Highly Functionalized Cyclopentane Derivatives by Tandem Michael Addition/Radical Cyclization/Oxygenation Reactions

Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single‐electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single‐electron transfer oxidant. Ester enolates were coupled with α‐benzylidene and α‐alkylidene β‐dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the cyclization mode from a 5‐exo pattern for terminally substituted olefin units to a 6‐endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6‐tetramethyl‐1‐piperidinoxyl, and two C?C bonds and one C?O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported.     

自由基环化制备β-内酰胺的理论研究

使用密度泛函方法在UB3LYP/6-311＋＋G(3df, 2p)水平上对自由基环化合成β-内酰胺的四种反应途径进行理论研究. 结合Marcus理论对影响反应的热力学及动力学因素进行分析, 发现氨基甲酰基自由基4-exo环合反应是理想的动力学控制过程; 酰胺自由基的4-exo环合反应与5-endo环合反应相比是动力学有利的转化过程; 单取代的酰胺烷基自由基的4-exo环合反应是一类动力学和热力学都较为不利的反应; 羰基自由基加成亚胺N＝C双键的4-exo环合反应与5-endo环合反应相比动力学不利而热力学有利.     

Alkyl radical cyclization to vinylogous carbonates for the stereoselective synthesis of unsymmetrical dioxa-cage compounds: effect of conformation on the rate of cyclization versus reduction

An efficient strategy for the stereoselective construction of unsymmetrical dioxa-cage compounds containing ether linkages employing a 6-exo-trig alkyl radical cyclization to vinylogous carbonates is developed. The radical precursors are prepared from the diols obtained from the Diels-Alder adducts via iodoetherification followed by addition of the alcohol to the ethyl propiolate. The geometrical constrains play important role in deciding the outcome of the reaction as cyclization versus simple reduction. Formation of the mono-oxa-cage compounds via a 5-exo-trig intramolecular alkyl radical cyclization to olefin is also described. The dioxa-cages could also be assembled employing a tandem oxymercuration reduction-radical cyclization to vinylogous carbonates protocol with equal efficiency and with reduced number of steps.     

Formal total synthesis of (±)-fragranol via template catalyzed 4-exo cyclization

A novel approach to the synthesis of (±)-fragranol is described that relies on a radical 4-exo cyclization. This key step is catalyzed by a cationic titanocene complex with a pending amide ligand. In this manner the radical and its acceptor are bound to the titanocene center in a two-point mode. By this interaction the 4-exo cyclization that is not supported by gem-dialkyl substitution is rendered thermodynamically and kinetically favorable. Moreover, the crucial intermediates and transition structures become highly ordered. This results in a good diastereoselectivity of cyclobutane formation. From the key-intermediate, the formal total synthesis of the natural product can be completed in a few steps.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

Diversity-Oriented Synthesis of Bioactive Azaspirocycles

A collection of novel azaspirocyclic β-arylethylamines was prepared in good yield and excellent diastereoselectivity by an expedient strategy that features condensation of a cyclic ketone with an amino allylsilane and a tandem aza-Sakurai cyclization to generate several different spirocyclic N-heterocycles. Subsequent elaboration of the spirocyclic scaffold was achieved via Pictet-Spengler cyclizations, Suzuki cross-coupling reactions, N-functionalizations, and olefin refunctionalization reactions to create a diverse library of compounds, several of which have nanomolar affinity for the sigma 1 receptor and transmembrane protein 97 (TMEM97).     

Computational Study on Chemoselective Difunctionalization of Unactivated Alkenes with Radical-mediated Remote Functional Group Migration

A computational study of the radical-mediated chemoselective difunctionalization of the tertiary alcohol substituted aliphatic alkenes is carried out employing density functional theory (DFT) and high-level coupled-cluster methods, such as coupled-cluster singles and doubles with perturbative triples [DLPNO-CCSD(T)]. Our results indicate that the cyclic vinyl radical plays an important role in the progression of the reactions. Our computations demonstrated that the chemoselective difunctionalization of unactivated alkenes with radical-mediated remote functional group migration is suitable for the 5- and 6-exo-dig cyclization, as opposite to 3- and 4-exo-dig cyclization suffering from cyclic intermediate with high energy. Our results show that the migration of nitrile group is more preferable than that of alkynyl group for the molecules including both cyano group and alkynyl group. For the 5- and 6-exo-dig cyclization, the rate-determining step is the homolysis of the C−C σ-bond in the cyclic intermediate, which results in the hydroxyl alkyl radical.     

Stereoselective synthesis of cyclic ethers using vinylogous sulfonates as radical acceptors: effect of E/Z geometry and temperature on diastereoselectivity

Treatment of the E-vinylogous sulfonates 1a-g with tris(trimethylsilyl)silane and triethylborane, in the presence of air, furnished the cyclic ethers 2/3a-g with good to excellent diastereoselectivity favoring the cis-isomer 2. This study demonstrated the level of stereocontrol in a 6-exo radical cyclization and may be attributed to the type of radical intermediate. Hence, the modest selectivity obtained for the cyclization of 1e may be a function of the acyl radical geometry (sp2) and high inversion barrier (29 kcal/mol) as compared to the alkyl (1 kcal/mol) and vinyl (2.9 kcal/mol) radicals. This is consistent with the acyl radical cyclization having an earlier transition state than the corresponding alkyl and vinyl radicals. The modest diastereoselectivity can be improved dramatically using the Z-vinylogous sulfonate (> or =34:1; R = Ph) to promote kinetic trapping of the s-trans rotamer I and III, respectively (Figure 1). The 5-exo alkyl radical cyclization reaction under nonreductive Keck-allylation conditions was also examined, in which 8 was formed in 91% overall yield. This transformation provides a convenient method for in situ homologation and should be applicable to target directed synthesis.     

Synthesis of cyclopropyl silyl ethers and their facile ring opening by photoinduced electron transfer as key step in radical/radical cationic cascade reactions

Various ring-fused cyclopropyl silyl ethers with an benzylic, olefinic or acetylenic side chain have been synthesized. Upon oxidative photoinduced electron transfer (PET) the cyclopropane ring opens and forms a reactive β-keto radical, which undergoes intramolecular cyclization. In some cases we observed only formation of ring opened non-cyclized products. With olefinic side chain 5-exo-trig mode of cyclization rather than 6-endo-trig mode of cyclization takes place whereas in case of acetylenic side chain we observed 6-endo cyclization.     

Cyclopolymerization. II. Mechanism of the free-radical polymerization of N-n-propyldimethacrylamide

The mechanism of cyclopolymerization was investigated by using N-n-propyldimethacrylamide (PDMA). Completely cyclized polymers were formed on polymerization of PDMA by a radical initiator. Moreover, those copolymers of PDMA and various monomers, such as styrene, methyl methacrylate, and vinyl acetate, obtained did not contain any detectable pendent double bonds. The kinetic investigation showed that the termination reaction proceeded between the cyclized radicals. The attempted polymerization of N-n-propyl-N-isobutyrylmethacrylamide, the monofunctional counterpart of PDMA, was failed. These results appear to confirm that cyclopolymerization of PDMA proceeds through a concerted mechanism which has been proposed for the mechanism of the cyclopolymerization of various difunctional monomers. Measurement of the ESR spectra of propagating radical has, however, revealed that the rate-determining step of the cyclopolymerization of PDMA is not intermolecular propagation but intramolecular cyclization, which indicates that the cyclization reaction proceeds in a stepwise way. This apparent contradiction was explained based upon thermodynamic considerations.     

Intramolecular addition of carbon radicals to aldehydes: synthesis of enantiopure tetrahydrofuran-3-ols

A simple and efficient substrate-controlled asymmetric synthesis of enantiopure tetrahydrofuran-3-ols by a 5-exo-trig radical cyclization is described. This cyclization occurs when a δ-carbon radical adds intramolecularly to the carbonyl group of an aldehyde. The δ-carbon radicals can be efficiently produced from the tin hydride mediated deselenenylation of 5-phenylseleno-3-oxapentanals, which were easily prepared starting from commercially available enantiopure epoxides or chlorohydrins.     

Tandem [1,5]-H shift/6π-electrocyclizations of ketenimines bearing 1,3-oxathiane units. Computational assessment of the experimental diastereoselection

N-Aryl ketenimines bearing a 1,3-oxathiane function at the ortho position of the keteniminic nitrogen atom convert into spiro[1,3-oxathiane-2,4′(3′H)quinolines] under mild thermal treatment. These cyclization processes are interpreted in terms of a two-step tandem sequence involving a [1,5]-H migration followed by a 6π-electrocyclic ring closure. Moreover, the cyclization of 1,3-oxathiane-ketenimines having two different substituents at the terminal carbon atom of the ketenimine moiety provided spiroquinolines bearing two stereocenters, the C3 and C4 atoms, with moderate diastereoselectivity. A DFT study support that the mechanism of these conversions consists of a [1,5]-H shift/6π-electrocyclization sequence, in which the [1,5]-H shift is the rate-limiting step. A quantitative kinetic analysis of the cyclization of an oxathiane-ketenimine with a prochiral ketenimine function explains the sense and degree of the experimentally observed diastereoselectivity.     

Total Syntheses of Kopsaporine,Kopsinol and Kopsiloscine A

Kopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure-unit-based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza-Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all-carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α-hydroxyketone moiety, and a bioinspired retro-Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.     

Tandem radical addition reactions to substituted indoles under atom-transfer and oxidative conditions

The dimethyl methylmalonyl radical was generated upon photolysis of dimethyl bromomethylmalonate or treatment of dimethyl methylmalonate with Mn(OAc)₃·2 H₂O. This radical was added to an exocyclic olefin appended to 1-acyl or 3-acyl indoles, with subsequent cyclization to generate 1,2- or 2,3- fused indole derivatives, respectively.     

Synthesis of Multifluoromethylated γ-Sultines by a Photoinduced Radical Addition–Polar Cyclization

Despite the significance of sultines in synthesis, medicine, and materials science, the chemistry of sultines has remained unexplored due to their inaccessibility. Herein, we demonstrate the development of a photoredox-catalyzed multifluoromethyl radical addition/SO₂ incorporation/polar cyclization cascade approach to multifluoromethylated γ-sultines. The reactions proceed by single electron transfer induced multifluoromethyl radical addition to an alkene followed by SO₂ incorporation, and single-electron reduction for polar 5-exo-tet cyclization. Key to the success of the protocol is the use of easily oxidizable multifluoroalkanesulfinates as bifunctional reagents. The reactions proceed with excellent functional-group tolerance to deliver γ-sultines in moderate to excellent yields.     

Total Synthesis of Leucosceptroids A and B

Leucosceptroids A and B are sesterterpenoids with potent antifeedant and antifungal activities. A more efficient gram‐scale total synthesis of leucosceptroid B and the first total synthesis of leucosceptroid A are presented. The key transformations include an aldol reaction between a substituted dihydrofuranone and an (S)‐citronellal‐derived aldehyde, a SmI₂‐mediated intramolecular ketyl–olefin radical cyclization, and final‐stage alcohol oxidation.     

Efficient 1,6-addition reactions of 3-substituted oxindoles: Access to isoxazole-fused 3,3′-disubstituted oxindole scaffolds and hexahydro-1h-pyrido[2,3-b]indol-2-one scaffolds

Developed herein is a new methodology for a hybrid of two pharmacophoric oxindole and isoxazole motifs to construct isoxazole-fused 3,3′-disubstituted oxindole scaffolds via an efficient 1,6-addition reaction of 3-substituted oxindoles to 3-methyl-4-nitro-5-alkenylisoxazoles, which might generate novel drug-like molecules for biological screenings. The method gives an easy access to a series of isoxazole-fused 3,3′-disubstituted oxindoles with 26 examples in high yields (up to 92% yield) and good diastereoselectivity (up to >20:1), which makes possible the synthesis of libraries under similar circumstances. Subsequently, a sequential Michael addition/amidation/reductive cyclization process was designed for accessing this hexahydro-1H-pyrido[2,3-b]indol-2-one scaffold, which is a key structural skeleton found in a large number of biologically active natural products and pharmaceutical compounds. Hexahydro-1H-pyrido[2,3-b]indol-2-one scaffold 7cg could be obtained in 42.5% overall yield after 4 steps.     

Intramolecular Vinyl Radical Cyclization Reactions of cyclohexadienes derived from sequential additions to (arene)(tricarbonyl)chromium complexes. Preliminary communication

Cyclohexa-1,3-dienes 7–10 with a 1,5,6-substitution pattern were prepared in a one-pot reaction sequence by sequential addition of MeLi and propargyl bromides to the tricarbonylchromium complex 1a . These products were subjected to radical cyclization procedures. Vinyl radical generation by Bu₃Sn addition to the propargyl group in 7–10 was followed by regio- and diastereoselective intramolecular ring closure. Two different 5-exo-trig cyclizations are possible via different vinyl radical intermediates and cyclization to one or the other of the termini of the cyclohexadiene moiety. Internal alkynes reacted to yield exclusively the cis-fused hexahydroindene products 12–14 , whereas the terminal alkyne yielded bicyclo[3.2.1]octenes 11 as sole products.     

Divergent Asymmetric Total Synthesis of (−)-Voacafricines A and B

A divergent asymmetric total synthesis of voacafricines A and B, hexacyclic monoterpene indole alkaloids, has been accomplished featuring the following key steps: a) a catalyst-controlled asymmetric Pictet–Spengler reaction of 6-methoxytryptamine with a chiral α-ketoester affording a 1,1-disubstituted tetrahydro-β-carboline in excellent yield and diastereoselectivity; b) oxidative cleavage of a 3,5-disubstituted cyclopentene furnishing a dialdehyde intermediate, which was effectively differentiated through spontaneous cyclization with the neighboring hydroxy and secondary amine functions; c) intramolecular nucleophilic addition of a tertiary amino nitrogen atom to the in situ generated oxonium species generating stereoselectively an unprecedented 8-alkyl octahydro-2H-5,8-methanofuro[2,3-b]azepin-8-ium motif bearing five contiguous stereocenters. The synthesis confirmed the absolute configuration of these two natural products.     

Carbocyclen aus Monosacchariden. III. Zur Diastereoselektivität der Bildung von Cyclopentanderivaten. Umsetzungen in der Galactosereihe

Carbocycles from monosaccharides. III. Concerning the diastereoselective formation of cyclopentane derivatives. Transformations in the galactose series. The diastereoselectivity of the intramolecular nitrone-olefine cycloaddition of 1 , 3 and 4 (Scheme 1), yielding only 2 , 5 and 6 but none of the isomers 8 , 9 and 10 is explained by assuming a kinetic control and postulating that the relative activation energies of the two relevant transition states in the cyclization of e.g. 1 can be estimated from the conformers A and B , the latter being destabilized by a synperiplanar arrangement of the nitrone function and the 2-alkoxy-group (Scheme 2). It is further postulated, that this destabilization is responsible for the formation of (2,3)-trans configurated products. Since 2 , 5 and 6 are presumably thermodynamically more stable than 8 , 9 and 10 , a case was investigated, where the cycloaddition can either give thermodynamically less stable (2,3)-trans-product such as 12 or a thermodynamically more stable (2,3)-cis-product such as 13. 12 and 13 could both be formed from the aldehyde 25 via the nitrone 11 (Schemes 3 and 5). Treatment of the galactoside 16 first with Zn in aqueous butanol (forming among other products 25 and its 2-debenzyl-oxy-derivative) and then with N-Methyldroxylamine yielded the isoxazolidines 12 (72%), 13 (2%) and 27 (7%) (Schemes 4 and 6). Similarily, the anomeric silylated galactosides 17 and 23 gave 29 (78% from 17 , 77% from 23 ) and 27 (5% and 3%). Upon desilylation, 29 gave 32 , which was converted into 12 . The structure of the isoxazolidines was unambiguously deduced from their NMR. spectra and those of their derivatives 33 and 34 . Compound 32 was further transformed into its deoxyderivative 36 . The high diastereoselectivity of the cycloaddition restricts the number of diastereomeric, pentasubstituted cyclopentanes available by this method. However, cyclization of the 2-Hydroxy-aldehyde 37 (Scheme 8) gave the kinetically less favoured isomer 40 in a higher proportion, showing the differential influence of hydrogen-bonds on the relevant activation energies. Thermolysis of 32 gave 40 (79%) and 41 (11%). The structure of 41 was deduced from its NMR. spectra and those of its derivatives 42 and 43 . Thermolysis of 29 gave, after desilylation, 41 (42%), 40 (22%) and 32 (13%) and thermolysis of 6 lead to a 25 : 75 equilibrium with 44 (combined yield 90%). These transformations illustrate means leading to additional isomers and are in agreement with the proposed explanation of the diastereoselectivity in question.