A concise asymmetric route to the bridged bicyclic tropane alkaloid ferruginine using enyne ring-closing metathesis

[reaction: see text] Enyne metathesis has been used to prepare bridged azabicycles and applied in a short asymmetric synthesis of the tropane ferruginine. A Grubbs first generation catalyst proved to be superior to the second generation catalyst in the enyne metathesis reaction.     

Pd-catalyzed arylation/ring-closing metathesis approach to azabicycles

Palladium-catalyzed arylation followed by Grignard addition to imines and ring-closing metathesis, using Grubbs’ catalysts, provides a route to six-, seven-, and eight-membered azabicycles.     

Asymmetric Reductive and Alkynylative Heck Bicyclization of Enynes to Access Conformationally Restricted Aza[3.1.0]bicycles

Conformationally restricted azabicycles are becoming increasingly important in medicinal research. Asymmetric Heck bicyclization of enynes proceeds to give medicinally useful aza[3.1.0] and aza[4.1.0] bicycles with excellent enantioselectivity. The key organopalladium species after bicyclization can be trapped by silanes and terminal alkynes.     

Diastereoselective synthesis of cis-3- and 3,5-alkylpyrrolizidines

Cis-3 and 3,5-substituted pyrrolizidines can be prepared from β-enaminolactones. Substituted pyrrolidinoketones lead to these compounds by an amino reductive annelation with a low diastereomeric excess, but a best access to these azabicycles consists in preparing cis-2,5-disubstituted pyrrolidines which are then transformed into the expected heterocycles.     

Reactions of nitrenes with strained olefins. Nitrene additions to the bicyclo[2.2.1]hept-2-ene system

The synthesis of two examples of the 3-azatricyclo[3.2.1.0^2,4] octane ring system is described. The product azabicycles are obtained in low yields and are stable in refluxing chlorobenzene. The lead tetraacetate oxidation of 3-amino-2-methvl-4-quinazoIone leads to high yields of the deaminated compound.     

Chlorosulfonyl isocyanate reactions with N-(alkoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes. Regiospecific two-atom insertion pathways

Addition of the uniparticulate electrophile chlorosulfonyl isocyanate to the nitrogen atom of N-(alkoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 1 is followed by ring cleavage and recombination. The parent 4-methyl, 5-methyl, 5-bromo, and 5-phenyl azabicycles 1a-f afforded novel 2,4-diaza-3-oxo-bicyclo[4.2.0]oct-7-enes 10a-f. The 3-endo-phenyl azabicycle 1g rearranged to a 6-styryl-1,3-diaza-2-oxo-cyclohex-4-ene 12.     

Rhodium(III) catalyzed synthesis of isoquinolone fused azabicycles through C–H activation of N-pivaloyloxy benzamides

Herein we describe an efficient one pot strategy toward highly functionalized isoquinolone fused azabicycles having great synthetic potential via C–H activation of N-pivaloyloxy benzamides under very mild conditions. The reaction is accomplished at room temperature within one hour in good to excellent yields and is found to be compatible with a range of diazabicyclic olefins and benzamides. The present strategy offers an easy route for the synthesis of biologically relevant compounds which possess multiple points for divergent synthesis. N–N bond cleavage of synthesized compounds may enable their significant role as effective precursors for the preparation of diaminocyclopentane fused isoquinolones.     

Generation of Complex Azabicycles and Carbobicycles from Two Simple Compounds in a Single Operation through a Metal‐Free Six‐Step Domino Reaction

Aza‐ and carbobicyclic compounds possess favorable pharmaceutical properties, but they are difficult to access. Herein, we demonstrate an unprecedented organocatalytic two component six‐step chemodivergent domino reaction, which provides a straightforward, sustainable and atom economical route to difficult‐to‐access complex bicyclic architectures: azabicycles and carbobicycles, whose ratios can be controlled by the applied electrophiles and catalysts. Detailed NMR and X‐ray studies on the structures and relative stereochemistry of selected compounds are presented. Mechanistic investigations of the chemoselective branching step have been carried out with DFT methods in conjunction with semiempirical van der Waals interactions. This new domino reaction opens up a new vista of generating, in a single operation, new bioactive compounds with strong antiviral properties (EC₅₀ up to 0.071 μm for human cytomegalovirus (HCMV)) outperforming clinically used ganciclovir (EC₅₀ 2.6 μm ).     

Indolizinones as synthetic scaffolds: fundamental reactivity and the relay of stereochemical information

Indolizinones are under-explored N-heterocycles that react with exquisite chemo- and stereoselectivity. An exploration of the fundamental reactivity of these azabicycles demonstrates the potential to relay stereochemical information from the ring-fusion to newly formed stereocenters on the bicyclic core. The indolizinone diene undergoes selective hydrogenation and readily participates in Diels-Alder cycloadditions as well as ene reactions. The vinylogous amide embedded in the five-membered ring is resistant to reaction when the diene is in place. However, removal of the diene allows for diastereoselective hydrogenation of, and 1,4-additions to, the vinylogous amide. These fundamental reactions with indolizinones have provided a structurally diverse array of products that hold promise in the context of natural product synthesis.     

Synthesis of New Functionally Substituted 9-Azabicyclo[4.2.1]nona-2,4,7-trienes by Cobalt(I)-Catalyzed [6π + 2π]-Cycloaddition of N-Carbocholesteroxyazepine to Alkynes

Catalytic [6π + 2π]-cycloaddition of N-carbocholesteroxyazepine with functionally substituted terminal alkynes and 1,4-butynediol was performed for the first time under the action of the Co(acac)₂(dppe)/Zn/ZnI₂ three-component catalytic system. The reaction gave previously undescribed but promising 9-azabicyclo[4.2.1]nona-2,4,7-trienes (in 79–95% yields), covalently bound to a natural metabolite, cholesterol. The structure of the synthesized azabicycles was confirmed by analysis of one- and two-dimensional (¹H, ¹³C, DEPT ¹³C, COSY, NOESY, HSQC, HMBC) NMR spectra.     

The first and second cinchona rearrangement. Two fundamental transformations of alkaloid chemistry

Stereochemistry, products, and driving forces of the "first and second Cinchona rearrangement" have been investigated and a unified theory is presented. The first cage expansion affords [3.2.2]azabicyclic alpha-amino ether and is formulated via a configurationally stable bridgehead iminium ion and quasiequatorial nucleophilic attack. The second cage expansion affords beta-functionalized [3.2.2]azabicycles. In this case a nonclassical nitrogen-bridged cation is postulated to account for retention of configuration and potential reversibility of the cage expansion. The second rearrangement is favored for the so-called cinch bases (6'-R = H) in trifluoroethanol. Stereoelectronic factors, electron demand at C9, ground state conformation, and solvent type are crucial in all cases. A two-step protocol for preparing 9-epi-configured Cinchona alkaloids from 9-nat precursors is described.     

Selectfluor as a nucleofuge in the reactions of azabicyclo[n.2.1]alkane beta-halocarbamic acid esters (n = 2,3)

The ability of Selectfluor to act as a nucleofuge for hydrolysis of beta-anti-halides was investigated with N-alkoxycarbonyl derivatives of 6-anti-Y-7-anti-X-2-azabicyclo[2.2.1]heptanes and 4-anti-Y-8-anti-X-6-azabicyclo[3.2.1]octanes. The azabicycles contained X = I or Br groups in the methano bridge and Y = F, Br, Cl, or OH substituents in the larger bridge. The relative reactivities of the halides were a function of the azabicycle, the halide, and its bridge and the addition of Selectfluor or HgF(2) as a nucleofuge. All halide displacements occurred with retention of stereochemistry. Selectfluor with sodium bromide or sodium chloride, but not sodium iodide, competitively oxidized some haloalcohols to haloketones. A significant 15.6 Hz F...HO NMR coupling was observed with 4-anti-fluoro-8-anti-hydroxy-6-azabicyclo[3.2.1]octane.     

Nitrogen inversion in cyclic amines and the bicyclic effect

The hitherto unsolved problem of the origin of the unusually high nitrogen inversion-rotation (NIR) barriers in 7-azabicyclo[2.2.1]heptanes (the bicyclic effect) was examined using the natural bond orbital (NBO) approach. Reinvestigating the NIR barrier for tropane by DNMR, we found that NIR barriers increase smoothly on going from nitrogen-bridged bicyclic systems of a larger ring size to the smaller ring homologous systems. The experimental NIR barriers are reproduced with good accuracy using the MP2/6-31G level of theory. The NBO analysis for these and other azabicycles led to the conclusion that the height of these barriers is mostly determined by the energy of the sigma-orbitals of the C(alpha)(-)C(beta) bonds as well as the nitrogen lone pair. Thus, the bicyclic effect is actually an extreme case of a common C(alpha-)N-C(alpha) tripyramid geometry-NIR barrier dependence for N-bridged bicyclic amines. By establishing the rate-determining role of the C(alpha-)N-C(alpha) tripyramid fragment for NIR, we have derived the first sufficiently accurate quantitative correlations amine geometry-NIR barrier for monocyclic as well as bicyclic N-H and N-Me amines (i.e., for an amine set which also includes the bicyclic effect systems).     

Enol ethers as substrates for efficient Z- and enantioselective ring-opening/cross-metathesis reactions promoted by stereogenic-at-Mo complexes: utility in chemical synthesis and mechanistic attributes

The first examples of catalytic enantioselective ring-opening/cross-metathesis (EROCM) reactions that involve enol ethers are reported. Specifically, we demonstrate that catalytic EROCM of several oxa- and azabicycles, cyclobutenes and a cyclopropene with an alkyl- or aryl-substituted enol ether proceed readily in the presence of a stereogenic-at-Mo monopyrrolide-monoaryloxide. In some instances, as little as 0.15 mol % of the catalytically active alkylidene is sufficient to promote complete conversion within 10 min. The desired products are formed in up to 90% yield and >99:1 enantiomeric ratio (er) with the disubstituted enol ether generated in >90% Z selectivity. The enol ether of the enantiomerically enriched products can be easily differentiated from the terminal alkene through a number of functionalization procedures that lead to the formation of useful intermediates for chemical synthesis (e.g., efficient acid hydrolysis to afford the enantiomerically enriched carboxaldehyde). In certain cases, enantioselectivity is strongly dependent on enol ether concentration: larger equivalents of the cross partner leads to the formation of products of high enantiomeric purity (versus near racemic products with one equivalent). The length of reaction time can be critical to product enantiomeric purity; high enantioselectivity in reactions that proceed to >98% conversion in as brief a reaction time as 30 s can be nearly entirely eroded within 30 min. Mechanistic rationale that accounts for the above characteristics of the catalytic process is provided.     

Radical and Radical–Ionic Multicomponent Processes

All in one pot! Radical, radical–ionic, and radical–organometallic MCR are highly convergent processes, representing a useful pathway to molecular and structural diversity (see scheme). This concept article highlights recent developments in the field and shows the potential of the strategy for the economical elaboration of various kinds of organic substrates.

     

Regio‐, Peri‐, and Torquoselectivity in Hydroxy Heptatrienyl Cation Electrocyclizations: The Iso/Homo‐Nazarov Reaction

Competition : The electrocyclizations of 1‐ and 3‐hydroxyheptatrienyl cations (see scheme) have been computationally studied at the B3LYP/6‐311G(d) level. The 1‐hydroxy system clearly favors a 4e^? over a 6e^? process, while for the 3‐hydroxy isomer these mechanisms compete.

     

Synthesis of substituted pyrrolidines by sequential radical cyclization and N-acyliminium ion reactions

Readily available N-acyl-2-pyrrolines are converted into functionalized -alkoxy-β-iodopyrrolidines by N-iodosuccinimide promoted alcohol addition to the enamine group. These compounds are readily cyclized using a sodium cyanoborohydride-catalytic tributylstannane system affording functionalized pyrrolidines in good yields. The cyclized products undergo N-acyliminium ion reactions, such as BF₃·OEt₂ mediated addition of allyltrimethylsilane.     

Domino Reactions Based on Combinatorial Bond Transformations in Electron‐Deficient Tertiary Enamines

Electron‐deficient enamines such as enaminones and enaminoesters are moieties showing widespread application in organic synthesis. Among the various available electron‐deficient enamines, the N,N‐disubstituted amino‐functionalized ones (tertiary enamines) represent a class of special enamines with distinct properties and important applications. Based on our longstanding interest in exploring novel synthetic methods using electron‐deficient tertiary enamines, we present herein the research advances in organic synthesis via domino reactions making use of the combinatorial C–N, C=C, C–H, and other bond transformations of electron‐deficient tertiary enamines.

     

Catalytic Isofunctional Reactions—Expanding the Repertoire of Shuttle and Metathesis Reactions

Transfer hydrogenation, alkene metathesis, and alkyne metathesis possess great value to the synthetic chemistry community. One of the key features of these processes is their reversibility, which can be attributed to the presence of the same number and type of functional groups in both the reactants and products, making these reactions isofunctional. These classic reactions have recently inspired the development of novel shuttle and metathesis reactions that offer great promise for synthetic chemistry. This Review describes and systematically categorizes both recent and older examples of shuttle and metathesis reactions other than transfer hydrogenation and alkene/alkyne metathesis.     

Toward a Symphony of Reactivity: Cascades Involving Catalysis and Sigmatropic Rearrangements

Catalysis and synthesis are intimately linked in modern organic chemistry. The synthesis of complex molecules is an ever evolving area of science. In many regards, the inherent beauty associated with a synthetic sequence can be linked to a certain combination of the creativity with which a sequence is designed and the overall efficiency with which the ultimate process is performed. In synthesis, as in other endeavors, beauty is very much in the eyes of the beholder. It is with this in mind that we will attempt to review an area of synthesis that has fascinated us and that we find extraordinarily beautiful, namely the combination of catalysis and sigmatropic rearrangements in consecutive and cascade sequences.

1 Sometimes the assessment of beauty is nearly unanimous. The first four notes of Beethoven’s 5th Symphony (Symphony No.5 in C minor, Op.67) represent perhaps the most well‐known and popular motif in classical music. The orchestral score is shown in the background of the cover graphic. Accessed March 20, 2013 from http://imslp.org/wiki/Symphony_No.5,_Op.67_%28Beethoven,_Ludwig_van%29 .