P-hydroxyester

Reformatsky reaction is the formation of p-hydroxyesters by reaction of a-bromoacid ester and a carbonyl compound, usually in the presence of zinc... 

Chadha et al, have published a series of papers on the deracemization of P-hydroxyesters using whole cells of Candida parapsilosis. For example, deracemization of racemic ethyl 2-hydroxy-4-phenylbutanoic acid (22 R = H) yielded the (S) enantiomer in 85-90% yield and >99% ee (Figure 5.15) [26]. 

For this reaction, CALB catalyzes the amidation between a racemic P-hydroxyester and racemic amines, leading to the corresponding amide with very high enantiomeric and diastereomeric excesses. Besides, the remaining ester and amine are recovered from the reaction media, also showing good enantiomeric excesses. By this method, three enantioenriched interesting compounds are obtained from an easy one-step reaction. 

Hydride and 1,2-alkyl shifts represent the most common rearrangement reactions of carbenes and carbenoids. They may be of minor importance compared to inter-molecular or other intramolecular processes, but may also become the preferred reaction modes. Some recent examples for the latter situation are collected in Table 23 (Entries 1-10, 15 1,2-hydride shifts Entries 11-15 1,2-alkyl shifts). Particularly noteworthy is the synthesis of thiepins and oxepins (Entry 11) utilizing such rearrangements, as well as the transformations a-diazo-p-hydroxyester - P-ketoester (Entries 6, 7) and a-diazo-p-hydroxyketone -> P-diketone (Entry 8) which all occur under very mild conditions and generally in high yield. 

Sharpless and his group have also studied a series of selective transformations of r/jreo-2,3-dihydroxy esters (6) -prepared by catalytic ADH of a,P-unsaturated esters 5- which lead to very useful and highly elaborated synthetic intermediates [36], such as a-(sulfonyloxy)-P-hydroxyesters (2), P-acetoxy-a-bromo esters or a-acetoxy-p-bromo esters (8 and 9), threo- and erythro-glycidxc. esters QO and U.) and P-hydroxy esters (12). The substituent at the p-position plays an important role in determining the regiochemistry of the bromination of the 2,3-dihydroxy esters whereas a P-alkyl substituent leads to p-acetoxy-a-bromo esters, a phenyl group directs formation of the a-acetoxy-P-bromo esters (Scheme 10.5). 

Scheme 9 (a) Friedel-Crafts-type alkylation of P-hydroxyesters. (b) Bi(OTf)3-catalyzed synthesis of fluorenes... 

This methodology has also been extended to the alkylation of p-hydroxyester 6 in order to obtain the p-carboxy-substituted diarylalkane 7 (Scheme 9a). The... 

As described previously [63], P-ketoester 111 [Fig. (31)] was subjected to Baker s yeast reduction to afford the optically active P-hydroxyester 112 (60-80% yield). Dianion alkylation of 112 with (E)-3-methyl-4-(0-tert-butyldimehtylsilyl)-2-butene afforded the desired a-alkyl product 113 in 58-70% isolated yield. 

Masked chiral a-hetero substituted carboxylic acid enolates have also shown utility in dia-stereoselective additions to nitroalkenes. For example, derivatives of a-hydroxycarboxylic acids, e.g. l,3-dioxolan-4-ones (187) a-amino acids, e.g. 1,3-imidazolidin-4-ones (188) and a-amino-fi-hydroxy-carboxylic acids, e.g. methyl 1,3-oxazolidin-4-carboxylates (189) and methyl l,3-oxazolin-4-carboxy-lates (190), have been employed.1S0a Further, diastereoselective additions of chiral (3-hydroxyesters (191), via the enediolates, to nitroalkenes (40) afford predominant anr/ -P-hydroxyesters (192 Scheme... 

The same methodology was also applied to the DKR of (5-hydroxyesters. In the latter case, the reaction was carried out in tandem with an aldol reaction and the P-hydroxyester formed, after neutralization, underwent DKR using the immobilized lipase from Candida antarctica and a ruthenium catalyst [8]. 

Lucas, M, and Gucllc, J. P., Addition de reac-tits de ReformaLsky. sur las a- cl P-aminoce-lones. Synthese dc f et 8-amino-p-hydroxyesters, J. Chem. Res.. 214, 1978. 

In most cases, the Reformatsky reaction is not very stereospecific and mixtures of erythro- and threo-p-hydroxyesters are obtained when asymmetric a-haloesters are used as reagents (equation 79). The erythro threo ratio appears to depend on the solvent polarity and the reaction time. However, it is of current interest to develop highly stereocontrolled asymmetric Reformatsky reactions. To date, high diastereoselectivities could be achieved only in a few cases either by substitution of zinc with other metal... 

An electrocatalytic method for the reductive N-O bond cleavage of 3-methoxyisoxazoline in the presence of Ni bpy was studied. The nickel complex, generated in situ, acts as the actual electron source. Under these conditions, isoxazoline 59 afforded a mixture of p-hydroxyester 60 and p-hydroxynitrile 61 in high overall yields, and in different ratios depending on the amount of Ni°bpy used <03TL8217>. 

Reaction of benzaldehyde with the vinylidene 1,3-dithiolane 310 in the presence of a stoichiometric amount of 311 afforded the disubstituted 1,3-dithiolane 312 in 88% yield, from which, upon radical desulfurization, P-hydroxyester 313 was formed in 82% yield (Scheme 42) <1997TA3371, 1997TL3553, 1999TA2871, 2000TL6599, 2000TL7511>. 

Bandraege, S, Josephson, S, Moerch, L, Vallen, S, Asymmetric synthesis of p-hydroxyesters by Reformatsky reactions and amide base mediated condensations, Acta Chem. Scand. Ser. B, 35, 273-277, 1981. 

Araki, S., Ito, H., Butsugan, Y. Synthesis of P-hydroxyesters by Reformatsky reaction using indium metal. Synth. Commun. 1988,18, 453-458. 

Depending upon whether (S)- or (M)-BINAP was chosen, either enantiomer of the P-hydroxyester (in >97% yield with ee > 99%) formed.24 These results are comparable to the enantioselectivity achieved using enzymes from baker s yeast ... 

The hydrolysis of hydroxy, amino or unsaturated esters is usually accompanied by side reactions, loss of chirality or isomerization. Various esters have been selectively hydrolysed at room temperature and in high yields under high pressure in the presence of V-methylmorpholine or Pr2NEt. For example, the hydrolysis of the p,Y-unsaturated diester 105 into p-hydroxyester 106 occurred chemoselectively in 100% yield at high pressure in methanol solution subsequent high-pressure induced hydrolysis of 106, in CH3CN/H2O (60 1) as medium, afforded the desired hydroxy acid 107 as a single product (Scheme 7.27). The usual aqueous procedures produced a mixture of products. 

Cyclic sulfates of 1,2-diols 2.14 are transformed into monoalcohols by NaCNBHj in refluxing THF at pH 4-5 followed by hydrolysis, or regioseiectively to p-hydroxyesters by NaBH4 in DMA when R = COO -Pr [GS3] (Figure 2.10). 

The carbonyl ene-reaction between isobutene and methyl glyoxylate gave a good yield of P-hydroxyester in 95% ee when the catalyst is a dichlorotitanium-binolate [81]. 

Orlistat (32 tetrahydrolipstatin, Xenical ) is a potent inhibitor of pancreatic lipase [23] which has been launched for the treatment of obesity in 1998. Large amounts of 32 required for clinical development were obtained using a route based on the enantioselective reduction of P-ketoester 29 to provide P-hydroxyester R)-30 followed by diastereoselective elaboration strategies (via (S,S,i )-31, Scheme 6)... 

Oppolzeds sultams 1.133 are also efficient auxiliaries in asymmetric aldol reactions [209,404,407,457,1271], Boron, titanium or Sn (IV) enolates of W-pro-pionoylsultams lead stereoselectively to either enantiomeric syn aldol at -78°C. These products are easily purified by fractional crystallization (Figure 6.83). After treatment with Li0H/H202 and CH2N2, syw-P-hydroxyesters are obtained with an excellent enantiomeric excess. The drawback of this method is the need to use an excess of aldehyde to obtain good chemical yields. As in the case of oxazolidi-... 

Chiral 2-substituted benzaldehyde chromium tricarbonyl complexes have been reacted with chloroacetophenone in the presence of KO-fert-Bu [544], After decomplexation, the E-epoxyketone is obtained with a high selectivity (Figure 6.88). This Darzens reaction with ClCF COO-tert-Bu is poorly stereoselective. Condensation of the same aldehydes with methyl aaylate or acrylonitrile in the presence of DABCO, followed by decomplexation, also leads highly selectively to P-hydroxyesters or -nitriles 6.105 (Y = COOMe or CN) [547] (Figure 6.88). An anti aldol product is also obtained with a high selectivity from a chromium complex and the titanium enolate of PhCF OCF COS-tert-Bu at -78°C [1281, 1282], Chiral aminals of a-ketoaldehydes react with lithium or sodium enolates of ethyl acetate. After treatment with acid, compounds 6.106 are obtained with a high enantiomeric excess (Figure 6.88). 

Heterocyclic p-ketoesters have also been used as substrates for reduction, where the products often have use in the synthesis of pharmaceutical agents or natural products. Representative examples of heterocyclic p-hydroxyesters formed using Baker s yeast are given in Fig. 9-28165-71 . 

Representative examples of acyclic p-hydroxyesters obtained by dynamic resolu-... 

Alcoholysis of y-and P-lactones gives access to enantiomerically pure y-hydrox-yesters and y-lactones (17-24) and P-hydroxyesters and p-lactones (55-63), respectively. Enantiomerically pure enol acetates 67a and the y-acetoxybutenolide 51/ewt-51 have been obtained by hydrolysis of the corresponding racemic substrates. 

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