Deprotection/activation

Such biosyntheses were models for the Merrifield-synthesis [8] (Fig. 3), which culminated in the development of fully automated peptide synthesizers [9]. In a repeated reaction cycle a N-terminal protected amino acid, which is attached with its C-terminal end to an insoluble solid support, is deprotected, activated and lengthened by a second protected amino acid unit. The deprotect -ing and coupling steps can be repeated until the entire peptide is assembled. 

The combination of pept(o)id-introducing MCRs with subsequent and efficient post-condensation transformations, especially ring-closing protocols, is an efficient concept to produce (cyclic) pseudopeptides. The most important versions make use of protected or convertible functional building blocks to allow later condensation, specially cycfization. Most relevant are Ugi-deprotection-cyclization (UDC), Ugi-activation-cyclization (UAC), and the Ugi-deprotection-activation-cycfization (UDAC), which take advantage of the diverse functionalities incorporated into the previously synthesized MCR-adduct as bi- or polyfunctional building block (Fig. 3) [15, 16]. 

Scheme 18 Synthesis of cyclodepsipeptides by a domino MCR/deprotection/activation/cycliza-tion strategy...

For the synthesis of bombyxin IV (53) 192 regioselective formation of three disulfide bonds was achieved by exploiting the differentiated acid-stability of the 5-Trt vs the 5-tBu protection in 49 that allowed the air-mediated intramolecular disulfide formation in the A-chain (Scheme 23). For subsequent activation of the third cysteine residue from the precursor S-tBu derivative the rather drastic conditions of TfOH/TFA (1%) were applied in presence of di(2-pyridyl) disulfide which despite the strong acidity allowed a concomitant deprotection/ activation of this residue to give 50. Subsequent reaction of 50 with the B-chain derivative 51 established the intrachain heterodisulfide cross-link in 52 which on oxidation gave bombyxin IV (53). 

The coexistence of the two groups that participate in the amide bond formation on the same molecule implies that protection of one of the groups during the coupling process and subsequent deprotection-activation process are also necessary [153] Nevertheless, as the protected groups are always identical, the chemistry of protection-deprotection may also be sequence independent. 

While orthogonal protecting groups for the aspartic acid side chain are available (40, 63, 66), at least two synthetic steps are required for deprotection, activation and coupling, which potentially lowers overall reaction yields. The... 

During multiple repetitions of protection/deprotection, activation and separation steps, simplifications can, in principle, be introduced by either canceling or combining certain steps. This is the basis of solid-support preparations (see Chapters 2,3, and 4), but it also leads to simplifications of the conventional solution-phase synthesis. Such procedures, which can be classified as unconventional, will be summarized in this section. 

More recently, Fei and coworkers have employed the Ugi/deprotection/activation/ cyclization strategy for their synthesis of DKPs 191 using CIC IW3 (Scheme 7.66) [74] Anhydrous HCl, which forms in situ, helps deprotect the Boc group and activates the amide carbonyl group derived from IW3. 

Fig. 23. Representative protecting groups for phenolic and carboxylic acid-based systems, (a) The polymer-based protecting groups are fisted in order of increasing activation energy for acid-catalyzed deprotection, (b) Acid-labile monomeric dissolution inhibitors, a bifunctional system based on protected bisphenol A. (c) Another system that combines the function of dissolution inhibitor and PAG in a single unit.

The efficiency of this method was demonstrated by the elegant two-step synthesis of aspartame [87], Protection of the a-amino group and activation of the a-carboxylic group are accomplished in only one step Deprotection of the amino functionality occurs during aminolysis, such as with methyl phenylalaninate (H-Phe-OMe in equation 15)... 

The cleavage of this group proceeds by initial reduction of the sulfoxide, which then makes the resulting methylthiobenzyl ether labile to trifluoroacetic acid. Thus, any method used to reduce a sulfoxide could be used to activate this group for deprotection. 

A facile way of promoting the cyclization is to increase the nucleophilicity of the aryl system when possible. In the total synthesis of diazadiquinomycins A and B, for example, the authors were able to effect a double Knorr cyclization with concomitant in situ oxidation to the internal diquinone 23 by deprotecting the hydroquinone thereby lowering the activation barrier for the desired transformation. If the hydroquinone is left protected as the di-MOM ether, the reaction does not take place. ... 

The methoxy derivative 536, prepared from the aminoquinolone, was transformed into 537. Selective hydrolysis of 537 gave 538 which was treated with COCI2 followed by MeONH2 HCl to afford 539 that was cyclized upon treatment with PhI(OCOCF3)2 to give 540. Deprotection with K2CO3 afforded 541 which had central nervous system activity (95WOP9504056) (Scheme 91). 

Spirapril (37) is a clinically active antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared fkim l-carbobenzyloxy-4-oxopro-line methyl ester (33) by reaction with ethanedithiol and catalytic tosic acid. The product (34) is deprotected with 20% HBr to methyl l,4-dithia-7-azospiro[4.4 nonane-8-carboxylate (35), Condensation of this with N-carbobenzyloxy-L-alanyl-N-hydroxysuccinate leads to the dipeptide ester which is deblocked to 36 by hydrolysis with NaOH and then treatment with 20% HBr. The conclusion of the synthesis of spirapril (37) follows with the standard reductive alkylation [11]. 

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