Cobalt-mediated Pauson-Khand reaction

Although the cobalt-mediated Pauson-Khand reaction was discovered more than 30 years ago, few asymmetric versions of this reaction have so far been developed. Up to now, the only direct method of controlling the enantioselectivity of intermo-lecular cobalt-mediated Pauson-Khand reactions involves the use of alkaloid N-oxides [59-62]. 

Table 4.7 Cinchona alkaloid N-oxide promoted asymmetric cobalt-mediated Pauson-Khand reaction.

A combination of Co-mediated amino-carbonylation and a Pauson-Khand reaction was described by Pericas and colleagues [286], with the formation of five new bonds in a single operation. Reaction of l-chloro-2-phenylacetylene 6/4-34 and dicobalt octacarbonyl gave the two cobalt complexes 6/4-36 and 6/4-37 via 6/4-35, which were treated with an amine 6/4-38. The final products of this domino process are azadi- and azatriquinanes 6/4-40 with 6/4-39 as an intermediate, which can also be isolated and separately transformed into 6/4-40 (Scheme 6/4.11). 

Under the conditions of the cobalt-mediated carbonylative A-oxide-promoted cocyclization (Pauson-Khand reaction) at room temperature, compound 547 provides exocyclic 1,3-diene 548 as the major product (>98%) together with only traces of the corresponding carbonylative product 549. Owing to the relative instability of the diene, it is more efficient to perform a one-pot cobalt cyclization/Diels-Alder process after A-oxide-promoted cyclization of the cobalt complexes. Compound 550 is obtained as a single diastereomer in 39% overall yield if MTAD is used as a dienophile (Scheme 90) <2003JOC2975>. 

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... 

Some of the most striking examples for an intramolecular Pauson-Khand reaction involving a tetrasubstituted double bond are the cobalt-mediated cyc-lizations of bicyclopropylidene derivatives 234 leading to the interesting spirocyclopropanated tricyclic products 235. The successful cyclizations even of the trimethylsilyl-substituted enynes 234 demonstrate the unique reactivity of the strained double bond in the bicyclopropylidene moiety of these molecules (Scheme 55) [145]. 

Pauson-Khand Cycloaddition. Pauson Khand cycloaddition (see Pauson-Khand Reaction) is a cobalt-mediated method to prepare cyclopentenone from the cyclization of an alkyne with an alkene and CO (equation 14). This method is widely used to produce cychc ketones. Originally, stoichiometric amounts of Co2(CO)g were used in these reactions with the cobalt carbonyl being the CO source. However, it was shown that a strict temperature profile and high-purity reagents allowed the use of catalytic amounts of Co2(CO)g for reactions with 1 atm of CO. Currently, there is intense interest in developing catalytic cobalt starting materials for use in Pauson-Khand reactions. 

Pauson-Khand Bicyclization. Alkynyl and enol ether derivatives have been studied in the cobalt-mediated intramolecular Pauson-Khand reaction and found to provide high diastere-oselectivity, superior to previous work with the auxiliary 2-phenylcyclohexanol. The 3-substituted auxiliary alcohol (3) provides higher selectivity than the 2-substituted analog. Also, the alkynyl ether derivatives exhibit higher reactivity and selectivity than the corresponding enol ether derivatives (eq 6). 

Enantioselectivities up to 44 % were reached in intermolecular PKRs when chiral aminoxides R 3N—>0 were used [19]. Although the mechanism is not known, it seems likely that the chiral A-oxide discriminates between the prochiral carbonyl cobalt units, either oxidizing one carbon monoxide selectively to produce a vacant site for the alkene insertion, or stabilizing a vacant site on one of the cobalts preferentially. This approach was modified by application of chiral precursor substrates [20]. Albeit the synthesis of the latter is cumbersome, the concept was successfully applied in several total syntheses, for example of hirsutene [21], brefeldine A [22], /9-cuparenone [23], and (+)-15-norpentalenene [24] (eq. (10)). Stoichiometric amounts of the mediator compound Co2(CO)8 are still necessary in this useful version of the Pauson-Khand reaction. 

In the laboratory of S.L. Schreiber, the total synthesis of (+)-epoxydictymene was accomplished by the tandem use of cobalt-mediated reactions as key steps. The eight-membered carbocycle was formed via a Nicholas reaction, while the five-membered ring was annulated by the Pauson-Khand reaction. Several P.-K. conditions were explored and the best diastereoselectivity was observed when NMO was used as a promoter. The annulated product was isolated as an 11 1 mixture of diastereomers. 

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... 

The Pauson-Khand reaction is a cobalt mediated [2+2+1] cycloaddition of an alkene (8.233), an alkyne (8.234) and carbon monoxide to give a cyclopentenone (8.235). 

Chapter 17 closes with a brief presentation of the Pauson-Khand reaction. The Pauson-Khand reaction (PKR) is a formal [2+2+1] cycloaddition reaction involving an alkyne, an alkene, and carbon monoxide to form a cyclopentanone shown generically in Equation 17.71. The Pauson-Khand reaction was initially reported as a stoichiometric reaction mediated by cobalt carbonyl, but it has been translated into a catalytic process in recent years. Most recently, it has developed into an enantioselective catalytic process. Complexes of Ti, Mo, W, Fe, Co, Ni, Ru, Rh, Ir, and Pd have all been shown to catalyze this reaction. 

The currently accepted mechanism of the Pauson-Khand reaction mediated by cobalt carbonyl systems was proposed by Magnus. This mechanism is summarized in Scheme 17.39. The reaction is initiated by irreversible replacement of CO from the starting... 

Energies for the intermediates in the Pauson-Khand reaction mediated by cobalt carbonyl. 

Pauson-Khand reaction (PKR) first reported in 1973 is formally a cobalt-mediated [2-I-2-I-1] cycloaddition involving an alkene, an alkyne, and carbon monoxide to form a cyclopentenone (145,146). The synthetic utility of the PKR was initially limited due to the poor regioselectivity observed in the intermolec-ular reaction when unsymmetrical alkynes and alkenes are used. However, the inherent regiocontrol of the intramolecular variant of the PKR has considerably expanded the synthetic utility of the reaction (147). A variety of transition metals have been shown to catalyze the PK reaction including Rh, Ti Zr, Ir, and Ru (148,149). 

Another cobalt-mediated cyclization reaction is the Pauson Khand reaction (PKR). In a [2 -H 2 - - 1] fashion, the reaction of TMSA with alkenes delivers regioselectively silylated cyclopen-tenones. Following the trend typically observed in the PKR, the bulky TMS-group is always positioned a to the carbonyl group (eqs 37 and 38)7 ... 

The carbonylation reactions are very important in synthesis and for industrial applications as well. The Pauson-Khand reaction, the well-known cobalt-mediated procedure, combines an alkyne, an alkene, and a carbon monoxide ligand into cyclopentenones (Eq. 39) [36]. 

An additional advantage of the intramolecular protocol stems from the opportunity to prepare easily the required polyfunctional precursors via cobalt carbonyl stabilized propargyl cations. The approach based on the tandem utilization of Co-mediated alkylation and Pauson-Khand annulation was developed in Schreiber s studies to elaborate short pathways for the synthesis of polycyclic compounds. An example of the efficiency of this protocol is the two-step transformation of the acyclic precursor 409 into the tricyclic derivative 410. The cobalt-complexed acetal 409 was first transformed into the cyclooctyne derivative 411 via intramolecular reaction of the in situ generated propargyl cation 409a with the allylsilane moiety. Cyclooctyne 411 underwent smooth cycloaddition in the presence of carbon monoxide to give the target compound 410 with excellent stereoselectivity. 

The cobalt-mediated cycloaddition of an alkyne, an alkene, and CO leading to a cyclopentenone has been known as the Pauson-Khand (PK) reaction [78], Due to its synthetic importance, numerous variants - especially catalytic reactions - have been developed to date [79]. The first ruthenium-catalyzed PK reaction of enynes has been achieved using Ru3(CO)i2 by two research groups independently (Scheme... 

There are several examples known where methylenecyclopropanes have been employed as cosubstrates in reactions of the Khand—Pauson type. Generally, this cobalt-mediated reaction is performed with hexacarbonyldicobalt complexes of alkynes, preferably strained alkenes such as norbornene or cyclobutene, and carbon monoxide to produce cyclopent-2-enones. Stoichiometric amounts of cobalt (in the form of the alkyne complexes) are normally needed. Methylenecyclopropane (1) can be employed as the strained alkene and reacts with a variety of alkynes to yield spiro-fused products. Silica gel or zeolites function as promoters of the reaction, giving rise to improved yields. ... 

Apart from cobalt carbonyl catylyzed hydroformylation, Pauson-Khand (PK) reaction is another type of reaction catalyzed with bimetallic carbonyl complex. Formally Pauson-Khand (PK) is a [2 -i- 2 -i- 1] cycloaddition of an alkyne, an alkene, and a CO group into cyclopentenone [128-130]. This process was initially discovered in 1973 [131], and early studies focused on using dicobalt octacarbonyl as both reaction mediator and the source of the carbonyl functional group. Since several variants of the original thermal protocol were introduced, PK reaction has received more and more fundamental and organic synthesis interests [132, 133]. 

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