Synthesis and solid-phase application of a 9-xanthenyl handle

Article abstract of DOI:10.1515/znb-2001-0609

The acid-labile 5-[(9-aminoxanthen-2-yl)oxy]valeric acid was prepared in a six-step route. The usefulness of the resulting handle was investigated with solid-phase peptide synthesis of cholecystokinin-8 sulfate and the phosphorylated fragment of the ζ-sub

Full text of DOI:10.1515/znb-2001-0609

Synthesis and Solid-Phase Application of a 9-Xanthenyl Handle
Csaba Somlai3, Péter Hegyesb, R óbert Fenyö3, G abor K. Tótha, Botond Penke3,
and Wolfgang Voelterc
a University of Szeged, Department of Medical Chemistry, Dom ter 8, H-6720 Szeged,
Hungary
b University of Szeged, Department of Organic Chemistry, Dom ter 8, H-6720 Szeged,
Hungary
c Abteilung für Physikalische Biochemie, Physiologisch-chemisches Institut der
Universität Tübingen, Hoppe-Seyler-Strasse 4, D-72076 Tübingen, Germany
Reprint requests to Dr. C. Somlai.
Fax: (36) 62-545 971. E-mail: scsaba@mdche.szote.u-szeged.hu
Z. Naturforsch. 56b, 526-532 (2001); received November 2, 2000
Polymer Support, Solid-Phase Synthesis, Xanthene
The acid-labile 5-[(9-aminoxanthen-2-yl)oxy]valeric acid was prepared in a six-step route.
The usefulness of the resulting handle was investigated with solid-phase peptide synthesis of
cholecystokinin-8 sulfate and the phosphorylated fragment of the ^-subunit of the T-cell
receptor complex 138-144.
Introduction
care (easy loss of the 9-hydroxy functional group),
preparation of the appropriate 2-substituted com-
pound (XAL2) proved to be much easier and less
risky [13].
Until now, a series of polymers and handles
have been used in the solid-phase peptide synthe-
sis [1- 10] to obtain acid-sensitive peptides and/or
partially or fully protected peptide fragments. Pro-
tected peptide amides can be released from xan-
thenyl-modified resins under very mild conditions
Results and Discussion
Based in part on our experience [14] and in part
without the risk of prem ature side-chain deprotec- on a reasonable literature procedure [13], the de-
tion [11-13]. Earlier studies on the preparation
and the application of different xanthene-derived
sired target compound, 5-[(9-aminoxanthen-2-yl)-
oxy]valeric acid (XAL2) was prepared on a six step
compounds as handles for solid-phase peptide syn- route (Scheme 1) starting from o-chlorobenzoic
thesis [11-14] prom pted us to try the large-scale
synthesis of 5-[(9-aminoxanthen-2-yl)oxy]valeric
acid (XAL2) and to reinvestigate its efficiency in
this field. On the other hand, we reported in 1994
acid and 4-methoxyphenol applying the Ullmann
reaction [17]. The diphenyl ether derivative 1, ob-
tained in 70% yield, was treated with dehydrating
agents to give 2-methoxyxanthone 2. 2-Hydroxy-
[14] that semiempirical quantumchemical m ethods xanthone 3 was prepared by refluxing of 2 in 2,6-
(A M I, MNDO, PM3) and programs (AMPAC,
MOPAC, PcMOL) may be useful tools to design
new acid-sensitive handles [14-16]. According to
our results, there is a close relationship between
the calculated enthalpy and free enthalpy values
lutidine in the presence of Lil for 2 days or by
heating of 2 in pyridine hydrochloride at 210° C
for 3 h. The phenolic function of 3 was alkylated
with ethyl 5-bromovalerate to give 4. The free acid
5 could be collected after saponification of 4. The
of protolytic cleavage reactions and the experi- 9-oxo group of 5 was selectively transformed to
mentally measured acid-labilities of the com- the corresponding amino function by reducing 5
pounds. As a result 5-[(9-hydroxyxanthen-3-yl)-
oxy]valeric acid (XAL3) was selected and
synthesized, and its acid-lability was checked using
5% TFA in CH2C12. As the final reduction step of
this synthesis as well as the isolation of the end-
product met with some difficulties and required
with N aBH 4 followed by stirring the mixture with
(NH4)H C 0 3 for 24 h at room tem perature as re-
ported by Han and associates [13]. 5-[[9-[(9-Fluor-
enylmethyloxycarbonyl)amino]xanthen-2-yl]oxy]-
valeric acid (Fmoc-XALa 7) was prepared accord-
ing to the standard literature method [18] and at-
0932-0776/2001/0600-0526 $06.00 © 2001 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
D
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C. Somlai et al. ■Synthesis and Solid-Phase Application of a Xanthenyl Handle
527
X O O H
K2C 0 3, Cu, Cul
^ - ^
C O O H ^ " \^ O C H 3
© L
* J 0 T
® C „
~
1
ACjO, cc.H2S 0 4
80°C,1h
90%
pyridine hydrochloride
210 °C, 3h
OCH-,
94%
Br(CH2)4COOEt
87 %
K2C 03, acetone,
15h reflux
MeOH / aq. KOH
----3--5---4-0---°-C-,--1-h---
1
98%
1.NaBH4 in aq.NaOH,
MeOH, 50 °C
90%
2. (NH4)HC03, 24h
dioxane/H20
O'CHACOOH
m K ( , tFm x> O S u
©(CH^COOH
71 %
Scheme 1. Synthesis of Fmoc-XALa handle 7.
creatic exocrine secretion, gallbladder contraction,
and may also act as a neurotransm itter in the
central nervous system, was readily assembled by
tached to 4-methylbenzhydrylamino-poly(styrene-
co-1% divinylbenzene) resin. The coupling was al-
lowed to proceed in a manual Merrifield vessel by
shaking with DCC/HOBt in DM F at room tem - the stepwise Fmoc/'Bu solid-phase procedure [19].
perature and gave 0.50-0.59 mmol/g loading.
Cholecystokinin sulfate ester [CCK-8 sulfate,
Asp-Tyr(S03H)-Met-Gly-Trp-Met-Asp-Phe-NH2],
The side chain carboxyls of aspartates were pro-
tected as the tert-butyl esters, and other residues
were unprotected. Fm oc-Tyr(S03Na)-C)H was
an acid-labile octapeptide, which stimulates pan- produced and tested in our laboratory. Coupling
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528
C. Somlai et al. • Synthesis and Solid-Phase Application of a Xanthenyl Handle
occh^ co o h
Polymer
DCC/HOBt
DMF
Fmoc-XAL2 handle
7
MBHA resin
0S 03h
H-Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2
CCK-8 sulfate
+
Scheme 2. Synthesis of CCK-8 sulfate on XAL2 handle.
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C. Somlai et al. ■Synthesis and Solid-Phase Application of a Xanthenyl Handle
529
of Fmoc amino acids to the Fmoc-XAL^-MBHA
polym er was performed using the D CC/HOBt
protocol, except for Fm oc-Tyr(S03N a)-OH which
was introduced via the BOP/HOBt/NM M method
[20], U pon completion of chain assembly, the pep-
A sp-G ly-Leu-Tyr(P03H 2)-Gln-Gly-Leu-NH2, a
phosphotyrosine-containing heptapeptide of the £-
subunit of the T-cell receptor complex was synthe-
sized by SPPS Fmoc-methodology using the Fmoc-
XAL2-M BHA polymer and a modified synthesis
tidyl-resin was obtained in ca. 96% yield. As we protocol. The side chain of aspartic acid was pro-
found, the peptidyl-aminoxanthene bond could be
selectively cleaved with 50% TFA in CH2C12 in
the presence of scavangers (thiocresokani-
sole:DMS, 1:1:4) at room tem perature (Scheme 2).
Different cleavage times (5, 15, 30, and 60 min)
were used to check the peptide composition of the
cleavage mixture. HPLC analysis indicated that
tected by O lBu, the phenolic hydroxyl of the tyro-
sine residue rem ained unprotected. Couplings
were perform ed with DCC with the exception of
Gin, which was incorporated as H O Bt ester. A fter
coupling of Tyr, the phenolic hydroxyl was phos-
phitylated using di-terr-butyl-A^,N-diethyl phos-
phoramidite [21], then the phosphite was oxidized
15 min cleavage proved to be the optimal one, to phosphate using terr-butyl hydroperoxide. Elon-
yielding 45% sulfated peptide and 15% of unsul-
fated CCK-8 , though tert-butyl protection of the
side chain of the aspartates was still present to the
gation of the peptide chain was completed and the
resulting crude phosphopeptide was detached
from the resin by TFA/DCM / anisole (62:30:8) at
extent of -40% during this period. Desulfation be- 0° C within 1,5 h. One more hour was needed for
came prominent (74%) and only 14% of sulfate
ester could be detected using 60 min cleavage
(Fig. 1). It should be noticed that these findings
are significantly different from those reported by
Barany’s group [13] using 15 min cleavage: -70%
of the total peptide material was the desired CCK-
8 sulfate, and the cleavage mixture contained also
10% of unsulfated CCK-8 and only 20% of CCK-
8 sulfate retaining terr-butyl side chain protection.
the deprotection of the phosphate ester group. The
free peptide was precipitated with diethyl ether,
dissolved in water and lyophilized (Fig. 2).
In conclusion, our synthetic route to the 3-sub-
stituted xanthene derivative can be successfully
applied for the large-scale preparation of 5-[(9-
aminoxanthen-2-yl)oxy]valeric acid. The solid-
phase application of this handle has been dem on-
strated for the syntheses of the acid-labile sulfated
80
desulfated peptide
fert-butylated peptide
60
40
20
-
o
£
a)
Q-
0
15
30
45
60
time [min]
Fig. 1. Relationship between the crude peptide composition and cleavage time.
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530
C. Somlai et al. • Synthesis and Solid-Phase Application of a Xanthenyl Handle
Fig. 2. HPLC profile of the crude phosphopep-
tide. Conditions: Lichrosorb-100 RP 18 Column
(250x4.6 mm, 10,wm particle size); mobile phase
60% acetonitrile, 0.1% TFA; gradient elution
from 5% to 80%; flow rate 0.8 ml/min.
Time (min)
CDCI3): (5 = 3.82 (s, 3 H, OMe), 6.76-8.18 (8 H,
aromatic H). - C14H 120 4 (242.2): calcd. C 68.85,
H 4.95; found C 69.20, H 4.76.
and phosphorylated tryptophan-containing amino
acid sequences.
Experimental
2-Methoxyxanthone (2)
All reagents and solvents were of reagent grade
and purchased from Sigma-Aldrich Kft (Budapest,
Hungary). 9-Fluorenylmethylsuccinimidyl carbon-
ate was received from Bachem (California, USA).
Melting points were obtained with a PAMK VEB
apparatus and are uncorrected. TLC was per-
formed on silica gel precoated glass plates 60 F254
(Merck). Spectral data were acquired on a Bruker
AN 400 MHz spectrom eter (]H NM R and 13C
NM R). Microanalyses were carried out with a
CHN analyser (Prague).
Acid 1 (60 g, 245.7 mmol) was dissolved in Ac20
(400 ml) and concd H 2S 0 4 (16 ml), the solution
was stirred at 80° C for 1 h and poured onto ice-
water. The greenish solid precipitate was filtered,
washed with water to neutral, and dried. 50 g
(90%) of product was obtained. An analytical
sample was recrystallized from acetone/water.
M.p. 132.5-134.5° C. - Rf = 0.63 (EtOAc/n-hex-
ane 1:1). - !H NM R (400 MHz, CDC13): <5 = 3.78
(s, 3 H, s, OM e), 7.13-8.22 (7 H, aromatic H). -
C i4H 10O 3 (226.2): calcd. C 74.33, H 4.46; found C
74.67, H 4.33.
2-[(4-Methoxyphenyl)oxy]benzoic acid (1)
o-Chlorobenzoic acid (50 g, 320 mmol) was dis-
solved in DM F (350 ml) and anhydrous K2C 0 3
2-Hydroxyxanthone (3)
a.) 2-M ethoxyxanthone (2, 32 g, 141.6 mmol)
was dissolved in 2 ,6-lutidine (280 ml) and then an-
hydrous Lil (48 g, 358.8 mmol) was added. The
mixture was heated under reflux and N2 atmo-
sphere for 2 days. A fter diluting with water, the
(110 g,
596 mmol),
4-methoxyphenol
(46 g,
362 mmol), Cu powder (1.28 g, 20 mmol), Cul
(1.28 g, 6.74 mmol) and Clealand’s reagent (1 g,
6.4 mmol) were added. The reaction mixture was
heated under reflux for 6 h in N2 atmosphere.
DM F was evaporated in vacuo, then the oily resi- solution was acidified with HC1 to pH = 2. The
precipitate was filtered, washed with water and
dried to give 3 (29.2 g, 97%). An analytical sample
was recrystallized from ethyl acetate/«-hexane.
M.p. 238-242° C. - Rf = 0.42 (EtOAc/n-hexane
1:1).
due was poured onto ice-water acidified with HC1
to pH = 2. The crude product was precipitated as
an oil, which solidified on standing overnight at
0° C. The brown precipitate was filtered, washed
with water, dried and recrystallized from acetone/
water, 54.8 g (70%). M.p. 139-141° C. - Rf = 0.26
b.) 2-M ethoxyxanthone (2, 33 g, 146 mmol) and
pyridine hydrochloride (100 g, 865 mmol) were
(benzene:M eOH 9:1).
-
JH NM R (400 MHz,
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C. Somlai et al. • Synthesis and Solid-Phase Application of a Xanthenyl Handle
531
small portions over 30 min under stirring, which
was continued for at room tem perature
(checking by TLC). A fter adding (N H 4)H C 0 3
heated at 210° C for 3 h in N2. The mixture was
cooled and poured onto ice-water, acidified with
HC1 to pH = 2. The precipitate was filtered off,
1
h
washed with water and dried, 29 g (94%). An ana- (228 g, 450 mmol), stirring was continued for 24 h
lytical sample was recrystallized from acetone/n- at room tem perature while a white-yellow suspen-
sion was formed, which was acidified to pH = 5 -
6 by careful addition of 10% aqueous citric acid.
The product was collected by filtration, washed
with water, dried and used without further purifi-
cation. Yield 27 g (90%), M.p. 133-143° C. - Rf =
0.25 (CH 2Cl2/M eO H 7:3).
hexane. M.p. 238-239° C. - Rf = 0.42 (EtOAc/n-
hexane 1:1). - lH NMR (400 MHz, CD3OD): (3 =
3.30 (m, 1 H, OH), 7.28-8.24 (7 H, aromatic H). -
C13H 80 3 (212.2): calcd. C 73.58, H 3.80; found
C 73.73, H 3.94.
Ethyl 5-[(9-oxoxanthen-2-yl)oxy]valerate (4)
5-[[9-[(9-Fluorenylmethyloxycarbonyl)-
amino]xanthen-2-yl]oxy]valeric acid (7)
2-Hydroxyxanthone (3, 42 g, 198 mmol) was sus-
pended in anhydrous acetone (21), then anhy-
drous K2C 0 3 (142 g, 1030 mmol) and ethyl 5-bro-
m ovalerate (81.9 ml, 514.5 mmol) were added. The
reaction mixture was refluxed for 15 h with stir-
ring. The cooled mixture was filtered to remove
inorganic salts and washed with acetone. The
filtrate was evaporated in vacuo to dryness and the
residue was crystallized from EtOAc/w-hexane to
give 4 (58.6 g, 87%) product. M.p. 62-64° C. -
Rf = 0.67 (EtOAc/«-hexane 1:1). - !H NM R (400
MHz, CDC13): <3 = 1.25 (b, J = 7.1 Hz, 3 H, Me),
1.83 (m, 4 H, CH2), 2.38 (t, J = 6.9 Hz, 2 H, CH2),
4.05 (m, 2 H, CH2), 4.15 (q, J = 7.1 Hz, 2 H, CH2),
7.24-8.32 (7 H, aromatic H). - C20H 2o 0 5 (340.3):
calcd. C 70.58, H 5.92; found C 70.85, H 6.13.
N aH C 0 3 (12.1 g, 144.4 mmol) was suspended in
dioxane/water (1200 ml, v/v 1:1), then 5-[(9-amino-
xanthen-2-yl)oxy]valeric acid 6 (22.6 g, 72.2 mmol)
and Fmoc-ONSu (26.8 g, 79.5 mmol) were added.
The reaction mixture was stirred for 10 h at room
tem perature, acidified with A cOH to pH = 6.3
while the product was precipitated as a light-yel-
low solid. The product was collected by filtration,
washed with water, dried and crystallized from
EtOAc/n-hexane. Yield 27.3 g (71%). M.p. 205-
206° C. - Rf = 0.53 (EtOAc/M eOH 5:1). - !H
NM R (400 MHz, C D 3SOCD3): (3 = 1.60-1.80 (m,
4 H, CH2), 2.25 (t, / = 2 Hz, 2 H, CH2), 3.90 (m,
2 H, CH 2), 4.27 (t, J = 5.8 Hz, 1 H, CH), 4.44 (d,
J = 5.8 Hz, 2 H, CH 2), 5.92 (d, J = 7.6 Hz, 1 H,
CH), 6.85-7.95 (15 H, aromatic H), 8.31 (d, J =
7.8 Hz, 1 H, NH). - C33H 29N 0 6 (535.60): calcd.
C 74.00, H 5.45, N 2.61; found C 74.13, H 5.30,
N 2.41.
5-[(9-Oxoxanthen-2-yl)oxy]valeric acid (5)
Aqueous KOH (40 g, dissolved in 200 ml of
water) was added to the suspension of ethyl ester
4 (82 g, 241.2 mmol) in M eOH (600 ml). A fter stir-
ring for 1 h at 35-40° C, the reaction mixture was
homogeneous and was poured onto ice-water,
acidified with HC1 to pH = 2. A white precipitate
was formed quickly, which was collected, washed
with water, and dried. Yield: 73.7 g (98%). M.p.
146-149° C. - Rf = 0.69 (CH2Cl2/M eOH 7:3). -
*H NM R (400 MHz, CD3SOCD3): <5 = 1.60-1.85
(m, 4 H, CH2), 2.15 (t, / = 2 Hz, 2 H, CH2), 4.10
(t, J = 2.1 Hz, 2 H, CH2), 7.40-8.30 (7 H, aromatic
H). - C18H 160 5 (312.3): calcd. C 69.22, H 5.16;
found C 68.87, H 5.05.
Introduction o f compound 7 onto MBHA resin
M BHA hydrochloride resin (70 g, 1.03 mmol/g)
was swelled in CH 2C12 (700 ml), then neutralized
by 10% TEA /C H 2C12. A fter washing by CH2C12,
M eO H and CH2C12 (3 x with each), the coupling
was done in DM F (700 ml) using Fmoc-XALa
(70 g, 130.7 mmol), DCC (26.9 g, 130.7 mmol) and
H O B t (8.8 g, 65.4 mmol) for 24 h at room tem per-
ature (checking by Kaiser test [22]). The resin was
filtered, washed with DMF, CH2C12 and M eOH,
then dried. 120 g (0.50-0.59 mmol/g) of modified
resin was obtained.
5-[(9-Aminoxanthen-2-yl)oxy]valeric acid (6)
Keto acid 5 (30 g, 96 mmol) was suspended in
H 20 , then dissolved by adding a solution of 1 M
aqueous NaO H (110 ml, 110 mmol). NaBH4 was
added in a single portion. The reaction mixture
was stirred for 2.5 h at 50-52° C, cooled to 10° C
and solid N aH C 03 (54 g, 200 equiv.) was added in
Analysis o f the composition o f the cleavage mixture
for CCK-8 sulfate
A fter deprotection of the Fmoc group by 20%
piperidine/DM F, the peptidyl resin (50 mg) was
suspended in the cleavage coctail (TFA:CH2C12:-
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532
C. Somlai et al. • Synthesis and Solid-Phase Application of a Xanthenyl Handle
thiocresol: anisole:DMS, 50:38:2:2:8, 1 ml) and
stirred at room tem perature for 5 min. The resin
constructing Fig. 1. The same procedure was ap-
plied using cleavage times of 10, 15, 30, and
was filtered, washed with TFA (0.5 ml), and diiso- 60 min.
propyl ether (5 ml) was added to the filtrate. The
Acknowledgements
precipitate was collected by filtration and checked
by HPLC. HPLC m easurements were perform ed
on a Hewlett Packard 1050 instrument [conditions:
The research was supported by the Hungarian
Research Foundation (OTKA, No. 22551/1997).
Lichrosorb 100 10RP 18 column (250x4.6 mm); The authors wish to thank E. M enyhärth, E. M.
mobile phase 60% acetonitrile, 0.1% TFA; gradi-
ent elution from 5% to 80%; flow rate 0.8 ml/min;
220 nm]. The intensities of the peaks was used for
Dösai and I. Nögrädi for the excellent technical
assistance and R. Ferenci for his contribution pre-
paring the manuscript.
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