Novel synthetic approach to multibenzoylated nucleosides

Article abstract of DOI:10.1080/00397910801916280

An improved and highly efficient synthetic approach to multibenzoylated nucleosides bearing free 5'-hydroxyl groups is described here. By employing t-butyldimethylsilyl (TBDMS) rather than the more commonly used dimethoxytrityl (DMTr) as a temporary 5'-OH

Full text of DOI:10.1080/00397910801916280

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Novel Synthetic Approach to
Multibenzoylated Nucleosides
Xue‐Feng Zhu a & A. Ian Scott a
a Center for Biological Nuclear Magnetic Resonance (NMR), Department of
Chemistry , Texas A&M University , College Station, Texas, USA
Published online: 25 Apr 2008.
To cite this article: Xue‐Feng Zhu & A. Ian Scott (2008) Novel Synthetic Approach to Multibenzoylated
Nucleosides, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:9, 1346-1354, DOI: 10.1080/00397910801916280
To link to this article: http://dx.doi.org/10.1080/00397910801916280
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Synthetic Communicationsw, 38: 1346–1354, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801916280
Novel Synthetic Approach
to Multibenzoylated Nucleosides
Xue-Feng Zhu and A. Ian Scott
Center for Biological Nuclear Magnetic Resonance (NMR), Department
of Chemistry, Texas A&M University, College Station, Texas, USA
Abstract: An improved and highly efficient synthetic approach to multibenzoylated
nucleosides bearing free 50-hydroxyl groups is described here. By employing
t-butyldimethylsilyl (TBDMS) rather than the more commonly used dimethoxytrityl
(DMTr) as a temporary 50-OH protecting group of the starting nucleoside, this method-
ology provides the expected products in nearly quantitative yields, thereby substan-
tially reducing the cost and effort of synthesis.
Keywords: Deprotection, multibenzoylation, nucleoside, protection
INTRODUCTION
Multibenzoylated nucleosides bearing free 50-hydroxyl groups serve as the
key starting materials in the synthesis of small oligonucleotides such as dinu-
cleotides and trinucleotides.[1] For example, the preparations of the dinucleo-
tide pdCpA,[2] which has important utility in synthetic amino acid
mutagenesis technology, or the trinucleotides 2-5 A, 2-5 core, and their
analogs,[3] which are known for their antiviral and antitumor activity, have
0
0
started from N6,N6,O2 ,O3 -tetrabenzoyladenosine as a suitably protected
0
0
nucleoside. More important, N6,N6,O2 ,O3 -tetrabenzoyladenosine and other
multibenzoylated nucleosides have wide applications in the synthesis of
nucleoside antibiotic angustmycin A analogs,[4] sugar nucleotides,[5] the
Received in Poland September 6, 2007
Address correspondence to A. Ian Scott, Center for Biological NMR, Department of
Chemistry, Texas A&M University, P. O. Box 30012, College Station, Texas 77842-
3012, USA. E-mail: xzhu2@gnf.org
1346

Multibenzoylated Nucleosides
1347
Scheme 1.
50-terminal cap structure of U1 RNA,[6] diadenosine polyphosphate mimics,[7]
and 40 a-branched 20-deoxyadenosine.[8]
0
0
The synthetic approach to N6,N6,O2 ,O3 -tetrabenzoyladenosine was orig-
inally developed by Khorana and coworkers during their seminal investigation
of oligonucleotide synthesis 50 years ago and involved the following sequence:
(i) direct tritylation of 50-OH of adenosine 1, (ii) benzoylation of the trityl deri-
vaties 2, and (iii) detritylation under acidic conditions.[9] This two-purification,
three-step procedure was further simplified by Schultz to a one-purification,
three-step methodology.[2a] The improved procedure employed the dimethox-
ytrityl (DMTr) group, rather than trityl (Tr) or monomethoxytrityl (MMTr)
groups, as the temporary protector for the 50-OH function, resulting in its depro-
tection under much milder conditions. The tritylation step was also accelerated
by adding catalytic amounts of 4-N,N-dimethylaminopyridine (DMAP).
Without any workup or purification of 5, benzoylation was subsequently
executed in one flask. Although the overall yield of 4 is improved from 39%
to 67%, both Khorana’s and Schultz’s protocols use a large excess of
benzoyl chloride to secure complete benzoylation. In addition, both methods
require the use of predried nucleoside substrate (Scheme 1).
RESULTS AND DISCUSSION
In connection with our work on the synthesis of oligonucleotides, we have
developed a one-pot, three-component procedure for preparation of dinucleo-
tides.[2b] This efficient approach requires a multibenzoylated nucleoside such
as 4 as one of the key components. Initially, we synthesized 4 by repeating
Schultz’s protocol with the following modifications: (i) directly using com-
mercially available adenosine, thus omitting the tedious and time-consuming

1348
X.-F. Zhu and A. I. Scott
pretreatment process; (ii) utilizing a slight excess of benzoyl chloride for ben-
zoylation, thereby further simplifying the workup; (iii) performing the detrityla-
tion with 2% trifluoroacetic acid (TFA) in dichloromethane at rt. Unfortunately,
this method proved not to be routinely reproducible in our hands, in spite of
numerous attempts to vary the reaction time, reaction temperature, concen-
tration, and equivalents of DMTrCl, DMAP, and benzoyl chloride. Even
˚
addition of 4-A molecular sieves as drying agents to the mixture of pyridine
and adenosine before tritylation did 0not improve the yield, which varied from
0
0
46% to 80%. Also, N6,N6,O2 ,O3 ,O5 -pentabenzoyladenosine was isolated as a
main by-product, suggesting that the tritylation step was incomplete. This obser-
vation is in accordance with the results reported by Khorana, who obtained the
pure trityl derivative 2 in only 50% yield. The poor efficiency of this method
prompted us to develop a new and efficient procedure for synthesizing
0
0
N6,N6,O2 ,O3 -tetrabenzoyladenosine 4.
The trityl family of protecting groups such as MMTr and DMTr have
been used extensively in the preparation of nucleosides and nucleotides
mainly because of their exceptional selectivity of protection at primary
rather than secondary hydroxyl groups and high acid lability.[10] However,
the tritylation process suffers from low yields, probably because of the
steric bulk of these groups. Another reason for the low efficiency of the
reaction is that trityl groups may react with the exocyclic amino group of
adenine. It is already well-established that Tr and MMTr are good amino pro-
tecting groups in amino acids[10] and that MMTr and DMTr are occasionally
used for the protection of the amino group of guanine.[11] Crucial for the
success of our novel synthetic strategy leading to 4 is the ability to identify
a protecting group that would be installed at the 50-OH in a very efficient
and highly selective way and that would also be sufficiently acid labile to
be removed in the final step, where the amino and hydroxyl groups of the
product are fully protected by alkaline labile benzoyl groups. Based upon
these considerations, we chose the tert-butyldimethylsilyl (TBDMS) group
to replace the family of trityl groups as a temporary blocking group.
Although TBDMS is widely used as a hydroxyl protecting group in nucleoside
and nucleotide chemistry, to our knowledge, its use in preparing multibenzoy-
lated nucleosides has never been report. Its use offers several advantages. First
of all, as a protecting group, TBDMS (MW 115.28) is superior to DMTr (MW
303.38) in terms of atom economy efficiency. TBDMSCl is also much cheaper
than DMTrCl. Second, its size is not as great as DMTr, but it is still bulky
enough to provide preference for silylation of the primary hydroxyl
function. Excellent selectivity was achieved for 50-OH when pyridine was
used as both solvent and base. Finally, TBDMS can be exclusively cleaved
by a “cocktail” method developed by us.[12] Stirring 8 with the reagent
TFA-H2O-THF (1:1:4) at rt for 3 h leads to quantitative liberation of 4
(Scheme 2).
The success of this work encouraged us to consider extending the meth-
odology to the synthesis of a variety of multibenzoylated nucleosides, and the

Multibenzoylated Nucleosides
1349
Scheme 2.
results are summarized in Table 1. As anticipated, in each case the target
compound was obtained in excellent yield. Even 20-deoxyadenosine monohy-
30
drate 9 can be used directly to prepare N6,N6,O -tribenzoyl 20-deoxyadeno-
sine 11 provided that 1 additional equivalent of TBDMSCl was used to
consume the water molecule contained in the starting nucleoside.
In conclusion, the synthetic methodology developed here is not only simpler
in execution and workup than those previously reported, but also the overall
yields of expected products are significantly increased. On the other hand, the
overall costs are markedly reduced by directly using commercially available
nucleosides, employing the less expensive TBDMSCl as protecting reagent
and avoiding the use of a large excess of benzoyl chloride. Therefore, the
current approach represents an important and useful improvement in this field.
EXPERIMENTAL
All reactions were performed using commercially available solvents and
reagents without inert gas protection. As new compounds, intermediates 8,
10, 13, and 16 were isolated and characterized by high-resolution NMR spec-
1
troscopy and þFAB mass spectrometry. H (500 MHz) and 13C (125 MHz)
NMR spectra were recorded in CDCl3 on a Bruker ARX-500 spectrometer.
Coupling constants are expressed in hertz. The chemical shifts and coupling
constants in ABX patterns of the 50 protons in compounds 8 and 13 were cal-
culated using the PCPMR program developed by M. Saunders (Yale University)
and K. E. Gilbert and J. J. Gajewski (Indiana University) in 1980. þFAB mass
spectra were obtained on a VG analytical 70s high-resolution double-focussing
magnetic-sector mass spectrometer.
0
0
N6,N6,O2 ,O3 -Tetrabenzoyladenosine (4)
To a precooled mixture of adenosine (99%) 1 (540 mg, 2.0 mmol) and pyridine
(10 mL), TBDMSCL (99%) (396 mg, 2.6 mmol) was added in one portion at
0 8C. After stirring for 2 h at 0 8C, and the reaction mixture was allowed to
warm to rt and was further stirred for 7 h. Then the resulting mixture was
cooled to 0 8C, and benzoyl chloride (99%) (1.12 mL, 9.6 mmol) was added
dropwise via a syringe during 30 min. The ice bath was then removed, and the
reaction mixture was stirred at rt overnight (about 8 h). The resulting mixture

Table 1. Preparation of multibenzoylated nucleosides
Intermediate yield (silylation &
benzylation)
Substrate
TBDMSCl (eq.)
1.30
BzCl (eq.)
4.8
Product yield (desilylation)
1.25
2.35
1.25
1.30
3.6
3.6
3.6
3.2

Multibenzoylated Nucleosides
1351
was diluted with 100 mL of CH2Cl2 and washed with brine (40 mL), and the
aqueous layer was further extracted with CH2Cl2 (2 ꢀ 40 mL). The combined
extracts were dried over Na2SO4 and evaporated at reduced pressure. The
dried residue was then dissolved in THF (36 mL), and aqueous TFA (18 mL,
TFA–H2O ¼ 1:1) was slowly added. After stirring for 3 h at rt, the reaction
mixture was cautiously neutralized with equimolar amounts of aqueous
NaHCO3 (9.72 g in 100 mL H2O) at 0 8C and extracted with CH2Cl2
(4 ꢀ 50 mL). The combined extracts were dried over anhydrous Na2SO4 and
evaporated at reduced pressure. The residue was subjected to flash chromato-
graphy on silica gel (Eluent: hexane–EtOAc ¼ 4:1 to 1:1 then CH2Cl2
–
CH3OH ¼ 100:5) to provide the pure product 4 as a white solid (1.36 g,
99.5%). In a large-scale synthesis, purification of the desired product can be
achieved by simply stirring crude 4 with warm benzene, followed by cooling
and filtration, thus avoiding a chromatographic step. Following a similar
procedure, compounds 11, 14, and 17 were obtained as white solids.
0
0
0
O5 -tert-Butyldimethylsilyl-N6,N6,O2 ,O3 -tetrabenzoyladenosine (8)
1H NMR (500 MHz, CDCl3) d 8.64 (s, 1H), 8.50 (s, 1H), 7.99 (dd, J ¼ 8.2, 0.9
Hz, 2H), 7.89 (dd, J ¼ 8.2, 1.0 Hz, 2H), 7.84 (dd, J ¼ 8.2, 0.9 Hz, 4H), 7.56
(t, J ¼ 7.4 Hz, 1H), 7.51 (t, J ¼ 7.4 Hz, 1H), 7.46 (t, J ¼ 7.5 Hz, 2H), 7.40
(t, J ¼ 7.8 Hz, 2H), 7.35–7.31 (m, 6H), 6.67 (d, J ¼ 7.0 Hz, 1H, 10-H),
6.06 (dd, J ¼ 7.0, 5.4 Hz, 1H, 20-H), 5.90 (dd, J ¼ 5.4, 2.2 Hz, 1H, 30-H),
4.55 (ddd, J ¼ 2.2, 2.2, 2.2 Hz, 1H, 40-H), 4.05 (dd, J ¼ 14, 2.2 Hz, 1H,
50-H), 4.03 (dd, J ¼ 14, 2.2 Hz, 1H, 50-H), 0.96 (s, 9H), 0.18 (s, 3H), 0.16
(s, 3H); 13C NMR (125 MHz, CDCl3) d 172.2 (2C), 165.5 (1C), 164.9 (1C),
153.2 (1C), 152.4 (1C), 151.9 (1C), 142.8 (1C), 134.0 (2C), 133.7 (1C),
133.6 (1C), 132.9 (2C), 129.8 (2C), 129.7 (2C), 129.5 (4C), 128.9 (1C),
128.7 (4C), 128.5 (2C), 128.4 (1C), 128.3 (2C), 127.6 (1C), 85.4 (1C), 84.8
(1C), 74.7 (1C), 72.5 (1C), 63.3 (1C), 26.0 (3C), 18.5 (1C), 25.3 (1C),
25.4 (1C); HRMS [M þ Na]þ found: 820.2770; C44H43O8N5SiNa requires
m/z 820.2779.
50
30
O -tert-Butyldimethylsilyl-N6,N6,O -tribenzoyl-20-deoxyadenosine
(10)
1H NMR (500 MHz, CDCl3) d 8.64 (s, 1H), 8.43 (s, 1H), 8.06 (dd, J ¼ 8.3, 1.1
Hz, 2H), 7.85 (dd, J ¼ 8.3, 1.1 Hz, 4H), 7.60 (t, J ¼ 7.4 Hz, 1H), 7.47
(t, J ¼ 7.6 Hz, 4H), 7.34 (t, J ¼ 7.8 Hz, 4H), 6.64 (dd, J ¼ 8.3, 6.1 Hz, 1H,
10-H), 5.66 (dd, J ¼ 3.6, 1.4 Hz, 1H, 30-H), 4.38 (ddd, J ¼ 2.7, 2.7, 1.4 Hz,
40-H), 4.01 (dd, J ¼ 11.2, 2.7 Hz, 1H, 50-H), 3.95 (dd, J ¼ 11.2, 2.7 Hz, 1H,
50-H), 2.86–2.77 (m, 2H, 20-H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 172.2 (2C), 166.0 (1C), 152.8 (1C), 152.2 (1C),

1352
X.-F. Zhu and A. I. Scott
151.8 (1C), 142.9 (1C), 134.1 (2C), 133.6 (1C), 132.9 (2C), 129.7 (2C), 129.5
(4C), 129.3 (1C), 128.7 (4C), 128.6 (2C), 127.7 (1C), 86.0 (1C), 84.5 (1C), 75.9
(1C), 63.6 (1C), 39.1 (1C), 26.0 (3C), 18.4 (1C), 25.3 (1C), 25.5 (1C); HRMS
[M þ Na]þ found: 700.2597; C37H39O6N5SiNa requires m/z 700.2567.
0
0
0
O5 -tert-Butyldimethylsilyl-N3,O2 ,O3 -tribenzoyluridine (13)
1H NMR (500 MHz, CDCl3) d 8.10 (d, J ¼ 8.3 Hz, 1H), 7.99 (d, J ¼ 7.5 Hz,
2H), 7.91 (dd, J ¼ 8.3, 1.0 Hz, 2H), 7.86 (d, J ¼ 7.5 Hz, 2H), 7.57
(t, J ¼ 7.6 Hz, 1H), 7.55 (t, J ¼ 7.6 Hz, 1H), 7.48 (t, J ¼ 7.5 Hz, 1H), 7.39
(t, J ¼ 7.8 Hz, 4H), 7.28 (t, J ¼ 7.8 Hz, 2H), 6.56 (d, J ¼ 7.3 Hz, 1H, 10-H),
5.90 (d, J ¼ 8.3 Hz, 1H), 5.73 (dd, J ¼ 5.5, 1.3 Hz, 1H, 30-H), 5.63 (dd,
J ¼ 7.3, 5.5 Hz, 1H, 20-H), 4.46 (ddd, J ¼ 1.7, 1.3, 1.3 Hz, 1H, 40-H), 4.05
(dd, J ¼ 14, 1.7 Hz, 1H, 50-H), 4.02 (dd, J ¼ 14, 1.3 Hz, 1H, 50-H), 1.00
(s, 9H), 0.23 (s, 3H), 0.21 (s, 3H); 13C NMR (125 MHz, CDCl3) d 168.4
(1C), 165.5 (1C), 165.4 (1C), 161.7 (1C), 149.5 (1C), 139.3 (1C), 134.9 (1C),
133.7 (1C), 133.6 (1C), 131.4 (1C), 130.5 (2C), 129.9 (2C), 129.7 (2C),
129.0 (2C), 128.9 (1C), 128.6 (2C), 128.4 (2C), 128.3 (1C), 103.2 (1C), 85.9
(1C), 84.5 (1C), 74.4 (1C), 72.9 (1C), 63.5 (1C), 25.9 (3C), 18.4 (1C), 25.4
(1C), 25.5 (1C); HRMS [M þ Na]þ found: 693.2277; C36H38O9N2SiNa
requires m/z 693.2244.
0
0
0
O5 -tert-Butyldimethylsilyl-N4,O2 ,O3 -tribenzoylcytidine (16)
1H NMR (500 MHz, CDCl3) d 8.75 (s, 1H, NH), 8.44 (d, J ¼ 6.9 Hz, 1H, 6-H),
7.97–7.96 (m, 2H), 7.95–7.94 (m, 2H), 7.89–7.87 (m, 2H), 7.60–7.52
(m, 3H, 2 arom. H þ 6-H), 7.51–7.48 (m, 3H), 7.39–7.33 (m, 4H), 6.76
(d, J ¼ 6.39 Hz, 1H, 10-H), 5.75 (dd, J ¼ 5.32, 2.74 Hz, 1H, 30-H), 5.63
(dd, J ¼ 6.39, 5.41 Hz, 1H, 20-H), 4.49 (ddd, J ¼ 2.74, 1.82, 1.67 Hz, 1H,
40-H), 4.08 (dd, J ¼ 11.58, 1.82 Hz, 1H, 50-H), 4.00 (dd, J ¼ 11.58, 1.67
Hz, 1H, 50-H), 0.99 (s, 9H), 0.21 (s, 3H), 0.20 (s, 3H); 13C NMR (125
MHz, CDCl3) d 166.5 (1C), 165.4 (1C), 165.1 (1C), 162.3 (1C), 154.7 (1C),
144.4 (1C), 133.5 (1C), 133.4 (1C), 133.1 (1C), 132.9 (1C), 129.9 (2C),
129.7 (2C), 128.9 (2C), 128.8 (1C), 128.6 (1C), 128.4 (2C), 128.3 (2C),
127.5 (2C), 97.4 (1C), 86.8 (1C), 84.2 (1C), 75.4 (1C), 72.1 (1C), 62.9
(1C), 25.9 (3C), 18.3 (1C), 25.5 (1C), 25.6 (1C); HRMS [M þ Na]þ
found: 692.2437; C36H39O8N3SiNa requires m/z 692.2404.
ACKNOWLEDGMENTS
This work was supported by grants from the Texas Advanced Technology
Research Program and the Robert A. Welch Foundation.

Multibenzoylated Nucleosides
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