Synthesis of 2′-deoxy-9-deaza nucleosides using heck methodology

Article abstract of DOI:10.1021/jo400913k

During the synthesis of a series of 2′-deoxy-9-deaza nucleosides using Heck methodology, the necessity for a pyrrole protecting group was discovered. The results of this brief study revealed that the benzyloxymethyl (BOM) group proved optimal, and Heck coupling using Jeffery conditions increased the coupling yield significantly. The results are reported herein.

Full text of DOI:10.1021/jo400913k

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Synthesis of 2'-deoxy-9-deaza-nucleosides using Heck methodology
Kartik Temburnikar, Kelin Brace, and Katherine L. Seley-Radtke
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400913k • Publication Date (Web): 27 Jun 2013
Downloaded from http://pubs.acs.org on July 2, 2013
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Synthesis of 2'ꢀdeoxyꢀ9ꢀdeazaꢀnucleosides using Heck methodology
Kartik Temburnikar, Kelin Brace and Katherine L. SeleyꢀRadtke*
University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA
kseley@umbc.edu
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Abstract: During the synthesis of a series of 2'ꢀdeoxyꢀ9ꢀdeaza nucleosides using Heck
methodology, the necessity for a pyrrole protecting group was discovered. The results of this
brief study revealed that the benzyloxymethyl (BOM) group proved optimal, while Heck
coupling using Jeffery conditions increased the coupling yield significantly. The results are
reported herein.
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In the course of our efforts to introduce base modifications to nucleosides1ꢀ4 for use in studies
of modified DNA, a series of 2'ꢀdeoxyꢀ9ꢀdeazanucleosides were envisioned wherein the
nucleobase is connected to the 2'ꢀdeoxyribofuranosyl moiety via a carbonꢀcarbon bond, thus
rendering them C-nucleosides.5ꢀ9 In addition to imparting resistance to hydrolytic and enzymatic
cleavage due to the more stable carbonꢀcarbon "glycosidic" bond7,9ꢀ10, the change also results in
altering the Hꢀbonding accepting N7 to an NH, an Hꢀbond donor, for 2'ꢀdeoxyꢀ9ꢀ
deazanucleosides such as 1 and 2 (Fig. 1). This allows these compounds to engage in alternative
hydrogen bonding patterns such as Hoogsteen baseꢀpairing which may find use in complex
oligonucleotide structures or investigating polymerases.11ꢀ15 Similarly, Hamm et al have
evaluated alternate hydrogen bonding patterns for 2'ꢀdeoxyꢀ9ꢀdeazaguanosine to study the
promutagenic characteristics of 8ꢀoxoꢀ2'ꢀdeoxyguanosine.15
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Figure 1: 2'ꢀdeoxyꢀ9ꢀdeazanucleosides and altered hydrogen bonding patterns.
Klein et al first reported the synthesis of 9ꢀdeazanucleosides by construction of the base at
the anomeric carbon, resulting in the formation of epimers (2:1 β:α) thereby lowering the yield of
the desired βꢀproduct.16ꢀ18 Subsequently Pankiewicz and Sartorelli reported an approach using
Friedel Crafts conditions.5ꢀ6 This route however, also suffered similar issues, and only provided
the desired βꢀanomer in 21ꢀ25% yields, along with the αꢀanomer (9%).6 As a result, an
alternative was sought that would be both stereospecific and higher yielding.
In that regard, crossꢀcoupling methodology appeared to be an attractive route and the
synthesis of 2'ꢀdeoxyꢀ9ꢀdeazanucleosides 1 and 2 was undertaken using Heck coupling
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methodology described by Daves et al. In their report Daves optimized the Heck conditions for
synthesizing 2'ꢀdeoxyformycin B and found that the protecting group on the sugar moiety
affected the regioꢀ and stereoselectivity of the coupling reaction, thereby enabling synthesis of a
single stereoisomer.8 Similarly, during our attempts to realize 1 and 2, we observed that
protection of the pyrrole NH was essential, and that the choice of the specific protecting group
affected the outcome of the coupling reaction. Herein we report a new route for the synthesis of
2'ꢀdeoxyꢀ9ꢀdeazaxanthosine 1 and 2'ꢀdeoxyꢀ9ꢀdeazaguanosine 2 with greatly improved yields for
the coupling reaction.
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The synthesis of 1 was approached by preparation of bisꢀOꢀbenzylated pyrrolo[3,2ꢀ
d]pyrimidine 3 (Scheme 1) as previously reported.19 Since iodine is generally considered a better
leaving group as compared to chlorine and bromine20ꢀ21, 7ꢀiodinated pyrrolo[3,2ꢀd]pyrimidine
was prepared by stirring 3 with Nꢀiodosuccinimide (NIS) in anhydrous methylene chloride
(CH2Cl2)22 to afford 4 in 90% yield (Scheme 1). Iodinated 4 was then subjected to Heck
coupling, however it resulted in a complex reaction mixture (Table 1) and nothing could be
isolated. Speculation that the catalyst was being inactivated by the unprotected nitrogen was
supported by a report uncovered in the literature.8 Consequentially, protection of the pyrrole
nitrogen was pursued in an effort to limit the side reactions.
Protection of the pyrrole nitrogen with tertꢀbutyl dimethyl silyl (TBDMS) appeared
attractive, however use of NaH and TBDMSCl failed to proceed at either room (22ꢀ25 ˚C) or
lower (0ꢀ4 °C) temperatures.23 Raising the temperature to 50 °C resulted in complete
consumption of the starting material in 1.5ꢀ2 hrs as followed by TLC. Upon quenching the
reaction with water however only starting material was recovered. As a result, it appeared that
cleavage was occuring during the workup due to the basic nature of the reaction mixture.
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Alternatively, the triisopropyl silyl (TIPS) group was tried, but no formation of the product was
observed by TLC. It is also worth mentioning that the acyl group was not pursued since it had
previously been reported to be unstable.8
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Subsequently, more stable protecting groups were sought, so the benzyl (Bn)2,
benzyloxymethyl (BOM)22, tosyl (Ts)23 and tertꢀbutoxycarbonyl (Boc)24 groups were explored as
shown in Scheme 1 and Table 1.
Scheme 1. Pyrrole protection and synthesis of 2'ꢀdeoxyꢀ9ꢀdeazaxanthosine.
Table 1. Protection of pyrrolo[3,2ꢀd]pyrimidine and Heck coupling.
Pyrrole protection
Product % yield
Heck coupling
R
H
Product
% yield
ꢀ
in situ
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Complex mixture
ꢀ
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TBDMS
Bn
11(R=H)
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0
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ꢀ
BOM
Ts
90
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Boc
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0
ꢀ
Benzyl protection of the pyrrole NH was achieved by treatment with NaH followed by in situ
generation of BnI from BnBr and tetrabutylammonium iodide (TBAI) to give 6.2 Protection with
BOM was accomplished in a similar manner using NaH followed by addition of BOMCl at room
temperature (RT) to obtain 7.22 Tosylation was accomplished using NaH and pꢀtoluenesulfonyl
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chloride (TsCl) at 0ꢀ4 ˚C to afford 8.23 Protection with Boc was achieved by stirring 4 with 4ꢀ
dimethylaminopyridine (DMAP) and diꢀtertꢀbutyloxycarbonyl anhydride (Boc2O) in CH2Cl2 at
RT to provide 9 in 53% yield.24
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Next, coupling the protected pyrrolo[3,2ꢀd]pyrimidines 4ꢀ9 with glycal 10 was attempted
using the Heck conditions reported by Daves (Scheme 1).8 The glycal was prepared by a method
previously described by our group.25 Upon Heck coupling, the enolꢀether intermediate8 (Scheme
1) was cleaved in situ using tetraꢀnꢀbutylammonium fluoride (TBAF) to give ketones 11ꢀ13
(Scheme 1).8,23 The yields are shown in Table 1. These results indicated a trend wherein a
benzyl, BOM or silyl group on the pyrrole NH did result in product, while the presence of
sulfonyl and carbonyl groups had the opposite effect and no reaction occurred.
Upon obtaining the coupled products (11ꢀ13), the ketone of the sugar was stereoselectively
reduced using triacetoxy borohydride8,26 (Scheme 1), followed by hydrogenolysis using
+
ammonium formate (NH4 HCOOꢀ) and Pd/C to cleave the base protecting groups.2,4 All attempts
to deprotect the pyrrole Bn of 17 failed, thus the BOM group appeared to be the better choice
Although the need for a pyrrole protecting group had now been established, the low yield
(17%) on the coupling reaction was still problematic. As a result, a series of ligands were
explored as shown in Scheme 2 and summarized in Table 2.8 These included bidentate 1,2ꢀ
bis(diphenylphosphino)ethane (dppe) and 1,1´ꢀbis(diphenylphosphino) ferrocene (dppf). It
should be noted that triphenylarsine (AsPh3) was utilized instead of the more standard
triphenylphospine (PPh3) due to its intrinsically higher nucleophilicity.8ꢀ9,21 Although the
reactions using Pd2dba3ꢁCHCl3 turned black, which is typical of palladiumꢀcatalyzed reactions8,
and 7 and 10 were successfully coupled to give a stable and isolable enolꢀether intermediate 18,
the yields remained consistently low at only 10ꢀ17%, even with the addition of more portions of
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catalyst. While we considered that the nitrogens might be interfering, since products were
forming, albeit in low yields, a more effective catalyst was sought.
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Scheme 2. Optimization of Heck coupling conditions.
Table 2. Comparison of Heck coupling conditions.
Catalyst
Additive
AsPh3
dppe
Base
Solvent Temp Product % Yield
Pd2dba3ꢁCHCl3
Pd2dba3ꢁCHCl3
Pd2dba3ꢁCHCl3
Pd2dba3ꢁCHCl3
Pd(OAc)2
nBu3N
nBu3N
nBu3N
nBu3N
DMF
DMF
DMF
50 ˚C
50 ˚C
50 ˚C
17
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10
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76
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13
dppf
AsPh3
CH3CN 50 ˚C
DMF 40 ˚C
nBu4N+Clꢀ NaHCO3
In that regard, since Pd(OAc)2 has also been used in Heck coupling of Cꢀnucleosides with
benzene, pyrimidine and pyridine bases as reported by Leumann27, Hocek28 and Benner29, we
thought it might be a viable alternative.7,9,27ꢀ29 To our delight, use of Pd(OAc)2 increased the
yield to 76%, a dramatic improvement. It should be noted that the combination of Pd(OAc)2 and
tetrabutylammonium chloride (TBAC) for use in Heck coupling is also known as Jeffery
conditions.21,30 Under these phosphineꢀfree conditions, the reduction of Pd(II) is accomplished
by tetralkyl ammonium salts.20ꢀ21 An additional benefit to coupling under Jeffery conditions is
that it also resulted in extremely clean reaction mixtures, thus allowing for more facile
purification of the coupled product. In contrast, use of Pd2dba3ꢁCHCl3 routinely afforded
complicated reaction mixtures that made their purifications tedious and unattractive.
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Interestingly, Jeffery conditions also resulted in cleavage of the 3'ꢀOTBDPS group during the
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coupling, resulting in ketone 13. In contrast, when Pd2dba3ꢁCHCl3 was used, the intermediate
silyl enolꢀether 18 was obtained which then had to be deblocked using TBAF to obtain 13
(Scheme 2). Speculation is that the chloride of tetraꢀnꢀbutylammonium chloride (TBAC) is
serving as the base that cleaves the Oꢀsilyl group analogous to the fluoride of TBAF.23 Thus, use
of the Jeffery conditions with the BOMꢀprotected pyrrole appeared to be optimal for Heck
coupling. Upon obtaining the coupled product 13 in enhanced yields, the 3'ꢀketo was then
subjected to stereoselective reduction followed by hydrogenolysis to obtain the desired 2'ꢀdeoxyꢀ
9ꢀdeazaxanthosine 1 in 25% over three steps.
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The optimized conditions for the synthesis of 1 were then applied to the preparation of 2'ꢀ
deoxyꢀ9ꢀdeazaguanosine 2 starting from the protected pyrrolo[3,2ꢀd]pyrimidine 19 (Scheme 3).19
Introduction of iodine on 19 with the pyrrole NH unprotected proved unsuccessful, consequently,
the pyrrole NH was protected with BOM to give 20 in 70% yield.22 Attempts to iodinate 20 in
methylene chloride (CH2Cl2) or tetrahydrofuran (THF) at RT resulted in the formation of 21 in
only 30% and 24% yields respectively. However when the NIS was added to a solution of 20 in
CH2Cl2 at 0ꢀ4 ˚C, 21 was obtained in 65ꢀ70% yields.
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Scheme 3. Synthesis of 2 ꢀdeoxyꢀ9ꢀdeazaguanosine.
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Next, to see if the trend with the catalysts continued, iodinated 21 was subjected to the Heck
coupling conditions using either Pd2dba3ꢁCHCl3 or Pd(OAc)2 (Scheme 3). Heck coupling of 21
with 10 in the presence of Pd2dba3ꢁCHCl3 gave the enolꢀether intermediate 22 in a 17% yield,
thereby matching the previously observed low yields. Under the Jeffery conditions, however a
mixture of 22 and 23 was obtained which, upon treatment with TBAF, afforded ketone 23
following cleavage of the 3'ꢀOTBDPS group in situ. Interestingly, 0.4 equivalents of Pd(OAc)2
were required for coupling 21 with 10 instead of the 0.2 equivalents as had been used with the
bisꢀbenzyloxy compound 7. The initial 0.2 equivalents of Pd(OAc)2 was insufficient to
completely couple 21 to 10, however upon addition of a second portion, 23 was obtained in 55%
yield. As reported in the literature20ꢀ21,30 under phosphineꢀfree conditions amines can effect the
reduction of Pd(II) to Pd(0) and coordination of the NCHNMe2 of 21 with Pd(OAc)2 was likely
occurring as Pd(II)ꢀnitrogen chelation is not uncommon,20ꢀ21 hence the need for the additional
portion of Pd(OAc)2.
As hoped, the Jeffery conditions once again proved superior and the coupled product 23 was
realized in 55ꢀ60% yields as compared to only 10ꢀ12% (over 2 steps) when Pd2dba3ꢁCHCl3 was
used. Compared to the coupling yield of 7 and 10 (76%), the yields for coupling 21 were
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somewhat lower (55%), however when one considers that the earlier reports using FriedelꢀCrafts
conditions only gave 21ꢀ25%, it still rendered this route far superior.5
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Moving forward, the 3'ꢀketo on 23 was stereoselectively reduced26 as before to afford 24 in
60% yield (Scheme 3). Deprotection of the benzyl, BOM and dimethylamino vinyl groups on 24
posed a choice for the order of sequential deprotection steps to obtain the desired 2'ꢀdeoxyꢀ9ꢀ
deazaguanosine 2. Subjecting 24 to hydrogenation to remove the benzyl and BOM groups first
led to differentially protected nucleosides that could not be readily separated, so removal of the
dimethylamino vinyl group was tried. Use of NaOH resulted in a tedious purification, however
ammonium hydroxide23 in MeOH was facile, and provided 25 in a 93% yield. Finally, removal
of the OBn and NꢀBOM groups by hydrogenolysis22 afforded 2 in a 66% yield from 25 and an
overall yield for 2 of 21% over 4 steps.
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In summary, the synthesis of 2'ꢀdeoxyꢀ9ꢀdeazaxanthosine 1 and 2'ꢀdeoxyꢀ9ꢀdeazaguanosine 2
using Heck/Jeffery methodology has been reported for the first time. During the course of their
syntheses, the necessity for protection of the pyrrole nitrogen to achieve successful coupling was
uncovered. In addition, the coupling yields were found to be optimal when using Jeffery
conditions (75% for 1 and 55% for 2) rather than the more standard Heck methodology.
Significantly, this represents a dramatic increase as compared to previously reported coupling
reactions using FriedelꢀCrafts conditions (21ꢀ25%), and will likely find use to improve the yields
for other related Cꢀnucleosides.
Experimental
General
All 1H and 13C NMR spectra were obtained from 400 MHz NMR. The spin multiplicities are
indicated by the symbols s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet),
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m (multiplet), br (broad) and coupling constants (J) reported in hertz. TLC was performed on
0.25 mm 60ꢀF254 precoated silica glass plates. Column chromatography was performed on silica
gel (32–63 ꢂ). Anhydrous solvents were obtained from solvent purification system. Melting
points are uncorrected. The FAB mass spectra were obtained using double focusing magnetic
sector mass spectrometer equipped with a Cs ion gun and fourier transform ion cyclotron
resonance equipped with ESI source.
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General procedure for iodination: To a stirring solution of 2,4ꢀbisꢀOꢀbenzylꢀ5Hꢀpyrrolo[3,2ꢀ
d]pyrimidine 3 (1.43 g, 4.3 mmol) in anhydrous CH2Cl2 (15 mL) under N2, NIS (1.069 g, 4.7
mmol) was added at which point the reaction mixture turned from pink to orange. The mixture
was stirred overnight until the TLC indicated the absence of starting material. The reaction
mixture was washed with aqueous Na2S2O3 (15 mL) followed by brine (15 mL). The organic
layer was dried over MgSO4, loaded onto silica and purified using column chromatography
eluting with 4:1 then 1:1 hexanes:EtOAc to obtain 4 as a paleꢀyellow solid (1.77 g, 3.88 mmol,
90%). Rf 0.4 in 1:3 hexanes: EtOAc. Mp 157.8ꢀ158.4 ˚C. 1H NMR (400 MHz, CDCl3): δ 5.53 (s,
13
4H), 7.32 ꢀ7.41 (m, 9H), 7.55ꢀ7.57 (m, 2H), 8.71 (br s, 1H, NH). C NMR: 57.3, 68.7, 69.3,
111.9, 127.9, 128.3, 128.6, 128.66, 128.7, 128.9, 132.4, 135.8, 137.2, 152.0, 156.9, 160.1. FABꢀ
MS m/z for C20H16IN3O2 calculated [M+H]+ 458.0360, found 458.0357.
2,4ꢀBisꢀbenzyloxyꢀ5ꢀNꢀ(tertꢀbutyldimethylsilyl)ꢀ7ꢀiodoꢀpyrrolo[3,2ꢀd]pyrimidine (5): A 60%
suspension of NaH in oil (106 mg, 4.2 mmol) was added to anhydrous THF (5 mL) under N2. To
this mixture, 7ꢀiodoꢀ2,4ꢀbisꢀbenzyloxyꢀ5Hꢀpyrrolo[3,2ꢀd]pyrimidine 4 (1.6 g, 3.5 mmol) was
added and the reaction mixture stirred at RT for 15 min. The stirring mixture was then heated to
˚
50 C, at which point a white precipitate formed. The mixture was cooled to RT and TBDMSCl
(687 mg, 4.55 mmol) was added under N2. The reaction mixture was then heated to 50 ˚C for 1.5
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hrs until TLC indicated the absence of starting material. The reaction mixture was cooled, the
THF evaporated and the crude product (5) used in the Heck coupling without further
purification.
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2,4ꢀBisꢀbenzyloxyꢀ5ꢀNꢀbenzylꢀ7ꢀiodoꢀpyrrolo[3,2ꢀd]pyrimidine (6): A solution of 4 (200 mg,
0.43 mmol) in anhydrous THF (5 mL) was cooled (0ꢀ4 ˚C), a 60% suspension of NaH in oil (26
mg, 0.65 mmol) was added and the mixture stirred for 15 min. The ice bath was removed and
reaction mixture was allowed to warm to RT. After stirring the reaction mixture at RT for 2 hrs,
tetrabutyl ammonium iodide (79.5 mg, 0.215 mmol) was added and mixture cooled on ice.
Benzyl bromide (77.3 ꢃl, 0.65 mmol) was added, the ice bath was removed after 5 min and the
mixture warmed to RT and stirred for 1 hr. The mixture was then refluxed (80ꢀ82 ˚C) for 2 hrs at
which point TLC indicated the absence of starting material. The mixture was cooled to RT,
quenched with water (10 mL), the organic layer separated and the aqueous layer extracted with
EtOAc (2 x 10 mL). The organic layers were combined, washed with brine (20 mL), dried over
MgSO4, then concentrated in vacuo. The residue was loaded onto silica and purified by column
chromatography eluting with 9:1 hexanes: EtOAc to obtain 6 a white solid (134 mg, 0.24 mmol,
56%). Rf 0.5 in 9:1 hexanes: EtOAc. Mp 113.8ꢀ116.2 ˚C. 1H NMR (400 MHz, CDCl3): δ 5.38 (s,
2H), 5.47 (s, 2H), 5.49 (s, 2H) 6.93ꢀ6.96 (m, 2H), 7.23ꢀ7.25 (m, 6H), 7.29ꢀ7.35 (m, 6H), 7.57ꢀ
7.59 (m, 2H). 13C NMR (400 MHz, CDCl3): δ 53.1, 55.9, 68.7, 69.3, 112.7, 126.9, 127.9, 128.3,
128.6, 128.9, 129.0, 135.9, 136.6, 137.2, 152.8, 157.4, 159.8. FABꢀMS for C27H22IN3O2
calculated [M+H+] 548.0829, found 548.0837.
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General procedure for N7 BOM protection: To a solution of 7ꢀiodoꢀ2,4ꢀbisꢀbenzyloxyꢀ5Hꢀ
pyrrolo[3,2ꢀd]pyrimidine 4 (1.25 g, 2.73 mmol) in anhydrous THF (5 mL) under N2, NaH (60%
suspension in oil, 132 mg, 3.28 mmol) was added and the mixture stirred at RT for 1 hr.
Benzyloxymethyl chloride (620 ꢃL, 3.28 mmol) was added dropwise at which point the reaction
mixture turned from yellow to offꢀwhite. The mixture was stirred for 1 hr at which point TLC
indicated the absence of starting material. The reaction mixture was quenched with water (10
mL), the organic layer separated and the aqueous layer extracted with EtOAc (2x 10 mL). The
organic layers were combined, washed with brine (20 mL) and dried over MgSO4. The organic
phase was concentrated in vacuo, loaded onto silica and purified via column chromatography
eluting with 4:1 hexanes:EtOAc to obtain 7 as a pale yellow solid (1.42 g, 2.45 mmol, 90%). Rf
0.6 in 3:1 hexanes: EtOAc. Mp 80.6ꢀ85.4 ˚C. 1H NMR: δ 4.36 (s, 2H), 5.51 (s, 2H), 5.56 (s, 2H),
5.60 (s, 2H), 7.11ꢀ7.15 (m, 2H), 7.24 (s, 1H), 7.31ꢀ7.36 (m, 11H), 7.58ꢀ7.59 (m, 2H), (400 MHz,
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CDCl3): δ. C NMR (400 MHz, CDCl3): δ 58.1, 68.6, 69.2, 70.3, 93.9, 112.4, 127.5, 127.91,
127.97, 128.1, 128.3, 128.4, 128.6, 128.9, 135.9, 136.6, 136.7, 137.1, 153.2, 157.2, 159.9. FABꢀ
MS for C28H24IN3O3 calculated [M+H+] 578.0935, found 578.0915.
2,4ꢀBisꢀbenzyloxyꢀ5ꢀNꢀ(tolueneꢀ4ꢀsulfonyl)ꢀ7ꢀiodopyrrolo[3,2ꢀd]pyrimidine (8): A solution of
7ꢀiodoꢀ2,4ꢀbisꢀbenzyloxyꢀ5Hꢀpyrrolo[3,2ꢀd]pyrimidine 4 (210 mg, 0.459 mmol) in anhydrous
THF (5 mL) under N2 was cooled (0ꢀ4 ˚C) and NaH (60% suspension in oil, 27.57 mg, 0.689
mmol) was added and the mixture stirred for 15 min. The ice bath was removed and the mixture
warmed to RT and stirred for 1 hr. The mixture was then cooled over ice, and tosyl chloride (131
mg, 0.689 mmol) added dropwise. The mixture was warmed to RT and stirred for 30 min until
TLC indicated the absence of starting material. The mixture was quenched with aqueous
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NaHCO3 (10 mL), the organic layer separated and the aqueous layer extracted with EtOAc (2 x
10 mL). The organic layers were combined, washed with brine (20 mL), dried over MgSO4,
concentrated in vacuo and loaded onto silica and purified by column chromatography eluting
with 9:1 hexanes:EtOAc to obtain 8 as an offꢀwhite solid (131 mg, 0.21 mmol, 46.6%). Mp
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174.7ꢀ176.9 ˚C. H NMR (400 MHz, CDCl3): δ 2.32 (s, 3H), 5.47 (s, 4H), 6.99 (d, 2H, J=8.12
Hz), 7.30ꢀ7.39 (m, 3H), 7.44ꢀ7.47 (m, 7H), 7.54 (d, 2H, J=6.84 Hz), 8.08 (s, 1H). 13C NMR (400
MHz, CDCl3): δ 21.7, 64.4, 69.5, 69.6, 110.6, 128.1, 128.4, 128.7, 128.9, 129.1, 129.7, 134.7,
135.3, 136.1, 136.7, 145.4, 156.8, 157.2, 161.2. FABꢀMS for C27H22IN3O4S calculated [M+H+]
612.0448, found 612.0453.
2,4ꢀBisꢀbenzyloxyꢀ5ꢀN-bocꢀ7ꢀiodopyrrolo[3,2ꢀd]pyrimidine (9): To a solution of 7ꢀiodoꢀ2,4ꢀ
bisꢀbenzyloxyꢀ5Hꢀpyrrolo[3,2ꢀd]pyrimidine 4 (100 mg, 0.218 mmol) in dry THF (5 mL), Boc2O
(96 mg, 0.437 mmol) and DMAP (145.33 mg, 0.0437 mmol) were added and the mixture stirred
for 1 hr until TLC indicated the absence of starting material. The solvent was removed in vacuo
and the residue purified by column chromatography eluting with 49:1 hexanes:EtOAc to obtain 9
as a white solid (65.1 mg, 116 mmol, 53.4%). Rf 0.5 in 19:1 hexanes: EtOAc. Mp 118.5ꢀ122.5
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˚C. H NMR (400 MHz, CDCl3): δ 1.51 (d, 9H), 5.59 (s, 2H), 5.50 (s, 2H), 7.38ꢀ7.30 (m, 6H),
13
7.47 (d, 2H), 7.56 (d, 2H), 7.91 (s, 1H). C NMR: δ 27.8, 64.3, 68.9, 69.5, 85.3, 110.9, 127.9,
128.4, 128.5, 128.8, 136.2, 136.5, 136.9, 147.2, 156.6, 157.9, 161.1. FABꢀMS m/z for
C25H24IN3O4 calculated [M+H]+ 558.0884, found MH+ 558.0885.
General procedure for Heck coupling using Pd2dba3ꢁCHCl3: In a dry flask under N2
containing AsPh3 (39.7 mg, 0.13 mmol) and Pd2dba3.CHCl3 (71.6 mg, 0.065 mmol), anhydrous
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DMF (3 mL) was added and stirred for 30 min. In a separate flask, to a solution of 2,4ꢀbisꢀ
benzyloxyꢀ5ꢀNꢀ(benzyloxymethyl)ꢀ7ꢀiodopyrrolo[3,2ꢀd]pyrimidine 7 (150 mg, 0.26 mmol) and
glycal 10 (184 mg, 0.52 mmol) in DMF (3 mL) triꢀnꢀbutylamine (185 ꢃL, 0.78 mmol) was
added. This mixture was then added to the Pd solution under N2 and stirred at RT for 30 min,
followed by stirring for 18 hrs at 50ꢀ55 ˚C at which point the TLC indicated consumption of 7.
The DMF was evaporated and the residue dissolved in CH2Cl2 (50 mL). The mixture was
filtered, the filtrate transferred to a dry flask and the CH2Cl2 evaporated. The residue was
dissolved in THF (5 mL) to which a 1M solution of TBAF in THF (2mL, 2 mmol) was added
and the mixture stirred for 1 hr at RT. The mixture was evaporated, the residue loaded onto silica
and purified via column chromatography eluting with 9:1 then 3:1 hexanes: EtOAc to give 13 as
offꢀwhite syrup (14.6 mg, 0.026 mmol, 10%). Rf 0.2 in 1:1 hexanes: EtOAc. 1H NMR (400 MHz,
CDCl3): δ 2.69 (dd, 1H, J=6.16 Hz, J=17.64 Hz), 3.19 (dd, 1H, J=11 Hz, J=17.88 Hz), 3.91ꢀ3.99
(br m, 2H), 4.08 (t, 1H, J=2.06 Hz), 4.3 (s, 2H), 5.34ꢀ5.37 (m, 1H), 5.40ꢀ5.48 (m, 2H), 5.54 (s,
2H), 5.60 (d, 2H, J=2.76 Hz), 7.11ꢀ7.13 (m 2H), 7.23ꢀ7.27 (m, 4H), 7.30ꢀ7.39 (m, 6H), 7.37ꢀ7.39
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(m, 2H), 7.45ꢀ7.46 (m, 2H). C NMR (400 MHz, CDCl3): δ 43.8, 62.9, 68.5, 69.2, 70.5, 71.9,
82.3, 113.6, 115.0, 127.5, 127.7, 127.8, 128.0, 128.2, 128.43, 128.47, 128.5, 128.7, 132.1, 135.9,
136.8, 137.4, 150.5, 157.2, 157.5, 214.9. ESIꢀMS m/ for C33H31N3O6 z calculated [M+H]+
566.2276, found 566.2285.
2,4ꢀBisꢀbenzyloxyꢀ5Hꢀ7ꢀ(βꢀDꢀglyceroꢀpentofuranꢀ3'ꢀulosꢀ1'ꢀyl)pyrrolo[3,2ꢀd]pyrimidine
(11): From 4 (540 mg, 1.18 mmol), 11 was obtained as a yellow syrup (80 mg, 0.18 mmol, 15%).
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Rf 0.5 in 19:1 CH2Cl2: MeOH. H NMR (400 MHz, CDCl3): δ 2.69 (dd, 1H, J=6.4 Hz, J=17.86
Hz ), 3.18ꢀ3.26 (m, 1H), 3.94ꢀ3.96 (m, 2H), 4.10ꢀ4.12 (m, 1H), 5.35ꢀ5.41 (m, 3H, -CH2, H1 ),
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5.50 (s, 2H), 7.25ꢀ7.44 (m, 11H), 8.7 (br s, 1H, NH). 13C NMR (400 MHz, CDCl3): δ 44.0, 62.9,
68.5, 69.2, 72.0, 82.3, 113.2, 114.7, 127.7, 127.8, 128.3, 128.5, 128.7, 135.8, 137.4, 149.2, 156.8,
159.6, 215.0. FABꢀMS for C25H23N3O5 calculated [M+H+] 446.1710, found 446.1709.
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2,4ꢀBisꢀbenzyloxyꢀ5ꢀNꢀbenzylꢀ7ꢀ(βꢀDꢀglyceroꢀpentofuranꢀ3'ꢀulosꢀ1'ꢀyl)pyrrolo[3,2ꢀ
d]pyrimidine (12): From 6 (570 mg, 1.04 mmol), 12 was obtained as a yellow syrup (73 mg,
1
0.136 mmol, 13%). Rf 0.5 in 1:1 hexanes: EtOAc. H NMR (400 MHz, CDCl3): δ 2.69 (dd, 1H,
J=6.2 Hz, J=17.64 Hz), 3.26 (dd, 1H, J=11 Hz, J=17.88 Hz), 3.91ꢀ3.99 (br m, 2H), 4.08ꢀ4.10 (m,
1H), 4.11ꢀ4.13 (m, 1H), 5.32ꢀ5.49 (m, 7H, -CH2, H1 ), 6.97ꢀ6.99 (m, 2H), 7.20ꢀ7.21 (m, 1H),
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7.23ꢀ7.26 (m, 5H), 7.28ꢀ7.32 (m, 5H), 7.43ꢀ7.46 (m, 2H). C NMR (400 MHz, CDCl3): δ 43.9,
52.6, 62.9, 68.5, 69.2, 72.0, 82.4, 113.73, 113.78, 127.0, 127.7, 127.8, 128.0, 128.2, 128.4, 128.6,
128.9, 132.1, 135.8, 137.2, 137.5, 149.8, 157.3, 159.3, 215.1. C32H29N3O5 calculated [M+H+]
536.2180, found MH+ 536.2181.
General procedure for Heck coupling using Jeffery conditions: In a dry flask, 2,4ꢀbisꢀ
benzyloxyꢀ5ꢀNꢀ(benzyloxymethyl)ꢀ7ꢀiodopyrrolo[3,2ꢀd]pyrimidine 7 (1.5 g, 2.59 mmol) and
TBAC (1.44 g, 5.18 mmol) were coꢀevaporated with CH3CN and under high vacuum for 1 hr. To
the flask 47.5% Pd(OAc)2 (245 mg, 0.52 mmol) and NaHCO3 (435 mg, 5.18 mmol) were added
under N2, followed by DMF (15 mL) and the mixture stirred to dissolve the organic components.
In a separate flask, glycal 10 (1.9 g, 5.38 mmol) was coꢀevaporated with CH3CN and dissolved
in DMF (7 mL). The solution of 10 in DMF was added to the previous solution and the mixture
˚
stirred at 40 C for 48 hrs at which point TLC indicated the absence of starting materials. The
DMF was evaporated, the residue dissolved in CH2Cl2 and filtered over celite. The filtrate was
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loaded onto silica, and the product purified using column chromatography eluting with 9:1 then
3:1 hexanes:EtOAc to give 13 as an offꢀwhite syrup (1.11 g, 1.96 mmol, 76%). Rf 0.2 in 1:1
hexanes: EtOAc. Spectral data of 13 matched as reported in the previous procedure.
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General procedure for the reduction of the 3'ꢀketone: A solution of 2,4ꢀbisꢀbenzyloxyꢀ5ꢀNꢀ
benzyloxymethyꢀ7ꢀ(βꢀDꢀglyceroꢀpentofuranꢀ3'ꢀulosꢀ1'ꢀyl)pyrrolo[3,2ꢀd]pyrimidine 13 (1.15 g,
1.97 mmol) in anhydrous acetonitrile (10 mL) and glacial AcOH (10 mL) was cooled to ꢀ10 to ꢀ5
˚C under N2. NaB(OAc)3H (500 mg, 2.36 mmol) was added in two 250 mg portions 15 min apart
and stirred at ꢀ10 to ꢀ5 ˚C for 30 min, then warmed to RT upon which TLC indicated the absence
of starting material. The solvents were evaporated and the residue purified by column
chromatography eluting with 99:1 CH2Cl2: MeOH to give 16 as offꢀwhite foam (670 mg, 60%).
Rf 0.5 in 19:1 CH2Cl2: MeOH. 1H NMR (400 MHz, CDCl3): δ 2.05 (dd, 1H, J=5.5, J=13.3 Hz),
2.77ꢀ2.84 (m, 1H), 3.74ꢀ3.79 (m, 1H), 3.95 (dd, 1H, J=2.3 Hz, J=12.38 Hz), 4.13 (br s, 1H), 4.36
(s, 2H), 4.69 (d, 1H, J=5.04 Hz), 5.35 (dd, 1H, J=5.26 Hz, 11.22 Hz), 5.43 (s, 2H), 5.52 (s, 2H),
5.59 (s, 2H), 5.84ꢀ5.87 (br d, 1H), 7.12ꢀ7.15 (m, 2H), 7.22ꢀ7.36 (m, 12H), 7.45ꢀ7.47 (m, 2H). 13C
NMR (400 MHz, CDCl3): δ 42.6, 53.6, 62.8, 64.2, 68.4, 69.2, 70.2, 74.9, 75.4, 88.7, 113.6,
115.9, 127.6, 127.7, 127.7, 127.9, 128.1, 128.2, 128.41, 128.46, 128.5, 128.7, 132.4, 136.1,
137.0, 137.6, 150.9, 157.0, 159.2. ESIꢀMS m/z for C33H33N3O6 calculated [M+H]+ 568.2442,
found 568.2438.
1'ꢀβꢀ[7ꢀ(2,4ꢀBisꢀbenzyloxyꢀ5H-pyrrolo[3,2ꢀd]pyrimidine)]ꢀ2'ꢀdeoxyribofuranose (14): From
11 (24 mg, 53.9 ꢃmol), 14 was obtained as a yellow syrup (8 mg, 17.8 ꢃmol, 33%). Rf 0.5 in
19:1 CH2Cl2:MeOH. 1H NMR (400 MHz, CDCl3): δ 2.04ꢀ2.07 (m, 1H), 2.79ꢀ2.86 (m, 1H), 3.77
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(m br, 1H), 3.95 (dd, 1H, J=1.84 Hz, J=12.36 Hz), 4.12 (s, 1H), 4.69 (d, 1H, J=4.6 Hz), 5.38 (dd,
1H, J=5.26 Hz, J=11.22 Hz), 5.44 (s, 2H), 5.51 (s, 2H), 5.97 (br s, 1H, OH), 7.26ꢀ7.41 (m, 9H),
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7.46ꢀ7.48 (m, 2H), 8.44 (br, 1H, NH). C NMR (400 MHz, CDCl3): δ 29.7, 42.8, 64.2, 68.4,
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69.2, 75.0, 75.9, 88.8, 113.2, 115.5, 127.6, 127.8, 128.3, 128.5, 128.7, 135.9, 137.5, 149.4, 156.6,
159.3. FABꢀMS for C25H25N3O5 calculated [M+H+] 448.1867, found 448.1872.
1'ꢀβꢀ[7ꢀ(2,4ꢀBisꢀbenzyloxyꢀ5ꢀNꢀbenzylpyrrolo[3,2ꢀd]pyrimidine)]ꢀ2'ꢀdeoxyribofuranose (15):
From 12 (70 mg, 0.13 mmol), 15 was obtained as a yellow syrup (60 mg, 0.11 mmol, 85%). Rf
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0.05 in 1:1 hexanes: EtOAc, 0.7 in 19:1 CH2Cl2: MeOH. H NMR (400 MHz, CDCl3): δ 2.07
(dd, 1H, J=5.28, J=13.08 Hz), 2.80ꢀ2.87 (m,1H), 3.80 (dd, 1H, J=1.4 Hz, J=12.38 Hz), 3.96 (dd,
1H, J=1.84 Hz, J=12.36 Hz), 4.14 (br s, 1H), 4.70 (d, 1H, J=4.6 Hz), 5.33ꢀ5.5.38 (m, 3H, -CH2,
H1 ), 5.42 (s, 2H), 5.46 (s, 2H), 6.97ꢀ7.00 (m, 2H), 7.18ꢀ7.20 (m, 1H), 7.24ꢀ7.33 (m, 11H),
7.46ꢀ7.49 (m, 2H). 13C NMR (400 MHz, CDCl3): δ 42.7, 52.5, 64.1, 68.3, 69.2, 75.0, 75.7, 88.7,
113.7, 114.4, 126.9, 127.6, 127.81, 127.85, 128.20, 128.28, 128.39, 128.6, 128.8, 132.4, 136.0,
137.53, 137.59, 150.0, 157.0, 159.0. FABꢀMS for C32H31N3O5 calculated [M+H+] 538.2336,
found MH+ 538.2343.
General procedure for hydrogenolysis: To a solution of 1'ꢀβꢀ[7ꢀ(2,4ꢀbisꢀbenzyloxyꢀ5ꢀ
benzyloxymethypyrrolo[3,2ꢀd]pyrimidine)]ꢀ2'ꢀdeoxyribofuranose 16 (660 mg, 1.16 mmol) in
MeOH (10 mL), 10% Pd/C (600 mg) was added, and the suspension heated to reflux.
Ammonium formate (1800 mg, 281 mmol) was added in three portions of 600 mg each over a
period of 8 hr, at which point the TLC indicated the absence of starting material. The solvent was
evaporated and the residue purified by column chromatography eluting with 99:1 CH2Cl2:MeOH
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then 98:2 CH2Cl2: MeOH to obtain 1 as a white solid (170 mg, 0.64 mmol, 55%). Mp 185.3ꢀ
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186.8 ˚C. H NMR (400 MHz, DMSO d6): δ 1.84ꢀ1.95 (m, 2H), 3.49ꢀ3.57 (m, 2H), 3.75 (br s,
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1H), 4.19 (br s, 1H), 4.96 (d, 1H, J=3.24 Hz), 5.05 (dd, 1H, J=5.92 Hz, J=10.08 Hz), 5.62 (br s,
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1H), 10.56 (br s, 1H, NH), 10.58 (br s, 1H, NH), 11.67 (br s, 1H, NH). C NMR (400 MHz,
DMSO d6): δ 43.0, 62.7, 73.6, 73.7, 87.7, 111.2, 111.5, 125.2, 132.7, 151.8, 156.3. FABꢀMS for
C11H13N3O5 calculated M+ 267.0855, found 267.0853; calculated [M+H+] 268.0928 found
268.0930.
1'ꢀβꢀ[7ꢀ(5ꢀBenzylpyrrolo[3,2ꢀd]pyrimidinꢀ2,4ꢀdione)]ꢀ2'ꢀdeoxyribofuranose (17): From 15
(44 mg, 82 ꢃmol), 17 was obtained as an offꢀwhite foam (15 mg, 42 ꢃmol, 50%). Rf 0.5 in 19:1
CH2Cl2: MeOH. 1H NMR (400 MHz, MeOH D3): δ 2.52ꢀ2.57 (m, 1H), 2.61ꢀ2.67 (m, 1H), 4.29
(d, 2H, J=2.28 Hz), 4.47 (d, 1H, J=1.36 Hz), 4.91 (d, 1H, J=5.04 Hz), 5.69 (dd, 1H, J=5.50,
13
J=10.98 Hz), 5.97 (s, 2H), 7.71ꢀ7.82 (m, 6H). C NMR: 43.2, 51.5, 63.0, 74.8, 75.0, 88.3,
111.0, 111.4, 127.8, 128.1, 129.0, 129.7, 134.2, 138.7, 152.9, 157.3. FABꢀMS for C18H19N3O5
calculated M+ 357.1324, found 357.1321; calculated [M+H+] 358.1397 found 358.1395.
Synthesis of 18: Using the general procedure for Heck coupling with Pd2dba3ꢁCHCl3 however
without TBAF, compound 7 (150 mg, 0.26 mmol) was reacted to give 18 as yellow syrup (33
mg, 0.042 mmol, 16.1%) following purification by column chromatography eluting with 19:1
then 9:1 hexanes: EtOAc. Rf 0.1 in 3:1 hexanes: EtOAc. 1H NMR (400 MHz, CDCl3): δ 1.08 (s,
9H), 3.95ꢀ4.02 (m, 2H), 4.28 (s, 2H), 4.31 (br s, 1H), 4.62 (br d, 1H, J=8.24 Hz), 4.81ꢀ4.82 (m,
1H), 5.44ꢀ5.5 (m, 6H), 5.82 (dd, 1H, J=1.36 Hz, J=3.58 Hz), 6.90 (s, 1H), 7.07ꢀ7.09 (m, 2H),
7.28ꢀ7.52 (m, 19H), 7.76ꢀ7.78 (m, 2H), 7.88ꢀ7.90 (m, 2H). 13C NMR (400 MHz, CDCl3): δ 14.3,
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19.3, 21.6, 26.4, 60.4, 62.6, 68.2, 69.2, 70.2, 83.9, 102.9, 113.1, 117.8, 127.5, 127.7, 127.9,
128.11, 128.18, 128.30, 128.39, 128.44, 128.6, 129.9, 130.1, 131.4, 132.0, 135.5, 136.0, 136.1,
137.0, 137.7, 150.3, 151.1, 156.8, 159.4. FABꢀMS for C49H49N3O6Si calculated [M+H+]
804.3463, found 804.3441.
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2ꢀ[(Dimethylamino)methyleneimino]ꢀ4ꢀbenzyloxyꢀ5ꢀNꢀbenzyloxymethylꢀpyrrolo[3,2ꢀ
d]pyrimidine (20): From 19 (300 mg, 1.02 mmol), 20 was obtained as a syrup (278 mg, 0.67
mmol, 65%). Rf 0.5 in 1:1 hexanes: EtOAc. 1H NMR (400 MHz, CDCl3): δ 3.03 (s, 3H), 3.09 (s,
3H), 4.55 (s, 2H), 5.54 (s, 2H), 5.88 (s, 2H), 6.28 (d, 1H, J=3.24 Hz), 7.17 (d, 1H, J=2.76 Hz),
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7.22ꢀ7.27 (m, 7H), 7.35ꢀ7.38 (m, 3H), 8.45 (s, 1H). C NMR (400 MHz, CDCl3): δ 35.1, 40.9,
45.3, 70.3, 76.4, 103.1, 114.4, 126.8, 127.7, 127.92, 127.99, 128.2, 128.4, 131.0, 137.7, 138.9,
145.3, 154.8, 155.8, 156.4. ESIꢀMS m/z for C24H25N5O2 calculated [M+H+] 416.2081, found
416.2077.
7ꢀIodoꢀ2ꢀ[(Dimethylamino)methyleneimino]ꢀ4ꢀbenzyloxyꢀ5ꢀbenzyloxymethylꢀpyrrolo[3,2ꢀ
d]pyrimidine (21): From 20 (1.7 g, 4.09 mmol), 21 was obtained as an offꢀwhite solid (1.42 g,
1
2.6 mmol, 64%). Rf 0.5 in 3:1 hexanes:EtOAc. Mp 168ꢀ172 ˚C. H NMR (400 MHz, CDCl3): δ
3.04 (s, 3H), 3.14 (s, 3H), 4.57 (s, 2H), 5.54 (s, 2H), 5.86 (s, 2H), 7.21ꢀ7.28 (m, 9H), 7.34ꢀ7.37
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(m, 2H), 8.60 (s, 1H). C NMR (400 MHz, CDCl3): δ 35.2, 41.1, 45.4, 58.6, 70.6, 76.6, 114.4,
126.9, 127.8, 127.9, 128.2, 128.4, 134.4, 137.4, 138.7, 145.8, 155.2, 155.4, 157.1. FABꢀMS m/z
for C24H24IN5O2 calculated [M+H+] 542.1047, found 542.1052.
Coupling of 21 and 10 using Jeffery conditions: General procedure for Heck coupling under
Jeffery conditions was used. First 24 hrs did not indicate consumption of 21. A second portion of
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Pd(OAc)2 (0.2 eq.) was added and the mixture stirred at 40 ˚C for another 24 hrs upon which the
TLC indicated the absence of 21. The DMF was evaporated, the residue dissolved in CH2Cl2 (50
mL) and filtered over celite. The filtrate was loaded onto silica, and the mixture (22 and 23) was
separated via column chromatography eluting with 9:1 then 3:1 hexanes:EtOAc to give 22 as
light brown syrup (66 mg, 86 ꢃmol, 31%). Rf 0.4 in 3:1 hexanes: EtOAc. Further elution with 2:1
hexanes: EtOAc afforded 23 as dark yellow syrup (40 mg, 75.6 ꢃmol, 27%). Rf 0.1 in 3:2
hexanes: EtOAc. Spectral data for 22. 1H NMR (400 MHz, CDCl3): δ 1.12 (s, 9H), 3.06 (s, 6H),
4.03 (dd, 2H, J=11.44 Hz, J=25.2 Hz), 4.15 (dd, 1H, J=6.88 Hz, J=14.42 Hz), 4.38 (br s, 1H),
4.56 (d, 2H, J=3.2 Hz), 4.82 (d, 1H, J=2.28 Hz), 5.56 (dd, 2H, J=14.2 Hz, J=35.72 Hz), 5.72 (d,
1H, J=4.6 Hz), 5.83 (s, 2H), 6.95 (s, 1H), 7.22ꢀ7.33 (m, 10H), 7.39ꢀ7.48 (m, 6H), 7.76 (d, 2H,
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J=6.88 Hz), 7.86 (d, 2H, J=6.88 Hz), 8.71 (s, 1H). C NMR (400 MHz, CDCl3): δ 14.39, 19.4,
21.2, 26.5, 29.7, 34.9, 40.7, 45.4, 60.5, 62.7, 70.5, 76.9, 78.4, 83.6, 104.1, 115.9, 117.2, 126.8,
127.6, 127.7, 127.90, 127.98, 128.0, 128.2, 128.4, 129.8, 130.1, 130.3, 131.8, 132.1, 135.5,
135.8, 137.7, 139.0, 143.1, 149.7, 155.0, 155.9, 157.8. ESIꢀMS m/z for C45H49N5O5Si calculated
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[M+H+] 768.3575, found 768.3584. Spectral data for 23. H NMR (400 MHz, CDCl3): δ 2.67
(dd, 1H, J=6.4 Hz, J=17.88 Hz), 3.01 (s, 3H), 3.08 (s, 3H), 3.16 (dd, 1H, J=6.4 Hz, J=17.88 Hz),
3.82ꢀ3.89 (m, 2H), 4.06ꢀ4.07 (m, 1H), 4.58 (s, 2H), 5.31 (dd, 1H, J=6.4 Hz, J=11 Hz), 5.84 (dd,
4H, J=10.56 Hz, J=23.82 Hz), 7.18 (s, 1H), 7.22ꢀ7.28 (m, 8H), 7.35ꢀ7.37 (m, 2H), 8.29 (s, 1H).
13C NMR (400 MHz, CDCl3): δ 35.0, 40.9, 44.3, 45.5, 62.8, 70.6, 72.4, 76.4, 82.1, 115.1, 116.1,
126.9, 127.8, 128.0, 128.2, 128.4, 129.3, 137.5, 138.5, 142.5, 155.5, 155.7, 157.3, 215.5. ESIꢀ
MS m/z for C29H31N5O5 calculated [M+H+] 530.2398, found 530.2399.
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pentofuranꢀ3'ꢀulosꢀ1'ꢀyl)pyrrolo[3,2ꢀd]pyrimidine (23): Using the previous procedure, 21 (1.4
g, 2.58 mmol) was subjected to Heck coupling to provide a mixture of 22 and 23. The solvent
was evaporated, the residue dissolved in CH2Cl2 (100 mL), filtered and the filtrate transferred to
a dry flask. To this a 1M solution of TBAF in THF (2 mL, 2 mmol) was added and the mixture
was stirred for 1 hr, until the TLC indicated the absence of 22. The mixture was evaporated to
dryness, the residue loaded onto silica and purified using column chromatography eluting with
3:1 then 2:1 hexanes: EtOAc to give 23 as dark yellow syrup (732 mg, 1.38 mmol, 54%).
Spectral data of 23 matched that reported in the previous procedure.
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1'ꢀβꢀ[7ꢀ(2ꢀ[(Dimethylamino)methyleneimino]ꢀ4ꢀbenzyloxyꢀ5ꢀbenzyloxymethyl) pyrrolo[3,2ꢀ
d]pyrimidine)]ꢀ2'ꢀdeoxyribofuranose (24): From 23 (732 mg, 1.38 mmol), 24 was obtained as
a pink syrup (420 mg, 0.79 mmol, 57%). Rf 0.5 in 19:1 CH2Cl2: MeOH. 1H NMR (400 MHz,
CD3OH): δ 2.01 (dd, 1H, J=5.52 Hz, J=13.28 Hz), 2.68 (td, 1H, J=5.04 Hz, J=12.18 Hz), 3.02 (s,
3H), 3.10 (s, 3H), 3.67 (d, 1H, J=12.36 Hz), 3.87 (d, 1H, J=11.88 Hz), 4.12 (s, 1H), 4.56 (d, 2H,
d, J=2.32 Hz), 4.60 (br d, 1H, J=4.56 Hz), 5.32 (dd, 1H, J=5.04 Hz, J=10.98 Hz), 5.50 (dd, 2H,
J=14.2 Hz, J=20.64 Hz), 5.86 (s, 2H), 7.14 (s, 1H), 7.16ꢀ7.30 (m, 8H), 7.34ꢀ7.36 (m, 2H), 8.25
(s, 1H). 13C NMR (400 MHz, CDCl3): δ 34.9, 40.7, 43.4, 45.5, 64.0, 70.4, 75.5, 75.9, 76.3, 88.5,
115.7, 116.1, 126.9, 127.7, 127.90, 127.94, 128.2, 128.4, 129.5, 137.6, 138.6, 142.5, 155.3,
157.0. ESIꢀMS m/z for C29H33N5O5 calculated [M+H+] 532.2554, found 532.2558.
1 ꢀβꢀ[7ꢀ(2ꢀAminoꢀ4ꢀbenzyloxyꢀ5ꢀbenzyloxymethyl)pyrrolo[3,2ꢀd]pyrimidine)]ꢀ2'ꢀdeoxyꢀ
ribofuranose (25): To a solution of 24 (420 mg, 0.79 mmol) in MeOH (5 ml) in a heavy walled
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glass tube (w/screw cap), portions of NH4OH (1 mL) were added each day for 7 days until the
TLC indicated the absence of starting materials. The solvents were removed, the residue
extracted with CH2Cl2 (30 mL), the organic phase dried over MgSO4, concentrated, loaded onto
silica, and purified via column chromatography eluting with 99:1 CH2Cl2:MeOH to obtain 25 as
a white foam (350 mg, 0.735 mmol, 93%). Rf 0.45 in 19:1 CH2Cl2: MeOH. 1H NMR (400 MHz,
DMSO d6): δ 1.93 (dd, 1H, J=5.26, J=12.58 Hz), 2.04ꢀ2.11 (m, 1H), 3.40ꢀ3.42 (m, 2H), 3.67ꢀ
3.69 (m, 2H), 4.15 (br s, 1H), 4.47 (s, 2H), 4.90 (d, 1H, J=3.68 Hz), 4.98 (t, 1H, J=5.52 Hz), 5.05
(dd, 1H, J=5.52 Hz, J=10.54 Hz), 5.22 (s, 2H), 5.67 (s, 2H), 6.33 (s, 2H, NH2), 7.16ꢀ7.30 (m,
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10H), 7.41 (s, 1H). C NMR (400 MHz, DMSO d6): δ 42.0, 43.4, 63.3, 70.0, 72.4, 73.2, 76.6,
87.9, 112.0, 116.3, 127.2, 127.5, 127.92, 127.97, 128.7, 128.8, 130.7, 137.3, 138.4, 144.8, 151.7,
154.6. ESIꢀMS m/z for C26H28N4O5 calculated [M+H+] 477.2132, found 477.2135.
1'ꢀβꢀ[7ꢀ(2ꢀAminoꢀ5Hꢀpyrrolo[3,2ꢀd]pyrimidinꢀ4ꢀone)]ꢀ2'ꢀdeoxyribofuranose or 9ꢀdeazaꢀ2'ꢀ
deoxyguanosine (2): General procedure for hydrogenolysis was used. From 25 (350 mg, 0.73
mmol), 2 was obtained as a white solid (128 mg, 0.48 mmol, 66%). Mp >300 ˚C. Rf 0.5 in 4:1
CH2Cl2: MeOH. 1H NMR (400 MHz, DMSO d6): δ 1.86 (dd, 1H, J=5.26 Hz, J=12.62 Hz), 2.13
(td, 1H, J=5.04 Hz, J=11.69 Hz), 3.37 (ddd, 2H, J=4.12 Hz, J=11.66 Hz, J=11.44 Hz), 3.69 (t,
1H, J=4.12 Hz), 4.15 (br s, 1H), 4.85 (d, 1H, J=3.64 Hz), 5.05 (dd, 1H, J=5.28 Hz, J=10.76 Hz),
5.66 (br s, 2H, NH2), 5.81 (br s, 1H), 7.09 (d, 1H, J=3.2 Hz), 10.41 (br s, 1H, NH), 11.33 (br s,
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1H, NH). C NMR (400 MHz, DMSO d6): δ 42.6, 63.8, 73.6, 73.9, 88.3, 113.8, 115.7, 126.1,
151.3, 155.4, 164.0. ESIꢀMS m/z for C11H14N4O4 calculated [M+H+] 267.1087, found 267.1089.
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The 1H, 13C NMR spectra and High Resolution Mass Spectrometry (HRMS) for compounds 1ꢀ25
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