Synthesis of new quinuclidine derivatives via Pd-mediated cross-coupling and cross-benzannulation reactions

New functionalized quinuclidines were prepared via palladium-catalyzed addition reactions of terminal alkynes (donors) to internal alkynes (acceptors). The enantiopure terminal alkynes were derivatives of quincoridine and quincorine, two semi-natural Cinchona alkaloids. The processes exhibited high chemoselectivity and excellent diastereoselectivity, the E-enynes being obtained as single products in almost all cases. The synthesis of new tetra and pentasubstituted benzene derivatives in good yields by [2+2+2] benzannulation of the diynes, obtained by the palladium-catalyzed homodimerization of 10,11-didehydro quincoridine and 10,11-didehydro quincorine, with terminal alkynes and in fair yield by [4+2] benzannulation of an enyne derivative of 10,11-didehydro quincoridine with 2,4-hexane-diyne are reported.     

Central-to-axial chirality transfer in the benzannulation reaction of optically pure Fischer carbene complexes in the synthesis of allocolchicinoids

A method for the synthesis of allocolchicinoids is explored that involves the benzannulation reaction of Fischer chromium carbene complexes with alkynes. The benzannulation reaction is employed to install the aromatic C-ring via the reaction of an α,β-unsaturated carbene complex in which the carbene complex is attached to a seven-membered ring that is to become the B-ring of the allocolchicinoids. Two different regioisomeric series can be accessed depending on which position the carbene complex is on the seven-membered ring. A key issue that is addressed is the stereochemistry of the newly formed axis of chirality that results from a stereo-relay from an existing chiral center on the seven-membered ring at the position destined to be C(7) in the allocolchicinoids. The level of stereochemistry is dependent on the position of the carbene complex on the seven-membered ring. A mechanism is proposed to account for this stereochemical dependence and to account for the observed effects of temperature and solvent on the stereoselectivity. Finally, the benzannulation reactions of optically pure complexes are examined and quite surprisingly one, but not both, of the diastereomeric products is racemized. The racemization can be prevented with the proper choice of solvent and temperature. A mechanism is proposed to account for the racemization of only one of the diastereomers of the product that involves the intermediacy of an o-quinone methide chromium tricarbonyl complex.     

Studies into diastereoselective Dötz benzannulations for the synthesis of axially chiral biaryls

A series of racemic chiral ortho substituents on 1-phenylhex-1-yne have been found to control the atroposelective formation of a biaryl from Dötz benzannulation with pentacarbonyl(methoxyphenylmethylene)chromium(0). The results show there is a subtle balance between the chiral ortho substituent controlling atroposelectivity with a dr 3-5:1 and allowing benzannulation to proceed in yields of 44-67%.     

Regioselective solvent-dependent benzannulation of conjugated enynes

The transformation of enynes under cobalt-catalysis leads to symmetrical benzannulation products in dichloromethane. In tetrahydrofuran the cobalt-catalysed reactions afforded the unprecedented unsymmetrical benzannulation products in moderate to good yields and good regioselectivities. In addition, cyclotrimerisation of the alkyne subunit can be realised when electron-deficient enynes are applied in the cobalt-catalysed transformations to generate 1,2,4-trivinylbenzene derivatives using tetrahydrofuran as solvent.     

The Preparation and Evaluation of Electron Poor Benzylidene Fischer Carbene Complexes: Studies Toward the Total Synthesis of (+)-Olivin

The continued exploration into the fate of the benzannulation reaction is put forth using the electronic nature of substituents on the aryl ring of benzylidene Fischer carbene complexes as a handle to predict, using σ-para values as a guide, the outcome of the reaction based on the accepted mechanism. The design of this work focuses on evaluation of the synthetic utility of the benzannulation reaction and the means by which this reaction may be improved to be a better synthetic tool in the preparation of complex natural products as this is illustrated in our ongoing total synthesis of (+)-olivin which uses the benzannulation reaction as the key convergent synthetic step. To accomplish these tasks, the preparation of several electron poor benzylidene Fischer carbene complexes was carried out and their reaction with simple alkyne substrates studied. While much is known about the preparation of electron rich benzylidene Fischer carbene complexes, little is known about the preparation of their electron poor counterparts. Thus efforts toward developing useful preparative methods of these elusive targets has also been studied. While the use of both carbon and oxygen based aryl substituents has been explored, to date the preparation of benzylidene carbene complexes containing oxygen based aryl substituents has been exploited to a greater degree since these systems carry more immediate synthetic importance. This is so because the skeletal core of many of the natural products that have been targeted with the benzannulation reaction including (+)-olivin contain a highly oxygenated polycyclic aromatic core. The enhancement in efficiency of the benzannulation reaction using this synthetic methodology is demonstrated by the successful completion of the convergent synthetic step in the total synthesis of (+)-olivin.     

A quantum chemical study of the haptotropic rearrangements of Cr(CO)(3) on naphthalene and phenanthrene systems

First-principles gradient-corrected density functional theory electronic structure calculations of the haptotropic rearrangement of a Cr(CO)(3) unit on naphthalene and phenanthrene derivatives are reported. Coupled-cluster calibration studies of Cr(CO)(3) complexes with benzene and naphthalene derivatives confirm the accuracy of the applied Becke exchange and Perdew correlation functionals. Characteristic points on the energy hypersurface (reactants, products, intermediates, and transition states) were located for various substituents on the aromatic skeleton. It is argued that a -OH/-O(-) substituent may provide a means to steer the haptotropic shift depending on the pH value, i.e., to construct a molecular switch. In addition, the mechanism of the [3 + 2 + 1] benzannulation of chromium pentacarbonyl naphthylcarbene complexes with alkynes was investigated, and the preference of the angular benzannulation leading to phenanthrene complexes of Cr(CO)(3) over the linear benzannulation leading to corresponding anthracene complexes is explained.     

Rhodium‐Catalyzed Oxidative Benzannulation of N‐Pivaloylanilines with Internal Alkynes through Dual C−H Bond Activation: Synthesis of Highly Substituted Naphthalenes

An efficient method was developed for the synthesis of highly substituted naphthalenes through rhodium‐catalyzed oxidative benzannulation of N‐pivaloylanilines with internal alkynes. The benzannulation reaction proceeded smoothly through dual C?H bond activation to produce the corresponding highly substituted naphthalene products in satisfactory to good yields.     

Dötz Benzannulation Reactions: Heteroatom and Substituent Effects in Chromium Fischer Carbene Complexes

We have carried out a theoretical investigation of the Dötz reaction between acetylene and a series of chromium Fischer‐type carbenes [(CO)₅Cr?C(X)R] with different representative substituents (R=CH?CH₂, Ph) and heteroatom ligands (X=OH, NH₂, OCH₃, N(CH₃)₂) by using density functional theory with the B3LYP functional. We have studied the Dötz and chromahexatriene mechanisms of benzannulation and also the reaction mechanism leading to cyclopentannulation. For the benzannulation, it was found that the most likely mechanism in the case of vinylcarbenes is the chromahexatriene route, whereas for phenylcarbenes, the Dötz route via a ketene intermediate is clearly the most favorable. The reactions leading to the cyclopentannulated and benzannulated products are more exothermic with vinylcarbenes than with phenylcarbenes and also more exothermic with alkoxycarbenes than with aminocarbenes. The relative stability of the cyclopentannulated products as compared with the benzannulated products increases for bulkier X substituents and on going from alkoxy‐ to aminocarbenes. The kinetic data concurs with the experimental product distribution found for vinylcarbenes, by which mainly benzannulated products are obtained, and dimethylaminophenylcarbenes, which lead exclusively to cyclopentannulated adducts.     

Synthesis of phthalides and 3,4-dihydroisocoumarins using the palladium-catalyzed intramolecular benzannulation strategy

A novel method for the synthesis of phthalides and 3,4-dihydroisocoumarins via the palladium-catalyzed intramolecular benzannulation of bis-enyne and enyne-diyne systems is described. Various kinds of substituted phthalides 9 and 17 and 3,4-dihydroisocoumarins 19 were synthesized from 8, 16, and 18, respectively, in moderate to excellent yields. The benzannulation reaction proceeded chemoselectively to give the corresponding fused ring compounds A without the formation of the regioisomeric products B (eq 6). Furthermore, this methodology was applied to the synthesis of biologically active 3-n-butylphthalide 23.     

An unusual decarboxylative benzannulation and biaryl formation during copper(I)-promoted halogen atom transfer radical cyclization of 2-allylaryl trichloroacetates

CuCl/bpy-promoted halogen atom transfer radical cyclization of 2-allylaryl trichloroacetates in refluxing benzene gave benzannulated chloroarenes and benzannulated symmetrical biaryls along with reductive dehalogenation products. The unusual decarboxylative benzannulation and biaryl formation might be explained by a further intramolecular radical addition on the benzene ring of the eight-membered lactone intermediate, initially formed through 8-endo-trig halogen atom transfer radical cyclization, followed by decarboxylation, radical dimerization and dehydrochlorination reactions.     

Chromene chromium carbene complexes in the syntheses of naphthopyran and naphthopyrandione units present in photochromic materials and biologically active natural products

The carbene complex 5-(2,2-dimethyl-2H-chromene)methoxylmethylene chromium pentacarbonyl will undergo a benzannulation reaction with phenylacetylene, 1-pentyne, 3-hexyne, and trimethylsilylacetylene to give 7-hydroxy-10-methoxy-3H-naphtho[2.1-b]pyrans as the primary product. These compounds are difficult to obtain pure due to their sensitivity to air. If the benzannulation reaction is performed in conjunction with protection of the phenol function at C-7, then good to excellent yields of 7-alkoxy-10-methoxy-3H-naphtho[2.1-b]pyrans are afforded. If the 7-hydroxy products are captured by triflic anhydride, then the resulting aryl triflate can be used to access 3H-naphtho[2.1-b]pyrans bearing C-7 carbon substituents. The 7-hydroxy products can be oxidized to 3H-naphtho[2,1-b]pyran-7,10-diones which are stable. The chromenyl carbene complex reacts with 1,6-bis(triisopropylsilyl)-1,3,5-hexatriyne to give a 2,3-dihydro-2,2-dimethylbenzo[de]chromene, a product type that has not been seen before in the reaction of Fischer carbene complexes with alkynes. A mechanism is proposed for this process that involves alpha,beta-hydride elimination from a chromacyclobutane intermediate. Chromenyl tungsten complexes react with alkynes to give products that result from cyclization without CO insertion.     

Dramatic acceleration of the pd-catalyzed [4+2] benzannulation reaction of enynes and diynes in the presence of lewis acids and bases: expanded scope and new mechanistic insights

Dramatic acceleration of the palladium catalyzed [4+2] benzannulation and sequential [2+2+2] trimerization reactions in the presence of a Lewis acid/phosphine combination or in the presence of Bronsted bases has been explored. These novel sets of conditions allowed for remarkable enhancement of reaction rates and broadening of the substrate scope and for a significant improvement of reaction yields, particularly for problematic pentasubstituted benzenes. It was found that the real nature of Lewis acid acceleration does not only lie in the isomerization of conjugated enynes but also in the direct acceleration of the [4+2] benzannulation reaction. These experimental findings, combined with the deuterium-labeling studies and DFT calculations, led to a mechanistic rationale, which (a) reasonably accounts for the observed acceleration of the reaction by Lewis acid and bases; (b) provides a viable alternative route for the ring-closing step in the mechanism of benzannulation; (c) clarifies the mechanism of hydrogen migration; and (d) for the first time provides a rationale for the origins of the remarkable stereoselectivity of the hydrogen migration during the benzannulation reaction.     

Total Syntheses of Xiamycins A,C, F,H and Oridamycin A and Preliminary Evaluation of their Anti‐Fungal Properties

Divergent and enantiospecific total syntheses of the indolosesquiterpenoids xiamycins A, C, F, H and oridamycin A have been accomplished. The syntheses, which commence from (R)‐carvone, employ a key photoinduced benzannulation sequence to forge the carbazole moiety characteristic of these natural products. Late‐stage diversification from a common intermediate enabled the first syntheses of xiamycins C and F, and an unexpected one‐pot oxidative decarboxylation, which may prove general, led to xiamycin H. All synthetic intermediates and the natural products were tested for anti‐fungal activity. Xiamycin H emerged as an inhibitor of three agriculturally relevant fungal pathogens.     

Total Syntheses of Xiamycins A,C, F,H and Oridamycin A and Preliminary Evaluation of their Anti‐Fungal Properties

Divergent and enantiospecific total syntheses of the indolosesquiterpenoids xiamycins A, C, F, H and oridamycin A have been accomplished. The syntheses, which commence from (R)‐carvone, employ a key photoinduced benzannulation sequence to forge the carbazole moiety characteristic of these natural products. Late‐stage diversification from a common intermediate enabled the first syntheses of xiamycins C and F, and an unexpected one‐pot oxidative decarboxylation, which may prove general, led to xiamycin H. All synthetic intermediates and the natural products were tested for anti‐fungal activity. Xiamycin H emerged as an inhibitor of three agriculturally relevant fungal pathogens.     

An open-and-shut strategy: preparation of benzo-fused indanes by ring-opening of a vinylogous acyl triflate and metal-catalyzed Asao-Yamamoto benzannulation

A two-step strategy for the synthesis of benzo-fused indanes is outlined herein. The strategy draws on two independent methodologies: the tandem addition/fragmentation of vinylogous acyl triflates (VATs) and the intramolecular benzannulation of o-alkynylphenyl ketones. Reduction of this strategy to practice involves the use of aryltriazenes as masked aryl iodides; a synthetic equivalent of 2-iodophenyllithium is featured. Benzo-fused indanes are prepared efficiently and in high yield.     

Benzannulation of Triynes to Generate Functionalized Arenes by Spontaneous Incorporation of Nucleophiles

The thermal reaction of ester‐tethered 1,3,8‐triynes provides novel benzannulation products with concomitant incorporation of a nucleophile. Evidence suggests that this reaction proceeds via an allene‐enyne intermediate generated by an Alder‐ene reaction in the first step. Depending on the substituent of the alkyne moiety on the allene‐enyne intermediate, the subsequent transformation can take one of two different paths, each leading to discrete aromatization products. The benzannulation of a silane‐substituted 1,3,8‐triynes provides arene products with a nucleophile incorporated onto the newly formed benzene core, whereas an aryl substituent leads to nucleophile trapping at the benzylic carbon atom connected to the aryl substituent. The formation of these two different products results from the involvement of two regioisomeric allene‐enyne intermediates.     

Synthesis of arylnaphthalene lignan scaffold by gold-catalyzed intramolecular sequential electrophilic addition and benzannulation

An intramolecular approach to generate compounds containing an arylnaphthalene lignan scaffold in high yields is presented. It involves a sequential intramolecular electrophilic attack of carbonyl on arylalkyne followed by benzannulation catalyzed by gold salt. AuCl(3) in combination with AgSbF(6) works better to effect this transformation. Selected products have been converted into arylnaphthalene lactone natural products such as justicidin E, taiwanin C, and retrojusticidin B.     

A formal synthesis of aflatoxin B2: a Dötz benzannulation approach

A Dötz benzannulation reaction has been utilized in the synthesis of the furo[2,3-b]furan core of aflatoxin B2.     

Extended Dötz-like cyclization reactions towards the synthesis of eight-membered ring-containing polycycles: scope and theoretical studies

The reaction between cyclobutene-containing dienyl Fischer carbene complexes (FCCs) and alkynes has been studied from both an experimental and a theoretical point of view. We have found that the reaction follows different pathways depending on the nature of the terminal double bond of the carbene complex. Thus, eight-membered carbocycles have been obtained from an extended D?tz-like reaction of dienyl FCCs and indolyl- or benzofuryl-substituted alkenyl FCCs. On the other hand, phenyl- and naphthyl-substituted alkenyl FCCs follow a typical benzannulation pathway giving rise to cyclohexadienones. DFT calculations have allowed us to formulate detailed mechanistic proposals and to provide an explanation for the formation of either the benzannulation products or the eight-membered carbocycles.     

A highly diastereoselective oxa-Pictet-Spengler approach to (+)-astropaquinone B and (+)-astropaquinone C and the formation of astropaquinone B dimer

A concise and highly diastereoselective synthesis of (+)-astropaquinone B and (+)-astropaquinone C is reported. The synthetic strategy is based on an efficient combination of Dötz benzannulation using a chiral alkyne to construct the naphthalene unit and a highly diastereoselective oxa-Pictet-Spengler reaction to install the trans-configured pyran ring as the key steps.