Desymmetrisation

Subsequently, these catalysts were evaluated in the enantioselective desymmetri-sation of achiral trienes, and three distinct trends in catalyst selectivity were found. Firstly, catalysts 56a-b with two phenyl moieties on the backbone of the A -heterocycle exhibited higher enantioselectivity than those with a fused cyclohexyl group as the backbone 55a-b. Secondly, mono-ort/io-substituted aryl side chains induced greater enantioselectivity than symmetrical mesityl wing tips. Thirdly, changing the halide ligands from Cl to I" increased the enantioselectivity. As a result, catalyst 56b turned out to be the most effective. For example, 56b in the presence of Nal was able to promote the desymmetrisation of 57 to give chiral dihydrofuran 58 in up to 82% conversion and 90% ee (Scheme 3.3). 

Rovis and co-workers have applied the asymmetric intramolecular Stetter reaction to the desymmetrisation of cyclohexadienones 140, generating a quaternary stereocentre and forming hydrobenzofuranones 141 in excellent yields and enantiose-lectivities. Substitution at the two, four and six-positions is tolerated, and even substitution at the three-position is accommodated (Scheme 12.29) [65]. 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

Rovis and co-workers have extended the application of redox transformations to generate chiral acylazolium species from a-haloaldehydes 245 and the NHC derived from pre-catalyst 247, allowing the desymmetrisation of mei o-hydrobenzoin 246 to give ester 248 in good yield and enantioselectivity (Scheme 12.54) [30]. 

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]. 

Rejzek, M., Stockman, R.A., van Maarseveen, J.H., Hughes, D.L. (2005) Combining Two-Directional Synthesis and Tandem Reactions Desymmetrisation by Intramolecular Cycload-dition/Triazoline Fragmentation. Chemical Communications, 4661 662. 

Kielbasinski, P., Rachwalski, M., Mikolajczyk, M. et al. (2007) Enzyme-promoted desymmetrisation of prochiral bis(cyanomethyl) sulfoxide. Advanced Synthesis and Catalysis, 349, 1387-1392. 

Camell, A.J., Barkely, J. and Singh, A., Desymmetrisation of prochiral ketones by catal3ftic enantioselective hydrolysis of their enol esters using enzymes. Tetrahedron Lett., 1997, 38, 7781-7784 Allan, G.R., Carnell, A.J. and Kroutil, W., One-pot deracemisation of an enol acetate derived from a prochiral cyclohexanone. Tetrahedron Lett., 2001, 42, 5959-5962. 

Bergeron, S., Chaplin, D.A., Edwards, J.H., Ellis, B.S.W., Hill, C.L., Holt-Tiffin, K., Knight, J.R., Mahoney, T., Osborne, A.P. and Ruecroft, G., Nitrilase-catalysed desymmetrisation of 3-hydroxyglutaronitrile preparation of a statin side-chain intermediate. Org. Proc. Res. Dev.,... 

Allan, G., Camell, A.J., Escudero Hernandez, M.L. and Pettman, A., Desymmetrisation of 4,4-disubstituted cyclohexanones by enzyme-catalysed resolution of their enol acetates. J. Chem. Soc. Perkin Trans. 1, 2000, 3382. 

Camell, A.J., Barkley, J. and Singh, A., Desymmetrisation of prochiral ketones by catalytic enantioselective hydrolysis of their enol esters using enzymes. Tetrahedron Lett., 1997,38,7781. 

Hence, a reaction of Type I will involve a racemic or achiral/me,t(9 nncleophile which will react enantioselectively with an achiral acyl donor in the presence of a chiral catalyst, while on the other hand, a reaction of Type II will associate an achiral nncleophile and a racemic or udm lmeso acyl donor in the presence of a chiral catalyst. In both cases, when a racemic component is implicated the process constitntes a KR and the maximum theoretical yield of enantiomerically pure product, given perfect enantioselectivity, is 50%. When an achiral/mera component is involved, then the process constitutes either a site-selective asymmetric desymmetrisation (ASD) or, in the case of tt-nucleophiles and reactions involving ketenes, a face-selective addition process, and the maximum theoretical yield of enantiomerically pure product, given perfect enantioselectivity, is 100%. 

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],... 

Redy RA, Tschierske C (2006) Bent-core liquid crystals polar order, superstructural chirality and spontaneous desymmetrisation in soft matter systems. J Mater Chem 16 907-961... 

Willis MC (1999) Enantioselective desymmetrisation. J Chem Soc Perkin Trans 1 1765-1784... 

Landais, Y. Desymmetrisation of Dienylsilanes. Stereoselective Access to Cyclitols and Carba-Sugars. 1998 [92]... 

The enantiotopic methyl groups of the phosphine-borane complexes 429 and 430 can similarly be desymmetrised by rc-BuLi-(-)-sparteine. On coupling and deprotection, valuable chiral diphosphines 431 are formed.185... 

Desymmetrisation of the enantiotopic methyl groups of 432 with a chiral lithium amide base leads to atropisomeric amides in good enantiomeric excess.186... 

Desymmetrisation by enantioselective ortholithiation has been achieved with ferrocenylcarboxamides 434,187 and also (with chiral lithium amide bases) a number of chromium-arene complexes.188 The chromium arene complex 435, on treatment with s-BuLi-(-)-sparteine, gives 436 enantioselectively, and reaction with electrophiles leads to 437. However, further treatment with r-BuLi generates the doubly lithiated species 438, in which the new organolithium centre is more reactive than the old, which still carries the (-)-sparteine ligand. Reaction of 438 with an electrophile followed by protonation therefore gives ent-431.m... 

One does not immediately associate a reaction which generates sp1 carbon centres with asymmetric inductive capability, however the development of non-racemic catalysts such as 40, 41 and 42 (Fig. 6) has allowed the efficient synthesis of optically active alkenes via the kinetic resolution (KR) of dienes and the desymmetrisation of meso-alkenes via either RCM or ROM-CM. For a short review of asymmetric metathesis see Ref. [85]. 

A synthesis of (S)-cx-tocotrienol, in which the phytyl group of tocopherol is replaced by a famesyl side chain, (six steps, 19% ee = 98%) is based on the enzymatic desymmetrisation of the achiral 2,2-di(hydroxymethyl)chroman 16 <02TL7971>. 

---