Pauson-Khand bicyclization

Asymmetric Pauson-Khand bicyclization.1 Efficient asymmetric Pauson-Khand bicyclizations of enynes are possible using (lS,2R)-( + )-phenylcyclohexanol (13, 244 14, 128-129) as the chiral auxiliary. Thus the (E)-enol ether (1) derived... 

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). 

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. 

Hetero Pauson-Khand reactions with an aldehyde or ketone component have been shown to afford synthetically versatile y-butyrolactones. Buchwald [50] and Crowe [51] independently showed that aliphatic enones and enals react with CO under Cp2Ti(PMe3)2 mediation (Scheme 11). CO insertion and thermal (or oxidative) decomposition gave diastereomerically pure bicyclic y-butyrolactones and stable Cp2Ti(CO)2. Imines did not react under the reaction conditions. 

Co complexes, Buchwald reported the Ti-catalyzed carbonylative coupling of enynes-the so-called Pauson-Khand-type reaction [28]-and realized the first such catalytic and enantioselective reaction using a chiral Ti complex [29]. Here, a variety of enynes were transformed into bicyclic cyclopentenones with good to high ee-values however, several steps were required to prepare the chiral Ti catalyst, while the low-valent complex proved to be so unstable that it had to be treated under oxygen-free conditions in a glove box. 

The Ir-tolBINAP catalyst also functions well in the desymmetrization of dienynes, where a highly enantioselective and diastereoselective Pauson-Khand-type reaction proceeded to give vinyl-substituted bicyclic cyclopentenones with two chiral centers (Scheme 11.19) [31]. 

Allenyne represents an interesting substrate for the intramolecular Pauson-Khand(-type) reaction, where an allene moiety acts as an ene component. Here, there are two possible reaction pathways (Scheme 11.21) (i) the reaction of an external tr-bond of allene moiety gives a bicyclic dienone (type A) or (ii) the reaction of an internal 7i-bond gives a bicyclic cyclopentenone with an alkylidene substituent (type B). 

Scheme 1.3.28 Asymmetric synthesis of bicyclic amino acids via Pauson-Khand cycloaddition of vinyl sulfoximines.

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... 

Bicyclic cyclotrigermanes, thermolysis, 3, 793 Bicyclic imidazoles, via intramolecular C-H functionalizations, 10, 138 Bicyclic siloxanes, rational synthesis, 3, 655 Bicycloctasilane dianion, preparation, 3, 466468 Bicyclo[5.3.0]decadiene, via [5+2]-cycloadditions, 10, 613 Bicyclo[5,3,0]-decanes, via Pauson-Khand reaction, 11, 361 Bicyclononasilane anions, preparation, 3, 466-468 Bicyclo[3.3.0]-octanones, via carbonylative carbocyclization, 11, 427... 

When enyne cycloisomerization takes place in the presence of an unsaturated molecule an insertion reaction can occur. Thus, Ru3(CO)12 catalyzes the cycloisomerization of 1,6-enynes under a CO atmosphere to give an insertion of carbon monoxide and the formation of bicyclic cyclopentenones as a catalytic Pauson-Khand reaction [78] (Eq. 57). 

Hua has used the products of Pauson-Khand cycloadditions for syntheses of optically active pental-enene and racemic pentalenolactone E methyl ester. The racemic ketone in the first case was converted to the necessary optically active intermediate by kinetic resolution via 1,4-addition of an optically active allyl sulfoxide anion. These represented the first synthesis of natural products containing the angularly fused triquinane skeleton from bicyclic Pauson-Khand products (equation 53 and Scheme 20). ... 

An intramolecular reaction of 1,5- and 1,6-enynes with isonitriles takes place in the presence of Ni(COD>2 (COD = 1,5-cyclooctadiene) and phosphines, giving bicyclic cyclopentenone imines (equation 5). Stereochemical characteristics in substituted systems appear to pardlel those in the intramolecular Pauson-Khand enynes with substituents in propargylic positions cyclize preferentially to products in which those substituents occupy exo positions relative to the newly created ring fusion. It is likely that these reactions proceed via similar mechanisms involving insertion into bonds of metallacycles, although the order of incorporation of the three two-electron systems into the precursor to the final product is open to question in the nickel system. 

Prior to the development of enyne bicyclization reactions promoted by Zr and other Group IV metals, the Co-catalyzed enyne bicyclization-carbonylation reaction (the Pauson-Khand reaction ) was known. This reaction is discussed in Volume 5, Chapter 9.1. In the Pauson-Khand reaction, the overall transformation is the conversion of enynes into bicyclic enones, and the organometallic bicyclic intermediates are usually neither readily available nor isolated. The use of Co2(CO)s, an 18-electron species, necessitates relatively high reaction temperatures. These and other limitations suggested the desirability of developing alternative enyne bicyclization reactions. 

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. 

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