P-Hydroxy carboxylic acids

Non-Kolbe electrolysis of alicyclic p-hydroxy carboxylic acids offers interesting applications for the one-carbon ring extension of cyclic ketones (Eq. 35) [242c]. The starting compounds are easily available by Reformatsky reaction with cyclic ketones. Some examples are summarized in Table 13. Dimethylformamide as solvent and graphite as anode material appear to be optimal for this reaction. 

An OH and a COOH group can be eliminated from P-hydroxy carboxylic acids by refluxing with excess DMF dimethyl acetal. Mono-, di-, tri-, and tetrasubstituted... 

Fragmentation of 1,3-diols 7-34 Decarbonylation of p-hydroxy carboxylic acids and of p-lactones 7-36 Elimination of CO and C02 from bridged bicydic compounds 7-43 Pyrolysis of P-hydroxy olefins 7-44 Pyrolysis of allylic ethers... 

Chiral hydroxy carboxylic acids The chiral acetals 2, available from (2R, 4R)-pentanediol (12,375-378), couple with ketene f-butyl f-butyldimethylsiiyl acetal (3) in the presence of TiCl4 (0.5 equiv.) to give adducts that are hydrolyzed by TFA-H20 to 4 and 5. The mixture is converted on oxidation and p-elimination into essentially pure (3R)-p-hydroxy carboxylic acids (6). 

P-Hydroxy carboxylic acids. Optically active jS-hydroxy carboxylic acids can be obtained from optically active propargyl alcohols (10, 320) such as 1 by the sequence shown in equation (I). The alcohols (1) can also be converted into optically active a-hydroxy carboxylic acids (equation II).1... 

P-Hydroxy carboxylic acids (12,3).2 This acetate on double deprotonation with LDA undergoes diastereoselective aldol reactions with aldehydes. The adducts are easily hydrolyzed to optically active P-hydroxycarboxylic acids with release of (R)-(+)-1,1,2-triphenyl-1,2-ethanediol, the precursor to 1. Optically pure acids can be obtained by crystallization of the salt with an optically active amine such as (S)-(—)-1 -pheny lethylamine. 

This reaction can also be used to convert 6-alkyl-l,3-dioxan-4-ones, available from P-hydroxy carboxylic acids,2 to ryn-l,3-diols. 

Ankati, H., Zhu, D., Yang, Y, Biehl, R.R., and Hua, L. 2009. Asymmetric synthesis of both antipodes of P-hydroxy nitriles and P-hydroxy carboxylic acids via enzymatic reduction or sequential reduction/hydrolysis. Journal of Organic Chemistry, 74 1658-62. 

Dehydrative decarboxylation. The convc sion of p-hydroxy carboxylic acids to alkenes by reaction with a DMF dialkyl acetal iirvolves an r/n/Z-elimination, and thus is complementary to the known. yv/i-elimination of these hydroxy acids via a P-lactone (5, 22 9, 504). These reactions were used to obtain both the (E)- and the (Z)-l-alkoxy-l,3-... 

Aldol-type reactions. In the presence of I r. h, these ketals condense with aldehydes to form p-hydroxy carboxylic acids (equation 1) ir with imines to form P-lactams (equation 11). 

Decarboxylative dehydration of -hydroxy carboxylic acids (9, 504). Study of the stereochemistry of this reaction indicates that syn-P-hydroxy carboxylic acids are usually converted into (E)-alkenes (equation I), in contrast, the anti-isomers are converted... 

P-HYDROXY CARBOXYLIC ACIDS (R)-2-Ace-toxy-1,1,2-triphenylethanol. Ketene bis(trimethylsilyl) ketals. Titanium(IV) chloride. 

LDA prepared in this way is recommended for regioselective preparation of the less thermodynamically stable enol ether and for generation of dianions of carboxylic acids. The reaction of dianions prepared with this base with aldehydes provides a stereoselective route to y,8-unsaturated p-hydroxy carboxylic acids (equation II). 

An OH and a COOH group can be eliminated from p-hydroxy carboxylic acids... 

Dehydmtive decarboxylation of p-hydroxy carboxylic acids. Olefins are formed when 3-hydroxy carboxylic acids are refluxed with excess DMF di-iiiclhyl acetal in CHClj for 5-10 hr. Yields generally are fair to good (50-90%). 

Later, the route that employs cyclization of p-hydroxy carboxylic acids under action of benzenesulfonyl chloride and pyridine was used to prepare a series of a,a-difluoro-p-lactones 65 (Scheme 2.30). The compounds 65 were shown to be convenient precursors to the corresponding 1,1-difluoroalkenes 66 afforded in excellent yields by extrusion of CO2 in solution at 150-180°C. 

Introduction of 3,5-dimethyl and 4-substituent on the Phebox skeleton revealed a weak substituent effect on the degree of asymmetric induction (Scheme 15) [28,29). When trimethylsUyl acrylate was used as enolate source, the P-hydroxy carboxylic acid was obtained directly upon mild acid hydrolysis. In the production of carboxylic acid 49, an enantiomeric excess of 96% ee was attained using the N02-substituted Phebox-Rh catalyst. 

Through this approach formation of chiral P-hydroxy carboxylic acids with appropriate carbon frameworks is the key step of the method. Evans [92] reported an asymmetric synthesis of the carbapenem PS-5 in which the two stereocenters of the P-lactam ring were efficiently established via an asymmetric aldol addition reaction (Scheme 34). In this approach, the boron enolate 214 was... 

The growing interest in trifluoromethylated organic compounds as pharmaceuticals has led to a new focus on the development of facile methods for introducing a CF3 group into useful optically intermediate. Ishihara and co-workers developed a TiCU-catalyzed Evans-aldol reaction, giving the non-Evans syn product, a-trifluoromethyl-p-hydroxy carboxylic acid... 

P-Lactones from p-hydroxy carboxylic acids with HGA and CGA reagents... 

In the next two examples, synthesis of a-alkyl-P-hydroxy carboxylic acids with high diastereo- and enantioselectivity is presented. We shall see how transformation of the reaction conditions, especially addition of an achiral auxiliary agent, inverts the direction of diastereoselectivity. Both examples treat rather complex organometallic reactions hence, their study might be proper after consulting chapters on organometallic reactions in organic chemistry textbooks. 

Since with stereochemically defined P-hydroxy carboxylic acids the configuration at the P-center is retained in the oxetanone product, the attack of PhS02Cl should occur at the COOH group (with formation of a mixed anhydride 7) rather than at the OH group (with formation of an O-sulfonate) of the educt [5] ... 

Though in the absence of catalyst, the Si-H bond resists ROH or RCO2H, a- or p-hydroxy carboxylic acids and HSi(OEt)3 or MeHSi(OEt)2 gives H2 rapidly, while silylated tartaric acid provides for an optically active hydroxy diphosphine. TBAF catalyses the alcoholysis of Si-H, Si-Si and Si-N bonds. The base catalysed hydrolysis of Me2PhSiOPh involves deprotonation of the solvated Si-O bond while neutral alumina allows for selective cleavage of ly and 2V silyl ethers 8,... 

Kob1996a Kobayashi, S., Hachiya, I. and Yasuda, M., Aldol Reactions on Solid Phase. Sc(OTf)3-Catalyzed Aldol Reactions of Polymer-Supported Silyl Enol Ethers with Aldehydes Providing Convenient Methods for the Preparation of 1,3-Diol, P Hydroxy Carboxylic Acid, and jS-Hydroxy Aldehyde Libraries, Tetrahedron Lett., 37 (1996) 5569-5572. 

Later, Yamamoto and coworkers developed the axially chiral ester 183 for asymmetric acetate aldol additions. After formation of the lithium enolate with LDA, the reaction with various aldehydes yielded P-hydroxy esters 184 in very high diastereoselectivity. It was shown, for two adducts, that a nearly quantitative saponification leads to P-hydroxy carboxylic acids 176 and liberates phenol 185 in nearly quantitative yield and undiminished optical purity (Scheme 4.40) [100]. The authors discuss a twist-boat as well as an open transition state for rationalizing the preferred Re-face attack to the aldehyde, observed with (R,R)-configured acetate 183. Yamamoto s procedure is impressive because of its stereoselectivity, but one has to be aware that the chiral auxiliary 185 is by far not as readily accessible as others also enabling the asymmetric acetate aldol addition. 

Van Draanen NA, Arseniyadis S, Crimmins MT, Heathcock CH. Protocols for the preparation of each of the four possible stereoisomeric a-alkyl-p-hydroxy carboxylic acids from a single chiral aldol reagent. J. Org. Chem. 1991 56 2499-2506. 

Barth, R. and Roush, W.R. (2010) Enantioselective synthesis of a a-methylene-P-hydroxy carboxylic acid derivative via a diaste-reoselective aldol/P-elimination sequence Application to the C(15)-C(21) fragment of tedanolide C. Org. Lett, 12, 2342-2345. 

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