Serine silylation

To effect A -tritylation of serine, Me2SiCl2 should be used in the silylation step. 

An interesting example from carbohydrate chemistry is the boron trifluoride-diethyl ether complex catalyzed nucleophilic addition of silyl enol ethers to chiral imines (from n-glyceralde-hyde or D-serinal)22. This reaction yields unsaturated y-butyrolactones with predominantly the D-arabino configuration (and almost complete Cram-type erythro selectivity). 

N -Fmoc serine benzyl ester 2, which could be prepared as shown or purchased commercially, was smoothly converted to the crystalHne O-methylthiomethyl (MTM) ether 3 in high yield via a Pummerer-Hke reaction using benzoyl peroxide and dimethyl sulfide in acetonitrile [39]. This common intermediate was used to synthesize both 5 and 8 [40]. Both Ogilvie [41] and Tsantrizos [42] had reported that I2 was an effective activator with similar MTM ether substrates. The H promoted nucleosidation reaction between O-MTM ether 3 and bis-silylated thymine 4 produced the nucleoamino acid 5 in 60% isolated yield (100% based on recovered 3). Hydrogenolytic deprotection of the benzyl ester with H2, Pd/C in MeOH gave the thymine-containing nucleoamino acid 6 in quantitative yield. 

Silyl-derived linker 36 was prepared in three steps from a silyl ether of serine and incorporated for Fmoc/tBu-based assembly of protected gly-copeptide blocks (Scheme 11) [42]. The a-carboxylic acid function of serine was protected as an allyl ester. Deprotection by a Pd(0) catalyst in the presence of dimedone liberated the carboxylic acid in order for subsequent... 

Silyl esters have also been transformed successfully [137] another example reports the O-acylation of serine with a /l-alkynyl carboxylic acid anhydride accompanied by an in situ isomerization of the alkyne to the allene [138],... 

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 octitol derivative 184 has been prepared via BF3 etherate-promoted addition of (R)-y-OTBS allylic stannane (i )-181 to enal 180 derived from L-serine (O Scheme 69) [319]. This leads to a single i yw-adduct 182 which is converted to the silyl ether 183. This compound... 

Hydroxyl (serine) and sulfhydryl groups (cysteine) are also silylated. These derivatives can be used in peptide synthesis by the phosphoryl chloride, imidazole, mixed anhydride, or p-nitrophenyl ester methods. An attractive feature is that the silyl groups are removed merely by treatment with water in the normal workup. Trimethylchlorosilane is not suitable because of the amphoteric nature of the amino acids. 

The linker was prepared starting from serine benzyl ester 68 according to Scheme 30. First, the hydroxyl function was protected as a silyl ether. The amino group was then reacted with phosgene to allow for further reaction with a substituted phenol (the educt). Finally, the benzyl ester was subjected to hydrogenolysis yielding unit 69, with the latter bearing a carboxylic acid function for attachment to the solid support to yield 66 ready for use in combinatorial synthesis. 

Recently, it has been shown that nucleophilic addition of neat dimethyl trimethylsilyl phosphite to serine-derived P-lactonc at I ()() C for 24 h leads specifically to the carboxylic trimethylsilyl ester by preferential transfer of the trimethylsilyl group. A simple aqueous workup induces hydrolysis of the silyl ester to give the N- and P-protected free carboxylic acid ready for activation and coupling. 

Preparation of the chiral oxazolidine-aldehyde 64 from D-serine 59 required various steps, including conversion into the silyl ether 60, reaction with ketone 61 to provide oxazolidine silyl ether 62 and subsequent desilylation of the tert-butyldiphenylsiloxy group. Oxidation of the hydroxy functionality and hydrogeno-lytic cleavage of the benzyl ester then gave the corresponding aldehyde 63. The acid functionality of 63 was then coupled to aminomethylated Merrifield resin (Scheme 12.26). 

Aldol reaction has a new list of chiral catalysts, and they include 61, 62, and 63. The presence of a hydrophobic silyl group to mask the hydroxyl residue of serine in 63 is important, L-serine itself being inactive is an indication. 

The DL-serine uracil derivative 580 was prepared from OL-serine methyl ester hydrochloride by V-benzoylation to give 578 chloromethylation gave 579, which then was substituted by the silylated uracil (88ZOB2404). 

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. ... 

Oxazoline Fragmentation. As shown in eq 52, a serine-derived oxazoline can be reacted with TMS-Br to produce N N)-protected -halogeno a-amino esters. This reaction is achieved with TMS-Br which first A -silylates the oxazoline. This renders the /3-carbon of the Q -amino ester susceptible to nucleophilic attack by the bromide anion. The attack of the halogen anion leads to ring opening of the oxazoline and generation of the A-protected /3-bromoalanine derivative. 

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