Fluorous mixture synthesis of fluorous-Fmoc reagents using a one-pot double tagging strategy

Article abstract of DOI:10.1016/j.tetlet.2013.02.008

The concise synthesis of fluorous Fmoc (f-Fmoc) reagents bearing C ₃F₇ or C₄F₉ or C₆F ₁₃ chains were achieved by fluorous mixture synthesis. The fluorous tagging process was effectively conducted using Heck type reaction of the bis-diazonium salt and the corresponding fluorous olefine, each bearing a different fluorous tag, by a one-pot double tagging strategy. At the final stage, each f-Fmoc reagent was separated from the mixture of three f-Fmoc reagents by fluorous solid phase extraction.

Full text of DOI:10.1016/j.tetlet.2013.02.008

Tetrahedron Letters 54 (2013) 2060–2062
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fluorous mixture synthesis of fluorous-Fmoc reagents using a one-pot
double tagging strategy
⇑
Yuya Sugiyama, Kazuki Ishihara, Yuka Masuda, Yuki Kobayashi, Hiromi Hamamoto, Masato Matsugi
Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The concise synthesis of fluorous Fmoc (f-Fmoc) reagents bearing C3F7 or C4F9 or C6F13 chains were
achieved by fluorous mixture synthesis. The fluorous tagging process was effectively conducted using
Heck type reaction of the bis-diazonium salt and the corresponding fluorous olefine, each bearing a dif-
ferent fluorous tag, by a one-pot double tagging strategy. At the final stage, each f-Fmoc reagent was sep-
arated from the mixture of three f-Fmoc reagents by fluorous solid phase extraction.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 7 January 2013
Revised 29 January 2013
Accepted 1 February 2013
Available online 16 February 2013
We would like to dedicate this Letter to
Professor Takayuki Shioiri on his 77th
birthday.
Keywords:
Fluorous-Fmoc reagent
Fluorous mixture synthesis
Fluorous solid phase extraction
Fluorous HPLC
Organic molecules bearing small fluorous tags such as C6F13 and
C8F17 are called light fluorous molecules,1 and the separation tech-
nique for light-fluorous tagged molecules using fluorous solid
phase extraction (FSPE)2 has proven to be widely applicable in sep-
arating fluorous molecules from organic molecules.3 Also, the sep-
aration of fluorous-tagged compounds can be effectively carried
out by fluorous HPLC.4 The separation properties of light-fluorous
compounds, mentioned above, make these fluorous molecules use-
ful substrates in an encoded mixture synthesis in the liquid phase.5
We reported a synthesis of fluorous Fmoc reagents (1a, b) bearing a
C4F9 tag and a C6F13 tag (Fig. 1), and showed that these protecting
reagents had the potential to be applicable in the fluorous mixture
synthesis of various peptides.6 The fluorous Fmoc reagents were
designed to have two similar fluorous tags symmetrically attached
to the fluorene core in order to serve as effective protecting groups
for chiral amino acids.7 We would like to describe herein a novel
effective synthesis of f-Fmoc reagents by fluorous mixture synthe-
sis based on a one-pot fluorous tagging strategy.
the molecule, and we paid particular attention to ensuring that the
reaction did not stop after the first Heck reaction. For example,
when 1.0 equiv of fluorous-alkene was used as the substrate, 49%
yield of the double-tagged product was obtained (Scheme 1). This
corresponds to 99% yield with regard to the alkene used. During
the reaction, we observed that the bis-diazonium salt 2 did not dis-
solve in the MeOH; however, the Heck-products were soluble in
the reaction solvent. We believe that the mono-diazonium salt
resulting after the first Heck reaction may be much more soluble
than the bis-diazonium salt, or that the second Heck reaction rate
is faster on the mono-diazonium salt. This result led us to envision
the possibility that a one-pot double tagging of the fluorene skele-
ton using different fluorous-tags could be achieved. Needless to
We have demonstrated that the Heck-type reaction8 of a bis-
diazonium salt with RfCH@CH2 is extremely effective9 in the intro-
duction of a perfluoroalkyl chain to 9H-fluorene skeleton.6 In this
reaction, there was the need to incorporate two fluorous-tags into
⇑
Corresponding author. Tel.: +81 52 832 1151; fax: +81 52 835 7450.
E-mail address: matsugi@meijo-u.ac.jp (M. Matsugi).
Figure 1. Fluorous Fmoc (f-Fmoc) reagents.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.008

Y. Sugiyama et al. / Tetrahedron Letters 54 (2013) 2060–2062
2061
Scheme 1. Double tagging Heck type reaction using bis-diazonium salt 2.
Scheme 2. Preparation of bis-diazonium salt 2.
Figure 2. Chart of analytical fluorous HPLC; conditions: FluoroFlashÒ column;
254 nm; flow rate; 1.0 ml/min; 0–30 min: 80% MeCN to 100% MeCN; over 30 min:
100% MeCN.
(0.3 mmol) was treated with excess 2 (0.9 mmol) under Heck
conditions for 30 min at 40 °C. Subsequently, the fluorinated olefin
bearing C4F9 tag (0.3 mmol) was added to the reaction mixture and
stirred for 30 min. After cooling the reaction mixture to 4 °C, the
fluorinated olefin bearing C3F7 tag (0.3 mmol) was added to the
reaction mixture at the same temperature and further stirred for
30 min. Next, FSPE was conducted as follows: (1) The reaction
mixture of organic reagents and fluorous-tagged compounds were
loaded onto fluorous silica gel (60 times the weight of the crude
product) with aq MeOH. (2) This was followed by a first elution
with aq MeOH (MeOH/H2O = 4/1). During this first elution, the
non-tagged organic compounds (reagents and non-fluorous
by-products) were rapidly washed from the column while the
fluorous-tagged compounds were retained. (3) A second elution
with toluene washed the fluorous fraction of fluorous compounds
(3a–c) and a trace of unknown brown pigment off the column.
After a short column chromatography to remove the pigment,
3a–c was obtained in high purity as a mixture of three compounds
(Scheme 3). The fluorous HPLC (FluoroFlashÒ column, 4.6 mm i.d.,
150 mm length)11 analysis of the FSPE product showed that the
double tagged-compounds were effectively produced in almost
the same ratio by the Heck reaction as shown in Figure 2. The
Scheme 3. One-pot double tagging Heck type reaction of 2 using different fluorous
olefin.
say, fluorous Fmoc reagent must be a symmetrical structure to use
for the purpose of protection of chiral amino acids, which have
asymmetric center. Therefore an almost perfect control of the reac-
tivity in the double tagging process is required.
First, as shown in Scheme 2, the hydrogenation of dinitrofluo-
rene 4 provided the corresponding diaminofluorene in 99% yield.
After the derivation to the corresponding bis-diazonium salt 2,
Heck-type reaction was conducted using the conditions described
below (Scheme 3). First, the fluorinated olefin bearing C6F13 tag
Scheme 4. Mixture synthesis of f-Fmoc reagents (1a–c).

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Y. Sugiyama et al. / Tetrahedron Letters 54 (2013) 2060–2062
Acknowledgments
This research was partially supported by the Ministry of Educa-
tion, Science, Sports and Culture, Grant-in-aid for Scientific Re-
search (C), 23580154. We thank Professor Dennis P. Curran,
University of Pittsburgh, for useful suggestions of the fluorous
Fmoc synthesis. We also thank Meiji Seika Pharma Co., Ltd for
funding this work.
Supplementary data
Figure 3. Chart of analytical fluorous HPLC; conditions: FluoroFlashÒ column;
254 nm; flow rate; 1.0 ml/min; 0–30 min: 80% MeCN to 100% MeCN; over 30 min:
100% MeCN.
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2013.02.008.
References and notes
C3F7-Fmoc 3c, the C4F9-Fmoc 3a, and the C6F13-Fmoc 3b appeared
at 3.0 min, 4.2 min, and 12.3 min respectively.
1. Zhang, Q.; Luo, Z.; Curran, D. P. J. Org. Chem. 2000, 65, 8866–8873; (b) Curran, D.
P. A User’s Guide to Light Fluorous Chemistry. In The Handbook of Fluorous
Chemistry; Gladysz, J., Horváth, I., Curran, D. P., Eds.; Wiley-VCH: Weinheim,
2004; pp 128–155.
2. Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714–6715.
3. (a) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837–11865; (b) Curran, D.
P. Separations with Fluorous Silica Gel and Related Materials. In The Handbook
of Fluorous Chemistry; Gladysz, J., Horváth, I., Curran, D. P., Eds.; Wiley-VCH:
Wienheim, 2004; pp 101–127.
4. (a) Kamiusuki, T.; Monde, T.; Yano, K.; Yoko, T.; Konakahara, T.
Chromatographia 1999, 49, 649–656; (b) Kamiusuki, T.; Monde, T.; Yano, K.;
Yoko, T.; Konakahara, T. J. Chromatogr. Sci. 1999, 37, 388–394.
5. (a) Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766–
1769; (b) Curran, D. P. Aldrichim. Acta 2006, 39, 3–9.
6. Matsugi, M.; Yamanaka, K.; Inomata, I.; Takekoshi, N.; Hasegawa, M.; Curran, D.
P. QSAR Comb. Sci. 2006, 25, 713–715.
7. Najera, C. Synlett 2002, 1388–1403.
8. Heck, R. F. Acc. Chem. Res. 1979, 12, 146–151.
9. For example: Masllorens, J.; Bouquillon, S.; Roglans, A.; Henin, F.; Muzart, J.
Organomet. Chem. 2005, 690, 3822–3826.
Subsequent hydrogenation, hydroxymethylation,10 chlorocarb-
onylation, and the condensation with the sodium salt of N-
hydroxysuccinimide (NaOSu) provided a mixture of target fluorous
Fmoc reagents (1a–c), each encoded by different fluorous-tags. Ex-
cept for the reaction step (e), the series of reactions were con-
ducted without purification with column chromatography until
reaction step (g) in Scheme 4. Then FSPE purification of the crude
mixture was performed to give an almost pure mixture of 1a–c
(173 mg), judging from the 1H NMR.
Finally, we conducted a preparative fluorous-HPLC of the mix-
ture of 1a–c to obtain each pure f-Fmoc reagent. Figure 3 shows
the chart of the analytical fluorous-HPLC (FluoroFlashÒ column)11
of the f-Fmoc mixture. The C3F7-Fmoc 1c, the C4F9-Fmoc 1a, and
the C6F13-Fmoc 1b appeared at 2.3 min, 3.0 min, and 7.2 min
respectively. Since we already confirmed that 1a–c were resistant
to aqueous conditions, we used the same condition for the prepara-
tive f-HPLC (FluoroFlashÒ HPLC column, 20 mm i.d., 250 mm
length).12 The target fluorous Fmoc reagents 1a, 1b, and 1c13 were
isolated in 33 mg (74%), 33 mg (60%), and 29 mg (74%) respec-
tively, in 5 step yields from a mixture of 3a–c.
In summary, we have achieved a concise fluorous mixture syn-
thesis of f-Fmoc reagents (1a–c) via a one-pot double tagging strat-
egy in the Heck reaction step of the synthetic route. This method
provides a reasonable solution to obtaining small amounts of var-
ious f-Fmoc reagents that are required for peptide synthesis.
10. Carpino, L. A. J. Org. Chem. 1980, 45, 4250–4252.
11. Analytical FluoroFlashÒ column, 4.6 mm i.d., 150 mm length is available from
Fluorous Technologies Inc.; http://www.fluorous.com/.
12. Preparative FluoroFlashÒ HPLC column, 20 mm i.d., 250 mm length is available
from Fluorous Technologies Inc.; http://www.fluorous.com/.
13. Characterization data for novel compound; (f-Fmoc: 1c): white crystals; mp
154.0–155.0 °C; 1H NMR (270 MHz, CDCl3) d: 2.33–2.53 (m, 4H), 2.84 (s, 4H),
2.98–3.04 (m, 4H), 4.31 (t, J = 7.3 Hz, 1H), 4.58 (d, J = 7.3 Hz, 2H), 7.28 (d,
J = 7.8 Hz, 2H), 7.46 (s, 2H), 7.70 (d, J = 8.1 Hz, 2H); 19F NMR (466 MHz, CDCl3)
ppm À127.6 (4F), À115.4 (4F), À80.4(6F); HRMS [FAB] m/z calcd for
C
29H21NO5F14 729.1196, found: 729.1169; 3c: pale yellow crystals; mp
120.0–121.0 °C; 1H NMR (270 MHz, CDCl3) d: 3.97 (s, 2H), 6.17–6.32 (m, 2H),
7.21–7.29 (m, 2H), 7.52 (d, J = 7.8 Hz, 2H), 7.70 (s, 2H), 7.82 (d, J = 7.8 Hz, 2H);
19F NMR (466 MHz, CDCl3) ppm À127.4 (4F), À111.8 (4F), À80.1 (6F).