Asymmetric intramolecular Pd(II)-catalysed oxycarbonylation of alkene-1,3-diols

The first example of asymmetric oxycarbonylative bicyclisation of racemic pent-4-ene-1,3-diol (±)- 1 catalysed by palladium(II) with chiral bis(oxazoline) ligands was investigated. The kinetic resolution of (±)- 1 in the presence of chiral catalyst, p -benzoquinone in acetic acid under carbon monoxide atmosphere (balloon) afforded both optically enriched 2,6-dioxabicyclo[3.3.0]octan-3-ones ( R , R) - 2 and ( S , S) - 2 , respectively.

Typically, alkoxycarbonylation of alkenyl alcohols is catalysed by 10 mol % of the palladium(II)-salt in the presence of an oxidant (CuCl 2 , p-benzoquinone, O 2 ).Generally, the most efficient catalytic system for intramolecular oxycarbonylation of unsaturated polyols, originally developed for the Wacker process, contains palladium(II) chloride as a catalyst, copper(II) chloride as an oxidant, sodium acetate in acetic acid as a buffer, the reaction taking place under carbon monoxide atmosphere (balloon) at room temperature.In accordance with the diastereoselective cis-ring formation, racemic pent-4-ene-1,3-diol (±)-1 afforded under these reaction conditions racemic 2,6-dioxabicyclo[3.3.0]octan-3-one(±)-2 in 60% yield. 3 An asymmetric version of this type reaction has not been reported so far.To the best of our knowledge, previously reported works on related asymmetric Wacker-type oxidations have been limited to the monocyclisation of alkenes and alkynes.For instance, Kato, Akita et al. 5 described desymmetrisation of cyclic meso-2-methyl-2-propargyl-1,3-cyclohexane-diols 5a,c and -1,3diones 5b using methoxycarbonylation catalysed with palladium(II)-complex, bearing chiral bis(oxazoline) ligands.Chiral bis(oxazolines) based on binaphtyl (Boxaxs 6 ) or biphenyl backbone 7 were also successfully applied in the asymmetric Wacker-type cyclisation of allylphenols. 8Sasai and co-workers 9 reported oxidative cyclisation of alkenyl alcohols 9a,b and aminoalkenes 9c with spiro bis(isoxazolines) (SPRIXs 9d ).There is no report in the literature dealing with enantioselective oxycarbonylative bicyclisation of unsaturated polyols.We wish to report here the first example of kinetic resolution of alkene-diol by intramolecular Pd(II)catalysed oxycarbonylation.

Results and Discussion
Firstly, the catalytic system for kinetic resolution of unsaturated diols was examined.The racemic pent-4-ene-1,3-diol 10 (±)-1 has been chosen as a model substrate for screening the reaction conditions.The transformation was carried out with different chiral PdX 2 -[(R,S)indabox] complexes, p-benzoquinone in acetic acid under carbon monoxide atmosphere (balloon).Chiral palladium(II)-complexes were generated in situ from PdX 2 and a slight excess of chiral ligand A {(3aR, 8aS) - (8,8a- In accordance with a kinetic resolution process, the reaction was performed with 50% conversion by use of 0.5 equivalent of p-benzoquinone.Conversion control was made by GC with methyl benzoate as an internal standard.The reaction was quenched after 50% of the starting material had been consumed.The bicyclic product 2 and the remaining diol 1 were separated by flash chromatography.The enantiomeric excess of lactone (R,R)-2 was determined by GC analysis with a chiral stationary phase (BGB 175 and BGB 173 column).The absolute configuration of (R,R)-2 was assigned by comparison of the specific rotation value with the literature data ( 20 ] [ D a = +62 (c 0.9, CHCl 3 ) for (R,R)-2 prepared from D-glucose; 11 20 ] [ D a = -67 (c 0.639, CHCl 3 ) for (S,S)-2 prepared by microbial regiodivergent Baeyer-Villiger oxidation with 99% ee 12 ).
As shown in Table 1, the reaction catalysed with PdCl 2 -{(R,S)-indabox (A)} (entry 1) and Pd(BF 4 ) 2 -{(R,S)-indabox} complexes (entry 4) afforded only racemic lactone 2. Moderate selectivities were achieved using Pd(OAc) 2 -{(R,S)-indabox} (entry 2) and Pd(OCOCF 3 ) 2 -{(R,S)-indabox} catalysts (entry 3).It is apparent that catalytic activity of palladium complexes in the present reaction was strongly dependent upon the nature of the anionic part of the catalyst.It is notable that in transformation of 1 to 2 the use of dichloromethane or tetrahydrofuran as solvents did not give satisfactory results in terms of both conversion and enantioselectivity.a Reaction was treated after 50% of starting material had been consumed (GC control).b Isolated yield after flash column chromatography.b Enantiomeric excesses were determined using gas chromatography with chiral stationary phase.
Having found reaction conditions for a kinetic resolution process of the diol (±)-1 by Pd(II)catalysed oxycarbonylation, our attention was turned to the screening of chiral ligands (Scheme ARKAT USA, Inc. 2).Chiral C 2 -symmetric bisoxazolines have been chosen due to their ability to create stable palladium(II)-complexes. 13,14 The reaction was carried out under optimised reaction conditions for kinetic resolution of (±)-1 using 5 mol % of Pd(OAc) 2 and 7.5 mol % of ligands A-H in glacial acetic acid, respectively.A cationic 6b acetate complex Pd-(OAc) 2 -{(R,S)-indabox A} was found to be catalytically so highly active that the amount of the catalyst could be reduced to 2.5 mol %.The conversion was controlled by the amount of reoxidant (0.5 equivalents of p-benzoquinone).After completion the reaction, the solids were filtered off, solvent was evaporated and the product and glucose. 15The NMR spectral data were in good agreement with those reported in the literature.4g,15 Scheme 2. Kinetic resolution of alkene-1,3-diols (±)-1, (±)-3 and (±)-5 in asymmetric Pd(II)catalysed oxycarbonylation.

Conclusions
In summary, we have presented a kinetic resolution process of racemic alkene-1,3-diols (±)-1, (±)-3 and (±)-5 catalysed by palladium(II) with chiral bis(oxazolines).This is the first report of an enantioselective oxycarbonylative bicyclisation.Conversion of substrate is controlled by reoxidant, which represents novelty in kinetic resolution processes.Further studies to improve the performance of asymmetric catalysts for this transformation are now under way.