Coupling racemization-free

S Pass, B Amit, A Parchomik. Racemization-free photochemical coupling of peptide segments. (Fmoc-amino-acid chlorides) J Am Chem Soc 103, 7674, 1981. 

Indeed, there were those who described the azide coupling method as racemization-free. [15l However, this viewpoint proved to be overly optimistic. In 1970, Sieber reported that during a synthesis of calcitonin M by the azide method, significant epimerization occurred during two of the segment condensation steps in one of these reactions 40% of the epimerized product was observed. 16 There is a crucial detail in the experimental procedure here. The workers used tert-butyl nitrite to convert a peptide hydrazide into a peptide azide, but did not isolate the azide as was typical for research at that time. Instead, they neutralized the active intermediate in situ with DIPEA and added the amino segment for acylation. This demonstrates another important theme in the control of epimerization, the presence of a tertiary amine in the reaction mixture, even if only as a neutralization equivalent, can result in the formation of epimerized products. Indeed, most observations of racemization during... 

Pass, S., Amit, B. and Patchornik, A. (1981) Racemization - free photochemical coupling of peptide segments. Journal of the American Chemical Society, 103, 7674-7675. 

We have also developed a chemistry that allows us to attach the Fab to only the inner surfaces of the nanotubes. While still within the pores of the template membrane, the inner surfaces were treated with 3-aminopropyltrimethoxysilane. The template membrane was then dissolved and the amino sites on the inner surfaces were coupled to free amino groups on the Fab fragment using the well-known glutaraldehyde coupling reaction [4]. When 18 mg of these interior-only Fab-modified nanotubes were incubated with 1 mL of a 10 pM racemic mixture of the drug, 80% of the RS (and none of the SR) enantiomer was extracted. 

Hydrolyzing enzymes, especially proteases, constitute an alternative to chemical synthesis. The principal advantages are the use of unprotected side chain amino acids (except cysteine), racemization-free couplings (especially in fragment couplings) and the specificity of the involved enzyme. As a consequence, the number of synthetic steps is drastically reduced and the procedures are environmentally safe. 

DECP is an efficient and valuable reagent for amide formation, and both aliphatic and aromatic acids react with aliphatic and aromatic amines. In combination with EtjN, DECP is a coupling reagent for the racemization-free peptide synthesis in DMP, CH2CI2, or THE with excellent yields.359-378 -dso useful for solid-phase peptide synthesis in both the stepwise and fragment-... 

Coupling of amino acids with a-amino esters. This coupling to peptides can be effected with the phosphinatc (1 equiv.) and diisopropylethylaminc in DMF at 25°. Yields are generally >90%, and the reaction is racemization free. The reagent can also be used for solid-phase peptide synthesis. 

DEPC serves as a coupling agent for the synthesis of simple amides, esters, a-aminonitriles, and aryl thiocyanates it is also used as an efficient coupling agent for racemization-free peptide synthesis. Amides of various types can be obtained by the simple mixing of carboxylic acids and amines with DEPC in the presence of triethylamine. Both aromatic and aliphatic acids easily react with aromatic and aliphatic... 

Sewald. N. Efficient, racemization-free peptide coupling of A-alkyl amino acids by using amino acid chlorides generated in situ. Total syntheses of the cyclopeptides cyclosporin O and omphalotin A. Angew. Chem. Int. Ed. Engl. 2002. 41, 4661-4663. 

Besides the extensive applications of the Lawesson s reagent as already mentioned, this reagent has been used to synthesize many five- and six-membered phosphoms heterocycles, and sulfur-containing heterocycles in addition, this compound has also been used as the racemization-free coupling reagent in peptide synthesis, and the 1,3-dipole indicator. ... 

Among his many excellent coworkers Wolfgang Konig (Plate 20) also a student of F. Weygand, is mentioned here because of his large share in the development of racemization-free coupling methods. 

Scheme 3.9 Racemization-free coupling of (R)-3-amino pentane nitrile [66, 201-203].

Modern coupling agents such as BOP, HBTU, TBTU, and HATU are well suited for the racemization-free coupling of amino acids. These reagents were tested in various solvents during the condensation of the resin-bound prOthymosin a (ProTa) 95-109 fragment with Fmoc-ProTa(87-94)-OH which contains Glu(tBu) as the C-terminal amino acid (Figure 2). The 70-90%... 

Use as a Protecting Group for Nitrogen. Vedejs, who showed that benzothiazole-2-sulfonyl-aminoacids (Bts-aminoacids) could readily be converted to their acid chlorides without racemization, pioneered the use of the Bts group for the protection of amino acids. The acid chloride of Bts-protected amino acids were found to be effective for racemization free peptide couplings. The sulfonamide is readily prepared using... 

Bis-4-(2,2-dimethyl-l,3-dioxolyl)methyl carbodiimide (BDDC) 1034, a usefrd reagent for racemization-free esterifications, peptide couplings, and dehydration, has been prepared via the symmetrical urea 1033 by a reaction sequence involving an amine phosgmation [758]. 

The use of triphosgene as an acid activator has been reported in several recent applications. Eckert and Seidel activated the N-protected amino acid Tcboc-valine 1351 (Tcboc = 2,2,2-trichloro-fert-butyloxycarbonyl [1022] for a preparation, see also Section 4.3.2.1) with triphosgene/DMF/TEA for racemization-free coupling with valine benzyl ester to afford Tcboc-Val-Val-OBn in 85% yield [1023, 1024]. 

Racemization-free, triphosgene-mediated coupling in the solid phase was recently used by Them and Jung in a total synthesis of the nematicidal cyclododecapeptide Omphalotin A 1359 [1029]. 

Because of the convincing results even in penicillin chemistry, due to the smooth reaction conditions, carbodiimides and particndarly DCC became common coupling reagents in natural compound and peptide chemistry. In combination with binucleophiles, such as N-hydroxysuccinimide or N-hydroxybenzotriazole, the method is racemization-free [1248]. Other frequent applications are in esterifications and general dehydration reactions, and, more recently, in carbodiimide-mediated multicomponent reactions [1251] (see Section 4.S.3.5). All these reactions proceed through activated intermediates 1689. Thus, compounds with a carboxylic function 1688 can be coupled with a nucleophilic compound 1690 to afford the coupled product 1691 under extremely mild conditions. The resulting by-product dicydohexylurea 1693, however, is difficult to separate because of its ambivalent solubility properties, which usually complicate the whole work-up procedure. 

One great merit of the conventional solid-phase peptide synthesis has been its virtual freedom from racemization. With DCC or active esters coupling, virtually racemization-free products are obtained. As a test case, Bayer et al. (1971b) carried out the solid-phase peptide synthesis of a model dodecapeptide (LLeu-LAla)e. After the peptide was completely hydrolyzed, the resulting amino acids were analyzed for racemization by gas chromatography. No detectable recemization occurred. 

---