Acidolysis deprotection

In order to design syntheses of complex peptides containing several functional side chains, it is necessary to have a variety of methods of protection and deblocking at disposal. Therefore, it was a major step forward when in addition to reduction and acidolysis deprotection with weak bases, under mild conditions, became a practical possibility. The 9-fluorenylmethyloxycarbonyl (Fmoc) group (Carpino and Han 1970) is removed from the amino group by proton abstraction with secondary amines. A carbamoic add is generated, that, in turn, loses carbon dioxide and affords the free amine ... 

FIGURE 3.5 Deprotection of functional groups by acidolysis.5 Protonation followed by car-bocation formation during the removal of benzyl-based protectors by hydrogen bromide. Two mechanisms are involved in generating benzyl bromide from the protonated substrates. 

DEPROTECTION BY ACIDOLYSIS ferf-BUTYL-BASED PROTECTORS... 

FIGURE 3.6 Deprotection of functional groups by acidolysis. Protonation followed by carbocation formation during the removal of ferf-butyl-based protectors by hydrogen chloride.8 One mechanism is involved in generating the ferf-butyl cation, which is the precursor of two other molecules. 

JR McDermott, NL Benoiton. JV-Methylamino acids in peptide synthesis. III. Racemization during deprotection by saponification and acidolysis. Can J Chem 51, 2555,... 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

The popular acids for deprotection by acidolysis are hydrogen fluoride for benzyl-based protectors and trifluoroacetic acid for rerr-butyl-based protectors. The use of hydrogen fluoride for deprotection emerged from the observation that it is a good solvent for dissolving enzymes (because of the N-to-0 acyl shift see Section 6.6), and that the enzymatic activity is recovered (O-to-N acyl shift) in saline solution. Two different approaches are employed for removal of benzyl-based... 

O-Acylated Hmb is stable to acidolysis by TFA giving a useful additional feature to Hmb-containing peptides. Side-chain protection and the V -protection, if it is first replaced with Boc before Hmb O-acetylation, can be removed and backbone protection retained. After deacetylation of Hmb with aqueous hydrazine the peptide can be further purified before removal of the Hmb groups, useful when the product is poorly soluble. This feature is also useful for the purification of large polypeptides as the presence of backbone protection on the side-chain deprotected peptide prevents the formation of relatively stable folded structures that can complicate HPLC purification.1 11... 

Benzyl phosphates are less readily attacked by nucleophiles than methyl phosphates and they are more stable towards acidolysis than rm-butyl phosphates Benzyl phosphates are often used in complex polyfunctional targets because they are easily removed by hydrogenolysis. An indication of the reduced reactivity of benzyl phosphates is given in Scheme 7.17.32 Reaction of the phospho-nate diester 17.1 with one equivalent of 1 4-diazabicyclo[2 2 2]octane (DABCO) in refluxing toluene afforded the mono-deprotected derivative 17.2 in quantitative yield. Quinuclidine can also be used as the nucleophile. Assisted cleavage of benzyl phosphates is exemplified by the deprotection of the Shikimic Acid derivative in Scheme 7.18 using bromotrimethylsilane.33 34... 

As has been demonstrated, 2-(trimethylsilyl)ethoxymethyl (SEM) esters are selectively removed from amino acids and peptide derivatives in the presence of the most common N- and O-protecting groups applied in peptide chemistry including the urethane-type Boc, Z, Fmoc, and Troc as well as Bzl, tBu, and TBDMS ethers.The SEM ester is removed by acidolysis or with a fluoride ion source, e.g. TBAF in THF or HMPA or with aqueous HF in MeCN (—10°C).f l Deprotection with magnesium bromide in EtjO represents an even milder alternative that allows increased selectivity toward fluoride-labile silyl ethers or Fmoc groups. The SEM esters are prepared in 60-80% yield by stirring a mixture of 0.25 M N-protected amino acids in DMF with 0.8 equivalents of SEM-Cl and 1.1 equivalents of lithium carbonate at room temperature for 16 hours. 

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