Fmoc-protected alanine

The abihties of the tube-in-tube design was further expanded by Buba et al. (2013EJOC4509). For the synthesis of the oxazolidinone 36, formaldehyde was used in the gaseous state by heating paraformaldehyde to 80 °C. The tube-in-tube reactor needs to be kept at a temperature higher than 80 °C to prevent polymerization and subsequent precipitation of paraformaldehyde onto the membrane surface. Formaldehyde reacted with Fmoc-protected alanine 35 in the presence of a catalytic amount ofp-tolue-nesulfonic acid in acetonitrile to achieve N-Fmoc-L-4-methyl-oxazohdin-5-one 36 in excellent yield (91% Scheme 9) (2013EJOC4509). 

In 2004, Podlech and coworkers have reported some further advances in the photochemical treatment of Fmoc-protected diazoketones A and B, (Scheme 76), derived from leucine and alanine, respectively, with /V-(benzylidene)glycine and leucine methyl ester to produce a mixture of the corresponding diastereomeric trans-substituted p-lactams [175],... 

Coupling of the free amino derivative with Fmoc protected commercially available amino acids (alanine and phenylalanine) was accomplished via standard reaction conditions activated by DCC in anhydrous tetrahydrofiiran (THF) solution. Deprotection of synthesized peptides by treatment with aqueous methanol solution and catalytic amount of trimethylamine produced a new class of 5-thio-carbo peptides in 86% yield. This particular family of new stable peptidomimetics is conveniently protected and could be used for further additional functionalization at the primary -OH at C-6 of the thioglucose moiety. Further deprotection of the 1,2-0-isopropylidene block created another... 

Finally, using 4-deoxy-(l-5)-5-C-thiodisaccharide (6) previously synthesized in our laboratory as a starting template via conversion into amino derivative) after selective deprotection of 2-acetamido function at -C-2, we synthesized a third family of strategically important peptidomimetics. Again, coupling with Fmoc protected amino acids (alanine and phenylalanine) under the same reaction condition as before produces S-thio-peptides in 86% yield. Deprotection of the above target derivatives through standard aqueous methanol/triethylamine solution produces pure and stable derivatives. 

Figure 10.9 Synthetic scheme of A/-Fmoc-protected olefin substituted alanine.

C-Terminal cysteine residues linked via ester bonds to the solid support suffer extensive epimerization in the repetitive piperidine-mediated Fmoc cleavage steps of SPPS.P Moreover, p-elimination occurs to some extent from the S-protected cysteine residues with formation of dehydroalanine that reacts with the excess piperidine to form -(piper-idino)alanine as an adduct.These cysteine-related side reactions are thoroughly discussed in Section 2.6.6. 

In addition to the problems of racemization of S-protected cysteine residues during both their anchoring to hydroxymethyl-type resins and formation of peptide bonds (see Section 2.6.6.2), the synthesis of C-terminal Cys(Acm)-containing peptides using Fmoc/tBu chemistry has been observed to produce peptides with C-terminal P-(l-piperidyl)alanine (see Section 2.6.6.2).t l This type of side reaction can be reduced by nninimal exposure to piperidine, but it can not be suppressed completely. 

Burke. T.R., Jr., Smyth, M.S., Otaka, A., and Roller, P.P., Synthesis of 4-phosphono(difluoromethyl)-D.L-plieiiy I alanine and A-Boc and 7V-Fmoc derivatives suitably protected for sohd-phase synthesis of nonhydrolysable phosphotyrosyl peptide analogues, Tetrahedron Lett., 34, 4125, 1993. 

However, the chromophore in the DMB linker proved to be too sensitive to light, so a dithiane-protected structure, introduced by Chan [35] and Balasubramanian, was used to employ a safety-catch strategy. Using this strategy, peptides could be anchored to the linker by a C-terminal ester bond [36] or by an N-terminal carbamate bond [37] (Scheme 17.10). In a Fmoc-alanine releasing test, the dithiane was deprotected using methyl triflate or periodic acid, and photocleavage resulted in a 92% yield of Fmoc-Ala after 2 h. 

As previously mentioned, Cys is susceptible to a number of side reactions that should be considered before a synthesis. Peptides that have a C-terminal Cys can undergo elimination of the sulfhydryl protected side chain in both Boc and Fmoc SPPS [96,97]. In the latter case 3-(l-piperidi-nyl)alanine is known to form [97]. This has been noted for Cys(Bzl) in Boc SPPS [96] as well as Cys(Acm) and Cys(Trt) in Fmoc SPPS and is dependent on the solid support, the linker, and the side-chain protecting group... 

In a comparison of Cys(Acm) and Cys(Trt), elimination occurred more readily with Acm protection than with Trt protection [97]. A side reaction at the C-terminal residue has also been observed for Cys(SrBu) and is presumably the formation of the pipeiidiny 1-alanine adduct [98,99]. Esterification of Cys to a solid support and standard preactivation and Fmoc deprotection protocols used in Fmoc SPPS tend to result in racemization [83,84,100,101]. 

Watts et al. demonstrated multi-step solution-phase synthesis of peptides in a glass microreactor with quantitative yield in 20 min [94]. This should be compared with batch reactions where only moderate yields (40-50%) were obtained in 24 h. Common protecting groups were used, viz. Fmoc was selected for N-protection and Dmab ester for protection of the carboxylic add. The reaction was carried out in the microreactor under electroosmotic flow. Deprotection, which is required to extend the peptide chains beyond dipeptides, was also demonstrated with quantitative yield in the microreactor. In this first microreactor demonstration, only alanine-based peptides were synthesized in later work other amino acids were also used ]95, 96]. 

The incorporation of (Hmb)amino acid residues is conveniently achieved through 1-hydroxybenzotriazole activation of the Af,0-bis(Fmoc)-N-(Hmb)-protected pentafluorophenyl esters (Figure 4a). A number of groups have recently described the successful use of the N -Fmoc-iV-(Hmb)-amino acid derivatives (54, 55) in the synthesis of diflicult peptides. However, we have previously found that the monoFmoc derivatives of residues other than glycine or alanine couple slowly to resin-bound peptide chains (56). The slow coupling of these species is attributed to the formation of a relatively low... 

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