Mio- and Dio-Fmoc - Two modified Fmoc protecting groups promoting solubility

Article abstract of DOI:10.1055/s-2006-949632

Two novel Fmoc-derived protecting groups, Mio-Fmoc and Dio-Fmoc, were developed, which cause dramatically enhanced solubility of the corresponding derivatives in most organic solvents. Furthermore, the suitability of these groups in solid-phase peptide synthesis was highlighted. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-949632

LETTER
2235
Mio- and Dio-Fmoc – Two Modified Fmoc Protecting Groups Promoting
Solubility
M
P
io-
a
nd Dio-
a
Fmoc – Tw
b
o Modified
F
l
m
oc
P
o
rotecting Groups Wessig,* Sylvia Czapla, Kristian Möllnitz, Jutta Schwarz
Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax +49(30)20937450; E-mail: pablo.wessig@chemie.hu-berlin.de
Received 25 June 2006
Dedicated to Professor Louis A. Carpino
(
6 steps from fluorene to Bts-Fmoc chloride) and that it is
Abstract: Two novel Fmoc-derived protecting groups, Mio-Fmoc
and Dio-Fmoc, were developed, which cause dramatically en-
not commercially available so far.
hanced solubility of the corresponding derivatives in most organic In connection with one of our current research projects,
solvents. Furthermore, the suitability of these groups in solid-phase
peptide synthesis was highlighted.
the development of molecular rods with an oligospiroket-
al architecture, such as 1 (Figure 1), we required a protect-
Key words: protecting groups, solid-phase synthesis, solubility, ing group for the terminal piperidine moieties, which is
peptides
compatible with a Fmoc-based SPPS strategy. Not sur-
prisingly, the use of the parent Fmoc group produced ex-
tremely poorly soluble solids preventing any further
Protecting groups are of fundamental importance in mod- usability. The problem could not be circumvented with
ern synthetic organic chemistry. The successful total syn- the Dtb-Fmoc group, which provided only moderate en-
thesis of a huge number of natural products is mainly hancement of the solubility. This situation led us to devel-
based on proper employment of these groups. Undoubted- op two new Fmoc-derived protecting groups with
ly one of the most frequently used protecting groups for substantially higher solubility and straightforward syn-
amines is the Fmoc group, developed by Carpino more thetic accessibility. Herein, we report the synthesis of the
1
than 30 years ago. The utilization of the Fmoc group in- 2-(2-ethylhexyl)-fluorene-9-methoxycarbonyl (‘mono-
2
stead of the originally used Boc group has revolutionized isooctyl-Fmoc’, Mio-Fmoc) group, the 2,7-bis(2-ethyl-
solid-phase peptide synthesis (SPPS) and to this day most hexyl)-fluorene-9-methoxycarbonyl (‘diisooctyl-Fmoc’,
3
SPPS rely on the Fmoc strategy. In contrast to the vast Dio-Fmoc) group, the solubility of various derivatives, as
dissemination in SPPS, the Fmoc group has only found a well as the successful employment in SPPS.
limited use in solution synthesis, principally for two rea-
sons: Fmoc derivatives are often poorly soluble in many
O
O
organic solvents and the cleavage of the Fmoc group gen-
erates non-volatile byproducts (dibenzofulvene and its ad-
ducts with secondary amines). The solubility of Fmoc-
protected proteinogenic amino acids is mostly satisfactory
but appropriate derivatives of larger molecules (e.g.
peptidomimetics) are often scarcely soluble.
R1
R2
N
N
1
2
O
O
O
O
n
R1
N
R1
O
O
Figure 1 Oligospiroketals 1 and trispiranes 2
It seems reasonable to remedy the solubility problem by
the introduction of bulky groups onto the fluorene skele-
ton. In 2000 Stigers et al. reported the development of the
It is well known that the introduction of a 2-ethylhexyl
group (‘isooctyl’ group) often causes dramatically en-
hanced solubility of the appropriate derivatives. There-
fore, we decided to use this residue for our new Fmoc
groups.
2
,7-di-tert-butyl-Fmoc group (Dtb-Fmoc) and its proper-
7
4
,5
ties. The solubility of Dtb-Fmoc derivatives is consider-
ably enhanced in many solvents compared with the
appropriate Fmoc compounds. Unfortunately, the cleav-
age rate of Dtb-Fmoc groups is dramatically diminished Our synthesis started with the Friedel–Crafts acylation of
by the tert-butyl groups. In the same year Carpino report- fluorene 3 with 2-ethylhexanoyl chloride. Primarily we
ed the 2,7-bis(trimethylsilyl)-Fmoc (Bts-Fmoc) group planned to introduce two acyl groups into the 2- and 7-po-
6
which solved this problem. The cleavage times of Bts- sition of the fluorene skeleton simultaneously. In the liter-
Fmoc derivatives differ only marginally from those bear- ature several examples of two-fold acylation of fluorene
8
ing the Fmoc group. The disadvantage of the Bts-Fmoc have been reported. Surprisingly, we found that under
group is the relatively extensive preparation of the reagent typical previously described conditions [RCOCl (2
equiv), AlCl (2 equiv), CS , reflux] only one acyl group
3
2
is installed giving 2-(2-ethylhexanoyl)fluorene 4a in
quantitative yield. The same product could also be ob-
tained with one equivalent of the acid chloride and cata-
SYNLETT 2006, No. 14, pp 2235–2238
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949632; Art ID: G19006ST
0
1
.0
9
.2
0
0
6
©
Georg Thieme Verlag Stuttgart · New York

2
236
P. Wessig et al.
LETTER
lyst using dichloromethane as solvent in 86% yield. The ty, whereas the Dtb-Fmoc (2b) group showed only a mar-
reduction of the keto group with LiAlH /AlCl afforded 2- ginal improvement. An exact value for the solubility of 2c
4
3
(
2-ethylhexyl)fluorene (2-isooctyl-fluorene) 5a. In con- and 2d in Et O could not be determined because with de-
2
trast to 4a the fluorene skeleton of 5a is donor-substituted creasing amounts of solvent these compounds form highly
allowing a second acylation to give the ketone 6, which viscous solutions containing more than 100 gL–1 of the
was reduced with LiAlH /AlCl as well.
solute.
4
3
Finally, the chlorocarbonyloxymethyl moiety was intro-
duced in both 5a and 5b in three steps, consisting of car-
boxylation, reduction of the carboxylic acid with
BH ·Me S, and treatment with an excess of phosgene
Method A
DM
HN
OH
R
N
OH
R
N
O
7
8
9
3
2
9
TMSO
TMSO
OTMS
OTMS
(
Scheme 1).
10
TMSOTf
To prove the suitability of the new protecting groups, we
prepared four trispiranes 2a–d bearing Mio-Fmoc and
Dio-Fmoc groups as well as, for comparison, Dtb-Fmoc,
and the unsubstituted Fmoc groups.
O
O
O
O
Method Aa
FmocOSu, Et(i-Pr) N
R
N
N R
R
a Fmoc
2
b Dtb-Fmoc Dtb-Fmoc-Cl, Na CO
2
3
2
c Mio-Fmoc Mio-Fmoc-Cl, Na CO
2
3
d Dio-Fmoc Dio-Fmoc-Cl, Na CO
2
3
a)
R1
a
solvent: dioxane–H2O = 10:1
O
Scheme 2 Synthesis of trispiranes 2. (DM = Dess–Martin periodi-
nane).
3
4a
b)
Table 1 Solubility and Polarity of Compounds 2
R1
a)
R2
R2
MeOHa
Et Oa
2
Rfb
Compound R
O
6
5a
2
2
2
a
b
c
Fmoc
<0.1
0.36
13.53
3.23
0.53
2.26
> 100
0.32
0.41
0.37
0.78
b)
c)
Dtb-Fmoc
Mio-Fmoc
Dio-Fmoc
R2
R2
R2
O
2d
> 100
5
b
a
Solubility in gL–1.
CH Cl –MeOH (100:4).
O
Cl
c)
b
2
2
R2
R2
7a (Mio-Fmoc-Cl)
To assess the usability of Mio-Fmoc and Dio-Fmoc
groups in SPPS we protected the dipeptide H-GlyGly-OH
with these groups and coupled the products with Wang
resin pre-loaded with glycine. For comparison we used
also the commercially available Fmoc-GlyGly-OH as
well as Dtb-Fmoc-GlyGly-OH. The coupling yields and
O
O
Cl
7
b (Dio-Fmoc-Cl)
Scheme 1 Synthesis of Mio-Fmoc-Cl 7a and Dio-Fmoc-Cl 7b.
1
Reagents and conditions: a) R COCl (1 equiv), AlCl , CH Cl ; b) the average times for cleavage of the protecting groups are
3
2
2
LiAlH , AlCl , Et O; c) i) BuLi, THF, ii) CO , iii) BH ·Me S, iv) collected in Table 2. We found that coupling yields of
4
3
2
2
3
2
1
2
COCl . R = hept-3-yl, R = 2-ethylhexyl (‘isooctyl’).
2
dipeptides with solubility-enhanced Fmoc groups are
comparable with those of Fmoc-GlyGly-OH. The Dio-
The synthesis of the trispiranes is outlined in Scheme 2. 4- Fmoc group has cleavage times similar to the Dtb-Fmoc
Hydroxypiperidine was acylated with Fmoc-OSu or with group, but the Mio-Fmoc group is cleaved at twice the
the chloroformates (Dtb-Fmoc-Cl, 7a, 7b) giving the ure- speed of the Dtb-Fmoc group.
thanes 8 in very good yields. After oxidation of the hy-
droxy group with Dess–Martin periodinane the resulting
Finally, we investigated the influence of Fmoc substitu-
ents on the polarity of the corresponding compounds on
1
0
ketones 9 were treated with the tetrakis(trimethylsi-
the basis of R values. Whereas the Mio-Fmoc derivatives
f
1
1
lyl)ether of pentaerythritol 10 in the presence of catalyt-
have polarities similar to Dtb-Fmoc derivatives, the Dio-
Fmoc group decreases the polarity remarkably (Tables 1
and 2). This should be particularly useful for the purifica-
tion of Dio-Fmoc bearing products and for the separation
ic amounts of TMSOTf according to the procedure
1
2
described by Noyori to afford the trispiranes 2
Scheme 2).
(
The solubility of compounds 2 in MeOH and Et O is sum- of desired products from Dio-Fmoc bearing by-products
2
marized in Table 1. To our delight, 2c and 2d, bearing the (or corresponding conversion products), for example, by
new Fmoc groups, show dramatically improved solubili- flash column chromatography.
Synlett 2006, No. 14, 2235–2238 © Thieme Stuttgart · New York

LETTER
Mio- and Dio-Fmoc – Two Modified Fmoc Protecting Groups
2237
Table 2 Coupling, Cleavage, and Polarity of R-GlyGly-OH13
AlCl (8.8 g, 66.0 mmol, 1.1 equiv) in anhyd CH Cl (200
3
2
2
mL) 2-ethylhexanoyl chloride (11 mL) was added at 0 °C.
After stirring overnight, ice and concd HCl were poured into
the mixture until all the solids had been dissolved. The
phases were separated, the aqueous phase was extracted
twice with dichloromethane, the combined organic phases
were dried, and concentrated. The residue was purified by
flash chromatography (silica).
R
Coupling yield Cleavage Rfc
Rfd
a
b
(
%)
(min)
Fmoc
65
78
61
62
10
0.36
0.60
0.50
0.70
0.48
0.66
0.51
0.80
Dtb-Fmoc
Mio-Fmoc
40
2-(2-Ethylhexanoyl)fluorene (4a)
20
Flash chromatography (PE–CH Cl , 1:1) gave 15.1 g of 4a
2
2
Dio-Fmoc
50
(51.7 mmol, 86%) as a yellow solid; R 0.5 (PE–CH Cl ,
f 2 2
1
1
1
:1). H NMR (CDCl , 300 MHz): d = 0.81–0.93 (m, 6 H),
3
a
TBTU/HOBt, H-Gly-Wang resin.
2
.19–1.35 (m, 4 H), 1.46–1.64 (m, 2 H), 1.73–1.88 (m, 2 H),
.36–3.45 (m, 1 H), 3.92 (s, 2 H), 7.25 (dd, J = 6.8 Hz,
J = 1.0 Hz, 1 H), 7.36 (dt, J = 7.4 Hz, J = 1.5 Hz, 2 H),
.80 (d, J = 7.6 Hz, 2 H), 7.99 (dd, J = 8.1 Hz, J = 1.6 Hz,
b
0% piperidine in DMF, average time until complete cleavage in
3
3
min.
4
3
4
c
R-GlyGly-OH, EtOAc–PE–HCOOH (30:10:1).
Piperidino-dibenzo-fulvene adduct, CH Cl –MeOH (10:1).
3
3
4
7
1
d
2
2
4
13
H), 8.13 (d, J = 0.8 Hz, 1 H). C NMR (CDCl , 75 MHz):
3
d = 12.0, 13.9, 22.9, 25.6, 29.8, 31.9, 36.9, 47.7, 119.7,
In summary, we reported the syntheses and properties of
two novel protecting groups, Mio-Fmoc and Dio-Fmoc,
which cause dramatically enhanced solubility of appropri-
ate derivatives in most organic solvents. Furthermore, we
have shown that the structural modifications of the Fmoc
group only marginally influence their suitability in solid-
phase peptide synthesis.
125.2, 127.0, 127.5, 127.9, 136.3, 140.5, 143.3, 144.5,
146.1, 204.5.
2-(2-Ethylhexanoyl)-7-(2-ethylhexyl)fluorene (6)
Flash chromatography (PE–EtOAc, 10:1) gave 6.81 g of 6
16.83 mmol, 95%) as a yellow oil; R 0.5 (PE–EtOAc,
(
2
1
f
1
0:1). H NMR (CDCl , 300 MHz): d = 0.77–0.89 (m, 12 H),
.17–1.31 (m, 12 H), 1.39–1.60 (m, 3 H), 1.68–1.83 (m, 2
3
H), 2.49–2.61 (m, 2 H), 3.31–3.40 (m, 1 H), 3.86 (s, 2 H),
3
4
7
(
.13 (dd, J = 7.9 Hz, J = 1.2 Hz, 1 H), 7.30 (s, 1 H), 7.67
3
3
4
d, J = 7.8 Hz, 1 H), 7.93 (dd, J = 8.1 Hz, J = 1.5 Hz, 1 H),
8.07 (s, 1 H). C NMR (CDCl , 75 MHz): d = 10.8, 12.0,
1
3
Acknowledgment
3
1
4
1
3.9, 14.1, 22.9, 23.0, 25.4, 25.6, 28.8, 29.8, 31.9, 32.3, 36.8,
0.4, 41.3, 47.6, 119.3, 120.4, 124.8, 126.0, 127.5, 128.1,
35.9, 138.1, 142.3, 143.3, 144.6, 146.4, 204.5.
The financial support of this work by the Deutsche Forschungsge-
meinschaft (Heisenberg fellowship to P.W.) is gratefully acknow-
ledged.
Reduction of 2-Ethylhexanoyl Groups; General
Procedure B
AlCl (12 g, 90.0 mmol, 1.7 equiv) was placed in a 500-mL
References and Notes
3
round-bottom flask and anhyd Et O (300 mL) was added
2
(
(
1) Carpino, L. A.; Han, G. Y. J. Org. Chem. 1972, 22, 3404.
2) Grant, G. A. Synthetic Peptides: A User’s Guide; Oxford
University Press: Oxford, 2002.
cautiously dropwise with external cooling with an ice bath
and stirring. A solution of 4a (51.7 mmol) or 6 in anhyd Et O
2
(100 mL) was added dropwise. After stirring for 30 min
(
3) Chan, W. C.; White, P. D. Fmoc Solid Phase Peptide
Synthesis. A Practical Approach; Oxford University Press:
Oxford, 2004.
LiAlH (3.42 g, 90.1 mmol, 1.7 equiv) was added portion-
4
wise. The mixture was refluxed for 90 min and then allowed
to cool to r.t. The excess of LiAlH was destroyed with
4
(4) Stigers, K. D.; Koutroulis, M. R.; Chung, D. M.; Nowick, J.
S. J. Org. Chem. 2000, 65, 3858.
EtOAc and then dil. HCl was added until gas evolution
ceased. The phases were separated, the organic phase was
(
(
(
5) Dtb-Fmoc-Cl is available from Sigma Aldrich.
6) Carpino, L. A.; Wu, A. J. Org. Chem. 2000, 65, 9238.
7) Selected applications: (a) Chi, C.; Im, C.; Wegner, G. J.
Chem. Phys. 2006, 124, 24907. (b) Egbe, D. A. M.; Nguyen,
L. H.; Hoppe, H.; Mühlbacher, D.; Sariciftci, N. S.
Macromol. Rapid Commun. 2005, 26, 1389. (c) Bunz, U. H.
F. Chem. Rev. 2000, 100, 1605.
dried with MgSO , and evaporated. The residue was purified
by flash chromatography (silica).
2-(2-Ethylhexyl)fluorene (5a)
4
Flash chromatography (PE–CH Cl , 100:3) gave 8.49 g of
2
2
5a (30.5 mmol, 59%) as a yellow solid; R 0.4 (PE–EtOAc,
f
1
100:3). H NMR (CDCl , 300 MHz): d = 0.99–1.09 (m, 6 H),
1.36–1.51 (m, 8 H), 1.69–1.80 (m, 1 H), 2.68–2.80 (m, 2 H),
3.98 (s, 2 H), 7.29 (d, J = 7.8 Hz, 1 H), 7.39 (dt, J = 7.4 Hz,
J = 1.2 Hz, 1 H), 7.45 (s, 1 H), 7.48 (t, J = 6.9 Hz, 1 H),
7.64 (d, J = 7.4 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.87 (d,
J = 7.4 Hz, 1 H). C NMR (CDCl , 75 MHz): d = 10.8,
3
3
3
(
8) Carpino, L. A.; Chao, H. G.; Tien, J. J. Org. Chem. 1989, 54,
4
3
4302.
3
3
(
9) We found that the sequence consisting of carboxylation of
1
4
3
13
lithiated fluorenes followed by the reduction of the
3
1
5
carboxylic acid with borane gives clearly better yields than
the commonly employed treatment of the lithiated fluorenes
with formaldehyde or paraformaldehyde.
14.2, 23.1, 25.4, 28.9, 32.4, 36.8, 40.3, 41.3, 119.4, 119.5,
124.9, 125.8, 126.2, 126.6, 127.8, 139.2, 140.7, 141.8,
143.1, 143.3.
(
10) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
277.
2,7-Bis(2-ethylhexyl)fluorene (5b)
Flash chromatography (PE) gave 4.47 g of 5b (11.44 mmol,
(
7
1
68%) as a colorless oil; R 0.6 (PE). H NMR (CDCl , 300
f
3
(
(
11) Sprung, M. M.; Nelson, L. S. J. Org. Chem. 1955, 20, 1750.
12) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,
MHz): d = 0.85–0.93 (m, 12 H), 1.29–1.38 (m, 16 H), 1.62–
1.64 (m, 2 H), 2.55–2.67 (m, 4 H), 3.85 (s, 2 H), 7.15 (d,
3
1
3
21, 1357.
J = 7.7 Hz, 2 H), 7.32 (s, 2 H), 7.65 (d, J = 7.7 Hz, 2 H).
3
(
13) Friedel–Crafts Acylation of Fluorenes; General
Procedure A
C NMR (CDCl , 75 MHz): d = 10.8, 14.2, 23.1, 25.4, 28.9,
3
32.3, 36.7, 40.3, 41.4, 119.0, 125.8, 127.7, 139.4, 140.1,
143.2.
To a stirred mixture of fluorene (3 or 5a, 60.2 mmol) and
Synlett 2006, No. 14, 2235–2238 © Thieme Stuttgart · New York

2
238
P. Wessig et al.
LETTER
3
3
3
Fluorene-9-carboxylic Acids; General Procedure C1
Fluorene 5a or 5b (19.4 mmol) was dissolved in anhyd THF
J = 7.5 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.70 (d, J = 7.5
1
3
Hz, 1 H). C NMR (CDCl , 75 MHz): d = 10.8, 14.1, 23.0,
3
(30 mL) and cooled to –78 °C. n-BuLi (1.6 M, hexane; 15
25.4, 28.8, 32.3, 40.3, 41.3, 46.0, 73.6, 119.8, 119.9, 125.0,
125.8, 126.8, 128.1, 129.2, 138.8, 141.4, 141.5, 142.4,
150.7.
mL, 24 mmol, 1.2 equiv) was added dropwise and then the
solution was stirred for 1 h. A stream of carbon dioxide,
obtained by evaporation of dry ice was passed through a
drying jar, into the solution for 30 min, while warming to r.t.
The mixture was acidified with dil. HCl to pH 1 and
2,7-Bis(2-ethylhexyl)fluorene-9-methyl Chloroformate
(Dio-Fmoc-Cl) (7b)
Yields: C1, 89%; C2, 60%; C3, 97%. H NMR (CDCl , 300
1
3
extracted with Et O. The solvent was evaporated and the
residue was purified by flash chromatography.
MHz): d = 0.85–0.90 (m, 12 H), 1.26–1.35 (m, 16 H), 1.54–
2
3
1.62 (m, 2 H), 2.53–2.66 (m, 4 H), 4.23 (t, J = 7.6 Hz, 1 H),
3
3
Fluorene-9-methanols; General Procedure C2
Substituted fluorene-9-carboxylic acid (17.24 mmol) was
dissolved in anhyd THF (100 mL) and then BH ·Me S (3.5
4.52 (d, J = 7.7 Hz, 2 H), 7.18 (d, J = 7.8 Hz, 2 H), 7.33 (s,
3
13
2 H), 7.61 (d, J = 7.8 Hz, 2 H). C NMR (CDCl , 75 MHz):
3
d = 10.8, 14.1, 23.0, 25.4, 28.8, 32.3, 40.3, 41.3, 45.9, 73.8,
119.5, 125.8, 129.2, 139.0, 141.0, 142.4, 150.7.
Solid-Phase Peptide Synthesis
3
2
mL, 30.9 mmol, 2.1 equiv) was added dropwise at 0 °C.
After warming to r.t. the solution was stirred for 2 h; crushed
ice and an aq solution of tartaric acid were added cautiously
until gas evolution ceased. The mixture was extracted
The assembly of the peptides was performed in a mechanical
1
6
shaker with a fritted glass reactor. Wang resin (1 mmol/g,
200–400 mesh) is used as the solid support which is
several times with Et O, the organic phases were washed
2
1
7
twice with a sat. aq solution of NaHCO , dried, and
preloaded with Fmoc-Gly-OH. The preloaded resins (50
mg, loading 0.89 mmol/g) were swollen in DMF (0.5 mL)
for 5 min, and than the excess solvent was removed by
filtration. The Fmoc protecting group was removed by
treating twice with 20% piperidine in DMF (5 min and 15
min) and then the resin was washed 5 times with DMF. The
coupling step was performed by the Fmoc strategy using
3
evaporated. The residue was purified by flash
chromatography giving the fluorene-9-methanols.
Fluorene-9-methyl Chloroformates; General Procedure
C3
Fluorene-9-methanol (4.18 mmol) was stirred with a
solution of phosgene (10% in toluene, 7.79 mmol, 1.9 equiv)
in a sealed flask overnight. The solvent was removed in
vacuo and the residue was purified by flash chromatography.
1
8
TBTU/HOBt as activation reagents. In a typical
experiment, each Fmoc-dipeptide (Table 2) was introduced
by a common coupling (60 min) using a two-fold excess of
the dipeptide, activation of reagents, and a three-fold excess
of DIPEA in DMF (0.5 mL). After washing five times with
DMF and twice with CH Cl the resin was dried in high
2-(2-Ethylhexyl)fluorene-9-methyl Chloroformate (Mio-
Fmoc-Cl) (7a)
Instead of flash chromatography the residue of C1 was
purified by dissolution in an aq solution of K CO and
2
3
2
2
extracted several times with Et O. After acidification with
vacuum. The substitution levels of the loaded resins were
determined spectrophotometrically by Fmoc cleavage.
2
3
dil. HCl to pH 1 the product was extracted with CH Cl . The
2
2
solution was dried and evaporated giving the pure fluorene-
-carboxylic acid. Yields: C1, 90%; C2, 55%; C3, 70%;
(14) Burtner, R. R.; Cusic, J. W. J. Am. Chem. Soc. 1943, 65, 262.
(15) Krogh, E.; Wan, P. Tetrahedron Lett. 1986, 27, 823.
(16) Wang, S. J. Am. Chem. Soc. 1973, 95, 1328.
(17) Dörwald, F. Z. Organic Synthesis on Solid Phase: Supports,
Linkers, Reactions; Wiley-VCH: Weinheim, 2000.
(18) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D.
Tetrahedron Lett. 1989, 30, 1927.
9
1
R 0.6 (PE–EtOAc, 100:2). H NMR (CDCl , 300 MHz): d =
f
3
0
2
2
.85–0.89 (m, 6 H), 1.20–1.34 (m, 8 H), 1.56–1.62 (m, 1 H),
3
.52–2.64 (m, 2 H), 4.23 (t, J = 7.6 Hz, 1 H), 4.44–4.57 (m,
3
3
4
H), 7.18 (d, J = 7.8 Hz, 1 H), 7.27 (dt, J = 7.4 Hz, J = 1.0
3
Hz, 1 H), 7.33 (s, 1 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.53 (d,
Synlett 2006, No. 14, 2235–2238 © Thieme Stuttgart · New York