Collective total synthesis of stereoisomeric yohimbine alkaloids.

Stereoisomeric polycyclic natural products are important for drug discovery-based screening campaigns, due to the close correlation of stereochemistry with diversified bioactivities. Nature generates the stereoisomeric yohimbine alkaloids using bioavailable monoterpene secolaganin as the ten-carbon building block. In this work, we reset the stage by the development of a bioinspired coupling, in which the rapid construction of the entire pentacyclic skeleton and the complete control of all five stereogenic centers are achieved through enantioselective kinetic resolution of an achiral, easily accessible synthetic surrogate. The stereochemical diversification from a common intermediate allows for the divergent and collective synthesis of all four stereoisomeric subfamilies of yohimbine alkaloids through orchestrated tackling of thermodynamic and kinetic preference.

Total Synthesis of Spiro[cyclohexane-2-indoline] Alkaloids: A Regio- and Diastereoselective Spirocyclization Approach.

A direct spirocyclization approach for the chemical synthesis of spiro[cyclohexane-2-indoline] alkaloids is reported. The absolute stereochemistry was introduced by a desymmetrizing Dieckmann condensation, and the relative stereochemistry was controlled by the manipulation of the kinetic and thermodynamic pathways of the spirocyclization. By contrast to the biogenetic proposal involving the diester-type alkaloid as the precursor, we demonstrate that chemically a common lactone-type intermediate could bridge the chemical synthesis of this class of natural products.

Total Synthesis of (+)-Gilbertine: A Cyclopentanone-Based Approach.

From methyl jasmonate, the concise asymmetric total synthesis of uleine alkaloid gilbertine was reported. The synthesis demonstrated the power of a cyclopentanone-based approach involving the coupling of 2-aminobenzaldehyde and diazo-cyclopentanone for the rapid assembly of the hydrocarbazole natural product.

A Local Desymmetrization Approach to Piperidinyl Acetic Acid γ-Secretase Modulators.

A desymmetrization-based approach for the synthesis of piperidinyl acetic acid γ-secretase modulators has been developed. The synthetic sequence features the use of N-tert-butanesulfinyl imine reduction and a diastereoselective lactam formation to set up the chiral centers. The synthetic utility is demonstrated by the concise asymmetric synthesis of γ-secretase modulator GSM-1.

Asymmetric Total Synthesis of Asperversin A.

Asperversin A represents the first example of a steroid-sterigmatocystin heterodimer. We report the concise asymmetric total synthesis of this natural product in 11 steps (the longest linear sequence). The polycyclic ring system was constructed by a cascade dialdehyde cyclization and the late stage xanthene formation by a phenol-assisted reductive alkylation and a SNAr reaction. The acetal linkage with ergosterol peroxide was furnished by a glycosylation-inspired approach.

Organocatalytic enantioselective direct alkylation of phloroglucinol derivatives: asymmetric total synthesis of (+)-aflatoxin B2.

The organocatalytic enantioselective Friedel-Crafts alkylation of phloroglucinol derivatives with enals is reported, providing general access to the benzylic chiral centers shown in a variety of phloroglucinol natural products. The synthetic utility is demonstrated by the very concise asymmetric total synthesis of aflatoxins B2.

Divergent Coupling of 2-Carbonyl-anilines and Diazo-cyclopentanones: Asymmetric Total Synthesis of (+)-Leucomidine A.

The direct coupling of 2-carbonyl-anilines and diazo-cyclopentanones, promoted by a rhodium catalyst and diphenyl phosphate, is reported for the divergent generation of both carbazolones and indolones. The strategy allows for the successful transfer of the substituents/functionality and the chirality of the coupling partners into the functionalized heterocyclic products, thus serving as the strategic basis for natural product synthesis as demonstrated by the concise asymmetric total synthesis of (+)-leucomidine A.

Organocatalytic Enantioselective Cross-Vinylogous Rauhut-Currier Reaction of Methyl Coumalate with Enals.

The organocatalytic enantioselective intermolecular cross-vinylogous Rauhut-Currier (RC) reaction of methyl coumalate with α,ß-unsaturated aldehydes is reported, and the enals are activated by iminium catalysis to serve as the Michael acceptors and methyl coumalate is used as an activated diene to generate a latent enolate. The excellent selectivity is driven by the aromaticity of methyl coumalate, and the post transformation of this heterocyclic structure into other electron-deficient arenes and heterocycles have addressed, in part, the challenging selectivity issues of the intermolecular cross-RC reactions and the limited scope of iminium catalysis.

A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel.

Piezo1 represents a prototype of eukaryotic mechanotransduction channels. The full-length 2547-residue mouse Piezo1 possesses a unique 38-transmembrane-helix (TM) topology and is organized into a three-bladed, propeller-shaped architecture, comprising a central ion-conducting pore, three peripheral blade-like structures, and three 90-Å-long intracellular beam-resembling structures that bridge the blades to the pore. However, how mechanical force and chemicals activate the gigantic Piezo1 machinery remains elusive. Here we identify a novel set of Piezo1 chemical activators, termed Jedi, which activates Piezo1 through the extracellular side of the blade instead of the C-terminal extracellular domain of the pore, indicating long-range allosteric gating. Remarkably, Jedi-induced activation of Piezo1 requires the key mechanotransduction components, including the two extracellular loops in the distal blade and the two leucine residues in the proximal end of the beam. Thus, Piezo1 employs the peripheral blade-beam-constituted lever-like apparatus as a designated transduction pathway for long-distance mechano- and chemical-gating of the pore.

Unified Total Syntheses of Structurally Diverse Akuammiline Alkaloids.

The unified total syntheses of structurally diverse akuammiline alkaloids deformylcorymine (1), strictamine (2), and calophyline A (3) are reported. The strategy mimics the biosynthesis in nature at a strategic level, which allows for structural diversification from a common synthetic precursor by late-stage ring migrations.

Catalytic Enantioselective Aza-pinacol Rearrangement.

The first catalytic enantioselective asymmetric aza-pinacol rearrangement is reported. The reactions are catalyzed by a chiral phosphoric acid and proceed via a highly organized transition state involving a cyclic aza-ortho-xylylene intermediate to afford the indoline structures with good to excellent enantioselectivity. The synthetic utility of this method is demonstrated by the asymmetric synthesis of a key intermediate to the natural product minfiensine and the identification of a chiral lead compound to repress antibiotic resistance.

Total Synthesis of (±)-Grandilodine B.

The first total synthesis of the opened-type Kopsia alkaloid grandilodine B is reported. Four stereocenters of this alkaloid, three of them quaternary, are stereoselectively generated by a Diels-Alder reaction, a diastereoselective cyanation of tertiary alcohol, and a facial-selective nitrone 1,3-dipolar cycloaddition.

Bio-Inspired Fragmentations: Rapid Assembly of Indolones, 2-Quinolinones, and (-)-Goniomitine.

Inspired by the biogenetic origin of goniomitine, new synthetic bio-inspired fragmentation strategies for the synthesis of functionalized 2-quinolinones and indolones have been developed. Remarkable synthetic efficiency was achieved by telescoping several transformations into one-pot reactions, allowing for the direct coupling of 2-alkynyl-anilines and diazo ketones. The synthetic utility was demonstrated by the 5-step asymmetric total synthesis of (-)-goniomitine from 2-ethyl-cyclopentanone.

Sample injection strategy to increase throughput in counter-current chromatography: Case study of Honokiol purification.

Counter-current chromatography (CCC) has been widely used as a preparative separation method to purify natural products from plant extracts and fermentation broths. Traditionally, throughput optimization in CCC has focused on sample concentration and sample volume. In this paper sample injection was considered as consisting of three variables: injection flow rate, post-injection flow rate and sample solvent. The effects of these parameters were studied using a honokiol purification from a Magnolia officinalis bark extract as a case study aiming to achieve the highest throughput/yield ratio for greater than 99% purity of this potential anti-cancer drug obtained for submission to the Chinese FDA. An injection method was established that increased the throughput of honokiol by 46.5% (from 3.05g/h to 4.47g/h), and decreased the solvent consumption of mobile phase and stationary phase per gram of honokiol by 40.0% (from 0.68L/g to 0.41L/g) and 48.4% (from 0.40L/g to 0.21L/g) respectively. These results show the importance of understanding the whole injection process when optimizing a given CCC separation.

Divergent Synthesis of Hydro-γ-Carbolines and Multisubstituted Indoles through Grob Fragmentation/Mannich Cyclization.

A distinct strategy for the divergent synthesis of hydro-γ-carbolines and multisubstituted indoles is reported. The stereochemical outcomes and a control experiment indicate that the reactions likely proceed through Grob fragmentation/Mannich cyclization rather than a concerted aza-pinacol rearrangement.

Total Synthesis of Calophyline A.

Reported herein is the total synthesis of calophyline A, an indoline natural product possessing distinct ring connectivity which has not been synthesized previously. The synthetic route features several key transformations, including an aza-pinacol rearrangement to construct the nitrogen-containing bridged [3.2.2] bicycle, a Heck cyclization to assemble the fused 6/5/6/5 ring system, and a challenging late-stage aldol reaction to generate both a neopentyl quaternary stereogenic center and an oxygen-containing bridged [3.2.1] bicycle.

An Indoxyl-Based Strategy for the Synthesis of Indolines and Indolenines.

An indoxyl-based strategy for the synthesis of indolines and indolenines via unprecedented aza-pinacol and aza-semipinacol rearrangements was developed. This method provides direct access to the core structures of several classes of indole alkaloids. The synthetic utility was demonstrated by the divergent synthesis of an array of functionalized polycyclic structures from a common intermediate and the formal total synthesis of the indoline natural product minfiensine. The reversed reactivity of indoxyl as a building block compared to that of indole offers a conceptually distinct disconnection strategy for indoline- and indolenine-containing heterocycles and natural products.

Rapid Assembly of Functionalized Hydrodibenzofurans via Semipinacol Rearrangements.

A distinct strategy via unprecedented semipinacol rearrangements for the synthesis of functionalized hydrodibenzofurans is reported. The versatile reactivity of benzofuran-3-one as a building block enabled the convergent coupling of simple starting materials and, thus, allowed for the facile variation of R group and the construction of hydrodibenzofurans with fused rings.

Efficient assembly of polysubstituted pyrroles via a (3 + 2) cycloaddition/skeletal rearrangement/redox isomerization cascade reaction.

An unprecedented cascade strategy, used in conjunction with a redox isomerization, for the synthesis of 3-allyl pyrroles is reported. In a single step, readily accessible simple starting materials are transformed into highly substituted pyrroles with high efficiency. The products obtained contain allyl substituents, which can be readily elaborated to other useful functional groups. The reaction proceeds through an unusual (3 + 2) cycloaddition/skeletal rearrangement/redox isomerization pathway.

Theoretical and experimental analysis of the reaction mechanism of MrTPS2, a triquinane-forming sesquiterpene synthase from chamomile.

Terpene synthases, as key enzymes of terpene biosynthesis, have garnered the attention of chemists and biologists for many years. Their carbocationic reaction mechanisms are responsible for the huge variety of terpene structures in nature. These mechanisms are amenable to study by using classical biochemical approaches as well as computational analysis, and in this study we combine quantum-chemical calculations and deuterium-labeling experiments to elucidate the reaction mechanism of a triquinane forming sesquiterpene synthase from chamomile. Our results suggest that the reaction from farnesyl diphosphate to triquinanes proceeds through caryophyllyl and presilphiperfolanyl cations and involves the protonation of a stable (-)-(E)-ß-caryophyllene intermediate. A tyrosine residue was identified that appears to be involved in the proton-transfer process.