Peptide derivatives halogenation

Amino acids with appropriate (3-substituents have frequently been employed as DHA precursors, particularly in the form of peptide chain subunits. Most commonly used derivatives for such elimination reactions are (3-hydroxy- and (3-sulfanyl-a-amino acids. Amino acids with (3-halogen substituents 57-9" are also used, but these require more drastic elimination conditions and, therefore, are not preferred. Mannich bases of monoalkyl acylamino mal-onates have also found use as precursors of AAla derivatives. 91,92 The major advantage of this approach is that the elimination reaction can be carried out as the final step in the synthesis of unsaturated peptides. 

C-Terminal ketone derivatives of peptides have been used as effective inhibitors for a variety of proteases including serine, cysteine, and aspartyl proteases. 271 This class of peptides includes diazomethyl ketones (Section 15.1.2), halomethyl ketones (Section 15.1.3), and fluoromethyl ketones (Section 15.1.4). In general, the A -amino group and side chain must be protected. The diazomethyl ketones serve as good intermediates for conversion into chloromethyl and bromomethyl ketones. Fluoromethyl ketones, the most widely known class of peptide haloketones, can also be prepared from diazomethyl ketones or by halogen-exchange reactions. Other methods for the synthesis of fluoromethyl ketones are described in Section 15.1.4. 

Fluoromethyl ketones are one of the most widely used classes of peptidyl a-fluoroalkyl ketones, second only to trifluoromethyl ketones. Peptidyl fluoromethyl ketones are very effective as irreversible inhibitors of cysteine proteases the first reported use of a fluoromethyl ketone compound was the use of Z-Phe-Ala-CH2F as an irreversible inhibitor of cathepsin BJ2,31 Today, many lysine and arginine derivatives have been synthesized as potential inhibitors for trypsin and trypsin-like enzymesJ3 There are four basic methods for the synthesis of peptide fluoromethyl ketones (1) the reaction of HF with peptide diazomethyl ketones (Section 15.1.4.1.1), (2) a halogen-exchange reaction with a chloro-, bromo-, or iodomethyl ketone (Section 15.1.4.1.2), (3) a Henry nitro-aldol condensation reaction (Section 15.1.4.1.3), and (4) a modified Dakin-West acylation reaction (Section 15.1.4.1.4). 

Protection of carboxyl groups. The deblocking reaction discussed above with 2 is also applicable to a halogenated protected derivative of the terminal carboxyl group of peptides. The N-protected amino acid is converted by the Passerini reaction with an o-halo aldehyde into a protected derivative such as 4. The derivative is cleaved by reiietion with 2 at 20° in acetonitrile or methanol (equation III). 

In order to determine the degree and rate of consumption of NBS by other functional groups in a peptide chain, a number of amino acids and their derivatives were treated with NBS, the disappearance of positive halogen being followed by thiosulfate titration. As summarized in Table... 

In terms of stability in the repetitive N -deprotection steps required for the synthesis of larger peptides and proteins, only the Z group and particularly its halogenated derivatives are compatible with the Boc/Bzl strategy for N -protection, while among the other groups discussed in Section 2.1.1.1.1, the Fmoc, Teoc, Msc, and particularly Aloe groups have found application in terms of an additional level of selectivity as required in special cases for postsynthetic site-specific chemical manipulations of the peptide chain on resin or in solution. 

The selective halogenation of glycine residues in peptides is demonstrated by the bromination of the derivatives of valylglycine 17a, glycylvaline 18a, and the cyclic dipeptide 19a to give only the corresponding bromides 17b, 18b and 19b [29, 30]. This selectivity can be exploited in combination with the other effects discussed... 

Not only was it possible to prepare the acid chloride of a halogen acyl derivative of an amino acid, but also that of a di-, tri-, etc., peptide by exactly the same means. Thus, the compound bromisocapronyl-diglycyl-glycyl chloride can be obtained, and by condensing it with the esters of amino acids and of polypeptides Fischer has prepared a hexa-, a hepta-, and a deca- peptide (see tabulation). 

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