Pauson-Khand cyclization

An interesting family of polycyclic pyrroles was described in 2005 using again the synthetic sequence of a Stetter reaction for the preparation of the starting 1,4 diketones followed by a microwave-assisted Paal-Knorr condensation [35]. For example, cyclopentenone 23 (obtained in a Pauson-Khand cyclization) reacted imder Stetter reaction conditions to give the amino ketone 25 (Scheme 8). The microwave-assisted Paal-Knorr cyclization of 25 with different amines gave a small collection of tricychc pyrrole 2-carbox-amides. 

One of the most powerful methods for bicyclic ketone construction is the intramolecular Pauson-Khand reaction (14 ->15). Although catalytic methods for this transformation have been put forward, they are not always successful. Jihua Chen and Zhen Yang of Peking University have now found (Organic Lett. 2005, 7, 593) that the cyclization proceeds quickly and efficiently with 5 mol % of the commercial grade of Co,(CO), if it is run in the presence of the inexpensive tetramethylthiourea. The authors have also reported (Organic Lett. 2005, 7, 1657) that TMTU is beneficial to the Pd-catalyzed version of the reaction. These advances will make the Pauson-Khand cyclization a more generally practical procedure. 

Palladium-mediated, Heck carbon-carbon bond formation has been used to introduce diversity via a scheme based on Pauson-Khand cyclizations, to generate fused bicyclic amino acid derivatives.47,48 The sequence of... 

The l-propargyl-4-vinylazetidine derivative 374 undergoes Pauson-Khand cyclization at room temperature when reacted with cobalt octacarbonyl and trimethylamine /V-oxidc (TMANO) to give the tricyclic azetidine 375 (Equation 50). But when l-allyl-4-ethynylazetidine 376 is used, product 377 is obtained (Equation 51). In both cases, moderate yields with the formation of a single isomer of the products is achieved <1996TL6901, 1998JOC6786>. 

Pauson-Khand cyclization of vic-enyne derivatives of /3-lactams gave good yields of fused tricyclic compounds. The 1,4-disubstituted 2-azetidinone 391 and cobalt octacarbonyl gave the alkyne-cobalt carbonyl complex, which on thermolysis gave the tricycle 392 in 95% yield (Equation 54). When the complexes of 393 with cobalt octacarbonyl were treated with TMANO, a lower yield (65%) of 394 was obtained (Equation 55). A single diastereoisomer was formed in each case <1996TL6901>. 

Nickel-catalyzed cyclization of a 1,3-diene side chain of the substituted pyrrolidones yields a precursor to the indolizidine alkaloid (—)-elaeokanine C (Equation 86) <1997TL3931>. Other metal-catalyzed reactions include the Rh-induced in situ carbene generation and subsequent cyclization onto the heteroatom to yield piperidines <1997T16565, 1997JOC67>. Pauson-Khand cyclizations have also been used (Equation 87) <1997T6611>. 

The preparation of carbohydrate-derived spiroacetals by RCM was reported by van Boom and co-workers <00EJO873> (Scheme 45). The Pauson-Khand cyclization of these enynes was reported in the same manuscript. 

Scheme 53. Cyclopentenone derivatives via Pauson-Khand cyclization.

Their retro synthetic study was based around the Pauson-Khand cyclization (6), which couples an alkene, an alkyne, and a carbon monoxide source (typically dicobalt octacarbonyl) to give a cyclopentenone ring (Fig. 3.5, top). This reaction has been widely used for synthetic purposes, and some excellent reviews (7,8) have covered its principal features and the recent improvements to its experimental conditions. This reaction, in its intramolecular version, is ideal for the assembly of the l//-[2]pyrindi-none scaffold in two distinct versions, differing in the stereochemistry of the ring junction (Fig. 3.5, bottom). Hence, the readily available unsaturated amino acid derivatives 3.1a,b undergo intramolecular Pauson-Khand reaction to produce the two unsamrated scaffolds 3.2a,b. 

Once the strategy was selected, the validation of the relevant cyclization in solution and the determination of its stereochemical outcome and yield were carried out. The synthetic scheme is reported in Fig. 3.6. The commercially available allyl (3.3) and propargylglycines (3.7) were sequentially tosylated and alkylated with propargyl and allyl bromide, respectively, to give 3.5 and 3.9. The intramolecular Pauson-Khand cyclization produced the two isomers 3.6 and 3.10, with different stereochemistries, in a stereospecific reaction (the chiral allylglycine produced 3.6 as a single enantiomer. 

Figure 3.5 Retrosynthetic study Pauson-Khand cyclization to l//-[2]p5Tindinones 3.2a,b.

In a similar manner, cyclopropane-containing benzvalene can be used as the alkene component in intermolecular Pauson-Khand reactions.Several examples of intermolecular Pauson-Khand cyclizations of methylenecyclopropanes and alkynes are reported to give bicyclic car-bocycles. Ethynylcyclopropyl-substituted chromium carbonyl complexes have also been used in palladium-catalyzed coupling reactions. 

The first report of a catalytic intermolecular cyclization was made by Pauson and Khand in 1974 [22], but the scope was limited to gaseous acetylene as the alkyne partner, strained olefins such as norbornene and norbornadiene as the alkene component, and TON s (turnover numbers) were modest (8-11). Several subsequent reports detailed the production of cyclopentenones from a substoi-chiometric amount of Co2(CO)g, but none were as efficient as Pauson s initial work [23,24]. Using ethylene as the alkene component, Rautenstrauch demonstrated the first efficient catalytic Pauson-Khand cyclization with a TON of 220, Eq. (5) [25]. A more general catalyst system employing (indenyl)Co(cod) was recently reported by Chung and Jeong, Eq. (6) [26]. The reaction was quite effec-... 

In 2001, Tanimori and coworkers described a Pauson-Khand cyclization reaction to construct the tetracyclic indolidine core of asperparaline C (125) [96], as shown in Fig. (31). The starting enyne... 

In concluding this section on the reactions of propargylium complexes with nucleophiles, we note that use of appropriate unsaturated nucleophiles as reaction partners with the cobalt cations or unsaturated electrophiles in the Ade reaction of Co-compleced 1,3-enynes [213-215] offers an efficient route to variously substituted a,(i)-enynes, valuable precursors for intramolecular Pauson-Khand cyclizations (Scheme 4-64) [96, 98]. This tandem methodology has been employed to produce, among others, bicyclo[3.3.0]octenones and their 3-oxa analogs [22, 216, 217], the fusicoccin sesquiterpenoid skeleton [218], linear and angular fused tri- and tetracyclics [219], and fenestrane derivatives [220]. 

When the biscobalthexacarbonyl complex 17, prepared from 2-acetoxy-3,4,6-tri-O-acetyl-D-glucal, was treated with NMNO, a Pauson-Khand reaction occurred to give the fused cyclopentenone 18 in virtually quantitative yield. Treatment of 17 with triflic add caused epimerization at C-1, and the stereoisomer also underwent Pauson-Khand cyclization eflfidently. ... 

Pauson-Khand Cyclization, Pauson-Khand Cycloaddition)... 

The reaction was first reported by Khand and Pauson et al. in 1973d It is the dicobalt octacarbonyl [Co2(CO)8l mediated or promoted one-step synthesis of a,p-unsaturated cyclopentenone from the [2+2+1] cycloaddition of alkyne, alkene and carbon monoxide, through an intermediate of alkynedicobalt hexacarbonyl complex. Therefore, this reaction is generally known as the Pauson-Khand reaction, Pauson-Khand cyclization, or Pauson-Khand cycloaddition. Occasionally, this reaction is also referred to as the Pauson-Khand annulation, Pauson-Khand multicomponent cycloaddition, Pauson-Khand carbonylative cocyclization, Pauson-Khand bicyclization, Khand annulation, Khand cycloaddition, Khand cyclization (cyclisation ), or Khand reaction.Among these names, the Pauson-Khand reaction is the one used most often. 

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