A [4 + 4] annulation strategy for the synthesis of eight-membered carbocycles based on intramolecular cycloadditions of conjugated enynes

A [4+4] annulation strategy for the synthesis of eight-membered carbocycles is reported that proceeds via a cascade involving two pericyclic processes. In the first step, the [4+2] cycloaddition of a conjugated enyne with an electron-deficient cyclobutene generates a strained six-membered cyclic allene that isomerizes to the corresponding 1,3-cyclohexadiene. In the second step, this bicyclo[4.2.0]octa-2,4-diene intermediate undergoes thermal or acid-promoted 6-electron electrocyclic ring opening to furnish a 2,4,6-cyclooctatrienone. The latter transformation represents the first example of the promotion of 6-electron electrocyclic ring opening reactions by acid.     

Chemodivergent,Regio- and Enantioselective Cycloaddition Reactions between 1,3-Dienes and Alkynes

Alkynes and 1,3-dienes are among the most readily available precursors for organic synthesis. We report two distinctly different, catalyst-dependent, modes of regio- and enantioselective cycloaddition reactions between these classes of compounds providing rapid access to highly functionalized 1,4-cyclohexadienes or cyclobutenes from the same precursors. Complexes of an earth abundant metal, cobalt, with several commercially available chiral bisphosphine ligands with narrow bite angles catalyze [4+2]-cycloadditions between a 1,3-diene and an alkyne giving a cyclohexa-1,4-diene in excellent chemo-, regio- and enantioselectivities. In sharp contrast, complex of a finely tuned phosphino-oxazoline ligand promotes unique [2+2]-cycloaddition between the alkyne and the terminal double bond of the diene giving a highly functionalized cyclobutene in excellent regio- and enantioselectivities.     

Interplay of orbital symmetry and nonstatistical dynamics in the thermal rearrangements of bicyclo[n.1.0]polyenes.

CASSCF and CASPT2 calculations have been carried out on some of the thermal rearrangements of bicyclo[2.1.0]pentene (BCP), bicyclo[4.1.0]hepta-2,4-diene (BCH), bicyclo[6.1.0]nona-2,4,6-triene (BCN), and 9,9-dicyanobicyclo[6.1.0]nona-2,4,6-triene (DCBCN). In addition, experiments have been conducted to determine the stereoselectivity and temperature dependence of the nondegenerate rearrangement of 9,9-dicyanobicyclo[6.1.0]nona-2,4,6-triene-exo-15N. The calculations and experiments allow a consistent picture to be drawn for these reactions. The principal conclusions are as follows. (1) The ring-walk rearrangements of BCP, BCN, and DCBCN are pericyclic reactions occurring with a strong preference for inversion of configuration at the migrating carbon. However, the ring-walk rearrangement of BCH is a nonpericyclic reaction. (2) The rearrangement of DCBCN to 9,9-dicyanobicyclo[4.2.1]nona-2,4,7-triene occurs with a preferred stereochemistry corresponding to a 1,3 migration with retention. However, this reaction is not a pericyclic process; the stereoselectivity is probably of dynamic origin. (3) Cyano substituents can significantly reduce the activation energy for a reaction occurring via a singlet biradical, but they do not necessarily cause the intermediate to sit in a deeper local minimum on the potential energy surface.     

Photochemical,thermal, and base-induced access to hydroazulene derivatives via two-carbon ring-enlargement reactions of condensed electrophilic cyclobutenes

Enamines, silyl enol ethers, and beta-keto ester anions derived from bicyclo[3.3.0]octan-2-one efficiently underwent a formal [2 + 2] cycloaddition reaction with DMAD and ethyl propynoate leading to a large variety of electrophilic cyclobutenes. The latter were transformed into polyfunctionalized bicyclo[5.3.0]decane (or hydroazulene) ring systems in high yields by fragmentation of the cyclobutene moiety. These two-carbon ring-enlargement reactions were utilized as a synthetic tool for the construction of a polyfunctionalized hydroazulene derivative that represents a potential precursor of the tricyclic framework of ingenol.     

Reduced classical trajectory equations for electronically non-adiabatic transition on photochemical pericyclic reactions

It may be difficult to use the classical trajectory equations (CTE) for the estimation of electronically non-adiabatic transition probabilities in photochemical pericyclic reactions because of many nuclear degrees of freedom. In order to avoid this difficulty, the CTE were reformulated in terms of the reaction path coordinates, and the reduced CTE were derived, in which the system was restricted to move one-dimensionally along the postulated reaction path. As an application, the non-adiabatic decay from the lowest excited state to the ground state was investigated for the conrotatory and disrotatory processes of the photochemical electrocyclic reaction of 1,3-cis-butadiene to form cyclobutene.     

Ring closing enyne metathesis: control over mode selectivity and stereoselectivity

Ring closing enyne metathesis to form 10-15-membered rings was achieved by using a tartrate-derived linker to attach ene and yne subunits. The exo/endo selectivity of the ring closure reaction of these substrates was found to be a function of ring size, whereby larger rings (12-15) give endo-products selectively, while smaller rings (5-11) give exo-products. The E/Z selectivity of the resultant macrocyclic 1,3-dienes was not predictable except for 10- and 11-membered rings. However, both the exo/endo-mode selectivity of the ring closure and the E/Z selectivity of the 1,3-dienes were improved by performing these reactions under ethylene atmosphere. The presence of ethylene induces a selective cross metathesis between the alkyne moiety and ethylene to generate an acyclic 1,3-diene which can undergo ring closing diene metathesis between the isolated olefin and the distal monosubstituted double bond of the 1,3-diene to generate exclusively the endo-product with high E-selectivity.     

A ring-closing metathesis approach to the bicyclo[4.3.1]decane core of caryolanes

A synthesis of highly substituted and sterically congested bicyclo[4.3.1]decenes, a structure embedded in the core 4,7,6-tricyclic system of natural caryolanes, was successfully achieved via a ring-closing metathesis (RCM) reaction of syn-1,3-diene substituted cyclohexanols. The construction of the diene substrates, starting from 4-acetoxy-3-methyl-2-cyclohexen-1-one, employed diastereoselective copper-mediated conjugate addition and Grignard reactions. An X-ray crystal structure determination of a key synthetic intermediate confirmed the relative stereochemistry of the RCM bicyclic product.     

Computational study of the mechanisms of the photoisomerization reactions of bicycloalkene

The mechanisms of the photochemical isomerization reactions were investigated theoretically using a model system, bicyclo[4,1,0]hept-3-ene (1), with the CASSCF (six-electron/six-orbital active space) and MP2-CAS methods and the 6-311(d,p) basis set. The structures of the conical intersections, which play a decisive role in such phototranspositions, were obtained. The intermediates and transition structures of the ground state were also calculated to assist in providing a qualitative explanation of the reaction pathways. Our model investigations suggest that the preferred reaction route for bicyclo[4,1,0]hept-3-ene is as follows: reactant → Franck-Condon region → conical intersection → intermediate → transition state → photoproduct. Two reaction paths, which lead to final photoproducts, have been identified: (path I) ring expansion and (path II) ring closure. The former is more favorable than the latter. Also, our theoretical findings strongly indicate that there is a substantial interaction between the cyclopropane moiety and the isolated carbon-carbon double bond in the excited state of 1.     

From a Si3‐Cyclopropene to a Si3S‐Bicyclo[1.1.0]butane to a Si3S‐Cyclopropene to a Si3S2‐Bicyclo[1.1.0]butane: Back‐and‐Forth,and In‐Between

Compact and highly reactive bicyclo[1.1.0]butanes constitute one of the most fascinating classes of organic compounds. Furthermore, interplay of bicyclo[1.1.0]butanes with their valence isomers, such as buta‐1,3‐dienes and cyclobutenes, is among the fundamental pericyclic transformations in organic chemistry. Herein we report the back‐and‐forth interconversion between the cyclotrisilenes and thiatrisilabicyclo[1.1.0]butanes, allowing for the synthesis of novel representatives of such classes of highly reactive organometallics. The peculiar structural and bonding features of the newly synthesized compounds, as well as the mechanism of their isomerization, were verified both experimentally and computationally.     

From a Si3‐Cyclopropene to a Si3S‐Bicyclo[1.1.0]butane to a Si3S‐Cyclopropene to a Si3S2‐Bicyclo[1.1.0]butane: Back‐and‐Forth,and In‐Between

Compact and highly reactive bicyclo[1.1.0]butanes constitute one of the most fascinating classes of organic compounds. Furthermore, interplay of bicyclo[1.1.0]butanes with their valence isomers, such as buta‐1,3‐dienes and cyclobutenes, is among the fundamental pericyclic transformations in organic chemistry. Herein we report the back‐and‐forth interconversion between the cyclotrisilenes and thiatrisilabicyclo[1.1.0]butanes, allowing for the synthesis of novel representatives of such classes of highly reactive organometallics. The peculiar structural and bonding features of the newly synthesized compounds, as well as the mechanism of their isomerization, were verified both experimentally and computationally.     

Studies on the thermal ring-opening reactions of cis-3,4-bis(organosilyl)cyclobutenes

Three cis-3,4-bis(organosilyl)cyclobutenes were synthesized, and their thermal ring-opening reactions were studied. The ring-opening reaction of cis-3,4-bis(trimethylsilyl)cyclobutene proceeded remarkably faster than that of cis-3,4-dimethylcyclobutene. The significant rate acceleration was explained by assuming (i) stabilization of the transition state by electron delocalization from the cyclobutene HOMO to the Si-CH3 sigma* orbital, (ii) destabilization of the ground state by intramolecular interaction between the C-Si sigma orbitals and the pi orbital of cyclobutene, and (iii) through-space steric repulsion of the two bulky trimethylsilyl groups in a cis arrangement. The ring-opening reaction of unsymmetrical cis-3,4-bis(arylsilyl)cyclobutenes having electronically different arylsilyl groups was also examined. The inward preference increased in the order, p-CH3OC6H4-Si, C6H5-Si, p-CF3C6H4-Si, supporting the interpretation of the origin of the inward preference of silyl substituents on the basis of a stabilizing interaction between the cyclobutene HOMO and the Si-C sigma* orbital at the transition state.     

Cyclobutene Formation in PtCl2‐Catalyzed Cycloisomerizations of Heteroatom‐Tethered 1,6‐Enynes

Aza(oxa)bicyclo[3.2.0]heptenes are accessed through the PtCl₂‐catalyzed cycloisomerizations of heteroatom‐tethered 1,6‐enynes featuring a terminal alkyne and amide as the solvent. It is shown that the weak coordinating properties of the solvent and alkyl substituent(s) at the propargylic carbon atom favor the formation of cyclobutenes instead of other possible cycloisomerization products such as 1,3‐diene derivatives or cyclopropane‐fused heterocycles.     

Electrocyclic ring opening of cis-bicyclo[m.n.0]alkenes: the anti-Woodward-Hoffmann quest

The dubbed anti-Woodward-Hoffmann ring-opening reaction of cis-bicyclo[4.2.0]oct-7-ene to yield cis,cis-cycloocta-1,3-diene has been intensively studied with robust, high-level computational methods. This reaction has been found to proceed through a conrotatory allowed pathway to afford cis,trans-cycloocta-1,3-diene followed by E to Z isomerization, instead of a disrotatory forbidden pathway, as suggested. Computational calculations of kinetic isotope effects are consistent with this interpretation and the experimental values. The study of lower bicyclic homologues with [3.2.0], [2.2.0] and [2.1.0] skeletons indicates the feasibility of a mechanistic change towards the anti-Woodward-Hoffmann disrotatory path. This is clearly favored for the ring opening of the highly strained cis-bicyclo[2.1.0]pent-2-ene and is highly competitive with the conrotatory path for cis-bicyclo[2.2.0]hex-2-ene. Therefore, the rearrangement of the smallest bicyclic cyclobutene is predicted computationally to be an anti-Woodward-Hoffmann disrotatory electrocyclic ring-opening reaction.     

Ab initio study of the pathways and barriers of tricyclo[4.1.0.0(2,7)]heptene isomerization

The thermal isomerization of tricyclo[4.1.0.0(2,7)]heptene has been studied using computational chemistry with structures determined at the MCSCF level and energies at the MRMP2 level. Both the allowed conrotatory and forbidden disrotatory pathways have been elucidated resulting in cycloheptatriene isomers. Four reaction channels are available for the conrotatory pathway depending on which bond breaks first in the bicyclobutane moiety leading to enantiomeric pairs of (E,Z,Z)-1,3,5-cycloheptatriene and (Z,E,Z)-1,3,5-cycloheptatriene intermediates. The activation barrier is calculated to be 31.3 kcal·mol?1 for two channels and 37.5 kcal·mol?1 for the other two. The lower activation barrier leading to the (E,Z,Z)-1,3,5-cycloheptatriene enantiomeric pair is proposed to be due to resonance within the transition state. The same behavior was observed for the disrotatory pathway with activation barriers of 42.0 kcal·mol?1 and 55.1 kcal·mol?1 for the two channels, again with one transition state resonance stabilized. The barriers for trans double bond rotation of the intermediate cycloheptatrienes are determined to be 17.1 and 17.4 kcal·mol?1, about 5 kcal·mol?1 more than that for the seven carbon diene (E,Z)-1,3-cycloheptadiene. The electrocyclic ring closure of the trans cycloheptatrienes have been modeled and barriers determined to be 11.1 and 11.9 kcal·mol?1 for the formation of bicyclo[3.2.0]hepta-2,6-diene. This structure was previously reported as the end product for thermolysis of the parent tricyclo[4.1.0.0(2,7)]heptene. The thermodynamically more stable cycloheptatriene can be formed from bicyclo[3.2.0]hepta-2,6-diene through a two step process with a calculated pseudo first-order barrier of 36.4 kcal·mol?1. The trans-cycloheptatrienes reported herein are the first characterization of a small seven-membered ring triene with a trans double bond.     

Transition Metal Cation Salts in Organic Synthesis

Reaction of lithium diisopropylamide (LDA) with (η⁴-1,3-cyclohexadiene)Fe(CO)₃ complexes bearing functionalized side chains at C-5, under an atmosphere of carbon monoxide, gives bridged bicyclo[3,2,1]octene and bicyclo[3,3,1]nonene systems after electrophilic quenching. Under the same reaction conditions, intramolecular cyclization of acyclic (η⁴- 1,3-butadiene)Fe(CO)₃ complexes with functionalized side chains at the terminal position of the diene ligands furnishes fused bicyclo[3.3,0]octanone and bicyclo[4.3.0]nonanone derivatives after acid quenching. The addition of a variety of the highly functionalized zinc-copper reagents RCu(CN)ZnI to the (η⁷-cycloheptatrienyl)Cr(CO) gives (η⁶-cyclohepta-1,3,5-triene)Cr(CO)₃ complexes with a functionalized side-chain at the C-7 position of the ring. Intramolecular cyclization of ester-subsbtuted adducts using lithium diisopropylamide generates fused bicyclo[5.3.0]decane and bicyclo[5.4.0]undecane derivatives. The addition of a variety of the highly functionalized zinc-copper reagents RCu(CN)Znl to the (η⁴-cyclohexa-1,3-diene)Mo(CO)₂(Cp) at the terminus of the coordinated diene ligand gives [Mo(π-allyl)(CO)₂(Cp)](Cp = cyclopentadienyl) complexes with the functionalized side-chain at the C-4 position of the ring. Intramolecular cyclization of the (π-allyl)molybdenum complex containing a pendant propanoic acid unit generates the δ-lactone derivative.     

Formal synthesis of optically active ingenol via ring-closing olefin metathesis

The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.     

Photochemical reactions. 142nd communication. Photochemistry of a 6,7-epoxy-1,3-diene of the ionone series

On singlet excitation (λ = 254 nm), the epoxydiene (E)- 3 underwent (E)/(Z)-isomerization, electrocyclic ring closure of the diene side chain leading to the cyclobutenes 4A + B , and rearrangement to the cyclohexanones 5A + B . Compounds 5A + B were presumably formed in a series of processes including a 1,3-acyl shift of the homoconjugated ketone 8 , arising from (Z)- 3 by a 1,5-H-shift accompanied by cleavage of the C,O-bond of the oxirane.     

Conformations and reactions of bicyclo[3.2.1]oct-6-en-8-ylidene

Bicyclo[3.2.1]oct-6-en-8-ylidene (1) can assume either the conformation of "classical" carbene 1a or that of foiled carbene 1b in which the divalent carbon bends toward the double bond. Oxadiazoline precursors for the generation of 1 were prepared, followed by photochemical and thermal decomposition as well as flash vacuum pyrolysis (FVP) of a tosyl hydrazone sodium salt precursor, to give a number of rearrangement products. Matrix isolation experiments demonstrate the presence of a diazo intermediate and methyl acetate in all photochemical and thermal precursor reactions. The major product from rearrangements of "classical" bridged carbene 1a is bicyclo[3.3.0]octa-1,3-diene as a result of an alkyl shift, while dihydrosemibullvalene formed from a 1,3-C-H insertion. In contrast, thus far unknown strained bicyclo[4.2.0]octa-1,7-diene formed by a vinyl shift in foiled carbene 1b. The experimental results are corroborated by density functional theory (DFT), MP2, and G4 computations.     

Ab initio study on deactivation pathways of excited 9H-guanine

The complete active space with second-order perturbation theory/complete active space self-consistent-field method was used to explore the nonradiative decay mechanism for excited 9H-guanine. On the 1pipi* (1L(a)) surface we determined a conical intersection (CI), labeled (S0pipi*)(CI), between the 1pipi* (1L(a)) excited state and the ground state, and a minimum, labeled (pipi*)min. For the 1pipi* (1L(a)) state, its probable deactivation path is to undergo a spontaneous relaxation to (pipi*)min first and then decay to the ground state through (S0pipi*)(CI), during which a small activation energy is required. On the 1n(N)pi* surface a CI between the 1n(N)pi* and 1pipi* (1L(a)) states was located, which suggests that the 1n(N)pi* excited state could transform to the 1pipi* (1L(a)) excited state first and then follow the deactivation path of the 1pipi* (1L(a)) state. This CI was also possibly involved in the nonradiative decay path of the second lowest 1pipi* (1L(b)) state. On the 1n(O)pi* surface a minimum was determined. The deactivation of the 1n(O)pi* state to the ground state was estimated to be energetically unfavorable. On the 1pisigma* surface, the dissociation of the N-H bond of the six-membered ring is difficult to occur due to a significant barrier.     

A DFT study of the pericyclic/pseudopericyclic character of cycloaddition reactions of ethylene and formaldehyde to buta-1,3-dien-1-one and derivatives

Cycloaddition reactions of ethylene and formaldehyde to buta-1,3-dien-1-one and derivatives were studied by performing a density functional theory study with the 6-31+G* basis set. Reactants, products, and transition states for each reaction were localized, and the path connecting reactants and products was also obtained. Magnetic properties were evaluated along the reaction path to elucidate the characteristics of the reactions studied. Also, a natural bond orbital analysis was performed to study the orbital interactions in the transition states. Calculations indicate that all reactions are pericyclic except three cases, which are pseudopericyclic reactions. In the latter, transition states are almost planar, and magnetic properties do not reveal aromatization enhancement in their transition states. Also, though the participation of lone pairs diminish the pericyclic character of the reactions, sometimes this participation is not enough to generate a change to a pseudopericyclic path. Overall, magnetic properties reveal as a good criterion to elucidate the characteristics of the reactions studied, though a combined application of several criteria is recommended.