Fluorenylmethyl Carbamates Fmoc Protection

The 9-fluorenylmethoxycarbonyl group, developed by Carpino and co-workers in 1972 [257], has become one of the most widely used protective groups for aliphatic or aromatic amines in solid-phase synthesis. For solid-phase peptide synthesis in particular, this protective group plays an important role [258] (Section 16.1). The Fmoc group is not well suited for liquid-phase synthesis because non-volatile side products are formed during deprotection. 

As in the case of Boc protection, the Fmoc group is not usually introduced on solid phase, but rather in solution, by the use of an activated Fmoc derivative (e.g. the chloroformate Fmoc-Cl or O-Fmoc-.V-hydroxysuccinimide, Fmoc-OSu) and aqueous base (Experimental Procedure 10.3)., V-/ lkylamino acids bound to cross-linked polystyrene have been Fmoc-protected by treatment with Fmoc-Cl (4 equiv.) and DIPEA (6 equiv.) in DCM for 2 h [132,259], Primary amines on insoluble supports can also be converted into Fmoc derivatives under these conditions [260]. 

The stability of Fmoc amines towards various bases has been investigated in detail [258,261,262]. Ammonia and primary or secondary aliphatic amines in polar aprotic solvents lead to swift deprotection. Further reagents claimed to be useful for Fmoc deprotection are 2% DBU in DMF [263,264], 1% DBU + 1% HOBt in DMF (4 x 2 min no cleavage of thiol esters occurs [265]), KF/NEt3 in DMF [238], 40% Et2NFl 

Fxperimcniul PruccJine 10.3 Fmoc piotccuon ol ((-amino acids [270,271] 

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Moving ahead with this analysis, the retrosynthetic sword next cut the D-ring diketopiperazine ring of 6 (see Scheme 1) at the indicated amide linkage to reveal 7 as a protected amino acid precursor. Although the selection of a methyl ester and a 9-fluorenylmethyl carbamate (Fmoc) group to protect these new functionalities... 

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