Glycosylation of Pyrrolo[2,3- d]pyrimidines with 1- O-Acetyl-2,3,5-tri- O-benzoyl-β- d -ribofuranose: Substituents and Protecting Groups Effecting the Synthesis of 7-Deazapurine Ribonucleosides

Article abstract of DOI:10.1021/acs.joc.8b00343

Glycosylation of nonfunctionalized 6-chloro-7-deazapurine with commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose (45%) followed by amination and deprotection gave tubercidin in only two steps. Similar conditions applied for the synthe

Full text of DOI:10.1021/acs.joc.8b00343

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Note
Glycosylation of Pyrrolo[2,3-d]pyrimidines with 1-O-Acetyl-2,3,5-
tri-O-benzoyl-#-D-ribofuranose: Substituents and Protecting
Groups Effecting the Synthesis of 7-Deazapurine Ribonucleosides
Sachin Asaram Ingale, Peter Leonard, and Frank Seela
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00343 • Publication Date (Web): 18 Jun 2018
Downloaded from http://pubs.acs.org on June 18, 2018
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Glycosylation of Pyrrolo[2,3-d]pyrimidines with 1-O-Acetyl-2,3,5-tri-O-benzoyl-β-D-
ribofuranose: Substituents and Protecting Groups Effecting the Synthesis of
7-Deazapurine Ribonucleosides
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Sachin A. Ingale,a,b Peter Leonarda and Frank Seelaa,b*
aLaboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotechnology,
Heisenbergstrasse 11, 48149 Münster, Germany and bLaboratorium für Organische und
Bioorganische Chemie, Institut für Chemie, Universität Osnabrück, Barbarastrasse 7,
49069 Osnabrück, Germany
Prof. Dr. Frank Seela
Phone: +49ꢀ(0)251ꢀ53406ꢀ500; Mobile 49ꢀ(0)173ꢀ7250ꢀ297
Fax: + 49ꢀ(0)251ꢀ53406ꢀ587
Eꢀmail: Frank.Seela@uniꢀosnabrueck.de
Home page: www.seela.net
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Table of Contents
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ABSTRACT
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Glycosylation of nonꢀfunctionalized 6ꢀchloroꢀ7ꢀdeazapurine with commercial available 1ꢀOꢀ
acetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀribofuranose (45% yield) followed by amination and
deprotection gave tubercidin in only two steps. Similar conditions applied for the synthesis of
7ꢀdeazaguanosine employing pivaloylated 2ꢀaminoꢀ6ꢀchloroꢀ7ꢀdeazapurine gave 18%
glycosylation yield. Less bulky isobutyryl or acetyl protected amino group directed the
glycosylation toward the exocyclic amino substituent. 7ꢀHalogenated intermediates were
glycosylated followed by dehalogenation to overcome the low glycosylation yield in the
synthesis of 7ꢀdeazaguanosine.
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Pyrrolo[2,3ꢀd]pyrimidine (7ꢀdeazapurines) are naturally occurring and have been isolated as
monomeric nucleosides as well as constituents of nucleic acids.1,2 Most of them are
ribonucleosides such as tubercidin (1a) and its 7ꢀsubstituted derivatives toyocamycin (1b) and
sangivamycin (1c) (Figure 1) (if not otherwise stated purine numbering is used throughout the
manuscript and systematic numbering in the Experimental Part). Other nucleosides such as
5’ꢀdeoxyꢀ7ꢀiodotubercidin have been discovered from marine organisms and can carry
halogens in the 7ꢀposition.3 Queuosine (2b) or archaeosine (2c) and related derivatives (2d)
represent 7ꢀsubsituted 7ꢀdeazaguanine ribonucleosides, which are found in tRNA and formed
by postꢀmodification of ribonucleic acids via transglycosylation.4 Dapiramicin A (3)
represents a nucleoside related molecule with an unusual glycosylation site. Here, the sugar
moiety is linked to the amino group of the 7ꢀdeazapurine base.5
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As the shape of the 7ꢀdeazapurine nucleosides closely resembles that of purine nucleosides
they have been incorporated in DNA and RNA by polymerases using triphosphates or in
oligonucleotides by solid phase synthesis employing phosphoramidite chemistry.6,7 7ꢀDeazaꢀ
2'ꢀdeoxyguanosine triphosphate replaced dGTP in the Sanger dideoxy sequencing and the
pyrrolo[2,3ꢀd]pyrimidine skeleton was used to introduce fluorescence dyes in chain
terminators for conventional sequencing.8 Also sequencing by synthesis makes use of
7ꢀdeazapurine nucleotides.9
A series of restriction enzymes inhibit DNA cleavage when purine bases were replaced by 7ꢀ
deazapurines. Whereas many of them accepted 7ꢀdeazaadenosine in place of dA only a few
could cleave sequences containing 7ꢀdeazaguanosine.6a,b Similar results observed on the same
and on other restriction enzymes were reported more recently.10a Furthermore, poly(7ꢀ
deazaguanylic) acid can code for poly (lysine) in a ribosomal translation assay.10b The
literature of 7ꢀdeazapurine nucleoside synthesis and their occurrence has been reviewed.11
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Figure 1. Naturally occurring 7ꢀdeazapurine nucleosides.
Various protocols have been developed for purine or pyrimidine nucleoside synthesis and
were applied to 7ꢀdeazapurine nucleosides.12 For 7ꢀdeazapurine 2'ꢀdeoxyribonucleosides the
most efficient synthesis protocol uses nucleobase anion glycosylation.13 The method
developed in our laboratory, makes use of the increased reactivity of the pyrrolyl anion and
proceeds in the stereoꢀ and regioselective formation of βꢀDꢀ2'ꢀdeoxyribonucleosides. This
protocol was later utilized to a number of baseꢀmodified 2'ꢀdeoxyribonucleosides and is now
the method of choice for their synthesis.17a However, the procedure could not be applied for
the synthesis of ribonucleosides as long as acyl protecting groups are present at the 2ꢀposition
of the sugar moiety. The use of common ribosugars such as 1ꢀOꢀacetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀ
Dꢀribofuranose (4) resulted in the undesired formation of orthoamides when the pyrrole ring
was not functionalized.14 The problem was not observed when benzyl protecting groups were
employed, which do not participate in neighbour group interactions.15 A stereocontrolled 7ꢀ
deazapurine glycosylation was reported by Robins and Revankar using 5ꢀTBDMSꢀ2,3ꢀ
isopropylidene protected ribofuranosyl chloride (Wilcox sugar) for the synthesis of βꢀDꢀ
ribonucleosides.16a Our laboratory prepared βꢀD and αꢀDꢀ7ꢀdeazapurine ribonucleosides
employing nucleobase anion glycosylation16b,c These protocols are now widely used for the
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synthesis of base modified ribonucleosides. In some cases solvent and temperature were
changed.11b,16dꢀf Although glycosylation with this sugar halide is high yielding the protocol is
laborious.
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Later, we found that the commonly used 1ꢀOꢀacetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀribofuranose (4)
can be employed in the glycosylation of 7ꢀdeazapurines when 7ꢀhalogenated nucleobases are
used.17 We showed that 7ꢀfunctionalized 7ꢀdeazapurine nucleosides can be synthesized in
excellent yields in a stereoꢀ and regioꢀcontrolled way when a one pot glycosylation reaction
without isolation of the silylated 7ꢀdeazapurine bases is used and Vorbrüggen conditions are
employed.17 The 7ꢀiodo derivatives open us the way to introduce clickable side chains in
nucleosides and oligonucleotides. However, we failed to apply this route to nonꢀ
functionalized 6ꢀchloroꢀ7ꢀdeazapurine18 and 2ꢀaminoꢀ6ꢀchloroꢀ7ꢀdeazapurine19, the most
suitable starting materials for the syntheses of tubercidin20 or 7ꢀdeazaguanosine21. The reason
is the reduced reactivity of the pyrrole nitrogen, which is increased by 7ꢀhalogen substituents
making the system more purine like. Furthermore, glycosylation of pyrrole carbons of 7ꢀ
deazaguanine can take place as shown by SnCl4 promoted reactions.22 As methylation
experiments on the free 7ꢀdeazaguanine base demonstrated that under alkaline conditions the
most reactive site is the lactam nitrogen. This position is also the privileged site for
glycosylation.23 Consequently we studied the trimethylsilyl trifluoromethanesulfonate
(TMSOTf) promoted reaction in more detail and characterized side products effecting the
glycosylation reactions.
The synthesis protocol for the glycosylation of 6ꢀchloroꢀ7ꢀdeazapurine starts with the
silylation of the nucleobase with N,Oꢀbis(trimethylsilyl)acetamide (BSA), followed by the
addition of the sugar 4 and TMSOTf in a oneꢀpot reaction. To this end, the reaction
temperature was altered, the ratio of sugar vs nucleobase was changed and the reaction times
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were varied. In more detail, the glycosylation of 6ꢀchloroꢀ7ꢀdeazapurine (5) with the
ribosugar 4 proceeded most efficiently when the reaction time was limited to 16 h and the
temperature to 50 °C (Scheme 1). The sugar vs base ratio was 2.5:1. Side products were
removed after chromatographical workꢀup and could be easily separated as they showed
completely different mobilities as the glycosylation product 6. Applying these conditions the
glycosylation yield was 45% (for details see the Experimental Section). Earlier studies
without unambiguous assignment of nucleoside structure (6) used mercury oxide catalyzed
glycosylation (18% yield).23d Previously, anhydro sugars have been used for the synthesis of
pyrimidine ribonucleosides or those with an altered ribose moiety.24a,b Later, an anhydrosugar
was used for the synthesis of the 7ꢀdeazapurine nucleoside 6 (49% glycosylation yield).24c
However, in our work the standard sugar for ribonucleoside synthesis is used. As we show
later only one more step is necessary to access tubercidin in high overall yield.
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One side product of the glycosylation, which was formed to a minor extent (6%), was
characterized (Scheme 1). Its structure was assigned to nucleoside 7 as the 1HꢀNMR displayed
two sets of signals for the nucleobase and only one for the sugar residue. Further evidence
was made on the basis of 1Hꢀ1HꢀCOSY, HSQC and HMBC spectra (see the Supporting
Information). A similar compound was isolated after nucleobase anion glycosylation of a 2,6ꢀ
disubstituted 7ꢀdeazapurine.16c The formation of 7 is the result of an addition elimination
reaction.
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Scheme 1. Glycosylation of 6-Chloro-7-deazapurine
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Encouraged by these results and the high yields reported for the glycosylation of halogenated
nucleobases 8b,c17a,25 with 1ꢀOꢀacetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀribofuranose (4) the
conditions were used for the glycosylation of pivaloyl protected 2ꢀaminoꢀ6ꢀchloroꢀ
pyrrolo[2,3ꢀd]pyrimidine (8a)25, which is the key intermediate to access 7ꢀdeazaguanosine. A
2ꢀfold excess of ribosugar 4 over the pivaloylated nucleobase 8a was employed, TMSOTf
was used as catalyst and the temperature was kept at 50 °C (Scheme 2, for details see the
Experimental Section). TLC monitoring showed that the glycosylation reaction proceeds
much slower in comparison to 6ꢀchloroꢀ7ꢀdeazapurine 5. Therefore, the reaction time was
extended to 24 h. After chromatographical workꢀup the glycosylation product 9a was isolated
in 18%. No side product formation was observed but a significant amount of starting material
was not consumed. Anyhow, due to the facile workꢀup this route enables a quick preparation
of the nucleoside.
To improve reactivity of the base the influence of amino protecting groups was evaluated and
the isobutyryl group was chosen as an alternative (→10a26). For comparison, the 7ꢀ
halogenated nucleobases 10b and 10c were also investigated (see the Experimental Section
and Scheme S1 in the Supporting Information). Glycosylation of 10a-c was performed under
the same reaction conditions as described for 9a (Scheme 2). As a result, glycosylation did not
take place at the pyrrole nitrogen nor at heterocyclic nitrogens as reported for other cases.
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Instead, the isobutyrylated amino group was glycosylated (→11a-c). Such side product
formation was already reported occurring in low yield for guanine and 7ꢀdeazapurine 2'ꢀ
deoxyribonucleosides.17a,27 A further change of protecting groups – an acetyl protected amino
group and a diphenylcarbamoylꢀ (DPC) protected oxo group (12)28ꢀ gave also the amino
glycosylated nucleoside (→13) (Scheme 2). Accordingly, only the bulky pivaloyl group
protects the amino nitrogen from the side reaction. In order to mask the amino group more
efficiently phthaloyl protection was chosen. To this end, 2ꢀphthalimidoꢀ6ꢀchloroꢀ7ꢀ
deazapurine (14) was synthesized and employed in the glycosylation reaction (for details see
the Experimental Section and Scheme S2 in the Supporting Information). Unfortunately, this
group was not stable during the procedure. As shown later a combination of the pivaloyl
group together with a halogen in 7ꢀposition has to be used to drive the glycosylation to the
pyrrole nitrogen resulting in efficient synthesis.17a
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Scheme 2. Glycosylation of Protected 7-Deazapurines
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Earlier work on 7ꢀdeazapurines reported on the glycosylation of pyrimidine nitrogens or
pyrrole carbons.22,23 Hence, the glycosylation positions were confirmed with the help of two
dimensional NMR spectra. In general a shift of C1’ signal (1.1ꢀ1.5 ppm downfield) and the
C4’ (1.5ꢀ1.8 ppm upfield) are shifted when the glycosylation position was altered form
pyrrole nitrogen to the amino group (Table S1, Supporting Information). For nucleoside 9a
glycosylated at the pyrrole nitrogen crossꢀpeaks of Cꢀ4 and Cꢀ8 of the nucleobase with the
anomeric sugar proton Cꢀ1’ are observed in the HMBC spectra. These crossꢀpeaks are not
obtained in case of the amino glycosylated nucleosides 11aꢀc and 13. In these cases, crossꢀ
peaks appeared from Cꢀ2 of the nucleobase to the anomeric proton at Cꢀ1’ of the sugar moiety
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(Figure 2). Furthermore, a crossꢀpeak between the carbonyl carbon of the acyl protecting
group and the anomeric proton was obtained excluding glycosylation of pyrimidine nitrogens.
This was further evidenced as no significant differences were observed in the UVꢀspectra of
the compounds as well as for the chemical shifts of the nucleobase carbons.
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Figure 2. Crossꢀpeaks obtained by 2DꢀNMR spectra confirming the glycosylation position.
In order to access 7ꢀdeazaguanosine (2a) compound 9a was treated with 0.5 M NaOMe to
afford the 6ꢀmethoxy nucleoside 1516c (82%), from which 7ꢀdeazaguanosine 2a was obtained
according to the literature (Scheme 3).16a,29 Following this route an overall yield of 13%
starting from 8a was obtained. The corresponding 7ꢀdeazaadenosine (1a, tubercidin) was
obtained by treatment of compound 6 with NH3/MeOH (85%, Scheme 4). Thus, tubercidin
was prepared from 6ꢀchloroꢀ7ꢀdeazapurine (5) and commercially available 1ꢀOꢀacetylꢀ2,3,5ꢀ
triꢀOꢀbenzoylꢀβꢀDꢀribofuranose (4) in 38% overall yield in 2 steps (Scheme 1 and 4).
According to the high glycosylation yields already reported for the halogenated nucleobases
8b,c an alternative strategy was employed to access 7ꢀdeazaguanosine (2a). For this 16a,b
were prepared according to the literature.17a Then, the halogenated nucleosides (16a,b) were
treated with ammonium formate/Pd to remove the halogen (Scheme 3). Following this route
7ꢀdeazaguanosine (2a) was obtained in 36% via the bromo compound 8b and 30% via the
iodo compound 8c.
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Scheme 3. Synthesis of 7-Deazaguanosine (2a)
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For comparison, tubercidin was synthesized by dehalogenation20b,30 using
compounds 18a,b17b. The dehalogenation yields were 65% using 18a and 45% employing
18b. Formation of the protected chloro compound 6 from the protected 6ꢀchloroꢀ7ꢀiodoꢀ7ꢀ
deazapurine ribonucleoside gave quantitative yields when the Grignard reagent iPrMgCl•LiCl
was used.30c Here, the overall yields were 17% (bromo) and 18% (iodo) which is lower than
obtained via direct glycosylation (Scheme 1 and 4). Overall yields are calculated on the
nucleobases as starting materials. From 6 the deprotected 6ꢀchloroꢀ7ꢀdeazapurine
ribonucleoside (17) was prepared by treatment with K2CO3/MeOH (75%) (Scheme 1 and 4).
Overall yields of tubercidin synthesized via glycosylation of 7ꢀhalogenatedꢀ6ꢀchloroꢀ7ꢀ
deazapurines followed by dehalogenation were 17% from 18a and 18% for 18b. The reaction
routes require always four reaction steps (additional halogenation and dehalogenation) and
yields differ between the methods30aꢀc. The direct glycosylation of the 6ꢀchloroꢀ7ꢀdeazapurine
with the ribosugar 4 gives tubercidin in 38% overall yield and requires only two steps.
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Scheme 4. Synthesis of Tubercidin (1a)
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In conclusion, glycosylation yield and glycosylation position of 7ꢀdeazapurines with 1ꢀOꢀ
acetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀribofuranose (4) depend strongly on 7ꢀsubstituents (H vs
halogen) and amino protecting groups. Up to now, established one pot glycosylation protocols
could not efficiently be applied to 6ꢀchloroꢀ7ꢀdeazapurine and 2ꢀaminoꢀ6ꢀchloroꢀ7ꢀ
deazapurine the most suitable starting materials for the syntheses of tubercidin or 7ꢀ
deazaguanosine. Now, glycosylation of 6ꢀchloroꢀ7ꢀdeazapurine (5) with 4 (45% yield)
followed by amination and sugar deprotection gave tubercidin (1a) in 38% yield using
controlled reaction conditions. This represents the method of choice for the synthesis of
tubercidin as glycosylation uses cheap sugar sources requires only two steps and can be
performed in multigram scale.
Similar conditions applied to 7ꢀdeazaguanosine (2a) using the pivaloylated 2ꢀaminoꢀ6ꢀchloroꢀ
7ꢀdeazapurine (8a) gave 18% glycosylation yield. To improve the glycosylation less bulky
isobutyryl or acetyl residues were used. As a result the glycosylation was directed to the
exocyclic amino group. The resulting products are related to the antibiotic dapiramicin. 7ꢀ
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deazaguanosine (2a) was obtained by an alternative route using glycosylation of 7ꢀ
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halogenated derivatives followed by dehalogenation in good overall yield (36%).
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EXPERIMENTAL SECTION
General Methods and Materials. All chemicals and solvents were of laboratory grade as
obtained from commercial suppliers and were used without further purification. Thinꢀlayer
chromatography (TLC) was performed on TLC aluminium sheets covered with silica gel 60
F254 (0.2 mm). Flash column chromatography (FC): silica gel 60 (40ꢀ60 ꢁM) at 0.4 bar. UVꢀ
spectra were recorded on a UVꢀspectrophotometer: λmax (ε) in nm, ε in dm3 molꢀ1 cmꢀ1. NMR
spectra were measured at 599.74 MHz for 1H and 150.82 MHz for 13C. Hꢀ13C correlated
1
(HMBC, HSQC) NMR spectra were used for the assignment of the 13C signals (Table S1,
Supporting Information). The J values are given in Hz; δ values in ppm relative to Me4Si as
internal standard. For NMR spectra recorded in DMSOꢀd6, the chemical shift of the solvent
peak was set to 2.50 ppm for 1H NMR and 39.50 ppm for 13C NMR. ESIꢀTOF mass spectra of
nucleosides were recorded on a MicroꢀTOF spectrometer.
Glycosylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5).
N,OꢀBis(trimethylsilyl)acetamide (BSA, 5.007 g, 6.0 mL, 24.61 mmol) was added to a stirred
suspension of 4ꢀchloroꢀ7Hꢀpyrrolo[2,3ꢀd]pyrimidine (5)18 (3.0 g, 19.53 mmol) in anh. MeCN
(10 mL). The solution became clear and 1ꢀOꢀacetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀβꢀDꢀribofuranose (4,
24.619 g, 48.80 mmol) was added followed by the addition of trimethylsilyl
trifluoromethanesulfonate (TMSOTf, 5.894 g, 4.8 mL, 26.52 mmol). The reaction mixture
was stirred at 50 °C for 16 h, cooled to rt and diluted with CH2Cl2 (50 mL). The organic phase
was washed with saturated NaHCO3, dried and applied to FC (silica gel, CH2Cl2/MeOH,
99:0.5).
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4-Chloro-7-[(2,3,5-tri-O-benzoyl)-β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine
(6). From the fastest migrating zone compound 6 was obtained as colorless foam (5.2 g, 45%).
TLC (silica gel, CH2Cl2/MeOH, 99:1) Rf 0.4. λmax (MeOH)/nm 226 (ε/dm3 mol−1 cm−1 54900),
275 (8100), 280 (7500). 1H NMR (600 MHz, DMSOꢀd6) δ 4.66ꢀ4.71 (m, 1H, Hꢀ5’), 4.79ꢀ4.89
(m, 2H, Hꢀ5’, Hꢀ4’), 6.18 (t, J = 5.4 Hz, 1H, Hꢀ3’), 6.41 (t, J = 5.7 Hz, 1H, Hꢀ2’), 6.73 (d, J =
5.1 Hz, 1H, Hꢀ1’), 6.77 (d, J = 3.6 Hz, 1H, Hꢀ5), 7.40ꢀ7.53 (m, 6H, ArꢀH), 7.59ꢀ7.67 (m, 3H,
ArꢀH), 7.83ꢀ7.90 (m, 2H, ArꢀH), 7.95ꢀ7.97 (m, 4H, ArꢀH), 8.04 (d, J = 3.9 Hz, 1H, Hꢀ6), 8.57
(s, 1H, Hꢀ2). ESIꢀTOF m/z calcd for C32H24ClN3O7Na [M + Na+] 620.1195, found 620.1213.
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4-(4”-Chloro-7”H-pyrrolo[2,3-d]pyrimidin-7”-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-
d]pyrimidine (7). From the slower migrating zone compound 7 was obtained as colorless
foam (0.890 g, 6%). TLC (silica gel, CH2Cl2/acetone, 98:2) Rf 0.4. λmax (MeOH)/nm 226
(ε/dm3 mol−1 cm−1 69400), 274 (13600), 280 (13200), 300 (12500). 1H NMR (600 MHz,
DMSOꢀd6) δ 4.68ꢀ4.73 (m, 1H, Hꢀ5’), 4.80ꢀ4.85 (m, 1H, Hꢀ5’), 4.88ꢀ4.92 (m, 1H, Hꢀ4’), 6.19
(t, J = 5.7 Hz, 1H, Hꢀ3’), 6.48 (t, J = 6.0 Hz, 1H, Hꢀ2’), 6.81 (d, J = 6.0 Hz, 1H, Hꢀ1’), 6.94
(d, J = 3.6 Hz, 1H, Hꢀ5”), 7.00 (d, J = 3.9 Hz, 1H, Hꢀ5), 7.43ꢀ7.55 (m, 7H, ArꢀH), 7.60ꢀ7.70
(m, 3H, ArꢀH), 7.85ꢀ7.88 (m, 2H, ArꢀH), 7.97ꢀ8.02 (m, 3H, ArꢀH), 8.03 (d, J = 3.0 Hz, Hꢀ6”),
8.30 (d, J = 3.0 Hz, Hꢀ6), 8.76 (s, 1H, Hꢀ2), 8.78 (s, 1H, Hꢀ2”). ESIꢀTOF m/z calcd for
C38H27ClN6O7Na [M + Na+] 737.1522, found 737.1551.
4-Chloro-2-(N2-pivaloyl)amino-7-[(2,3,5-tri-O-benzoyl)-β-D-ribofuranosyl]-7H-
pyrrolo[2,3-d]pyrimidine (9a). To a stirred suspension of compound 8a25 (0.505 g, 2.00
mmol) in anhydrous MeCN (14 mL) was added BSA (0.488 g, 0.59 mL, 2.40 mmol) at room
temperature. After stirring for 30 min, TMSOTf (0.578 g, 0.47 mL, 2.60 mmol) was
introduced. Then, 1ꢀOꢀacetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀDꢀribofuranose (4) (2.018 g, 4.00 mmol)
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was added in three portions (every 4 h) and the reaction mixture was stirred at 50 °C for 24 h.
The solution was cooled to room temperature and diluted with CH2Cl2 (50 mL). The organic
phase was washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4) and the solvent
was evaporated. The residue was purified by FC (silica gel, CH2Cl2/MeOH, 99.8:0.2) to give
9a (0.250 g, 18%) as yellowish foam. TLC (CH2Cl2/MeOH, 98:2) Rf 0.42. λmax (MeOH)/nm
234 (ε/dm3 mol−1 cm−1 51600), 276 (10000), 281 (9800). 1H NMR (600 MHz, DMSOꢀd6) δ
1.19 (s, 9H, 3 x CH3), 4.66ꢀ4.69 (m, 1H, Hꢀ5’), 4.79ꢀ4.87 (m, 2H, Hꢀ5’, Hꢀ4’), 6.40ꢀ6.42 (m,
1H, Hꢀ2’), 6.49 (t, J = 6.0 Hz, 1H, Hꢀ3’), 6.56 (d, J = 4.2 Hz, 1H, Hꢀ1’), 6.66 (d, J = 4.2 Hz,
1H, Hꢀ7), 7.43ꢀ7.49 (m, 6H, ArH), 7.61ꢀ7.67 (m, 3H, ArH), 7.81 (d, J = 3.6 Hz, 1H, Hꢀ8),
7.89ꢀ7.95 (m, 6H, ArH), 10.26 (s, 1H, NH). ESIꢀTOF m/z calcd for C37H33ClN4O8Na [M +
Na]+ 719.1879, found 719.1889.
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4-Chloro-5-bromo-2-(N2-isobutyryl)amino-7H-pyrrolo[2,3-d]pyrimidine (10b). A stirred
solution of 10a26 (1.250 g, 5.24 mmol) in anhydrous DMF (30 mL) was treated with Nꢀ
bromosuccinimide (1.119 g, 6.29 mmol) and the reaction mixture was stirred at rt for 16 h.
Then reaction mixture was poured into ice water (300 mL), the precipitate was filtered,
washed with water (3 x 30 mL) and recrystallized from MeOH to give compound 10b (1.231
g, 74%) as a colorless solid. TLC (silica gel, CH2Cl2/MeOH, 98:2) Rf 0.19. λmax (MeOH)/nm
248 (ε/dm3 mol−1 cm−1 38400), 275 (6800). 1H NMR (600 MHz, DMSOꢀd6) δ 1.08 (d, J = 6.6
Hz, 6H, 2 x CH3), 2.74ꢀ2.81 (m, 1H, CH), 7.72 (s, 1H, Hꢀ8), 10.65 (s, 1H, NH), 12.70 (s, 1H,
NH). ESIꢀTOF m/z calcd for C10H10BrClN4ONa [M + Na]+ 338.9619, found 338.9619.
4-Chloro-5-iodo-2-(N2-isobutyryl)amino-7H-pyrrolo[2,3-d]pyrimidine (10c). As described
for 10b with 10a (2.470 g, 10.35 mmol), anhydrous DMF (100 mL) and Nꢀiodosuccinimide
(2.800 g, 12.45 mmol). Compound 10c (3.050 g, 81%) was obtained as a colorless solid. TLC
(silica gel, CH2Cl2/MeOH, 98:2) Rf 0.21. λmax (MeOH)/nm 251 (ε/dm3 mol−1 cm−1 38400),
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275 (9500). 1H NMR (600 MHz, DMSOꢀd6) δ 1.08 (d, J = 6.6 Hz, 6H, 2 x CH3), 2.74ꢀ2.81
(m, 1H, CH), 7.72 (s, 1H, Hꢀ8), 10.61 (s, 1H, NH), 12.69 (s, 1H, NH). ESIꢀTOF m/z calcd for
C10H10ClIN4ONa [M + Na]+ 386.9480, found 386.9482.
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4-Chloro-2-[(N2-isobutyryl){2,3,5-tri-O-benzoyl-β-D-ribofuranosyl}]amino-7H-
pyrrolo[2,3-d]pyrimidine (11a). As described for 9a with 10a (0.477 g, 2.00 mmol), MeCN
(14 mL), BSA (0.977 g, 1.17 mL, 4.80 mmol), TMSOTf (0.578 g, 0.47 mL, 2.60 mmol) and
1ꢀOꢀacetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀDꢀribofuranose (4) (2.018 g, 4.00 mmol). Purification by FC
(silica gel, CH2Cl2/MeOH, 99.5:0.5) gave 11a (0.670 g, 49%) as a yellowish foam. TLC
(CH2Cl2/MeOH, 98:2) Rf 0.23. λmax (MeOH)/nm 231 (ε/dm3 mol−1 cm−1 56000), 274 (7500),
281(6900). 1H NMR (600 MHz, DMSOꢀd6) δ 0.93 (d, J = 6.6 Hz, 3H, CH3), 1.10 (d, J = 6.6
Hz, 3H, CH3), 2.60ꢀ2.67 (m, 1H, CH), 4.33ꢀ3.36 (m, 1H, Hꢀ5’), 4.52ꢀ4.54 (m, 1H, Hꢀ5’),
4.62ꢀ4.64 (m, 1H, Hꢀ4’), 5.83 (t, J = 6.6 Hz, 1H, Hꢀ3’), 6.04ꢀ6.06 (m, 1H, Hꢀ2’), 6.35 (d, J =
3.6 Hz, 1H, Hꢀ1’), 6.55 (d, J = 3.6 Hz, 1H, Hꢀ7), 7.37ꢀ7.47 (m, 6H, ArH), 7.59ꢀ7.66 (m, 4H,
ArH, Hꢀ8), 7.77ꢀ7.79 (m, 2H, ArH), 7.83ꢀ7.85 (m, 2H, ArH), 7.90ꢀ7.91 (m, 2H, ArH), 12.64
(s, 1H, NH). ESIꢀTOF m/z calcd for C36H31ClN4O8Na [M + Na]+ 705.1723, found 705.1744.
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5-Bromo-4-chloro-2-[(N2-isobutyryl){2,3,5-tri-O-benzoyl-β-D-ribofuranosyl}]amino-7H-
pyrrolo[2,3-d]pyrimidine (11b). As described for 9a with 10b (0.635 g, 2.00 mmol), MeCN
(14 mL), BSA (0.488 g, 0.59 mL, 2.40 mmol), TMSOTf (0.578 g, 0.47 mL, 2.60 mmol) and
1ꢀOꢀacetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀDꢀribofuranose (4) (2.018 g, 4.00 mmol). Purification by FC
(silica gel, CH2Cl2/MeOH, 99.5:0.5) gave 11b (0.660 g, 43%) as a yellowish foam. TLC
(CH2Cl2/MeOH, 98:2) Rf 0.23. λmax (MeOH)/nm 232 (ε/dm3 mol−1 cm−1 53700), 274 (8100),
281 (7000). 1H NMR (600 MHz, DMSOꢀd6) δ 0.93 (d, J = 6.6 Hz, 3H, CH3), 1.10 (d, J = 6.6
Hz, 3H, CH3), 2.60ꢀ2.67 (m, 1H, CH), 4.33ꢀ4.36 (m, 1H, Hꢀ5’), 4.57ꢀ4.59 (m, 1H, Hꢀ5’),
4.63ꢀ4.65 (m, 1H, Hꢀ4’), 5.85 (t, J = 6.6 Hz, 1H, Hꢀ3’), 6.01ꢀ6.03 (m, 1H, Hꢀ2’), 6.36 (d, J =
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4.2 Hz, 1H, Hꢀ1’), 7.38ꢀ7.46 (m, 6H, ArH), 7.59ꢀ7.65 (m, 3H, ArH), 7.76ꢀ7.77 (m, 2H, ArH),
7.85ꢀ7.91 (m, 5H, ArH, Hꢀ8), 12.99 (s, 1H, NH). ESIꢀTOF m/z calcd for C36H30BrClN4O8Na
[M + Na]+ 783.0828, found 783.0811.
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4-Chloro-5-iodo-2-[(N2-isobutyryl){2,3,5-tri-O-benzoyl-β-D-ribofuranosyl}]amino-7H-
pyrrolo[2,3-d]pyrimidine (11c). As described for 9a with 10c (0.729 g, 2.00 mmol), MeCN
(14 mL), BSA (0.488 g, 0.59 mL, 2.40 mmol), TMSOTf (0.578 g, 0.47 mL, 2.60 mmol) and
1ꢀOꢀacetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀDꢀribofuranose (4) (2.018 g, 4.00 mmol). Purification by FC
(silica gel, CH2Cl2/MeOH, 99.5:0.5) gave 11c (0.685 g, 42%) as a yellowish foam. TLC
(CH2Cl2/MeOH, 98:2) Rf 0.27. λmax (MeOH)/nm 232 (ε/dm3 mol−1 cm−1 46800), 274 (8400),
281 (7200). 1H NMR (600 MHz, DMSOꢀd6) δ 0.92 (d, J = 6.6 Hz, 3H, CH3), 1.09 (d, J = 6.6
Hz, 3H, CH3), 2.59ꢀ2.65 (m, 1H, CH), 4.33ꢀ3.36 (m, 1H, Hꢀ5’), 4.55ꢀ4.58 (m, 1H, Hꢀ5’),
4.62ꢀ4.65 (m, 1H, Hꢀ4’), 5.84 (t, J = 6.0 Hz, 1H, Hꢀ3’), 6.01 (t, J = 5.4 Hz, 1H, Hꢀ2’), 6.35 (d,
J = 4.2 Hz, 1H, Hꢀ1’), 7.38ꢀ7.46 (m, 6H, ArH), 7.60ꢀ7.65 (m, 3H, ArH), 7.76 (d, J = 7.8 Hz,
2H, ArH), 7.85ꢀ7.90 (m, 5H, ArH, Hꢀ8), 12.97 (s, 1H, NH). ESIꢀTOF m/z calcd for
C36H30ClIN4O8Na [M + Na]+ 831.0689, found 831.0669.
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2-{[N2-Acetyl]-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)}amino-4-(O4-diphenylcarbamoyl)
-7H-pyrrolo[2,3-d]pyrimidine (13). As described for 9a with 1228 (0.150 g, 0.39 mmol),
MeCN (5 mL), BSA (0.142 g, 170 µL, 0.70 mmol), TMSOTf (0.112 g, 91 µL, 0.50 mmol)
and 1ꢀOꢀacetylꢀ2,3,5ꢀtriꢀOꢀbenzoylꢀDꢀribofuranose (4) (0.391 g, 0.77 mmol). The reaction
mixture was stirred at 50 °C for 6 h, cooled to room temperature, and diluted with CH2Cl2 (30
mL). The solution was washed with aqueous saturated NaHCO3 and brine. The combined
extracts were dried (Na2SO4), and the solvent was evaporated. Purification by FC (silica gel,
CH2Cl2/MeOH, 99.3:0.7) gave 13 (0.295 g, 92%) as yellowish foam. TLC (CH2Cl2/MeOH,
98:02) Rf 0.19. λmax (MeOH)/nm 231 (ε/dm3 mol−1 cm−1 69600), 274 (11900), 281(11300). 1H
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NMR (600 MHz, DMSOꢀd6) δ 2.10 (s, 3H, CH3), 4.32ꢀ3.35 (m, 1H, Hꢀ5’), 4.43ꢀ4.45 (m, 1H,
Hꢀ5’), 4.62ꢀ4.65 (m, 1H, Hꢀ4’), 5.85 (t, J = 6.6 Hz, 1H, Hꢀ3’), 6.16 (dd, J = 6.3 Hz, J = 3.6
Hz, 1H, Hꢀ2’), 6.42 (d, J = 3.6 Hz, 1H, Hꢀ1’), 6.59 (d, J = 3.6 Hz, 1H, Hꢀ7), 7.27ꢀ7.30 (m, 4H,
ArH), 7.38ꢀ7.76 (m, 16H, ArH, Hꢀ8), 7.72ꢀ7.74 (m, 2H, ArH), 7.82ꢀ7.83 (m, 2H, ArH), 7.91ꢀ
7.93 (m, 2H, ArH), 12.49 (s, 1H, NH). ESIꢀTOF m/z calcd for C47H37N5O10Na [M + Na]+
854.2433, found 854.2442.
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4-Chloro-2-phthalimido-7H-pyrrolo[2,3-d]pyrimidine (14). To a solution of 2ꢀaminoꢀ4ꢀ
chloroꢀ7Hꢀpyrrolo[2,3ꢀd]pyrimidine19 (1.000 g, 5.93 mmol) in DMF (10 mL) was added Nꢀ
carbethoxyphthalimide (9.752 g, 44.49 mmol), and the reaction mixture was heated at 100 °C
for 24 h. To the reaction mixture was added iceꢀwater (30 mL) and the resulting precipitate
was collected and purified by FC (silica gel, CH2Cl2/MeOH, 99:1) to give 14 (0.690 g, 39%)
as colorless solid. TLC (CH2Cl2/MeOH, 95:05) Rf 0.51. 1H NMR (600 MHz, DMSOꢀd6) δ
6.76 (d, J = 3.6 Hz, 1H, Hꢀ7), 7.88 (d, J = 3.6 Hz, 1H, Hꢀ8), 7.96ꢀ7.97 (m, 2H, ArꢀH), 8.03ꢀ
8.04 (m, 2H, ArꢀH), 12.96 (s, 1H, NH). ESIꢀTOF m/z calcd for C14H7ClN4O2Na [M + Na]+
321.0150, found 321.0158.
2-Amino-4-methoxy-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (15).
Method A (from compound 9a). Compound 9a (0.310 g, 4.45 mmol) was dissolved in 0.5 M
NaOCH3/MeOH (7 mL) and the reaction mixture was refluxed for 3 h. After completion of
the reaction (TLC monitoring), the solvent was evaporated and the residue was purified by FC
(silica gel, CH2Cl2/MeOH, 96:4) to give the product 15 (0.108 g, 82%) as a colorless solid.
Method B (by dehalogenation of compounds 16a or 16b). Compound 16a17a (0.221 g, 0.59
mmol) or 16b17a (0.250 g, 0.59 mmol) was suspended in EtOH (15 mL), then Pd on activated
charcoal (0.030 g) and ammonium formate (0.372 g, 5.90 mmol) were added. The reaction
mixture was refluxed for 1 h in case of 16a and for 20 h in case of 16b. After completion of
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the reaction (TLC monitoring), the hot reaction mixture was filtered and washed with hot
EtOH. The combined filtrates were evaporated and the residue was purified by FC (silica gel,
CH2Cl2/MeOH, 96:4) to give 15 (0.137 g, 79%, from compound 16a and 0.119 g, 68%, from
compound 16b) as a colorless solid. Analytical data were identical to those reported in the
literature.16c
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4-Chloro-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (17). Compound 6 (0.500 g,
0.83 mmol) was dissolved in MeOH (10 mL). Then, K2CO3 (0.020 g) was added and the
reaction mixture stirred for 30 min at rt (TLCꢀmonitoring). The solvent was evaporated and
the remaining residue was applied to FC (silica gel, CH2Cl2/MeOH, 9:1). After evaporation of
the solvent and crystallization from H2O compound 17 (0.180 g, 75%) was obtained as
colorless solid. Analytical data were identical to data reported in the literature.16b
4-Amino-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (Tubercidin, 1a)
Method A (from compound 6). Compound 6 (0.75 g, 1.25 mmol) was treated with
NH3/MeOH (200 mL) at 130 °C in a steel bomb for 16 h. Then, the solvent was evaporated
and the remaining residue was applied to FC (silica gel, CH2Cl2/MeOH, 3:2). The solvent was
evaporated and the remaining residue was crystallized from MeOH to give compound 1a as
colorless solid (0.284 g, 85%). Analytical data were identical to data reported in the
literature.16b,20b
Method B (by dehalogenation of compound 18a). Compound 18a (2.0 g, 5.79 mmol), was
suspended in EtOH (100 mL), then Pd on activated charcoal (0.100 g) and ammonium
formate (0.600 g, 9.51 mmol) were added and the mixture was stirred under reflux for 3 h.
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The hot reaction mixture was filtered and the filter cake was washed several times with hot
MeOH (10 x 10 mL). The combined filtrates were evaporated to dryness and the remaining
residue was triturated with a small amount of MeOH (~ 2ꢀ3 mL). The resulting precipitate
was filtered, washed with acetone and dried. The resulting amorphous solid (1.8 g containing
salt) was recrystallized from H2O to give colorless crystals of 1a (1.0 g, 65%). Analytical data
were identical to data reported in the literature.16b,20b
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Method B (by dehalogenation of compound 18b). Compound 18b (0.250 g, 0.64 mmol)
was suspended in EtOH (15 mL), then Pd on activated charcoal (0.030 g) and ammonium
formate (0.402 g, 6.38 mmol) were added. Afterwards, the reaction mixture was refluxed for 5
h. After complete conversion (TLC monitoring), the hot reaction mixture was filtered and
washed with hot EtOH. The combined filtrate was evaporated and the residue was purified by
FC (silica gel, CH2Cl2/MeOH, 90:10) to give 1a (0.077 g, 45%) as a colorless solid.
Analytical data were identical to data reported in the literature.16b,20b
ASSOCIATED CONTENT
Supporting Information
1Hꢀ, 13C, 1Hꢀ1HꢀCOSY, HSQC and HMBC NMR spectra of all compounds.
AUTHOR INFORMATION
Corresponding Author
*Phone: +49(0)25153406500. Fax: +49(0)25153406857.
*Eꢀmail: Frank.Seela@uniꢀosnabrueck.de
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
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We thank Dr. L. Müller for critical reading the manuscript. We also thank Dr. Letzel,
OrganischꢀChemisches Institut, Universität Münster, Germany, for the measurement of the
mass spectra and Prof. Dr. B.Wünsch, Institut für Pharmazeutische und Medizinische Chemie,
Universität Münster, to provide us with 600 MHz NMR spectra. Financial support by
ChemBioTech, Münster, Germany is gratefully acknowledged.
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