Racemic 2-substituted aldehydes

I.3.3.3.3.2.2. Simple Diastereoselection Reactions of Racemic -Substituted Allylboron Reagents with Achiral Aldehydes and Ketones... 

Despite the fact that enzymatic aldol reactions are becoming useful in synthetic carbohydrate chemistry, the preparation of aldehyde substrates containing chiral centers remains a problem. Many a-substituted aldehydes racemize in aqueous solution, which would result in the production of a diastereomeric mixture, which is not always readily separable. 

Parchinsky et al. (2011) reported synthesis of symmetrically and unsymmetrically substituted chiral, racemic 1-azaadamantanes via BF3.0Et2-promoted aza-Prins reaction under microwave irradiation. Reaction of ( )-[(4-methylcyclohex-3-en-l-yl) methyljamine with an equimolar amount of an aldehyde in the presence of 1.0 equiv. of Bp3.0Et2 at ISO C for 1 h gives predominantly bicyclic piperidines whereas in presence of excess amount of the aldehydes, symmetrically substituted 1-azaadamantanes are the major products. The yield of the products ranges from 52-83%. 

Aluminum oxide catalyzed addition of ethyl nitroacetate to racemic 2,3-cpoxy aldehydes 7 affords substituted 4,5-dihydroisoxazole 2-oxides through a regio- and stereospecific tandem nitroaldol cyclization process. High diastereoselectivities are observed in the reaction of cis-epoxyaldehydes to yield the ethyl, vi7 -4.5-dihydro-4-hydroxy-5-( I -hydroxyalkyl)-3-isoxazole-carboxylate 2-oxides, with tram configuration at the ring positions, whereas reactions of trans-and 3,3-disubstituted 2,3-epoxyaldehydes proceed with lower selectivities28. 

Diastereoselective and enantioselective [3C+2S] carbocyclisations have been recently developed by Barluenga et al. by the reaction of tungsten alkenylcarbene complexes and enamines derived from chiral amines. Interestingly, the regio-chemistry of the final products is different for enamines derived from aldehydes and those derived from ketones. The use of chiral non-racemic enamines allows the asymmetric synthesis of substituted cyclopentenone derivatives [77] (Scheme 30). 

In many cases, the racemization of a substrate required for DKR is difficult As an example, the production of optically pure cc-amino acids, which are used as intermediates for pharmaceuticals, cosmetics, and as chiral synfhons in organic chemistry [31], may be discussed. One of the important methods of the synthesis of amino acids is the hydrolysis of the appropriate hydantoins. Racemic 5-substituted hydantoins 15 are easily available from aldehydes using a commonly known synthetic procedure (Scheme 5.10) [32]. In the next step, they are enantioselectively hydrolyzed by d- or L-specific hydantoinase and the resulting N-carbamoyl amino acids 16 are hydrolyzed to optically pure a-amino acid 17 by other enzymes, namely, L- or D-specific carbamoylase. This process was introduced in the 1970s for the production of L-amino acids 17 [33]. For many substrates, the racemization process is too slow and in order to increase its rate enzymes called racemases are used. In processes the three enzymes, racemase, hydantoinase, and carbamoylase, can be used simultaneously this enables the production of a-amino acids without isolation of intermediates and increases the yield and productivity. Unfortunately, the commercial application of this process is limited because it is based on L-selective hydantoin-hydrolyzing enzymes [34, 35]. For production of D-amino acid the enzymes of opposite stereoselectivity are required. A recent study indicates that the inversion of enantioselectivity of hydantoinase, the key enzyme in the... 

Stereochemical Control by the Aldehyde. A chiral center in an aldehyde can influence the direction of approach by an enolate or other nucleophile. This facial selectivity is in addition to the simple syn, anti diastereoselectivity so that if either the aldehyde or enolate contains a stereocenter, four stereoisomers are possible. There are four possible chairlike TSs, of which two lead to syn product from the Z-enolate and two to anti product from the A-enolate. The two members of each pair differ in the facial approach to the aldehyde and give products of opposite configuration at both of the newly formed stereocenters. If the substituted aldehyde is racemic, the enantiomeric products will be formed, making a total of eight stereoisomers possible. 

This and similar catalysts are effective with silyl ketene acetals and silyl thioketene acetals.155 One of the examples is the tridentate pyridine-BOX-type catalyst 18. The reactivity of this catalyst has been explored using a- and (3-oxy substituted aldehydes.154 a-Benzyloxyacetaldehyde was highly enantioselective and the a-trimethylsilyoxy derivative was weakly so (56% e.e.). Nonchelating aldehydes such as benzaldehyde and 3-phenylpropanal gave racemic product. 3-Benzyloxypropanal also gave racemic product, indicating that the (i-oxy aldehydes do not chelate with this catalyst. 

Entry 6 uses diisopropoxytitanium with racemic BINOL as the catalyst. Entry 7 shows the use of (CH3)2A1C1 with a highly substituted aromatic aldehyde. The product... 

Allylic substitution reactions catalyzed by metalacyclic iridium-phosphoramidite complexes form branched products from linear allylic esters with high regioselec-tivity. However, reactions with racemic, branched allylic esters would be particularly valuable because they are readily accessible from a wide array of aldehydes and vinylmagnesium halides. However, iridium-catalyzed allylic substitution reactions of branched allylic esters have so far occurred with low enantioselectivities [45, 75]. 

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

Non-racemic a-substituted allylic silanes, in particular crotylsilanes, are very attractive reagents despite their rather tedious preparation. They were found to provide very high transfer of chirality in their additions to achiral aldehydes under Lewis acid catalysis (Eq. 114). These reagents have been tested several times in the context of natural product synthesis. Their diastereoselectivity (syn/anti) depends on several factors, including the natme of the aldehyde substrate, the reagent, and the natme of the Lewis acid employed. For example, the syn product can be obtained predominantly in the reaction of Eq. 114 by switching to the use of a monodentate Lewis acid such as BF3. 

Aldehyde-derived SAMP/RAMP-hydrazones are alkylated in good overall chemical yields and excellent enantiomeric purities (see Table 4). Asymmetric inductions of up to 86% ee, obtained from alkylation reactions in tetrahydrofuran, were optimized to >90% ee by using diethyl ether as solvent8. Phenyl-substituted aldehydes are alkylated to products of lower enantiomeric purity (23-31 % ee), probably due to partial racemization of the sensitive aldehydes6, 25. 

Reduction of alkylated aldehyde-derived SAMP-hydrazones, followed by reductive N —N cleavage of the resulting hydrazines with Raney nickel, furnishes /(-substituted primary amines in good chemical yields and without racemization in 94-99% ee (see Table 5)31. 

Starting from the findings of the racemic cross-benzoin condensation [66], and assuming that aldehydes not accepted as donor substrates might still be suitable acceptor substrates, and vice versa, a mixed enzyme-substrate screening was performed in order to identify a biocatalytic system for the asymmetric cross-carboligation of aromatic aldehydes. For this purpose the reactions of 2-chloro-(40a), 2-methoxy- (40b) and 2-methylbenzaldehyde (40c), respectively, were studied with different enzymes in combination with benzaldehyde (Scheme 2.2.7.23) [67]. The three ortho-substituted benzaldehyde derivatives 40a-40c were... 

Monoacetals of substituted succinaldehydes (162), readily prepared by hydroformylation of optically active a,(3-unsaturated aldehyde acetals, were used to synthesize 3-substituted thiophenes having an optically active substituent (163). In these cases, while the use of hydrogen sulfide and HC1 in methanol at room temperature was more convenient, comparison with formation of (163) by the Paal synthesis from an appropriately substituted succinic acid salt gave products having about the same amount of racemization (73JOC2361). 

One of the most valuable and widely used applications of C=N bond hydrogenation is in the field of reductive alkylation, in which an aldehyde or ketone is condensed with an amine and reduced in situ with an appropriate catalyst to give a substituted product. This very valuable reaction has most notably been employed for the racemic synthesis of amino acids from a-ketoesters and acids. This type of reduction can be very powerful, as illustrated by the synthesis of tetrahydro-b-carbolines 64 (76% yield) by the reductive coupling of 65 and 66 under conditions of 1 atm of hydrogen and palladium on carbon catalyst277. 

For example, aldehydes having an a-alkyl substituent have been reported to be stereochemically unstable during Ugi condensation [3], On the contrary, a-alkoxy substituted aldehydes do not racemize. 

---