Additives, enantioselective oxirane

Hi. Role of additive. There are some reports in the literature of the beneficial effect of powerful donor solvents such as DBU on the reactivity and enantioselectivity of HCLA-mediated oxirane rearrangements for both stoichiometric and catalytic processes. However, this effect is not general (see above) and the role of such additives is still unclear. In one study, the influence of the concentration of DBU on the relationship between the ee s of catalyst and the product for the enantioselective isomerization of cyclohexene oxide mediated by substoichiometric amount of HCLA 56a (20 mol%) in the presence of LDA (2 equiv) has been investigated. At high DBU concentration (6 equiv), the enantiomeric... 

Organometallic compounds asymmetric catalysis, 11, 255 chiral auxiliaries, 266 enantioselectivity, 255 see also specific compounds Organozinc chemistry, 260 amino alcohols, 261, 355 chirality amplification, 273 efficiency origins, 273 ligand acceleration, 260 molecular structures, 276 reaction mechanism, 269 transition state models, 264 turnover-limiting step, 271 Orthohydroxylation, naphthol, 230 Osmium, olefin dihydroxylation, 150 Oxametallacycle intermediates, 150, 152 Oxazaborolidines, 134 Oxazoline, 356 Oxidation amines, 155 olefins, 137, 150 reduction, 5 sulfides, 155 Oxidative addition, 5 amine isomerization, 111 hydrogen molecule, 16 Oxidative dimerization, chiral phenols, 287 Oximes, borane reduction, 135 Oxindole alkylation, 338 Oxiranes, enantioselective synthesis, 137, 289, 326, 333, 349, 361 Oxonium polymerization, 332 Oxo process, 162 Oxovanadium complexes, 220 Oxygenation, C—H bonds, 149... 

In addition to being highly efficient catalysts for the preparation of asymmetric oxiranes (see Section 1.04.2.6.1), chiral metal-salen complexes can mediate the enantioselective nucleophilic ring opening of epoxides Jacobsen reviewed this area in 2000 <2000ACR421>. 

Along with the development of chiral Lewis acid catalysts, a chiral trialkanolamine (42) has been used to prepare the catalyst (43) (Eq. 19). By use of this zirconium complex as a catalyst, enantioselective addition of the azide to meso epoxides was achieved [20a]. Thus, the oxirane ring was opened by /-PrMe2SiN3 to give the adduct (44) with high enantioselectivity (Eq. 20). In another example, a diamide ligand (45), which behaves as a tetradentate ligand, was used to achieve a similar reaction (Eqs 21 and 22) [20b]. 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

The synthesis of the enantiopure AB segment 184 [68] by Shibasaki et al. [178] relied on the enantioselective opening of the oxirane ring of the readily available meso-epoxide 177 with p-anisidine [179,180], followed by two steps with 1,3-chiraUty transfer. After extensive experimentation the best enantiomeric excess was obtained with a catalyst prepared from Pr(0-f-Pr)3-(Jl)-BINAP in the ratio 1 1.5 with three equivalents of triph-enylphosphine oxide as an additive. Thus, reaction of 177 with p-anisidine in the presence of 10 mol% of the chiral catalyst provided fraws-aminoalcohol 178 in 80% yield with a moderate enantiomeric excess (65% ee), which was raised to 95% ee by one recrystaUization in 40% yield (Scheme 36). Methy-lation of 178 and Hofmann degradation of the resulting quaternary salt with butyllithium at -78 °C gave aUyhc alcohol 179. Oxymercuration of alcohol 179 with Hg(OAc)2 in methanol, followed by sodium borohydride reduction [181]... 

In addition, several research groups have also developed enantioselective syntheses [130] and enzymatic processes [131] for this class of drugs. A 1-aryloxy-3-chloropropan-2-ol can for example be esterified enantioselectively with vinyl acetate in presence of a Pseudomonas-lipase. The unreacted, enantiomerical-ly-enriched (l )-chlorohydrins are then transformed with potassium t-butoxide to the corresponding oxiranes, which are without isolation reacted further to the target compound. In case of penbutolol, the enantiomericaUy pure (S)-beta-blocker is obtained by recrystallisation of its hydrochloride salt... 

Alexakis also studied the enantioselective domino reactions catalyzed by a Cu complex of phosphoramidite 28. The 1,4-addition products of this reaction can be employed in an enolate trapping with vinyl oxiran 40 with Pd(0) catalysis (Scheme 11.9) [18]. This domino process afforded the known precursor 43 in the synthesis of the anticancer agent clavularin B (44) [19]. 

Aziridine-2-phosphonates spiro-fused with 2-oxindole (790) have been prepared by a straightforward Horner-Wadsworth-Emmons reaction of ethyl 7V- [(4-nitrophenyl)sulfonyl]oxy -carbamate (791) and 3-(phosphoryl-methylene)oxindoles (792) in the presence of calcium oxide. Oxindoles (792) were also transformed into novel oxirane-2-phosphonates (793), as oxygen analogues of (790), by reaction with H202/Na0H (Scheme 201). " Cinchonine-based thiourea (797) catalysed asymmetric Michael addition of simple p-oxo-alkyl phosphonates (794) to nitro olefins (795), which afforded valuable a-substituted p-oxo phosphonates (796) in satisfactory yields with good to excellent enantioselectivities (up to 98% ee) (Scheme 202). ... 

In addition to the enantioselective synthesis of oxiranes through the use of electrophilic oxidants as described above, there have also been significant advances in the development of nucleophilic oxidation catalysts for the epoxi-dation of electron-deficient substrates. Shibasaki has reported an effective chiral catalyst system readily prepared from equimolar amounts of BINOL (102), Ph3As = 0, and La(Oi-Pr)3 (Scheme 9.12) [101]. Use of 1-5 mol % of the chiral lanthanide catalyst permits the epoxidation of a,/3-unsaturated ketones. The method has also been extended to include a,/funsaturated imi-dazolides as substrates to provide convenient access to chiral carboxylic acids [102]. As an example, asymmetric epoxidation of enone 101 proceeded in excellent selectivity and yield (96% ee, 94%) [103], The resulting epoxide 103 was subsequently converted into (-i-)-decursin (104), a potent cytotoxic agent associated with protein kinase C activation. 

In addition to asymmetric deprotonation. Cope observed that cyclic epoxides in the presence of base give rise to products derived from transannular reactions [110], Boeckman carried out a study of oxiranes fused to medium-size rings and noted that the more commonly observed deprotonation of oxiranes can be suppressed at low temperature, permitting the formation of bi-cyclic structures [118]. In such cases, a-lithiation of an epoxide followed by 1,1-elimination generates a carbene that participates in a subsequent CH-insertion process (cf. 131). An enantioselective version of this reaction was investigated by Hodgson (Scheme 9.15) [119]. Thus, in the presence of sparteine (130), treatment of cyclooctene oxide 129 with i-PrLi affords bicyclic alcohol 132 in 84% ee. 

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