Asymmetric desymmetrisation

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 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... 

Part VI - Asymmetric Desymmetrisation of a Diels-Alder Adduct... 

Normally, silyl enol ethers are considered to react with aldol substrates via an aldol mechanism, but Mikami and coworkers, in their examples, showed that the reaction involves an ene mechanism. This is clear from the regiochemistry of the product (7.186) that is isolated from the reaction of silyl enol ether (7.184) and aldehyde (7.185) before hydrolysis. The same catalyst system has been used for the asymmetric desymmetrisation of the diene (7.187) with aldehyde (7.183). The ... 

Epoxides are effectively ring-opened in the presence of lanthanide salts, and Schaus and Jacobsen have shown that the asymmetric desymmetrisation of cyclic mesu-epoxides with TMSCN can be achieved with up to 92% ee using ytterbium... 

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. 

Hoveyda and Snapper developed an excellent method for asymmetric silylation by employing a newly developed chiral imidazole catalyst, 45 (Scheme 22.10). By virtue of catalyst 45, silylative asymmetric desymmetrisation of meso-1,l-dioX 46 (Scheme 22.10A) and a-symmetric triol 48... 

Scheme 22.9 Asymmetric desymmetrisation by catalytic sulfonylation with Miller s peptide-based catalyst.

Scheme 22.11 Asymmetric desymmetrisation by cooperative catalysis with chiral general base catalyst 45 and achiral nucleophilic catalyst 54.

A DKR of a 5-hydroxytricyclodecadienone using (S)-prolinol or its methyl ether as the chiral mediator led to the corresponding enaminones. This approach, which constituted an asymmetric desymmetrisation of a Diels Alder... 

The catalytic asymmetric desymmetrisation of meso anhydrides via the addition of an alcohol nucleophile represents a simple and elegant method for... 

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],... 

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]. 

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>. 

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. 

The mnemonic device used to predict the sense of enantioselectivity in the AD reaction can also be used in the AA process. Typical examples include the asymmetric aminohydroxylation of alkenes (5.63-5.67), all with excellent enantioselectivity. Heterocyclic groups are tolerated in the AA reaction and high ees have been obtained for the aminohydroxylation of furanoyl acrylates such as (5.65). ° In common with the AD reaction, pyrrolyl- and pyridyl-substituted olefins are difficult substrates and blocking of the nitrogen is required for enantioselective aminohydroxylation. However, indoles such as (5.66) undergo aminohydroxylation with good ee. The AA reaction has also been applied to the desymmetrisation of dienylsilane (5.67) by Landais and coworkers. Whilst the enantioselectivity is not perfect, the reaction is still remarkably regio- and diastereoselective. 

The first asymmetric Heck reactions were reported by Shibasaki in 1989. Typical examples from this group include the desymmetrising cyclisation of vinyl... 

Enantioselective vanadium and niobium catalysts provide chemists with new and powerful tools for the efficient preparation of optically active molecules. Over the past few decades, the use of vanadium and niobium catalysts has been extended to a variety of different and complementaiy asymmetric reactions. These reactions include cyanide additions, oxidative coupling of 2-naphthols, Friedel-Crafts-type reactions, pinacol couplings, Diels-Alder reactions, Mannich-type reactions, desymmetrisation of epoxides and aziridines, hydroaminations, hydroaminoalkylations, sulfoxida-tions, epoxidations, and oxidation of a-hydroxy carbo) lates Thus, their major applications are in Lewis acid-based chemistiy and redox chemistry. In particular, vanadium is attractive as a metal catalyst in organic synthesis because of its natural abundance as well as its relatively low toxicity and moisture sensitivity compared with other metals. The fact that vanadium is present in nature in equal abundance to zinc (albeit in a more widely distributed form and more difficult to access) is not widely appreciated. Inspired by the activation of substrates in nature [e.g. bromoperoxidase. 

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]. 

Lormann, M.E.P., Nieger, M. and Erase, S. (2006) Desymmetrisation of bicy-clo[4.4.0]decadienes a planar-chiral complex proved to be most effective in an asymmetric Heck reaction./. Organomet. Chem., 691, 2159-61. 

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