Aldehydes hydroxyaldehydes

A variety of 1,3-oxazolidines have been used as chiral formyl anion equivalents for addition to aldehydes. Thus, for example, reaction of N-protected norephedrine with Bu3Sn-CH(OEt)2 gives 48, and transmetallation with BuLi followed by addition of benzaldehyde affords the expected adduct 49. The selectivity at the newly formed alcohol center is poor, but the situation can be salvaged by oxidation and re-reduction, which affords the product 50 with >95% d.e. It is then a simple matter to hydrolyze off the oxazolidine, although the resulting hydroxyaldehydes... 

The (racemic) tmns disulfoxide of 1,3-dithiolane 59 is readily deprotonated at C2 by lithium hexamethyldisilazide, and the resulting anion reacts with aldehydes at -78°C with moderate to excellent diastereoselectivity to give mainly the products 60, although subsequent cleavage of these to give the a-hydroxyaldehydes was not described (97JOC1139). 

The natural acceptor aldehyde can be considerably varied among phosphorylated as well as unphosphorylated hydroxyaldehydes, which are both converted at comparable rates (Table 5)13-44 47. Although the catalytic reaction creates only a single stereocenter, the enzymes from yeast or spinach efficiently distinguish between adjacent configurations with preference for (3SAR)-i>yn isomeric ketose products44 47, which nicely parallel those derived from FruA reactions (Section 1.3.4.6.1). 

Dithioacetal monoxide anions react with carbonyl compounds in a similar way affording the corresponding a-hydroxy aldehyde dithioacetal oxides 428. Ogura and Tsuchihashi, who performed this reaction for the first time using the anion of methyl methylthiomethyl sulphoxide 324, obtained in this way a series of a-hydroxyaldehydes 429504 (equation 257). 

Aldehydes up to a chain length of four nonhydrogen atoms are tolerated as acceptors. 2-Hydroxyaldehydes are relatively good acceptors, and the D-isomers are preferred over the t-isomers [180]. Reactions that lead to thermodynamically unfavorable structures may proceed with low stereoselectivity at the reaction center [181]. Recently, a single-point mutant aldolase was found 2.5 times more effective than the wild type in accepting unphosphorylated glyceraldehyde [182,183]. 

The aldols are j8-hydroxyaldehydes and, like all j8-hydroxycarhonyl-compounds, they easily lose water and become converted into a-j8-unsaturated aldehydes. From aldol as starting material a technical route to butadiene is provided and possibly, in the future, to a synthetic rubber. 

Aldehyde (B) also has hydrogen a to the carbonyl and can generate an enolate anion the aldol reaction follows as with the first aldehyde to give the product shown. However, dehydration of the P-hydroxyaldehyde is not favoured. 

Ru(OH)(PPh3)(salen) is made from Ru(NO)Cl3(PPh3)2, (salen=iV,iV -ethan-l,2-bis-(salicyliden-amine) and ethyldi-ixopropylamine in EtOH. As Ru(OH)(PPh3) (salen)/02/CH3Cl3 or CHCI3 it preferentially oxidised primary alcohols to aldehydes while l-phenyl-l,n diols (n = 2 to 5) were oxidised by Ru(PPh3)(OH)(salen)/ O /CHClj to lactols or the n-hydroxyaldehyde [813]. 

It is noteworthy that the indenyl complex RuCl(ri -C9H7)(PPh3)2l4 provides an efficient catalyst precursor for the anti-Markovnikov hydration of terminal alkynes in aqueous media, especially in micellar solutions with either anionic (sodium dode-cylsulfate (SDS)) or cationic (hexadecyltrimethylammonium bromide (CTAB)) surfactants [38]. This system can be applied to the hydration of propargylic alcohols to selectively produce P-hydroxyaldehydes, whereas RuCl(Cp)(PMe3)2 gives a,P-unsat-urated aldehydes (the Meyer Schuster rearrangement products)(Scheme 10.8) [39]. 

Mukaiyama et al. developed a rather general and versatile method for the preparation of optically active a-hydroxyaldehydes by using the diamine (99) as chiral adjuvant. Thus, one Grignard reagent (R MgX) is reacted with the aminal (102) of methyl glyoxylate. In the next step a second kind of Grignard reagent (R2-MgX) is diastereoselectively added to the ketoaminal, and the desired chiral a-hydroxy-aldehyde (103) is obtained by hydrolysis 117-1I8). 

The ready availability of the transketolase (TK E.C. 2.2.1.1) from E. coli within the research collaboration in G. A. Sprenger s group suggested the joint development of an improved synthesis of D-xylulose 5-phosphate 19, which was expensive but required routinely for activity measurements [27]. In vivo, transketolase catalyzes the stereospecific transfer of a hydroxyacetyl nucleophile between various sugar phosphates in the presence of a thiamine diphosphate cofactor and divalent cations, and the C2 donor component 19 offers superior kinetic constants. For synthetic purposes, the enzyme is generally attractive for its high asymmetric induction at the newly formed chiral center and high kinetic enantioselectivity for 2-hydroxyaldehydes, as well as its broad substrate tolerance for aldehyde acceptors [28]. 

In both reactions with the meso substrates, no intermediary monoadduct could be detected. Consequently, a potential kinetic preference of the aldolase for either of the competing enantiotopic hydroxyaldehyde moieties within the starting substrates could not be investigated. No matter which of the enantiotopic aldehyde groups is attacked first, however, the second addition steps must be kinetically faster in each case, probably supported by the presence of an anionic charge in the intermediates, which should improve the substrate affinity to the enzyme. 

One of the most important reactions of aldehydes and ketones is the Aldol condensation. In this reaction, an enolate anion is formed from the reaction between an aldehyde or a ketone and an aqueous base, e.g. NaOH. The enolate anion reacts with another molecule of aldehyde or ketone to give (3-hydroxyaldehyde or (3-hydroxyketone, respectively (see Section 5.3.2). 

Aldol condensation reaction may be either acid or base catalysed. However, base catalysis is more common. The product of this reaction is called an aldol, i.e. aid from aldehyde and ol from alcohol. The product is either a P-hydroxyaldehyde or P-hydroxyketone, depending on the starting material. For example, two acetaldehyde (ethanal) molecules condense together in the presence of an aqueous base (NaOH), to produce 3-hydroxybutanal (a P-hydroxyaldehyde). 

In this proper sense, aldol condensation includes reactions producing j3-hydroxyaldehydes or j3-hydroxyketones by self-condensation or mixed condensation of aldehydes and ketones these reactions are, in fact, additions of a C—H bond activated by the carbonyl to the C=0 bond of the other molecule, viz. 

Hemiacetals are more readily formed from aldehydes than from ketones.77 4-Hydroxybutanal and 5-hydroxypentanal exist preponderantly as cyclic hemiacetals, containing only 11.4 and 6.1%, respectively, of the free aldehyde.79 These often-quoted data were, however, obtained for solutions in 3 1 1,4-dioxane-water, and, if experience gained with the hydroxyketones75 is also valid for the hydroxyaldehydes, the proportion of aldehyde would be much higher in aqueous solution (for which data are not yet available). 

Oxathiolane 3,3-dioxide (332) metallates in its 2-position to yield an anion which reacts with various electrophiles (alkyl halides and carbonyl compounds) to give substituted oxathiolanes (333) in good to excellent yield (79TL3375). Pyrolysis of these alkylated products affords the corresponding aldehydes or 2-hydroxyaldehydes in addition to sulfur dioxide and isobutylene (Scheme 71). The oxathiolane (332) thus becomes another member of the already burgeoning class of carbonyl anion equivalents. 

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