Highly selective synthesis of bicyclic quinolizidine alkaloids and their analogues via double RCM reaction of N-alkynyl-N-(1,omega)-alkadienyl acrylamides

The double ring-closing metathesis reaction of N-alkynyl-N-(1,omega)-alkadienyl acrylamides 1 using first- or second-generation Grubbs' catalyst afforded, in a highly selectively manner, the fused bicyclic quinolizidine alkaloid derivatives and their analogues bearing a 1,3-diene moiety, which may further undergo a Diels-Alder reaction with a dienophile to afford N-containing polycyclic compounds. The excellent selectivity of fused/dumbbell-mode cyclization has been realized by the higher reactivity of the electron-rich C=C bond or carbon-carbon triple bond combined with the lower reactivity of the electron-deficient C=C bond toward metallocarbenes and the thermodynamically more stable nature of fused bicyclic compounds 3 vs dumbbell-type bicyclic compounds 4.     

Bridged to Fused Ring Interchange. Methodology for the Construction of Fused Cycloheptanes and Cyclooctanes. Total Syntheses of Ledol, Ledene, and Compressanolide

The type two intramolecular Diels-Alder reaction (T2IMDA) is an efficient method for the formation of medium rings. The methodology is particularly effective for the construction of seven- and eight-membered rings. A strategy for the synthesis of functionalized cycloheptanes and cyclooctanes has been developed that involves a bridged to fused ring interchange. The T2IMDA provides a synthesis for rigid bridged bicyclic molecules that can be stereoselectively elaborated before ozonolysis of the bridgehead double bond. Following oxidative cleavage, aldol condensation provides fused bicyclic ring systems that otherwise are difficult to synthesize. This methodology is amenable to the synthesis of terpene natural products. This is demonstrated here through total syntheses of (+/-)-ledol and (+/-)-ledene and a formal synthesis of (+/-)-compressanolide.     

Catalytic (3+2) Palladium‐Aminoallyl Cycloaddition with Conjugated Dienes

We describe the design and application of tailored aminoallyl precursors for catalytic (3+2) cycloaddition with conjugated dienes via a Pd‐aminoallyl intermediate. The new cycloaddition reactions override the conventional (4+3) selectivity of aminoallyl cation cycloaddition through a sequence of Pd‐allyl transfer and ring closure. A variety of highly substituted or fused pyrrolidine rings were synthesized using the cycloaddition, and can further undergo [1,3] N‐to‐C rearrangement to five‐membered carbocycles with a different palladium catalyst. The utility of the (3+2) cycloaddition is also demonstrated by the preparation of various derivatives from the bicyclic pyrrolidine products.     

Acetonitrile Activation Promoted by Divalent Nickel Species with Bicyclic Guanidinate Ligands

Three compounds are described from reactions of divalent nickel species and bicyclic guanidinate ligands. These compounds encompass a variety of nuclearities with one being triangular and having an hour-glass shape and the formula Ni₃(tbn)₆·2LiCl, 1, where tbn is a bicyclic guanidinate anion with fused 5/6 membered rings. A dinuclear compound [(??²-Imeth)Ni(??-tbo)]₂Cl₂, 2, contains two fused 5/5 membered rings (tbo) that bridge two divalent nickel atoms and also contains a chelating unit in each metal center. The neutral Imeth (1-(2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazol-1-yl)ethanimine) is an imino-containing ligand produced by the Ni(II) catalyzed reaction of tbo with acetonitrile. A mononuclear species, [(??²-hpp)Ni(hpp)(Hhpp)]Cl, 3, is obtained from reaction of NiCl₂ with the bicyclic guanidinate ligand with two fused six-member rings in contact with moisture. In all compounds each of the Ni atoms has a local square-planar arrangement common in d⁸ species.     

Synthetic study of manzamine B: synthesis of the tricyclic central core by an asymmetric Diels-Alder and RCM strategy

Tricyclic core of manzamine B was successfully synthesized through asymmetric Diels-Alder reaction and RCM strategy. Cr-salen-F complex was found to be the most effective catalyst in DA reaction of aminodienes with heterocyclic dienophiles to give up to 97% ee. In the construction of 11-membered ring by RCM, first-Grubbs cat. gave better stereoselectivity.     

Molybdenum-mediated cleavage reactions of isoxazoline rings fused in bicyclic frameworks

The molybdenum-mediated cleavage reactions of isoxazoline rings fused in bicyclic frameworks were investigated. A tandem N-O bond cleavage-retro aldol reaction of an isoxazoline ring fused in a bicyclic framework led to the cleavage of the bicyclic framework. These reactions provide a novel stereoselective synthesis of substituted cyclopentene rings, cyclopentane rings, and attached-ring systems. [reaction: see text]     

Synthesis of 2′-O,3′-O bicyclic adenosine analogues using ring closing metathesis

The synthesis of 2′-O,3′-O bicyclic adenosine derivatives is presented as the first examples of a new family of 13-membered ring bicyclic nucleoside analogues. Cyclisation was achieved through ring closing metathesis (RCM) on a diene intermediate using Grubbs’ catalyst. The Z and E isomers were purified and characterised.     

Total Synthesis of (−)‐Pepluanol B: Conformational Control of the Eight‐Membered‐Ring System

The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo‐epoxidation to control the eight‐membered‐ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight‐membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif.     

Functionalizable Stereocontrolled Cyclopolyethers by Ring‐Closing Metathesis as Natural Polymer Mimics

Whereas complex stereoregular cyclic architectures are commonplace in biomacromolecules, they remain rare in synthetic polymer chemistry, thus limiting the potential to develop synthetic mimics or advanced materials for biomedical applications. Herein we disclose the formation of a stereocontrolled 1,4‐linked six‐membered cyclopolyether prepared by ring‐closing metathesis (RCM). Ru‐mediated RCM, with careful control of the catalyst, concentration, and temperature, selectively affords the six‐membered‐ring cyclopolymer. Under optimized reaction conditions, no metathetical degradation, macrocycle formation, or cross‐linking was observed. Post‐polymerization modification by dihydroxylation afforded a novel polymer family encompassing a poly(ethylene glycol) backbone and sugar‐like functionalities (“PEGose”). This strategy also paves the way for using RCM as an efficient method to synthesize other stereocontrolled cyclopolymers.     

Lewis acid-promoted intermolecular carbonyl-ene reaction of enantiopure 4-oxoazetidine-2-carbaldehydes. Rapid entry to novel fused polycyclic beta-lactams

Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes with various activated alkenes gives 4-[(1'-hydroxy)homoallyl]-beta-lactams with a very high level of syn diastereofacial selectivity. The above homoallylic alcohols are used for the diastereoselective preparation of fused bicyclic, tricyclic, and tetracyclic beta-lactams of nonconventional structure using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences. In addition, a novel domino process was discovered, the C4-N1 beta-lactam bond breakage/intramolecular Diels-Alder reaction.     

Synthesis of cyclic hydrazines by ring-closing metathesis of dienes and enynes tethered by an N-N bond

Ring-closing metathesis of dienes and enynes tethered by an N-N bond produced 6- to 10-membered cyclic 1,2-diaza compounds. The enyne RCM adducts were further transformed by Diels-Alder reaction into aromatic compounds.     

Kinetically controlled ring-closing metathesis: synthesis of a potential scaffold for 12-membered salicylic macrolides

For the synthesis of a 12-membered salicylic macrolide scaffold, ring-closing metathesis (RCM) of a omega-diene compound was planned. The stereochemical outcome of the RCM reaction changed depending on the type of Ru catalyst that was used; a "first-generation" Grubbs catalyst produced exclusively the E isomer and "second-generation" catalysts provided a mixture of the E and Z isomers under kinetic control (not thermodynamic control). Considerations for the E/Z selectivity are described.     

Eleuthesides and their analogs: V. Medium- and large-ring lactones based on levoglucosenone

Ozonolysis of the bridging double bond in bicyclic enol ethers obtained by the Michael reaction and subsequent intramolecular etherification afforded chiral decanolides fused to a tetrahydropyran ring. Three-step procedures were developed for the synthesis of chiral lactones with medium and large rings via oxidative cleavage with pyridinium chlorochromate of mixed bicyclic ketals which were prepared by treatment with methanolic HCl of Michael adducts derived from levoglucosenone and cyclopenta-, cyclohexa-, cyclohepta-, and cyclododecanone.     

A facile synthesis of (Z)-1, 6-disubstituted-7H-benzo[b][1,5]diazonin-7-one derivatives via arylation-allylation-RCM pathway of anthranilamide and isatoic anhydride

A facile and efficient method has been developed for the synthesis of (Z)-6-allyl-1-phenyl-1,2,5,6-tetrahydro-7H-benzo[b][1,5]diazonin-7-one and (Z)-1,6-diphenyl-1,2,5,6-tetrahydro-7H-benzo[b][1,5]diazonin-7-one from anthranilamide via N-arylation/N-allylation and from isatoic anhydride via ring opening/N-arylation/N-allylation followed by ring closing metathesis using Grubbs-II catalyst as a key step. Grubbs-II catalyst was found to be superior over Grubbs-I catalyst in terms of reaction time and yield of the product, and the routes developed were suitable to synthesize benzo fused nine membered nitrogen heterocycles. The requirement of diallylated substrates with protected amine and amide nitrogen is suitable for RCM has been established for the synthesis of diazoninone derivatives.     

Synthesis of New Iminosugar Derivatives Based on (S)-(1,2,3,6-Tetrahydropyridazin-3-yl)methanol

(S)-(1,2,3,6-Tetrahydropyridazin-3-yl)methanol was synthesized in two steps by the Diels-Alder reaction of penta-2,4-dien-1-ol with diethyl azodicarboxylate in the presence of (S)-BINOL as chiral catalyst. The subsequent Boc-protection of the 2-position of the pyridazine ring, ring-closing carbonylation of the hydroxy group, and deprotection afforded a bicyclic iminosugar analog. The structure of the isolated compounds was proved by NMR, IR, and mass spectra and elemental analyses.

     

A versatile method for carbon-nitrogen bond formation via ene reactions of acylnitroso compounds

The use of acylnitroso compounds of the general formula RCONO as enophiles in the formation of carbon-nitrogen bonds is described. Both inter- and intramolecular ene reactions have been studied. For the intermolecular examples, nitrosocarbonylmethane, thermally liberated from its Diels-Alder adduct with 9,10-dimethylanthracene, is reacted with various olefins giving the corresponding N-alkylhydroxamic acids in moderate to high yields, providing an efficient method for allylic amidation. The regiochemistry of the intermolecular reaction is observed to be the result of kinetic control, and the direction of addition is consistent with attack by the olefin on electron-deficient nitrogen. Several examples of intramolecular ene cyclization are demonstrated, providing efficient entry into both spiro and fused bicyclic nitrogen containing systems which can be viewed as derived from annulation of 5- and 6- membered nitrogen containing rings onto 5- and 6-membered carbocycles, respectively. Various examples of this hetero-annulation scheme are described. Experimental details are also privided describing typical reaction procedures.     

Tandem catalysis: generating multiple contiguous carbon-carbon bonds through a ruthenium-catalyzed ring-closing metathesis/Kharasch addition

Tandem catalysis can offer unique and powerful strategies for converting simple starting materials into more complex products in a single reaction vessel while generating less waste and minimizing handling. In this regard, Grubbs' ruthenium alkylidene (Cy3P)2Cl2Ru=CHPh is shown to catalyze two mechanistically distinct transformations to offer a unique protocol that effects multiple bond changes in a single operation. A tandem ruthenium-catalyzed olefin ring-closing metathesis (RCM)/Kharasch addition allows for the facile preparation of bicyclic [3.3.0], [4.3.0], and [5.3.0] ring systems in one step from the appropriately functionalized acyclic precursors. For substrates where the intramolecular Kharasch addition fails, an intermolecular Kharasch addition is possible. By combining the intra- and intermolecular Kharasch additions with RCM, three new contiguous carbon-carbon bonds with multiple stereocenters can be generated by the ruthenium catalyst in a controlled fashion in one operation through two mechanistically distinct pathways.     

Radical‐Mediated 1,2‐Formyl/Carbonyl Functionalization of Alkenes and Application to the Construction of Medium‐Sized Rings

A novel radical 1,2‐formylfunctionalization of alkenes involving 1,2(4,5)‐formyl migration triggered by addition of various carbon‐ and heteroatom‐centered radicals to alkenes has been developed for the first time, thus providing straightforward access to diverse β‐functionalized aldehydes with good efficiency, remarkable selectivity, and excellent functional group tolerance. Analogous transformations mediated by a keto‐carbonyl migration have also been effected under similar conditions. This method was used to access ring systems including various benzannulated nine‐, ten‐, and eleven‐membered rings, complex 6‐5(6,7)‐6(5) fused rings, and bridged rings with diverse functionalities.     

Synthesis of the fused polyether core of hemibrevetoxin B by two-directional ring-closing metathesis

The tetracyclic fused polyether core of the marine natural product hemibrevetoxin B has been prepared in an efficient manner by using a strategy in which ring-closing metathesis (RCM) reactions were employed for ring synthesis. Simultaneous construction of the A and D rings was accomplished by double two-directional RCM of a tetraene. [reaction: see text]     

A Metal‐Bridged Tricyclic Aromatic System: Synthesis of Osmium Polycyclic Aromatic Complexes

Aromaticity is one of the most important concepts in organic chemistry. A variety of metalla‐aromatic compounds have been recently prepared and in most of those examples, the metal participates only in a monocyclic ring. In contrast, metal‐bridged bicyclic aromatic molecules, in which a metal is shared between two aromatic rings, have been less developed. Herein, we report the first metal‐bridged tricyclic aromatic system, in which the metal center is shared by three aromatic five‐membered rings. These metalla‐aromatics are formed by reaction between osmapentalyne and arene nucleophiles. Experimental results and theoretical calculations reveal that the three five‐membered rings around the osmium center are aromatic. In addition, the broad absorption bands in the UV/Vis absorption spectra of these novel aromatic systems cover almost the entire visible region. This straightforward synthetic strategy may be extended to the synthesis of other metal‐bridged polycyclic aromatics.