Hydroxy adds, chiral

Addition of the chiral azaenolate obtained from metalation of (4A,55 )-4,5-dihydro-2-methyl-4-methoxymethyl-5-phenyloxazole (6, see Section D.1.1.1.4.3.3) to aldehydes shows lowdiastere-ofacial selectivity. Acidic hydrolysis of the aldol adducts gives 3-hydroxy adds 7 in 31 -87% yield and less than 25% ee18. 

Alcohol oxidoreductases capable of oxidizing short chain polyols are useful biocatalysts in industrial production of chiral hydroxy esters, hydroxy adds, amino adds, and alcohols [83]. In a metagenomic study without enrichment, a total of 24 positive clones were obtained and tested for their substrate specifidty. To improve the detedion frequency, enrichment was performed using glycerol or 1,2-propanediol and further 24 positive clones were deteded in this study. 

The conventional synthesis of trans-2,5-dialkyl phospholanes starting from a chiral 1,4-diol is shown in Scheme 24.1. Originally, these 1,4-diols were obtained via electrochemical Kolbe coupling of single enantiomer a-hydroxy adds [25], but this method proved to be commercially impracticable and has since been replaced by more viable biocatalytic routes [26]. Reaction of the chiral 1,4-diol with thionyl chloride followed by ruthenium-catalyzed oxidation with so-... 

Development of an efficient synthesis of chiral 2-hydroxy adds... 

Carboxylic acid derivatives that have a-substituents can exist as chiral compounds. The resolution of the enantiomers of such compounds is a useful process, leading to the preparation of a-amino acids, a-hydroxy adds and other a-substituted carboxylic acids and their derivatives in enantiomerically enriched form. In addition, the racemization of such compounds can be achieved by a deprotonation/reprotonation sequence, as shown in Fig. 9-13. 

The chiral 1,3-dioxanes 21 and 25 are obtained from the biopolymer poly[(R)-3-hydroxybutyric acid] (PHB) by hydrolysis providing the chiral fS-hydroxy add 28, which is condensed with aldehydes. 

Galaverna G, Corradini R, Dossena A, MarceUi R (1999) Histamine-modified cationic P-cyclodextrins as chiral selectors for the enantiomeric separation of hydroxy adds and carboxylic adds by capillary electrophoresis. Electrophoresis 20 2619-2629... 

Chiral acyliminiums were used for the preparation of enantiopure piperidines [267]. Recently, the use of enantio-enriched y-alkoxyallyltins onto chiral acyl iminiums [268] provided a new entry into the synthesis of potential precursors of a-amino-/3-hydroxy adds or aminosugars, with a total control of the stereochemistry. 

Furthermore, both (E)- and (Z)-enolborinates add to aldehydes in a stereoconvergcnt manner, giving predominantly, syn-/J-hydroxycarbonyl compounds49. In contrast, only moderate induced diastereoselectivity is obtained in the reaction of achiral aldehydes with C2-symmetric enolborates, whereby the chiral information is located in the ligand at the metal atom50. The ee of the product /1-hydroxy ketones ranges from 4 to 72%. 

Ethyl (bornylideneamino)acetate (2) and the imines of (-)-(lf ,2, 5 )-2-hydroxy-3-pinanone and glycine, alanine and norvaline methyl esters were particularly successful as Michael donors. The chiral azaallyl anions, derived from these imines by deprotonation with lithium diisopropylamide in THF at — 80 C, add to various a,/i-unsaturated esters with modest to high diastereoselectivity (see Section 1.5.2.4.2.2.5.). Thus, starting with the imine 2, (R1 = CH,) and ethyl ( )-2-butcnoate, the a,/i-dialkylated glutamate derivative 3 is obtained as a single diastercomer in 90% yield91-92. 

An obvious way to target chiral compounds is to start with a compound in which the chiral center is already present. Here natural products and derivatives offer a rich pool of generally inexpensive starting materials. Examples include L-hydroxy and amino adds. Sometimes, just one out of many chiral centers is predestined to remain, as in the synthesis of vitamin C from D-glucose, or in the preparation of (S)-3-hydroxy-y-butyrolactone from ladose. 

In order to add more diversity to the succinyl moiety, another asymmetric carbon can be introduced, e.g. formation of 18 (Scheme 8). The second chiral center is created by using methyl, (arylsulfanyl)methyl, morpholinomethyl, and hydroxy groups. The typical matrix metalloprotease inhibitors are shown in Scheme 2. 

Add the solution of 2-hydroxy-3-trimethylammoniopropyl-/)-cyclo-dextrin (10 3mol/L) (100 pL chiral selector solution to 100 mg carbon paste) to the carbon paste to obtain the modified carbon paste. 

Control over the absolute configuration in cyclohexenone photocycloadditions has been achieved by auxiliary-induced diastereoselectivity. In particular, esters related to compound 26, which are derived from a chiral alcohol but not from methanol, lend themselves as potential precursors, from which the chiral auxiliary can be effectively cleaved [42, 43]. In a recent study, the use of additives was advertised to increase the diastereomeric excess in these reactions [44], An intriguing auxiliary-induced approach was presented by Piva et al., who employed chiral 13-hydroxy-carboxylic adds as tethers to control both the regioselectivity and the diastereoselectivity of intramolecular [2 + 2]-photocycloaddition reactions [45]. In Scheme 6.14 the reaction of the (S)-mandelic acid derived substrate 38 is depicted, which led with very good stereocontrol almost exclusively to product 39a, with the other diastereoisomer 39b being formed only in minor quantities (39a/39b = 96/4). Other acids, such as (S)-lactic acid, performed equally well. The chiral tether could be cleaved under basic conditions to afford enantiomerically pure cydobutane lactones in good yields. 

Diastereoselective alkoxymercuration. Benzyloxymercuration-demercuration of protected chiral 8-hydroxy-a,p-unsaturated esters proceeds regioselectively to add the OR group in the p-position and with moderate diastereoselectivity. Higher diastcreoselectivity... 

Adam, W., Lazarus, M., Boss, B., Saha-Moller, C.R., Humpf, H.-U. and Schreier, P. (1997) Enzymatic resolution of chiral 2-hydroxy carboxylic adds... 

Transmetalation of the ( )-0-Li-enolate derived from the stabase -protected glycine ethyl ester (11) with 1.1 equiv of (1) affords the chiral Ti enolate (12), which adds with high re selectivity to various aldehydes. By mild acidic cleavage of the silyl protecting group, the primary product (13) can be transformed to various Af-derivatives (14) of D-t/treo-a-amino-p-hydroxy acids in 45-66% yield and with excellent enantio- and syn(threo) selectivity (97-99%) (eq 3). An exception with lower enantioselectivity is glyoxylic ester (ethyl ester 78% ee t-butyl ester 87% ee). 

Several lactic acid derivatives were used by Gessner et al. for the determination of the enantiomeric purity of flavor substances such as chiral alcohols from natural sources. Diastereomeric 0-acetyl-, propionyl-, and hexanoyllactic acid esters of the chiral alcohols were separated by GLC (155). A report from the same laboratories described characterization of several chiral aroma substances that are S-lactones. The lactones were hydrolyzed to the corresponding hydroxy acids, and the acid moiety was esterified to the isopropyl ester. The remaining hydroxyl group was esterified with (R)-2-phenylpropionic add chloride or [30], and the diastereomeric derivatives were separated using preparative silica gel LC. The derivatives were also separated on an analytical scale by GLC (156). 

Deprotonation of a-silyloxy ketones with LDA furnishes (Z)-lithium enolates, whereas treatment of ketones with n-Bu2BOTf in the presence of /-Pr2EtN gives the corresponding (Z)-(0)-boron enolates. Interestingly, reaction of the Li-enolates with r-PrCHO proceeds with opposite facial preference to that of the boron enolates. Thus, the Si face of the Li-enolate adds to the Si face of the aldehyde and the Si face of the boron enolate adds to the Re face of the aldehyde to furnish the chiral P-hydroxy ketone enantiomers shown below. The reason for the different face selectivity between the lithium enolate and the boron enolate is that lithium can coordinate with three oxygens in the aldol Zimmerman-Traxler transition state, whereas boron has only two coordination sites for oxygen. 

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