Threonine silylation

Schraml et al.(137) found that the Si resonances of a series of silyl ester, alkoxy-silyl, and amino-silyl derivatives appear in different regions of the spectrum. On the basis of this information they suggested that Si NMR can be used for the structure elucidation of silylated hydroxy- or aminoacids. The silicon chemical shifts for DL-serine [55] and DL-threonine [56 ] are shown in ppm. The variation in the shielding for the alkoxy-silyl group demonstrates the previously noted sensitivity of Si NMR to the nature of R in Mc3SiOR. (140)... 

The trimethylsilyl group was the first to be developed and is widely used for the protection of serine and threonine (Table 6). Chlorotrimethylsilane, l,14 3,3,3-hexamethyldisilazane, and A(0-bis(trimethylsilyl)acetamide are commercially available reagents used for the conversion of alcohols into the corresponding trimethylsilyl derivatives.Furthermore, trimethylsilyl cyanide has been used to protect the side chains of serine, threonine, and ty-rosine.f This silyl protection allows the formation of A -carboxyanhydrides from H-Ser(TMS)-OH and H-Thr(TMS)-OH, and their application in peptide synthesis in the aqueous phase.f l The TMS group can be removed under various conditions, depending on the kind of functional group to which it is bound the TMS ethers are more stable than related amino or carboxy derivatives.These differences in stability allow the direct application of completely silylated hydroxy amino acids in peptide synthesis.b ... 

The perfection of this strategy makes use of the L-threonine-derived 2S,ZR acid 61 and tert-h xiy iV-(p-methoxybenzyl)glycinate as the active methylene partner [28d]. After condensation to amide 62, base treatment (LHMDS) induced epoxydation (at 0 °C) and then (25 °C) cyclization. This double inversion mechanism produced a single epimer, 63a, which, through acid 63b, was converted to target 11 by silylation, ester hydrolysis, lead tetraacetate and CAN (or peroxydisulfate) oxidation. 

Azetidinyl-4-ketones are closer than azetidinyl-4-carboxylic esters to the target 4-acyloxy derivatives 11, 29, 36. Thus, Hanessian s version of the threonine route [29], utilizing a-keto anions, can be considered an improvement over Shiozaki s a-carboxyanion strategy, especially when its aptitude for being scaled-up for industrial production is considered. The key-step, cyclization of amide 68a (prepared from epoxyacid 64 and fV-anisylphenacylamine) to azeti-dinone 28a, is carried out by simple treatment with K2CO3 at ambient temperature silylation, CAN-mediated cleavage and oxidation with mono-perphthalic acid complete the sequence to synthon 29b. 

As additional examples, we can first note the use of silylated serine or threonine for the addition of 2-phenylpropanal to vinylsulfone, giving the corresponding adduct in good yields (85-90%) but low ee (44-45%). As a second example, an aza-Michael reaction has been described with the ethyl methyl imidazolium salt of glycine as a catalyst. As a last example, the interest in tert-leucine can be noticed as it could act as a cocatalyst with a pyrrolidine bearing a thiopyridine. The ion-pair catalyst catalysed the domino oxa-Michael-Mannich reaction of salicylic aldehydes with cyclohex-2-enones. ... 

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. 

L-Threonine-derived catalysts were also found to be useful in direct asymmetric Mannich reactions. Lu and coworkers [43] demonstrated that O-silylated threonine... 

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