J . Org. Chem. 2001, 66, 4261-4266
4261
F lu or ou s Boc (F Boc) Ca r ba m a tes: New Am in e P r otectin g Gr ou p s
for Use in F lu or ou s Syn th esis
Zhiyong Luo,1a J ohn Williams,1b Roger W. Read,1c and Dennis P. Curran*
Department of Chemistry and Center for Combinatorial Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
curran@pitt.edu
Received J anuary 29, 2001
The first fluorous variants of the Boc (tert-butyloxycarbonyl) group have been prepared and tested
for their suitability as nitrogen protecting groups. A group with two fluorous chains and an ethylene
spacer, (RfCH2CH2)2(CH3)COC(O)-, was readily attached to a representative amine but was difficult
to cleave. In contrast, groups with two fluorous chains and a propylene spacer, (RfCH2CH2CH2)2-
(CH3)COC(O)-, or one fluorous chain and an ethylene spacer, (RfCH2CH2)(CH3)2COC(O)-, were
F
readily formed and cleaved. The fluorous alcohol component of the Boc group can be removed by
evaporation and can be recovered and reused. The utility of the new FBoc group (C8F17CH2-
CH2)(CH3)2COC(O)- was demonstrated in 16 and 96 compound library synthesis exercises.
Separations can be achieved either by manual, parallel fluorous solid-phase extraction, or automated,
serial fluorous chromatography. The results provide additional confirmation of the value of “light”
fluorous synthesis techniques, and the new fluorous Boc groups expand the applicability of fluorous
synthesis techniques to many classes of nitrogen-containing organic compounds.
In tr od u ction
liquid extraction is replaced by a solid-liquid extraction
over fluorous reverse phase silica gel (silica gel with a
fluorocarbon bonded phase).5 Elution conditions are
selected such that organic (nontagged) reagents, reac-
tants, byproducts, etc. are not retained during an initial
pass through the column, but the fluorous-tagged com-
pounds are retained. A second pass with a more power-
fully eluting solvent then extracts the fluorous-tagged
compounds off the column. Fluorous solid phase extrac-
tions are especially straightforward to conduct, either
individually or in parallel.
Light fluorous synthesis techniques were first demon-
strated with simple perfluoroacyl amides, as illustrated
by the example in eq 1. Isonipecotic acid 1a was coupled
with acid chloride 2 to give fluorous-tagged amino acid
3. Reaction of 3 with isoquinoline 4a (and other amines)
under standard amide coupling conditions, followed by
fluorous solid-phase extraction to remove all the reagent
and reactant remnants, provided clean amide 5. This was
deprotected with base to provide amino amide 6. While
these experiments clearly demonstrated the potential use
of small fluorous tags coupled with solid phase extraction,
the practical utility is limited because perfluoroacyl
groups are a relatively minor class of amide protecting
groups. Some problems were also encountered in the
cleavage of the perfluoroacyl groups, although several
different hydrolytic and reductive conditions were devel-
oped.
In the recently introduced technique of “fluorous
synthesis”, small organic molecules are attached to
fluorous (highly fluorinated) tags.2 After reactions, these
fluorous-tagged molecules can be separated from non-
tagged molecules by liquid-liquid extraction between an
organic solvent and a fluorocarbon solvent. Unfortu-
nately, unduly large numbers of fluorine atoms (60-120)
can be needed to provide substantial solubilities of the
fluorous-tagged molecules in fluorinated solvents,3 and
this leads to a number of practical problems including
high molecular weights and low solubilities of the tagged
molecules.
To unlock the potential of fluorous synthesis, we have
more recently introduced “light fluorous” techniques.4
Many fewer fluorines are used in the tag, and the liquid-
(1) (a) Current address: Fluorous Technologies, Inc., UPARC,
Pittsburgh, Pennsylvania. (b) Current address: Neurocrine Bio-
sciences, Inc., 10555 Science Center Drive, San Diego, California
92121. Work by this author was performed at CombiChem, Inc.,
which is now
a part of DuPont Pharmaceuticals. (c) School of
Chemistry, The University of New South Wales, Sydney NSW 2052,
Australia.
(2) (a) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; J eger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823. (b) Curran, D. P. Cancer J .
1998, 4 Supp. 1, S73. (c) Curran, D. P. Angew. Chem., Int. Ed. Engl.
1998, 37, 1175. (d) Curran, D. P.; Hadida, S.; Studer, A.; He, M.; Kim,
S.-Y.; Luo, Z.; Larhed, M.; Hallberg, M.; Linclau, B. In Combinatorial
Chemistry: A Practical Approach; Fenniri, H., Ed.; Oxford University
Press: Oxford, in press; Vol. 2.
(3) (a) Studer, A.; Curran, D. P. Tetrahedron 1997, 53, 6681. (b)
Studer, A.; J eger, P.; Wipf, P.; Curran, D. P. J . Org. Chem. 1997, 62,
2917. (c) Curran, D. P.; Ferritto, R.; Hua, Y. Tetrahedron Lett. 1998,
39, 4937. (d) Linclau, B.; Singh, A. K.; Curran, D. P. J . Org. Chem.
1999, 64, 2835.
(5) (a) Curran, D. P.; Hadida, S.; He, M. J . Org. Chem. 1997, 62,
6714. (b) Kainz, S.; Luo, Z. Y.; Curran, D. P.; Leitner, W. Synthesis
1998, 1425. (c) Curran, D. P.; Luo, Z.; Degenkolb, P. Bioorg. Med.
Chem. Lett. 1998, 8, 2403. (d) Curran, D. P.; Hadida, S.; Kim, S. Y.;
Luo, Z. Y. J . Am. Chem. Soc. 1999, 121, 6607.
(4) Curran, D. P.; Luo, Z. Y. J . Am. Chem. Soc. 1999, 121, 9069.
10.1021/jo010111w CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/16/2001