Chiral oxazolidine auxiliaries

Strongly electron-deficient y9-ketoamidyi radicals on chiral oxazolidine auxiliaries have also been shown to trap allylstannanes with high levels of selectivity (Eq. (13.16), Table 13-5) [26]. High diastereoselectivity in these reactions is obtained with bulky R groups on the chiral auxiliary and by lower reaction temperatures. 

Two-dimensional techniques (HETCOR) also give information about triad and tetrad configuration [42]. The H multiplets at 1.89 and 1.5 ppm couple to three secondary carbon atoms at 34.94,34.23, and 33.42 ppm in the C spectrum. These methylene carbons do not show crosspeaks with any other region in the proton spectra. Thus, these results show that the major isomer isolated from the ACT reaction of 24 is all isotactic. Although this characterization does not allow determination of the absolute stereochemistry of 27, the tentative assignment shown is consistent with expectations based upon previous work done with chiral oxazolidine auxiliaries. 

Chiral oxazolidine compounds have also been used as chiral auxiliaries for asymmetric Diels-Alder reactions. Adam et al.8 demonstrated the cycloaddition of optically active 2,3-dimethyl oxazolidine derivatives with singlet oxygen. As shown in Scheme 5-9, the reaction of chiral substrate 39 with singlet oxygen provides product 40 in high diastereomeric ratio. 

Chiral /3,/3-diaryIpropionic acid moieties are often found in compounds showing biological activities, such as antiarrhythmics vasodilators antidepressives " , antihistamines and controllers of cerebral insufficiency ". In the course of synthetic studies of chiral -diaryIpropionic acid derivatives, Merck researchers developed stereoselective conjugate addition of aryllithium reagents to the a,/ -unsaturated fert-butyl esters 18 bearing a chiral imidazolidine or oxazolidine auxiliary at the ortho position of an aryl group. The addition furnished chiral -diaryIpropionic acid derivatives 19 with... 

A study of enantioselective additions of diethylzinc to benzaldehyde, using chiral carboline and oxazolidine auxiliaries, has examined the requirements to allow the conformations of the free ligands to be related to the ees and transition states, given that several steps intervene.228... 

The 4,5-double bond of 2(3//)-oxazolones participates in thermal [4 + 2] cycloaddition reactions. With dialkyl azodicarboxylates the addition occurs at 80 C to give the cycloadducts 430 (Scheme 97). With a chiral substituent attached to N(3), diastereoselectivities as high as 72% can be obtained. Cycloadditions with cyclopentadiene or benzofuran require higher temperatures and longer reaction times, but can yield highly efficient chiral oxazolidin-2-one auxiliaries. 

As far as auxiliary-induced stereoselection is concerned, remarkably high levels of allylic diastereocontrol were achieved in the base-catalyzed addition of benzyl alcohol to the chiral oxazolidines 13 8. 

Stereoselective syntheses of 5-isoxazolidinones were also achieved through addition of lithiated chiral oxazolidines to nitrones. In solution, the spiro-fused isoxazolidine 554 was in equilibrium with its open hydroxylamino form 553. Acidic hydrolysis of the chiral auxiliary afforded the highly enantioenriched isoxazolidinone 555 in good yield (Scheme 134) <2003OL2723, 2003JOC9861>. 

Banks, M. R., Cadogan, J. I. G., Gosney, I., Grant, K. J., Hodgson, P. K. G., Thorburn, P. Synthesis of enantiomerically pure (5S)-4-aza-2-oxa-6,6-dimethyl-7,10-methylene-5-spiro[4.5]decan-3-one, a novel chiral oxazolidin-2-one from (-)-camphene for use as a recyclable chiral auxiliary in asymmetric transformations. Heterocycles 1994, 37,199-206. 

A chiral oxazolidine prepared from a,j6-unsaturated aldehydes and ( —)- or (-l-)-ephedrine efficiently induced asymmetric cyclopropanation with excess of diazomethane in the presence of palladium acetate, e.g. formation of 24 from ( —)-ephedrine and ( )-cinnamaldehyde 24 was cyclopropanated to give 25 and the auxiliary removed giving... 

An C2isy access to chiral oxazolidine-2-thione auxiliaries 198 using carbon disulfide and chiral amino alcohols in the presence of K2CO3 and H2O2 has been reported <04JOC3990>. Efficient removal of the 4-phenyloxazolidinethione auxiliary from Af-acyl derivatives was achieved by treatment with EtSH in the presence of a catalytic amount of DBU <04TL7715>. 

A p-aryl-a,p-unsaturated ferf-butyl ester 7 bearing a chiral imidazolidine (or oxazolidine) auxiliary at an ortho position undergoes stereoselective conjugate addition of an aryllithium reagent 8, furnishing a p,p-diarylpropionic acid derivative 9 in up to 97% ee (Scheme 3) [17],... 

Chiral Auxiliary-hased Epoxidation of Substituted Alkenes. High diastereoselectivities were found for the m-CPBA or dimethyldioxirane epoxidation of chiral oxazolidine-substituted alkenes bearing a strongly basic urea group (eq 29). However, in most cases, the diastereoselectivities were superior with dimethyldioxirane. 

Oxazolidine 198 was produced from condensation of (R)-phenylg-lycinol and fluoral ethyl hemiacetal as a 62 38 tram/cis diastereomeric mixture. The enantiopure trans-198 was obtained through an epimeriza-tion with p-toluenesulfonic acid that realized the selective precipitation of the desired diastereoisomer. The repetition of this crystallization-induced dynamic resolution (CIDR) protocol on mother liquors allowed an almost complete conversion of the initial mixture into the desired trans-198. This chiral oxazolidine was used as chiral auxiliary for the synthesis of a-fluorocarboxylic acids and P-fluoroalcohols in a one-pot procedure that also allowed its recovery without loss of optical purity (13JOC3487). 

Both cis (10) and irons diastereoisomers of aryl and alkyl chiral oxazolidine sulfonium salts derived from (-)-(/ )-2-phenylglycinol have been demonstrated to be good to excellent chiral auxiliaries for the diastereoselective synthesis of (2/ ,35)-tra j -epoxyamides (11, Scheme A) The diastereoselective outcome depends on the stereochemistry of the chiral centre at the C(4) position of the oxazole moiety (<98% de with R configuration). 

Disubstituted 2-oxazolidines as chiral auxiliaries synthesis from 2-oxazolones 97YZ339. 

The related serine derived (4S)-4-methoxycarbonyl-3-(l-oxopropyl)-2-thiono-l,3-oxazolidine 11, and the cysteine derived (4A)-4-methoxycarbonyl-3-(l-oxobntyl)-2-thiono-1,3-thiazolidine 13, also serve as efficient chiral auxiliaries in boron- and tin(II)-mediated aldol condensations98. Thus, conversion of 11 into the boron or tin enolate, followed by reaction with 2-methylpropanal affords predominantly one adduct. Subsequent methanolysis and chromatographic purification delivers the syu-methyl ester in 98% ee. 

These examples and those in Scheme 2.6 illustrate the key variables that determine the stereochemical outcome of aldol addition reactions using chiral auxiliaries. The first element that has to be taken into account is the configuration of the ring system that is used to establish steric differentiation. Then the nature of the TS, whether it is acyclic, cyclic, or chelated must be considered. Generally for boron enolates, reaction proceeds through a cyclic but nonchelated TS. With boron enolates, excess Lewis acid can favor an acyclic TS by coordination with the carbonyl electrophile. Titanium enolates appear to be somewhat variable but can be shifted to chelated TSs by use of excess reagent and by auxiliaries such as oxazolidine-2-thiones that enhance the tendency to chelation. Ultimately, all of the factors play a role in determining which TS is favored. 

Imide Systems. Imide compounds 22 and 23, or Evans reagents, derived from the corresponding oxazolidines are chiral auxiliaries for effective asymmetric alkylation or aldol condensation and have been widely used in the synthesis of a variety of substances. 

Table 2-5 summarizes the results of the asymmetric alkylation (Scheme 2-17) of the lithium enolates derived from 22 or 23.28 When chiral auxiliary 22 or 23 is involved in the alkylation reactions, the substituent at C-4 of the oxazolidine ring determines the stereoselectivity and therefore controls the stereogenic outcome of the alkylation reaction. 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

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