Murrastifoline-F: first total synthesis, atropo-enantiomer resolution, and stereoanalysis of an axially chiral N,C-coupled biaryl alkaloid.

The first total synthesis of the Murraya alkaloid murrastifoline-F (3), an unsymmetric, N,C-bonded heterobiarylic biscarbazole, is described. Starting from the likewise naturally occurring-but here synthetically prepared-"monomer" murrayafoline-A (6), lead tetraacetate-mediated oxidative non-phenolic biaryl coupling gives 3 as the main regioisomer. The existence of this natural product as a pair of stable atropo-enantiomers was demonstrated analytically through LC-CD investigations. Preparatively, the racemate resolution succeeded by O-demethylation, derivatization with Mosher's reagent, and chromatographic separation of the resulting diastereomers. The absolute configurations of the atropisomers were assigned by CD spectroscopy in combination with quantum chemical CD calculations at the stage of the alkaloid 3 and by ROESY experiments of the diastereomeric Mosher derivatives. In the root extract of the curry leaf plant Murraya koenigii (Rutaceae), murrastifoline-F (3) was found to exist as a 56:44 mixture in favor of the M-enantiomer, by LC-CD coupling.     

Synthesis of Methylene‐Bridged Biscarbazole Alkaloids by using an Ullmann‐type Coupling: First Total Synthesis of Murrastifoline‐C and Murrafoline‐E

We describe the total synthesis of methylene‐bridged biscarbazole alkaloids by using a late‐stage Ullmann‐type coupling of fully functionalised carbazole subunits. The carbazole derivatives were synthesised via a sequence of palladium(0)‐ and palladium(II)‐catalysed coupling reactions. Our approach has provided bismurrayafoline‐A, bismurrayafolinol, chrestifolines B–D, and the first total synthesis of murrastifoline‐C and murrafoline‐E.     

Novel approach to biscarbazole alkaloids via Ullmann coupling - synthesis of murrastifoline-A and bismurrayafoline-A

Unprecedented Ullmann couplings of murrayafoline-A with either 6-bromo- or 4-bromocarbazole derivatives provide highly efficient synthetic routes to the biscarbazole alkaloids murrastifoline-A (6 steps, 66% overall yield) and bismurrayafoline-A (6 steps, 28% overall yield).     

Total synthesis of (-)-incarvilline, (+)-incarvine C, and (-)-incarvillateine

The first total syntheses of new monoterpene alkaloids (-)-incarvilline, (+)-incarvine C, and (-)-incarvillateine, corresponding to the natural enantiomers, have been accomplished. The strategy for the synthesis of these natural products utilized 6-epi-incarvilline as a common precursor, which was assembled by a three-component coupling reaction using (4S)-4-siloxy-2-cyclopenten-1-one to construct an appropriately trisubstituted cyclopentanone, followed by ring closure to the cis-perhydro-2-pyrindine skeleton by means of a reductive Heck-type reaction. Furthermore, topochemically controlled [2 + 2] photodimerization of cinnamic acid derivatives in the solid state for the stereospecific construction of a 1,2,3,4-tetrasubstituted cyclobutane ring was also investigated as a means to access (-)-incarvillateine.     

The enantiospecific,stereospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-majvinine, (+)-10-methoxyaffinisine,and (+)-N(a)-methylsarpagine,as well as the total synthesis of the alstonia bisindole alkaloid macralstonidine

The first stereospecific, enantiospecific total synthesis of the ring-A oxygenated sarpagine indole alkaloids (+)-N(a)-methylsarpagine (8), (+)-majvinine (14), and (+)-10-methoxyaffinisine (49), as well as the first total synthesis of the Alstonia bisindole alkaloid macralstonidine (9), has been accomplished. This approach employed the Sch?llkopf chiral auxiliary for the stereospecific construction of the desired d-(+)-tryptophan unit required for the asymmetric Pictet-Spengler reaction. In addition, the strategy was doubly convergent for the enolate-mediated Pd(0) coupling process and the asymmetric Pictet-Spengler reaction can be employed to synthesize both macroline (2) and N(a)-methylsarpagine (8), the coupling of which provides macralstonidine (9). This approach to ring-A substituted alkoxyindole alkaloids should find wide application for the synthesis of other alkaloids for it is stereospecific and either enantiomer can be prepared with ease.     

Non-biaryl atropisomers in organocatalysis

A new class of 6'-hydroxy cinchona alkaloids, with a non-biaryl atropisomeric functionalisation at position 5' of the quinoline core can be prepared by an easy amination procedure. These are the first derivatives for which the principle of atropisomerism is engrafted in the classical core of the cinchona alkaloids. The aminated cinchona alkaloids are effective organocatalysts for the Michael addition of beta-keto esters to acrolein and methyl vinyl ketone, in up to 93 % ee (ee=enantiomeric excess), as well as for the asymmetric Friedel-Crafts amination of a variety of 2-naphthols, permitting the preparation of the latter in up to 98 % ee. The aminated 8-amino-2-naphthol itself is the first chiral organocatalyst based on non-biaryl atropisomerism. The two enantiomers of this chiral primary amine can be used for the direct alpha-fluorination of alpha-branched aldehydes. The fluorinated compounds can thereby be accessed in up to 90 % ee.     

Stereoselective Mannich Reactions in the Synthesis of Enantiopure Piperidine Alkaloids and Derivatives

Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six-membered nitrogen-containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool-based (internal asymmetric induction), (2) chiral auxiliary-based (relayed asymmetric induction) and (3) asymmetric catalysis-based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.     

Recent advances in organocatalytic asymmetric synthesis of polysubstituted pyrrolidines

Chiral substituted pyrrolidines are important N-heterocyclic structural motifs, existing in many natural products, drug candidates, ligands and organocatalysts. We summarise herein the recent (between January 2010 and July 2013) developments on synthesising the chiral polysubstituted pyrrolidines through asymmetric organocatalysis. The organocatalytic strategies for constructing the pyrrolidine scaffolds can be divided into one-step and sequential approaches, respectively. The straightforward one-step approach is mainly the [3+2] cycloaddition based on the iminium activation, chiral Brønsted acid catalysis, bifunctional organocatalysis and SOMO activation. In the sequential approach (multi-step or one-pot reactions), the primary construction of chiral linear precursors is followed by the sequential cyclisation. Other important strategies, such as the organocatalytic bromoaminocyclisation were also described. These organocatalytic strategies have enriched the synthetic chemistry of chiral pyrrolidines, especially towards the target-, diversity- and application-oriented synthesis. New organocatalytic approaches are thus expected for the facile construction of polysubstituted pyrrolidines with well-controlled stereochemistry and for the practical synthesis of pyrrolidine-related natural alkaloids, drug candidates and functional proline derivatives.     

Catalytic Atroposelective C7 Functionalisation of Indolines and Indoles

Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry. In particular, axially chiral indole- and indoline-based frameworks have been recognised as important heterobiaryl classes because they are the core units of bioactive natural alkaloids, chiral ligands and bioactive compounds. Among them, the synthesis of C7-substituted indole biaryls and the analogous indoline derivatives is particularly challenging, and methods for their efficient synthesis are in high demand. Transition-metal catalysis is considered one of the most efficient methods to construct atropisomers. Here, we report the enantioselective synthesis of C7-indolino- and C7-indolo biaryl atropisomers by means of C−H functionalisation catalysed by chiral RhJasCp complexes.     

Preparation for Supramolecular Complexes of Chiral Diols BDPDD,DMBDPD and BINOL with Some Prochiral Compounds

Interaction between chiral diols BDPDD,DMBDPD and BINOL with prochiral compounds was examined and some new supramolecular complexes were prepared.It was found that these chiral hosts could include prochiral guests,α，β-unsarurated compounds or pinperazinedione derivatives to give inclusion crystals in different molar ratio.Formations of these supramolecular complexes were characterized by the data of IR and ^H NMR spectra.     

Chemistry and pharmacology of analgesic indole alkaloids from the rubiaceous plant, Mitragyna speciosa

The leaves of a tropical plant, Mitragyna speciosa KORTH (Rubiaceae), have been traditionally used as a substitute for opium. Phytochemical studies of the constituents of the plant growing in Thailand and Malaysia have led to the isolation of several 9-methoxy-Corynanthe-type monoterpenoid indole alkaloids, including new natural products. The structures of the new compounds were elucidated by spectroscopic and/or synthetic methods. The potent opioid agonistic activities of mitragynine, the major constituent of this plant, and its analogues were found in in vitro and in vivo experiments and the mechanisms underlying the analgesic activity were clarified. The essential structural features of mitragynines, which differ from those of morphine and are responsible for the analgesic activity, were elucidated by pharmacological evaluation of the natural and synthetic derivatives. Among the mitragynine derivatives, 7-hydroxymitragynine, a minor constituent of M. speciosa, was found to exhibit potent antinociceptive activity in mice.     

Two new naturally occurring optical polyacetylene compounds from Torricellia angulata var intermedia and the determination of their absolute configurations

Four compounds were isolated from Torricellia angulata var intermedia (Harms.) Hu (Torricelliaceae), followed by formation of derivatives, which gave two new polyacetylene compounds 3 and 4 with respectively a chiral carbon center whose absolute configurations were determined unambiguously by the recently developed extended Mosher's method. This is the first time to obtain natural polyacetylenes possessing a chiral hydroxyl group.     

Enantioselective Double Manipulation of Tetrahydroisoquinolines with Terminal Alkynes and Aldehydes under Copper(I) Catalysis

Tetrahydroisoquinoline alkaloids with a C1 stereogenic center are a common unit in many natural and non‐natural compounds of biological importance. Herein we describe a novel Cu^I‐catalyzed highly chemo‐ and enantioselective synthesis of chiral tetrahydroisoquinoline‐alkaloid derivatives from readily available unsubstituted tetrahydroisoquinolines, aldehydes, and terminal alkynes in the presence of the ligand (R,R)‐N‐pinap. This synthetic operation installs two substituents in the 1‐ and 2‐positions.     

Development of a novel synthetic method for ring construction using organometallic complexes and its application to the total syntheses of natural products

Organometallic complexes are useful tools in synthetic organic chemistry. We investigated a novel synthetic method for ring construction using organometallic complexes and synthesized natural products and biologically active substances using these methods. Metalacycles formed from an early transition metal and diene, enyne, and diyne are stable under the reaction conditions and they are easily converted into compounds with functional groups by the addition of various agents. We have developed a novel synthetic method of heterocycles from enyne and diene using Cp2ZrBu2. The total syntheses of (-)-dendrobine, (+/-)-mecembrane, and (+/-)-mecembrine were achieved using this procedure. To synthesize these natural products as a chiral form, a novel palladium-catalyzed asymmetric allylic amination was developed, and chiral 2-arylcyclohexenylamine derivatives were synthesized. From these compounds, the total syntheses of (-)-mesembrane, (-)-mesembrine, (+)-crinamine, (-)-haemanthidine, and (+)-pretazetine were achieved. By further development of this procedure, a chiral 2-siloxymethylcyclohexenylamine derivative could be synthesized and the novel synthesis of indole derivatives was developed from this compound. From this indole derivative, (-)-tsubifoline and (-)-strychnine were synthesized.     

激子手性方法用于多氧取代环己烯类化合物的研究

多氧取代环己烯是一类比较独特的天然产物,分子中多具有四个手性中心,立体化学多变,尽管用化学衍生物方法确定了部分化合物的绝对构型,但对已报道的化合物中仍有大部分未能确定其构型。在阐明分子相对构型的基础上,应用激子手性方法确定此类化合物的绝对构型,并利用Alchemy程序进行了分子动力学计算,对此类化合物的圆二色性规律进行了总结。     

Chiral selectivity of guanosine media in capillary electrophoresis

Gels formed by self-association of monomeric guanosine compounds join numerous other agents such as cyclodextrins, crown ethers, chiral surfactants, antibiotics, proteins, and polysaccharides for chiral separations. Guanosine gels (G-gels) are self-assembled networks of hydrogen-bonded tetrads formed by guanosine nucleotides and their derivatives. The tetrads stack upon themselves to form columnar, helical aggregates that are stabilized by π-π interactions and centrally located cations. Previous work showed the effectiveness of G-gels formed by guanosine-5'-monophophate for separation of the enantiomers of the cationic drug propranolol using capillary electrophoresis. Subsequently, it was found that not all chiral compounds could be resolved into their enantiomers, leading us to investigate in this work the structural features that appear to be correlated to enantiomerically selective interactions of chiral compounds with G-gels. For those compounds (anionic 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate and zwitterionic tryptophan) for which enantiomeric resolution was achieved, the effects of experimental conditions and G-gel composition were examined. For other compounds with no net charge (hydrobenzoin and zwitterionic amino acids and derivatives), the migration times were used as an indicator of the extent of interaction with the G-gel run buffer. It was found that the extent of interaction alone does not determine the chiral selectivity of the G-gel, indicating that the mechanism of chiral separation involves particular structural characteristics of the chiral compounds.     

Catalytic Asymmetric Tandem Reaction of Tertiary Enamides: Expeditious Synthesis of Pyrrolo[2,1‐a]isoquinoline Alkaloid Derivatives

Reported is a new and efficient strategy for rapid construction of the chiral tetrahydropyrrolo[2,1‐a]isoquinolin‐3(2H)‐one structure from unique tertiary enamide synthons. A Cu(OTf)₂/chiral Pybox complex catalyzes the intramolecular enantioselective addition of tertiary enamides to ketonic carbonyls with subsequent diastereoselective interception of the resulting acyliminium by tethered electron‐rich aryl moiety. The tandem reaction produces diverse tetrahydropyrrolo[2,1‐a]isoquinolin‐3(2H)‐one derivatives as the sole diastereoisomers in good to excellent yields with up to 98.5 % ee. The transformations of the resulting heterocycles into various hexahydropyrrolo[2,1‐a]isoquinoline derivatives were also demonstrated. The cyclization products, which are difficult to obtain by other synthetic means, are structural motifs found in many bioactive alkaloids.     

Indole-Containing Natural Products 2019–2022: Isolations,Reappraisals, Syntheses,and Biological Activities

Indole alkaloids represent a large subset of natural products, with more than 4100 known compounds. The majority of these alkaloids are biologically active, with some exhibiting excellent antitumor, antibacterial, antiviral, antifungal, and antiplasmodial activities. Consequently, the natural products of this class have attracted considerable attention as potential leads for novel therapeutics and are routinely isolated, characterized, and profiled to gauge their biological potential. However, data on indole alkaloids, their various structures, and bioactivities are complex due to their diverse sources, such as plants, fungi, bacteria, sponges, tunicates, and bryozoans; thus, isolation methods produce an incredible trove of information. The situation is exacerbated when synthetic derivatives, as well as their structures, bioactivities, and synthetic schemes, are considered. Thus, to make such data comprehensive and inform researchers about the current field’s state, this review summarizes recent reports on novel indole alkaloids. It deals with the isolation and characterization of 250 novel indole alkaloids, a reappraisal of previously reported compounds, and total syntheses of indole alkaloids. In addition, several syntheses and semi-syntheses of indole-containing derivatives and their bioactivities are reported between January 2019 and July 2022.     

苯并呋喃-2,3-二酮和丙酮的不对称Aldol反应

以脯氨酸作为催化剂催化苯并呋喃-2,3-二酮与丙酮的不对称Aldol反应, 高选择性地合成了一系列3位含有手性季碳中心的苯并呋喃酮类化合物.     

Asymmetric Hydrogenation of In Situ Generated Isochromenylium Intermediates by Copper/Ruthenium Tandem Catalysis

The first asymmetric hydrogenation of in situ generated isochromenylium derivatives is enabled by tandem catalysis with a binary system consisting of Cu(OTf)₂ and a chiral cationic ruthenium–diamine complex. A range of chiral 1H ‐isochromenes were obtained in high yields with good to excellent enantioselectivity. These chiral 1H ‐isochromenes could be easily transformed into isochromanes, which represent an important structural motif in natural products and biologically active compounds. The chiral induction was rationalized by density functional theory calculations.