N-(9-Fluorenylmethyloxycarbonyl)oxysuccinimide

[82911-69-1]  · C19H15NO5  · (MW 337.34)

Alternate Name: Fmoc-OSu.

Physical Data: mp 151 °C.

Solubility: soluble in organic solvents such THF, dioxane, DMF, CH2Cl2 as well as alcohols. Please see also the section on Fmoc-Cl in this encyclopedia; Fmoc-OSu undergoes many of the same reactions as Fmoc-Cl, but at a somewhat slower rate than Fmoc-Cl.

Form Supplied in: white solid.

Analysis of Reagent Purity: HPLC and NMR.

Preparative Methods: the title reagent can be prepared by reaction of fluorenylmethanol with phosgene and N-hydroxysucci-nimide,1 by treating Fmoc-Cl with N-hydroxysuccinimide2 or by reacting 9-fluorenylmethanol with succinimidyl chlorofo-rmate.3

Handling, Storage, and Precautions: store dry.

Purification: recrystallization from chloroform/ether.

The 9-fluorenylmethoxycarbonyl protecting group for amines was introduced in 1970 by Carpino.4 It is exceptionally stable towards acid; thus, carboxylic acids that contain Fmoc-groups can be converted to acid chlorides with thionyl chloride5 or tert-butyl esters using H2SO4 and isobutene.6 In addition, Fmoc-groups are unaffected by HBr in HOAc or CF3COOH and, therefore, allow the selective deprotection of Cbz and Boc groups.

The traditional Fmoc protection of amino acids uses Fmoc-Cl in a Schotten-Baumann-type procedure.4,7 It was later found that this procedure can lead to the formation of significant amounts of Fmoc oligopeptides that can be difficult to remove.2

Two methods have been developed that allow the synthesis of Fmoc amino acids free of any corresponding Fmoc oligopeptides: one procedure uses Fmoc-OSu in mixtures of water and organic solvent together with a base,1,2,3 whereas the other consists of silylation of an amino acid with TMS-Cl and a tertiary amine base in an organic solvent followed by treatment with Fmoc-Cl.8 Concepts from each of these methods have recently been combined into a procedure that affords Fmoc amino acids in high purity under neutral, anhydrous conditions.9 In this procedure a pertrimethylsilyl amino acid (2) is formed with N-methyl-N-(trimethylsilyl)trifluoroacetamide; 2 is then treated with Fmoc-OSu, followed by methanol (1).

For large scale Fmoc amino acid preparations, the less expensive N,O-bis(trimethylsilyl)acetamide (BSA) may be employed. This is illustrated with the scale-up of a photolinker 3 for combinatorial chemistry, which was achieved using this anhydrous method (2).9

Other less reactive Fmoc-reagents in addition to Fmoc-OSu have been used to introduce the Fmoc-group, such as Fmoc-benzotriazole (4)3 and Fmoc-pentafluorophenyl (5).10

The use of the Fmoc protection group in peptide synthesis has been extensively reviewed.11

The Fmoc-group is susceptible to hydrogenolysis but at a slower rate than O-benzyl systems. One can, therefore, expect some selectivity as has been shown in a one-pot conversion of benzyl carbamates (6) into fluorenylmethyl carbamates (7) by hydrogenation with a poisoned catalyst (3).12

Cleavage of the Fmoc-group is achieved via a rapid nonhydrolytic elimination mechanism by treatment of the Fmoc-compound 8 with an amine base such as ammonia, piperidine, morpholine, triethylamine, and others, usually in polar solvents such as DMF, NMP or acetonitrile.13 Other bases that have been used include TBAF14 and DBU.15 Generally a large excess of amine base is used because it acts as a scavenger to trap the liberated dibenzofulvene (9) to form 10 (4).16

A drawback of the Fmoc-group is that Fmoc-protected compounds frequently show low solubility in common organic solvents. In addition, the by-products of the deprotection step can often only be removed via a chromatographic step. This has recently led to the development of Fmoc* (11) as a more soluble alternative to Fmoc.17

An added benefit of 11 is that the piperidine adduct that forms upon deprotection with piperidine in DMF is highly lipophilic and can be removed from a DMF solution of the deprotected amine by extraction with hexane.

Another convenient and scaleable procedure for removing the Fmoc-group in solution uses catalytic DBU in the presence of a polymer-supported thiol scavenger (12) (5). The resin is commercially available and can be recycled.16

It was recently demonstrated that Fmoc-OSu can be converted into 2-nitro Fmoc-OSu (13) in one step by treatment with nitric acid (6).18 The nitro compound 13 can then be used as a photocleavable protecting group.

Related Reagents.

Fmoc-Cl.


1. Ten Kortenaar, P. B. W.; Van Dijk, B. G.; Peeters, J. M.; Raaben, B. J.; Adams, P. J. H. M.; Tesser, G. I., Int. J. Pept. Prot. Res. 1986, 27, 398.
2. Sigler, G. F.; Fuller, W. D.; Chaturvedi, N.; Goodman, M.; Verlander, M., Biopolymers 1983, 22, 2157.
3. Paquet, A., Can. J. Chem. 1982, 60, 976.
4. Carpino, L. A.; Han, G. Y., J. Am. Chem. Soc. 1970, 92, 5748.
5. Carpino, L. A.; Cohen, B. J.; Stephens, K. E.; Sadat-Aalaee, S. Y.; Tien, J.-H.; Langridge, D. C., J. Org. Chem. 1986, 51, 3732.
6. Kelly, R. C.; Gebhard, I.; Wicnienski, N., J. Org. Chem. 1986, 51, 4590.
7. Chang, C. D.; Waki, M.; Ahmad, M.; Meienhofer, J.; Lundell, E. O.; Haug, J., Int. J. Pept. Prot. Res. 1980, 15, 59.
8. Bolin, D. R.; Sytwu, I. I.; Humiec, F.; Meienhofer, J., Int. J. Pept. Prot. Res. 1989, 33, 353.
9. Raillard, S. P.; Mann, A. D.; Baer, T. A., Org. Prep. Proc. Int. 1998, 30, 183.
10. Schön, I.; Kisfaludy, L., Synthesis 1986, 303.
11. Udenfriend, S.; Meienhofer, J., The Peptides; Academic: San Diego, 1987; Vol. 9, p 1.
12. Dzubeck, V.; Schneider, J., Tetrahedron. Lett. 2000, 41, 9953.
13. Greene, T.; Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999, p 506.
14. Schmidt, U.; Mundinger, K.; Mangold, R.; Lieberknecht, A., J. Chem. Soc. Chem. Comm. 1990, 1216.
15. Ueki, M.; Amemiya, M., Tetrahedron. Lett. 1987, 28, 6617.
16. Sheppeck, J. E., Jr; Kar, H.; Hong, H., Tetrahedron. Lett. 2000, 41, 5329.
17. Stigers, K. D.; Koutroulis, M. R.; Chung, D. M.; Nowick, J. S., J. Org. Chem. 2000, 65, 3858.
18. Henkel, B.; Bayer, E., Synthesis 2000, 1211.

Stephen P. Raillard

Affymax Research Institute, Santa Clara, CA, USA



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