P-Hydroxy acids

Apart from lactic and hydroxyacetic acids, other a- and P-hydroxy acids have been small-volume specialty products produced in a variety of methods for specialized uses. y-Butyrolactone [96 8-0] which is the monomeric inner ester of y-hydroxybutyric acid [591-81-17, is a large-volume chemical derived from 1,4-butanediol (see Acetylene-derived chemicals). 

P-Hydroxy acids lose water, especially in the presence of an acid catalyst, to give a,P-unsaturated acids, and frequendy P,y-unsaturated acids. P-Hydroxy acids do not form lactones readily because of the difficulty of four-membered ring formation. The simplest P-lactone, P-propiolactone, can be made from ketene and formaldehyde in the presence of methyl borate but not from P-hydroxypropionic acid. P-Propiolactone [57-57-8] is a usehil intermediate for organic synthesis but caution should be exercised when handling this lactone because it is a known carcinogen. 

The condensation of aromatic aldehydes with anhydrides is called the Perkin reaction When the anhydride has two a hydrogens (as shown), dehydration always occurs the P-hydroxy acid salt is never isolated. In some cases, anhydrides of the form (R2CHC0)20 have been used, and then the hydroxy compound is the product since dehydration cannot take place. The base in the Perkin reaction is nearly always the salt of the acid corresponding to the anhydride. Although the Na and K salts have been most frequently used, higher yields and shorter reaction times have been reported for the Cs salt. Besides aromatic aldehydes, their vinylogs ArCH=CHCHO also give the reaction. Otherwise, the reaction is not suitable for aliphatic aldehydes. ... 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

Beta-H elimination reactions, 20 157 P-HCG (beta subunit human chorionic gonadotropin), 9 64 P-hydroxy acids, 14 130, 131 P-hydroxyethyl esters, 10 487 Betaine, 2 65... 

P-Hydroxy acids, 14 130, 131 y-Hydroxy acids, 14 131 a-Hydroxyadipaldehyde, 1 279 Hydroxyalkyl alkyl peroxides,... 

Diastereomeric excesses of up 56% have been claimed for the preparation of a-amino-P-hydroxy acids via the aldol condensation of aldehydes with f-butyl N-(diphenylmethylene)glycinate [63]. It might be expected that there would be thermodynamic control of the C-C bond formation influenced by the steric requirements of the substituents, but the use of cinchoninium and cinchonidinium salts lead to essentially the same diastereoselectivity. The failure of both tetra-n-butylammo-nium and benzyltriethylammonium chloride to catalyse the reaction is curious. 

Lipopolysaccharides (LPS) P-hydroxy-acids Gram-negative bacteria... 

Several small peptides 781 possessing an N-terminal p-hydroxy acid have been obtained using the azirine-oxazolone method developed by Heimgartner. ... 

A method to prepare 2a based on the work of a related analog [4] was employed for the first mulh-kilogram campaign. In this approach, 2a was prepared from lactam 5, which is derived from an optically enriched P-hydroxy acid. This method requires introduction of the amino group as an 0-benzylhydroxylamine, which we hoped would sufficiently protect the amino group of 2b during amide formation with triazole 3. 

Adam Baeza Liu J. Am. Chem. Soc. 1972, 94, 2000. For other methods of converting p-hydroxy acids to P-lactones, see Merger Chem. Ber. 1968, 101, 2413 Blume Tetrahedron Lett. 1969, 1047. 

A three-carbon unit can be introduced on ketosugars under Reformatsky conditions, as recently demonstrated by several groups [33,34], The analogous Dreiding-Schmidt procedure has also been applied in this case with successful double stereodifferentiation [35]. This is exemplified on ketone 18 which yields lactone 20 as a single isomer (see Scheme 10). The condensation on ketosugars of trimethylsilylacetate [36] or acrylate [33], in the presence of fluoride ion, has also been used with success for the synthesis of P-hydroxy acids or ra-methylene-y-lactones, respectively. 

A. Golfbiowski and J. Jurczak, a-Amino-P-hydroxy acids in the total synthesis of amino sugars, Synlett p. 241 (1993). 

Since the allyl function represents a latent carboxy unit, diastereomerically pure homoallylic alcohols syn-21 or anti-21, obtained by condensation of allylic metals 26 with chiral a-amino aldehydes or acetals (Scheme 6), have been used to prepare the corresponding y-amino-p-hydroxy acids (Scheme 7). 

Pure homoallylic alcohols are converted into y-amino-p-hydroxy acids by protection as the TBDMS ether or A(0-acetonide followed by degradative oxidation of the terminal alkene using a catalytic amount of ruthenium(III) chloride and sodium periodate (Scheme... 

The use of the aldol condensation to synthesize y-amino-p-hydroxy acids suffers from several drawbacks, such as possible racemization either of the initial carboxy group during its transformation to the a-amino aldehyde, or during any subsequent manipulations of the sensitive CHO moiety. An alternative route involves the direct activation of the carboxy group of the N-protected a-amino acids 30 followed by alkylation with enolates 17 to produce the corresponding p-oxo esters 31.[36 521 The P-oxo esters can be selectively reduced under various conditions to produce diastereomeric mixtures of the target compounds 18 but with retention of the chirality of the initial a-amino acid (Scheme 8). 

Based on the structure of biologically active pseudopeptides and molecular modeling studies, y-amino-p-hydroxy acids which are functionalized at their y-amino, P-hydroxy and/or a-methylene positions have been incorporated into various molecular constructions. Original methods have been developed for their preparation. 

N-Methylated and N,0-dimethylated y-amino-p-hydroxy acids are present in natural compounds of marine origin, e.g. hapalosin1 and dolastatin 10J9 ... 

N-Methylated y-amino-p-hydroxy acids are accessible by the usual synthetic sequences, i.e. aldol condensation or y-amino-P-oxo ester reduction, starting from the corresponding N-methylated a-amino acids, but are obtained with low diastereoselectivity. 61-63 Alternatively, Brown allylboration of the ALBoc-ALMe amino aldehyde 16 (R1 = Bzl, X=Boc, Y = Me) gives the allyhc N-methylated intermediate 27 in 64% yield and 90% de (Scheme 12). 64 Oxidative cleavage of the alkenol is performed using the two-step ozonolysis and sodium chlorite oxidation sequence. 

O-Methylation of N-methylated derivatives under basic conditions is disappointing, 5063 but improved results are obtained using trimethyloxonium tetrafluoroborate (Scheme 13), or boron trifluoride-diethyl ether complex with diazomethane. 671 Conversely, methylation of the proline derived P-hydroxy acid using sodium hydride and iodomethane, as well as using trimethyloxonium tetrafluoroborate, gives the dolaproine unit (8) of dolastatin 10 in good yield. 68,691... 

The control of the three consecutive asymmetric centers in a-alkylated y-amino-p-hydroxy acids is achieved by aldol condensation of a chiral aldehyde and a chiral reagent (Scheme 17 and Table 6), e.g. boron enolate 43,150 79 oxazolidinones of Evans type lit80 or 45 [68>69>801 or Brown s or Roush s crotylorganoboron reagents 46[81 and 47J81,82 respectively. 

Scheme 17 Chiral Enolates for a-Alkylated y-Amino-p-hydroxy Acids...

Just like the common amino acids, the enantiomeric purity of y-amino-P-hydroxy acids is established by formation of diastereomeric derivatives and their analysis by HPLC or NMR spectrometric techniques. In addition to derivatization of the y-amino group, the P-hydroxy moiety of this class of compounds may also possibly be derivatized. 

The formation of oxazolidines 54 or oxazolidinones 55 is currently utilized to assign the absolute stereochemistry of diastereomers of 1,2-amino alcohols, based on H NMR analysis of the H4 and H5 protons of these heterocycles. In the case of y-amino-p-hydroxy acids, the internally cyclized pyrrolidinone 56 is also suitable for determination of the relative configurations of the y-amino and p-hydroxy groups (Scheme 23). 

The y-amino-p-hydroxy acid derived oxazolidinones 55 are prepared from the corresponding N-unprotected y-amino-p-hydroxy ester derivatives by reaction with phosgene,1119,391 carbonyl diimidazole,[41] or benzyl chloroformate.[86] Alternatively, cyclization is obtained from the N-carbamate protected derivatives, i.e. from the TV-isopropenyloxycarbonyl derivatives under heating,[381 or from the TV-Boc or N-Z derivatives under basic conditions. [68 81 87] By analogy, the p,y-diamino acid analogue is converted into the imidazolidinone 57 by treatment of the unprotected compound with phosgene.[83 88]... 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

Reduction by NADPH to form the P-hydroxy acid derivative ... 

Two reports appeared simultaneously in 1988 describing the electrophilic animation with DTBAD of P-hydroxybutyrate and its l,3-dioxan-4-one protected form [22] and of various P-hydroxy esters [23]. The authors obtained similar results. P-Hydroxy esters 46 or 48 were deprotonated at the a-carbon with LDA (2 equiv.) in THF at low temperature and the resulting enolates reacted rapidly with DTBAD at -78 °C to give an easily separable mixture of syn and anti adducts 47 or 49 in which the anti diastereomer was the major compound. The adducts are very useful intermediates since compounds with anti stereochemistry are not easily accessible by other established methods for a-amino P-hydroxy acids synthesis (Schemes 24 and 25). 

This method gives the aminated products with complete control of stereochemistry, and the subsequent deprotection and hydrogenolysis of the hydrazine functionality yield the desired a-amino P-hydroxy acid derivatives. 

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