Aldol threonine

This type of yvn-seleclivc aldol addition has been applied in the synthesis of the unusual L-threonine based amino acid, (2,S, 3/ ,6F)-3-hydroxy-4-methyl-2-methylamino-6-octenoic acid, of cyclosporine104, of the cyclic hexapeptide echinocandin105, and of the antibiotic ionomycin97. 

Figure 10.45 Aldol reactions catalyzed in vivo by serine hydroxymethyl transferase and by threonine aldolases.

The metabolism of P-hydroxy-a-amino adds involves pyridoxal phosphate-dependent enzymes, dassified as serine hydroxymethyltransferase (SHMT) (EC 2.1.2.1) or threonine aldolases (ThrA L-threonine selective = EC 4.1.2.5, L-aHo-threonine selective = EC 4.1.2.6). Both enzymes catalyze reversible aldol-type deavage reactions yielding glycine (120) and an aldehyde (Eigure 10.45) [192]. 

Ketone donors bearing a-heteroatoms are particularly useful donors for the enamine-catalyzed aldol reactions (Scheme 18). Both anti and syn aldol products can be accessed in remarkably high enantioselectivities using either proline or proline-derived amide, sulfonamide, or peptide catalysts. The syn selective variant of this reaction was discovered by Barbas [179]. Very recently, Luo and Cheng have also described a syn selective variant with dihydroxyacetone donors [201], and the Barbas group has developed improved threonine-derived catalysts 71 (Scheme 18) for syn selective reactions with both protected and unprotected dihydroxyacetone [202]. 

PLP-dependent enzymes catalyze the following types of reactions (1) loss of the ce-hydrogen as a proton, resulting in racemization (example alanine racemase), cyclization (example aminocyclopropane carboxylate synthase), or j8-elimation/replacement (example serine dehydratase) (2) loss of the a-carboxylate as carbon dioxide (example glutamate decarboxylase) (3) removal/replacement of a group by aldol cleavage (example threonine aldolase and (4) action via ketimine intermediates (example selenocysteine lyase). 

The product of the PNP enzyme, FDRP 9 has been purified and characterised. The evidence suggests that FDRP 9 is then isomerised to 5-fluoro-5-deoxyribulose-1-phosphate 10, acted upon by an isomerase (Scheme 7). Such ribulose phosphates are well-known products of aldolases and a reverse aldol reaction will clearly generate fluoroacetaldehyde 11. Fluoroacetaldehyde 11 is then converted after oxidation to FAc 1. We have also shown that there is a pyridoxal phosphate (PLP)-dependent enzyme which converts fluoroacetaldehyde 11 and L-threonine 12 to 4-FT 2 and acetaldehyde in a transaldol reaction as shown in Scheme 8. Thus, all of the biosynthetic steps from fluoride ion to FAc 1 and 4-FT 2 can be rationalised as illustrated in Scheme 7. 

Not only can the a-methylene carbanion be produced and stabilized, but it can also undergo base-catalyzed aldol-type reactions without decomposition of the chelate ring. The most-studied reactions involve carbanion additions to acetaldehyde to produce threonine and allothreonine. This can be achieved for bis(glycinato)copper(II),48,49 tris(glycinato)cobalt(III)50,51 or glycinato-bis(l,2-diaminoethane)cobalt(III),52 with the best yield being obtained in the last case, where the... 

One of the first reactions reported on the activation of the a C—H bond was the aldol condensation reaction of glycine, coordinated to Cu11, with acetaldehyde to yield threonine.72 The reaction, which is base catalyzed, proceeds under far milder conditions than for free glycine. Similar reactions have been reported with other metal ions and aldehydes again the postulated intermediate is a carbanion.69 70 By using resolved Co111 complexes, e.g. A-(+)-[Co(en)2(GlyO)]2+, some stereoselectivity can be obtained in the threonine product.73... 

Stereochemically controlled synthesis of this subunit, which contains five stereogenic centers, is important to an efficient bleomycin synthesis. (2S,3S,4i )-4-(/er/-Butoxycarbonyl-amino)-3-hydroxy-2-methylpentanoic acid (15) was obtained via a stereoselective syn aldol addition of a boron Z-enolate with (27 )-2-(tert-butoxycarbonylamino)propanal (Scheme 4). Similarly, the L-threonine subunit 18 was prepared by diastereoselective syn aldol addition of an N- acy I ox azo I i di n one stannous Z-enolate with acetaldehyde. The bithiazole unit 19 was prepared using a direct DCC-promoted condensation of 3-(methylsulfanyl)propylamine. Convergent access to tetrapeptide S was obtained by coupling of acid 15 and deprotected 18 to give dipeptide 20, followed by further coupling with the bithiazole 19 to ultimately give tetrapeptide S (21). 

Kobayashi (1989) reported the formation of Sotolon in wines by an aldol condensation of acetaldehyde and a-ketobutiric acid (derived from threonine) followed by lactonization (Fig. 7.11). During aging, ethanol is converted into acetaldehyde, thus allowing the formation of Sotolon (Silva Ferreira et ah, 2003). 

General Procedure for O-tert-Butyl-L-Threonine Catalyzed Cross-Aldol Reactions of Ketone Donors and Aldehyde Acceptors [2] (p. 23)... 

The synthetic manipulation of O-glycosylamino acid molecules is usually more complex because they may undergo the acid-catalysed anomerisation of glycosidic bonds (Figure 3.3) and they are also usually more sensitive to acid conditions, due to their aldolic nature (e.g. serine and threonine derivatives). However, the acid-sensitivity is modulated by saccharide and peptide nature. 

The glycine-dependent aldolases are pyridoxal 5-phosphate dependent enzymes that catalyze the reversible aldol reaction, where glycine and an acceptor aldehyde form a (i-hydroxy-a-amino acid (Scheme 5.47).74 Serine hydroxymethyltransferases, SHMT (EC 2.1.2.1), and threonine aldolases, two types of glycine dependent aldolases, have been isolated. In... 

Nunes proposed also a second mode of biogenesis, based on L-threonine (Scheme 6). This scheme makes first use of an aldol condensation, analogous to the early proposal of Leete, followed by esterification to the lactone. In both schemes the last step is a selective methylation of N by S-adenosyl-methionine. 

All the compounds produced a burnt sugary aroma, which became more burnt and heavy as the substituted alkyl chain increased in length. It is interesting that the ethyl substituted lactone II has a 100 times lower threshold value than that of sotolon, and that this compound has been considered to be an FIC in the protein hydrolysate. This was because it had been prepared from threonine by heating with hydrochloric acid and subsequent dehydration, hydrolysis, condensation (Aldol type) and decarboxylation, and it showed a strong curry-like or herbal aroma at concentrations higher than 1 ppm,... 

The enzymatic aldolization of (/ )-glyceraldehyde acetonide with glycine catalyzed by L-threonine aldolase from Candida humicola gave the key intermediates for the synthesis of 3,4-dihydroxyprolines in six steps (Fujii et al. 2000). 

Liu JQ, Odani M, Yasuoka T et al. (2000b) Gene cloning and overproduction of low-specificity D-threonine aldolase from Alcaligenes xylosoxidans and its application for production of a key intermediate for parkinsonism drug. Appl Microbiol Biotechnol 54 44-51 Machajewski TD, Wong CH (2000) The catal)rtic asymmetric aldol reaction. Angew Chem Int Ed... 

In a similar vein, bullqr silojqr derivatives of serine and threonine have been found to be hydrophobic enough to furnish the expected adducts with good enantioselectivities. In the presence of tert-butyldimethylsi-lylojy L-threonine (OTBDMS-L-Thr), the aldol reaction between cyclohexanone and benzaldehyde in water was effective with only 2 mol% of the catalyst (yield 58% ee 96%) in favour of the anti-isomer (dr 8 1). This catalyst proved to be remarkably effective with various aromatic aldehydes and the adducts were obtained in excellent yields and nearly perfect ee in water. The anti- or q n-aldol products were obtained respectively from cyclohexanone or TBDMS protected p-hydroxyaldehyde. 

In the 2010s, Aitken et al. demonstrated that a solvent-free organocata-lysed aldol reaction could be achieved by addition of 2-hydroigr-cyclobutanone 11 n = 1) to 4-nitrobenzaldehyde in the presence of L-threonine (Scheme 12.4). The temperature played an important role in the stereochemical outcome, as the -adduct 12 was obtained at low temperature, whereas the same reaction performed at 25 °C and/or in wet DMF led mainly to the a t/-adduct regardless of the amino acid structure. 

The aldol reaction in the presence of an acyclic amino acid has been harnessed in total synthesis. Takabe reported the organocatalytic ot-hydro)ymethylation of a cyclic ketone in aqueous formaldehyde with L-threonine, as the key step for the formal synthesis of chiral jasmine lactone. In a similar way, the team of Chen and Chai prepared several cyclohexanone derivatives. Much more recently, a synthesis of phaitanthrin A by aldol reaction of tryptanthrin with acetone in the presence of the potassium salt of L-phenylalanine has been performed in gram-scale quantities. Numerous derivatives have been obtained with yields of up to 98% and ee of up to 99%. 

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