Pauson-Khand reaction stereoselective

The complex of o-substituted anisole 203 is planar chiral, and can be used for diastereoselective generation of two new stereogenic centres in the products. Propargylation and allylation of 203 gave 204 regio- and stereoselectively. Hydrolysis of 204 afforded the cyclohexenone 205, and its intramolecular Pauson-Khand reaction gave 206 diastereoselectively. The two reactions were completely diastereoselective, and the planar chirality in 203 was efficiently transferred to the three new stereogenic centers in 206 [51]. 

Two remarkable intramolecular reorganizations of the Diels-Alder adducts of methyl 2-chloro-2-cyclopropylideneacetate (1-Me) onto furans should be mentioned here. In a reaction of 1-Me with 2,5-bis(trimethylsilyl)furan (263) the unstable adduct 264 underwent a spontaneous deprotection followed by ring opening to give the dioxospiro[2.5]octene derivative 265 (Scheme 76) [7 m]. The Pauson-Khand reaction of the transformed Diels-Alder adducts 70, 71 of 1-Me have been discussed above (Scheme 18), however, when the compounds endo,-exo-62 e were treated under Pauson-Khand conditions, but at higher temperature, the interesting Co2(CO)8-promoted stereoselective rearrangement, in the presence as well as in the absence of an alkyne component, has been observed. The cis- and frans-substituted 6-methylenespiro[2.4]hexanes 266 were isolated as main products in these reactions (Scheme 76) [19b]. 

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. 

Martin et al. disclosed that [Rh(CO)2Cl]2 catalyzes highly regio- and stereoselective allylic alkylation using a-substituted sodiomalonates. The new C - C bond was formed at the carbon bearing the leaving group [22]. Owing to the known ability of Rh(I) complexes to catalyze carbocyclizations such as the Pauson-Khand reaction (PKR) [23,24] or [5 + 2] cycloadditions [25], Martin anticipated that the aforementioned reaction could be the first step of... 

Similarly, intramolecular Pauson-Khand reactions can be utilized for tetrahydrofuran synthesis, when the tethers are oxa substituted. Ligand effects on stereoselectivity in Rh(i)-catalyzed asymmetric Pauson-Khand-type reactions have been investigated and ee s of up to 92% have been achieved with the 2,2-bis(diphenyl-phosphanyl)-l,l-binaphthyl (BINAP) ligand and a Rh(i) precatalyst (Equation 91). However, it has to be noted that the ee is highly substrate dependent, and considerably lower in most other cases <2006S4053>. 

An intermolecular Pauson-Khand reaction of a dihydrofuran intermediate was used to prepare a benz[ indenone, allowing for the first synthesis of a zirconocene benz[/]indene complex <03OL3153>. A stereoselective intermolecular Pauson-Khand reaction of 3-(R)-methyldihydrofuran was used to construct the desired diastereoisomer of oxabicyclo[3.3.0]octanone ring shown below in the total synthesis of the sesterterpene terpestacin <03JA11514>. 

Castro, J., Moyano, A., Pericas, M. A., Riera, A. A qualitative molecular mechanics approach to the stereoselectivity of intramolecular Pauson-Khand reactions. Tetrahedron 1995, 51, 6541-6556. 

Breczinski, P. M., Stumpf, A., Hope, H., Krafft, M. E., Casalnuovo, J. A., Schore, N. E. Stereoselectivity in the intramolecular Pauson-Khand reaction towards a simple predictive model. Tetrahedron 1999, 55, 6797-6812. 

Pauson-Khand reaction. The intermolecular Pauson-Khand reaction of N- 2-alkenoyl)bomane-IO,2-sultams is totally stereoselective. The catalytic P-K reaction is promoted by small quantities of DME (or other hard bases including water). Reactions carried out in supercritical carbon dioxide are very efficient regardless of the substitution pattern of the alkyne unit. ... 

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. 

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). 

Since the targeted streptazolin-related natural products have a C2-unit at the C6-position, we first prepared the 2-oxazolone-alkyne derivative 82 with the simplest C2-unit, an ethyl group, at the triple bond terminus to not only identify suitable ring-closing conditions, but also to determine the level of stereoselectivity that could be expected in the intramolecular Pauson-Khand reaction. Thus, the 2-oxazolone-alkyne derivative 82, required for the intramolecular Pauson-Khand reaction in our retrosynthesis, was easily prepared from the known alcohol 78 by conventional means, as shown in Scheme 18. Oxidation of 78 was... 

We have developed a novel and efficient procedure for constructing 7-hydroxy-6-substituted-9-oxa-1 -azatricyclo[6.2.1.0 ]undec-5-ene-7,10-diones by the intramolecular Pauson-Khand reaction of the 2-oxazolone species with the required alkyne appendages. In addition, by taking advantage of this newly developed method, we have achieved the first total synthesis of ( )-8 3-hydroxystreptazolone (70) in a highly stereoselective manner. Synthesis of ( )-7-( /7/-8(3-hydroxystreptazolone... 

Kozaka T, Miyakoshi N, Mukai C (2007) Stereoselective total syntheses of three Lycopodium alkaloids, (-)-magellanine, (-r)-magellaninone, and (-l-)-paniculatine, based on two Pauson-Khand reactions. J Org Chem 72 10147-10154... 

A similar Nicolas-Pauson-Khand combination was used in a synthesis of the ketone analogue of biotin 7.98, required for biochemical studies (Scheme 7.25). In this case, the Nicholas reaction was intermolecular, between allyl thiol as the nucleophile and carbocation 7.94 generated from alcohol 7.93. The Pauson-Khand reaction was then between the dicobalt complexed alkyne 7.95 and the double bond from the thiol moiety. The Pauson-Khand reaction proceeded with no stereoselectivity, and the diastereoisomers had to be chromatographically separated at a later stage. The synthesis was completed by reduction of the alkene of cyclopentenone 7.96, without using palladium-catalysed hydrogenation due to the sulfide moiety, and ester hydrolysis. 

The developed solid-supported, chemoselective Pauson-Khand reaction has been subsequently applied toward the preparation of complex tricyclic scaffolds for diversity-oriented synthesis." The triple bond was introduced into the substrate via a stereoselective Ferrier reaction generating the ene-yne 86, followed by immobilization on the solid support. The subsequent Pauson-Khand reaction yielded the desired tricyclic product 87 in an efficient fashion (however, no yields were provided), which was further elaborated toward structurally complex small molecule libraries (Scheme 6.20). 

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