Threonines aldol reactions

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

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]. 

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. 

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

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... 

One of the first reactions reported on the activation of the a C—H bond was the aldol condensation reaction of glycine, coordinated to Cu , with acetaldehyde to yield threonine. 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. By using resolved Co " complexes, e.g. A-(-f)-[Co(en)2(GlyO)] , some stereoselectivity can be obtained in the threonine product. ... 

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%. 

Scheme 2.196 Aldol reactions catalyzed by L-threonine aldolase...

Aldol reactions have been catalyzed by aldolases as well as by catalytic antibodies. For example, L-threonine aldolase was applied to C—C bond formation of an aldehyde with glycine. The resulting adduct could be further converted to a precursor of N-acetyl-4-deoxy-D-mannosamine, a potent inhibitor of N-acetylneuraminic acid synthetase (Fig. 10.39(a)). "... 

Alternatively, threonine can also be catabolized by cleavage through a PLP-dependent retro-aldol reaction (Section 17.6) to yield acetaldehyde... 

An antibody that mimics threonine aldolase, which uses pyridoxal as the cofactor to catalyze the aldol reaction of glycine with aldehydes, has also been reported. Antibody 10H2 catalyzed the retro-aldol reaction of jd-hydroxy-a-amino acid in the presence of pyridoxal [55]. 

L-Threonine-derived catalysts were demonstrated to be remarkably effective for the direct aldol reaction. Lu et al. investigated the potential of serine and threonine analogs in the direct asymmetric aldol reaction in aqueous medium [28]. While L-serine and L-threonine were found to be ineffective, sUylated threonine and serine derivatives were wonderful catalysts for the direct aldol reaction of cyclohexanone and aromatic aldehydes in the presence of water, affording the aldol adducts in excellent yields and with nearly perfect enantioselectivities. L-Serine-derived 9a was inferior to the corresponding threonine-based catalysts. The reaction could be extended to hydroxyacetone, and sy -diols were obtained with very good enantioselectivities (Scheme 3.6). Subsequently, Teo and coworkers also employed silylated serine catalysts for the same reaction [29]. Very recently, Cordova et al. [30] reported a co-catalyst system consisting of 8a and l,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea, and applied such catalytic pairs to the direct aldol reaction between ketones and aromatic aldehydes both cyclic and acycUc ketones were found to be suitable substrates. 

Scheme 3.6 Protected L-threonine or L-serine for the direct aldol reaction.

Scheme 3.7 Direct aldol reaction promoted by 0-Bu -L-threonine.

By introducing large acyl groups to the hydroxyl function of threonine, Fu et al. developed a series of threonine-surfactant catalysts, and found catalyst 10 was most efficient in promoting highly enantioselective aldol reactions of cyclic ketones and aromatic aldehydes [33]. 

Figure 17.13 Threonine catalyzed aldol reaction (a) and the corresponding stereocontrolling transition states (b) obtained through DFT studies. (R = p-nitrophenyl).

Although the number of successful applications of primary amino acids in stereoselective organocatalysis is far fewer than for the secondary amine, a few interesting examples are worth pointing out. The diversity of primary amino acids in aldol and Mannich reactions has been reviewed recently [48]. Several primary amino acids, such as alanine, valine, tryptophan, and threonine have been used as orga-nocatalysts. For instance, Barbas and coworkers have demonstrated the use of a L-threonine catalyzed protocol towards the synthesis of syn-l,2-diols through direct aldol reaction between a-hydroxyketones and para-nitrobenzaldehyde (Figure 17.13) [49]. 

Scheme 22.24 Asymmetric aldol reactions catalyzed by IL-tagged serine, threonine, or lysine derivatives.

T. Nishiyama, S.S. Mobile, T. Kajimoto, M. Node, Synthesis of thymine polyoxin C by using L-threonine aldolase-catalyzed aldol reaction. Heterocycles 71 (2007) 1397-1405. 

The limitations imposed by the thermodynamic relahons due to the reversible nature of the aldol reactions, may be overcome by introducing an ensuing complementary enz3unatic reaction in a cascade fashion. In this way, it is possible to improve the stereochemical outcome of threonine aldolases by selectively transforming one of the diastereosiomers in situ by the action of another enzyme. Toward this end, utilization of L-ThrA in tandem with L-t5u-osine decarboxylase (LTyrDC, PLP-dependent) to produce (I )-2-amino-l-phenylethanol in 89% isolated yield represents a significant example (Scheme 10.28) [194]. 

Fujii, M., Miura, T., Kajimoto, T., and Ida, Y., Facile S5mthesis of 3,4-dihydroxyprolines as an application of the L-threonine aldolase-catalyzed aldol reaction. Sunlett 2000, 7, 1046-1048. 

Threonine Aldolase-Catalyzed Aldol Reactions Using Giycine and an Aidehyde... 

Synthesis of L-threo-3,4-dihydroxy-phenylserine via asymmetric aldol reaction of 3,4-dihydroxyben-zaldehyde and glycine with a recombinant whole-cell catalyst containing a threonine aldolase. 

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