amino acids such as a-aminoisobutyric acids or N-substituted
amino acids, respectively.1d In comparison with amino acid
chlorides, which are generally more reactive than the acid
fluorides, the latter are unique in several ways: (a) tert-butyl
and trityl side chain protecting groups can be accommodated;
(b) conversion to the corresponding oxazolone in the
presence of tertiary organic bases does not occur, thus
minimizing the danger of stereomutation; and (c) coupling
reactions occur readily in the complete absence of an organic
base, again avoiding possible loss of configuration. In view
of these properties, the acid fluorides resemble activated
esters more than acid chlorides or acid bromides. In
employing Fmoc amino acid fluorides in practical peptide
synthesis, difficulties were encountered only in the case of
two amino acids: histidine and arginine. In the former case,
while Fmoc-His(Trt)-F has been synthesized and used in
coupling reactions, its long-term stability is in doubt. For
sulfonamide-protected arginine derivatives, e.g., Fmoc-Arg-
(Pbf)-OH, the corresponding acid fluorides could not be
synthesized due to their facile cyclization to the correspond-
ing lactam.
More interestingly, conversion of the acid to the acid
fluoride was also observed via treatment with N-HATU or
N-HBTU in the presence of additive PTF.6 In this way
excellent syntheses of difficult peptides could be achieved
in cases where N-HBTU itself gave poor results due to the
sluggish reactivity of OBt esters. Examples include the
syntheses of 5, Aib67,68ACP(65-74)amide 6, and alamethicin
amide 77 for all of which the products obtained with and
without PTF additive are compared in Figures 1, 3, 4, and 5
(Supporting Information).
By this means, the relatively inexpensive reagents N-
HBTU or N-TBTU provide peptides of equal or greater
quality than those obtained via N-HATU or isolated acid
fluorides. Regardless of which coupling reagents are used
in these reactions, a tertiary base such as DIEA is required
in the activation step. At least in the case of systems that
undergo facile loss of configuration, the presence of a base
may be deleterious and at any rate is not required for the
actual coupling step in the case of acid fluorides.8 It is thus
particularly significant that acid fluorides can be generated
in the absence of base via carbodiimides.9 The carbodiimide
method of peptide activation is believed to involve transient
formation of a labile O-acylisourea 8, which in the presence
of a second equivalent of carboxylic acid is converted to
the symmetric anhydride 9, which represents the active
coupling species.10 Now it has been found that in the presence
of PTF and DCC or DIC, the putative O-acylisourea
intermediate is diverted to the acid fluoride.
Recently the fluoroformamidinium salt TFFH 3 has been
shown to act as a coupling reagent that proceeds via in situ
conversion to an acid fluoride.2
Reagent 3 can be handled in air in the same way as the
common onium reagents3 such as N-HATU4 and N-XBTU
(X ) H, T)5 by base-catalyzed activation. For some amino
acids, e.g., Fmoc-Aib-OH, it was found that the use of TFFH
gave results that were less satisfactory than those obtained
with isolated amino acid fluorides. The deficiency was traced
to inefficient conversion to the acid fluoride, which under
the conditions used (2 equiv of DIEA) was accompanied by
the corresponding symmetric anhydride and oxazolone. On
the other hand it is now shown that if a fluoride additive
such as 4 (PTF) is present during the activation step, the
latter two products are avoided and a maximum yield of acid
fluoride is obtained. Assembly of the difficult pentapeptide
5 via TFFH coupling in the presence of 4 gave a product of
quality similar to that obtained via isolated acid fluorides
(Supporting Information).
Under optimum conditions, in a nonpolar solvent such as
DCM, the activation is rapid, thus serving to guarantee an
(1) (a) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H.-G.; DeSelms, R. H.
J. Am. Chem. Soc. 1990, 112, 9651. (b) Carpino. L. A.; Mansour, E. M. E.;
Sadat-Aalaee, D. J. Org. Chem. 1991, 56, 2611. (c) Kaduk, C.; Wenschuh,
H.; Beyermann, M.; Forner, K.; Carpino. L. A.; Bienert, M. Lett. Pept. Sci.
1995, 2, 285. (d) Carpino, L. A.; Beyermann, M.; Wenschuh, H.; Bienert,
M. Acc. Chem. Res. 1996, 29 (6), 268.
(2) Carpino, L. A.; El-Faham, A. J. Am. Chem. Soc. 1995, 117, 5401.
(3) (a) Carpino, L. A.; Imazumi, H.; El-Faham, A.; Ferrer, F. J.; Zhang,
C.; Lee, Y.; Foxman, B. M.; Henklein, P.; Hanay, C.; Mu¨gge, C.; Wenschuh,
H.; Klose, J.; Beyermann, M.; Bienert, M. Angew. Chem., Int. Ed. 2002,
41, 441. (b) Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J.
Chem. Soc., Chem Commun. 1994, 201.
(6) Infrared studies showed that under the conditions used, preactivation
of a protected acid with N-HATU or N-HBTU in the presence of 4 gave a
mixture of the acid fluoride and the OAt or OBt ester, respectively. However,
conversion to the acid fluoride was never complete.
(7) For the first solid-phase syntheses of these hindered sequences via
isolated Fmoc amino acid fluorides, see: Wenschuh, H.; Beyermann, M.;
Krause, E.; Brudel, M.; Winter, R.; Schu¨mann, M.; Carpino, L. A.; Bienert,
M. J. Org. Chem. 1994, 59, 3275.
(8) Wenschuh, H.; Beyermann, M.; El-Faham, A.; Ghassemi, S.; Carpino,
L. A.; Bienert, M. J. Chem. Soc., Chem. Commun. 1995, 669.
(9) The recent appearance of a paper by Chen and co-workers (J. Fluor.
Chem. 2002, 115, 75) on the generation of acid fluorides via DCC/Py-
(HF)n has prompted us to record our results in this area.
(4) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
(5) (a) Dourtoglou, V.; Gross, B.; Lambropoulou, V.; Zioudrou, C.
Synthesis 1984, 572. (b) Knorr, R.; Treciak, A.; Bannworth, W.; Gilllessen,
D. Tetrahedron Lett. 1989, 1927.
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