Oxazolidinones condensation with aldehydes

Intermolecular Radical Addition Chiral N Acylhydrazones SS Table 2.1 Amination of oxazolidinones and condensation with aldehydes (Scheme 2.1). 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

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. 

The central point of Evans s methodology is the induction of a 7t-enantiotopic facial differentiation through a conformationally rigid highly ordered transition state. Since the dialkylboron enolates of AT-acyl-2-oxazolidinones exhibit excellent syn-diastereoselectivity syn.anti >97 3) when reacted with a variety of aldehydes, Evans [14] studied the aldol condensation with the chiral equivalents 32 and 38. which are synthesised from fS)-valine (35) and the hydrochloride of (15, 2R)-norephedrine (36) (Scheme 9.11), respectively, and presently are commercially available. 

Oxazolidinones are the products of the acid-catalyzed condensation of a-hydroxyamides with aldehydes and ketones (equation 178). Tertiary amides derived from pyruvic acid undergo intramolecular cyclization when irradiated (equation 179) (78JOC419). Treatment of the a-bromo amide (308) with sodium hydride yields inter alia the dimeric oxazolidinone (309), presumably by way of an a-lactam, which adds to the carbonyl group of a second molecule of the amide (equation 180) (80JCS(P1)2249). 

Hexafluoroacetone has also demonstrated unusual reactivity when condensed with the boron cnolatc of an optically active oxazolidinone or the boron enolate of the sultam derived from camphorsulfonic acid s to give products 3 and 4, respectively. The absolute stereochemistry of the products 3 and 4 is the opposite of that formed on addition to nonfluorinated ketones and aldehydes. This change was attributed to the involvement of an open transition state in the aldol reaction, a consequence of the diminished basicity of fluorinated carbonyl oxygens. 

Decarboxylative condensations of N-substituted or N-unsubstituted a-amino acids with carbonyl compounds offer the most convenient generation of a wide variety of azomethine ylides (Section II,E). The intermediacy of 5-oxazolidinones is ascertained by the fact that in several cases 5-oxazolidinones have been actually isolated and their thermolysis leads to the generation of azomethine ylides (76CSR377 77MI1 87BCJ4079). As the decarboxylation of the 5-oxazolidinone intermediates would take place stereospecifically in a concerted manner, 2,4-trans- and 2,4-cis-isomers of the 5-oxazolidinones give rise to anti- and syn-azomethine ylides, respectively. Condensations of cyclic a-amino acids with aldehydes produce 2,4-trans bicyclic oxazolidinones as thermodynamically more stable products. Accordingly, the exclusive formation of anti-ylides is expected in the decarboxylation route (Section II,E). 

The propionate derivative of oxazolidinone 214 was allowed to condensate with the aldehyde 215 to furnish 216 in 87% yield. Borohydride reduction of 216 gave diol 217. Selective tosylation of the primary alcohol resulted in spontaneous cyclization to give the pyrrolidinium tosylate salt, which was converted to its chloride salt 218 in 83% yield. Selective mono-deprotection of the salt afforded the free hydroxyl 219, which was acetylated and then subjected to hydrogenolysis in the presence IM hydrochloric acid to allow the isolation of the C(4)Me analogue 220 as its hydrochloride salt in quantitative yield. 

Oxazolidinones can be used as synthetic intermediates. An example is the conversion of 6.220 to 6221, which was followed by ring opening to give d.222.i30 Oxidation to the aldehyde and Wittig oleflnationl l gave 6223. This conjugated ester was "chain extended in six steps (18% yield), which included condensation with... 

One of the most active areas of organoborane chemistry this year has been the application of boron enolates to enantioselective aldol condensations. Thus the enolate (82), derived from (5)-valinol, reacts with aldehydes R CHO to give, after cleavage of the oxazolidinone residue with R OH, the alcohols (83) with an erythro threo selectivity greater than 140 1, whereas the enolate (84), obtained from (IS, 2/ )-norephedrine, gives alcohols (85) with a selectivity of at least 500 1. Somewhat lower levels of selectivity are observed with the azaenolates (86) and (87) which give predominantly threo- and erythro-alcohols (88) and (89), respectively. ... 

Reaction of isatin or thioisatin 263 with (R)-(—)-thiaproline afforded thiazolo-oxazolidinones 264 as precursor of azomethine ylides, obtained by decarboxylation, for 1,3-dipolar cycloadditions (Equation 116) <2002SC435, 2004PS2549>. Condensation of 5-(alkylamino)methyl-2-pyrazolines 265 with ketones or aldehydes led to tetrahy-dro-imidazo[l,5-7]pyrazoles 266 (Equation 117) <1998JCCS375>. 

As described in Scheme 25, the first method starts with the conversion of an a-amino acid into a p-amino-p-alkyl aldehyde. Then, the chiral aldol condensation between the resulting aldehyde and an oxazolidinone derivative is carried out. In the last step, removal of the oxazolidinone provides the desired product. 

In 1992 Ghosh and co-workers provided the first example of the utility of rigid cis-1 -amino-2-indanol-derived oxazolidinone 36 as the chiral auxiliary in the asymmetric. vv//-aldol reaction.60-61 Aldol condensation of the boron enolate of 37 with various aldehydes proceeded with complete diastereofacial selectivity. Effective removal and recovery of the chiral auxiliary was carried out under mild hydrolysis conditions (Scheme 24.6). As both enantiomers of the chiral auxiliary were readily available, both enantiomers of the. yyn-aldol could be prepared with equal asymmetric induction. 

A highly versatile auxiliary is the Evans oxazolidinone imide (Figure 5.4c, see also Scheme 3.16), available by condensation of amino alcohols [86,87] with diethyl carbonate [86]. Deprotonation by either LDA or dibutylboron triflate and a tertiary amine affords only the Z(0)-enolate. Scheme 5.12 illustrates open and closed transition structures that have been postulated for these Zf0)-enoIates under various conditions, and Table 5.4 lists typical selectivities for the various protocols. The first to be reported (and by far the most selective) was the dibutylboron enolate (Table 5.4, entry 1), which cannot activate the aldehyde and simultaneously chelate the oxazolidinone oxygen [75]. Dipolar alignment of the auxiliary and approach of the aldehyde from the Re face of the enolate affords syn adduct with outstanding diastereoselection, presumably via the closed transition structure illustrated in Scheme 5.12a [75]. The other syn isomer can be formed under two different types of conditions. In one, a titanium enolate is postulated to chelate the oxazolidinone... 

Diazabicyclo[4.3.0]nonene-based peptidomimetics with a quaternary chiral centre are prepared via intramolecular condensation of A -aminopropyl-y-lactam [27]. Reductive amination of oxazolidinone aldehydes with A -monoprotected propylenediamine give A -phthalimidopropyl lactams however, trials of cyclization to bicyclic amidines after deprotection under dehydration conditions are unsuccessful. To solve this problem, the phthalimides are converted to thiolactams with Lawesson reagent. Deprotection followed by treatment with mercury (11) chloride (HgCl2) yields desired cyclic amidines (Scheme 3.14). 

Fulleropyrrolidines are synthesized through the addition of azomethine ylides as 1,3-dipolar compounds to fullerene (Scheme 3.7). This reaction is known as the Prato reaction. There are several methods of generating azomethine ylides. In the Prato reaction, a decarboxylation route is employed with the use of easily available aldehydes and a-amino acid derivatives. Both starting materials undergo dehydrative condensation to give 5-oxazolidinones, which generate azomethine ylides with elimination of CO2. Azomethine ylides react with Cgo and produce fulleropyrrolidines in moderate yields. 

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