Block coupling methods

Assuming that the diabatic space can be truncated to the same size as the adiabatic space, Eqs. (64) and (65) clearly define the relationship between the two representations, and methods have been developed to obtain the tians-formation matrices directly. These include the line integral method of Baer [53,54] and the block diagonalization method of Pacher et al. [179]. Failure of the truncation assumption, however, leads to possibly important nonremovable derivative couplings remaining in the diabatic basis [55,182]. 

The reaction of 5a-bromo-a-tocopherol (46) with amines was further elaborated into a procedure to use this compound as a protecting group Toe for amines and amino acids (Fig. 6.35).62 The protection effect was due to a steric blocking of the amino function by the bulky tocopheryl moiety rather than due to conversion into a non-nucleophilic amide derivative, and the Toc-protected amino acids were employed in the synthesis of dipeptides according to the dicyclohexylcarbodiimide (DCC) coupling method.64 The overall yield of the reaction sequence was reported to be largely dependent on the coupling reaction, since both installation and removal of the... 

The NCA coupling method is conceptually simple and elegant. This method is now used in efficient large scale production of peptides, for example for the preparation of semi-synthetic dipeptides Enalapril and Lisinopril (Ref. 247). The synthesis of Ala-Pro which is the key building block to synthesize Enalapril is diagrammed in scheme 195. 

Anionic-Cationic (Ion Coupling) Methods. Anionic-cationic termination reactions have been reported (57) to be useful in the synthesis of block polymers of the type THF-S and THF-S-THF (Reaction 13) ... 

Solid-phase coupling of protected peptide segments to one another generally does not proceed with nearly the facility of stepwise SPPS with protected amino acid building blocks [95,97]. Coupling methods are nominally the same, but because of solubility considerations and overall limits on achievable concentrations, reaction times are often on the order of hours or even days. As reaction times increase, so does the likelihood of racemi-zation, so special precautions must be taken to reduce this risk [41,118]. 

Vitamin A and the carotenoids are products of the terpene metabolism. Industrial manufacturing processes are based on modular building blocks. Universal methods to couple these building blocks are the Wittig reaction, the Horner-Wadsworth-Emmons reaction, the sulfone coupling according to Julia, the Muller-Cunradi enol ether condensation and the Saucy-Marbet rearrangement. 

Anionic-cationic polymerization n. A method of preparing multi-block copolymers using a combination of anionic and cationic) (ion coupling) methods. 

The overall synthetic strategy toward the tetrapeptide scaffold of telaprevir requires four key amino acid building blocks (45-49, Scheme 8), which can be coupled using standard peptide coupling methods. As in the synthesis of boceprevir, the P2 domain (48), which contains the bicyclic proline mimic, is the most synthetically challenging fragment of telaprevir, particularly in the context of a scalable route for commercialization. Likewise, the synthesis of the PI ketoamide domain (49) has required significant revision and optimization in the transition from discovery to process scale. 

Both the approaches described above, that is, substituting for boundary concentrations, or adding algebraic equations to express boundary conditions, can be applied to more complex mechanisms involving more than one species, including coupled systems. With the latter, there is probably not much to be gained by the block-matrix method, because of the number of coefficients on each line. 

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