Exocyclic Diene Research Articles

Total Synthesis of Bioactive Tricyclic Marine Alkaloids, Lepadiformine and Related Compounds

Abstract The first total synthesis of tricyclic marine alkaloids (±)-fasicularin (2) and (±)-lepadiformine (5) has been accomplished. The key common strategic element for the synthesis is the stereocontrolled intramolecular hetero-Diels–Alder reaction of an N-acylnitroso moiety with an exocyclic diene with or without bromine substitution to control the syn-facial or anti-facial selectivity, respectively. This reaction leads to the trans- or cis-fused decahydroquinoline ring systems 13 or 23 involving the simultaneous introduction of the nitrogenated quaternary center in a single step. On further elaboration of the six-membered or five-membered ring A, the trans-fused adduct 13 provided either (±)-fasicularin (2) or (±)-lepadiformine (5). The hydrochloride salt of synthetic (±)-5 was found to be identical with the isolated natural sample of lepadiformine, however, the tricyclic amino alcohol 4 that has the proposed structure of lepadiformine in a non-zwitterionic form, derived from the cis-fused adduct 23, was found to be different from lepadiformine by spectral comparison. These results thus unambiguously established the relative stereochemistry of lepadiformine, formerly assigned incorrectly, as shown by 5. The synthesis of natural (−)-enantiomer of lepadiformine was then undertaken using a highly efficient protocol involving a new variant of the N-acyliminium ion-initiated intramolecular spirocyclization in which a conjugated diene was exploited as a π nucleophile. Thus, the synthesis is accomplished in nine steps with 31.4% overall yield, making this the most selective and shortest synthesis of lepadiformine to date. Direct comparison of chiral HPLC analysis of synthetic (−)-lepadiformine and the natural product allowed to assign the absolute configuration of natural lepadiformine to be 3R,5S,7aR,11aR.

Low and high temperature bromination of exocyclic dienes: high temperature bromination. Part 16

The electrophilic addition of bromine to an exocyclic diene, 5,6-dimethylenebicyclo[2.2.1]hept-2-ene, in CCl 4 at 0°C led to the formation of non-rearranged (73%) and rearranged products (27%). However, high temperature bromination of the exocyclic diene at 77°C suppressed the formation of the rearranged products. Similarly, bromination of 9,10-dimethylenetricyclo[6.2.1.0 2,7]undeca-2,4,6-triene at −10°C gave only the exo-1,2-addition product. Bromination at +5°C resulted in the formation of a mixture consisting of exo-1,2- and 1,4-addition products in a ratio of (1:4). High temperature bromination at 77°C resulted in the formation of the endo-1,2-addition product. Furthermore, it has been shown that the 1,4-addition product converts smoothly to the 1,2-addition product. The formation mechanism of the products is discussed and supported by calculations.

New strategies and building blocks for functionalised 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene derivatives, including pyrrolo-annelated derivatives and pi-extended systems with intramolecular charge-transfer.

A range of new functionalised 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene (TTFAQ) derivatives have been synthesised from the key di(halomethyl) building blocks, 10-[4,5-bis(bromomethyl)-1,3-dithiol-2-ylidene]-anthracene-9(10H)-one 10, 10-[4,5-bis(chloromethyl)-1,3-dithiol-2-ylidene]anthracene-9(10H)-one 11 and 9-[4,5-bis(chloromethyl)-1,3-dithiol-2-ylidene]-10-[4,5-bis(hexylsulfanyl)- 1,3-dithiol-2-ylidene]-9,10-dihydroanthracene 18. A Diels-Alder strategy comprising trapping of the transient exocyclic diene 19, which is derived from 18, with 1,4-naphthoquinone leads to the aromatised TTFAQ anthraquinone system 21. Horner-Wadsworth-Emmons olefination of 21 with the anion generated from reagent 22 gave the fused bis(TTFAQ) structure 23. Pyrrolo-annelated derivatives 30-34 have been obtained in a sequence of reactions from compound 10. Mono-formylation of the pyrrole ring of 32 and 33 under Vilsmeier conditions gave 35 and 36 which upon reaction with 2,4,5,7-tetranitrofluorene gave the donor-pi-acceptor diads 38 and 39. Cyclic voltammetry (CV) in solution for all the TTFAQ derivatives shows the typical quasi-reversible two-electron oxidation wave of the TTFAQ core at potentials which vary slightly depending on the substituents. For example, the value of Eox is raised by the electron withdrawing anthraquinone and tetranitrofluorene units of 21 and 38, respectively. The CV of the conjugated TTFAQ dimer 23 showed two, two-electron oxidation waves corresponding to the sequential formation of 23(2+) and 23(4+) (delta Eox = 130 mV) providing evidence for a significant intramolecular electronic interaction, i.e. the dication 23(2+) acts as a conjugated donor-pi-acceptor diad, thereby raising the oxidation potential of its partner TTFAQ unit. Spectroelectrochemical studies on 23 support this explanation. A strong intramolecular charge transfer band at lambda max 538 nm is seen in the UV-Vis spectra of the TTFAQ-pi-tetranitrofluorene diads 38 and 39. The X-ray crystal structures are reported for compounds 30, 33 and 34. The pyrrolo-TTFAQ moiety adopts a saddle-shape with the central ring of the dihydroanthracene moiety folded along the C(9) ... C(10) vector in each case. Significant intermolecular interactions are observed in the structures.

Reaction of 2,2-bis(trifluoromethyl)-1,1-dicyanoethylene with 6,6-dimethylfulvene: cycloadditions and a rearrangement.

Reaction of 2,2-bis(trifluoromethyl)-1,1-dicyanoethylene (BTF; 1) with 6,6-dimethylfulvene (2) affords the expected Diels-Alder cycloadduct, 7-(1-methylethylidene)-3,3-bis(trifluoromethyl)bicyclo[2.2.1]hept-5-ene-2,2-dicarbonitrile (3), in good yield. The cycloadduct 3 is unstable and exists in equilibrium with the starting materials in less polar solvents. In more polar environment, the [4 + 2] adduct 3 either reverts to starting materials, or, in a competing process, is converted to the formal [2 + 2] adduct, 2-(1-methylethylidene)-7,7-bis(trifluoromethyl)bicyclo[3.2.0]hept-3-ene-6,6-dicarbonitrile (6). In the presence of acid, 3 is converted to a third isomeric form, 1,3a,5,6-tetrahydro-7-methyl-5,5-bis(trifluoromethyl)-4H-indene-4,4-dicarbonitrile (8). Both 6 and 8 are formed with complete regiospecificity. Quantum mechanical calculations and X-ray crystallographic studies of this ensemble of reactions by BTF, and the analogous set of reactions by its progenitor, tetracyanoethylene (TCNE), reveal several interesting facets. The conversion of 3 to 6 occurs in certain polar solvents, in the presence of silica gel and alumina, as well as in the solid state. Single crystals of 3 were observed by X-ray crystallography to undergo crystal-to-crystal rearrangement to 6. The conversion of 3 to 8 proceeds by the initial retro-Diels-Alder reaction followed by isomerization of the fulvene to 1-isopropenyl-1,3-cyclopentadiene that then reacts with BTF to give the alternative Diels-Alder product as a single regioisomer. A hybrid density functional theory (DFT) method at the B3LYP/6-31G(d) level of theory gave calculated relative energies of 0.0, -9.0, and -18.8 kcal/mol for 3, 6, and 8, respectively. The same method was also used to correctly predict the regiochemical outcome of the cycloaddition of BTF with 1-isopropenyl-1,3-cyclopentadiene. Finally, an explanation is offered for the preference of the persubstituted cyanoolefins BTF and TCNE to add to the exocyclic diene portion of 1-isopropenyl-1,3-cyclopentadiene and the contrasting preference of 2-acetyloxy-2-propenenitrile to add to the endocyclic diene.

Stereoselective Synthesis of 4,5-Diethylidene-Oxazolidinones as New Dienes inDiels-Alder Reactions

The N-substituted isomeric (4Z,5Z)- and (4E,5Z)-4,5-diethylideneoxazolidin-2-ones 5 and 6 were synthesized, the latter being favored during the one-step process from the α-diketone 1c and different isocyanates. The steric interaction between the N-substituent and the Me group attached to the exocyclic diene moiety plays a decisive role in controlling the observed stereoselectivity, as suggested by the calculated free energies of the two isomers. Both dienes undergo efficient additions to symmetric dienophiles in thermal Diels-Alder reactions to yield the adducts 11 and 13, respectively. These molecules displayed interesting C−H⋅⋅⋅π, and C−H⋅⋅⋅X (X=O, Cl) interactions according to their X-ray crystal structures. Isomers 6 suffered highly stereo- and regioselective additions with nonsymmetrical dienophiles such as methyl vinyl ketone or methyl propiolate. Steric interactions, promoted by the inward-pointing Me group in 6, seem to explain such selectivity. These results have also been rationalized by ab initio calculations in terms of the FMO theory.

Theoretical study of reactions of α-diimines with p(III) acid halides by semiempirical quantum-chemical methods

Stability of potential products of α-diimine reactions with P(III) acid halides was characterized by PM3 semiempirical quantum-chemical calculations with full geometry optimization. The energetic favorability of formation of diazaphospholene (oxodiazaphospholene) or diazaphospholane cyclic structures with an exocyclic diene system from acyclic diimines and cyclohexanediimine and the unfavorability of formation of similar structures from dihydropyrazines was demonstrated. Dihydropyrazines should prefer phosphorylation involving one of the C = N bond. The calculation results fairly agree with available experimental data and allow prognosis of the probability of formation of one or another structure in new reactions.

Synthesis of 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Tic) Derivatives by Cycloaddition Approaches

A new and general synthetic methodology for the preparation of functionalized 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives by a cycloaddition strategy is described. The synthesis of various enyne building blocks 12, 13, 21, and 22 containing an α-amino acid moiety using Schiff base 8 as a glycine equivalent has been achieved under mild reaction conditions. These building blocks have been utilized in the synthesis of inner-outer ring dienes 23 and 24 and exocyclic dienes 26 and 29, the key steps being an enyne metathesis reaction and cycloisomerization. Various topographically constrained Tic derivatives have been synthesized using dienes containing an α-amino acid moiety through Diels−Alder reactions. For the first time, [2+2+2] cyclotrimerization, as promoted by Wilkinson’s and Vollhardt’s catalysts, has been used for the synthesis of various highly functionalized Tic derivatives.

Cyclization of alkenyl radicals in 5- and 6-(pi-Exo)-exo-dig modes: new entry to exo-cyclic dienes

Radical cyclizations of alkenyl iodides in both 5- and 6-(pi-exo)-exo-dig modes were effected by tributyltin hydride and AIBN to give exo-cyclic dienes fused to five- and six-membered rings in good yields.

First Total Synthesis of the Marine Alkaloids (±)-Fasicularin and (±)-Lepadiformine Based on Stereocontrolled Intramolecular Acylnitroso-Diels−Alder Reaction

The first total synthesis of tricyclic marine alkaloids (±)-fasicularin (2) and (±)-lepadiformine (5) was accomplished. The key common strategic element for the synthesis is the stereocontrolled intramolecular hetero-Diels−Alder reaction of an N-acylnitroso moiety to an exocyclic diene with or without bromine substitution to control the syn-facial or anti-facial selectivity, respectively, leading to the trans- or cis-fused decahydroquinoline ring systems 21 or 39 involving the simultaneous introduction of the nitrogenated quaternary center in a single step. On further elaboration of the six-membered or five-membered ring A, the trans-fused adduct 21 provided either (±)-fasicularin (2) or (±)-lepadiformine (5). The hydrochloride salt of synthetic (±)-5 was found to be identical with the isolated natural sample of lepadiformine; however, the tricyclic amino alcohol 4 having the proposed structure of lepadiformine in a nonzwitterionic form, derived from the cis-fused adduct 39, was found to be different from lepadiformine by spectral comparison. These results thus unambiguously established the relative stereochemistry of lepadiformine, formerly assigned incorrectly, to be 3R*,5S*,7aR*,11aR* shown by 5.

Electron-Transfer-Induced Diels–Alder Reactions of Indole and Exocyclic Dienes: Synthesis and Quantum-Chemical Studies

Regio- and stereoselectivities of radical-cation Diels–Alder reactions (see equation) can be explained and predicted by quantum-chemical calculations. The cycloadditions between indole and exocyclic dienes are catalyzed by photoinduced electron transfer.

Electron-Transfer-Induced Diels-Alder Reactions of Indole and Exocyclic Dienes: Synthesis and Quantum-Chemical Studies

Regio- and stereoselectivities of radical-cation Diels–Alder reactions (see equation) can be explained and predicted by quantum-chemical calculations. The cycloadditions between indole and exocyclic dienes are catalyzed by photoinduced electron transfer.

Evidence for the intermediacy of an alkyne rather than an allene in the base-induced reaction of 3-bromo-6,7-benzobicyclo[3.2.1]octa-2,6-diene

In order to reveal the real intermediate in the base-promoted reaction of 1, 2-methyl derivative 16 has been synthesized and its HBr elimination reaction studied. Reaction of 16 with potassium t-butoxide did not form the corresponding allene intermediate 17 under the same reaction conditions as described for 1. Under more drastic conditions exocyclic diene 18 was formed. These results provide evidence for the intermediacy of the alkyne 3 in the base-promoted reaction of 1.

Radical cation Diels–Alder reaction between indoles and exocyclic 1,3-dienes with incorporated intentional cleaving points

A photoinduced electron transfer catalyzed radical cation Diels–Alder reaction between exocyclic dienes, containing an N–O or N–N bond as an intentional cleaving point in the ring moiety, and indoles yields, after cleavage of the N–O or N–N bond, highly functionalized tetrahydrocarbazole derivatives, products of a formal Diels–Alder reaction between indole and open chain 1,3-dienes.

The first Diels–Alder reaction of a 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene derivative: synthesis and crystal structure of a novel donor–π–anthraquinone diad

An exocyclic diene derivative of 9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene undergoes Diels–Alder reaction with naphthoquinone to provide the D–π–A diad 10.

Synthesis of 3,4-disubstituted furans via unsaturated cyclic peroxides arising by photooxygenation of 2,3-bis (bromomethyl)-1,3-butadiene and derived exocyclic dienes

The reaction of 2,3-bis (bromomethyl)-1,3-butadiene ( 3) with singlet oxygen resulted in the formation of a peroxide ( 4) which rearanged with CoTPP to bis(bromomethyl)furan. Zinc-induced debromination of cycloadducts which were obtained from the [2+4] Diels-Alder reactions of 3 with DMAD and benzyne gave exocyclic dienes 7 and 11 from which fused ring furans were prepared by photooxygenation followed by rearrangement. 4,5-Dimethylene-1,2-dioxane ( 14) was synthesized by zinc-induced debromination of 4. The cycloaddition reactions of 14 with MTAD, singlet oxygen and DMAD were studied.

Site-Selective Diels-Alder Reactions of 7-(Methoxyimino)-4-methylchromene-2,8-dione with Alkenes.

Regio- and site-selective Diels-Alder reactions of o-quinone monooxime 1 are reported. The electron rich dienophiles 2, 4, 6, 8, and 10 react with the exocyclic diene system of monooxime 1 leading to the coumarin derivatives 3, 5, 7, 9, 11, and 12. The electron deficient dienophiles 13a,b and 18 react with the quinoid and the pyrone diene systems of compound 1 affording the cycloadducts 14a,b, 17a,b, and 19.

Convergent approaches to the Vitamin D skeleton using a transition metal catalyzed carbometalation/capture strategy

Two concise, highly convergent strategies for the synthesis of Vitamin D derivatives are presented. Beginning with synthons of exceedingly low complexity, each approach utilizes a transition metal catalyzed intramolecular carbometalation for the stereoselective formation of the critical (bis)exocyclic diene subunit.

ChemInform Abstract: Aromatization of Hydrocarbons by Oxidative Dehydrogenation Catalyzed by the Mixed Addenda Heteropoly Acid H5PMo10V2O40.

The mixed addenda heteropoly acid H{sub 5}PMo{sub 10}V{sub 2}O{sub 40} dissolved in 1,2-dichloroethane with tetraglyme, forming the (tetraglyme){sub 3}-H{sub 5}PMo{sub 10}V{sub 2}O{sub 40} complex, catalyzes the aromatization of cyclic dienes at moderate temperatures in the presence of molecular oxygen. Dehydrogenations of exocyclic dienes such as limonene show that dehydrogenation is preceded by isomerization to their endocyclic isomers. Aromatization takes place by successive one-electron transfers and proton abstractions from the organic substrate to the heteropoly acid the latter being reoxidized by dioxygen coupled with the formation of water.

Aromatization of hydrocarbons by oxidative dehydrogenation catalyzed by the mixed addenda heteropoly acid H5PMo10V2O40

The mixed addenda heteropoly acid H{sub 5}PMo{sub 10}V{sub 2}O{sub 40} dissolved in 1,2-dichloroethane with tetraglyme, forming the (tetraglyme){sub 3}-H{sub 5}PMo{sub 10}V{sub 2}O{sub 40} complex, catalyzes the aromatization of cyclic dienes at moderate temperatures in the presence of molecular oxygen. Dehydrogenations of exocyclic dienes such as limonene show that dehydrogenation is preceded by isomerization to their endocyclic isomers. Aromatization takes place by successive one-electron transfers and proton abstractions from the organic substrate to the heteropoly acid the latter being reoxidized by dioxygen coupled with the formation of water.

Conjugated exocyclic dienes by addition of 2-(benzyloxymethyl)-3-(bromozincmethyl)-1,3-but adiene to aldehydes, ketones and imines followed by Pd(0)-catalyzed cyclization

Abstract Reaction of 2-(benzyloxymethyl)-3-(bromozincmethyl)-1,3-butadiene with aldehydes, ketones and imines afforded addition products 6 , which underwent Pd(0)-catalyzed cyclization to the conjugated exocyclic dienes 7 .