1.2- Dien-4-ynes, synthesis

Scheme 87 Synthesis of the tricyclic skeleton 443 of guanacastepene A (444) via diene-yne RCM [182]...

The first metal-catalyzed [4 +2]-reaction of tethered dienes with 7r-systems was reported by Wender and Jenkins using alkynes initially as the two-carbon component.21 This study was based on the earlier observation by Wender and Ihle that in the [4 + 4]-cycloaddition of bis-dienes a competing side-reaction is the [4 + 2]-cycloaddition of the diene with a mono-ene portion of a second diene. The extension of this reaction to the synthesis of seven-membered rings by trapping the metallacycloheptadiene with CO, a formal [4 + 2 + l]-cycloaddition, has been shown in preliminary studies to be feasible. For example, tethered diene-yne 160 can be converted to cycloheptadienone 163 in an Rh(l)-catalyzed [4 + 2 + l]-reaction with CO, albeit the [4 + 2]- and [2 + 2 + l]-reaction products dominate (Equation (29)). The mechanistic scheme (Scheme 44) illustrates the possible metallacyclic intermediates leading to the observed products and provided the conceptual basis for the realization of three novel reaction types ([4 + 2], [2 + 2 + 1], and [4 + 2 + 1 ]).1... 

Our initial studies focused on the transition metal-catalyzed [4+4] cycloaddition reactions of bis-dienes. These reactions are thermally forbidden, but occur photochemically in some specific, constrained systems. While the transition metal-catalyzed intermole-cular [4+4] cycloaddition of simple dienes is industrially important [7], this process generally does not work well with more complex substituted dienes and had not been explored intramolecularly. In the first studies on the intramolecular metal-catalyzed [4+4] cycloaddition, the reaction was found to proceed with high regio-, stereo-, and facial selectivity. The synthesis of (+)-asteriscanoHde (12) (Scheme 13.4a) [8] is illustrative of the utihty and step economy of this reaction. Recognition of the broader utiHty of adding dienes across rc-systems (not just across other dienes) led to further studies on the use of transition metal catalysts to facilitate otherwise difficult Diels-Alder reactions [9]. For example, the attempted thermal cycloaddition of diene-yne 15 leads only... 

The Diels—Alder reaction is one of the most important methodologies for organic synthesis. Heterocycles 135 has been synthesized by the intramolecular Diels—Alder reaction using diene—ene or diene— yne compounds 134, which have a heteroatom in a... 

Enyne metathesis RCM can be performed in tandem with RCM using appropriately spaced diene-yne substrates. Many examples of this reaction featuring various degrees of complexity have been reported. Representative examples of tandem enyne metathesis-RCM are depicted in Scheme 30 and include (i) formation of the fused bicyclic compound 257 from dienyne 255 for securinine total synthesis/ (ii) synthesis of cyclic ethers (e.g., 261 and 262) from diene-alkynes (e.g, 258) and control of the product distribution through alkene substitution pattern,and (iii) double tandem RCM-enyne metatheses (conversion of 263 into 266) of appropriate polyene-polyyne systems. 

Recently, an enantioselective intramolecular [2-f2-f2] cycloaddition of 1,4-diene-ynes 16 for the synthesis of bicycle[2.2. l]heptene skeletons 17 was also reported by the Shibata laboratory (Scheme 7) (17). The products from this type of substrates represent a unique class of cycloadducts that possess two quaternary carbon stereocenters. Depending on the substituents (R ) on the alkene moiety, chiral cyclohexadienes 18 with a quaternary carbon stereocenter were obtained. 

The development of new procedures for the creation of C-C bonds is of major importance in organic synthesis. In this respect, gold catalysis has emerged as a very efficient synthetic tool, allowing the generally easy and efficient formation of such bonds by addition of various carbone nucleophiles onto alkynes, allenes, and alkenes. These transformations, which can be performed in an intra- or intermolecular manner, are extremely varied. It should however be noted that tlie cycloisomerization of ene-ynes, diene-ynes, or ene-allenes remains the most frequently encountered. A very short selection of such transformations is presented in Scheme 16.16 [15g,k, 20]. 

Scheme 29 Synthesis of substituted hexahydroazulenes 138 from simple 1-methoxyalkylidene complexes 135 and l,3-dien-8-ynes 136 [96]...

Another intramolecular ene-yne metathesis followed by an intermolecular metathesis with an alkene to give a butadiene which is intercepted by a Diels-Alder reaction was used for the synthesis of condensed tricyclic compounds, as described by Lee and coworkers [266]. However, as mentioned above, the dienophile had to be added after the domino metathesis reaction was completed otherwise, the main product was the cycloadduct from the primarily formed diene. Keeping this in mind, the three-component one-pot reaction of ene-yne 6/3-94, alkene 6/3-95 and N-phenylmaleimide 6/3-96 in the presence of the Grubbs II catalyst 6/3-15 gave the tricyclic products 6/3-97 in high yield (Scheme 6/3.28). 

Bromoalkynes also couple with vinylstannanes readily to result in enynes. Synthesis of protected enynals via cross-coupling of vinylstannanes with 1-bromoalkynes in the presence of a catalytic amount of Pd(II) has been reported (equation 143)252. Hiyama and coworkers extended the Stille methodology for sequential three-component coupling of trimethylstannyl(trimethylsilyl)acetylene with a vinyl iodide in the first step and cross-coupling of the intermediate trimethylsilylethyne with another alkenyl iodide in the presence of tris(diethylamino)sulphonium trimethyldifluorosilicate in the second step to generate a dienyne (equation 144)253. Both steps occur under palladium catalysis, in one-pot, to result in stereodefined l,5-dien-3-ynes. 

Intramolecular [2 + 2 + 2] cycloadditions belong to the same type of valence isomerization as those of 1,5-unsaturated compounds to cyclobutanes.70 The cobalt-mediated cyclization of l-en-5-ynes stereoselectively converts enediynes directly to bicyclo[4.2.0]hexa-l,3-dienes, as single diastereomers, when a stoichiometric amount of dicarbonyl(cyclopentadienyl)cobalt is used. This cyclization90 has a high efficiency (92%). An example is the synthesis of the protoilludane framework 23 from the enediyne precursor 22.71... 

An efficient synthesis of hexafluorobut-2-yne25,26 combined the knowledge that hexafluorocy-clobutene thermally rearranges to hexafluorobuta-1,3-diene (vide supra) and that cesium or potassium fluoride isomerize dienes to alkynes (see Section 5.1.2.3.). Thus, when hexafluoro-cyclobutene is passed over cesium or potassium fluoride at 590-600 C, hexafluorobut-2-yne is obtained in yields up to 90%, with 95% recovery of material. 

Considerable synthetic scope exists for the application of diene-based and ene-yne-based ring-closing metathesis reactions to the synthesis of 1,3-oxazepine and 1,3-thiazepine derivatives. Particular emphasis on type e reactions is likely to be very fruitful. 

J. Marco-Contelles, Synthesis of polycyclic molecules via cascade radical carbocycliza-tions of dienynes the first SnPh3 radical-mediated (2 + 2 + 2] formal cycloaddition of dodeca-l,6-dien-ll-ynes, Chem. Commun. (Cambridge), (1996)2629-2630. 

Along with diene and diyne metathesis, ene-yne metathesis has also been employed to form macrocycles. This type of metathesis is performed with the catalysts used for olefin metathesis, and the yields are improved in the presence of ethylene, which forms the highly reactive [Ru]=CH2 species. Shair and coworkers took advantage of this reaction twice in the course of their total synthesis of longithorone A [40]. When ene-ynes 51 and 52 are treated with ruthenium complex G1 under an atmosphere of... 

The same palladium-catalyzed domino cyclization-anion capture sequence involving carbopalladation of allene (69), which was employed by Grigg et al. for the synthesis of diene 70 (Scheme 10) can yield 1,3,5-hexatriene 194, when starting from 2-bromo-l-ene-6-yne 193 instead of the aryl iodide 68 (Scheme 32) [52], Under the conditions of its formation, 194 immediately undergoes thermal 67r-electrocyclization to give the bicyclic product 195. 

Stereospecific synthesis of (2Z,4E,6E)-3,7,11-trimethyl-2,4,6,10-dodecatetraene, trans (Cio)-allofamesene 49), isolated from Perilla fmtscem Makino, was realized by the ptdladium-catalyzed cross-coupling of 4,8-dimethyl-l,3,7-nonatrienyl-l,3,2-benzodioxaborole 48) with (Z)-2-bromo-2-butene. The benzodioxaborole derivative 48) was prepared by hydroboration of 4,8-dimethylnona-3,7-dien-l-yne 47), obtained via two steps from geranial, with 1,3,2-benzodioxaborole (Eq- 112) Bombykol and its geometrical isomers were also synthesized selectively... 

This sequence has been used by the group of Lallemand in an approach to the total synthesis of clerodine including the use of chiral 1,3-dienylboronates ". Extension of this work to the IMDA is illustrated in figure 10 24. The bicyclic lactone (18) has been obtained stereoselectively in an 47 % isolated yield from the yne diene (17) in a one pot sequence with control of the relative stereochemistry of five asymmetric centers including a quaternary one. 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

In the synthesis off 18]annulene, the 35 g. of crude cyclooctadecadiyne (4) obtained in the first step is dissolved in 800 ml. of benzene and heated to boiling on a water bath in a 2-1. round-bottomed flask fitted with a reflux condenser and a calcium chloride tube. A solution of potassium t-butoxide, prepared from 44 g. of potassium and I 1. of dry t-bulyl alcohol by boiling under reflux under nitrogen until the metal dissolved, is added and the mixture refluxed for 30 min. to isomerize three yne groups to diene units. The workup is tedious and includes chromatography. 

Isomerization of alkynes to dienes is a useful synthetic approach since alkyne derivatives are readily available. Even though alkyne migrations along the chain under basic conditions are well known, isomerizations of isolated alkyne to 1,3-diene do not take place easily. For some alkynones, this reaction takes place readily with triphenylphosphine . Utilizing isomerization of a yne-one as a key reaction, Guo and Lu reported a three-step synthesis of an anti-cancer agent ostopanic acid starting from pent-4-ynal (equation 166) . ... 

In more complex reaction cascades an additional alkyne-insertion step can occur. Thus starting with intramolecular carbopalladation of a vinyl iodide to a carbon-carbon triple bond, followed by two intramolecular alkene-insertion steps and termination with dehydropalladation, a palladium-catalyzed synthesis of l-(5 -methylbicyclo[3.1.0]hex-T-yl)-5,5-bis(carboethoxy)cyclo-hexadiene (52) starting from l-iodo-4,4-bis(carboethoxy)-ll-methyldodeca-l,ll-dien-6-yne (51) is achieved. ... 

A wide variety of main group heteroatom-containing ring systems are formed by the reaction of appropriate reagents with metallacycles derived from cycloaddition of Cp2Zri with ynes, diynes, dienes, enynes or alkynenitriles. This is an exceptionally general process of considerable potential, especially for the synthesis of less-common types of heterocycles (Schemes 15 and 16). ... 

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