HOBt as an additive

It is not necessary to add HOBt as an additive to the coupling reaction when using HBTU activation. Microwave irradiation provides ample enhancement of the coupling efficiency to render the HOBt unnecessary. Also, it has been demonstrated that HOBt does not reduce racemization during the coupling reaction [11]. 

The problem of epimerization during carbodiimide-mediated coupling of amino acids can also be overcome by the use of an alternative coupling agent. Once such system that still employs HOBT as an additive involves the use of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) and N-... 

The DCC/HOSu proceduref l has been extensively apphed to fragment condensations in solution. In racennization-prone coupling steps this procedure was generally found to be superior to the DCC/HOBt method (see Section 3.5.1.2.2) even if HOBt (14) is more efficient as an additive in terms of acylation rates. 

It was found that addition of HOBt improves the efficiency of the BOP-mediated coupling, Therefore, HOBt is widely used as an additive (one equiv per equiv of reagent) in the case of BOP or PyBOP, as well as HOAt, when AOP or PyAOP are used. The cause of this effect is unknown, but it is worth noting that the addition of HOBt should result in a decrease in pH and thus in a decrease of the reaction rate. The usefulness of HOBt or HOAt as additives was recently questioned (see Table 2, entry 1 vs 2 and 4 vs 5). It is, however, established that these additives generally reduce epimerization in fragment coupling steps iyide infra and Table 1). 

Contemporary methods for sohd-phase couplings of peptide fragments are based on the use of phosphonium or uronium salts. HOBt was introduced as an additive with BOP, and more recently HOAt was used as an alternative in carbodiimide couplings instead of HOBt and shown to be more effective. Phosphonium and uronium salts of HOAt, namely PyAOP, HATU, and HAPyU, have also been used with success in CSPPS. 

A strategy based on silver-ion mediated selective activation of a C-terminal thiolcarboxyl group initially reported by Blake [48] was modified by Aimoto et al., employing the more oxidation- and hydrolysis-resistant thioester in place of thioacid and HOBt or 3,4-dihydro-3-hydroxy-4-oxo-l,2,3-benzotriazine (HOOBt) as an additive to facilitate the formation of the activated ester (Scheme 8) [49,143]. This activated ester-based coupling requires the protection of side-chains of Lys... 

Access to HOBt has been limited due to restrictions on air transportation. As an alternative, Oxyma can be used as an additive. Alternatively, the use of additives can be eliminated completely and HBTU can be used alone. Furthermore, other coupling reagent such as HATU or COMU can also be used. 

Related redox transformations allow the conversion of ynals to a,P-nnsaturated esters [33], as well as the ring expansion of formyl P-lactams [34], oxacycloalkane-2-carboxaldehydes [35], and 2-acyl-1-formyIcyclopropanes [36], Farther developments allow the synthesis of amides from a range of a-fnnctionalised compounds, but require an additive (imidazole, HO At or HOBt) for efficient amidation [37],... 

DCC or EDC with an additive This is probably the most common method of coupling segments, with HOBt and HOObt competing as the most efficient additives. HOAt may be on par with the other two. The additive is essential to reduce isomerization to acceptable levels (see Sections 2.25 and 2.26). An important variant is supplementation of the reaction mixture with a cupric ion that minimizes or eliminates isomerization by preventing any oxazolone that is formed from enolizing (see Section 7.2). 

Rovis and Vora sought to expand the utility in alpha redox reactions to include the formation of amides [116]. While aniline was previously demonstrated as an efficient nucleophile in this reaction (Scheme 29), attempts to develop the scope to include non-aryl amines as various primary and secondary amines resulted in low yields. The discovery of a co-catalyst was the key to effecting amide formation (Table 15). Various co-catalysts, including HOBt, HOAt, DMAP, imidazole, and pentafluorophenol, are efficient and result in high yields of a variety of amides including those involving primary and secondary amines with additional functionality. 

The utility of carbodiimide reagents was too important to consider abandoning them. Instead, it rapidly became obvious that carbodiimide activation could be used to prepare in situ active esters. Numerous nucleophilic additives were discovered and prepared for use in these reactions. The most important of these additives was 1,2,3-benzotriazol-l-ol (HOBt, 1), first reported for use in peptide synthesis by Konig and Geiger in 1970.[2(l As an example of a typical result, 1.2 equivalents of HOBt was added to the DCC coupling of Boc-Leu-Phe-OH to H-Val-OtBu in DMF as a solvent. Less than 1% of the l-d-l epimerized tripeptide was formed. When the reaction was carried out in the absence of HOBt, the amount of l-d-l product formed was 14.3%. Addition of HOBt to DCC reactions converts the intermediate G-acylisourea (2) (and any symmetrical anhydride) into the HOBt active ester 3 (Scheme 8). 

To the filtered resin after step 6, add a soln of Boc amino acid (2.0 mmol), BOP (884 mg, 2.0 mmol), and HOBt (306 mg, 2.0 mmol) in the minimum amount of solvent needed to mix the resin. Add DIPEA (0.39 mL, 2.0 mmol). Mix until the Kaiser test is negative. The procedure is similar for couplings mediated by HATU (1 mmol = 380.2 mg), but in this case the DIPEA should be increased to 4 mmol. Since BOP does not activate TFA for reaction, the entire procedure in Section 4.3.2.1.2.1 can be shortened even further by eUmination of a separate neutralization step (step 5). In this case the well-washed resin after TFA deprotection is treated directly with the coupling mixture, and DIPEA is increased to neutralize all TFA salts on the resin. If the Kaiser test does not rapidly become negative, an additional equivalent of DIPEA should be added. The fact that TFA can bind nonstoichiometricaUy to peptide backbones means that additional DIPEA may be needed in certain cases when this modification is used. A large excess of base should be avoided, as it can promote racemi-zation. 

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