Y-Hydroxyaldehydes

Epoxides provide another useful a -synthon. Nucleophilic ring opening with dianions of carboxylic acids (P.L. Creger, 1972) leads to y-hydroxy carboxylic acids or y-lactones. Addition of imidoester anions to epoxides yields y-hydroxyaldehyde derivatives after reduction (H.W. Adickes, 1969). 

Though anions of allyl ethers, the extra functionality allows regiospecific heteroatom-directed lithiation 160 in the manner of chapter 7. Hence reaction of 160 with an aldehyde goes through a six-membered cyclic transition state 161 to give the enol derivative 163 and hence the y-hydroxyaldehyde 164. 

Cyclic hemiacelals and acetals are readily formed from y-hydroxyaldehydes,44s 45° ketones,451 or acetals.452 455 Either the carbonyl compound or the alcohol451 is deblocked before sponlaneous cyclization occurs. Aldehydes are regularly synthesized from alkenes via ozonolysis450 or periodate cleavage.449 Acetal 7. a starting material for nucleoside analogs, is prepared directly by transacetalization of alcohol 6 with 1 % ethanol/hydrogen chloride.452... 

Hydroperoxides, as optically active oxidizing agents 289-291 Hydrosulphonylation 172 /J-Hydroxyacids 619 a-Hydroxyaldehydes, synthesis of 330 a-Hydroxyalkyl acrylates, chiral 329 j -Hydroxycarboxylic esters, chiral 329 3-Hydroxycycloalkenes, synthesis of 313 Hydroxycyclopentenones, synthesis of 310 -Hydroxyesters 619 synthesis of 616 Hydroxyketones 619, 636 Hydroxymethylation 767 a-Hydroxysulphones, synthesis of 176 / -Hydroxysulphones 638, 639 reactions of 637, 944 electrochemical 1036 synthesis of 636 y-Hydroxysulphones 627 synthesis of 783... 

In 1919, he resumed his position as assistant in the Berlin Institute and, in 1920, obtained his Habilitation with a thesis on the ring-chain tautomer-ism of y- and 5-hydroxyaldehydes. In 1922, Helferich was called to the position of Departmental Head at the Kaiser Wilhelm Institute for Fibre Chemistry in Berlin-Dahlem. However, he never actually occupied this position, for, in the autumn of that year, he accepted a personal chair in organic chemistry at the University of Frankfurt in the Institute headed by Julius von Braun. 

In his first independent work, Helferich prepared y-hydroxyvaleral-dehyde (4-hydroxypentanal) by reduction and ozonolysis of methylhep-tenone, readily available from citral by a retro-aldol reaction. He was able to show that, similarly to the saccharides, this hydroxyaldehyde exists in... 

It has been demonstrated by Pancrazi, Ardisson and coworkers that an efficient kinetic resolution takes place when an excess (2 equivalents) of the racemic titanated alkenyl carbamate rac-334a (R = Me) is allowed to react with the enantiopure )-hydroxyaldehyde 341 or alternatively the corresponding y-lactol 340, since the mismatched pair contributes to a lower extent to the product ratio (equation 91) . Under best conditions, the ratio of the enantiomerically pure diastereomers 3,4-anti-4,5-syn (342) and 3,4-anti-4,5-anti (343) is close to 14 1. Surprisingly, approximately 9% of the iyw,iyw-diastereomer 344 resulted when the starting (ii)-crotyl carbamate was contaminated by the (Z)-isomer. The reasons which apply here are unknown. Extra base has to be used in order to neutrafize the free hydroxy group. The pure awft, awfi-product 345 was obtained with 85% yield from the reaction of the (W-oxy-substituted titanate rac-334b and lactol 340. 345 is an intermediate in the asymmetric synthesis of tylosine . ... 

The starting material is an O-protected a-hydroxyaldehyde which is submitted to an (E)- or (Z)-selective olefination. After O-deprotection, the allylic alcohol is rearranged to the y.d-un-saturaled ethyl ester with >99% chirality transfer. 

All y- and <5-hydroxyaldehydes and -hydroxyketones are in equilibrium with their cyclic hemiacetals, the position of equilibrium depending on... 

Normally, lithium aluminum hydride is too vigorous a reagent for the reduction of lactones to the he-miacetal (hydroxyaldehyde lactol) stage, but, in certain circumstances under carefully controlled conditions, it can be used successfully. Usually, lactones give diols with LiAlH4 but, with 0.25 equiv., hemiacetals have been prepared from -y-lactones in high yield (Scheme Sodium bis(2-meth-... 

Lactones are in principle reducible to hydroxyaldehydes, and when applied to lactones of sugar acids the method works well because cyclic acetal or ketal formation stabilizes the carbonyl function and prevents overreduction [3,96-100]. In particular, d-ribose may be prepared from the cathodic reduction of D-ribono-y-lactone as in Eq. (24) the optimum conditions for this reaction include careful buffering of the electrolyte [97-100]. 

The disconnections for this homoaldol are not obvious. Just as a conjugated (a,p-unsaturatcd) enal is derived from an aldol, we can consider deriving this unconjugated (p,y-unsaturated) enal 72 from a hydroxyaldehyde. We might initially prefer FGI to 73 as the 1,3-relationship is easy to make. But 73 will dehydrate to the conjugated (a,P-unsaturated) enal. Instead we must set up a 1,4-diO relationship 74 so that we can disconnect to an aldehyde RCHO and the homoenolate 75 of propanal. 

Hydrazones. The hydrazone of crotyloxyacetaldehyde undergoes [2,3]Wittig rearrangement resulting in protected -y,5-unsaturated a-hydroxyaldehyde with stereocenters at C-2 and C-3. ... 

Ester synthesis. Use of this reagent permits the formal oxidation, of a-hydroxyaldehydes and y-ketoaldehydes to the corresponding esters. ... 

As a rule of thumb, oxidation of the (S)- or pro-(S ) hydroxyl group occurs selectively with HLADH (Scheme 2.143). In the case of 1,4- and 1,5-diols, the intermediate y- and 8-hydroxyaldehydes spontaneously cyclize to form the more stable five- and six-membered hemiacetals (lactols). The latter are further oxidized in a subsequent step by HLADH to form y- or 5-lactones following the same (S)-or pro-(5) specificity [1035]. Both steps - desymmetrization of the prochiral or meso-diol and kinetic resolution of the intermediate lactol - are often highly selective. By using this technique, enantiopure lactones were derived from... 

Hydroxyaldehydes. n-Butyllithium added at -78° during 15-20 min. to a soln. of 2-methyl-2-thiazoline in tetrahydrofuran, stirred ca. 1.5 hrs., a soln. of cyclohexanone in the same solvent added at -78°, then allowed to warm slowly to room temp., the resulting intermediate (Y 94% purity > 95%) treated with Al-amalgam in moist ether, and refluxed 1.5-2 hrs. thiazolidine deriv. (Y 97% purity > 90%) treated with a soln. of HgClg in aq. 20%-acetonitrile, and stirred 2 hrs. at room temp. -> 2-(l-hydroxycyclohexyl)acetaldehyde. Overall Y 51%. -... 

A soln. of 2-hydroxybenzophenone and chloracetonitrile in dimethylformamide refluxed 25 min. with 6 moles K-carbonate 2-cyano-3-phenylbenzofuran. Y 90%. F. e., also amides with diloracetamide, s. L. Rene and R. Royer, Bl. 1971, 4329 with NaOH, from o-hydroxyaldehydes, cf. T. Lesiak and S. Nielek, Rocz. Chem. 47, 1053 (1973) (Eng) C. A. 79, 115404. 

Good yields of aldehydes from esters as well as hydroxyaldehydes from lactones can be obtained by reduction with NaAlH4 at low temp.— E NaAlH4 in tetra-hydrofuran added gradually at —45 to —60° to a soln. of methyl hydro-cinnamate in the same solvent, and the product isolated after 3 hrs. stirring -> hydrocinnamaldehyde. Y 80%.—Similarly d-Valerolactone 8-hydroxy-valeraldehyde. Y 75%. F. e. s. L. I. Zakharkin et al., Tetrah. Let. 1963, 2087. 

Hydroxamic acid gives a strong color with ferric chloride. This reaction is suitable for the detection of aldehydes in the presence of ketones. Aromatic / -hydroxyaldehydes, / -aminobenzaldehyde, vanillin, / -dimethyl-aminobenzaldehyde, salicylaldehyde, and aliphatic aldehydes with a hydroxy group in the y-position do not react. A positive reaction is observed with benzyl ketones in strongly alkaline media. It is necessary, therefore, to keep the mixture distinctly but not excessively alkaline. This reaction can be utilized for the separation of aldehydes from their mixture with ketones by converting the acid to its insoluble copper salt. Paper chromatography can be used for the identification of aldehydes in mixtures (41). 

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