Six-membered Carbocycles Research Articles

Enantioselective Cross-[4 + 2]-Cycloaddition/Decarboxylation of 2-Pyrones by Cooperative Catalysis of the Pd(0)/NHC Complex and Chiral Phosphoric Acid.

Here, we describe a cooperative Pd(0)/chiral phosphoric acid catalytic system that allows us to realize the first chemo-, regio-, and enantioselective sequential cross-[4 + 2]-cycloaddition/decarboxylation reaction between 2-pyrones and unactivated acyclic 1,3-dienes. The key to the success of this transformation is the utilization of an achiral N-heterocyclic carbene (NHC) as the ligand and a newly developed chiral phosphoric acid as the cocatalyst. Experimental investigations and computational studies support the idea that the Pd(0)/NHC complex acts as a π-Lewis base to increase the nucleophilicity of 1,3-dienes via η2 coordination, while the chiral phosphoric acid simultaneously increases the electrophilicity of 2-pyrones by hydrogen bonding. By this synergistic catalysis, the sequential cross-[4 + 2]-cycloaddition and decarboxylation reaction proceeds efficiently, enabling the preparation of a wide range of chiral vinyl-substituted 1,3-cyclohexadienes in good yields and enantioselectivities. The synthetic utility of this reaction is demonstrated by synthetic transformations of the product to various valuable chiral six-membered carbocycles.

Pogocablanols A–G, a new class of sesquiterpenoids with an unprecedented bicyclic sesquiterpenoid skeleton from Pogostemon cablin (patchouli) and their activities

Pogocablanols A–G (1–7), seven new compounds with an unprecedented sesquiterpenoid skeleton, were isolated from the aerial parts of Pogostemon cablin. This novel type of sesquiterpenoids, named pogocablane-type sesquiterpenoids, possesses a bicyclic nonisoprenoid system, including a five-membered carbocycle with a methyl group, a six-membered carbocycle with two methyl groups, and a methylene connecting the two carbocycles. Particularly, three isomers have an interesting 1-oxaspiro[4,4]nonane moiety. Their structures and absolute configurations were determined using extensive spectroscopic evidence, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Pogocablanols A–D (1–4) exhibited a concentration-dependent inhibitory effect on rat jejunum smooth muscle contraction induced by acetylcholine, with Emax values varying from 48.87 ± 4.01% to 69.02 ± 7.54%. Preliminary structure–activity relationship analysis suggested that the oxaspirocycle and the pyran ring in pogocablanols are important structural features for the relaxing effects on jejunum smooth muscle. This study offered crucial support for more investigation and development of P. cablin by showing that these pogocablane-type sesquiterpenoids had the potential to be applied in pharmaceutical and functional food formulations.

Insights into Stereoselectivity Switch in Michael Addition-Initiated Tandem Mannich Cyclizations and Their Extension from Enamines to Vinyl Ethers.

Both cis- and trans- tetracyclic spiroindolines are the core of many important biologically active indole alkaloids, but the divergent synthesis of these important motifs is largely hampered by the limited stereoselectivity control. A facile stereoinversion protocol is reported here in Michael addition-initiated tandem Mannich cyclizations for constructing tetracyclic spiroindolines, providing an easy access to two diastereoisomeric cores of monoterpene indole alkaloids with high selectivity. The mechanistic studies including in situ NMR experiments, control experiments, and DFT calculations reveal that the reaction undergoes a unique retro-Mannich/re-Mannich rearrangement including a C-C bond cleavage that is very rare for a saturated six-membered carbocycle. Insights into the stereoinversion process have been uncovered, and the major effects were determined to be the electronic properties of N-protecting groups of the indole with the aid of Lewis acid catalysts. By understanding these insights, the stereoselectivity switching strategy is also smoothly applied from enamine substrates to vinyl ether substrates, which are enriched greatly for the divergent synthesis and stereocontrol of monoterpene indole alkaloids. The current reaction also proves to be very practical and was successfully applied to the gram-scale total synthesis of strychnine and deethylibophyllidine in short routes.

Stereoselective Synthesis of Highly Functionalized Cyclohexenes via Strong-Acid-Mediated Endocyclic C-C Bond Cleavage of Monocyclopropanated Cyclopentadienes.

A stereoselective, solvent- and metal-free endocyclic C-C bond cleavage of monocyclopropanated cyclopentadienes mediated by strong acids was developed, leading to highly functionalized six-membered carbocycles with high stereocontrol. The critical step for this ring-expansion is the formation of a cyclopropyl carbocation that undergoes endocyclic ring opening via an SN2'-type attack of various nucleophiles. Subsequent synthetic transformations show the versatility of the resulting cyclohexenes for the synthesis of new compounds with nonconventional substitution patterns.

Stereoselective synthesis of five- and six-membered carbocycles via Matteson homologation/ring closing metathesis

The Matteson homologation is found to be a versatile tool for the stereoselective synthesis of polyunsaturated alkyl boronic esters, which can be used for the construction of five- and six-membered carbocycles via ring-closing metathesis.

N-Heterocyclic Carbene-Catalyzed Enantioselective Synthesis of Carbocycle-Fused Uracils via Formal [4 + 2] Annulation/Lactone Formation/Decarboxylation Cascade.

An unprecedented organocatalytic asymmetric construction of novel six-membered carbocycle fused uracils has been demonstrated by the reaction of the remotely enolizable 6-methyluracil-5-carbaldehydes with 2-bromoenals. The reaction involves an N-heterocyclic carbene-catalyzed formal [4 + 2] annulation of o-quinodimethane (oQDM) dienolates with α,β-unsaturated acylazoliums, followed by a cascade lactone formation/decarboxylation process. This protocol unlocks a new platform to access enantioenriched carbocycle-fused uracils.

The xanthate route to six-membered carbocycles

Convergent routes to various six-membered carbocyclic architectures exploiting the unique radical chemistry of xanthates are described in this brief review. Three approaches are discussed. The first is the modification of existing cyclohexane building blocks, namely, cyclohexanones, cyclohexenones and cyclohexenes. The second deals with the construction of six-membered carbocycles by associating the chemistry of xanthates with classical ionic reactions, especially the Robinson annulation, the Michael addition and the Horner–Wadsworth–Emmons condensation. Finally, the third route is the formation of six-membered rings by direct six- exo and, but more rarely, six- endo cyclisation modes. Many of the complex structures presented herein would be tedious to obtain by more traditional methods.

Catalytic Asymmetric Inverse‐Electron‐Demand Diels–Alder Reactions of 2‐Pyrones with Indenes: Total Syntheses of Cephanolides A and B

An inverse-electron-demand Diels-Alder (IEDDA) reaction could complement the conventional normal-electron-demand Diels-Alder reaction in the synthesis of six-membered carbocycles. However, catalytic asymmetric all-carbon-based IEDDA reactions are underdeveloped. Herein, we disclosed a copper-catalyzed asymmetric IEDDA reaction using electron-deficient 3-carboalkoxyl-2-pyrones and electronically unbiased indenes as reactants. This method enables the rapid and enantioselective construction of a wide range of hexahydrofluorenyl bridged-lactone scaffolds. Using this method, asymmetric total syntheses of cephanolides A and B were accomplished.

Palladium-Catalyzed Asymmetric (4 + 2) Annulation of γ-Methylidene-δ-valerolactones with Alkenes: Enantioselective Synthesis of Functionalized Chiral Cyclohexyl Spirooxindoles.

An unprecedented asymmetric catalytic (4 + 2) annulation reaction of aryl-substituted γ-methylidene-δ-valerolactones (GMDVs) with isatin-derived para-quinone methides (p-QMs) has been developed under the catalysis of palladium(0) and (S,S,S)-(-)-Xyl-SKP, offering a new approach for the diastereo- and enantioselective synthesis of chiral cyclohexadienone-fused cyclohexyl spirooxindoles. Significantly, three highly congested contiguous tetrasubstituted carbon atoms embedded in bispirocyclic skeleton, of which two are vicinal quaternary stereogenic centers, are forged in an effective and selective manner (up to 99% yield, up to 95% ee, >20/1 dr). The current reaction represents the first exploration of enantioselective catalytic (4 + 2) annulation forming the six-membered carbocycles in the chemistry of both GMDVs and p-QMs.

Regioselective synthesis of substituted cyclohexa-1,3-dienes via the base-mediated cyclisation of α,β-unsaturated carbonyl compounds and γ-phosphonylcrotonates

The base-mediated reaction of α,β-unsaturated carbonyl compounds and γ-phosphonylcrotonates under an argon atmosphere readily furnishes substituted cyclohexa-1,3-dienes. The cyclisation proceeds with complete regioselectivity to afford products that are readily amenable to further redox manipulations. The presented method allows the rapid and regioselective syntheses of six-membered carbocycles at three different oxidation levels.

Theoretical predication of Diels-Alder reactions of highly strained dienophiles

Using density functional theory M06-2X functional in combination with 6-311++G** basis set, we have obtained six types of highly strained dienophiles (1-6). The Diels-Alder reactions of 1-6 with butadiene (A), cyclopentadiene (B) and 3,6-bis(trifluoromethyl)-tetrazine (C) have been investigated. Calculated results show that these Diels-Alder reactions are both thermodynamically and kinetically feasible. The endo Diels-Alder reactions of 1-6 with A and B are more favorable than their exo Diels-Alder reactions, which originates from the distortion energy differences of A and B. The low activation energy of the Diels-Alder reactions of 1-6 with C arises from the electron-withdrawing group CF3 in C, which is consistent with the previous results (J. Am. Chem. Soc. 2013, 135, 15642). The Diels-Alder reactions of 1-6 with the three dienes give a family of novel propellanes but not six-membered carbocycles.

Vinyl sulfone-modified carbohydrates: Michael acceptors and 2π partners for the synthesis of functionalized sugars and enantiomerically pure carbocycles and heterocycles.

Increasing demands for molecules with skeletal complexity, including those of stereochemical diversity, require new synthetic strategies. Carbohydrates have been used extensively as chiral building blocks for the synthesis of various complex molecules. On the other hand, the vinyl sulfone group has been identified as a unique functional group, which acts either as a Michael acceptor or a 2π partner in cycloaddition reactions. A combination of the high reactivity of the vinyl sulfone group and the in-built chiralities of carbohydrates has the potential to function as a powerful tool to generate a wide variety of enantiomerically pure reactive intermediates. Since CS bond formation in carbohydrates is easily achieved with regioselectivity, further synthetic manipulations of these thiosugars has led to the generation of a wide range of vinyl sulfone-modified furanosyl, pyranosyl, acyclic, and bicyclic carbohydrates. Several approaches have been studied to standardize the preparative methods for accessing vinyl sulfone-modified carbohydrates at least on a gram scale. Reactions of these modified carbohydrates with appropriate reagents afford a large number of new chemical entities primarily via (i) Michael addition reactions, (ii) desulfostannylation, (iii) Michael-initiated ring-closure reactions, and (iv) cycloaddition reactions. A wide range of desulfonylating reagents in the context of sensitive molecules such as carbohydrates have also been extensively studied. Applications of these strategies have led to the synthesis of (a) amino sugars and branched-chain sugars, (b) C-glycosides, (c) enantiomerically pure cyclopropanes, five- and six-membered carbocycles, (d) saturated oxa-, aza-, and thio-monocyclic heterocycles, (e) bi-and tricyclic saturated oxa and aza heterocycles, (f) enantiomerically pure and trisubstituted pyrroles, (g) 1,5-disubstituted 1,2,3-triazolylated carbohydrates and the corresponding triazole-linked di- and trisaccharides, (h) divinyl sulfone-modified carbohydrates and densely functionalized S,S-dioxothiomorpholines, and (i) modified nucleosides. Details of reaction conditions were incorporated as much as possible and mechanistic discussions were included wherever necessary.

Cooperative physisorption and chemisorption of hydrogen on vanadium-decorated benzene.

3d TM-decorated carbon composites have been proved to be a new generation of hydrogen storage materials. However, detailed hydrogen storage mechanisms are still unclear. Investigation of the H2 dissociation and H migration on the 3d TM-decorated six-membered carbocycles is very critical for better understanding the hydrogen storage mechanism. In this paper, the processes of chemisorption and physisorption of multiple H2 molecules on synthesized VC6H6 were simultaneously investigated for the first time. The Gibbs free energy calculations show that the optimal chemisorption pathway with the hydrogen storage capacity of 5.97 wt% is exothermic by 2.83 kcal mol−1. Both the continuous hydrogenation giving the product of VC6H11–3H and reverse dehydrogenation could run smoothly at room temperature. The physisorption with a hydrogen storage capacity of 4.48 wt% will be exothermic by 13.49 kcal mol−1. The H2 molecules can be physisorbed at any temperature under 416 K and readily desorbed above 480 K at 1 atm. In summary, physisorption and chemisorption synergistically boost the hydrogen storage property of complex VC6H6. Our study provides a comprehensive picture of the interaction between hydrogen and VC6H6 and opens a new window for optimizing the future hydrogen storage materials.

Phosphine-Catalyzed Chemo- and Diastereoselective [2 + 2 + 2] and [3 + 2] Annulations of γ-Methyl Allenoates with Doubly Activated Olefins: Syntheses of Highly Substituted Cyclohexanes and Cyclopentenes.

Phosphine-catalyzed chemoselective [2 + 2 + 2] and [3 + 2] annulations of γ-methyl allenoates with doubly activated olefins have been developed, which afford highly substituted cyclohexanes bearing five continuous stereogenic centers and cyclopentenes bearing three continuous stereogenic centers, respectively, in generally high yields with excellent diastereoselectivity. The [2 + 2 + 2] annulation represents an unprecedented reactivity pattern of γ-methyl allenoates with activated C═C bonds to access six-membered carbocycles. In addition, the study herein also evidences that the acidic protic additives such as benzoic acid can exert influence on chemoselectivity of phosphine-catalyzed annulation reactions involving allenoates.

NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles.

This Account is aimed at highlighting the recent developments in the N-heterocyclic carbene (NHC)-catalyzed generation of α,β-unsaturated acylazolium intermediates and their subsequent reactivity with (bis)nucleophiles thereby shedding light on the power of this NHC-bound intermediate in organocatalysis. This key intermediate can be generated by the addition of NHCs to α,β-unsaturated aldehyde or acid derivatives. A wide variety of bisnucleophiles can add across the α,β-unsaturated acylazoliums to form various five and six-membered heterocycles and carbocycles. Moreover, suitably substituted nucleophiles can add to this intermediate and result in valuable products following cascade processes. Employing chiral NHCs in the process can result in the enantioselective synthesis of valuable compounds. In 2013, we developed a unified strategy for the enantioselective synthesis of dihydropyranones and dihydropyridinones by the NHC-catalyzed formal [3 + 3] annulation of 2-bromoenals with readily available 1,3-dicarbonyl compounds or primary vinylogous amides. This reaction takes place under mild conditions with low catalyst loading. Interestingly, employing enolizable aldehydes as the bisnucleophiles in this annulation afforded chiral 4,5-disubstituted dihydropyranones in spite of the competing benzoin/Stetter pathways. Moreover, the use of cyclic 1,3-dicarbonyl compounds such as 4-hydroxy coumarin/pyrazolone afforded the coumarin/pyrazole-fused dihydropyranones. In addition, a [3 + 2] annulation for the synthesis of spiro γ-butyrolactones was demonstrated using 3-hydroxy oxindoles as the bisnucleophile. The interception of α,β-unsaturated acylazolium intermediates with malonic ester derivatives having a γ-benzoyl group resulted in the enantioselective synthesis of functionalized cyclopentenes via a cascade process involving a Michael-intramolecular aldol-β-lactonization-decarboxylation sequence. The use of cyclic β-ketoamides as the coupling partner for catalytically generated α,β-unsaturated acylazoliums resulted in the enantioselective synthesis of spiro-glutarimide and the reaction proceeds in a Michael addition-intramolecular amidation pathway. We have recently demonstrated the enantioselective synthesis of tricyclic δ-lactones with three contiguous stereocenters by the reaction of enals with dinitrotoluene derivatives bearing electron-withdrawing groups, under oxidative conditions. This atom-economic cascade reaction proceeds in a Michael/Michael/lactonization sequence tolerating a range of functional groups. This technique was also used for the N-H functionalization of indoles for the enantioselective synthesis of pyrroloquinolines following the aza-Michael/Michael/lactonization sequence. The use of α-arylidene pyrazolinones as the bisnucleophiles for the tandem generation of dienolate/enolates combined with the NHC-catalyzed generation of α,β-unsaturated acylazoliums resulted in the enantioselective synthesis of pyrazolone-fused spirocyclohexadienones. This formal [3 + 3] annulation proceeds via the vinylogous Michael/spiroannulation/dehydrogenation sequence to afford spirocyclic compounds with an all-carbon quaternary stereocenter. It is reasonable to believe that the chemistry of α,β-unsaturated acylazoliums, catalytically generated through NHCs, will continue to flourish and will lead to amazing results. Future challenges in this area include the applications of this key intermediate in the synthesis of biologically active natural products and drugs.

Adsorption of multiple H2 molecules on the complex TiC6H6: An unusual combination of chemisorption and physisorption

The hydrogen physisorption properties of diverse examples of Ti-decorated six-membered carbocycles have been established and intensively investigated. However, fewer investigations have been devoted to the chemical reactions occurring during the process of hydrogen storage. Herein, for the first time, a variety of plausible hydrogenation intermediates and physisorption complexes involving multiple H2 molecules on the complex TiC6H6 has been investigated simultaneously. The relative Gibbs free energies of TiC6H6-nH2 (n = 1–4) isomers and the minimum-energy pathways of the successive hydrogenation steps show that the overall reactions to give the hydrogenation product TiC6H11-3H is exothermic by 11.07 kcal/mol in terms of ΔG (298.15 K). It indicates that a facile switch of hydrogen addition and release with superior capacity of 6.02 wt % can be quickly achieved with simply regulated by increasing/decreasing the hydrogen pressure, which is consistent with the recent experiment on hydrogen adsorption in TiC6H6 at room temperature. The physisorption processes show that three H2 molecules can be efficiently trapped below 210 K and desorbed completely at 935 K. More importantly, chemisorption and physisorption will convert in certain circumstances, which indicates that the mechanism of the bonding of H2 molecules on TiC6H6 is an unusual combination of chemisorption and physisorption.

Anomalous Direction of the Ene Reaction of Pulegone with 4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione

The ene reaction of pulegone with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione, apart from the two previously described products, epimeric 1-[(1S,4R)- and 1-[(1R,4R)-4-methyl-2-oxo-1-(prop-1-en-2-yl)cyclohexyl]-4-phenyl-1,2,4-triazolidine-3,5-diones, gave one more isomer, 1-{1-methyl-1-[(4R)-4-methyl-6-oxocyclohex-1-en-1-yl]ethyl}-4-phenyl-1,2,4-triazolidine-3,5-dione. The latter is formed as a result of addition of 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione to the Me2C= carbon atom of pulegone (anti-Markovnikov addition) and double bond migration to the six-membered carbocycle.

Oxidopyrylium-Alkene [5 + 2] Cycloaddition Conjugate Addition Cascade (C3) Sequences: Scope, Limitation, and Computational Investigations.

Oxidopyrylium-alkene [5 + 2] cycloaddition conjugate addition cascade (C3) sequences are described. Intramolecular cycloadditions involving terminal alkenes, enals, and enones were investigated. Substrates with tethers of varying lengths delivered five- and six-membered carbocycles and heterocycles thus demonstrating the scope and limitation of the cycloaddition-conjugate addition cascade. Several experiments and theoretical calculations provide evidence for the proposed mechanistic pathway.

Difunctionalization of Cyclopropylanilines and Cyclobutylanilines

We have previously developed photoredox conditions for ring opening of cyclopropylanilines and cyclobutylanilines. Distonic radical cations are presumably the intermediates. Although commonly producing in gas phase such as in the ionization chamber of a mass spectrometer, in solution phase, the methods for generating them are quite limited. Bearing a spatially separated radical and cation within the same molecule, these species possess bimodal reactivities that are distinct from those of radicals, ions, or classical radical ions (the radical and the ion reside at the same atom). In the [3+2] annulation of cyclopropylanilines and the [4+2] annulation of cyclobutylanilines developed by us, only one pi bond of alkenes, alkynes, dienes, enynes, or diynes reacts with the radical and the cation moiety of the distonic radical cations sequentially to form a five-membered and six-membered carbocycle respectively. Therefore, the two reactions don’t maximize the distonic radical cations’ bimodal reactivity. We have recently focused on identifying a suitable nucleophile and a radical acceptor to orthogonally intercept the cation and the radical moiety, which allows us to capitalize the distonic radical cations’ bimodal reactivity fully. Herein, we report our efforts in harvesting the distonic radical cations' bimodal reactivity, which results in 1,3-difunctionalization of cyclopropylanilines and 1,4-difunctionalization of cyclobutylanilines.

Tunable Synthesis of Functionalized Cyclohexa-1,3-dienes and 2-Aminobenzophenones/Benzoate from the Cascade Reactions of Allenic Ketones/Allenoate with Amines and Enones.

A TEMPO-dependent tunable synthesis of functionalized cyclohexa-1,3-dienes and 2-aminobenzophenones/benzoate from the one-pot cascade reactions of allenic ketones/allenoate with amines and enones is presented. Mechanistically, the construction of the entitled six-membered carbocycles involves the in situ generation of an enaminone intermediate via the conjugate addition of allenic ketone with amine followed by its catalyst- and base-free [3+3] annulation with enone along with the simultaneous introduction of the valuable amino and carbonyl groups.