Aldehydes hydroxycarboxylic acid

Oxy-aldehyd, n, hydroxy aldehyde, -ammo-niak, n, oxyammonia (hydroxylamine), -azoverbindung, /. hydroxyazo compound, -benzol, n, hydroxybenzene (phenol), -bem-steinsaure. /, hydroxysuccinic acid (malic acid). -biazol, n. oxadiazole, oxdiazole. -bitumen, n, oxidized bitumen, -carbon-s ure, /, hydroxycarboxylic acid, -chlnoltn, n. hydroxyquinoline, -clunon, n. hydroxy-quinone. -chlorid, n. oxychloride, -chlor-kupfer, n. copper oxychloride, -cyan, n. oxycyanogen. 

Similar methodology has been applied in the syntheses of 2-amino-3-hydroxycarboxylic acids in high diastereomeric and enantiomeric purity. Two separate pathways give either the antt- or. WM-products. The first strategy relies on haloacetate precursors derived either from (S )-valine 17"- oi or from norephedrine 18102, which are converted into the boron enolates103 and subsequently reacted with aldehydes to deliver. ym-adducts99 102. The diastereomeric ratio, defined as the ratio of the desired diastereomer/the sum of all others, is 50 1 for the former and about 95 5 for the latter adducts. 

The second approach for the synthesis of 2-amino-3-hydroxycarboxylic acids starts with a chiral isothiocyanate which is added, via the tin enolate, to aldehydes. The initially formed adducts are immediately derivatized to the heterocycles, from which. yj 7-2-amino-3-hy-droxycarboxylic acids result after a three-step procedure. The diastereomeric ratios of the intermediate bis-heterocyclic products range from 93 7 to 99 1 (desired isomer/sum of all others)104. 

An entry to. yyrt-2-methoxy-3-hydroxycarboxylic acids is also opened using similar methodology. Thus the norephedrine derived (4/ ,5S)-3-(2-methoxy-l-oxoethyl)-4-methyl-5-phenyl-1,3-oxazolidine-2-one 23105a, as well as the phenylalanine derived (4S)-4-benzyl-3-(2-methoxy-l-oxoethyl)-l,3-oxazolidin-2-one 25105b, can be added to aldehydes via the boron enolates to give, after oxidative workup, the adducts in a stereoselective manner (d.r. 96 4, main product/sum of all others). Subsequent methanolysis affords the methyl esters. 

Acetylsultam 15 is also used for stereoselective syntheses of a-unsubstituted /1-hydroxy-carboxylic acids. Thus, conversion of 15 into the silyl-A/O-ketene acetal 16 and subsequent titanium(IV) chloride mediated addition to aldehydes lead to the predominant formation of the diastereomers 17. After separation of the minor diastereomer by flash chromatography, alkaline hydrolysis delivers /f-hydroxycarboxylic acids 18, with liberation of the chiral auxiliary reagent 1919. 

The addition of doubly deprotonated HYTRA to achiral4 5 as well as to enantiomerically pure aldehydes enables one to obtain non-racemic (3-hydroxycarboxylic acids. Thus, the method provides a practical solution for the stereoselective aldoi addition of a-unsubstituted enolates, a long-standing synthetic problem.7 As opposed to some other chiral acetate reagents,7 both enantiomers of HYTRA are readily available. Furthermore, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered easily. Aldol additions of HYTRA have been used in syntheses of natural products and biological active compounds, and some of those applications are given in Table I. (The chiral center, introduced by a stereoselective aldol addition with HYTRA, is marked by an asterisk.)... 

Similar polyacetals were prepared by BASF scientists from CO-aldehydic aliphatic carboxylic acids (189,190) and by the addition of poly(hydroxycarboxylic acid)s such as tartaric acid to divinyl ethers (191) as biodegradable detergent polymers. 

Lewis acid-promoted asymmetric addition of dialkylzincs to aldehydes is also an acceptable procedure for the preparation of chiral secondary alcohol. Various chiral titanium complexes are highly enantioselective catalysts [4]. C2-Symmet-ric disulfonamide, chiral diol (TADDOL) derived from tartaric acid, and chiral thiophosphoramidate are efficient chiral ligands. C2-Symmetric chiral diol 10, readily prepared from 1-indene by Brown s asymmetric hydroboration, is also a good chiral source (Scheme 2) [17], Even a simple a-hydroxycarboxylic acid 11 can achieve a good enantioselectivity [18]. 

The electrocarboxylation of aldehydes and ketones leads to the corresponding a-hydroxycarboxylic acids that can easily be converted into carboxylic acids via a hydrogenation reaction [7]. It has been reported that the electrocarboxylation of aromatic ketones occurs through the reaction of C02 onto the activated carbon atom of the carbonyl group of the ketyl radical anion generated upon electron transfer to the ketone [7]. Otherwise, the aforementioned intermediate is likely to be a resonance hybrid (see Equation 12.23), and its electrophilic reaction with C02 may take place both at the carbon or the oxygen atom [42, 43]. 

The presence of oe-hydroxycarboxylic acids together with a-aminoacids could lead to an estimate of the local concentration of ammonia when these molecules were synthesised. Such an estimation method implies the assumption that the syntheses of the two classes of molecules were simultaneous and started from the same organic substrate, i.e. aldehydes25 . From aldehydes, aminoacids can be obtained by the Strecker synthesis (aldehyde, HCN, NH3 in aqueous solution), while hydroxyacids can be synthesised from the cyanhydrin synthesis (aldehyde + HCN) followed by a hydrolysis. Nevertheless, it must be emphasised that all aminoacids detected in carbonaceous chondrites cannot be obtained by the Strecker synthesis. This remark limits the interest of the previous arguments concerning the concentration of NH3 during the accretion phase. 

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. 

The /3-lactone was formed by the cyclization of a 3-hydroxycarboxylic acid with sulfonyl chloride. An alternative synthesis attempted to control all stereochemical relationships in the molecule using the properties of silyl moieties attached to substrates and reagents <20040BC1051>. Stereoselective reactions of this type included the use of silyl groups in enolate alkylations, hydroboration of allylsilanes, and an anti Se2 reaction of an allenyl silane with an aldehyde and ry -silylcupration of an acetylene. The /3-lactone was again formed by the standard sulfonyl chloride cyclization method. 

An aldol addition involves the addition of the a-C atom of a carbonyl compound, a carboxylic acid, a carboxylic ester, or a carboxylic amide to the C=0 double bond of an aldehyde or a ketone. The products of aldol additions are /3-hydroxylcarbonyl compounds (aldols), /i-hydroxycarboxylic acids, /Thydroxycarboxylic esters, or j3-hydroxycarboxylic amides. 

The simple diastereoselectivity of aldol reactions was first studied in detail for the Ivanov reaction (Figure 13.45). The Ivanov reaction consists of the addition of a carboxylate enolate to an aldehyde. In the example of Figure 13.45, the diastereomer of the /1-hydroxycarboxylic acid product that is referred to as the and-diastereomer is formed in a threefold excess in comparison to the. vy/j-diastereoisomer. Zimmerman and Traxler suggested a transition state model to explain this selectivity, and their transition state model now is referred to as the Zimmer-man-Traxler model (Figure 13.46). This model has been applied ever since with good success to explain the simple diastereoselectivities of a great variety of aldol reactions. 

Interest in the synthesis of enantiopure 2-hydroxycarboxylic acids via asymmetric enzymatic transformations is still increasing and two pathways have risen into prominence recently. The first is based on enantioselective hydrocyanation of the appropriate aldehyde in the presence of an oxynitrilase (hydroxynitrile lyase, EC 4.1.2.10), which gives rise to the corresponding enantiomerically pure cyanohydrin, followed by chemical hydrolysis in the presence of strong acid (Figure 16.1, route a). This latter step generates copious quantities of salt and is not compatible with sensitive functional groups, which is a serious limitation. 

In conclusion, the bienzymatic transformation of aldehydes and HCN into the enantiomerically pure 2-hydroxycarboxylic acids is feasible. The stereochemistry can be steered either by the hydroxynitrile lyase or by both enzymes in combination and the hydrocyanation equilibrium is no longer an issue because it can be shifted to complete conversion. The formation of large amounts of amide, in particular (S)-4a, somewhat reduces the immediate practical value of our procedure. Ways to obviate this unwanted side-reaction will be discussed later. 

Hydrocyanation of aldehydes opens access to the synthetically valuable cyanohydrins, precursors for hydroxycarboxylic acids, a-hydroxyketones and /S-ami-noalcohols. Applying the principles of homogeneous catalysis to this reaction it is possible to obtain cyanohydrins in the optically active form, depending on how well the catalyst-ligand system is adapted to the substrate. 

In the Cannizzaro reaction, the hydride ion that is being used to effect this reduction may come from an aldehyde that lacks an a-hydrogen atom, e.g. methanal or benzaldehyde. The receiving molecule may be a second molecule of the same aldehyde or a different one. The reaction requires a strong base, and the rate law is found to depend on the square of the concentration of the aldehyde and either the concentration or the square of the concentration of the base used. Overall a carboxylate anion and an alcohol are formed from two molecules of the aldehyde(s). The reaction may occur intramolecularly, i.e. a-ketoaldehydes give the a-hydroxycarboxylic acids on treatment with hydroxide ions. A variation of this process is called the Tollens reaction. In this case, a ketone or aldehyde that contains an a-hydrogen is treated with formaldehyde in the presence of Ca(OH)2. 

Secondary arsinepropionic acids (55) undergo acid-catalyzed addition to aldehydes, yielding the 5-hydroxycarboxylic acids (56), which further lactonize to give the 1,3-oxarsinan-6-ones (57) (Scheme 8) <78JOM( 155)195>. 

Oxetan-2-ones decarboxylate on heating to give olefins. The synthesis of olefins starting from / -hydroxycarboxylic acids or from ketenes and aldehydes can thus be carried out as an alternative to the WiTTiG reaction. 

Optically active 3-amino-2-hydroxycarboxylic acid derivatives are often key components of medicinally important compounds. The synthesis of isopropyl (2i ,35)-3-amino-4-cyclo-hexyl-2-hydroxybutyrate (126) (Scheme 28) takes advantage of a [2 + 2]-cycloaddition reaction of the chiral imines 123, prepared from 63, to assemble the important diastereomeric azetidinone 124 as the crucial precursor for completion of this novel synthesis. Protection of the hydroxy group of 63 as either the TBS ether 119 or the tert-buty ether 120, followed by a DIBAL reduction at —78 °C, produces smoothly one of the aldehydes 121 or 122. Condensation of these aldehydes with either di-p-anisylmethylamine or benzylamine in the presence of anhydrous magnesium sulfate affords the four possible chiral imines 123a—d (Scheme 26). 

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]. 

Synthetic approaches to fluorinated p-lactones (oxetane-2-ones) are very similar to oxetane synthesis. Usually p-lactones are prepared either by cycloaddition of ketenes to aldehydes or ketones or by cyclodehydration of p-hydroxycarboxylic acids. 

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