Photoredox-Catalyzed Deformylative 1,4-Addition of 2′-Deoxy-5′- O-phthalimidonucleosides for Synthesis of 5′-Carba Analogs of Nucleoside 5′-Phosphates

Article abstract of DOI:10.1021/acs.joc.8b00637

A concise approach for the synthesis of the 5′-carba analogs of nucleoside 5′-phosphates from 2′-deoxy-5′-O-phthalimidonucleosides by a visible-light-mediated deformylative 1,4-addition was developed. This method enabled rapid and facile generation of 4′-carbon radicals of nucleosides. Moreover, this synthetic strategy was applicable to the 5′-carba analogs of nucleoside 5′-phosphates as well as other 5′-carba nucleosides bearing methoxycarbonyl, cyano, and N-methylsulfamoyl groups.

Full text of DOI:10.1021/acs.joc.8b00637

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Article
Photoredox-catalyzed Deformylative 1,4-Addition of
2#-Deoxy-5#-O-phthalimidonucleosides for Synthesis
of 5#-Carba Analogs of Nucleoside 5#-Phosphates
Yuta Ito, Airi Kimura, Takashi Osawa, and Yoshiyuki Hari
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00637 • Publication Date (Web): 23 Aug 2018
Downloaded from http://pubs.acs.org on August 23, 2018
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Photoredox-catalyzed
Deformylative
1,4-Addition
of
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2ʹ-Deoxy-5ʹ-O-phthalimidonucleosides for Synthesis of 5ʹ-Carba Analogs of
Nucleoside 5ʹ-Phosphates
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Yuta Ito, Airi Kimura, Takashi Osawa, and Yoshiyuki Hari*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Nishihama,
Yamashiro-cho, Tokushima 770-8514, Japan.
ABSTRACT: A concise approach for the synthesis of the 5ʹ-carba analogs of
nucleoside 5ʹ-phosphates from 2ʹ-deoxy-5ʹ-O-phthalimidonucleosides by a visible
light-mediated deformylative 1,4-addition was developed. This method enabled rapid
and facile generation of 4ʹ-carbon radicals of nucleosides. Moreover, this synthetic
strategy was applicable to the 5ʹ-carba analogs of nucleoside 5ʹ-phosphates as well as
other 5ʹ-carba nucleosides bearing methoxycarbonyl, cyano and N-methylsulfamoyl
groups.
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INTRODUCTION
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Resistance of modified nucleotides against enzymatic degradation by phosphatase and
phosphodiesterase is one of the most important requirements in the search for
nucleoside drugs.1 To improve the stability of nucleotides, various chemical
modifications have been investigated to date.2 In particular, the 5ʹ-carba analogs of
nucleoside 5ʹ-phosphates are quite stable against chemical and enzymatic hydrolysis
because the 5ʹ-oxygen-phosphorus bond is replaced with a non-hydrolyzable
carbon-phosphorus bond. Therefore, the 5ʹ-carba analogs have recently attracted
considerable attention as antiviral agents or as chemical modifications for short
interfering RNA.3
In general, the synthesis of 5ʹ-carba analogs is typically achieved via
Horner-Wadsworth-Emmons (HWE) olefination (or Wittig olefination) of aldehydes
with bisphosphonates followed by hydrogenation (Scheme 1a).3,4 This conventional
method has often been used for the synthesis of 2ʹ-deoxyribonucleosides and
ribonucleosides. However, multi-step reactions including several protection and
deprotection steps are required due to the presence of highly reactive functional groups
such as hydroxyl and amino groups. The selective protection of the secondary hydroxyl
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group at the 3ʹ-position in the synthesis of 5ʹ-aldehyde intermediate from
2ʹ-deoxyribonucleosides is particularly tedious. An alternative method for the synthesis
of 5ʹ-carba analogs, based on an approach using a 4ʹ-carbon radical generated from a
Barton ester, by Barton and co-workers is known (Scheme 1b).5 However, this synthetic
method has some drawbacks, e.g., (i) troublesome protection-deprotection processes is
required for the preparation of the Barton ester, and (ii) a 2-thiopyridyl group remains
after the reaction. Despite the drawbacks, the reports are quite impressive, and we
considered that it would provide a convenient and efficient synthetic tool for the
preparation of the 5ʹ-carba analogs of nucleoside 5ʹ-phosphates if the 4ʹ-carbon radicals
could be easily generated from readily available nucleoside derivatives. Very recently,
Inoue and co-workers reported the generation of 4ʹ-carbon radicals by radical
decarbonylation from the 5ʹ-acyl tellurides of 2ʹ-O,3ʹ-O-isopropylideneuridines and
used it for the total synthesis of polyoxins J and L, and their fluorinated analogs.6 As
such, a new generation method of 4ʹ-carbon radicals of nucleosides will contribute to
development of useful nucleoside analogs.
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Scheme 1. Strategies for the Synthesis of 5ʹ-Carba Analogs of Nucleosides
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Recently, Chen and co-workers demonstrated visible light-mediated selective C(sp3)-H
allylation and alkenylation reactions of N-alkoxyphthalimides through an intramolecular
1,5-hydrogen atom transfer (1,5-HAT) induced by alkoxy radicals (Scheme 2a, route
A).7 On the other hand, when the N-alkoxyphthalimide (R = Me) synthesized from a
secondary alcohol was used, the β-fragmentation of the alkoxy radical involving the
elimination of acetaldehyde partially proceeded to give an α-alkoxy radical (Scheme 2a,
route B). Thus, if a photoredox reaction of a 2ʹ-deoxy-5ʹ-O-phthalimidonucleoside,
which can be prepared from natural nucleosides in one step by the Mitsunobu reaction,8
preferentially undergoes β-fragmentation of the alkoxy radical, that is radical
deformylation, 4ʹ-carbon radicals might be easily generated (Scheme 2b). The 4ʹ-carbon
radicals would then add to vinylphosphonates to produce 5ʹ-carba analogs of
nucleosides. This straightforward strategy would offer significant advantages over the
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aforementioned methods with regard to ease of synthesis and handling. Herein, we
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report the concise synthesis of 5ʹ-carba analogs of nucleosides from
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2ʹ-deoxy-5ʹ-O-phthalimidonucleosides by
a
photoredox-catalyzed deformylative
1,4-addition reaction. In addition, this methodology can be successfully applied for the
construction of various 5ʹ-modified nucleosides.
Scheme 2. Novel Strategy for Synthesis of 5ʹ-Carba Analogs of Nucleosides
RESULTS AND DISCUSSION
In the preliminary investigations, 5ʹ-O-phthalimidothymidine 1a and diethyl
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vinylphosphonate 2a were selected as model substrates for the optimization of the
reaction conditions (Table 1). In the presence of fac-Ir(ppy)3 as a photocatalyst and
Hantzsch ester as a reductant and hydrogen source,9 treatment of 1a with 1.5 equiv. of
2a in DCM under irradiation with a 32 W compact fluorescent lamp (CFL) underwent
reductive cleavage of an N-O bond in the N-alkoxyphthalimide moiety to afford
thymidine 4 in 43% yield; the desired 5ʹ-carba analog 3 was only detected in trace
amounts (entry 1). Remarkably, the solvent played a crucial role in this reaction. The
substrate 1a could not be dissolved in the tested solvents (entries 1-4) because of its
polar nature. Although the reaction remained as a heterogeneous suspension in DCM,
MeCN and MeOH even after 1 h (entries 1-3, and Figure S1), a homogeneous solution
was formed in 1,4-dioxane (entry 4 and Figure S2). Prolonged reaction time to 24 h
using MeOH as a solvent became homogeneous solution to afford not only desired 3
(<34%, including impurities) but also the N-O reduction product 4 (36%) with complete
consumption of starting material 1a. In the conditions of entry 4, compound 3 was
obtained in 53% yield as a mixture of 4ʹ-epimers (β:α = 6:1), and interestingly, the
reaction preferentially produced desired 3β10, the structure of which was determined by
NOESY correlations (Figure S3). Using 2.0 or 1.0 equiv. of 2a somewhat reduced the
yield of desired 3 with an increased production of 4 (entries 5 and 6). The yield was
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only slightly improved though a large amount of 2a (10 equiv.) was used (entry 7).
Increasing the reaction temperature resulted in lower diastereoselectivity (entries 8 and
9). In the absence of fac-Ir(ppy)3, the reaction did not proceed after 1 h and only 14% of
3 was observed with a recovery of 74% of 1a even after 24 h (entries 10 and 11). On the
other hand, Chen’s group very recently succeeded in the generation of an α-alkoxy
radical from N-alkoxyphthalimide using only the Hantzsch ester without any
photocatalyst.11 Thus, in the reaction using 5 equiv. of Hantzsch ester and 3 equiv. of
2a,11 the desired 3 was afforded in 39% yield along with 38% of thymidine 4 and 22%
of the recovered 1a (entry 12). In the absence of the Hantzsch ester, the reaction did not
proceed after 24 h (entry 13). These experiments indicated that the conditions shown in
entry 4 gave the best results and that a combination of the photocatalyst and Hantzsch
ester was important for the efficient reaction. Notably, this reaction could be performed
on a gram scale without any loss in efficiency or diastereoselectivity (entry 14).
Table 1. Optimization of Reaction Conditions
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entry
solvent
T (°C)
time (h)
yield of 3 yield of 4
2a
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(equiv.)
1.5
1.5
1.5
1.5
2.0
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(β:α)a
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1
DCM
rt
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trace (–)
34% (4:1) 16%
33% (1:1)
43%
2
MeCN
rt
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3
MeOH
rt
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–
4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
rt
1
53% (6:1) 24%
44% (7:1) 42%
45% (5:1) 47%
58% (5:1) 31%
45% (4:1) 45%
52% (4:1) 41%
5
rt
1
6
rt
1
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rt
1
8
1.5
1.5
1.5
1.5
3.0
40
60
rt
1
9
0.5
1
10b
11b
12b,c
–
–
rt
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14% (4:1) 11%
39% (5:1) 38%
rt
13d
14e
1,4-dioxane
1,4-dioxane
1.5
1.5
rt
24
1
–
–
rt
57% (6:1) 31%
aDiastereomeric ratio was determined by H NMR analysis. No fac-Ir(ppy)3. 5 equiv.
1
b
c
d
e
of Hantzsch ester. No Hantzsch ester. A gram-scale reaction (2.6 mmol scale). ppy =
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The results of Table 1 and previous reports7,9 suggest a reaction mechanism in which
both Ir(ppy)3 and Hantzsch ester work (Scheme 3). Single-electron transfer from
IrII(ppy)3 to the N-alkoxyphthalimide 1a proceeds to form the radical anion A, in which
homolytic cleavage of the N-O bond gives the alkoxy radical B. The resulting B
undergoes β-fragmentation with elimination of formaldehyde, as expected, and
4ʹ-carbon radical C is generated. Then, the addition of C to the vinyl phosphonate 2a
yields α-phosphonyl radical D. Finally, hydrogen atom abstraction from radical
intermediate of Hantzsch ester provides desired 3.
Scheme 3. Plausible Reaction Mechanism
With the optimized conditions in hand, the photoredox-catalyzed deformylative
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1,4-addition reaction was extended to some vinylphosphonates and
2ʹ-deoxy-5ʹ-O-phthalimidonucleosides (Scheme 4). When diphenyl (2b) and dibenzyl
(2c) vinylphosphonates were used, the corresponding 5ʹ-carba analogs 5 and 6 were
isolated in moderate yields. The protecting groups of the phosphonates in 5 and 6
including 3 could be removed under different conditions.12-14 Interestingly, the reaction
proceeded with a protection-free purine analog, 2ʹ-deoxy-5ʹ-O-phthalimidoadenosine 1c,
to afford the corresponding phosphonate 7 in 61% yield and with a diastereoselectivity
of 4:1.
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Scheme 4. Scope of Vinylphosphonates and 2ʹ-Deoxy-5ʹ-O-phthalimidonucleosides
5ʹ-Modified thymidines bearing cyanomethyl and sulfamoylmethyl groups are
inhibitors of thymidine monophosphate kinase and biotin protein ligase, respectively, in
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Mycobacterium tuberculosis;15,16 however, the synthesis required 6 steps in a similar
way to that shown in Scheme 1a and the yields of the products were extremely low
(<5.4%).15 Thus, we next investigated the reactions using other electron-deficient
olefins, instead of vinylphosphonates, as radical acceptors (Scheme 5). When 1a was
treated with methyl acrylate under the optimized conditions, the expected reaction
proceeded to give 8, possessing an ester functionality, in 43% yield with a
diastereoselectivity of β:α = 10:1. The yield was improved to 61% upon increasing the
reaction temperature to 80 °C. Gratifyingly, olefins with nitrile and sulfonamide
moieties afforded 915 and 1015 in 54% and 51% yields, respectively. Based on these
results, the developed method would offer a highly efficient synthetic route for the
preparation of 5ʹ-modified nucleosides in a fewer number of steps as compared to
previous methods.
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Scheme 5. Scope of Electron-Deficient Olefins
b
aThe reaction was carried out at 80 °C for 0.5 h. The reaction was carried out at 70 °C
for 0.5 h.
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Next, viable protecting groups for the 3ʹ-hydroxyl groups were explored (Table 2).
3ʹ-Protected analogs could be synthesized over two steps via the Mitsunobu reaction
followed by 3ʹ-O-protection. Treatment of TBS-protected 11 under the photoredox
conditions afforded the β-adduct 1510 (β:α = >50:1) in 41% yield (entry 1). This
improvement of the diastereoselectivity was likely due to the limited access of 2a from
the α-side owing to the bulky nature of the 3ʹ-O-protecting group. Using the
acyl-protected compounds such as acetyl (12) and benzoyl (13) groups, improvements
in the diastereoselectivity (β:α = 13:1 and ca. 40:1) were also observed to give 16 and
1717 in 32% and 34% yields, respectively (entries 2 and 3). Furthermore,
3ʹ-O-benzyloxymethyl (BOM) protection gave desired product 18 as a sole isomer (β:α
= >50:1) (entry 4).
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Table 2. Effect of Protecting Groups at the 3ʹ-Position on Diastereoselectivity
entry substrate
11 (R1 = TBS)
reagent
product
yield (β:α)a
1
41% (>50:1)
2a
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12 (R1 = Ac)
13 (R1 = Bz)
14 (R1 = BOM)
32% (13:1)
2a
2a
2c
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18
34% (ca. 40:1)
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35% (>50:1)
aDiastereomeric ratio was determined by 1H NMR analysis.
To understand the high diastereoselectivity, the energy-minimized conformations of
4ʹ-carbon radical intermediates (R = H and Bz) were calculated using the Hartree-Fock
method with the 6-311G* basis using Spartan’16 (Figure 1a). As a result, the
3ʹ-hydroxyl group was determined to be in a pseudo-axial position, as shown in Figure
1a. Therefore, the addition of a 4ʹ-carbon radical would preferentially occur from the
less hindered β-side, which is opposite to the 3ʹ-hydroxyl group (Figure 1b). Protecting
groups in the 3ʹ-position, like a benzoyl analog shown in Figure 1a, would lead to a
more stereoselective reaction because of the steric hindrance. This theoretical finding
was also supported by Barton and co-workers, which indicated that 4ʹ-carbon radical
with
a
TBDPS group on the 3ʹ-hydroxyl group resulted in excellent
diastereoselectivity.5a,5b
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Figure 1. (a) Energy-minimized structures of 4ʹ-carbon radical intermediates. (b)
Possible mechanism for enhanced diastereoselectivity in the radical addition.
Finally, in order to demonstrate the practical utility of the developed method, the
formal synthesis of 5ʹ-carba analog of dUTP,4a which potently inhibits sterile alpha
motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), was
performed as shown in Scheme 6. Phosphonate 18 was obtained from commercially
available 2ʹ-deoxyuridine in 3 steps: (i) Mitsunobu reaction, (ii) BOM protection of the
3ʹ-hydroxyl group, and (iii) the developed photocatalytic reaction, as shown in entry 4
in Table 2. Subsequently, both the benzyl and BOM protecting groups were
simultaneously removed by hydrogenolysis to afford the 5ʹ-carba analog of dUMP 19,
which is a key intermediate in the synthesis of the 5ʹ-carba analog of dUTP. Although,
in another method,4a the deprotection of methyl phosphonate and the TBS group with
bromotrimethylsilane required microwave irradiation due to the suppression of
anomerization, anomerization at the 1ʹ-position was observed (the ratio of β- and
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α-anomer was 8:1). In contrast, our approach facilitated the facile deprotection under
mild conditions without anomerization and the 5ʹ-carba analog of dUMP was prepared
in only 4 steps.
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Scheme 6. Formal Synthesis of 5ʹ-Carba Analog of dUTPa
CONCLUSION
In conclusion, we developed a visible light-mediated deformylative 1,4-addition
reaction with 2ʹ-deoxy-5ʹ-O-phthalimidonucleosides. This method enabled the rapid and
facile generation of 4ʹ-carbon radicals without protection of the 3ʹ-hydroxyl group and
provided concise access to the 5ʹ-carba analogs of nucleoside 5ʹ-phosphates as well as
other 5ʹ-modified nucleosides. In addition, the diastereoselectivity was dramatically
improved upon protection of the 3ʹ-hydroxyl group, and 3ʹ-O-protected substrates could
be synthesized from natural nucleosides in only 2 steps: (i) Mitsunobu reaction and (ii)
protection at the 3ʹ-position. We believe that, in terms of simplicity and availability, the
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developed method will be a powerful tool for the synthesis of 5ʹ-carba analogs of
nucleosides. The synthesis of new and useful nucleosides using this procedure is
currently underway in our laboratory.
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EXPERIMENTAL SECTION
General Information. All moisture-sensitive reactions were conducted in well-dried
glassware under an Ar atmosphere. Anhydrous DCE, DCM, 1,4-dioxane, DMF, MeCN
1
and MeOH were used as received. H NMR, 13C NMR, and 31P NMR spectra were
recorded on a Bruker AVANCE III HD 500 equipped with a BBO cryoprobe or Agilent
13
31
400-MR. All C and P NMR spectra were proton-decoupled. Chemical shift values
were reported in ppm, relative to internal tetramethylsilane ( = 0.00 ppm for CDCl3),
acetone ( = 2.20 ppm for D2O) and residual solvent signals ( = 2.50 ppm for
DMSO-d6) for 1H NMR, solvent signals ( = 77.0 ppm for CDCl3 and  = 39.5 ppm for
DMSO-d6) for 13C NMR, and external 5% H3PO4 ( = 0.00 ppm) for 31P NMR. IR
spectra were recorded on a JASCO FT/IR-4200 spectrometer. High-resolution mass
spectrometry was performed on a Waters SYNAPT G2-Si (quadrupole/TOF). For
column chromatography, silica gel PSQ-60B (Fuji Silysia) was used. The progress of
the reaction was monitored by analytical thin-layer chromatography (TLC) on
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pre-coated
aluminum
sheets
(silica
gel
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F254
by
Merck).
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2ʹ-Deoxy-5ʹ-O-phthalimidonucleoside 1a-c8 and 1118, dibenzyl vinylphosphonate 2c19
and N-methylethenesulfonamide20 were synthesized according to previously reported
procedures.
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Preparation of 3ʹ-O-Protected 2ʹ-Deoxy-5ʹ-O-phthalimidonucleosides.
3ʹ-O-Acetyl-5ʹ-O-phthalimidothymidine
(12).
To
a
solution
of
5ʹ-O-phthalimidothymidine 1a (1.0 g, 2.58 mmol) in pyridine (10 mL), Ac2O (0.73 mL,
7.74 mmol) and DMAP (32.0 mg, 0.26 mmol) were added. After stirring for 2 h at room
temperature, the reaction mixture was quenched with sat. NaHCO3 aq. and extracted
with AcOEt. The combined organic layer was washed with water and brine, dried over
Na2SO4, and concentrated in vacuo. The crude residue was purified by column
chromatography (hexane/AcOEt = 1:2) to give compound 12 as a white solid (663 mg,
60%). 1H NMR (500 MHz, DMSO-d6): δ 11.35 (s, 1H), 7.88-7.84 (m, 4H), 7.64 (q, J =
1.0 Hz, 1H), 6.19 (dd, J = 9.0, 6.0 Hz, 1H), 5.37 (d, J = 6.0 Hz, 1H), 4.46-4.39 (m, 2H),
4.34-4.32 (m, 1H), 2.36 (ddd, J = 15.0, 9.0, 6.0 Hz, 1H), 2.28 (ddd, J = 14.5, 6.0, 1.5 Hz,
1H), 2.09 (s, 3H), 1.81 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ 170.0, 163.6, 163.0,
150.4, 135.6, 134.8, 128.6, 123.3, 110.1, 84.2, 81.4, 77.2, 74.3, 35.8, 20.8, 12.1. IR
(ATR) cm-1: 3028, 1790, 1726, 1694, 1664, 1472, 1363, 1242. HRMS (ESI-TOF): calcd
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for C20H19N3NaO8 [M + Na]+ 452.1070, found 452.1065.
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3ʹ-O-Benzoyl-5ʹ-O-phthalimidothymidine
(13).
To
a
solution
of
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5ʹ-O-phthalimidothymidine 1a (1.0 g, 2.58 mmol) in pyridine (15 mL), benzoyl chloride
(0.36 mL, 3.10 mmol) was added at 0 °C. After stirring for 5 h at room temperature, the
reaction mixture was quenched with sat. NaHCO3 aq. and extracted with AcOEt. The
combined organic layer was washed with water and brine, dried over Na2SO4, and
concentrated in vacuo. The crude residue was washed with Et2O to give compound 13
as a white solid (1.18 g, 93%). 1H NMR (500 MHz, DMSO-d6): δ 11.36 (s, 1H), 8.03 (d,
J = 7.5 Hz, 2H), 7.89-7.85 (m, 4H), 7.71 (dd, J = 7.5, 7.5 Hz, 1H), 7.69 (s, 1H), 7.56 (dd,
J = 7.5, 7.5 Hz, 2H), 6.32 (dd, J = 8.0, 6.5 Hz, 1H), 5.65 (d, J = 4.0 Hz, 1H), 4.55-4.48
(m, 3H), 2.54-2.45 (m, 2H), 1.83 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ 165.2,
163.6, 163.0, 150.4, 135.7, 134.8, 133.7, 129.4, 129.2, 128.8, 128.6, 123.3, 110.1, 84.4,
81.4, 77.2, 75.2, 36.0, 12.1. IR (ATR) cm-1: 3248, 1791, 1720, 1702, 1681, 1466, 1396,
1372, 1318, 1296, 1271. HRMS (ESI-TOF): calcd for C25H21N3NaO8 [M + Na]+
514.1226, found 514.1225.
General Procedure for the Synthesis of 5ʹ-Carba Analogs of Nucleosides. A
suspension of 2ʹ-deoxy-5ʹ-O-phthalimidonucleoside (0.2 mmol), olefin (0.3 mmol),
Hantzsch ester (76.0 mg, 0.3 mmol) and fac-Ir(ppy)3 (1.3 mg, 0.002 mmol) in
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1,4-dioxane (3 mL) was deaerated by Ar bubbling for 0.5 h. The mixture was stirred and
then irradiated with a 32 W compact fluorescent lamp at room temperature. After
stirring for 1 h, a yellow homogeneous solution was obtained. The crude solution was
directly purified by flash column chromatography (CHCl3/MeOH) to obtain the pure
product.
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1-[(3S,4R/4S)-6-(Diethoxyphosphinyl)-2,5,6-trideoxy-β/α-hexofuranosyl]thymine (3)10.
Purification of the crude solution by flash column chromatography (CHCl3/MeOH =
1
20:1 to 5:1) afforded compound 3 as a white solid (39.9 mg, 53%, β:α = 6:1). H NMR
(500 MHz, DMSO-d6): (major isomer) δ 11.29 (s, 1H), 7.40 (d, J = 1.0 Hz, 1H), 6.12
(dd, J = 7.0, 7.0 Hz, 1H), 5.29 (d, J = 4.5 Hz, 1H), 4.10-4.06 (m, 1H), 4.04-3.93 (m, 4H),
3.66-3.63 (m, 1H), 2.22 (ddd, J = 13.5, 7.0, 7.0 Hz, 1H), 2.04 (ddd, J = 13.5, 6.5, 4.0 Hz,
13
1H), 1.87-1.68 (m, 4H), 1.79 (d, J = 1.0 Hz, 3H), 1.23 (t, J = 7.0 Hz, 6H). C NMR
(126 MHz, DMSO-d6): δ 163.7, 150.5, 136.1, 109.9, 85.3 (d, J = 17.0 Hz), 83.3, 72.7,
61.0 (d, J = 6.0 Hz), 60.9 (d, J = 6.0 Hz), 38.3, 26.0 (d, J = 4.0 Hz), 21.1 (d, J = 140.5
Hz), 16.3 (d, J = 6.0 Hz), 12.1. 31P NMR (202 MHz, DMSO-d6): δ 32.0. IR (ATR) cm-1:
3367, 2984, 1683, 1470, 1270, 1229, 1207. HRMS (ESI-TOF): calcd for
C15H25N2NaO7P [M + Na]+ 399.1297, found 399.1292.
1-[(3S,4R/4S)-6-(Diphenoxyphosphinyl)-2,5,6-trideoxy-β/α-hexofuranosyl]thymine (5).
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Purification of the crude solution by flash column chromatography (CHCl3/MeOH =
8
9
1
20:1 to 5:1) afforded compound 5 as a white solid (48.8 mg, 52%, β:α = 7:1). H NMR
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(500 MHz, DMSO-d6): (major isomer) δ 11.31 (s, 1H), 7.43 (s, 1H), 7.39 (dd, J = 8.0,
7.5 Hz, 4H), 7.22 (t, J = 7.5 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.15 (dd, J = 7.0, 6.5 Hz,
1H), 5.34 (d, J = 4.5 Hz, 1H), 4.17-4.13 (m, 1H), 3.75-3.72 (m, 1H), 2.29-2.18 (m, 3H),
2.12-2.04 (m, 2H), 2.01-1.89 (m, 1H), 1.77 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ
163.7, 150.5, 149.9 (d, J = 7.0 Hz), 136.2, 129.9, 125.2, 120.54 (d, J = 2.0 Hz), 120.50
(d, J = 2.0 Hz), 109.9, 85.0 (d, J = 17.5 Hz), 83.3, 72.6, 38.2, 25.8 (d, J = 5.0 Hz), 22.3
(d, J = 140.5 Hz), 12.1. 31P NMR (162 MHz, DMSO-d6): δ 26.8. IR (ATR) cm-1: 3388,
3188, 3061, 1681, 1591, 1489, 1266, 1210. HRMS (ESI-TOF): calcd for
C23H25N2NaO7P [M + Na]+ 495.1297, found 495.1296.
1-[(3S,4R/4S)-6-(Dibenzyloxyphosphinyl)-2,5,6-trideoxy-β/α-hexofuranosyl]uracil (6).
Purification of the crude solution by flash column chromatography (CHCl3/MeOH =
1
20:1 to 5:1) afforded compound 6 as a white solid (49.6 mg, 51%, β:α = 6:1). H NMR
(500 MHz, DMSO-d6): (major isomer) δ 11.32 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H),
7.39-7.32 (m, 10H), 6.09 (dd, J = 7.0, 6.5 Hz, 1H), 5.59 (d, J = 8.0 Hz, 1H), 5.30 (d, J =
4.5 Hz, 1H), 5.01 (d, J = 4.5 Hz, 1H), 5.04 and 4.98 (ABq, J = 12.0 Hz, 2H), 5.02 and
4.97 (ABq, J = 12.0 Hz, 2H), 4.05-4.01 (m, 1H), 3.68-3.65 (m, 1H), 2.14 (ddd, J = 13.5,
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7.0, 7.0 Hz, 1H), 2.07 (ddd, J = 13.5, 6.5, 4.5 Hz, 1H), 1.99-1.67 (m, 4H). C NMR
(126 MHz, DMSO-d6): δ 163.0, 150.4, 140.7, 136.7 (d, J = 7.0 Hz), 128.5, 128.2 (d, J =
2.0 Hz), 127.7 (d, J = 6.0 Hz), 102.8, 85.4 (d, J = 18.0 Hz), 83.6, 72.5, 66.4 (d, J = 7.0
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Hz), 66.3 (d, J = 6.0 Hz), 38.6, 25.9 (d, J = 4.0 Hz), 21.3 (d, J = 139.5 Hz). P NMR
(202 MHz, DMSO-d6): δ 33.1. IR (ATR) cm-1: 3355, 2955, 1678, 1456, 1379, 1212.
HRMS (ESI-TOF): calcd for C24H27N2NaO7P [M + Na]+ 509.1454, found 509.1453.
1-[(3S,4R/4S)-6-(Diethoxyphosphinyl)-2,5,6-trideoxy-β/α-hexofuranosyl]adenine
(7).
Purification of the crude solution by flash column chromatography (CHCl3/MeOH =
1
20:1 to 5:1) afforded compound 7 as a white solid (46.9 mg, 61%, β:α = 4:1). H NMR
(500 MHz, DMSO-d6): (major isomer) δ 8.29 (s, 1H), 8.13 (s, 1H), 7.26 (s, 2H), 6.29
(dd, J = 7.0, 6.5 Hz, 1H), 5.35 (d, J = 4.5 Hz, 1H), 4.36-4.33 (m, 1H), 3.99-3.88 (m, 4H),
3.81-3.78 (m, 1H), 2.87 (ddd, J = 13.5, 6.5, 6.5 Hz, 1H), 2.27 (ddd, J = 13.5, 6.5, 4.5 Hz,
13
1H), 1.89-1.67 (m, 4H), 1.19 (t, J = 7.0 Hz, 6H). C NMR (126 MHz, DMSO-d6): δ
156.1, 152.5, 149.1, 139.7, 119.2, 86.0 (d, J = 17.0 Hz), 82.9, 72.9, 60.9 (d, J = 6.0 Hz),
60.8 (d, J = 6.0 Hz), 38.4, 26.1 (d, J = 4.5 Hz), 21.0 (d, J = 140.0 Hz), 16.2 (d, J = 5.5
Hz). 31P NMR (162 MHz, DMSO-d6): δ 32.0. IR (ATR) cm-1: 3321, 3184, 2984, 1642,
1598, 1575, 1474, 1330, 1296, 1232, 1208. HRMS (ESI-TOF): calcd for
C15H24N5NaO5P [M + Na]+ 408.1413, found 408.1415.
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1-[(3S,4R/4S)-6-Methoxycarbonyl-2,5,6-trideoxy-β/α-hexofuranosyl]thymine
(8).
8
9
Purification of the crude solution by flash column chromatography (CHCl3/MeOH =
10
11
12
13
14
15
16
17
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19
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20:1 to 5:1) afforded compound 8 as a white solid (36.3 mg, 61%, β:α = 7:1). H NMR
(500 MHz, DMSO-d6): (major isomer) δ 11.28 (br s, 1H), 7.38 (s, 1H), 6.11 (dd, J = 7.0,
7.0 Hz, 1H), 5.28 (br s, 1H), 4.07-4.04 (m, 1H), 3.64-3.61 (m, 1H), 3.58 (s, 3H), 2.40
(ddd, J = 7.5, 7.5, 2.0 Hz, 1H), 2.18 (ddd, J = 13.5, 7.0, 7.0 Hz, 1H), 2.03 (ddd, J = 13.5,
13
6.5, 4.0 Hz, 1H), 1.95-1.88 (m, 1H), 1.84-1.77 (m, 1H), 1.79 (s, 3H). C NMR (126
MHz, DMSO-d6): δ 173.1, 163.9, 150.6, 136.0, 109.8, 84.6, 83.3, 72.8, 51.3, 38.3, 29.9,
28.2, 12.1. IR (ATR) cm-1: 3452, 2931, 1707, 1656, 1628, 1474, 1366, 1267. HRMS
(ESI-TOF): calcd for C13H18N2NaO6 [M + Na]+ 321.1063, found 321.1062.
1-[(3S,4R/4S)-6-Cyano-2,5,6-trideoxy-β/α-hexofuranosyl]thymine (9)15. Purification of
the crude solution by flash column chromatography (CHCl3/MeOH = 20:1 to 10:1)
1
afforded compound 9 as a white solid (28.4 mg, 54%, β:α = 6:1). H NMR (500 MHz,
DMSO-d6): (major isomer) δ 11.30 (br s, 1H), 7.43 (s, 1H), 6.14 (dd, J = 7.0, 7.0 Hz,
1H), 5.34 (br s, 1H), 4.12-4.09 (m, 1H), 3.70-3.67 (m, 1H), 2.62-2.52 (m, 2H), 2.21
(ddd, J = 14.0, 7.0, 7.0 Hz, 1H), 2.05 (ddd, J = 14.0, 7.0, 4.0 Hz, 1H), 1.99-1.82 (m, 2H),
1.79 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ 163.7, 150.5, 136.2, 120.4, 109.9, 84.0,
83.5, 72.6, 38.1, 28.5, 13.3, 12.1. IR (ATR) cm-1: 3378, 3190, 2926, 2246, 1718, 1650,
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1475, 1269. HRMS (ESI-TOF): calcd for C12H15N3NaO4 [M + Na]+ 288.0960, found
288.0957.
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1-{(3S,4R/4S)-6-[(Methylamino)sulfonyl]-2,5,6-trideoxy-β/α-hexofuranosyl}thymine
(10)15. Purification of the crude solution by flash column chromatography
(CHCl3/MeOH = 10:1 to 5:1) afforded compound 10 as a white solid (33.9 mg, 51%,
1
β:α = 6:1). H NMR (500 MHz, DMSO-d6): (major isomer) δ 11.30 (br s, 1H), 7.41 (q,
J = 1.0 Hz, 1H), 6.93 (br s, 1H), 6.14 (dd, J = 7.0, 6.5 Hz, 1H), 5.40 (br s, 1H),
4.12-4.10 (m, 1H), 3.74-3.71 (m, 1H), 3.12-2.99 (m, 2H), 2.56 (s, 3H), 2.23 (ddd, J =
14.0, 7.0, 7.0 Hz, 1H), 2.08-1.99 (m, 2H), 1.95-1.87 (m, 1H), 1.80 (d, J = 1.0 Hz, 3H).
13C NMR (126 MHz, DMSO-d6): δ 163.8, 150.5, 136.1, 110.0, 83.7, 83.4, 72.8, 46.1,
38.1, 28.6, 27.1, 12.1. IR (ATR) cm-1: 3371, 2950, 2502, 1716, 1650, 1632, 1477, 1305.
HRMS (ESI-TOF): calcd for C12H19N3NaO6S [M + Na]+ 356.0892, found 356.0891.
1-[(3S,4R)-3-O-(tert-butyldimethylsilyl)-6-(diethoxyphosphinyl)-2,5,6-trideoxy-β-hexofu
ranosyl]thymine (15)10. Purification of the crude solution by flash column
chromatography (hexane/AcOEt = 1:3 to CHCl3/MeOH = 50:1) afforded compound 15
1
as a colorless oil (40.1 mg, 41%). H NMR (500 MHz, CDCl3): δ 8.57 (br s, 1H), 7.10
(d, J = 1.0 Hz, 1H), 6.20 (dd, J = 6.5, 6.5 Hz, 1H), 4.16-4.06 (m, 5H), 3.79-3.76 (m, 1H),
2.27 (ddd, J = 10.5, 6.5, 4.5 Hz, 1H), 2.08 (ddd, J = 13.5, 6.5, 6.5 Hz, 1H), 2.02-1.92 (m,
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2H), 1.95 (d, J = 1.0 Hz, 3H), 1.87-1.77 (m, 2H), 1.34 (t, J = 7.0 Hz, 3H), 1.33 (t, J =
7.0 Hz, 3H), 0.89 (s, 9H), 0.084 (s, 3H), 0.079 (s, 3H). 13C NMR (126 MHz, CDCl3): δ
163.4, 150.0, 135.1, 111.3, 86.0 (d, J = 17.0 Hz), 84.6, 74.7, 61.74 (d, J = 6.0 Hz), 61.67
(d, J = 6.0 Hz), 40.4, 26.6 (d, J = 5.0 Hz), 25.7, 22.3 (d, J = 143.5 Hz), 17.9, 16.5 (d, J =
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6.0 Hz), 12.6, -4.6, -4.9. P NMR (202 MHz, CDCl3): δ 31.1. IR (ATR) cm-1: 2929,
1688, 1471, 1367, 1249. HRMS (ESI-TOF): calcd for C21H39N2NaO7PSi [M + Na]+
513.2162, found 513.2158.
1-[(3S,4R/4S)-3-O-Acetyl-6-(diethoxyphosphinyl)-2,5,6-trideoxy-β/α-hexofuranosyl]thy
mine (16). Purification of the crude solution by flash column chromatography
(CHCl3/MeOH = 30:1 to 10:1) afforded compound 16 as a colorless oil (31.5 mg, 38%,
β:α = 13:1). 1H NMR (500 MHz, DMSO-d6): (major isomer) δ 11.29 (s, 1H), 7.49 (q, J
= 1.0 Hz, 1H), 6.12 (dd, J = 8.5, 6.0 Hz, 1H), 5.08-5.05 (m, 1H), 4.03-3.95 (m, 4H),
3.92-3.89 (m, 1H), 2.53-2.47 (m, 1H), 2.21 (ddd, J = 14.5, 6.0, 2.5 Hz, 1H), 2.05 (s, 3H),
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1.93-1.76 (m, 4H), 1.80 (d, J = 1.0 Hz, 3H), 1.23 (t, J = 7.0 Hz, 6H). C NMR (126
MHz, DMSO-d6): δ 169.9, 163.5, 150.3, 136.0, 109.9, 83.6, 82.8 (d, J = 17.5 Hz), 75.8,
60.91 (d, J = 6.0 Hz), 60.86 (d, J = 6.0 Hz), 34.9, 25.9 (d, J = 4.5 Hz), 20.9 (d, J = 140.5
Hz), 20.7, 16.1 (d, J = 5.5 Hz), 11.9. 31P NMR (202 MHz, DMSO-d6): δ 31.7. IR (ATR)
cm-1: 2983, 1737, 1685, 1469, 1369, 1233. HRMS (ESI-TOF): calcd for
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C17H27N2NaO8P [M + Na]+ 441.1403, found 441.1398.
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ymine (17)17. Purification of the crude solution by flash column chromatography
(CHCl3/MeOH = 100:1 to 50:1) afforded compound 17 as a colorless oil (32.7 mg, 34%,
β:α = ca. 40:1). 1H NMR (500 MHz,CDCl3): (major isomer) δ 8.91 (s, 1H), 8.04 (d, J =
8.0, 1.5 Hz, 2H), 7.61 (td, J = 7.5, 1.5 Hz, 1H), 7.47 (dd, J = 8.0, 7.5 Hz, 1H), 7.19 (q, J
= 1.0 Hz, 1H), 6.39 (dd, J = 8.5, 6.0 Hz, 1H), 5.30 (ddd, J = 6.5, 2.5, 2.5 Hz, 1H),
4.18-4.08 (m, 5H), 2.57 (ddd, J = 14.5, 6.0, 2.0 Hz, 1H), 2.30 (ddd, J = 14.5, 8.5, 6.5 Hz,
1H), 2.20-2.11 (m, 1H), 2.06-1.85 (m, 3H), 1.98 (d, J = 1.0 Hz, 3H), 1.34 (t, J = 7.0 Hz,
3H), 1.33 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 165.9, 163.4, 150.3, 134.5,
133.6, 129.7, 129.1, 128.5, 111.9, 84.5, 83.8 (d, J = 18.0 Hz), 76.6, 61.81 (d, J = 7.0 Hz),
61.76 (d, J = 7.0 Hz), 36.8, 27.1 (d, J = 4.5 Hz), 22.0 (d, J = 143.5 Hz), 16.5 (d, J = 6.0
Hz), 12.6. 31P NMR (162 MHz, CDCl3): δ 30.7. IR (ATR) cm-1: 2984, 1686, 1469, 1451,
1266, 1212. HRMS (ESI-TOF): calcd for C22H29N2NaO8P [M + Na]+ 503.1559, found
503.1552.
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Formal Synthesis of the 5ʹ-Carba Analog of dUTP.
2ʹ-Deoxy-5ʹ-O-phthalimidouridine (1b)8. To a solution of 2ʹ-deoxyuridine (1.89 g, 8.28
mmol), NHPI (1.49 g, 9.11 mmol) and Ph3P (2.53 g, 9.11 mmol) in DMF (20 mL),
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DIAD (2.12 mL, 10.8 mmol) was slowly added at 0 °C. After stirring for 4 h at room
temperature, the reaction mixture was concentrated in vacuo. The syrupy residue was
dissolved in Et2O (10 mL) and poured into cold water (30 mL). After stirring for 1 h at
0 °C, the precipitate was filtered and washed with CHCl3. The precipitated product was
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dried to give compound 1b as a white solid (2.25 g, 73%). H NMR (500 MHz,
DMSO-d6): δ 11.31 (s, 1H), 7.88-7.84 (m, 4H), 7.78 (d, J = 8.0 Hz, 1H), 6.19 (dd, J =
7.0, 7.0 Hz, 1H), 5.60 (d, J = 8.0 Hz, 1H), 5.47 (d, J = 4.5 Hz, 1H), 4.38-4.35 (m, 3H),
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4.10-4.08 (m, 1H), 2.15 (dd, J = 6.5, 4.5 Hz, 2H). C NMR (126 MHz, DMSO-d6): δ
163.0, 150.4, 140.6, 134.8, 128.6, 123.3, 102.0, 84.6, 84.1, 77.7, 70.5, 38.9. IR (ATR)
cm-1: 3471, 3237, 1789, 1726, 1686, 1457, 1369, 1236. HRMS (ESI-TOF): calcd for
C17H15N3NaO7 [M + Na]+ 396.0808, found 396.0807.
3ʹ-O-(Benzyloxymethyl)-2ʹ-deoxy-5ʹ-O-phthalimidouridine (14). To a suspension of
compound 1b (200 mg, 0.53 mmol) in DCE (5 mL), BOMCl (371 μL, 2.68 mmol) and
Ag2O (745 mg, 3.22 mmol) were added. After stirring for 24 h at reflux, the mixture
was added to BOMCl (371 μL, 2.68 mmol) and Ag2O (745 mg, 3.22 mmol). After
stirring for another 84 h at reflux, the heterogeneous reaction mixture was filtered
through Celite. The filtrate was washed with water and brine, dried over Na2SO4, and
concentrated in vacuo. The crude residue was purified by flash column chromatography
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(hexane/AcOEt = 1:1 to AcOEt) to give compound 14 as a white solid (123 mg, 47%).
1H NMR (400 MHz, CDCl3): δ 8.92 (br s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.88-7.84 (m,
2H), 7.81-7.76 (m, 2H), 7.38-7.27 (m, 5H), 6.36 (dd, J = 8.0, 6.0 Hz, 1H), 5.84 (dd, J =
8.0, 2.0 Hz, 1H), 4.89 and 4.87 (ABq, J = 8.0 Hz, 2H), 4.75-4.73 (m, 1H), 4.68 and 4.65
(ABq, J = 8.0 Hz, 2H), 4.45-4.39 (m, 2H), 4.31-4.29 (m, 1H), 2.54 (ddd, J = 14.0, 5.5,
2.5 Hz, 1H), 2.15 (ddd, J = 14.0, 8.0, 6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
163.5, 163.0, 150.4, 140.3, 137.3, 134.7, 128.6, 128.5, 127.9, 127.8, 123.7, 102.7, 94.0,
85.7, 82.8, 77.5, 77.0, 70.1, 38.6. IR (ATR) cm-1: 3025, 1790, 1731, 1681, 1456, 1375,
1274. HRMS (ESI-TOF): calcd for C25H23N3NaO8 [M + Na]+ 516.1383, found
516.1384.
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1-[(3S,4R)-3-O-(Benzyloxymethyl)-6-(dibenzyloxyphosphinyl)-2,5,6-trideoxy-β-hexofur
anosyl]uracil (18). A suspension of compound 14 (89.2 mg, 0.18 mmol), dibenzyl
vinylphosphonate (78.1 mg, 0.27 mmol), Hantzsch ester (68.6 mg, 0.27 mmol) and
fac-Ir(ppy)3 (1.2 mg, 0.002 mmol) in 1,4-dioxane (3 mL) was deaerated by Ar bubbling
for 0.5 h. The mixture was stirred and then irradiated with a 32 W compact fluorescent
lamp at room temperature. After stirring for 1 h, a yellow homogeneous solution was
obtained. The crude solution was directly purified by flash column chromatography
(hexane/AcOEt = 1:5 to AcOEt) to give compound 18 as a colorless oil (38.2 mg, 35%).
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1H NMR (500 MHz, CDCl3): δ 9.15 (br s, 1H), 7.37-7.26 (m, 15H), 7.20 (d, J = 8.0 Hz,
1H), 6.15 (dd, J = 6.5, 6.5 Hz, 1H), 5.67 (d, J = 8.0 Hz, 1H), 5.07 (d, J = 8.5 Hz, 2H),
5.07 (d, J = 8.5 Hz, 2H), 4.97 (dd, J = 8.5, 3.0 Hz, 2H), 4.94 (dd, J = 8.5, 3.0 Hz, 2H),
4.74 and 4.72 (ABq, J = 7.5 Hz, 2H), 4.59 and 4.55 (ABq, J = 8.0 Hz, 2H), 3.98 (ddd, J
= 7.0, 3.5, 3.5 Hz, 1H), 3.89-3.86 (m, 1H), 2.40 (ddd, J = 14.0, 6.0, 3.5 Hz, 1H),
1.98-1.72 (m, 5H). 13C NMR (126 MHz, CDCl3): δ 163.0, 150.0, 139.1, 137.2, 136.2 (d,
J = 6.0 Hz), 128.62, 128.55, 128.51, 128.03, 127.96, 127.92, 127.86, 102.8, 93.7, 85.0,
83.9 (d, J = 18.0 Hz), 78.9, 70.0, 67.4 (d, J = 7.0 Hz), 67.3 (d, J = 7.0 Hz), 37.7, 26.8 (d,
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J = 5.0 Hz), 22.5 (d, J = 142.5 Hz). P NMR (202 MHz, CDCl3): δ 32.0. IR (ATR)
cm-1: 3031, 2945, 1686, 1455, 1379, 1271, 1244, 1209. HRMS (ESI-TOF): calcd for
C32H35N2NaO8P [M + Na]+ 629.2029, found 629.2031.
1-[(3S,4R)-6-(Dihydroxyphosphinyl)-2,5,6-trideoxy-β-hexofuranosyl]uracil
(19)3f.
Compound 18 (31.2 mg, 0.05 mmol) was treated in MeOH (3 mL) at room temperature
under a hydrogen atmosphere in the presence of Pd(OH)2/C (30.0 mg). After stirring for
4 h, the reaction mixture was filtered and concentrated in vacuo. The crude product was
purified by Sep-Pak® Plus C18 cartridges (Waters, eluent: H2O to H2O/MeOH = 10:1).
The obtained solution was concentrated in vacuo and lyophilized to give compound 19
as a white solid (15.5 mg, 99%). 1H NMR (500 MHz, D2O): δ 7.70 (d, J = 8.0 Hz, 1H),
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6.24 (dd, J = 6.5, 6.5 Hz, 1H), 5.89 (d, J = 8.0 Hz, 1H), 4.35-4.32 (m, 1H), 4.00-3.97 (m,
1H), 2.40-2.37 (m, 2H), 2.01-1.75 (m, 4H). 13C NMR (126 MHz, D2O): δ 166.9, 152.2,
142.5, 103.0, 87.1 (d, J = 18.0 Hz), 86.1, 73.9, 38.6, 27.2 (d, J = 4.0 Hz), 24.8 (d, J =
135.5 Hz). 31P NMR (202 MHz, D2O): δ 24.6. IR (ATR) cm-1: 3194, 3088, 1721, 1659,
1476, 1434, 1270. HRMS (ESI-TOF): calcd for C10H14N2O7P [M − H]− 305.0539,
found 305.0538.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
at DOI:
Photos of the reaction solution, NOESY spectrum of compound 3, NMR spectra for
compounds and ab initio quantum mechanical calculation data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: hari@ph.bunri-u.ac.jp.
ORCID
Yoshiyuki Hari: 0000-0002-3903-7340
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