Difficult couplings

With these simplifications, and with various values of the as and bs, van Laar (1906-1910) calculated a wide variety of phase diagrams, detennining critical lines, some of which passed continuously from liquid-liquid critical points to liquid-gas critical points. Unfortunately, he could only solve the difficult coupled equations by hand and he restricted his calculations to the geometric mean assumption for a to equation (A2.5.10)). For a variety of reasons, partly due to the eclipse of the van der Waals equation, this extensive work was largely ignored for decades. 

E Falb, T Yechezkel, Y Salitra, C Gilon. In situ generation of Fmoc-amino acid chlorides using >/s-(trich loro methyl (carbonate and its utilization for difficult couplings in solid-phase peptide synthesis. J Pept Res 53, 507, 1998. 

M. Deber, M. K. Lutek, E. P. Heimer and A. M. Felix, Conformational origin of a difficult coupling in a human growth hormone releasing factor analog, Peptide Res., 1989,2, 184-188. 

This method has been applied preferentially to proline derivatives as coupling partners for the acid chlorides. The relatively strong activation of these intermediates may recommend them for the generally difficult coupling with secondary amines, as is the case with amino acid chlorides in the peptide series. 

Less reactive than acyl halides, but still suitable for difficult couplings, are symmetric or mixed anhydrides (e.g. with pivalic or 2,6-dichlorobenzoic acid) and HOAt-derived active esters. HOBt esters smoothly acylate primary or secondary aliphatic amines, including amino acid esters or amides, without concomitant esterification of alcohols or phenols [34], HOBt esters are the most commonly used type of activated esters in automated solid-phase peptide synthesis. For reasons not yet fully understood, acylations with HOBt esters or halophenyl esters can be effectively catalyzed by HOBt and HOAt [3], and mixtures of BOP (in situ formation of HOBt esters) and HOBt are among the most efficient coupling agents for solid-phase peptide synthesis [2]. In acylations with activated amino acid derivatives, the addition of HOBt or HOAt also retards racemization [4,12,35]. 

For the solid-phase synthesis of amides, it makes a significant difference whether the amine or the acid is linked to the support. Resin-bound amines are readily acy-lated by adding first a carboxylic acid and then a carbodiimide (Table 13.3). The acid/ carbodiimide ratio is not critical, because both the O-acylisourea (ratio 1 1) and the symmetric anhydride (ratio 2 1) will lead to N-acylation. It should, however, be borne in mind that the half-lives of O-acylisoureas are shorter than those of anhydrides, and for difficult couplings it might be advantageous to acylate with a symmetric anhydride (two equivalents of acid and one of carbodiimide). 

The effectiveness of KCN in promoting difficult couplings can be further shown in the reaction of a-amino a-branched p-lactams with a-amino esters [90]. 

The Ugi four-component reaction can frequently offer an interesting alternative to the difficult coupling between secondary amines and carboxylic acids when using traditional methods for amide bond formation. Guided by this premise, Armstrong and co-workers efficiently synthesized the N-methylated dipeptide 245 en route to motuporin 241 (Scheme 12.35) [124], an inhibitor of protein phosphatases [125]. 

For difficult couplings, as in the case of sterically hindered amino acids or peptide derivatives, it is advantageous to add catalytic amounts of DMAPt or 4-pyrrolidinopyr-... 

Forecast centers in the Baltic area mainly use the WAM model or modified versions, the Swedish Meteorological and Hydrological Institute (SMHI) uses the Hybrid Parametrical Shallow Water model HYPPAS (Gunther et. al., 1979). This model type presumes a char-acterisitc shape of the wind sea spectrum (JONSWAP spectrum, 7.10) as a result of the nonlinear wave interactions, and therefore the difficult coupling source term in the balance equation is omitted. 

Sometimes the coupling reaction of an activated carboxy group and a deprotected amino group is difficult to accomplish. These difficult couplings are usually sequence-dependent and not residue-specific. In these cases, a double coupling is required (i.e., repeat step 5-6 before step 7). 

Of all tandem methods, SFE-HPLC is the most difficult coupling system to use. The main reason lies in linking a separation step at high pressure and generating a gas in the interface with a chromatographic technique, which commonly works under lower pressure and uses a liquid as a mobile phase. For this reason, in most applications, the analytes are collected offline and later analyzed by HPLC. SFE-HPLC has been performed for only a few specific applications. " ... 

The first use of a polymer-supported Mukaiyama reagent for microwave-mediated synthesis of amides was presented in 2004 [125]. To prove its effectiveness, even in difficult coupling reactions, it was used in the microwave-accelerated synthesis of an amide from sterically hindered pivalic acid (Scheme 16.83). The mixture was subjected to microwave irradiation at 100 °C for 10 min and the desired product was obtained in 80% yield. 

During normal synthesis this may not be apparent as a significant problem, because the coupling reaction will occur before substantial y-lactam formation occurs. In a difficult coupling reaction, however, y-lactam formation may become more favorable than coupling. In these circumstances, extending the reaction time will not promote completion of the coupling. This was shown recently with the mi-... 

The combination of a chromatographic technique with mass spectrometry (MS) provides a powerful analytical tool. This is evidenced by the dominance of GC-MS as the method of choice in volatile mixture analysis. The difficult coupling of HPLC with mass... 

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