Desymmetrisation Reactions

In addition to kinetic resolution processes, the previously described peptide-catalysed acylation reaction of alcohols can be applied to desymmetrisation of meso compounds. In 2005, Miller and coworkers published the desymmetrisation of prochiral glycerol derivatives via enantioselective acylation of one primaiy alcohol function. A (3-tum histidine-based pentapeptide was identified as the most promising catalyst from a peptide libraiy and afforded the monoacylated product with up to 97% enantiomeric excess. One year later Miller and Hansen successfully demonstrated the desymmetrisation of a meso bis-phenol compound, which was found to be challenging because of the large distance between the two OH groups as well as between the desired site of functionalisation and the prochiral stereogenic centre of the substrate. The nucleophilic N-methylhistidine containing peptide 9 was identified as a powerful tool for monoacylation via extensive libraiy 

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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. 

Applications of the AD to epoxide transformation propranolol and diltiazem Part V - Jacobsen Epoxidation Part VI - Desymmetrisation Reactions Opening anhydrides Opening epoxides... 

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]. 

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. 

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%. 

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]. 

Microwave dielectric heating is a mild and efficient method for the one-pot and stepwise synthesis of symmetrical and N-desymmetrised NDI derivatives of amines and a-amino acids. For the synthesis of symmetrical NDI derivatives, the reaction is... 

The method described above and outlined in Scheme 1 is particularly suitable for the synthesis of symmetrically substituted NDIs but originally it was of limited value for the synthesis of naphthalenemonoimide (NMI) and N-desymmetrised NDI derivatives. This is due to the difficulty of selective imide formation in a cross-conjugated dianhydride containing two equivalent electrophilic sites such as 1,4,5,8-naphthalenetetracarboxylic dianhydride (NDA). For all the aliphatic amines and amino acids tested, carrying out the reaction for 5 min at 140 °C only led to the formation of a 1 2 1 statistical mixture of dianhydride monoimide diimide (Table 1). 

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>. 

One useful reaction is the desymmetrisation of 4-substituted cyclohexanones 59 to give the silyl enol ethers 60 using the chiral base 57. The chirality can be made more permanent by oxidative cleavage of the alkene to give the dicarboxylic acid 61, or by Pd(II) oxidation (chapter 33) to the enone 62. 

Comparison of desymmetrisation and kinetic resolutions Mono esterification ofdiols Part VII - Hetero Diels-Alder Reactions... 

But matters were really significantly improved by Chen et al.52 If one cinchona alkaloid works, what about the double cinchona alkaloid ligands that are used in the asymmetric dihydroxylation reactions Amazingly, these ligands work really well for desymmetrisations of anhydrides such as 230. Only 5% of catalyst is needed and they can be done at room temperature or 20 °C for better enantiomeric excess. Once again a range of anhydrides can be used 232-234. 

As we shall see further in Chapter 28, a kinetic resolution is the more rapid reaction of one enantiomer of starting material over the other. In the absence of anything fancy (like a dynamic kinetic resolution) they are limited to 50% yield of product (or starting material). But because a desymmetrisation starts with one achiral molecule (instead of a pair of enantiomers) this limitation is removed as are other complications we face in kinetic resolutions such as the build up of the wrong enantiomer which makes selectivity more difficult. However, it is worth noting that desymmetrisation and kinetic resolutions are brothers in the stereochemical world. 

Desymmetrisation of bis allylic esters such as 239 adds another dimension. Asymmetry is already introduced in the r 3 cation complex 240 by selection of one of the enantiotopic benzoates as leaving group. Attack of the nucleophile occurs on the same side as the other benzoate, as that is the side opposite the Pd atom and so there is strong regioselectivity for the site away from the second benzoate. Since the first formed product 241 is still an allylic benzoate, further reaction is possible. 

If the enhancement of enantiomeric excess did not impress you much (though it should, 99.96% is very difficult to achieve in one go ) perhaps an example where the ee is a bit lower after the first round will make the point more effectively. The bistriflate 82 contains a biaryl bond with restricted rotation so that replacing one of the triflates with something else will give us a chiral molecule (83a and 83b are enantiomers). As above, the first reaction is a desymmetrisation and the second reaction a kinetic resolution upon the products from the first. Both reactions are palladium mediated cross-couplings of an aryl triflate and phenyl Grignard. 

The starting material for the next desymmetrisation comes from an interesting reaction first described in chapter 19. The Pd-catalysed attack of AcOH on the mono-epoxide ( )-35 gives the racemic monoester 36. In order to convert this to a single enantiomer it is first made into the meso diester13 37. 

Now the acetyl cholinesterase from the electric eel (EEAC) efficiently desymmetrises the diacetate to give the enantiomerically pure monoester 36. The enzyme can be used as a lyophilised powder or is available (from Sigma) immobilised on agarose beads. This form is easy to use and easy to isolate after the reaction. Other cyclic examples work well as does the most impressive open chain example 38 with an Zi-alkene.14... 

We end this chapter with two much simpler reactions - a couple of desymmetrisations - each special in their own way. The hrst is amazingly efficient, using a lipase/esterase from a thermophilic organism supplied as a recombinant protein by the Diversa corporation. The symmetrical Diels-Alder adduct 231 is rapidly and perfectly desymmetrised to the monoacid61 232 at 70 °C. 

A tetrahydropyran that inhibits leukotriene biosynthesis Asymmetric synthesis of2-methyl-tetrahydropyran-4-one by kinetic resolution Part VI - Asymmetric Desymmetrisation of a Diels-Alder Adduct Ifetroban sodium a thromboxane receptor antagonist A laboratory synthesis starting with a Diels-Alder reaction Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent Laboratory and process routes compared Part VII - Asymmetric Synthesis of A Bicyclic 3-Lactone Lactacystin a naturalproteasome inhibitor... 

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