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The first total synthesis of dracaenins A and B is achieved in four steps. The synthesis features the convergent coupling of three readily available fragments with minimized use of protecting groups. The chemical synthesis enables the discovery of their activity in stimulating platelet aggregation, and thus, sheds light on the possible origin of the hemostatic effect of dragon's blood.

The migration selectivity of Cb-substituted-4aH-carbazoles has been studied by DFT methods. For n-Bu and Ph substituted sub-strates, C4 migration and Ca-C1 migration are all pericyclic. C4 migration is favorable for more aromatic transition states. For halo-gen substituted substrates, C4 migration locates in the junction zone of pericyclic reactions and pseudopericyclic reactions while Ca-C1 migration is pseudopericyclic. Ca-C1 migration is favorable due to more positive NPA charges and LUMO distributions on Ca than C4. The acid catalysts with large steric hindrance can adjust the reaction selectivity through to some extent.

The synthetic utility of rearrangement reactions in total synthesis for the rapid construction of core skeletons, the precise control of stereochemistry, and the identification of suitable synthons has been discussed.

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.

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.

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.

We report a mild method for the synthesis of 4aH-carbazole intermediates with significant synthetic flexibility and variability, and demonstrate the controllable rearrangements of such intermediates to carbazoles. The work further enriches the chemistry of 4aH-carbazoles in general and offers a consecutive rearrangements approach for the precise decoration of the “inert” carbazole ring specifically.

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.

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.

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.

In this account, we summarize our recent efforts in the total syntheses of several indole alkaloids, including minfiensine, calophyline A, deformylcorymine, strictamine, and goniomitine. Our central theme is to utilize skeletal rearrangements as key strategies for generating complex structures.1 Introduction2 The Development of an Aza-Pinacol Rearrangement3 Applications of Aza-Pinacol Rearrangements in Total ­Syntheses4 Strategy Extension: The Total Synthesis of Goniomitine5 Conclusion

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.

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.

Although the widespread usage of aza-pinacol and aza-semipinacol rearrangements as synthetic methods has not been found, these synthetic transformations offer novel tactics for the preparation of nitrogen-containing heterocycles and natural alkaloids. Herein, we briefly discuss the most recent developments in this area and present our strategy based on aza-pinacol rearrangements for the synthesis of indolines and indolenines. 1 Introduction 2 Recently Developed Aza-Pinacol and Aza-Semipinacol Rearrangements 3 Indoline/Indolenine Synthesis Employing Aza-Pinacol Rearrangements as the Key Strategy 4 Conclusion

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.

The organocatalytic enantioselective intermolecular cross-vinylogous Rauhut-Currier (RC) reaction of methyl coumalate with α,β-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.

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., Piezo1 is a large trimeric ion channel activated by mechanical stimulus. Here the authors identify chemical activators of Piezo1 that utilize a lever-like mechanotransduction pathway for long-range allosteric gating.

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.

A mild and operationally simple protocol for the direct C–H functionalization of the 1-position of tetrahydrocarbazoles is reported. The diastereoselective oxidative coupling process is mediated by tert-butyl hypochlorite, and allows the successful generation of 1-functionalized tetrahydrocarbazoles with good to excellent yields and good functional group tolerance.

A direct [3 + 2] annulation reaction between indoles and α,β-unsaturated ketones is reported, which allows for the efficient assembly of densely substituted, highly functionalized pyrrolo[1,2-a]indoles. Model reactions toward the originally assigned structure of yuremamine are also described, leading to the successful construction of the core with required functionality.

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.

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.

Although the widespread usage of aza-pinacol and aza-semipinacol rearrangements as synthetic methods has not been found, these synthetic transformations offer novel tactics for the preparation of nitrogen-containing heterocycles and natural alkaloids. Herein, we briefly discuss the most recent developments in this area and present our strategy based on aza-pinacol rearrangements for the synthesis of indolines and indolenines. 1 Introduction 2 Recently Developed Aza-Pinacol and Aza-Semipinacol Rearrangements 3 Indoline/Indolenine Synthesis Employing Aza-Pinacol Rearrangements as the Key Strategy 4 Conclusion

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 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.

A convergent method to access the fused indoline ring system present in a multitude of bioactive molecules has been developed. The strategy involves the condensation of hydrazines with latent aldehydes to ultimately deliver indoline-containing products by way of an interrupted Fischer indolization sequence. The method is convergent, mild, operationally simple, broad in scope, and can be used to access enantioenriched products. In addition, our approach is amenable to the synthesis of furoindoline and pyrrolidinoindoline natural products as demonstrated by the concise formal total syntheses of physovenine and debromoflustramine B. The strategy will likely enable the synthesis of more complex targets such as the communesin alkaloids.

An unprecedented organocatalytic asymmetric Michael addition of fluorine-containing carbon-centered nucleophiles to nitroolefins has been described. The process features the creation of a fluorine-containing quaternary carbon center and an adjacent chiral carbon center adducts with good to excellent level of enantioselectivity.

An unprecedented highly enantioselective cascade oxa-Michael-Michael reaction has been developed. The simple and practical process, efficiently catalyzed by chiral diphenylprolinol TMS ether, affords a powerful access to highly functionalized synthetically useful chiral chromans. Moreover, notably a new activation mode involving an aminal is disclosed for the first time.

An organocatalytic direct inverse electron demand Diels-Alder reaction of ketones with 1,2,4,5-tetrazines has been developed. The process is efficiently catalyzed by proline to give Diels-Alder adducts pyridazines in high yields.

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.

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 3.05 g/h to 4.47 g/h), and decreased the solvent consumption of mobile phase and stationary phase per gram of 35 honokiol by 40.0% (from 0.68 L/g to 0.41 L/g) and 48.4% (from 0.40 L/g to 0.21 L/g) 36 respectively. These results show the importance of understanding the whole injection process 37 when optimizing a given CCC separation. This research was supported by the National Natural Science Foundation of China (81302663), National High Technology Research and Development Program of China (863 Program) (2014AA020540) and 2011 Collaborative Innovation Program of China.

An efficient, organocatalytic, highly enantioselective, conjugate addition reaction of nitromethane with α,β-unsaturated aldehydes has been developed. The process serves as the key step for a practical 3-step synthesis of chiral baclofen, an anti-spastic drug.

A quinine-promoted, enantioselective Michael addition reaction of diphenyl phosphite with nitroalkenes has been developed. This methodology affords a facile access to enantiomerically enriched p-nitrophosphates, precursors for the preparation of synthetically and biologically useful β-amino-phosphonates.

A conjugate addition-aldol-dehydration reaction of alpha,beta-unsaturated aldehydes with 2-N-protected amino benzaldehydes has been developed. The process is promoted by (S)-diphenylprolinol TES ether to afford synthetically useful 1,2-dihydroquinolines in high enantioselectivities with good yields. [reaction: see text]

A direct [3 + 2] annulation reaction between indoles and α,β-unsaturated ketones is reported, which allows for the efficient assembly of densely substituted, highly functionalized pyrrolo[1,2-a]indoles. Model reactions toward the originally assigned structure of yuremamine are also described, leading to the successful construction of the core with required functionality.

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.

A mild and simple method for the direct C-H functionalization of the C-1 position of tetrahydrocarbazoles with good functional group tolerance is presented.

A method for organocatalytic, enantioselective Michael addition reactions of thioacetic acid with a range of trans-β-nitrostyrenes has been developed. The processes, promoted by the chiral amine thiourea organocatalyst, take place in high yields with up to 70% ee.

A new bifunctional binaphthyl-derived amine thiourea organocatalyst has been developed to promote enantioselective Morita−Baylis−Hillman reaction of cyclohexenone with a wide range of aldehydes. Th...

We report the total synthesis of (±)-aspidophylline A, one of many complex furoindoline-containing alkaloids that has not been synthesized previously. Our route features a number of key transformations, including a Heck cyclization to assemble the [3.3.1]-bicyclic scaffold as well as a late-stage interrupted Fischer indolization to install the furoindoline and construct the natural product’s pentacyclic framework.

This one-step operation allows for the efficient assembly of highly substituted pyrrole ring systems from simple starting materials.

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.