Ene-Yne Cyclization

A -tosyl pyrrole 6.275 was converted to a pyrrole 6.276 by treatment with a strong base, and thence to the natural product 6.277. 

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An extraordinary effect is noted for cydizalion of the carbonate derived from dihydrocar-vone (Table 14, entries 16 and 17). When R = H, no reaction is observed with the depicted substrate (Table 14, entry 16) or with the regioisomeric allylic carbonate22. Palladium cannot coordinate to the olefin because of steric reasons. However, cyclization occurs smoothly in the presence of an alkyne group in the molecule (Table 14, entry 17), because precoordination of palladium(O) to the alkyne enables the intramolecular formation of the initial palladium(O)-alkene complex and subsequent ionization to the tr-allyl complex. The product has been further elaborated via an ene-yne cyclization and eventually transformed into the alkaloid (-)-den-drobine. Entry 18 shows the preparation of a precursor for (-)-aspochalasin B23. Cyclization to the 11-membered ring proceeds with high diastereoselectivity which has been used to advantage during further transformations. 

Gold-catalysed ene-yne cyclization has been employed in two closely related and simultaneous syntheses of englerin A 6.278, a sesquiterpene that has shown anti-tumour activity (Scheme 6.111). Both syntheses relied upon the intramolecular nucleophilic trapping of the cyclopropyl carbene intermediate 6.280 by a ketone nucleophile, followed by counterattack of the anionic t -vinyl gold species onto the oxonium ion 6.281 formed in this way, to form the skeleton of the molecule, but differed in their approach to the other functionality. 

W(CO)6 in toluene at room temperature gave the tricyclic adduct 190a in 94% yield after acidic workup. This reaction forms the tungsten-containing azomethine ylide 191, which undergoes the [3 + 2]-cycloaddition with 189a. The rhodium(n)-catalyzed cyclization of the ene-yne-aldimine 192 with alkene 193 into the cyclopropane 194 was reported by Uemura and Ohe (Scheme 32).42c... 

Product stabilization is much more pronounced when the enediyne or ene-yne-allene starting materials are not already part of an aromatic system, since forming an aromatic system constitutes a much higher degree of stabilization than expanding an aromatic system (Fig. 24). Conjugation of the radical center provides additional stabilization to the 71-radical formed by the Myers-Saito and Schmittel cyclizations. 

Tandem cyclization of poly (ene-yne) has been achieved by Grubbs. In this reaction, a complex molecule is synthesized by one step from enyne 135 having alkenes and alkynes at appropriate positions [Eqs. (6.105)-(6.106)] " ... 

Removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a silyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. 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 Besides the aforementioned A-ring aromatic steroids and contraceptive agents, partial synthesis from steroid raw materials has also accounted for the vast majority of industrial-scale steroid synthesis. 

The reaction of a silirene with an alkyne in the presence of a palladium catalyst allows cyclization of two molecules of the alkyne with the silylene, as in equation 9 above. For example, Seyferth and coworkers have prepared the silole 33 in 80% yield from 1,1-dimethyl-2,3-bis (trimethylsilyl) silirene and phenylacetylene (equation 10)45. Without catalyst, this reaction yielded the silole 34 and the ene-yne 35, resulting respectively from ring expansion and cleavage by PhC=CH of the silirene. Under UV irradiation, 35 alone was formed. 

Enediynes, silane-initiated cascade cyclization, 11, 400 Ene reactions, allylsilanes, 9, 313 Energetics, key elementary reactions, 1, 617 Enes, niobium complexes, 5, 87 Ene-yne metathesis... 

Few examples of ene-yne cycloisomerization reactions are seen in the literature. The first results for ene-yne cycloisomerizations were with systems bearing an heteroatom (amine or oxygen) next to the alkene counterpart (forming an enamine or an enol ether). Indeed, Dake s group reported the cyclization of enesulfonamides on alkynes (69-70, Scheme 5.30) under catalysis by platinum and silver salts.85 Catalysis using AgOTf (1 1 mol%) was particularly efficient with systems such as 69 (Scheme 5.30)... 

Nicolaou, K. C. Maligres, P. Shin, J. De Leon, E. Rideout, D. DNA-cleavage and antitumor activity of designed molecules with conjugated phosphine oxide-allene-ene-yne functionalities, J. Am. Chem. Soc. 1990,112, 7825-7826. Schmittel, M. Kiau, S. Strittmatter, M. Steric effects in enyne-aUene thermolyses switch from the Myers-Saito reaction to the —C -cyclization and DNA strand cleavage, Tetrahedron Lett. 1996, 37, 7691-7694. 

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). 

The methods described thus far represent only a small subset of the available techniques for the formation of C-furanosides and C-pyranosides. Other useful methods include cyclizations of halo olefins and ene-ynes [224] and the direct modification of pyran ring systems [251]. Although not discussed further here, these examples are mentioned to illustrate the breadth of work accomplished in this area. 

Ring annulation by radical cyclization of ene-diynes and (Z)-allene-ene-ynes in a thermal reaction to give aromatics (electrocyclization). 

An interesting cyclization reaction was reported that involved the reaction of dienes, diynes, or ene-ynes with transition metals to form cyclopentenone derivatives in the presence of carbon monoxide.363 in a simple example, ene-yne 444 was heated with dicobalt octacarbonyl and CO to give a 68% yield of 445.364 jjjj transformation has become an important synthetic tool known as the Pauson-Khand reaction.365 jhe mechanism probably involves insertion of the alkene (or alkyne) into the transition metal bond, which is why it is presented in this section. Formally, it is a [2+2+l]-cycloaddition, but the accepted mechanism is the one proposed by Magnus,364 and shown in Figure 13.8.366 n has been stated that further study is required to... 

PalladiumfO) also catalyzed the 3-component reaction between unsaturated halides or triflates, propai gyl alcohols and the Michael acceptors alkylidenemalonates, leading to the formation of 3-alkylidenetetrahydrofurans <01JOC175>. Highly enantioselective formation of 2-alkylidenetetrahydrofurans was also realized by palladium-catalyzed ene-type cyclizations of 1,6-enynes <01AG(E)249, 01T5137> and l,2-dien-7-ynes <01JA8416>. 

Coarctate cyclization reactions using a conjugated ene—ene—yne precursor to form a heterocycle 12CC9441. 

Cyclopropanation proceeds through the formation of an electrophilic (2-furyl)carbene-chromium complex which in turn forms through 5-exo dig cyclization. As shown in Scheme 10.13, cyclization of ene-yne-ketone 15 begins with the nucleophilic attack of carbonyl oxygen to an internal carbon of an alkyne in q -alkyne complex A. A might be the most plausible pathway for generation of (2-furyl)carbene-chromium complex 18. A slipped, polarized q -complex B would be an alternatively possible intermediate. It is known that A is prone to isomerize to B, which has been... 

Cyclizations of ene—yne ketenes were su ested for the synthesis of dihydroisoquinoline 335 from 331 via the intermediate ketene 332 with subsequent oxidation in the degassed refluxing xylenes and modest dilution conditions (0.01—0.02 M concentrations), furnished the triones 335a—fin satisfactory yields as the only obviously identified products (Scheme 104) (1995JOC6460, 1999JOC6881). Formation of trione 335h shows that a sterically hindered amide is appropriate for ring closure if the amide... 

The formation of 2-alkenyl-substituted furans was observed in the palladium-catalyzed cross-coupling reactions between benzyl, aryl, or allyl bromides and conjugated ene-yne-ketones. This reaction involved oxidative addition, alkyne activation-cyclization, palladium carbene migratory insertion, P-hydride elimination, and catalyst regeneration (13JA13502). 

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