Chiral auxiliaries Pauson-Khand reaction

An enantioselective intramolecular Pauson-Khand reaction based on chiral auxiliary-directed 7t-face discrimination in acetylenic 0-alkyl enol ether-dicobalt hexacarbonyl complexes, which proceeds with good yields and high facial diastereoselectivity, has recently been developed by M.A. Pericas, A. Moyano, A.E. Greene and their associates. The method has been applied to an enantioselective formal synthesis of hirsutene. Moreover, the process is stereodivergent and the chiral auxiliary -rran5-2-phenylcyclohexanol- is recovered in a yield as high as 92% [18]. 

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. 

Stereoselectivity in the Pauson-Khand reaction. For the PK reaction to be useful in synthetic chemistry, it is important that the stereochemical outcome of the reaction can be controlled. Four different approaches have been employed in attempts to control the stereoselectivity of the PK reaction, namely the use of chiral precursors, chiral auxiliaries, chiral promoters and chiral metal complexes. 

Asymmetric intermolecular Pauson Khand reactions have been reahzed using a number of chiral auxiliaries chelating to the metal and/or attached to the alkyne. One example using a camphor-derived hgand is seen in Scheme 253. Moderate asymmetric induction has been observed using chiral amine A-oxides as the promoter. For example, (-F)-indohzino[3,4-b]quinoline A-oxide gave up to 53% ee. 

This intramolecular Pauson-Khand reaction leading to spiro cyclopropane-l,2 -bicyclo[3.3.0]-octenones of type 30 is diastereoselective when the precursor 29 contains a chiral auxiliary on a carbonyl group adjacent to the triple bond or a stereogenic center on the three-membered... 

Another approach to the stoichiometric enantioselective Pauson-Khand reaction involves the use of chiral auxiliaries. Extensive investigations on this subject have been carried out by Periods, Moyano, Greene, and coworkers. Initial reports detailed the use of frans-2-phenylcyclohexanol as a chiral auxiliary for the... 

Substantial progress has also been made in the chiral auxiliary-based approach to an enantioselective intermolecular Pauson-Khand reaction. Initial studies utilizing alkynes substituted with fra s-2-phenylcyclohexanol produced cyclopentenones with low drs, however, the diastereomers were easily separable... 

Schemes. trans-2-Phenylcyclohexanol as a chiral auxiliary for the intramolecular Pauson-Khand reaction...

Ester-based chiral auxiliaries have also beat used in other settings. P-Alk-oxyesters 1.27 of (R)-1 -phenylethanol 1.1 (R = Me, Ar = Ph) or (5)-1-naphthyl-ethanol 1.1 (R = Me, Ar = 1-Np) are transformed into dural synthons by reactions with a lithiated carbanion a to phosphorous followed by hydrogenolysis [194], Ethers 1.28 of chiral alcohols 1.1 undergo selective alkylations or hydroxyalkyla-tions [169]. The auxiliaries can be removed by hydrogenolysis. Enol or dienol ethers 1.29 and 1 JO suffer [2+2] [195, 196] or [4+2] cycloadditions [49, 197,198, 199], The best stereoselectivities are obtained when the chiral auxiliary is 1.1 (R = r-Pr, Ar=Ph), 1.4 (R=Ph), 1.5 (R = Ph), 1.10 or 1.13. These auxiliaries are cleaved either by acid treatment [199] or by other means in subsequent steps. Acetylene ethers G OC=CR derived from 1.5 (R=Ph) [199a] can undergo stereoselective Pauson-Khand reactions [200, 201], The auxiliaries are removed by treatment of the products with Sml2 in THF-MeOH. 

An enantiosdective intermolecular Pauson-Khand reaction between nor-bomene and chiral alkoxyacetylene bearing 10-methylthioisobomeol as the auxiliary has recently been successfully performed with high selectivity [1676]. 

Although tremendous advances in the catalytic Pauson-Khand reaction have been made, the development of an asymmetric version did not share the same degree of success. Several asymmetric Pauson-Khand reactions were reported using chiral auxiliaries. However, those systems required stoichiometric amounts of cobalt as well as the chiral source. Attempts at using a catalytic amount of cobalt did not give satisfactory results. By contrast, the use of titanium chiral catalyst S,Sy (EBTHI)Ti(CO)2 (EBTHI = ethylene-l,2-bis(tiM,5,6,7-tetrahydro-l-indenyl)... 

Asymmetric variants of the Pauson-Khand reaction have been explored employing chiral auxiliaries. Attachment of a chiral auxiliary to the alkene moiety gave good stereochemical induction (Scheme 7.19). This chemistry was used in a formal synthesis of hirsutene 7.69. Chiral auxiliaries can also be attached to the alkyne moiety. ... 

The extensive use of the Pauson-Khand 2-p 2-1-1-cycloaddition reaction in natural product synthesis has been reviewed. The use of chiral auxiliaries, chiral controllers, and chiral reagents in asymmetric versions of the Pauson-Khand reaction has been extensively reviewed. " Density functional theory (DFT) was used to 0... 

A chiral auxiliary-based method employing heteroatom binding shows considerable promise in nonracemic intermolecular Pauson-Khand chemistry. Scheme 5-3 depicts an acetylene synthetic equivalent bearing the 10-methylthioisobomeol moiety (15), which is capable of significant asymmetric induction upon Pauson-Khand cycloaddition. Loss of carbon monoxide from 15 may be effected thermally, or better yet, by reaction with IV-methylmorpholine N-... 

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