Pauson-Khand reaction applications

Recent developments have impressively enlarged the scope of Pauson-Khand reactions. Besides the elaboration of strategies for the enantioselective synthesis of cyclopentenones, it is often possible to perform PKR efficiently with a catalytic amount of a late transition metal complex. In general, different transition metal sources, e.g., Co, Rh, Ir, and Ti, can be applied in these reactions. Actual achievements demonstrate the possibility of replacing external carbon monoxide by transfer carbonylations. This procedure will surely encourage synthetic chemists to use the potential of the PKR more often in organic synthesis. However, apart from academic research, industrial applications of this methodology are still awaited. 

The asymmetric catalytic Pauson-Khand reaction met success in the late 1990s. Not only the conventional Co catalyst but also other metal complexes, such as Ti, Rh, and Ir, are applicable to the reaction. Asymmetric hydrocyanation of vinylar-enes is accomplished using Ni complex of chiral diphosphite. Further studies on the scope and limitation are expected. 

Enantiomerically pure trans-2-phenylcyclohexanol, first used by Whitesell as a chiral auxiliary has become a popular reagent in a number of asymmetric transformations. Some recent applications include asymmetric azo-ene reactions, [4 + 2]-cycloaddition reactions, ketene-olefin [2 + 2]-reactions, enolate-imine cyclocondensations, Pauson-Khand reactions," palladium annulations and Reformatsky reactions. Despite its potential, use of this chiral auxiliary on a preparative scale is currently limited by its prohibitive cost. 

Application of the intramolecular Pauson-Khand reaction to enynes derived from salicylaldehyde leads to the cyclopentenone 27 (Scheme 13) <99TL2817>. Intramolecular Diels-Alder reactions feature in syntheses of the bipyridyl 28 <99CC793> and benzopyrano[4,3-b]quinolines <99JCR254>. 

An application of the Pauson-Khand reaction for the synthesis of a carbaprostacyclin analogue (Scheme 11) [44] illustrates the power of organometallic methods for the activation of olefins and acetylenes. 

Rhodium(I)-catalysed Pauson-Khand reaction of allenynes has been shown to be applicable for constructing azabicyclo[5.3.0]decadienone and oxabicyclo[5.3.0] decadienone frameworks. The 10-monosubstituted-bicyclo[5.3.0] deca-l,7-dien-9-one ring system has been prepared by the rhodium(I)-catalysed Pauson-Khand reaction of allenynes under 10 atm of CO (Scheme 86).129... 

Applications of the Pauson-Khand reaction. The cyclopentenone moiety (and derivatives thereof) are abundant in nature and the PK reaction has led to improved synthetic pathways to a number of natural products and compounds exerting interesting biological effects. Synthetic chemists have been attracted to the reaction because it has the potential to create highly substituted cyclopentenone rings in one step, potentially reducing the number of steps required to access complex cyclopentenone frameworks. 

This review has already indicated numerous applications of dicobalt-alkyne complexes in organic synthesis. Like the Nicholas reaction (see Section II,D), the Pauson-Khand reaction has seen widespread use.175 This reaction is a three-component cycloaddition of alkynes with alkenes and carbon monoxide which occurs in the presence of octacarbonyldicobalt to afford cyclopentenones, as shown in Eq. (16). 

Sufficient information about the reaction has been gathered to allow fairly accurate predictions of yield as well as of stereo- and regioselectivity.176177 The reaction proceeds via the formation of hexacarbonylalkyne-dicobalt complexes and is remarkably tolerant of functional groups in both the alkyne and the alkene. The intramolecular Pauson-Khand reaction is an effective way of preparing bi- and polycyclic systems, and the cyclization of 1,6-heptenyne derivatives to give bicyclo[3.3.0]oct-l-en-3-ones has been the most popular application of the Pauson-Khand reaction in natural product synthesis [Eq. (17)]. 

Finally, sequential Pauson-Khand reactions (domino reactions) are possible [36, 37]. A particular fascinating application of this concept is the synthesis of a fenestrane by Keese and coworkers (Scheme 13) [36],... 

Initially, the Pauson-Khand reaction involved heating the substrate in a hydrocarbon solution at elevated temperatures and, as such, was not applicable to labile polyfunctional substrates. Later it was discovered that this cycloaddition could be greatly accelerated under the action of mild oxidants (morpholine... 

Application of the Pauson-Khand reaction to simple acylic alkenes has been limited by both low reactivity and lack of regiocontrol in incorporation of the alkene. Among simple alkenes, ethylene provides the most consistently useful results. Yields with terminal alkynes range from 30-60% (equations 9,15 and 16) internal alkynes have also been used with some success (equation 10). Forcing conditions (toluene, 130-160 C, 6()-80 atm, autoclave) are usually required for best results, although it has been recently demonstrated that the reaction proceeds, albeit slowly, at reduced pressures and temperatures (equation 17). ... 

Numerous synthetic applications of the intermolecular Pauson-Khand reaction have been reported. Pauson has reported a number of very direct applications of cycloadditions of ethylene in the synthesis of prostanoids and jasmone analogs (e.g. equations 15 and This is a reliable entry to 2-sub-... 

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. 

Castro, J., Moyano, A., Pericas, M. A., Riera, A., Alvarez-Larena, A., Piniella, J. F. Acetylene-Dicobaltcarbonyl Complexes with Chiral Phosphinooxazoline Ligands Synthesis, Structural Characterization, and Application to Enantioselective Intermolecular Pauson-Khand Reactions. J. Am. Chem. Soc. 2000,122, 7944-7952. 

The virtue of a methylenecyclopropane being a particularly reactive alkene in a Pauson-Khand reaction has also been utilized for intramolecular applications such as 29 to 30, 31 to 32 and 33 to 34. These examples include several cases of Pauson-Khand reactions with a te-trasubstituted alkene, which are very rare. 

The Pauson-Khand reaction [329, 330, 331, 332] has been applied in combinatorial chemistry for some years [333, 334, 335]. Its mild reaction conditions have allowed application in SPOS. In this Co2(CO)8-mediated reaction, an alkyne, an alkene, and a CO molecule initially bound to the Co reagent react to form cyclopentenone. If alkene and alkyne are tethered, tricyclic structures can be obtained. Thus, Ku-boto et al. reported the intramolecular Pauson-Khand reaction of DES-bound 2-3 di-dioxy 2,3-unsaturated propargyl glucoside (413). The latter were accessible from glucal via a Perrier reaction. The alkene and ketone moieties of the reaction products allowed further diversification (Scheme 83) [336]. 

Numerous synthetic applications of the inteimolecular Pauson-Khand reaction have been reported. Pauson has reported a number of very direct tqrplications of cycloadditions of ethylene in the synthesis of prostanoids and jasmone analogs (e.g. equations 15 and 16). - This is a reliable entry to 2-sub-stituted cyclopentenones. The suitability of cyclopentene and dihydrofuran as substrates has permitted the extension of this work to the preparation of still further varieties of prostaglandin analogs (e.g. equations 27 and 51). Simple 4,5-disubstituted 2-cyclopentenones are not as directly accessible, but may be prepared from the cycloaddition products of norbomadiene (equation 45). A sequence of conjugate addition followed by retro-Diels-Alder reaction affords the product (Scheme 5). Dihydrofuran cycloadditions have been used by Billington in the syntheses of the antibiotic methylenomycin B (Scheme 6), as well as cyclomethylenomycin A (synthetic precursor to the antibiotic methylenomycin A), cyclosarko-mycin (precursor to the antitumor agent sarkomycin) ° and the iridoid Jq>anese hop ether. ... 

Modern developments have included allyl groups functionalised at the ends, particularly those derived from silylated enals such as 72. The application shown here creates a cyclopentenone 74 by combination of the allyl nickel 73 with an alkyne and CO rather in the style of the Pauson-Khand reaction (chapter 6).18... 

The diastereocontrolled cyclization of chiral enynes has been extensively studied [11], and its application with optically active enynes represents a major focus in the efforts to synthesize optically active cyclopentenones via the Pauson-Khand reaction. For the purposes of this review, the discussion of this subject... 

Numerous applications of the latter methods to stereoselective20 25- 94 105 and asymmet-ric26-33,io6-r is organic ancj natural product synthesis have been described however, those methods which use a stoichiometric amount of the metal are not the subject of this section. Few examples of transition metal catalyzed cyclopentenone and cyclopentadienone syntheses starting from alkenes and alkynes have been reported 34. It should be noted, however, that considerable efforts (and the first positive results) towards the catalytic use of zirconium13 and cobalt (in the Pauson-Khand reaction)35 36- U6l 117 have been reported. 

On the basis of the above simple retrosynthetic analysis, ( )-8p hydroxystreptazolone (70) was chosen as our first target natural product in this investigation. We describe in detail the results relating (i) the development of the stereoselective and direct construction of the 9-oxa-l-azatricyclo[6.2.1.0 "]undec-5-ene-7,10-dione skeleton (e.g. 75) via the intramolecular Pauson-Khand reaction of 2-oxazolone derivatives and (ii) its successful application to the first total synthesis of ( )-8p-hydroxystreptazolone (70). 

A few applications of intramolecular Pauson-Khand reactions in organic synthesis have been reported. For example, total syntheses of asteriscanolide (Scheme 254) and cis-9-retinoic acid and tagretin analogs have been completed (Scheme 255). 

---