Cycloaddition reactions cyclopentenone synthesis

The Pauson-Khand Cycloaddition Reaction for Synthesis of Cyclopentenones... 

Schore, N. E. The Pauson-Khand cycloaddition reaction for synthesis of cyclopentenones. Org. React. 1991,40, 1-90. 

Keywords Fischer carbenes Template synthesis Cocyclization Cycloaddition Cyclopentadienes Cyclopentenones Domino reactions... 

Other examples of [2C+2S+1C0] cycloaddition reactions have been described by Herndon et al. by the use of chromium cyclopropyl(methoxy)carbenes. These complexes react with alkynes releasing ethene and forming cyclopenta-dienone derivatives, which evolve to cyclopentenone derivatives in the presence of chromium(O) and water [122] (Scheme 76). This reaction has been extended to intramolecular processes and also to the synthesis of some natural products [123]. These authors have also described another process involving a formal [2C+2S+1C0] cycloaddition reaction. Thus, the reaction of methyl and cyclo-propylcarbene complexes with phenylacetylene derivatives does not afford the expected benzannulated products, and several regioisomers of cyclopentenone derivatives are the only products isolated [124] (Scheme 76). 

The presence of a cyclopropyl moiety in the carbene complexes makes them useful for synthesis. The cyclopropylcarbene complexes 95 undergo a cycloaddition reaction with alkynes to give the cyclopentenones 96 [51]. The reaction course is explained as being metallacyclopentene fragmentation. (Scheme 34)... 

Transition-metal-promoted cycloaddition is of much interest as a powerful tool for synthesis of carbocyclic stmcture in a single step. Utilization of carbon monoxide as a component of the cycloaddition reaction is now widely known as the Pauson-Khand reaction, which results in cyclopentenone formation starting from an alkyne, an alkene, and carbon monoxide mediated by cobalt catalyst. Although mechanistic understanding is limited, a commonly accepted mechanism is shown in Scheme 4.16. Formation of dicobalt-alkyne complex followed by alkene... 

To date, the most commonly used transition metal-promoted cycloaddition in organic synthesis is the Pauson-Khand reaction. First reported by Pauson and Khandin 1973 [9],this transformation is the cobalt-mediated [2+2+1] cycloaddition of an alkyne, an alkene and carbon monoxide to form a cyclopentenone, Eq. (1). Although mechanistic understanding is Hmited, the accepted mechanism for the transformation is depicted in Fig. 2. Loss of two equivalents of CO followed by complexation of an alkyne produces 1. Subsequent loss of CO from... 

Acetylenes can undergo a number of thermal and transition metal promoted cycloaddition reactions. Besides the [2 + 2 + 2] cycloaddition (see Sect. 5) the reaction of acetylenes with late transition metal (so-called Fischer ) carbenes is noteworthy for the synthesis of highly and regioselectively functionalized naphthalene derivatives (Dotz reaction), while the co-cycloaddition of acetylenes with alkenes and carbon monoxide gives cyclopentenones (Pauson-Khand reaction) [159,160]. 

In the elaboration of cyclopentenones the Nazarov cyclization (not a cycloaddition reaction) also offers some advantages. Metal complexes including a V(IV) chelate of salen 60 and the Cu complex of ent-96B have been employed as catalysts. By structural demand of the substrate to induce rearrangement following the cyclization a synthesis of spirocycles is realized. 

Arene cis-diols can undergo cycloaddition reactions, acting as both diene and dienophile to produce homoadducts (12). Heteroadducts have also been synthesized, for example recent work by Banwell and coworkers exploited the reaction of toluene cw-diol with cyclopentenone as the initial step in their synthesis of complicatic acid and related triquinanes (20). We found that upon prolonged standing at room temperature in concentrated form, the acetorddes 5a and 5b were slowly converted to the Diels-Alder adducts depicted in Figure 2. 

SCHEME 3 Synthesis of the cycloaddition reaction precursor from cyclopentenone. 

Iron-stabilized oxallyl cations (generated in situ (eq 25) from a,o -dibromo ketones and Fe2(CO)9) react with alkenes. Noyori used this [3 + 2] cycloaddition reaction to produce cyclopentanone or cyclopentanone derivatives, as illustrated by a single-step synthesis of (i)-a-cuparenone (43) (eq 26). The reaction of a,a -dibromo ketones with enamines and Fe2(CO)9 yields substituted cyclopentenones in 50-100% yield (eq 27), as illustrated by the reaction with the a-morpholinostyrene (44). ... 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

An important procedure for the synthesis of cyclopentenones is the so-called Pauson-Khand reaction, which constitutes a formal [2 + 2 + 1] cycloaddition of an alkene, an alkyne, and carbon monoxide. Due to the increase in structural diversity of the available starting materials, the reaction has become an attractive target for scientific investigations [1-8]. The first successful example was reported by Pauson, Khand et al [9] in 1973 for the conversion of norbornene with the phenylacetylene-hexacarbonyldicobalt complex to give the corresponding cyclopentenone in 45% yield (Eq. 1). 

More recently, the total synthesis of isocarbacyclin, a therapeutically useful agent against numerous vascular diseases, was reported by Saito et al. [56]. Again, the crucial cycloaddition step was carried out using a stoichiometric amount of Co2(CO)8. The reaction was completed within 3h and gave 78% yield of the desired cyclopentenone (Eq. 8). 

The reaction of (trialkylsilyl)vinylketenes with nucleophilic carbenoid reagents, such as sulfur ylides and diazo compounds, has been used for synthesis of substituted cyclopentenones by stereoselective 4 + 1-annulation (Scheme 12). The strategy relies on the remarkable ability of silyl substituents to stabilize ketenes and suppress their tendency to undergo dimerization and 2 - - 2-cycloaddition. 

However, from the outset of this field, the limitations as well as the potentials of this cycloaddition were also apparent. For instance, the efficiency of this cycloaddition in an intermolecular manner was typically low unless strained olefins were used. Moreover, the use of unsymmetrical alkenes led to a mixture of the cyclopentenone regioisomers. Synthetic utility of this reaction is considerably expanded by the emergency of the intramolecular reaction. Schore introduced the first intramolecular version forming several rings simultaneously, which is now the most popular synthetic strategy in natural product synthesis because of its conceptual and operational simplicity. Additionally, the regiochemistry is no longer the problem in this variation. 

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