单萜吲哚生物碱的仿生合成

单萜吲哚生物碱因其骨架和官能团的丰富变化,加上它们的生物活性,多年来 一直哟引着一代又一代的化学家对其进行结构和合成研究,它们的共同生物合成前 体strictosidine是由色胺和单萜苷secologanin缩合形成的。自从secologanin可 以大量得到以后,以它为原料沿着可能的生物合成路线合成天然生物碱即仿生合成 就成为一个重要的研究领域。它对于理解和阐释生物碱的生物合成过程,为提供天 然来源极少的生物碱供药理试验及对促进有机合成化学的发展等都是有重要意义。 这方面的研究也取得了许多重要进展,成功合成了一些重要的单萜吲哚生物碱,如 育亨宾类、钩藤碱、异钩藤碱、卡得宾、利血平类似物、喜树碱等。     

Secologanin,a Biogenetic Key Compound—Synthesis and Biogenesis of the Iridoid and Secoiridoid Glycosides

The monoterpene glycoside secologanin is a key intermediate in the biosynthesis of most indole, cinchona, ipecacuanha, and pyrroloquinoline alkaloids, as well as of simple monoterpene alkaloids. More than a thousand alkaloids are formed from secologanin in vivo; this represents almost a quarter of this large group of natural products. It is also the parent compound of the secoiridoids. Many of the compounds derived from secologanin display a high degree of biological activity and are employed as pharmaceuticals, e.g., the dimeric indole alkaloid leurocristine (vincristine) which is used very successfully in the treatment of acute leukemia. A knowledge of the biosynthesis and biological reactions of secologanin provides a sound basis for the biosynthesis-orientated classification of numerous natural products and the taxonomy of many plants. Secologanin and structurally related substances can be synthesized in a few steps by stereocontrolled photochemical and thermal cycloadditions. Its biomimetic reaction with amines and amino acids yields other natural products and compounds of pharmacological interest.     

A new type of monoterpenoid indole alkaloid precursor from Alstonia rostrata

Currently, all monoterpenoid indole alkaloids (MIAs) have been derived from strictosidine, which originates from the condensation of tryptophan with secologanin in a 1:1 ratio. However, our phytochemical research on Alstonia rostrata revealed a potential new precursor for these compounds. We isolated the alstrostines A and B, and it was determined that they were derived from tryptophan and secologanin in a 1:2 ratio, which supported the presence of a new type of MIA precursor.     

Chemoselective derivatization of alkaloids in periwinkle

The terpene indole alkaloid biosynthetic pathway can utilize a secologanin substrate analog containing a handle for functionalization, and the resulting non-natural alkaloids can be chemoselectively derivatized in crude extracts of plant tissue.     

Total Syntheses of (−)-Secologanin, (−)-5-Carboxystrictosidine,and (−)-Rubenine

The first enantioselective total syntheses of (−)-secologanin ( 1 ), (−)-5-carboxystrictosidine ( 2 ), and (−)-rubenine ( 3 ) were accomplished in 10, 9, and 14 steps, respectively. The key transformation in the synthesis of 1 was a sequential anti-selective organocatalytic Michael reaction/Fukuyama reduction/spontaneous cyclization to form an optically active dihydropyran ring. In addition, the secologanin tetraacetate ( 16 ), which is a potential key intermediate for the bioinspired divergent syntheses of monoterpenoid indole alkaloids, was prepared in gram-scale in seven steps. The total syntheses of 2 and 3 , which are classified as glycosylated monoterpenoid indole alkaloids, were achieved through bioinspired transformations such as a diastereoselective Pictet–Spengler reaction, a site- and stereoselective epoxidation, and a site-selective epoxide ring-opening followed by a lactonization reaction.     

Two New Indole Alkaloids from Emmenopterys henryi

Two new indole alkaloids, 5‐oxodolichantoside ( 1 ) and deglycocadambine ( 2 ), were isolated from the twigs and leaves of Emmenopterys henryi, together with four known indole alkaloids and five known iridoids. The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses, including 1D‐ and 2D‐NMR experiments, and confirmed by single‐crystal X‐ray diffraction studies. This is the first report on the isolation of indole alkaloids from this species. The indole alkaloids were evaluated for their cytotoxic activities against five human cancer lines.     

Synthesis the Analog of Strictosidine and Vincoside from Geniposide

Strictosidine (1), a well-known monoterpene indole alkaloid glycoside^[1,2], is the precursor and building stone of nearly 2200 indole and related alkaloids and was first isolated by G. N. Smith from Rhazya^[3]. It is constructed in vivo from secologanin (2) and tryptamine (3) by plant species^[1], as well as in vitro in the presence of the enzyme strictosidine synthase, or under biomimetic conditions in aqueous solution at pH 4.5 (Scheme 1). In the coupling reaction, a new chiral center is formed with complete stereoselectivity in the presence of the enzyme, or together with vincoside (4) in a 1:1 ratio in the absence of the enzyme. Here we describe the preparation of the analog of strictosidine and vincoside from geniposide via the biomimetic conditions. 7 and 8 can be used as the starting material to synthesize other analogs of indole and related alkaloids.     

A Facile Chemoenzymatic Approach: One‐Step Syntheses of Monoterpenoid Indole Alkaloids

Facile chemoenzymatic syntheses of cytotoxic monoterpenoid indole alkaloids with novel skeletons and multiple chiral centers are described. Synthesis of these alkaloids was achieved by a simple one‐step reaction using strictosidine and 12‐aza‐strictosidine as the key intermediates. Strictosidines were prepared by coupling of secologanin with tryptamine and 7‐aza‐tryptamine, respectively, using the immobilized recombinant Rauvolfia strictosidine synthase. A detailed stereochemical analysis is presented herein. The results provide an opportunity for a chemoenzymatic approach that leads to an increased diversification of complex alkaloids with improved structures and activities.     

The effect of arsenicals on alkaloid production by cell suspension cultures of Catharanthus roseus

The effect of arsenic compounds on indole alkaloid production by cell suspension cultures of Catharanthus roseus was investigated. The analysis of indole alkaloids was achieved by using thermospray liquid chromatography-mass spectrometry (LC MS) which facilitated the rapid screening of alkaloid composition in cultures treated with different arsenicals at different times in their growth cycle. Treatment with dimethylarsinate (DMA), a non-selective herbicide, has a drastic inhibitory effect on alkaloid production although it is the least toxic arsenical to growth. Tryptamine, an early precursor in the biosynthesis of indole alkaloids, accumulates in cells treated with DMA, indicating that the initial step of condensation of tryptamine with secologanin is inhibited. Treatment with DMA during the early stationary phase of culture growth enhances the accumulation of some alkaloids, although some, such as catharanthine, are suppressed. The arsenicals arsenate and methylarsonate (MMA) have an inhibitory effect on alkaloid production when applied during the early growth stages. In contrast to MMA and DMA, arsenate has a stimulatory effect on catharanthine production when introduced to the culture during its early stationary phase. Thus the changes in the pattern of alkaloid accumulation on addition of arsenicals are dependent on the arsenic species and its concentration, as well as the time of application. This variable response indicates that each arsenical has a distinct mode of action on the secondary metabolic pathways of C. roseus.     

Redesign of a central enzyme in alkaloid biosynthesis

Plant alkaloids exhibit a diverse array of structures and pharmaceutical activities, though metabolic engineering efforts in these eukaryotic pathways have been limited. Strictosidine synthase (STR) is the first committed step in the biosynthesis of over two thousand terpene indole alkaloids. We describe a rational redesign of the STR binding pocket to selectively accommodate secologanin substrate analogs. The mutant is selective for a substrate that can be chemoselectively derivatized. Evidence that this substrate can be processed by later steps of the terpene indole alkaloid pathway is provided. The work demonstrates that the central enzyme of this alkaloid pathway can be redesigned and that the pathway can turn over the unnatural intermediate that is generated. Modulation of the substrate specificity of enzymes of this complex pathway is therefore likely to enable metabolic engineering efforts of these alkaloids.     

Indole alkaloids from Vinca major and V. minor growing in Turkey

A new indole alkaloid, 11-hydroxypolyneuridine, was isolated from Vinca major subsp. major L. and the known indole alkaloids vallesiachotamine and isovallesiachotamine from Vinca minor L. This is the first report on the alkaloids of both Vinca species growing in Turkey; vallesiachotamine and isovallesiachotamine were isolated from a Vinca species for the first time. V. minor may be considered as a new source for these two alkaloids due to their occurrence in high amount in the aerial parts of the plant. The alkaloid extracts of the two Vinca species were found to have high lipid peroxidation inhibitory and DPPH radical scavenging activities. Anticholinesterase activity of the extracts was also very strong.     

Kopsifolines A–F: a New Structural Class of Monoterpenoid Indole Alkaloids from Kopsia

Six new indole alkaloids, named kopsifolines A–F ( 1 – 6 ), with an unprecedented hexacyclic carbon skeleton, constituting a new structural group of monoterpenoid indole alkaloids, were obtained from the leaf extract of a Malayan Kopsia species, and their structures were established by spectroscopic analysis.     

Total Syntheses of (−)-Strictosidine and Related Indole Alkaloid Glycosides

A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler reaction with α-cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (−)-strictosidine, which is an important intermediate in biosynthesis. This two-step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet–Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (−)-strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (−)-strictosamide, (−)-neonaucleoside A, (−)-cymoside, and (−)-3α-dihydrocadambine.     

Seven New Monoterpenoid Indole Alkaloids from Gelsemium elegans

Seven new indole alkaloids were isolated from the roots of Gelsemium elegans Benth. and their structures were determined by spectroscopic analysis and chemical transformation from known alkaloids. Kounaminal ( 1 ) is a new koumine‐type alkaloid that contains an unusual aminal moiety. Humantenoxenine ( 2 ) and 15‐hydroxyhumantenoxenine ( 3 ) are humantenine‐type alkaloids that contain a novel β‐amino‐α,β‐unsaturated ketone residue. The other four novel alkaloids are two gelsedilam‐related and two gelsenicine‐related alkaloids.     

Identification of indole alkaloids in Nauclea officinalis using high-performance liquid chromatography coupled with ion trap and time-of-flight mass spectrometry

Indole alkaloids from Nauclea officinalis (Pierra ex Pitard) Merr are prospective agents for inflammation- related diseases. To speed up the process of discovering such bioactive compounds from natural origins, a mass spectrometry-based method was developed to screen N. officinalis for the presence of indole alkaloids. First, representative alkaloids were purified from herbs and analyzed using an ion trap (IT) mass spectrometer. Multi-stage mass spectra (MS(n))were utilized to establish the characteristic fragmentation pathways of indole alkaloids. It was shown that their fragmentation behaviors were correlated with the degree of unsaturation on ring-D of such alkaloids: if there is a double bond between C-3 and C-14, no fragments of ring cleavage are observed; otherwise, a fragment ion after reverse Diels-Alder cleavage of ring-D is observed as the base peak in their tandem mass spectrometry data. Then, herbal extracts of N. officinalis were analyzed using a combination of high- performance liquid chromatography (HPLC)/IT and HPLC/time-of-flight (ToF) systems. The structures of suspected alkaloids were deduced based on the accurate mass information from ToF and MS(n) from IT. Finally, a total of 10 indole and one indolizidine alkaloids were identified or tentatively characterized in extracts of N. officinalis. This work has demonstrated that the combination of MS(n) and ToF-MS can be used for rapid identification of monoterpenoid indole alkaloids in N. officinalis.     

Comparative study of fourteen alkaloids from Uncaria rhynchophylla hooks and leaves using HPLC-diode array detection-atmospheric pressure chemical ionization/MS method

The purpose of the study is to compare alkaloid profile of Uncaria rhynchophylla hooks and leaves. Ten oxindole alkaloids and four glycosidic indole alkaloids were identified using HPLC-diode array detection (DAD) or LC-atmospheric pressure chemical ionization (APCI)-MS method, and a HPLC-UV method for simultaneous quantification of major alkaloids was validated. The hooks are characterized by high levels of four oxindole alkaloids rhynchophylline (R), isorhynchophylline (IR), corynoxeine (C) and isocorynoxeine (IC), while the leaves contained high level of two glycosidic indole alkaloids vincoside lactam (VL) and strictosidine (S). The presented methods have proven its usefulness in chemical characterization of U. rhynchophylla hooks and leaves.     

Total Syntheses of (−)‐Strictosidine and Related Indole Alkaloid Glycosides

A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler reaction with α‐cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (?)‐strictosidine, which is an important intermediate in biosynthesis. This two‐step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet–Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (?)‐strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (?)‐strictosamide, (?)‐neonaucleoside A, (?)‐cymoside, and (?)‐3α‐dihydrocadambine.     

Angustilodine,an Unusual Pentacyclic Indole Alkaloid from Alstonia

Two new indole alkaloids, angustilodine ( 1 ), with an unprecedented pentacyclic carbon skeleton, and angustilocine ( 2 ), belonging to the seco‐angustilobine‐B group of alkaloids, were obtained from the leaf extract of the Malayan species Alstonia angustiloba, and their structures were established by spectroscopic analysis.     

Novel neuronal nitric oxide synthase (nNOS) selective inhibitor, aplysinopsin-type indole alkaloid, from marine sponge Hyrtios erecta

Two novel aplysinopsin-type indole alkaloids, 1 and 2, and three known indole alkaloids were isolated from the marine sponge Hyrtios erecta. These compounds exhibited selective inhibitory activity against the neuronal isozyme of nitric oxide synthase (nNOS). Furthermore, new quinolone 7 was also isolated from the same marine sponge. The chemical structures of these new compounds were elucidated on the basis of spectroscopic analysis.     

Synthesis of Pyrrolophenanthridine Alkaloids Based on C(sp3)H and C(sp2)H Functionalization Reactions

Assoanine, pratosine, hippadine, and dehydroanhydrolycorine belong to the pyrrolophenanthridine family of alkaloids, which are isolated from plants of the Amaryllidaceae species. Structurally, these alkaloids are characterized by a tetracyclic skeleton that contains a biaryl moiety and an indole core, and compounds belonging to this class have received considerable interest from researchers in a number of fields because of their biological properties and the challenges associated with their synthesis. Herein, a strategy for the total synthesis of these alkaloids by using C? H activation chemistry is described. The tetracyclic skeleton was constructed in a stepwise manner by C(sp³)? H functionalization followed by a Catellani reaction, including C(sp²)? H functionalization. A one‐pot reaction involving both C(sp³)? H and C(sp²)? H functionalization was also attempted. This newly developed strategy is suitable for the facile preparation of various analogues because it uses simple starting materials and does not require protecting groups.