A one-pot three-component reaction for the preparation of highly functionalized tryptamines

We have developed a general one-pot method to provide highly functionalized tryptamine derivatives, via a Fischer indole type pathway. In this article, we demonstrate optimal conditions for a one-pot indole synthesis, allowing for the synthesis of a broad scope of 2-methyl tryptamine derivatives and a precursor for the synthesis of the core structure of some akuammiline alkaloids. Additionally, further modification of the indole products is described.     

Synthetic entries to 6-fluoro-7-substituted indole derivatives

Three practical synthetic entries of functionalized 6-fluoro-7-substituted indole derivatives were developed in connection with the preparation of 7-fluoro-8-substituted-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid derivatives 11 . The first route, which permits group modification about position 8 of the pyranoindole skeleton, employs 2-bromo-3-fluoroaniline ( 18 ) as a key intermediate, the preparation of which was achieved by either a novel ortho metalation of 15 or via the intermediacy of 22 . The second route utilizes 32 to append a terminally functionalized three carbon side chain onto the indole template and in addition leads to 43 from 40 . The third route to the 7-fluoro-8-substituted-pyranoindole skeleton complements route two in that the synthetic pathway exploits 32 in a nucleophilic fashion to construct a terminally functionalized two carbon appendage onto the indole nucleus.     

Targeted quantitative analysis of monoterpenoid indole alkaloids in Alstonia scholaris by ultra-high-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry

Monoterpene indole alkaloids exhibit structural diversity in herbal resources and have been developed as promising drugs owing to their significant biological activities. Confidential identification and quantification of monoterpene indole alkaloids is the key to quality control of target plants in industrial production but has rarely been reported. In this study, quantitative performance of three data acquisition modes of ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry including full scan, auto-MS² and target-MS², was evaluated and compared for specificity, sensitivity, linearity, precision, accuracy, and matrix effect using five monoterpene indole alkaloids (scholaricine, 19-epi-scholaricine, vallesamine, picrinine, and picralinal). Method validations indicated that target-MS² mode showed predominant performance for simultaneous annotation and quantification of analytes, and was then applied to determine monoterpene indole alkaloids in Alstonia scholaris (leaves, barks) after extraction procedures optimization using Box-Behnken design of response surface methodology. The variations of A. scholaris monoterpene indole alkaloids in different plant parts, harvest periods, and post-handling processes, were subsequently investigated. The results indicated that target-MS² mode could improve the quantitative capability of ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry for structure-complex monoterpene indole alkaloids in herbal matrices. Alstonia scholaris, monoterpene indole alkaloids, quadrupole time of flight mass spectrometry, qualitative and quantitative analysis, ultra-high-performance liquid chromatography     

Synthesis of pyridino[3′,2′:4,5]pyrrolo[3,2-g]pyrrolo[3,4-e]indolizin-1,3-dione and pyrrolo[3,2-c]pyrazole skeletons

A three step synthesis of an isogranulatimide analogue, in which the imidazole moiety is replaced by a pyrrole unit and the indole heterocycle is replaced by a 7-azaindole moiety is described. Moreover, a novel synthetic pathway to the pyrrolo[3,2-c]pyrazole skeleton is reported.     

高效液相色谱和质谱法对产酸克雷伯氏菌SG-11生物合成吲哚-3-乙酸代谢途径的研究

产酸克雷伯氏菌 (Klebsiellaoxytoca)SG 1 1是从水稻根面分离的植物根际促生细菌 ,具有生物固氮能力。利用HPLC和GC MS对该菌的代谢产物进行了定性定量分析 ,结果表明该菌能产生较高浓度的吲哚 3 乙酸(IAA) ;对其代谢途径的研究结果证明 ,该菌以吲哚 3 丙酮酸代谢途径合成IAA。     

A new entry to polycyclic indole skeletons via palladium-catalyzed intramolecular heteroannulation

[reaction: see text] A one-step method was developed for elaboration of a variety of polycyclic indole skeletons via a novel palladium-catalyzed intramolecular indolization of 2-chloroanilines bearing tethered acetylenes. This novel intramolecular indolization method unveils an unusual syn amidopalladation pathway of a tethered alkyne.     

Engaging thieno[2,3-b]indole-2,3-dione for the efficient synthesis of spiro[indoline-3,4′-thiopyrano[2,3-b]indole] by reaction with N-substituted isatilidenes

A simple and efficient method, proceeding through a new mechanistic pathway, for the synthesis of spiro[indoline-3,4-thiopyrano[2.3-b]indole derivatives have been developed by exploiting the reaction of thieno[2,3-b]indole-2,3-dione with N-substituted isatilidenes. The compounds synthesized have been screened for antibacterial activity. The generality of the reaction and mechanistic rationale are presented.     

Domino carbocationic rearrangement of aryl-2-(1-N-methyl/benzyl-3-indolyl)cyclopropyl ketones: a serendipitous route to 1H-cyclopenta[c]carbazole framework

Aryl-2-(N-methyl/benzyl-3-indolyl)cyclopropyl ketones 2a-m are shown to undergo a novel unexpected domino carbocationic rearrangement in the presence of SnCl(4)/CH(3)NO(2) yielding 2-aroyl-3-aryl-1H-cyclopenta[c]carbazoles 3a-m in good yields. The possible mechanistic pathway for this interesting transformation involves a series of cascade events, (a) electrophilic ring opening of cyclopropyl ketone, (b) intermolecular enol capture of the resulting zwitterionic intermediate, (c) electrophilic dimerization of indole moieties to give tetrahydrocarbazole intermediate and its subsequent aromatization by elimination of an indole moiety and dehydrogenation, and (d) intramolecular aldol condensation of the side chain to give a cyclopentene ring. The overall transformation involves formation of three carbon-carbon bonds along with a fused benzene and a substituted cyclopentene ring in one-pot operation from simple indole precursors.     

Recent Advances on Direct Functionalization of Indoles in Aqueous Media

Indoles and their derivatives have dominated a significant proportion of nitrogen-containing heterocyclic compounds and play an essential role in synthetic and medicinal chemistry, pesticides, and advanced materials. Compared with conventional synthetic strategies, direct functionalization of indoles provides straightforward access to construct diverse indole scaffolds. As we enter an era emphasizing green and sustainable chemistry, utilizing environment-friendly solvents represented by water demonstrates great potential in synthesizing valuable indole derivatives. This review aims to depict the critical aspects of aqueous-mediated indoles functionalization over the past decade and discusses the future challenges and prospects in this fast-growing field. For the convenience of readers, this review is classified into three parts according to the bonding modes (C−C, C−N, and C−S bonds), which focus on the diversity of indole derivatives, the prominent role of water in the chemical process, and the types of catalyst systems and mechanisms. We hope this review can promote the sustainable development of the direct functionalization of indoles and their derivatives and the discovery of novel and practical organic methods in aqueous phase.     

Divergent Coupling of Benzocyclobutenones with Indoles via C−H and C−C Activations

Highly selective divergent coupling reactions of benzocyclobutenones and indoles, in which the chemoselectivity is controlled by catalysts, are reported herein. The substrates undergo C2(indole)–C8(benzocyclobutenone) coupling to produce benzylated indoles and benzo[b]carbazoles in the Ni- and Ru-catalyzed reactions. A completely different selectivity pattern C2(indole)–C2(benzocyclobutenone) coupling to form arylated indoles is observed in the Rh-catalyzed reaction. Preliminary mechanistic studies suggest C−H and C−C activations in the reaction pathway. Synthetic utility of this protocol is demonstrated by the selective synthesis of three different types of carbazoles from the representative products.     

基于龙胆苦苷的二吲哚甲烷类拟单萜吲哚生物碱类似物合成及其抗肿瘤、逆转紫杉醇耐药活性研究

以环烯醚萜类化合物龙胆苦苷为合成模块,利用拟单萜吲哚生物碱的仿生合成途径和组合化学的研究思路,与色胺类衍生物(吲哚结构的活性单元片段)通过缩合反应,首次合成了23个二吲哚甲烷类拟单萜吲哚生物碱类似物。利用核磁共振波谱(NMR)和高分辨质谱(HRMS)等谱学手段对合成化合物的结构进行了表征,并初步评价了其抗肿瘤活性和逆转耐药活性。活性结果表明,化合物4i脱掉糖基保护基后的化合物5i对3种肿瘤细胞系(TE-1,CAL-62和FaDu)的抑制作用强于阳性对照盐酸阿霉素(Dox)。通过与紫杉醇的联合用药,发现部分化合物如4m、4n、4o、4r等能够有效降低人肺癌细胞紫杉醇耐药株A549/Taxol对紫杉醇的耐药性,具有良好的逆转耐药潜力。     

A concise asymmetric total synthesis of aspidophytine

An expedient asymmetric total synthesis of aspidophytine is reported. A highly convergent strategy involving the sequential annulation of vinyl iodide 5 with indole 6 exploits varying modes of indole reactivity to provide aspidophytine in 23% over six steps from 5.     

A scalable Nenitzescu synthesis of 2‐methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile

2‐Methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile is a key intermediate in the synthesis of selective androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis of the title compound starting from 4‐nitro‐3‐(trifluoromethyl)phenol and tert‐butyl acetoacetate was developed, including a telescoped procedure for synthesis (without isolation) and Nenitzescu reaction of 2‐trifluoromethyl‐1,4‐benzoquinone. Conversion of the known Nenitzescu indole product to a novel triflate intermediate followed by palladium‐catalyzed cyanation afforded a penultimate carbonitrile. Removal of the C‐3 tert‐butyl ester group on the indole through a decarboxylative pathway completed the synthesis of the title compound in six steps (27% overall yield) from 4‐nitro‐3‐(trifluoromethyl)phenol (five steps, 37% overall yield from tert‐butyl acetoacetate). J. Heterocyclic Chem., (2011).     

Simultaneous determination of amino-alpha-carbolines and amino-gamma-carbolines in cigarette smoke condensate by high-performance liquid chromatography

A method for the simultaneous detection of amino-alpha-carbolines (2-amino-alpha-carboline and 2-amino-3-methyl-alpha-carboline) and amino-gamma-carbolines (3-amino-1,4-dimethyl-5H-pyrido [4,3-b]indole and 3-amino-1-methyl-5H-pyrido [4,3-b]indole) by high-performance liquid chromatography has been developed. It consists of a three-step purification using three different columns with fluorometric detection. With this method, we have demonstrated that both amino-alpha-carbolines and amino-gamma-carbolines are present in cigarette smoke condensate. The method may be useful for detecting these carcinogens in various materials.     

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.     

NiWS/γ-Al2O3催化剂上吲哚加氢脱氮反应:H2S和喹啉的影响

在连续固定床微反装置上考察了吲哚（IND）和1,2-二氢吲哚（HIN）在NiWS/γ-Al₂O₃催化剂上加氢脱氮（HDN）的反应以及 H₂S和喹啉（Q）对其加氢脱氮反应的影响。结果表明,碱性含氮化合物HIN较吲哚对其自身的加氢脱氮反应抑制作用更为明显。H₂S能够促进HIN的C（sp³）－N断裂,但抑制了邻乙基苯胺（OEA）的 C（sp²）－N断裂;同时吲哚加氢反应途径也受到了抑制。喹啉的添加严重降低了吲哚加氢脱氮反应的转化率和脱氮率;喹啉对吲哚加氢反应和C－N键断裂反应均产生明显的抑制作用。喹啉的抑制作用主要源于喹啉及其中间产物1,2,3,4-四氢喹啉（THQ1）和5,6,7,8 -四氢喹啉（THQ5）与吲哚及其中间产物的竞争吸附。     

An Isomeric Swapping of a Phenylhydrazone Derivative Discovered by Structural Study Revealing a Branched Pathway of Fischer Indole Synthesis

In an attempt to synthesize an indole derivative,methyl 5-nitro-1H-indole-2-carb-oxylate,an isomeric change of methyl 2-[2-(4-nitrophenyl) hydrazono] propanoate from E to Z geometry was observed.The two isomers were determined by single-crystal X-ray diffraction analysis.The Z isomer is stabilized in a six-membered ring conformation constructed by an intramolecular hydrogen bond.This isomeric change added a branched pathway in the mechanism of Fischer indole synthesis.     

A Straightforward Approach to Tetrahydroindolo[3,2‐b]carbazoles and 1‐Indolyltetrahydrocarbazoles through [3+3] Cyclodimerization of Indole‐Derived Cyclopropanes

A rapid new approach to produce biologically relevant bisindoles, namely indolyltetrahydrocarbazoles and indolo[3,2‐b]carbazoles, has been developed, based on the Ga(OTf)₃‐catalyzed [3+3] cyclodimerization of indole‐derived donor–acceptor cyclopropanes. Chemoselectivity of the process depends on the location of the three‐membered ring at the indole core.     

Effect of dimerization on vibrational spectra of eumelanin precursors

We have synthesized a compound ideally suited to the study of structure-function relationships in eumelanin synthesis. N-methyl-5-hydroxy-6-methoxy-indole (MHMI) has key functional groups strategically placed on the indole framework to hinder binding in the 2, 5, 6 and 7 positions. Thus, the dimer bound exclusively in the 4-4' positions was isolated and characterized. In order to study the difference in vibrational structure between the MHMI monomer and dimer, Raman spectra were acquired of both compounds, as well as indole, indole-2-carboxylic acid and 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Peaks were assigned to particular vibrational modes using B3LYP density functional theory calculations, and experimental and theoretical spectra displayed good agreement. Addition of functional groups to either benzene or pyrrole rings in the indole framework impacted vibrational spectra attributed to vibrations in either ring, and in some cases, peaks appearing unchanged between two compounds corresponded to different contributing vibrations. Dimerization resulted in an expected increase in the number of vibrational modes, but not a significant increase in the number of apparent peaks, as several modes frequently contributed to an individual observed peak. Comparison of spectral features of the monomer and dimer provides insight into eumelanin photochemistry, but final conclusions depend on the planarity of oligomeric structure in vivo.     

Rapid identification of enzyme variants for reengineered alkaloid biosynthesis in periwinkle

Monoterpene indole alkaloids from Catharanthus roseus (Madagascar periwinkle), such as the anticancer agents vinblastine and vincristine, have important pharmacological activities. Metabolic engineering of alkaloid biosynthesis can provide an efficient and environmentally friendly route to analogs of these synthetically challenging and pharmaceutically valuable natural products. However, the narrow substrate scope of strictosidine synthase, the enzyme at the entry point of the pathway, limits a pathway engineering approach. We demonstrate that with a different expression system and screening method it is possible to rapidly identify strictosidine synthase variants that accept tryptamine analogs not turned over by the wild-type enzyme. The variants are used in stereoselective synthesis of beta-carboline analogs and are assessed for biosynthetic competence within the terpene indole alkaloid pathway. These results present an opportunity to explore metabolic engineering of "unnatural" product production in the plant periwinkle.