[287381-46-8] · C23H27ClO2 · (MW 370.92)
(base-labile protecting group for primary and secondary amines with the resulting carbamates having improved solubility in organic solvents over those of the Fmoc protecting group)
Alternate Name: 2,7-di-tert-butyl-9-fluorenylmethoxycarbonyl chloride; carbonochloridic acid, [2,7-bis(1,1-dimethylethyl)-9H-fluoren-9-yl]methyl ester; Fmoc*-Cl.
Physical Data: mp 63-65 °C.
Solubility: soluble in organics (CH2Cl2, CHCl3, pentane, etc.); reacts with alcohols, amines, and water.
Form Supplied in: 2,7-di-tert-butyl-9-fluorenylmethanol chloroformate and its immediate synthetic precursor (2,7-di-tert-butyl-9-fluorenylmethanol) are available from Aldrich, with the immediate synthetic precursor priced considerably more economically.
Analysis of Reagent Purity: 1H NMR, IR, elemental analysis.
Preparative Methods: the title reagent can be prepared in three steps from fluorene1 by Friedel-Crafts alkylation with (CH3)3 CCl and FeCl3 to give 2,7-di-tert-butyl-9-fluorene, hydroxymethylation with n-BuLi and paraformaldehyde to give 2,7-di-tert-butyl-9-fluorenylmethanol, and conversion to the chloroformate with phosgene.
Purification: low-temperature (-78 °C) recrystallization from pentane.
Handling, Storage, and Precautions: treat with precautions typical of nonvolatile acid chlorides and chloroformates—avoid skin and eye contact; avoid breathing fumes, which may contain HCl, by working in a fume hood; open bottles carefully, as pressure may develop; protect from moisture; reactions with nucleophiles, such as amines, may be exothermic and should be performed with adequate dilution and cooling.
2,7-Di-tert-butyl-9-fluorenylmethyl chloroformate (Fmoc*-Cl) is useful as a base-labile protecting group for primary and secondary amines for applications in which the 9-fluorenylmethyl-oxycarbonyl (Fmoc) protecting group2 would generally be used but is precluded by the low solubility of the Fmoc carbamates.3 It may be coupled with amines in the presence of a suitable base, such as aqueous sodium carbonate, and the resulting carbamate may be subjected to various synthetic transformations (
The Fmoc-protecting group has emerged as one of the two most important a-amino protecting groups in peptide synthesis. Although Fmoc-protected versions of the 20 proteinogenic amino acids with good solubilities in organic solvents are available, the growing importance of combinatorial and peptidomimetic chemistry has created a demand for many other protected amino acids. In some cases, the Fmoc-protected versions of these amino acids or their synthetic precursors have poor solubility in organic solvents. The Fmoc*-protecting group provides what may be the only practical method of preparing and incorporating these amino acids in Fmoc-based peptide synthesis. Such is the situation with the unnatural amino acid Hao (5-HO2CCONH-2-MeO-C6H3-CONHNH2).4 Hao is readily prepared as its Fmoc*-protected derivative (Fmoc*-Hao) by the condensation of Fmoc*-hydrazine with 5-methoxy-2-nitrobenzoyl chloride, reduction of the resulting Fmoc*-protected nitrobenzoic hydrazide to the corresponding aminobenzoic hydrazide, followed by condensation with ethyl oxalyl chloride and saponification of the ethyl ester group (
Improvements in solubility of Fmoc*-protected amines of up to one-to-two orders of magnitude over their Fmoc-protected counterparts have been reported.1 Thus, the Fmoc-protected nitrobenzoic hydrazide 5-NO2-2-MeO-C6H3-CONHNH-Fmoc (1) exhibits extremely limited solubility in CHCl3 (1 mg mL-1) and limited solubility in THF (8 mg mL-1), while the corresponding Fmoc*-protected compound (5-NO2-2-MeO-C6H3-CONHNH- Fmoc*) (2) is freely soluble in both of these solvents (> 100 mg mL-1). The limited solubility of the Fmoc-protected compound precludes its use in the synthesis of Fmoc-Hao by a route analogous to that shown in
An alternative to the Fmoc*-protecting group, which bears trimethylsilyl groups in place of the two tert-butyl groups, has been reported to have even better solubility properties than Fmoc*.5 The removal of the 2,7-bis(trimethylsilyl)fluorenylmethyl protecting group with amine bases proceeds in a rate almost comparable to that of the removal of Fmoc, while the removal of Fmoc* has been reported to proceed at either a nearly comparable rate to that of Fmoc1 or somewhat more slowly.5 A major drawback of the 2,7-bis(trimethylsilyl)fluorenylmethyl protecting group is that 2,7-bis(trimethylsilyl)fluorenylmethyl chloroformate is not commercially available and its preparation from fluorene requires seven steps (as opposed to three for Fmoc*-Cl).5,6,7
9-Fluorenylmethyl chloroformate (Fmoc-Cl);
University of California, Irvine, California, USA