Hydroxy amides chiral

The enantioselective hydrogenation of a,fj- or / ,y-unsaturated acid derivatives and ester substrates including itaconic acids, acrylic acid derivatives, buteno-lides, and dehydrojasmonates, is a practical and efficient methodology for accessing, amongst others, chiral acids, chiral a-hydroxy acids, chiral lactones and chiral amides. These are of particular importance across the pharmaceutical and the flavors and fragrances industries. 

A-hydroxy hexapeptide 135, with alternating A-hydroxy amide units, introduced by Akiyama and coworkers ", is an additional fragment for introducing chirality to ferriox-... 

Not surprinsingly, the aldol addition of the lithium enolates derived from these systems proved to be unsatisfactory. However, the derived zirkonium enolates in these and related systems have proven to be exceptional 176). The amides (171) and (172), each of which is readily derived from (S)-proline and (S)-valine respectively, exhibit good stereoselectivity with a range of aldehydes. The optical purity of the P-hydroxy amides (173) was very good (>95% e.e.). However, this method has a limitation which has been associated with the acidic conditions that are required to hydrolize these chiral amides (173) to their derived carboxylic acids (174). While... 

Camphor- 10-sulfonic acid, 62 (S)-2-(l-Hydroxy-1-methylethyl)-pyrrolidine, 146 a-Methylbenzylamine, 185 Quina alkaloids, 264 Cycloaddition reactions 2-Oxazolidones, chiral, 225 Cyclopropanation Diiodomethane-Diethylzinc, 276 Simmons-Smith reagent, 275 Deprotonation Lithium amides, chiral, 159... 

A related reaction is the addition of isonitriles 75 to aldehydes 1 (the Passerini reaction). Denmark has demonstrated that SiCU, upon activation by a chiral Lewis base, which increased the Lewis acidity of the silicon (vide supra Scheme 7.14), can mediate this reaction to produce a-hydroxy amides 77 after aqueous work-up (Scheme 7.16). Phosphoramide 60 was employed as the chiral Lewis-basic catalyst [74]. Modification of the procedure for hydrolysis of 76 gives rise to the corresponding methyl ester (rather than the amide 77) [74]. (For experimental details see Chapter 14.5.5). 

This reaction can be also performed asymmetrically, when it is applied to a, 3-unsaturated amide derivatives bearing a chiral auxiliary [299]. Among several common auxiliaries, the frans-2,5-dinaphthylpyrrolidine unit proved to be optimal, giving a-hydroxy amides in 62-87% yield and diastereomeric ratios ranging from 78 22 up to 97 3 for the compound with (R)-configuration. 

Chiral -hydroxy amides. A metal enolate of (R)-l reacts with aldehydes to form adducts (2) that are desulfurized by Na/Hg to optically active hydroxy amides (3). The extent and the sense of chiral induction depends on the metal enolate. Use of n-butyllithium... 

Stereoselective reduction of chiral 2-alkyl-3-keto amides. The chiral propionamide (1) derived from tran.t-2,5-bis(methoxymethoxymethyl)pyrrolidine undergoes stereoselective acylation of the enolate in the presence of ZnCh to give 2-alkyl-3-oxo amides (2). These products undergo reduction with zinc borohydride to give syn-2-alkyl-3-hydroxy amides (3). 

The asymmetric hydroxylation of ester enolates with N-sulfonyloxaziridines has been less fully studied. Stereoselectivities are generally modest and less is known about the factors influencing the molecular recognition. For example, (/J)-methyl 2-hydroxy-3-phenylpropionate (10) is prepared in 85.5% ee by oxidizing the lithium enolate of methyl 3-phenylpropionate with (+)-( ) in the presence of HMPA (eq 13). Like esters, the hydroxylation of prochiral amide enolates with N-sulfonyloxaziridines affords the corresponding enantiomerically enriched a-hydroxy amides. Thus treatment of amide (11) with LDA followed by addition of (+)-( ) produces a-hydroxy amide (12) in 60% ee (eq 14). Improved stereoselectivities were achieved using double stereodifferentiation, e.g., the asymmetric oxidation of a chiral enolate. For example, oxidation of the lithium enolate of (13) with (—)-(1) (the matched pair) affords the a-hydroxy amide in 88-91% de (eq 15). (+)-(Camphorsulfonyl)oxaziridine (1) mediated hydroxylation of the enolate dianion of (/J)-(14) at —100 to —78 °C in the presence of 1.6 equiv of LiCl gave an 86 14 mixture of syn/anti-(15) (eq 16). The syn product is an intermediate for the C-13 side chain of taxol. 

Racemic compounds other than carboxylic acids have also been resolved by reaction with enantiomerically pure (1) and separation of the corresponding diastereomeric mixtures by physical methods. For example, reaction of a racemic p-substituted 7-butyrolactone with (1) yields a mixture of hydroxy amides, which can be separated by fractional recrystallization and chromatography (eq 3). Amide hydrolysis regenerates the chiral hydroxy acids, which spontaneously cyclize to produce the chiral lactones. 

A model (1), similar to that proposed for aldol-type condensation of a-sulfinyl esters, has been proposed to predict the chirality of the resulting p-hydroxy amides. 

The a-hydroxy acid-derived 2,4-oxazolidinediones have been successfully utilized as substrates for asymmetric alkylations with a chiral phase-transfer catalyst (Scheme 40). Using 1 mol% of the N-spiro chiral quaternary ammonium bromide catalyst 153, oxazolidinedinone 152 was alkylated in high yield and enantioselectivity and hydrolyzed in situ to give a-hydroxy amides 154 <2006AGE3839>. 

When an isocyanide is treated with a carboxylic acid and an aldehyde or ketone, an a-acyloxy amide is prepared. This is called the Passerini reaction. A SiCl4-mediated reaction in the presence of a chiral bis-phosphoramide gives an a-hydroxy amide with good enantioselectivity. The following mechanism has been postu-... 

In Eq. (14), Yoda et al. [50] studied the preparation of optically active lactones, with three contiguous stereogenic centers, from imides with two stereogenic centers. The precursor chiral imide was easily prepared from tartaric acid. Silylation of the 2,3-diol and addition of lipophilic Grignard reagents to the imide gave the ( -hydroxy amide. The authors are investigating the stereochemical consequences of their work. 

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>. 

Enantiomerically pure cyanohydrins can easily be modified chemically or enzymatically (Scheme 4.12B), providing access to chiral a-hydroxy acids, a-hydroxy amides, 2-aminoalcohols, and epoxides. Replacement of the hydroxyl functionahty by a better leaving group, such as a sulfonyl moiety (e.g. tosylate), allows the introduction of various other nucleophiles with inversion at the stereocenter [51a]. The structures of some bioactive molecules that have been synthesized using a biotransformation step with a hydroxynitrile lyase are depicted in Scheme 4.12B [51a, 52]. 

Chiral oxazolines Stille carbonylative coupling,4 Pd-catalyzed carbonylative coupling of Inflates of ketones and phenols with chiral amino alcohols provides )3-hydroxy amides, which cyclize to chiral oxazolines when treated with thionyl chloride. 

The asymmetric amino-hydroxylation reaction provides a very short synthesis of the side chain of the anticancer agent Taxol . The substrate isopropyl cinnamate was converted to the chiral 1,2-hydroxy amide 98 as essentially a single enantiomer after recrystallization (5.96). Hydrolysis then gave the required amine, as its hydrochloride salt. 

Hydroxy-amides. - Wittig rearrangement of acetamide (424) [LDA, -85 C] provides almost exclusively the erythro-a-hydroxy-amide (425). The likely transition-state geometry suggests that the presence of vinylic substituents larger than methyl should at least maintain this level of selectivity during rearrangement. Unfortunately similar reactions of chiral amides derived from prolinol result in only moderate asymmetric induction. 

Dimethyl(phenyl)silane reduces aldehyde and ketone carbonyls with the aid of fluoride ion or acid. a-Acylpropionamides, 1-aminoethyl ketones, and 1-alkoxyethyl ketones are readily converted into the corresponding -hydroxy amides, o -amino alcohols, and a-alkoxy alcohols, respectively. The stereoselectivity is complementary and generally high erythro (or syn) isomers are obtained with trifluoroacetic acid (TFA), whereas threo (or anti) isomers are obtained with fluoride ion activator (eq 1). The erythro selectivity in the acid-promoted carbonyl reduction is ascribed to a proton-bridged Cram s cyclic transition state. On the other hand, the threo selectivity in the fluoride-mediated reduction is explained in terms of the Felkin-Anh t) e model, wherein a penta-or hexacoordinated fluorosilicate is involved. No epimerization at the chiral center is observed during the reaction. 

In an altogether different procedure, chiral, a-hydroxy amides were coupled with A-sulfonylanilines in >99% ee when 1,2,4-triazole was used as additive (eq 10). In contrast, tertiary amine bases gave extensive racemization. 

Several triflates, treated with CO in the presence of Pd(PPh3)4 and chiral aminoal-cohols 18, gave the corresponding hydroxy amides 19 easily converted into the oxazolines 20 in good yield (Scheme 9.8) [35]. 

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