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![Structures and syntheses of prenylated molecules
a, Enzyme-catalysed prenylation for the synthesis of diverse bioactive natural products. b, Representative prenylated indoline alkaloids with a hexahydropyrrolo[2,3-b]indole skeleton. c, Catalytic asymmetric syntheses of prenylated pyrroloindoline natural products.](publication/326857159/figure/fig1/AS:941139733532694@1601396606396/Structures-and-syntheses-of-prenylated-molecules-a-Enzyme-catalysed-prenylation-for-the.png)
Structures and syntheses of prenylated molecules a, Enzyme-catalysed prenylation for the synthesis of diverse bioactive natural products. b, Representative prenylated indoline alkaloids with a hexahydropyrrolo[2,3-b]indole skeleton. c, Catalytic asymmetric syntheses of prenylated pyrroloindoline natural products.
Source publication
Prenylation is a ubiquitous process common to almost all living organisms, and a key transformation in organic synthesis. Dearomative prenylation reactions of tryptophan derivatives lead to various prenylated indoline alkaloids with diverse biological activities. However, enantioselective dearomative prenylations without a pre-installed stereogenic...
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Citations
... Obviously, it is a formidable task bearing several key challenges to the design of synthetic strategies to access the prenylated and reverseprenylated indolines: 1) unsymmetrical reaction sites of the dimethyl allyl groups often lead to a prominent regioselectivity problem with competitive prenylation (3,3-dimethylallyl) or reverse-prenylation (1,1dimethylallyl); 2) the synthesis of C3-reverse-prenylated indolines is a more difficult process with relatively low reactivity, since two vicinal all-carbon quaternary centers present substantial steric hindrance; 3) to control the diastereoselectivity at the C3 and C2 sites of indoline also faces significant obstacles. In principle, catalytic dearomative prenylation of readily available indoles via allylic substituent reactions has been recognized as one of the most straightforward methods to access the dimethylallyl-related indolines in a single step (Fig. 1c) [30][31][32][33][34][35] . However, these corresponding transformations usually depend on the use of electron-rich indoles via an intramolecular dearomative process, and the precious metals (Ir and Pd) are often necessary. ...
Prenylated and reverse-prenylated indolines are privileged scaffolds in numerous naturally occurring indole alkaloids with a broad spectrum of important biological properties. Development of straightforward and stereoselective methods to enable the synthesis of structurally diverse prenylated and reverse-prenylated indoline derivatives is highly desirable and challenging. In this context, the most direct approaches to achieve this goal generally rely on transition-metal-catalyzed dearomative allylic alkylation of electron-rich indoles. However, the electron-deficient indoles are much less explored, probably due to their diminished nucleophilicity. Herein, a photoredox-catalyzed tandem Giese radical addition/Ireland–Claisen rearrangement is disclosed. Diastereoselective dearomative prenylation and reverse-prenylation of electron-deficient indoles proceed smoothly under mild conditions. An array of tertiary α-silylamines as radical precursors is readily incorporated in 2,3-disubstituted indolines with high functional compatibility and excellent diastereoselectivity (>20:1 d.r.). The corresponding transformations of the secondary α-silylamines provide the biologically important lactam-fused indolines in one-pot synthesis. Subsequently, a plausible photoredox pathway is proposed based on control experiments. The preliminary bioactivity study reveals a potential anticancer property of these structurally appealing indolines.
... Among the myriad examples of stereoselective catalytic C-C bond-forming reactions, asymmetric allylic alkylation (AAA) is a particularly powerful method for the preparation of highly enantioenriched building blocks and natural products [1][2][3][4][5][6][7] . Despite the many targeted substrates, which include cyclic [8][9][10][11] , heterocyclic [12][13][14][15][16][17][18][19] and acyclic nucleophiles 20,21 , butenolides have attracted particular attention, as they constitute a common structural feature in many biologically active compounds [22][23][24][25][26][27][28][29] . Currently, however, the AAAs of such scaffolds are restricted to C-C formation at the C3 position [30][31][32][33] , giving a structural pattern that is relevant to a more limited number of natural products. ...
Metal-catalysed asymmetric allylic alkylation reactions have played a pivotal role in the construction of chiral compounds. When applied to the synthesis of butenolides, a common moiety present in many biologically active compounds, this reaction has always provided the C3-allylated products and only traces of the C5-allylated analogues. Here we report a Pd-catalysed C5-selective method that provides direct and highly enantioselective (up to >99% e.e.) access to a wide range of substituted butenolides using 2-substituted allyl acetates as the allylic partner. Mechanistic studies supported by density functional theory calculations have shown that the C5-selectivity observed is the result of a steric constraint induced by the substituent on the central carbon of the π–allyl complex forcing the reactive dienolate intermediate to expose its C5-reactive centre. The practicality, scalability and synthetic utility of the process was demonstrated through the total synthesis of three O-terpenoidal natural products: excavacoumarin B, D and E. The construction of C–C bonds with regio- and stereoselectivity is paramount in natural product synthesis and metal-catalysed asymmetric allylic alkylation reactions have played a key role, with high C3 selectivity demonstrated in butenolide synthesis. Now, a palladium-catalysed C5-selective method is reported, providing direct and highly enantioselective access to a range of diversely substituted butenolides.
... In 2018, an elegant enantioselective dearomative C3 prenylation of 3-substituted indoles was developed by You's group ( Figure 7C) [103]. With [Pd(prenyl)Cl] 2 and chiral phosphoramidite ligand allylphos as catalysts, 6-bromo Boc-tryptamine reacted with prenyl carbonate well to afford product 27a in 94% ee, which was a precursor of alkaloid (−)-flustramine B. Notably, L-tryptophan-based peptides were compatible with this process as well, followed by Et 2 NHpromoted lactamization/lactonization to form exo-type indoline diketopiperazines (e.g., mollenine A, 27b) with high diastereoselectivities. ...
Prenylated and reverse-prenylated aromatics are present in numerous natural terpenoids with a broad spectrum of pharmaceutical activity. In their biosynthesis, prenyl and reverse-prenyl motifs are selectively introduced via enzyme catalysis with dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) as the precursors. In recent years, considerable efforts have been devoted to emulating the biological process with chemical catalysis via the intermediacy of π-prenyl species. A set of elegant strategies including the Friedel–Crafts reaction, cross-coupling, C–H activation, Tsuji–Trost-like reactions, addition reactions, and radical coupling have been demonstrated. This review aims to highlight these advances and discuss the regioselectivity issues, which will definitely further expand their applications and promote the development of this field.
... Slight decrease in the yield was observed when the loading of PC was reduced to 2 mol% (entry 15). Moreover, solvents were also examined, and DMF was found to be the best comparing with solvents such as DMSO, DMA, and CH 3 CN (entries [16][17][18]. Finally, no desired product was obtained when the bromide or chloride analog of 1a was employed and most of the starting material was recovered (entries 19 and 20). ...
... In addition, N-protected aniline linkers with different protecting groups (such as Boc, Ac, Cbz and CO 2 Ph) were also tolerated (12)(13)(14)(15). Moreover, several substitution patterns on the aniline ring were allowed with the reaction to give desired products in satisfied yields (16)(17)(18)(19)(20)(21). Finally, spiroindolines could be delivered with quinolinyl substrates with the aniline linkers (22 and 23). ...
... Recently, in 2018, You group 108 have developed a palladium-catalyzed asymmetric dearomative prenylation of tryptamine derivatives 9i to afford 24h in 95% ee (Scheme 34). With 24h in hand, concise total syntheses of ()-flustramine B (1g), ()-debromoflustramine B (1g), ()-pseudophrynaminol (1o) were completed in few steps (Schemes 34). ...
... In comparisonw ith racemic resolution [4] and chiral induction [5] methods, asymmetric catalytic synthesis might be the most direct and efficient approach. [6] To date, homogeneousa symmetric catalysis based on chiral molecular complexes, [7] chiral organocatalysts, [8] anda rtificial metalloenzymes [9] have been the main subjects in this field, although some solid-supported heterogeneous asymmetric catalysts have been reported recently. [10] Heterogeneous asymmetric catalysis, however,w ould meet the multifaceted requirementso fb eing low cost, resource saving, and environmentally friendly,a nd these prominenta dvantages make heterogeneousa symmetric catalysis ap romising approach forachieving chiralcompounds in agreen way. ...
Owing to their permanent porosity, highly ordered and extended structure, good chemical stability, and tunability, covalent organic frameworks (COFs) have emerged as a new type of organic materials that can offer various applications in different fields. Benefiting from the huge database of organic reactions, the required functionality of COFs can be readily achieved by modification of the corresponding organic functional groups on either polymerizable monomers or established COF frameworks. This striking feature allows homochiral covalent organic frameworks (HCCOFs) to be reasonably designed and synthesized, as well as their use as a unique platform to fabricate asymmetric catalysts. This contribution provides an overview of new progress in HCCOF‐based asymmetric catalysis, including design, synthesis, and their application in asymmetric organic synthesis. Moreover, major challenges and developing trends in this field are also discussed. It is anticipated that this review article will provide some new insights into HCCOFs for heterogeneous asymmetric catalysis and help to encourage further contributions in this young but promising field.
... Over the past several decades, dearomative annulation of indoles has served as one of the most popular avenues for preparing polycyclic indoline skelotons [12][13][14][15] . Some powerful protocols like cyclopropanation 16,17 , 1,3-dipolar cycloadditions 18 , [2+ 2] photo-cycloadditions 19 , Diels-Alder [20][21][22] , and cascade electrophilic addition/annulation reactions [23][24][25][26] have been well established. In these cases, most of the strategies took advantage of the C2-C3 π bond or the inherent strong nucleophilicity of C3 position, and had the advantage of rapid construction for highly functionalized indoline frameworks in one step. ...
The dearomatization of arenes represents a powerful synthetic methodology to provide three-dimensional chemicals of high added value. Here we report a general and practical protocol for regioselective dearomative annulation of indole and benzofuran derivatives in an electrochemical way. Under undivided electrolytic conditions, a series of highly functionalized five to eight-membered heterocycle-2,3-fused indolines and dihydrobenzofurans, which are typically unattainable under thermal conditions, can be successfully accessed in high yield with excellent regio- and stereo-selectivity. This transformation can also tolerate a wide range of functional groups and achieve good efficiency in large-scale synthesis under oxidant-free conditions. In addition, cyclic voltammetry, electron paramagnetic resonance (EPR) and kinetic studies indicate that the dehydrogenative dearomatization annulations arise from the anodic oxidation of indole into indole radical cation, and this process is the rate-determining step.
... Recently in Nature Catalysis, You and coworkers reported an elegant catalytic system to address the aforementioned challenge. 8 This system consists of a catalytic amount of palladium precursor [Pd(prenyl)Cl] 2 and a newly developed chiral phosphoramidite ligand (Allylphos) together with a base Cs 2 CO 3 . Using unprotected indoles and methyl prenyl carbonate as the reaction partners, the desired prenylation reaction proceeded smoothly with the catalytic system, affording the 2-prenylated indolines in good yields with high enantioselectivities (Scheme 1B). ...
Recently in Nature Catalysis, You and co-workers reported a novel artificial catalyst system for asymmetric dearomative prenylation of indole derivatives. Compared with known enzymatic dearomative prenylation processes, this system features impressive generalities in substrate scope and functional-group tolerance.
Dearomatization has emerged as a powerful tool for rapid construction of 3D molecular architectures from simple, abundant, and planar (hetero)arenes.
