Fluorenylmethyl Fm Thioethers

The 9-fluorenylmethyl group, in the guise of the 9-fluorenylmethoxycarbonyl or Fmoc group, is the keystone in modern solid-phase peptide synthesis and we will examine its enormous influence in section 8.3.5. The great virtues of the 9-fluorenylmethyl group have also been adapted to the protection of carboxylic acids as 9-fluorenylmethyl esters (see section 6.5.3). Bodanszky and Bednarek realised the opportunity for extending the principle of 9-fluorenylmethyl activation, the aromaticity of the fluorenyl anion, to the protection of cysteine in peptide synthesis. 9-Fluorenylmethyl thioethers are stable towards iodine and acidic conditions, including HF, but they easily eliminate on treatment with piperidine or DBU. 

The utility of thiol esters and carbonates as protecting groups is limited by their vulnerability to hydrolysis. The poor overlap between the non-bonded electrons on the sul r atom (3p) and the rc-system of the carbonyl (2p) precludes or diminishes resonance stabilisation of the type enjoyed by normal esters thereby raising their ground state energy. The carbonyl group of the thioester is more electrophilic than a normal ester and hence more reactive. Thiocarbonate derivatives are marginally more stable. The 5-benzoyl derivative of cysteine is 95% hydrolysed in 30 minutes with 2 M ammonia whereas the 5-benzyloxycarbonyl derivative is only 20% hydrolysed in 30 minutes under the same conditions.  

Sign(fic nt oontiitHJtion from A reduces the reactivity of esters. 

Insignificant oorlributiori from B enhances the reactmty of thiol esters. 

The yV-[2,3t5,6-tetrafluoro-4-(N -piperidino)-phenyl]--/V-allyloxycarbonylamino-methyl (Fnam) group is an alternative allylic protector for thiols with higher acid stability than the Alocam group albeit at the expense of much greater complexity. The Fnam group is introduced by reacting the thiol with methyl ethyl 

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