Synthesis of new classes of boron-containing nucleotides

Article abstract of DOI:10.1081/NCN-100002335

Four different types of boron-modified nucleotides are reported: P-boranophosphorothioates, P-cyanoboranophosphates, P-boranomethylphosphonates, and P3′-N5′-boranophosphoramidates. Synthesis of dinucleoside borano-phosphorothioates and nucleoside P-borano-P-thiomonophosphates via a lithium sulfide method is described. The Li₂S method also provides an alternative way to synthesize phosphorothioates through a dinitrophenyl P(V) phosphotriester precursor. The mechanism of Li₂S substitution was investigated.

Full text of DOI:10.1081/NCN-100002335

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SYNTHESIS OF NEW CLASSES OF BORON-CONTAINING
NUCLEOTIDES
Jinlai Lin a & Barbara Ramsay Shaw b
a Paul M. Gross Chemical Laboratory, Department of Chemistry , Duke University ,
Durham, North Carolina, 27708-0346, U.S.A.
b Paul M. Gross Chemical Laboratory, Department of Chemistry , Duke University ,
Durham, North Carolina, 27708-0346, U.S.A.
Published online: 07 Feb 2007.
To cite this article: Jinlai Lin & Barbara Ramsay Shaw (2001) SYNTHESIS OF NEW CLASSES OF BORON-CONTAINING
NUCLEOTIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 587-596, DOI: 10.1081/NCN-100002335
To link to this article: http://dx.doi.org/10.1081/NCN-100002335
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 587–596 (2001)
SYNTHESIS OF NEW CLASSES OF
BORON-CONTAINING NUCLEOTIDES
Jinlai Lin and Barbara Ramsay Shaw∗
Paul M. Gross Chemical Laboratory, Department of Chemistry,
Duke University, Durham, North Carolina 27708-0346
ABSTRACT
Four different types of boron-modified nucleotides are reported: P-boranophos-
phorothioates, P-cyanoboranophosphates, P-boranomethylphosphonates, and
P3ꢀ-N5ꢀ-boranophosphoramidates. Synthesisofdinucleosideborano-phospho-
rothioates and nucleoside P-borano-P-thiomonophosphates via a lithium sul-
fide method is described. The Li2S method also provides an alternative way
to synthesize phosphorothioates through a dinitrophenyl P(V) phosphotriester
precursor. The mechanism of Li2S substitution was investigated.
INTRODUCTION
Novel modified nucleotides are currently attracting attention as probes in bio-
chemistry and molecular biology and as possible therapeutic agents against cancer
and viral diseases (1–2). These studies have highlighted certain challenges that
need further investigation. For example, there is a need for new analogs having
increased resistance towards nucleases, and an ability to be transported into cells
via mechanisms leading to biological activity. Previously our laboratory introduced
a boranophosphate, the first boronated phosphodiester analogue (3). Here, by in-
troducing borano-, thio-, cyanoborano-, amino-groups or their combinations into
phosphatebackbones, wepresentfournewclassesofboronatedp−hosphodiesterana-
== –
logues (Fig. 1): (a) the P-boranophosphorothioate [S P BH3] , wherein the two
nonbridging oxygen atoms in a phosphodiester group are replaced with sulfur and
∗Corresponding author. E-mail: brs@chem.duke.edu
587
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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LIN AND SHAW
−
== –
Figure 1. Novel internucleotide linkages: (a) P-boranophosphorothioate [S P BH3] , (b) P-
−
ꢀ
== –
cyanoboranophosphate [O P BH2CN] , (c) P-boranomethylphosphonate [CH3−P−BH3], (d) P3 -
N5ꢀ boranophosphoramidate [5ꢀNH−P−BH3]−.
−
== –
borane groups respectively; (b) the P-cyanoboranophosphate [O P BH2CN] ,
wherein one of the two nonbridging oxygen atoms in a phosphodiester group is re-
placed with a cyanoborane group; (c) the P-boranomethylphosphonate [CH3−P−
BH3], wherein the two nonbridging oxygen atoms in a phosphodiester group are
replaced with borane and methyl groups; and (d) the P3ꢀ-N5ꢀ-boranophosphorami-
dates [5ꢀNH−P−BH3]−, wherein one of the two nonbridging oxygen atoms in a
phosphodiester group is replaced with a borane group and the 5ꢀ-bridging oxygen
atom is replaced with an NH group.
RESULTS AND DISCUSSION
−
== –
1. P-boranophosphorothioate [S P BH3]
1a. Synthesis of Dinucleoside Boranophosphorothioate
By structurally combining the phosphorothioate (2) and boranophosphate (3)
backbones, we created a new phosphodiester DNa linkage, the boranophosphoro-
−
== –
thioate (4), [S P BH3] .
The modified dinucleoside phosphate 4 is the first example of a boranophos-
phorothioate compound.
The general procedure for the synthesis of dinucleoside P-boranophosphoro-
thioates is outlined in Scheme 1. The phosphite 1 (having 31P NMR signals at
135.9 and 134.8 ppm) (4) was treated with excess borane-methyl sulfide complex
to afford phosphite-borane 2 with a 31P NMR signal at 116.6 ppm (br). Dry com-
pound 2 was reacted with lithium sulfide to give 3 which was converted to 4 with
NH4OH/CH3OH. The overall yield of dithymidine P-boranophosphorothioate 4
(TSpBT) was about 28%. Successful separation of two diastereomers (Rp and Sp)
of 4 was achieved by reverse-phase HPLC. TSpBT I (the first eluted diastereomer,
4a): 31P NMR (D2O, 161.9 MHz) δ (ppm) 161.9 (br); 1H NMR (D2O, 400 MHz)
δ (ppm) 7.54 (s, 1 H, H6), 7.47 (s, 1 H, H6), 6.13 (t, 1 H, J = 6.8 Hz, H1ꢀ), 6.06
(t, 1 H, J = 6.8 Hz, H1ꢀ), 4.96–4.91 (m, 1 H, H3ꢀ), 4.40–4.37 (m, 1 H, H3ꢀ), 4.04–
3.89, 3.70–3.59 (2m, 6 H, H4ꢀ, H5ꢀ), 2.37–2.14 (m, 4 H, H2ꢀ), 1.77 (s, 3 H, 5-CH3),
1.70 (s, 3 H, 5-CH3), 0.58 (br, 3 H, BH3). TSpBT II (the second eluted diastereomer,
4b): 31P NMR (D2O, 161.9 MHz) δ (ppm) 161.7 (br); 1H NMR (D2O, 400 MHz)

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589
Scheme 1.
(ppm) 7.50 (s, 1 H, H6), 7.45 (s, 1 H, H6), 6.15 (t, 1 H, J = 6.8 Hz, H1ꢀ), 6.06 (t, 1 H,
J = 6.8 Hz, H1ꢀ), 4.80 (m, 1 H, H3ꢀ), 4.41 (m, 1 H, H3ꢀ), 4.17–3.83, 3.68–3.57 (2m,
6 H, H4ꢀ, H5ꢀ), 2.36–2.29, 2.22–2.13 (m, 4 H, H2ꢀ), 1.75 (s, 3 H, 5-CH3), 1.70 (s,
3 H, 5-CH3), 0.54 (br, 3 H, BH3).
Our studies show that the P-boranophosphorothioate group is very stable
toward acidic or basic hydrolysis at pH 3 or pH 11. The P-boranophosphorothioate
internucleotide linkage in dimer 4 is also quite stable toward cleavage by both
snake venom phosphodiesterase (SVPDE) and bovine spleen phosphodiesterase
(BSPDE) (4). As determined by partitioning into octanol/water, the TSpBT dimer
Figure 2. 31P NMR (D2O) spectrum of TSpBT 4.

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LIN AND SHAW
is 320- and 18-fold more lipophilic than normal TpT and TpBT) (dithymidime
boranophosphate) accordingly.
1b. Synthesis of Nucleoside P-borano-P-thiomonophosphate
By introducing both a BH3 and S into a nucleoside monophosphate (NMP),
it is possible to create new NMP analogues, nucleoside P-borano-P-thiomono-
phosphates (NMPαBS), such as thymidine P-borano-P-thiomonophosphate
(TMPαBS 9). The borano-thio-disubstitution of nucleoside monophosphate should
increase the lipophilicity relative to natural NMP and its stability against enzymatic
cleavage, thus facilitating studies of enzymes which utilize NMPs and enabling de-
terminationofthenatureofbondcleavage, thestereochemicalcourseforaparticular
NMP-mediatedactivity, and relatedmetalioneffects. Also, P-borano-P-thiomono-
phosphates could be very useful tools as prodrugs to increase the bioavailability.
The general procedure for the synthesis of thymidine P-borano-P-thiomono-
phosphate is shown as Scheme 2. 3ꢀ-O-acetylthymidine (0.5 mmol) was phosphi-
tylated with 2-cyanoethyl tetraisopropylphosphorodiamidite (i-Pr2N)2POCH2
CH2CN (0.55 mmol) catalyzed by tetrazole (0.25 mmol) in anhydrous DMF at
0◦C for 20 min under argon protection to give 5. Phosphite 5 was treated in situ
with 4-nitrophenol (0.6 mmol) and tetrazole (1.5 mmol) in anhydrous DMF at room
temperature for 30 minutes to afford 6 (31P NMR, around 134 ppm). Compound 6
Scheme 2.

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591
Figure 3. 31P NMR (D2O) spectrum of 9, TMPαBS.
was boronated by excess (CH3)2S:BH3 in CH2Cl2 to yield phosphite-borane 7 with
31P NMR signal around 116 ppm (br). After removing low-boiling point solvents
under reduced presure, the residue was dissolved with anhydrous DMF and treated
with lithium sulfide (1 mmol) at room temperature for 1 hour to obtain the crude
8, with 31P NMR signal around 166.1 ppm (br). Compound 8 was converted to
9 with 4 ml NH3/H2O/CH3OH. The resulting crude mixtures were separated by
−
ion-exchange chromatography on QA-Cellulose (HCO3 ) column, eluting with a
linear gradient of ammonium bicarbonate buffer. The desired fractions were col-
lected and dried by lyophilization to yield the ammnonium salt of TMPαBS 9 (33%
overall yield): 31P NMR (D2O) [Fig. 3] δ 131–128 ppm (br), a key signature of 9.
1H NMR(D2O, 400 MHz) δ (ppm) 7.67, 7.48 (2s, 2 isomers, 1 H, H6), 6.23–6.11
(unresolved, 1 H, H1ꢀ), 4.48–4.32 (m, 1 H, H3ꢀ), 4.13–3.96 (m, 1 H, H4ꢀ), 3.91–3.82
(m, 2 H, H5ꢀ), 2.29–2.18 (m, 2 H, H2ꢀ), 1.81, 1.77 (2s, 3 H, 5-CH3), −0.20 to 0.67
(br, 3 H, BH3); MS (FAB−): m/z for M− 335.
1c. Proposed Mechanism of Li2S Substitution and New Method for the
Preparation of Nucleoside Phosphorothioates from the Dinitrophenyl
P(V) Phosphotriester via Li2S Substitution
For the synthesis of P-boranophosphorothioates, the key step is the introduc-
tion of a thio-moiety via Li2S substitution. To better understand and investigate the
stereochemical course of Li2S substitution with nitrophenyl as a leaving group, we
synthesized a variety of modified triesters. It was found that the dinitrophenyl con-
taining phosphate triester, compound 11, is a very good precursor for the synthesis
of phosphorothioates.
Previously, phosphorothioate (2) oligonucleotides were prepared using phos-
phoramidite, H-phosphonateorH-phosphonothioateapproaches. Allthosemethods
share trivalent P(III) synthetic intermediates and utilize S8, H2S, or thiol to introduce
the S moiety into target molecules. Here, we report a new method for the preparation
of phosphorothioates from the pentavalent P(V) dinitrophenyl phosphotriester via
Li2S substitution and examine the mechanism.

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LIN AND SHAW
Scheme 3.
Thegeneralprocedureforthesynthesisofprotecteddinucleoside P-phosphor-
othioates is outlined in Scheme 3. Phosphite 10 (4) was treated with 2,4-dinitrophe-
nol and tetrazole in DMF for 30 min and then left standing, open to air for 30 min to
yield compound 11. Compound 11 was applied to silica gel HPLC column to give
two diastereomers of 11: HPLC conditions: Partisil M9 Whatman 10/50 column;
eluants were 3% methanol and 97% ethyl acetate; flow rate, 3.0 ml/min. For the
first eluted isomer, 11a: Rt (11a) = 14.4 min; 31P NMR (DMSO-d6, 161.9 MHz)
1
δ (ppm) 9.81; H NMR (DMSO-d6, 400 MHz) δ (ppm) 7.49 (s, 1 H, H6), 7.44
(s, 1 H, H6), 7.33–7.18 (3m, 9 H, Ar-H), 6.84 (d, J = 7.6 Hz, 4 H, Ar-H), 6.18
(t, 1 H, J = 7.0 Hz, H1ꢀ), 6.11 (t, 1 H, J = 7.0 Hz, H1ꢀ), 5.15 (unresolved m, 2 H),

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593
ꢀ
ꢀ
ꢀ
–
4.23–4.17 (m, 4 H, H3ꢀ, H4 ), 4.11–4.09 (m, 4 H, H5 ), 3.69 (s, 6 H, OCH3),
== –
2.34–2.18 (m, 4 H, H2 ), 2.01 (s, 3 H, O C CH3), 1.94 (s, 3 H, 5-CH3), 1.70
(s, 3 H, 5-CH3); For the second eluted isomer, 11b: Rt (11b) = 18.0 min, 31P
1
NMR (DMSO-d6, 161.9 MHz) δ (ppm) 10.63; H NMR (DMSO-d6, 400 MHz)
δ (ppm) 7.47 (s, 1 H, H6), 7.43 (s, 1 H, H6), 7.34–7.19 (3m, 9 H, Ar-H), 6.85–6.83
(m, 4 H, Ar-H), 6.19–6.06 (2t, 2 H, H1ꢀ), 5.11 (unresolved m, 2 H), 4.21–4.16
ꢀ
ꢀ
ꢀ
–
(m, 4 H, H3ꢀ, H4 ), 4.11–4.06 (m, 4 H, H5 ), 3.68 (s, 6 H, OCH3), 2.38–2.16
== –
(m, 4 H, H2 ), 2.01 (s, 3 H, O C CH3), 1.94 (s, 3 H, 5-CH3), 1.71 (s, 3 H,
5-CH3). 11a and 11b were reacted with lithium sulfide to give 12a (31P NMR at
54.2 ppm) and 12b (31P NMR at 53.4 ppm) respectively. After removing the DMT
protecting group by 2.5% CHCl2COOH in dichloromethane and deprotecting the
acetyl group by NH4OH/CH3OH, the Rp or Sp dithymidine phosphorothioate was
obtained. From empirical rules (2a), which allow the configuration of dinucleoside
phosphorothioates to be assigned on the basis of their 31P NMR chemical shift val-
ues and relative retention times on reverse phase HPLC, the absolute configuration
has been assigned to the diastereomers of 12 by comparison with these criteria.
Thus, 12a which resonates at lower field in the 31P NMR spectra was assigned to
the Rp-configuration, and 12b to the Sp-configuration.
The dinitrophenyl P(V) phosphate intermediates are useful synthons. They
are very stable in the dry air while trivalent P(III) intermediates are sensitive to air
oxidation. Also the dinitrophenyl is sufficiently stable at acidic conditions to sur-
vive the DMT removal step. Lithium sulfide is a solid that can be partly dissolved
in DMF. These advantages over the phosphite approach make the pentavalent P(V)
method easy to handle for the preparation of phosphorothioates. Further, the two
diastereomers of dinucleoside dinitrophenyl phosphate are easily and cleanly sep-
arated by silica gel HPLC. For example, the two diastereomers of 11 (5ꢀ-DMT
dithymidine 3ꢀ-acetyl dinitrophenyl phosphate) were obtained in 10 mg scale by
silica gel HPLC separation. By appropriately choosing the protecting group, dini-
trophenyl phosphate precursors will be very good building blocks for the synthesis
of oligonucleoside phosphorothioates with Rp or Sp phosphorothioate linkages in-
serted at certain positions.
The displacement of the dinitrophenyl group by lithium sulfide success-
fully introduces an S moiety into a phosphodiester under very mild conditions
(room temperature) with high efficiency (almost quantitative conversion). This
method with some modifications also has been applied to the syntheisis of the first
boranophosphorothioate (4).
It is important to know whether the Li2S substitution step is strereospecific
or not. After HPLC separation of the individual two diastereomers 11a and 11b,
which bear a dinitrophenyl leaving group at the P atom, the two diastereomers are
allowed to react with nucleophile, sulfide S2−. From the analysis of the 31P NMR
chemical shift data before and after the reaction, information about the configu-
ration around the P atom can be obtained and the mechanism of lithium sulfide
substitution can be inferred. Typically, at a given set of conditions (solvent, pH,
temperature etc.), the 31P NMR chemical shift depends soley on the substituents
and the configuration around P. For the two diastereomers 11a and 11b, the four

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LIN AND SHAW
groups at P are the same and the only difference is their relative steric order, the
configuration. After lithium sulfide substitution only one group, dinitrophenyl, was
replaced by S2−. If the other three groups remain in the same relative order as prior
to the reaction, then the configuration would be retained, and the 31P chemical shift
change (ꢀδa = δ12a − δ11a and ꢀδb = δ12b − δ11b) for the two diastereomers after
the reaction should be the same: ꢀδa − ꢀδb = 0. If the reaction occurs with inver-
sion of configuration at the P atom that bears the leaving group, the 31P chemical
shift change (ꢀδa = δ12a − δ11a and ꢀδb = δ12b − δ11b) for the two diastereomers
after the reaction should differ: ꢀδa − ꢀδb = 0. If the reaction proceeds through a
single SN1 mechanism, there would be a mixture of two new diastereomers and thus
two 31P NMR peaks after the reaction. We observed only one 31P NMR signal after
Li2S substitution (from 11 to 12). From 11a to 12a, the 31P chemical shift difference
ꢀδa was 44.35 ppm, while from 11b to 12b, 31P chemical shift difference ꢀδb was
42.77 ppm. The observed difference between ꢀδa and ꢀδb is 1.58 ppm, which is
definitely greater than experimental error. This difference and the observation that
there is only one diastereomer from Li2S substitution indicate that S2−substitution
of the dinitrophenyl group underwent total configuration inversion, i.e. via an SN2
mechanism.
In this section, the first example of synthesizing dinucleoside phosphoroth-
ioates via a pentavalent intermediate, dinucleoside dinitrophenylphosphate, follow-
ing Li2S treatment has been described, and the related sterochemical course has
been investigated. It was found that the replacement of a nitrophenyl group by S2−
likely occurs through an SN2 mechanism with total configuration inversion at the P
atom. Since the phosphorothioate precursor (pentavalent dinitrophenylphosphate)
is stable to oxygen and acidic conditions, and can be easily and stereospecifically
converted to phosphorothioates with Li2S treatment, this method should be per-
ceived as a convenient general approach for the synthesis of phosphorothioates,
especially for the introduction of a stereochemically pure Rp or Sp phosphoroth-
ioate linkage into oligonucleotides.
−
== –
2. P-cyanoboranophosphates [O P BH2CN]
The first dinucleoside cyanoboranophosphate compound, dithymidine cyano-
boranophosphate 13, TpBH CNT, was synthesized and its chemical structure was
2

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595
Figure 4. 31P NMR (D2O) spectrum of 13, TpBH CNT.
2
established via spectroscopic methods with a typical 31P NMR (Fig. 4) signal at
75 ppm (br).
– –
3. P-boranomethylphosphonates [CH3 P BH3]
The first dinucleoside boranomethylphosphonate compound, dithymidine bo-
ranomethylphosphonate 14, TBpMeT, was synthesized and its chemical structure
was established via spectroscopic methods with a typical 31P NMR (Fig. 5) signal
at 147.6 ppm.
ꢀ
ꢀ
ꢀ
−
– –
4. P3 -N5 -boranophosphoramidates [5 NH P BH3]
The first dinucleoside P3ꢀ-N5ꢀ boranophosphoramidate compound, dithymi-
ꢀ
dine P3ꢀ-N5ꢀ boranophosphoramidate 15, TBp5 −NHT, was synthesized and its chem-
ical structure was established via 31P NMR (Fig. 6), 1H NMR, and FAB+HRMS.
Tosummarize, wehavesynthesizedfourtotallynewtypesofboron-containing
phosphodiester compounds as model nucleic acid mimics. Their similarity to nat-
ural nucleic acids and anticipated unique properties such as high lipophilicity and
resistance to enzymatic cleavage, in conjuction with their potential utility as carriers
of 10B in boron neutron capture therapy (BNCT) (5) for the treatment of cancer,
Figure 5. 31P NMR (DMSO-d6) spectrum of 14, TBpMeT.

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LIN AND SHAW
ꢀ
Figure 6. 31P NMR (D2O) spectrum of 15, TBp5 NHT.
make the new boron analogues promising candidates for mechanistic, diagnostic
and therapeutic applications.
ACKNOWLEDGMENT
This work was supported by grants 1R01-GM57693-01 from NIH and DE-
FG05-97ER62376 from DOE to B.R.S.
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