Diols desymmetrisation

Scheldt and co-workers have nsed their in situ hydroxyazolium oxidation strategy to allow the desymmetrisation of diol 249 using chiral triazolium salt 187, giving mono-ester 250 in 80% ee (Scheme 12.55) [99]. 

A chiral complex was used in Ru(N0)Cl(salen )/02/UV/CHCl3 for oxidative desymmetrisation of meso-diols to optically active lactols and lactones, e.g. of cis-1,2 -bis(hydroxyhnethyl)-cyclohexane to (1/ , 6S, 7/ 5)-7-hydroxy-8-oxabicyclo[4.3.0] nonane, cf mech. Ch. 1 [363],... 

This procedure is elegant and useful, but conventional in that, like most enantioselective syntheses, it involves an achiral starting material desymmetrised by a chiral reagent. However, as shown in Scheme 3, the methodology was extended in a remarkable and unusual direction through the application of similar chemistry to racemic starting materials [7]. To allow a generalised discussion of this and subsequent procedures, it is helpful to introduce special stereochemical descriptors for use with 1,3-diols and their de-... 

The progression from desymmetrisation (Scheme 2) to deracemisation (Schemes 3-6) leads to a useful general insight. The desymmetrisation of <7-symmetric difunctional compounds (31 32, Scheme 7) is a common approach to asymmetric synthesis [14], and there may be various circumstances where the regeneration of functional symmetry, but with stereoinversion, is also possible (32 33). If 31 is now allowed to mutate into the asymmetrical 34, present as a racemate, it is likely that the desymmetrising reaction will yield 35 -i- 36, converging on 37 after the final step. Any desymmetrisation of cr-sym-metric (e.g. meso) diols may thus be extended, potentially, to deracemisation, and other substrates may lend themselves to analogous sequences. 

Sharpless asymmetric oxidation of the meso 1,4-diol 10 results in its desymmetrisation to the pyran-3-one, which exists as a mixture with the dihydrofuran, and the doubly oxidised bis-pyranone. Each of these hemiacetals can be individually trapped in good yield by careful choice of reaction conditions <03OBC2393>. 

Consider, for example, a hypothetical kinetic resolution of enantiomers (R) and (S)-239 by esterification of one of them. Compare this to the esterification and desymmetrisation of diol 241. In many ways, a desymmetrisation is a kinetic resolution but with the two enantiomers joined together in the same molecule. The features that make a reagent work well in a desymmetrisation, may well make it work in a kinetic resolution. Indeed, in Double Methods in Chapter 28 we see that this is the case. 

The desymmetrisation of meso-l,2-diols has been achieved by Oriyama using enantiopure diamines including (12.103),and also atropisomeric 4-aminopyridines. Metal-based catalysts have also been used to good effect in... 

Also, the Schreiner group published in 2009 a desymmetrisation approach of meso-(cyclo)alkane-l,2-diols applying the lipophilic peptide catalyst 7 (Scheme 13.8) already successfully used in kinetic resolution processes (Scheme 13.5) as previously described. The desymmetrisation step was combined in one pot with a direct TEMPO oxidation to the corresponding ot-aceto)y ketone in order to avoid racemisation of the monoacelylated intermediate. 

Hennecke developed enantioselective haloetherification reactions via desymmetrisation of in situ generated meso-iodonium intermediates (Scheme 2.37). Chiral sodium phosphate 58 was used for the cyclisation of symmetrical ene-diol substrates 59 with l-iodopyrrolidin-2-one (60), and the corresponding iodoetherification products 61 were obtained with up to 71% ee. 

Enantioselective desymmetrisation of meso-diols mediated by nonenzy-matic acyl transfer catalysts 12CSR7803. 

A number of other asymmetric enolate protonation reactions have been described using chiral proton sources in the synthesis of a-aryl cyclohexanones. These include the stoichiometric use of chiral diols [68] and a-sulfinyl alcohols [69]. Other catalytic approaches involve the use of a BlNAP-AgF complex with MeOH as the achiral proton source, [70] a chiral sulfonamide/achiral sulfonic acid system [71,72] and a cationic BINAP-Au complex which also was extended to acyclic tertiary a-aryl ketones [73]. Enantioenriched 2-aryl-cyclohexanones have also been accessed by oxidative kinetic resolution of secondary alcohols, kinetic resolution of racemic 2-arylcyclohexanones via an asymmetric Bayer-Villiger oxidation [74] and by arylation with diaryhodonium salts and desymmetrisation with a chiral Li-base [75]. 

Miller developed peptide-based iV-methylimidazole catalysts and applied them to acylative kinetic resolution of N-acylated amino alcohol 29 (Scheme 22.6). The p-hairpin secondary structure of the peptide backbone in catalysts 30 and 31 constitutes a unique environment for effective asymmetric induction. Acylative kinetic resolution of 29 with acetic anhydride in the presence of catalyst 31 proceeded with high s values (s = up to 51). The asymmetric acylation was further extended to remote asymmetric desymmetrisation of a o-symmetric nanometer-scale diol substrate, 32 (Scheme 22.7). Catalyst 33 enabled the enantiotopic hydrojq groups in 32 to be distinguished even though they are located 5.75 A from the prochiral stereogenic centre, and 9.79 A from each other. 

Asymmetric sulfonylation was also developed by Miller employing tetra-peptide catalyst 42. ° Desymmetrisation of a variety of meso-l,3-diols was examined. Asymmetric sulfonylation of rwyo-inositol derivative 35 with p-nitrobenzenesulfonyl chloride (p-NsCl) (43) as a sulfonyl donor in the presence of catalyst 42 gave monosulfonylated product 44 in high yield and enantiomeric excess (76% yield with 94% enantiomeric excess) (Scheme 22.9). 

Scheme 22.7 Remote desymmetrisation of a a-symmetric diol 32 by acylation with Miller s peptide-based iV-methylimidazole catalyst 33.

Scheme 22.8 Phosphoiylative desymmetrisation of meso-l,3-diols with Miller s peptide-based catalysts.

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