Chiral auxiliary also oxazoline

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

Mg11 complexes are also effective for controlling asymmetric radical reactions.33,34 Moreover, enantioselective radical reactions using chiral Mg11 complexes have been studied, and high enantioselectivities have been realized in the presence of stoichiometric or catalytic amounts of chiral auxiliaries such as bis-oxazolines (Scheme 8).35-39 In most cases, substrates having bidentate chelating moieties are required. 

Reagent control This involves the addition of a chiral enolate or allyl metal reagent to an achiral aldehyde. Chiral enolates are most commonly formed through the incorporation of chiral auxiliaries in the form of esters, acyl amides (oxazolines), imides (oxazolidinones) or boron enolates. Chiral allyl metal reagents are also typically joined with chiral ligands. 

Conversion of 2 to the highly crystalline oxazolidinone 3 with phosgene has been described by Thornton who has employed this substance as a chiral auxiliary in asymmetric aldol reactions of its N-propionyl derivative. Kelly has also used an oxazoline derived from 3 as a chiral auxiliary in asymmetric alkylation of a glycolate enolate. Oxazolidinone 3 has also been prepared from 2 with diethyl carbonate in the presence of potassium carbonate. The conversion of 2 to the oxazolidinone 3 is accomplished using triphosgene in this procedure because of the high toxicity of phosgene. 

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... 

As shown below (Section IV), the lithium enolates are remarkable vectors of asymmetry. Indeed, the development of many chiral auxiliaries has been associated (in particular through their ester derivatives) with the enolate chemistry. We conclude this section with the contribution of a group of mathematical chemists who have tried to quantify the desymmetrization induced on enolate orbitals by common chiral auxiliaries219. This unusual viewpoint suggests that when the allylic stereogenic center is in the / position, the (Z) isomer has more chirality content than its (E) counterpart. This paper also concludes that in the enolates derived from Meyers oxazolines, the lithium cation distorts the structure but has little influence on its chirality. 

It is generally true that restrictions on conformational mobility minimize the number of competing transition states and simplify analysis of the factors that affect selectivity. Chelation of a metal by a heteroatom often provides such restriction and also often places the stereocenter of a chiral auxiliary in close proximity to the a-carbon of an enolate. This proximity often results in very high levels of asymmetric induction. A number of auxiliaries have been developed for the asymmetric alkylation of carboxylic acid derivatives using chelate-enforced intraannular asymmetric induction. The first practical method for asymmetric alkylation of carboxylic acid derivitives utilized oxazolines and was developed by the Meyers group in the 1970 s (Scheme 3.16a), whose efforts established the importance and potential for chelation-induced rigidity in asymmetric induction (reviews [77-79]). In 1980, Sonnet [80] and Evans [81,82] independently reported that the dianions of prolinol amides afford more highly selective asymmetric alkylations (Scheme 3.16b). 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

Enantiomerically pure oxazolines and oxazolidinones have found widespread application in organic synthesis as chiral auxiliaries. They have been mainly used for the synthesis of enantiomerically pure amino acids but also as chiral auxiliaries to produce non-racemic enolates as pioneered by Evans.The reaction types proceeding with high stereocontrol include enolate alkylation, enolate oxidation, enolate halogenation, enolate amination, enolate acylation, aldol reaction and Diels-Alder reactions. 

There is another system, that of BINOL/BINAP, the Japanese dream of a universal chiral auxiliary [88], and there are striking similarities, but also fundamental differences, when compared with the TADDOLs (see Scheme 16). There is still a lot to do, and there are other competitors out there, sometimes referred to as preferred ligands (such as the semicorrine and oxazoline [89], the metallocene [90], the diaminocyclohexane [91], and the quinine/cincho-nine [92] systems). Everybody in the field of EPC synthesis dreams of hav-... 

Butyllithium is also used for the stereoselective a-Uthiation of chiral sulfonyl compounds/ chiral 2-alkenyl carbamates, various heterocyclic amine derivatives with chiral auxiliaries appended on the nitrogen (e.g. oxazoline or formamidine ... 

Transition metal-catalysed methods for carbenoid insertion into C-H bonds remain well documented. The asymmetric intramolecular Cu(II)-catalysed C-H insertion reactions of (i) a-diazo-/ -keto esters and phosphonates and (ii) a-diazo sulfones have been described. One can note that the optimal reaction conditions have been found to be quite similar regardless of the nature of the carbenoid precursor the best conditions featured CUCI2 as Cu(II)-source, bis(oxazoline) (68) as chiral ligand and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl] borate (i.e., NaBARF) as additive. Under the so-optimized reaction conditions, each of these carbenoid sources have been eonverted into five-membered cyclopentanone-based derivatives (69), whereas a-sulfonyl diazo esters (70) have led to six-membered cyclic compounds (71), thus featuring a distinct but well-known selectivity. In a related work, the asymmetric C-H insertion cyclization of (70) to (71) has also been achieved under Rh(II)-catalysis, using a combination of Rh2(5-pttl)4 (72) as chiral catalyst and menthyl ester as chiral auxiliary. As already mentioned in the previous section, allene-containing substrates (49) have been shown to undergo an intramolecular C-H insertion process under Rh(II)-catalysis. ... 

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

These reactions exhibit excellent diastereoselectivity derived from the chiral oxazo-lidinone auxiliary. The Lewis acid forms a chelate with the oxazoline and presumably also serves to enhance reactivity. In addition to ethyl, other primary, secondary, and tertiary alkyl radicals, as well as acetyl and benzoyl radicals were used successfully in analogous reactions. 

Addition of diethyl aluminum chloride at — 78 °C to a,/ -unsaturated oxazolidinone (154) affords an aluminum enolate that, on hydroxylation with (63a), gives the / -ethyl-a-hydroxy amide (155) with high anti selectivity (Equation (38)) <91AG(E)694>. Formation of the enolate of oxazoline thiol ester (156) under chelation (NaHMDS) and stereoelectronic (NaHMDS/HMPA) control gives the syn and anti alcohols (157), respectively, on hydroxylation with (63a) in good to excellent yield and better than 95% diastereoselectivity (Scheme 28) <93JOC6180>. A counterion dependent reversal in stereochemistry has also been reported for the hydroxylation of chiral amide enolates where the auxiliary was 2-pyrrolidinemethanol <85TL3539>. 

When hydrogen bonds can be formed between 2 and hydroxylic solvents such as CD3OD, the selectivity dropped considerably, as expected [119]. The [4 + 2] cycloaddition of 2 can also be highly diastereoselective with aliphatic dienes. With sorbic acid derivatives 194 having a removable chiral 2,2-dimethyl-oxazoline auxiliary, 195 was isolated with an almost perfect stereocontrol during the addition process (Scheme 51) [120],... 

From this short overview it appears that the majority of the recent studies on enantioselective cycloisomerizations have been focused so far on asymmetric Alder-ene type cyclizations with Pd and Rh catalysts, since these reactions represent an economical access into synthetically usefiil cyclopentene and cyclohexene frameworks (Sects. 10.2.1 and 10.3.1). For these processes, efficient chiral catalysts have been afforded mainly by atropisomeric diphosphines, but also DuPHOS, Skewphos and phosphine-oxazolines can occasionally represent suitable auxiliaries. 

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