces rate acceleration over the background reaction mediated by benzoic acid alone by stabilizing every intermediate and transition state leading up to and including the final selectivity-determining step. Distortion-interaction analyses of the transition structures for deprotonation predicted using density functional theory indicate that differential ?-? and C-H···? interactions within a scaffold organized by multiple hydrogen bonds dictate stereoselectivity. The principles underlying rate acceleration and enantiocontrol described herein are expected to have general implications for the design of selective transformations involving deprotonation of high-energy intermediates.

| S-EPMC5674793 | biostudies-literature

Weak Bronsted acid-thiourea co-catalysis: enantioselective, catalytic protio-Pictet-Spengler reactions.

Project description:The development of one-pot imine formation and asymmetric Pictet-Spengler reactions cocatalyzed by a chiral thiourea and benzoic acid is described. Optically active tetrahydro-beta-carbolines, ubiquitous structural motifs in biologically active natural products, are obtained in high ee directly from tryptamine and aldehyde precursors.

| S-EPMC2664157 | biostudies-literature

Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines.

Project description:The Pictet-Spengler reaction (PSR) involves the condensation and ring closure between a β-arylethylamine and a carbonyl compound. The combination of dopamine and ketones in a PSR leads to the formation of 1,1'-disubstituted tetrahydroisoquinolines (THIQs), structures that are challenging to synthesize and yet are present in a number of bioactive natural products and synthetic pharmaceuticals. Here we have discovered that norcoclaurine synthase from Thalictrum flavum (TfNCS) can catalyse the PSR between dopamine and unactivated ketones, thus facilitating the facile biocatalytic generation of 1,1'-disubstituted THIQs. Variants of TfNCS showing improved conversions have been identified and used to synthesize novel chiral 1,1'-disubstituted and spiro-THIQs. Enzyme catalysed PSRs with unactivated ketones are unprecedented, and, furthermore, there are no equivalent stereoselective chemical methods for these transformations. This discovery advances the utility of enzymes for the generation of diverse THIQs in vitro and in vivo.

| S-EPMC5382262 | biostudies-literature

Enantioselective Tandem Cyclization of Alkyne-Tethered Indoles Using Cooperative Silver(I)/Chiral Phosphoric Acid Catalysis.

Project description:Reported is the enantioselective synthesis of tetracyclic indolines using silver(I)/chiral phosphoric acid catalysis. A variety of alkyne-tethered indoles are suitable for this process. Mechanistic studies suggest that the in?situ generated silver(I) chiral phosphate activates both the alkyne and the indole nucleophile in the initial cyclization step through an intermolecular hydrogen bond and the phosphate anion promotes proton transfer. In addition, further modifications of the cyclization products enabled stereochemistry-function studies of a series of bioactive indolines.

| S-EPMC5997581 | biostudies-literature

A diastereoselective oxa-Pictet-Spengler-based strategy for (+)-frenolicin B and epi-(+)-frenolicin B synthesis.

Project description:An efficient diastereoselective oxa-Pictet-Spengler reaction strategy was developed to construct benzoisochroman diastereomers. The utility of the reaction was demonstrated in the context of both the total synthesis of naturally occurring pyranonaphthoquinones (+)-frenolicin B and epi-(+)-frenolicin B as well as a range of frenolicin precursor analogs. The method is versatile and offers exquisite stereocontrol and, as such, offers a synthetic advance for the synthesis of pyranonaphthoquinone analogs.

| S-EPMC3877857 | biostudies-other

Identifying the true origins of selectivity in chiral phosphoric acid catalyzed <i>N</i>-acyl-azetidine desymmetrizations.

Project description:The first catalytic intermolecular desymmetrization of azetidines was reported by Sun and coworkers in 2015 using a BINOL-derived phosphoric acid catalyst (J. Am. Chem. Soc. 2015, 137, 5895-5898). To uncover the mechanism of the reaction and the origins of the high enantioselectivity, Density Functional Theory (DFT) calculations were performed at the B97D3/6-311+G(2d,2p)/SMD(toluene)//B97D3/6-31G(d,p)/CPCM(toluene) level of theory. Comparison of four possible activation modes confirms that this reaction proceeds through the bifunctional activation of the azetidine nitrogen and the thione tautomer of the 2-mercaptobenzothiazole nucleophile. Upon thorough conformational sampling of the enantiodetermining transition structures (TSs), a free energy difference of 2.0 kcal mol-1 is obtained, accurately reproducing the experimentally measured 88% e.e. at 80 °C. This energy difference is due to both decreased distortion and increased non-covalent interactions in the pro-(S) TS. To uncover the true origins of selectivity, the TSs optimized with the full catalyst were compared to those optimized with a model catalyst through steric maps. It is found that the arrangements displayed by the substrates are controlled by strict primary orbital interaction requirements at the transition complex, and their ability to fit into the catalyst pocket drives the selectivity. A general model of selectivity for phosphoric acid-catalyzed azetidine desymmetrizations is proposed, which is based on the preference of the nucleophile and benzoyl group to occupy empty quadrants of the chiral catalyst pocket.

| S-EPMC8654023 | biostudies-literature

Highly enantioselective hydrogenation of enamides catalyzed by chiral phosphoric acids.

Project description:A highly enantioselective hydrogenation of enamides catalyzed by a dual chiral-achiral acid system was developed. By employing a substoichiometric amount of a chiral phosphoric acid and acetic acid, catalyst loadings as low as 1 mol % of the chiral catalyst were sufficient to provide excellent yield and enantioselectivity of the reduction product.

| S-EPMC2765520 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data