Amino solid-phase synthesis

Then N-Boc-O-benzylserine is coupled to the free amino group with DCC. This concludes one cycle (N° -deprotection, neutralization, coupling) in solid-phase synthesis. All three steps can be driven to very high total yields (< 99.5%) since excesses of Boc-amino acids and DCC (about fourfold) in CHjClj can be used and since side-reactions which lead to soluble products do not lower the yield of condensation product. One side-reaction in DCC-promoted condensations leads to N-acylated ureas. These products will remain in solution and not reaa with the polymer-bound amine. At the end of the reaction time, the polymer is filtered off and washed. The times consumed for 99% completion of condensation vary from 5 min for small amino acids to several hours for a bulky amino acid, e.g. Boc-Ile, with other bulky amino acids on a resin. A new cycle can begin without any workup problems (R.B. Merrifield, 1969 B.W. Erickson, 1976 M. Bodanszky, 1976). 

We shall describe here one step in the total synthesis of a protected heptatetracontapep-tide ( = 47 amino acids) by K. Hofmann (H.T. Storey, 1972), and compare the techniques and the results with those of solid-phase synthesis. 

First, they compared CSPs 1 and 3 prepared by the two-step solid-phase methodology with their commercially available counterparts (CSPs 2 and 4) obtained by direct reaction of the preformed selector with a silica support. Although no exact data characterizing the surface coverage density for these phases were reported, all of the CSPs separated all four racemates tested equally. These results shown in Table 3-3 subsequently led to the preparation of a series of dipeptide and tripeptide CSPs 5-10 using a similar synthetic approach. Although the majority of these phases exhibited selectivities lower or similar to those of selectors built around a single amino acid (Table 3-3), this study demonstrated that the solid-phase synthesis was a... 

Fig. 24 Solid-phase synthesis of 5-carboxamido-iV-acetyltriptamine. Reagents and conditions a piperidine 20%, DMA, rt, 60 min b 4-amino-3-iodo-benzoic acid, TBTU, HOBT, NEt3, DMAP, dioxane, MW 45 W, 3 min, 100%, open vessel c N-(4-Trimethylsilanyl-but-3-ynyl)-acetamide, Pd(OAc)2, PPhs, LiCl, NaOAc, DMA, MW 60 W, 2x13 min, 100%, open vessel d NIS, CH2CI2, MW 60 W, 14 min, 100%, open vessel e cleavage, TFA, 20%, CH2CI2, rt...

The amino acid 58 was used in the solid-phase synthesis of sequence-specific DNA binding polyamides containing N-methylimidazole and N-methylpyrrole amino acids <96JACS6141> and it was also reported that the imidazole-acridine conjugate 59 could effectively catalyze the cleavage of t-RNA <96TL4417>. 

Baird, E.E. and P.B. Dervan. Solid phase synthesis of polyamides containing imidazole and pyrrole amino acids./. 

WvRTZ, N.R., J.M. Turner, E.E. Baird, and P. B. Dervan. Fmoc solid phase synthesis of polyamides containing pyrrole and imidazole amino acids. Org. Lett. 2001, 3, 1201-1203. 

Thus, an effective solid phase synthesis of aPNA 21-mers was successfully developed. The resulting SPPS protocols can be applied to aU four nucleoamino acids as well as a variety of ancillary amino acids leading to diverse aPNAs structures. 

The techniques for automated solid phase synthesis were first highly developed for polypeptides and the method is abbreviated as SPPS. Polypeptide synthesis requires the sequential coupling of the individual amino acids. After each unit is added, it must be deprotected for use in the next coupling step. 

Phenylfluoren-9-yl polystyrene (Phfl) based resin 49 was applied in the solid-phase synthesis of hydroxyl and amino functions [57,58]. This resin has higher acid stability compared to the structurally similar trityl resin. Final release of the product is accomplished with TFA in high purity (Scheme 19). 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

Fitzpatrick LJ, Rivero RA. Solid phase synthesis of substituted amino-sulfonylureas using a sulfonylcarbamate linker. Tetrahedron Lett 1997 38 7479-7482. 

A-Acetylimidazole was found to be a very efficient terminating (capping) agent in the solid-phase synthesis of peptides.t40],[41] A terminating agent is used to block any N-terminal amino groups that have not reacted in the coupling steps.[40]... 

Recently, a solid-phase synthesis was used iteratively for the synthesis of organic substances like oligocarbamates [13] and oligoureas [14] by repeated coupling to amino-functionalized supports. In this way substance libraries [15] have been developed showing that iterative methods can also be employed in combinatorial chemistry [16]. 

A novel ring opening reaction of isoxazoles led to the formation of functionalized pyrroles <06S1021>. For example, treatment of isoxazole 52 with DBU led to the formation of pyrrole 53. A solid-phase synthesis of 3-amino-2,5-dicarboxylates was accomplished by transformation of pyrrol-3-one 54 <06JCC177>. The reaction between 54 and secondary amines led to the corresponding resin-bound aminopyrroles after enamine formation and loss... 

Table 13 Solid-phase synthesis of substituted 5-amino-1,2,4-triazole derivatives (Scheme 3)...

A systematic replacement of any amino acid in the sequence for photoreac-tive analogues allows a photoaffinity scanning of the binding interface. Since solid-phase synthesis is limited in the length of the peptide, Schultz et al. developed a sophisticated method which makes it possible to incorporate unnatural amino acids into large peptide sequences. The photoreactive amino acid was linked to transfer RNA, which inserted the amino acid into the required position by in vivo translation [44]. 

The major requirements for photoactivatable amino acids are that they should exhibit high optical purity and contain appropriate protecting groups for solid-phase synthesis there is also a particular advantage if they contain the radiolabel. While p-azido-phenylalanines can easily be labeled with 125I and... 

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