Mandelic acid derivatives

In contrast, highly stereoselective aldol reactions are feasible when the boron etiolates of the mandelic acid derived ketones (/ )- and (5,)-l- t,r -butyldimethylsiloxy-l-cyclohexyl-2-butanone react with aldehydes33. When these ketones are treated with dialkylboryl triflate, there is exclusive formation of the (Z)-enolates. Subsequent addition to aldehydes leads to the formation of the iyn-adducts whose ratio is 100 1 in optimized cases. 

Faber et al. have reported a novel process for the overall deracemization of racemic mandelic acid derivatives using a combination of an enantioselective lipase and a mandelate racemase activity from Lactobacillus paracasei (Figure 5.19) [32]. 

Toniolo reported the carbonylation of aromatic aldehydes containing electron-donating substituents with a Pd/PPh3 catalyst system in the presence of HC1 to give phenylacetic acid derivatives [64]. No activity was observed in the absence of PPI13 or HC1, and high yields could be achieved with alkanols as solvent (e.g., EtOH). It is believed that the mechanism involves HC1 addition to the aldehyde, with the resultant chlorohydrin being subject to oxidative addition to Pd, CO insertion, and alcoholysis. Upon Cl -o- OR substitution with the formed mandelic acid derivative, a second carbonylation takes place,... 

Dixon [75] also investigated the use of unconventional carbon donors, such as the mandelic acid derivative 119 in the highly stereoselective addition to -substituted nitro-olefms. The Michael product 120 was formed smoothly and can be converted in simple one-step procedures to generate various chiral building blocks for syntheses (Scheme 26). 

Later, the oxazolines 25 were examined to study the effects of matched/mismatched combinations of stereogenic centers on catalyzed aryl transfer reactions to aldehydes. Of these mandelic acid-derived catalysts, 25b gave the best results in terms of enantioselectivity (up to 35% ee), while diastereomer (l ,S)-25b proved to be superior to (S,S)-25b with respect to catalyst activity [29]. With both compounds, the absolute configuration of the product was determined by the oxazo-line moiety. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

Nitrilase l-Catalyzed Production of Mandelic Acid Derivatives Under Dynamic Kinetic Resolution Conditions (Scheme 20.1)... 

In the actual synthesis, aldol reaction 1 involved a lithium enolate whilst aldol reactions 2-4 used boron enolates based on the mandelic acid derivatives described above to incorporate fragments A, B, and C. The aldol products of reactions 2 1 were treated with fluoride and then NaIC>4 to release carboxylic acids which were derivatized or reduced as appropriate. 

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. 

Structural Isomers. Chromatograms illustrating the separation of ortho, meta and para isomers of cresol (22) and and xylene ( O)on RP columns are shown in Figures 4 and 5. They enable a comparison of the chromatographic properties and selectivities due to <. - and -CD complexation between positional isomers of the above compounds.Similar behaviour was observed for ortho,meta and para isomers of fluoronitrobenzene, chloronitrobenzene, iodoni-trobenzene, nitrophenol, nitroaniline, dinitrobenzene (22), nitrocinnamic acid (22) some mandelic acid derivatives (19,21,34) and ethyltoluene (28). Both [Pg.225]

Alkylamines and 1-acylisatins lead to 2 -acyl am i dobenzoyl form am i des due to opening of the heterocyclic ring294 295, which can be reduced to mandelic acid derivatives with NaBTLj or LiAlTk296. Under acidic conditions, the 2 -acylamidobenzoylformamides regenerate... 

Soon afterward, various types of carbon [40-44], oxygen [45], and phosphorous [46] Michael donors were successfully employed in the thiourea-catalyzed addition to nitroalkenes. In the presence of the bifunctional epi-9-amino-9-deoxy cinchonine-based thiourea catalyst 79a, the 5-aryl-l,3-dioxolan-4-ones 138 bearing an acidic a-proton derived from mandelic acid derivatives and hexafluoroacetone were identified by Dixon and coworkers as effective pronucleophiles in diastereo- and enantioselective Michael addition reactions to nitrostyrenes 124 [40]. While the diastereoselectivity obtained exceeded 98%, the enantiomeric excess recorded... 

Addition to 632 of chiral enolates generated from mandelic acid-derived (S) or (i )-2-hydroxy-l,2,2-triphenylethyl acetate (HYTRA) produces syn or /-dihydroxypentanoates of the type 647 or 648 [195]. In order to achieve the highest diastereoselectivity, the lithium enolates are transmetallated to magnesium in conjunction with carrying out the reaction at —125 to — 135 °C in THF/2-methylbutane cosolvent. 

Mandelic acid and its derivatives are utilized as convenient precursors for the introduction of a chiral center, and they possess the extra advantage of bearing a useful functional group. Many mandelic acid derivatives also act as chiral auxiliaries for the induction of a chiral center in stereoselective transformations. Numerous natural products, such as macrolides and ionophore antibiotics, possess a carbon framework that may be viewed synthetically as arising from a sequence of highly stereo- and enantioselective aldol condensations. Boron enolates, chiral auxiliaries derived from mandelic acids 1 or 2, provide remarkably high aldol stereoselectivity. 

Mandelic acid derivatives are useful resolving agents. While (/ )-( +)-phenethyl alcohol (77) is commercially available, it is relatively expensive. As shown in Scheme 16, (5)-l can be converted readily into multigram quantities of 77. Reduction of 1 with borane-dimethyl sulfide provides the diol 76, which is selectively tosylated at the primary hydroxy position and then detosylated with lithium aluminum hydride to provide 77 in 48% overall isolated yield (Scheme 16). The low yield is a result of the problematic tosylation step, in which ditosylation is unavoidable. 

A similar sequence of reactions utilizing 103 as the starting mandelic acid derivative provides as the major azetidinone 127, which is elaborated through a four-step sequence to (25, 3i )-3-amino-2-hydroxy-4-phenylbutyric acid (128) (Scheme 29) [36]. 

Mandelic acid-derived chiral (a-substituted) acetate enolate addition to aldehydes leading to chiral j5-hydroxycarboxylic acids illustrates the versatility of the readily available ester 63. The addition of phenylmagnesium bromide to methyl (i )-mandelate (63) gives the (i )-diol 152, which is acetylated to (i )-2-acetoxy-l,l,2-triphenylethanol (153) [(/ )-HYTRA]. Deprotonation with LDA at — 78 °C provides an enolate that is then transmetallated with magnesium bromide and further cooled to —115 °C before reaction with an aldehyde to produce 154 as the major diastereomer with a yield of 84-95%. Heating 154 in aqueous methanol containing potassium hydroxide provides the optically active j5-hydroxyacid 156 (Scheme 36) [41- 4]. 

Avecia, a former part of the Zeneca Group, developed a range of cheap and highly active titanium- or vanadium-based salen catalysts called CACHy catalysts (Scheme 23). They are based on Jacobsen s salen technology, but they are much more reactive and can, for example, be used in concentrations as low as 0.1 mol% in the cyanation of aryl aldehydes. The catalysts show similar reactivity with alkyl aldehydes and ketones and are applicable to the synthesis of the commercially important mandelic acid derivatives. 

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