Solid-phase synthesis of 5'-O-[N-(Acyl)sulfamoyl]adenosine derivatives

Article abstract of DOI:10.1002/ejoc.201200329

The solid-phase synthesis of 5'-O-[N-(acyl)sulfamoyl]adenosine derivatives is described. The use of a Rink amide polystyrene solid support together with an appropriately protected ribo-purine starting material allowed for the development of a highly reliable and practical route for the solid-phase synthesis of 5'-O-[N-(acyl)sulfamoyl]adenosines. The developed procedure enables the efficient parallel synthesis of the target compounds in high yields. These compounds are non-hydrolysable isosteres of acyl-adenylates, which play an important role in a range of different metabolic pathways such as ribosomal and non-ribosomal peptide synthesis, fatty acid oxidation or enzyme regulation; some adenylate-forming enzymes are potential drug targets.

Full text of DOI:10.1002/ejoc.201200329

FULL PAPER
DOI: 10.1002/ejoc.201200329
Solid-Phase Synthesis of 5Ј-O-[N-(Acyl)sulfamoyl]adenosine Derivatives
Itedale Namro Redwan,[a] Hanna Jacobson Ingemyr,[a] Thomas Ljungdahl,[a]
Christopher P. Lawson,[b] and Morten Grøtli*[a]
Keywords: Medicinal chemistry / Synthetic methods / Solid-phase synthesis / Enzymes / Nucleosides
The solid-phase synthesis of 5Ј-O-[N-(acyl)sulfamoyl]adenos- of the target compounds in high yields. These compounds
ine derivatives is described. The use of a Rink amide poly-
are non-hydrolysable isosteres of acyl-adenylates, which
styrene solid support together with an appropriately pro- play an important role in a range of different metabolic path-
tected ribo-purine starting material allowed for the develop-
ment of a highly reliable and practical route for the solid-
phase synthesis of 5Ј-O-[N-(acyl)sulfamoyl]adenosines. The
developed procedure enables the efficient parallel synthesis
ways such as ribosomal and non-ribosomal peptide synthesis,
fatty acid oxidation or enzyme regulation; some adenylate-
forming enzymes are potential drug targets.
Adenylate-forming enzymes play an important role in a
range of different metabolic pathways such as ribosomal
Introduction
In nature unreactive moieties such as the carboxylates are and non-ribosomal peptide synthesis, fatty acid oxidation
activated by adenylate-forming enzymes.[1] The activation or enzyme regulation.[1] Some of these enzymes are impor-
process involves the reaction of adenosine triphosphate tant potential drug targets, such as aminoacyl-tRNA syn-
(ATP) with the desired substrate and results in the forma- thetases,[2] Mycobacterium tuberculosis pantothenate syn-
tion of an acyl-adenylate and pyrophosphate (Scheme 1, thetase[3,4] and aryl acid adenylating enzymes involved in
step 1). In a second step this reactive group is replaced in a siderophore biosynthesis by Mycobacterium tuberculosis.[5,6]
nucleophilic substitution reaction to form esters, amides or The acyl-adenylate is assumed to bind tightly to the active
thioesters, which are common building blocks in nature site of adenylate-forming enzymes. Consequently, it is ex-
(Scheme 1, step 2). This process is comparable with the acti- pected that non-reactive analogues of the acyl-adenylate
vation of substrates by the formation of acid chlorides or would be potent inhibitors of these enzymes. This approach
anhydrides which are common in synthetic organic chemistry. has precedence in the inhibition of aminoacyl-tRNA syn-
Scheme 1. The two-step adenylation reaction catalyzed by adenylate-forming enzymes to acylate alcohols, amines or thiol moieties.
thetases by sulfamoyl adenylate analogues that mimic the
[a] Department of Chemistry and Molecular Biology, University
aminoacyl adenylate (aa-AMP) intermediate.[2,7]
of Gothenburg,
41296 Göteborg, Sweden
We previously reported the design and synthesis of sev-
eral non-hydrolysable sulfamoyl analogues of aa-AMP
which have been used by collaborators in structural studies
of a number of tRNA synthetases.[8–10] More recently, we
reported an improved solution-phase protocol for the syn-
thesis of sulfamoyloxy-linked aa-AMP analogues.[11]
Fax: +46-31-7721394
[b] Department of Chemical and Biological Engineering/Physical
Chemistry, Chalmers University of Technology,
41296 Gothenburg, Sweden
E-mail: grotli@cmb.gu.se
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200329.
Eur. J. Org. Chem. 2012, 3665–3669
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Herein we report a novel solid-phase strategy which en- ing and quantification of each reaction step performed on
ables the synthesis of structurally different 5Ј-O-[N-(acyl)- polymer supported compounds 3 and 4. The developed
sulfamoyl]adenosines from a common intermediate.[5,11–13] method included a small-scale cleavage followed by the use
The developed solid-phase protocol enables the straightfor- of toluene as the internal standard (see Supporting Infor-
ward parallel synthesis of several 5Ј-O-[N-(acyl)sulfamoyl]- mation).
adenosines in quantities sufficient for biological evaluation.
The first step in the synthesis consisted of protection of
the 2Ј- and 3Ј-hydroxys of commercially available 6-chloro-
purine riboside using benzaldehyde as both the solvent and
reagent in the presence of ZnCl2. The 2Ј,3Ј-benzylidene
acetal-protected compound 2 was obtained in 76% isolated
yield (Scheme 2).
The conditions required for the attachment of 2 to Rink
amide aminomethyl polystyrene (PS-Rink AM) were evalu-
ated utilising different bases, temperatures (both micro-
wave-assisted and conventional heating) and reaction time
before arriving at the conditions employed (Table 1).
Results and Discussion
Several key considerations were taken into account in or-
der to develop a strategy for the solid-phase synthesis of 5Ј-
O-[N-(acyl)sulfamoyl]adenosine derivatives. First, the syn-
thesis focused on the derivatisation of the 5Ј-position of the
ribose subunit. Consequently, the 2Ј,3Ј-hydroxy groups of
the ribose and the exocyclic amino function needed to be
protected or be used as points of attachment to the solid
support. Initially, we planned to attach the nucleosides to
the solid support via an acetal linkage.[14] The chemical
properties of a 2Ј,3Ј-acetal linkage allow for minimal pro-
tecting group manipulation throughout the synthesis and
cleavage under mild acidic conditions, which is essential to
keep the glycosidic bond intact. However, in our hands this
strategy resulted in very low yields in the solution phase
preparation of the building block that would be attached to
the resin (data not shown).
Table 1. Evaluated reaction conditions for the attachment of 2 to
PS-Rink AM.[a]
Entry
Base
T [°C]
t [h][c]
% Yield[c]
1
2
3
4
DIPEA
DIPEA
DBU
50
80[b]
50
20
2.5
20
22
52
64
80
DBU
80[b]
2.5
[a] Fmoc protective group cleaved from PS-Rink AM (1 equiv.,
An alternative strategy involving the attachment of 2Ј,3Ј- loading ≈ 1.0–1.1 mmol/g) using 20% piperidine in DMF and 2
(4 equiv.), base (4 equiv.), BuOH/DMSO (1:1). [b] Microwave-as-
sisted heating. [c] The yields were quantified using a derived HPLC
method with toluene as the internal standard.
O-benzylideneadenosine via the N-6 amino group to a trityl
linker was attempted. The trityl linker can be cleaved under
very mild conditions and would be compatible with the
chemical reactions planned to be performed on the solid
support. However, due to the low nucleophilicity of the N-
6 amine group only very low coupling yields were obtained
(data not shown).
The Fmoc deprotection of the PS-Rink AM was
achieved using 20% piperidine in DMF prior to the attach-
ment of 2. The initial conditions for the coupling of 2 uti-
lised DIPEA as the base at 50 °C for 20 h in a sealed reac-
We then considered attaching the 2Ј,3Ј-O-benzylidene-6-
tion vial (Entry 1). The desired resin bound 3 was obtained
chloropurine riboside to a Rink amide resin by a nucleo-
in 22% yield as indicated by the derived HPLC quantifica-
philic displacement reaction (Scheme 2). This Rink amide
tion method, in which toluene was used as the internal stan-
linker had previously been used for attaching various purine
dard. The reaction was repeated using microwave irradia-
tion at 80 °C for 2.5 h which afforded 3 in an improved 52%
derivatives and to make combinatorial libraries thereof.[15]
yield (Entry 2). The use of DBU as the base with conven-
tional heating at 50 °C for 20 h (Entry 3) increased the yield
further (64%), and using DBU with microwave irradiation
at 80 °C for 2.5 h afforded the highest yield for the attach-
ment of 2 (80%) (Entry 4).
Sulfamoylation of the 5Ј-hydroxy function typically in-
clude the use of sulfamoyl chloride in combination with
bases such as NaH,[16] DBU[4] or TEA.[17] Recently, we pub-
lished a high yielding solution-phase protocol for the sulf-
amoylation of the 5Ј-hydroxy using the combination of
sulfamoyl chloride and DMAP as reagents.[11] We antici-
pated that this procedure could be applied to the sulfamo-
ylation of the 5Ј-hydoxy group while attached to a solid
support (Scheme 3).
The sulfamoylation was performed by the addition of
sulfamoyl chloride and DMAP to resin 3. The reaction mix-
ture was then agitated for one hour at room temperature
followed by a thorough wash with DCM. This procedure
Scheme 2. Synthetic procedure leading to the polymer supported
synthetic precursor 3. Reagents and conditions: a) ZnCl2 (5 equiv.),
freshly distilled benzaldehyde, room temp, N2, 72 h. b) i. Fmoc pro-
tective group cleaved from PS-Rink AM (1 equiv., loading ca. 1.0–
1.1 mmol/g) using 20% piperidine in DMF and ii. 2 (4 equiv.),
DBU (4 equiv.), BuOH/DMSO (1:1), MW 80 °C, 2.5 h.
To provide an effective analysis tool, we developed a re- was repeated two more times resulting in the sulfamoylation
versed-phase HPLC method suitable for reaction monitor- of 3 in quantitative yields. This result confirmed that the
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Solid-Phase Synthesis of Adenosine Derivatives
Scheme 3. Sulfamoylation of compound. 3. Reagents and condi-
tions: a) sulfamoyl chloride (3ϫ 3.0 equiv.), DMAP (3ϫ
3.0 equiv.), DMF, 3ϫ 1 h, room temp, N2.
developed sulfamoylation protocols are suitable for both
solution-phase and solid-phase based methodologies.
In our published protocol for the acylation of the sulf-
amate moiety using our solution phase methodology, the
problems arising from the formation of an insoluble N,NЈ-
dicyclohexylurea were solved by the employment of the
polymer supported coupling reagent PS-N,NЈ-dicyclohex-
ylcarbodiimide (PS-DCC) in combination with DMAP, the
aminoacylation was achieved in high yield.[11] Analogously,
the acylation of polymer supported 4 was carried out using
N,NЈ-diisopropylcarbodiimide (DIC) in the presence of
DMAP. The N,NЈ-diisopropylurea formed during the reac-
tion was soluble and could therefore be easily removed after
completion of the reactions. The acids were activated using
DIC and DMAP in DCM for 30 min at room temperature
prior to addition to pre-swelled 4. The reaction mixtures
were then agitated at room temperature for 16 hours
(Scheme 4). In the case of compound 5e, the initial acyl-
ation was performed using Fmoc-phenylalanine. Subse-
quent removal of the Fmoc group with 20% piperidine in
DMF, careful washing of the resin followed by a second
aminoacylation and Fmoc deprotection furnished 5e.
This procedure enables effective acylation of the sulf-
amoyl functionality with structurally diverse acylating
agents without the formation of an insoluble urea by-prod-
Scheme 4. Acylation, cleavage and deprotection reactions to obtain
the target compounds 6a–6e, yields are given for three steps starting
with 4. Reagents and conditions: a) acid (20 equiv.), DIC
(20 equiv.), DMAP (20 equiv.), DCM, room temp, N2, 16 h. b) 5%
TFA in DCM, 3ϫ 30 min. c) ammonium formate (5 equiv.), 10%
Pd/C (10wt.-%/wt.), MeOH, 60 °C, 16 h. * Aminoacylation was
performed as in a) then 20% piperidine in DMF, 20 min, twice c)
as above.
above and compound 6d was isolated in 33% yield (over
three steps) after deprotection. Deprotection of 5e lead to
the isolation of 6e in 39% yield over six reaction steps. The
advantage of performing the cleavage from the polymer
support and deprotection in a two-step protocol allows the
utilization of a wide variety of acyl groups while preventing
any potential side-reactions which might arise from hetero-
functionalities present in the acylating agent.[11]
Conclusions
We have developed a general and efficient solid-phase
uct. The protocol is also useful for synthesising compounds protocol for the synthesis of structurally different 5Ј-O-[N-
with a wide range of structures/functional groups based on (acyl)sulfamoyl]adenosines from a common intermediate.
the choice of the attached acyl group.
Three different attachment approaches were investigated
After a thorough wash cycle, compounds 5a–5e were which resulted in the anchoring of 2Ј,3Ј-O-benzylidene-6-
cleaved from the polymer support using 5% TFA in DCM. chloropurine riboside to PS-Rink AM resin. Quantitative
The crude compounds 5a–5e were then deprotected using sulfamoylation of the polymer-supported intermediate was
ammonium formate and 10% Pd/C at 60 °C for 16 hours. achieved, followed by acylation using DIC and DMAP as
Compounds 6a and 6b were synthesized using Cbz-valine the coupling reagents. Cleavage and deprotection of the
and Cbz-alanine, respectively, for the aminoacylation fol- acylated products 5a–5e resulted in the target compounds
lowed by deprotection and isolation to afford the target 6a–6e. The target compounds were purified using prepara-
compounds in the yields indicated (Scheme 4, yields given tive HPLC, and the combined yields obtained over three
over three steps). The synthesis of 6c was performed using (six for 5e) reaction steps were in the range of 33–48%. The
2-O-benzyl-protected salicylic acid for the acylation of 4, developed solid-phase protocol enables the parallel, rapid
deprotection of crude 5c resulted in the isolation of the de- and efficient synthesis of structurally diverse 5Ј-O-[N-(acyl)-
sired product 6c in 38% yield over three steps. Hexanoic sulfamoyl]adenosines in quantities sufficient for biological
acid was activated using the reaction conditions discussed screening.
Eur. J. Org. Chem. 2012, 3665–3669
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M. Grøtli et al.
FULL PAPER
using toluene as the internal standard in MilliQ water and MeCN
(7:3) (8 mm, 46.7 mL) yielding 3 in 80% yields.
Experimental Section
General: All commercial chemicals were used as received without
further purification. Pyridine was dried with molecular sieves,
ZnCl2 was dried in vacuo and DCM was freshly distilled from CaH
prior to use. 1HNMR (400 MHz) and 13CNMR (100 MHz) spectra
were obtained using a Varian 400/54 spectrometer. Mass spectro-
scopic data were obtained using electrospray ionization (ESI). Col-
umn chromatography was performed using manual flash
chromatography with packed silica gel 60 (particle size 0.04–
0.063 mm) or by automated column chromatography using a Bi-
otage SP-4 system with pre-packed columns. Microwave reactions
were carried out in a Biotage Initiator instrument with a fixed hold
time using capped vials. The resin loadings for the Rink amide
(aminomethyl)polystyrene were about 1.2 mmol/g resin. Analytical
high performance liquid chromatography (HPLC) analysis was car-
ried out on a Waters separation module 2690 connected to a Waters
photodiode array detector 996 using an Atlantis® 5 μm C18 AQ
(250ϫ4.6 mm) column. Preparative high performance liquid
chromatography (HPLC) was carried out on a Waters 600 control-
ler connected to a Waters 2487 Dual λ Absorbance detector using
a Atlantis® Prep T3 (5 μm, C-18, 250ϫ19 mm) column. The reac-
tions performed in the solid phase were cleaved off the resins and
analysed by HPLC using standard curves and toluene as the in-
ternal standard.
Resin-Bound 2Ј,3Ј-O-Benzylidene-5Ј-O-sulfamoyladenosine (4):
Resin 2 (0.50 g, 0.11 mmol) was pre-swelled in DMF in a polyprop-
ylene fritted tube in a Bohdan Miniblock, sulfamoyl chloride
(0.17 g, 1.5 mmol) DMAP (0.18 g, 0.04 mmol) in DMF (2 mL) was
added dropwise to the resin and incubated for 1 h at room temp.
The resin was washed with DCM (2ϫ 3 mL) and the procedure
was repeated twice for the total time of 3 h. The resin was washed
with DMF (3ϫ 5 mL), DCM (3ϫ 5 mL), MeOH (3ϫ 5 mL) and
DCM (3ϫ 5 mL). The product (0.01 g, 0.011 mmol) was cleaved
off from the resin by the addition of TFA/DCM (5:95, v/v,
3*0.30 mL) for 1.5 h. The product was analyzed by HPLC and
quantified using toluene as an internal standard in MilliQ and
MeCN (7:3) (8 mm, 46.70 mL) yielding 4 in quantitative yield.
General Procedure for the Synthesis of 5Ј-O-[(N-Aminoacyl)sulf-
amoyl]adenosines 6a–6e: The substrate (2.0 mmol), DIC (0.31 mL,
0.25 g, 2.0 mmol) and DMAP (0.24 g, 2.0 mmol) were dissolved in
DCM (2 mL) and stirred at room temperature under N2 atm for
30 min. The solution was then added to resin 4 (0.40 g, 0.09 mmol),
which had been pre-swelled in DCM, in a polypropylene fritted
tube in a Bohdan Miniblock. The resin was agitated at room tem-
perature under a N2 atm for 16 h. The resin was washed with DMF
(3ϫ 5 mL), DCM (3ϫ 5 mL), MeOH (3ϫ 5 mL) and DCM (3ϫ
5 mL). The product was cleaved off from the resin by incubation
with TFA/DCM (5:95, v/v, 3ϫ 2.0 mL) for 1.5 h. The crude com-
pound was suspended in ammonium formate (5 equiv.), then 10%
Pd/C (10wt.-%/wt) was added to the evacuated reaction vessel and
the reaction mixture was stirred at 60 °C for 16 h. The reaction
mixture was filtered through Celite and the solvent was removed
under reduced pressure. The product was purified by preparative
HPLC (mobile phase; gradient 0–100% MeCN in water, 0.1%
TFA).
2Ј,3Ј-O-Benzylidene-6-chloropurine Riboside (2): 6-Chloropurine ri-
boside (2.0 g, 7.0 mmol) and ZnCl2 (4.8 g, 35 mmol) were sus-
pended in freshly distilled benzaldehyde (10 mL, 105 mmol), the
mixture was stirred for 2 d under an N2 atmosphere. The reaction
mixture was quenched by the addition of water (50 mL) and the
aqueous layer was extracted with EtOAc (3ϫ 100 mL). The com-
bined organic layers were washed with water (3ϫ 75 mL), dried
with MgSO4 and the solvent was removed under reduced pressure.
The product was purified using automated flash chromatography
(SP-4, stepwise gradient 0–20% v/v, MeOH in DCM) yielding a
white foam (diasteriomeric mixture endo, exo) (2.0 g, 5.3 mmol,
76%), m.p. 154–156 °C. LC/MS [M + H]+ = 375.0. Rf = 0.60
(MeOH/DCM, 1:10, v/v). 1H NMR (CDCl3): δ = 8.78 (d, J =
5.2 Hz, 2 H), 8.46 (s, 1 H), 8.36 (s, 1 H), 8.10 (d, J = 7.3 Hz, 2 H),
7.57–7.38 (m, 10 H), 6.31 (s, 1 H), 6.24 (d, J = 3.8 Hz, 1 H), 6.18
(d, J = 4.3 Hz, 1 H), 6.05 (s, 1 H), 5.36–5.34 (m, 1 H), 5.21–5.20
(m, 1 H), 4.72 (d, J = 2.56 Hz, 1 H), 4.59 (d, J = 2.3 Hz, 1 H),
4.08–4.02 (dd, J = 3.3, 6.2 Hz, 1 H), 4.02–3.98 (dd, J = 3.3, 6.2 Hz,
1 H), 3.89–3.88 (m, 2 H), 3.88–3.85 (m, 2 H) ppm. 13C NMR
(CDCl3): δ = 170.5, 152.2, 152.0, 151.8, 150.7, 150.6, 145.0, 136.1,
135.6, 130.1, 129.9, 129.2, 129.1, 128.6, 128.5, 126.8, 125.8, 125.6,
107.6, 105.1, 104.9, 93.0, 91.5, 87.1, 83.4, 80.7, 63.1 ppm. HRMS:
m/z [M + H]+ calcd. for C17H15ClN4O4: 374.0776, found 374.0779.
5Ј-O-[(N-L-Valinyl)sulfamoyl]adenosine (6a): Following the general
procedure using N-Cbz-l-valine as substrate compound 6a was ob-
tained as a white foam following purification by HPLC (15 mg,
38%). [α]2D0 = –14.4 (c = 0.1, DMSO). νmax (DMSO) = 3440, 3250,
˜
3070, 2250, 2130, 1620, 1310, 1220 cm–1. NMR spectroscopic data
were in agreement with published data.[11] HRMS: m/z [M + H]+
calcd. for C15H23N7O7S: 445.1374, found 445.1376. C15H23N7O7S
(445.45): calcd. C 40.44, H 5.20, N 22.01; found C 40.46, H 5.21,
N 22.10.
5Ј-O-[(N-L-Alanyl)sulfamoyl]adenosine (6b): Following the general
procedure using N-Cbz-l-alanine as substrate compound 6b ob-
tained as a white foam following purification by HPLC (18 mg,
48%). [α]2D0 = –10.8 (c = 0.1, DMSO). νmax (DMSO) = 3440, 3250,
˜
3070, 2250, 2130, 1620, 1310, 1220 cm–1. NMR spectroscopic data
were in agreement with published data.[18] HRMS: m/z [M + H]+
calculated for C13H19N7O7S: 417.1061, found 417.1064.
C13H19N7O7S (417.40): calcd. C 37.41, H 4.59, N 23.49; found C
37.45, H 4.60, N 23.51.
Resin-Bound 2Ј,3Ј-O-Benzylideneadenosine (3): Rink amide (ami-
nomethyl)polystyrene resin (0.50 g, 0.60 mmol, ca. 1.2 mmol/g
loading) was added to a polypropylene fritted tube in a Bohdan
MiniBlock. The resin was washed with DMF (5 mL) and the Fmoc
protecting group was removed by incubating with 20% piperidine
in DMF (0.4 mL) for 45 min. The resin was washed with DMF
(3ϫ 5 mL), THF (3ϫ 5 mL), DCM (3ϫ 5 mL) and MeOH (3ϫ
5 mL). The resin was pre-swelled in DMF, then compound 2
(0.90 g, 2.4 mmol), DBU (0.36 mL, 2.4 mmol) and nBuOH/DMSO
(1:1, v/v, 2 mL) were added to the resin in a pre-dried microvial
and run in the microwave for 2.5 h at 80 °C. The resin was washed
with DMF (3ϫ 5 mL), DCM (3ϫ 5 mL), MeOH (3ϫ 5 mL) and
DCM (3ϫ 5 mL). The product was cleaved off the resin (0.01 g,
0.01 mmol) by the addition of TFA/DCM (5:95, v/v, 3ϫ 0.25 mL)
for 1.5 h. The product was analyzed using HPLC and quantified
5Ј-O-[N-(2-Hydroxybenzoyl)sulfamoyl]adenosine (6c): Following the
general procedure using 2-(benzyloxy)benzoic acid as substrate
compound 6c was obtained as a white foam following purification
by HPLC (16 mg, 38%) [α]2D0 = –26.4 (c = 0.1, DMSO). ν
˜
max
(DMSO) = 3370, 3270, 3070, 2250, 2130, 1620, 1310, 1220 cm–1.
NMR spectroscopic data were in agreement with published data.[19]
HRMS: m/z [M + H]+ calculated for C17H18N6O8S: 466.0901,
found 466.0902. C17H18N6O8S (466.42): calcd. C 43.78, H 3.89, N
18.02; found C 43.81, H 3.90, N 18.04.
5Ј-O-[(N-Hexanoyl)sulfamoyl]adenosine (6d): Following the general
procedure using hexanoic acid as substrate compound 6d was ob-
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Solid-Phase Synthesis of Adenosine Derivatives
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tained as a white foam following purification by HPLC (13 mg,
33%). [α]2D0 = –15.6 (c = 0.1, DMSO). νmax (DMSO) = 3440, 3250,
˜
3070, 2250, 2130, 1620, 1310, 1220 cm–1. NMR spectroscopic data
were in agreement with published data.[12] HRMS: m/z [M + H]+
calculated for C16H24N6O7S: 444.1421, found 444.1422.
C16H24N6O7S (444.46): calcd. C 43.24, H 5.44, N 18.91; found C
43.25, H 5.46, N 18.93.
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5Ј-O-{[N-(N-L-Phenylalanyl)-L-phenylalanyl]sulfamoyl}adenosine
(6e): Following the general procedure up to the cleavage step using
N-Fmoc-l-phenylalanine as substrate, resin bound 5Ј-O-[N-(N-
Fmoc-l-phenylalanine)sulfamoyl]adenosine was obtained. The
Fmoc protecting group was removed by the addition of 20% piper-
idine in DMF (2 mL) and the resin was agitated for 45 min fol-
lowed by thorough washing. The general procedure up to the cleav-
age step was repeated once more and the Fmoc protecting group
removed as described above. Compound 6c was obtained as a white
foam following purification by HPLC (22 mg, 39%) [α]2D0 = –6.0
[8] S. C. K. Sukuru, T. Crepin, Y. Milev, L. C. Marsh, J. B. Hill,
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(c = 0.1, DMSO). ν
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Supporting Information (see footnote on the first page of this arti-
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quantification of the yields obtained for the reactions performed
on polymer supported compounds. 1H NMR spectra of target com-
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This work was supported by grants from the Swedish Research
Council (project number 62120083533), the Olle Engkvist Byggmä-
stare Foundation, and the Department of Chemistry and Molecu-
lar Biology, University of Gothenburg.
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Published Online: May 16, 2012
Eur. J. Org. Chem. 2012, 3665–3669
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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