Milder deprotection

The older Boc protocol has largely been superceded by the Fmoc protocol, which has several relevant advantages over it. The use of milder deprotection conditions for the Fmoc group and its complete orthogonality with a large number of side-chain... 

The synthetic strategy based on the minimum protection philosophy Pl (Section 4.1.2) favors the use of unprotected hydroxy groups, which leads to more soluble peptides and milder deprotection procedures,but also to a certain degree to side reactions involving the free hydroxy groups. The resulting side-products have to be removed by careful purification of the intermediate fragments. 

Although alkylation of phthalimide can now be performed under mild conditions as described in the preceding section, the final deprotection step still requires somewhat drastic conditions, e.g. the use of strong acid or base, or, alternatively, hydrazinolysis, at elevated temperature, due to the inherent stability of the phthaloyl group. This has prompted investigation of a number of alternatives to phthalimide which afford iV-alkyl derivatives amenable to milder deprotection. 

The synthesis of the amino amide 9 via alkylation/deprotection of an imidazolidinone is efficient and provides BIRT 377 in high purity and in relatively few steps. [7] However, Ae sequence involves a hydrolysis step which generally requires forcing conditions, and involves 3 steps that only achieve protection and deprotection of functional groups. We reasoned that if we could use an oxazolidinone ten late for a similar alkylation reaction, we should be able to use a milder deprotection procedure to isolate a derivative of the quaternary amino acid such as 23. On the basis of the literature, this would allow us to use the cheaper (L)-alanine. In addition, protection/deprotection strategies would be minimized. 

All attempts to use milder reaction conditions such as mixtures of TFA in DCM (95 5) at RT or DDQ failed, while microwave irradiation of compounds at 120 °C in a (1 1) or (1 2) TFA/DCM mixtures provided deprotected products in yields comparable to those obtained under conventional heating (69-96%). It should be noted that this microwave-enhanced procedure not only resulted in milder reaction conditions, but also represents a considerable shortening of reaction time (10-20 min compared to 6-12 h). 

A similar sequence that takes place under milder conditions uses 4-nitrophthalimides as the protecting group and /V-melhylhydrazine for deprotection.234 Reduction by NaBH4 in aqueous ethanol is an alternative method for deprotection of phthalimides. This reaction involves formation of an o-hydroxybenzamide in the reduction step. Intramolecular displacement of the amino group follows.235... 

A similar sequence that takes place under milder conditions uses 4-nitrophthalimides as the protective group and iV-mcthyIhydrazine for deprotection.81... 

Aliphatic and aromatic nucleophilic substitutions with p Fjfluoride are usually performed either on an immediate precursor of the target molecule (direct labelling using a one-step process) or on an indirect precursor followed by one or more chemical steps leading to the target radiotracer. The first approach, if highly desirable, is in fact rarely practicable. The reaction conditions are often not compatible with the structure or with the various chemical functions borne by the radiopharmaceutical. It is therefore common that the radiosynthesis comprises at least two chemical steps first the introduction of fluorine-18 followed by what is often a (multi)deprotection step. It is not unusual either that fluorine-18 is first incorporated into a much simpler and chemically more robust molecule which is then coupled to a more sensitive entity under milder conditions, possibly still followed by a final deprotection step. Suchlike multi-step procedures are possible thanks to the favourable half-life of fluorine-18. However, the more complicated the process, the more chance of side reactions and complicated final purifications (see also Section 2.3), which may seriously hamper the automation of the process. 

Deprotection of aryl methyl ethers may be effected under strongly acidic conditions (e.g. hydriodic acid, Section 9.6.11, p. 1253), but the milder methods employing either iodotrimethylsilane in chloroform solution at 20-50 °C for several hours,40 or boron tribromide at room temperature may be preferable.41... 

It has been found that the results of this new variant of the Mitsunobu procedure are generally comparable with the results of the traditional Mitsunobu reaction both with respect to the yields and enantiomeric excess (ee) of chiral compounds 26. Thus, products prepared from alcohol 86e using both methods had ee 70% and 72%, and from (Tl-methyl lactate 86i 92% and 99%, respectively. However the new variant of the Mitsunobu procedure has a significant synthetic advantage over the traditional procedure imides 26 can be transformed into primary amines under milder conditions in comparison with the deprotection of /V-alkylphthalimides (see Section 6.03.6.1.3). 

Both the Boc groups in substituted guanidine 1.87 can be removed with stannic chloride in ethyl acetate. The reagent is milder than the TFA and gives a high yield of deprotected product 1.88 in 88% yield. 

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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