Synthesis and properties of 1-(3′-dihydroxyboryl-2′,3′- dideoxyribosyl)pyrimidines

Article abstract of DOI:10.1039/c2ob26756j

Nucleoside analogues having a boronic acid in place of the 3-hydroxyl group of deoxyribose have been synthesized. The synthesis of 3′-dihydroxyboryl- 2′,3′-dideoxyribose was based on asymmetric homologation of boronic esters with (dihalomethyl)lithium, beginning from a (silyloxymethyl)boronic ester. A change of chiral director is required before introduction of the second stereocenter, and the direct displacement of (S,S)-1,2-dicyclohexyl-1,2- ethanediol by (1S,2S,3R,5S)-pinanediol was used for this purpose. Coupling of the pinanediol ester of the 1-acetoxy-3-dioxyboryl-5-tert-butylsilyloxy deoxyribose analogue with silylated pyrimidine bases was accomplished with trimethylsilyl bromide. The boronic acid nucleoside analogues were not cytotoxic toward Hep G2 (human hepatocarcinoma) cells. Decomposition occurred over a period of several hours at 37 °C, pH 7.4, with liberation of free pyrimidine base.

Full text of DOI:10.1039/c2ob26756j

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PAPER
Synthesis and properties of 1-(3′-dihydroxyboryl-2′,3′-dideoxyribosyl)-
pyrimidines†
Byung Ju Kim,a Jinhua Zhang,a Shenglan Tan,b Donald S. Matteson,*a William H. Prusoff‡b and
Yung-Chi Cheng*b
Received 7th September 2012, Accepted 16th October 2012
DOI: 10.1039/c2ob26756j
Nucleoside analogues having a boronic acid in place of the 3-hydroxyl group of deoxyribose have been
synthesized. The synthesis of 3′-dihydroxyboryl-2′,3′-dideoxyribose was based on asymmetric
homologation of boronic esters with (dihalomethyl)lithium, beginning from a (silyloxymethyl)boronic
ester. A change of chiral director is required before introduction of the second stereocenter, and the direct
displacement of (S,S)-1,2-dicyclohexyl-1,2-ethanediol by (1S,2S,3R,5S)-pinanediol was used for this
purpose. Coupling of the pinanediol ester of the 1-acetoxy-3-dioxyboryl-5-tert-butylsilyloxy deoxyribose
analogue with silylated pyrimidine bases was accomplished with trimethylsilyl bromide. The boronic acid
nucleoside analogues were not cytotoxic toward Hep G2 (human hepatocarcinoma) cells. Decomposition
occurred over a period of several hours at 37 °C, pH 7.4, with liberation of free pyrimidine base.
Introduction
Several dideoxynucleosides are known to have clinically useful
antiviral activity.1 5-Dihydroxyboryl-2′-deoxyuridine has been
found to inhibit the growth of Herpes simplex 1 in cell culture.2,3
2′,3′-Dideoxyribonucleosides having a boronic acid function in
place of the 3′-hydroxyl group have not been reported, and their
synthesis presented an interesting chemical challenge. The syn-
thetic route chosen was expected to provide new information
about asymmetric synthesis via (α-haloalkyl)boronic esters.4
The first stage of the problem was to prepare the boronic acid
analogue of deoxyribose in protected form, chosen as a pinane-
diol ester 1. Subsequent connection of 1 to a pyrimidine or
purine base followed by deprotection has led to the series of
target compounds 2.
The reaction of chiral boronic esters with (dichloromethyl)-
lithium provides an efficient route for the highly stereoselective
insertion and functionalization of two of the three stereocentres
of 2.4 The steric relationship between these two centres requires
either an inversion of one of them5 or removal of the first chiral
director and its replacement with a second that directs in the
opposite sense, for which there are a few reported examples but
no general method.6–8 The use of alkyltrifluoroborate salts as
intermediates or the direct replacement of 1,2-dicyclohexyl-1,2-
ethanediol by pinanediol appeared most promising for general
applicability.8
The synthetic strategy also requires differential protection of
the 4- and 5-hydroxyl groups of the (dideoxyribosyl)boronic
acid unit so that the 5-membered ring can be closed and the pyri-
midine or purine base connected before the 5-hydroxyl is
unmasked. Hydroxyl protection used previously in the boronic
ester chain extension has included benzyl,9,10 p-methoxybenzyl,5
and tert-butyldimethylsilyl.11
A possible alternative synthesis of 2a from commercially
available 2′,3′-didehydro-3′-deoxythymidine is suggested by the
asymmetric hydroboration of 2,5-dihydrofuran with diisopino-
campheylborane.12 We chose the (α-haloalkyl)boronic ester
route because of our interest in developing this chemistry and
also because the polar groups near the hydroboration site might
cause complications. After our work had begun, elaboration
of the CH2OH group of thymidine to CHvCH2 and
aDepartment of Chemistry, Washington State University, PO Box
644630, Pullman, WA 99164-4630, USA. E-mail: dmatteson@wsu.edu;
Fax: +1-509-335-8867; Tel: +1-509-335-3365
bDepartment of Pharmacology, Yale University School of Medicine,
PO Box 208066, New Haven, CT 06520-8066, USA.
E-mail: yccheng@yale.edu
†Electronic supplementary information (ESI) available: NMR spectra of
new compounds, plots and data on decomposition rates of 14. See DOI:
10.1039/c2ob26756j
‡Deceased April 3, 2011.
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straightforward hydroboration leading to a CH2CH2B(OH)2 sub-
stituent was reported.13 However, yields were poor in hydrobora-
tion of analogous vinyl deoxycytosine and deoxyguanosine
derivatives and hydroboration of a deoxyadenine derivative was
unsuccessful.14
The removal and replacement of chiral directors is avoided in
new methods of stereoselective synthesis involving insertion of
an asymmetric α-substituted alkyllithium into a carbon–boron
bond.15–19 Although these methods work very well for sequen-
tial insertion of carbon-substituted stereocentres, their adaptation
to introduction of oxygen-substituted stereocentres does not
appear feasible.
boronate11 with (dichloromethyl)lithium followed by the direct
displacement of DICHED from boron by (+)-(1S,2S,3R,5S)-pina-
nediol (from (+)-α-pinene). Our route began with (S)-DICHED
[(tert-butyldimethylsilyloxy)methyl]boronate (3c) prepared from
the (benzyloxymethyl)boronate 3a via debenzylation to the
(hydroxymethyl)boronic ester 3b (Scheme 1).11 (After this work
was completed, an old, simpler route to 3b via hydrolysis of
acyclic, labile (halomethyl)boronic esters to (hydroxymethyl)-
boronic acid dimer was revived and updated.20) Homologation
of 3c to 4 with (dichloromethyl)lithium, conversion to 5 with
sodium benzyl oxide, and replacement of (S)-DICHED by
(+)-(1S,2S,3R,5S)-pinanediol to form 6 proceeded smoothly.
Several analogous displacements of other diols by pinanediol
have been reported previously.21–23 The rigid geometry of pina-
nediol minimizes entropy loss in formation of its cyclic esters
with boron, and the displacement of DICHED is further favoured
by its precipitation from the reaction mixture.
Results
Synthesis of the protected deoxyribose analogue (10)
Reaction of 6 with (dibromomethyl)lithium (from LDA and
dibromomethane in situ)10 efficiently yielded bromo boronic
ester 7, which with allylmagnesium bromide was alkylated to 8.
The chosen route to the needed steric relationship involved
installation of the first stereocenter via homologation of an (S,S)-
1,2-dicyclohexyl-1,2-ethanediol (DICHED) (silyloxymethyl)-
Scheme 1 (a) 1. LiCHCl2, THF, −100 °C; 2. ZnCl2, −70 to 25 °C, 15 h. (b) PhCH2ONa. (c) 1. LiCHBr2(CH2Br2, THF, −70 °C, add LDA);
2. ZnCl2, −70 to 25 °C, 15 h. (d) CH2vCHCH2MgBr, −70 °C to 25 °C, 15 h. (e) NaIO4/K2OsO4, 2,6-lutidine, dioxane/H2O. (f) H2/Pd. (g) Ac2O,
DMAP. (h) Me3SiBr, CH2Cl2. (i) HCl, dioxane. ( j) PhB(OH)2, pentane/H2O–CH2OH.
9350 | Org. Biomol. Chem., 2012, 10, 9349–9358
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The diastereomeric purity of intermediates 4–8 was expected to
1
be >99% based on considerable precedent,4 and the H and 13C
NMR spectra did not indicate any noticeable amounts of
diastereomers.
Oxidation of the terminal vinyl group of 8 with sodium perio-
date and concurrent diol cleavage catalysed by potassium osmate
(or, less efficiently, ruthenium trichloride) led to aldehyde 9. Cat-
alytic hydrogenolysis over palladium completed the construction
of the protected deoxyribose analogue 10, which was acetylated
to 11 for connection to the pyrimidine bases.
Connection to silylated pyrimidines
Connection of 11 to fully trimethylsilylated pyrimidine bases
was accomplished by treatment with bromotrimethylsilane in
dichloromethane, a modification of the Vorbrüggen nucleoside
synthesis.24 Bromotrimethylsilane proved superior to trimethyl-
silyl triflate for this purpose. Treatment of the reaction mixture
from bis(trimethylsilyl)thymine with excess tetrabutylammonium
fluoride followed by aqueous workup yielded a mixture of the
silyloxy compounds α-12a and β-12a. TBS cleavage was
accomplished with hydrogen chloride in dioxane to provide
α-13a and β-13a.
The α- and β-13a were separated by chromatography on
silica. It appeared that the amounts of the two isomers were
roughly equal at the beginning, but the loss of α-isomer during
purification was greater and the isolated β/α ratio was ∼3.6 : 1.
The structure of the major isomer β-13a was assigned on the
basis of oxidation with alkaline hydrogen peroxide, which
yielded thymidine, confirmed by comparison of the proton NMR
spectrum with that of authentic thymidine. Removal of the
pinanediol to provide the boronic acids α- and β-14a was accom-
plished by treatment with phenylboronic acid in a two-phase
system of water and nonpolar solvent, which is known to extract
pinanediol phenylboronate into the nonpolar phase and leave
free water-soluble boronic acids in the aqueous phase.25
Scheme 2 (a) 1. LiCHCl2, THF, −100 °C; 2. ZnCl2, −70 to 25 °C,
15 h. (b) p-MeOC6H4CH2OLi (=PMBOLi), −70 to 25 °C. (c) CsF +
3 HF, H2O/Et2O.
converted via known chemistry9,10,26–28 to chloro boronic ester
16, and chloride displacement yielded p-methoxybenzyloxy
derivative 17 (Scheme 2). However, the crude 17 was used
directly and contained major impurities not immediately obvious
from casual inspection of the 1H NMR. Consequently the
caesium alkyltrifluoroborate salt 18 failed to yield a crystalline
precipitate under the usual reaction conditions,29 leaving a sig-
nificant equilibrium proportion of the pinanediol ester 17 among
the products.30 Laboriously obtained crystalline 18 contained
∼30% of a second trifluoroborate, perhaps derived directly from
16. An analytical sample of 18 was obtained by recrystallization.
Reaction of the crude salt 18 with (+)-(1S,2S,3R,5S)-pinanediol
in the presence of aqueous sodium bicarbonate yielded the pure
boronic ester 19, which has the correct chiral director for intro-
duction of the next stereocenter.
Assignment of α or β to 13b-d and 14b-d was based on corre-
lation of observed 4′–5′ H coupling constants with the Karplus
Cytotoxicity and instability of 14
1
equation. The 5-fluorouracil derivative β-13b was isolated by
thin layer chromatography but no α-13b was obtained. The iso-
lated β/α ratio for the iodouracil derivatives 13c was ∼5 : 3.
Approximately 1 : 1 β–α mixtures of the cytidine derivatives
12d–14d were not separated or entirely freed from other impuri-
ties by the chromatographic techniques used. The nature of the
impurities was not determined.
Hep G2 (human hepatocarcinoma cell line) cells were incubated
at 37 °C, pH 7.4, in a standard cell growth medium consisting of
90% RPMI-1640 and 10% FBS (foetal bovine serum). Cell
growth inhibition by β-14b was observed at an activity level cor-
responding to ∼5% of that of 2′-deoxy-5-fluorodeoxyuridine
(FUdR) (Fig. 1), initial estimated CC50 for β-14b = 0.075 μM,
for FUdR = 0.004 μM. Subsequent cytotoxicity measurements
on different samples of β-14b ranged from CC50 = 0.03 to
0.16 μM. Measurements on FUdR ranged from CC50 = 0.007 to
Unsuccessful alternative routes to 10
0.0095 μM. 5-Fluorouracil (FU) is much less toxic, CC50
=
An alternative to 8 having a cyano group in place of the terminal
vinyl, (1S,2S,3R,5S)-pinanediol [2-benzyloxy-l-cyanomethyl-3-
(t-butyldimethylsilyloxy)propyl]-boronate (cyano analogue of
aldehyde 9), was prepared from bromo boronic ester 7 and
lithioacetonitrile. Reduction of the crude cyano analogue of 9
with diisobutylaluminum hydride at −78 to 25 °C resulted in
unanticipated desilylation. The product mixture after aqueous
work up contained very little aldehyde, presumably because of
cyclic hemiacetal formation with the free hydroxyl group.
0.9–1.0 μM. The only compounds of the series that inhibited cell
growth were the deoxyfluorouridine analogue β-14b and the
deoxyiodouridine analogue β-14c.
Analysis of the solutions of the various 14 by HPLC showed
that considerable degradation occurred in a few hours at 37 °C,
pH 7.4. The HPLC retention times indicated that a major
product of the degradation of β-14b was 5-fluorouracil (FU),
confirmed by comparison with an authentic sample. The
decomposition products of β-14c are presumably analogous
though not as fully confirmed. Small percentages of the 2′-
deoxynucleosides from air oxidation of various 14 were present
In a brief exploration of another route to 10, the (benzyloxy-
methyl)boronic ester 15 of (−)-(1R,2R,3S,5R)-pinanediol was
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Fig. 1 Percentages of Hep G2 cells growing after 3 days in the pres-
ence of 2′,3′-dideoxy-5-fluorouridine-3′-boronic acid (β-14b) compared
with 2′-deoxy-5-fluorodeoxyuridine (FUdR) in 90% RPMI-1640 and
10% FBS (foetal bovine serum) growth medium.
Table 1 Half-lives (hours) of 14 in growth media, pH 7.4, 37 °C
Medium:
RPMI
RPMI–FBS 9 : 1
FBS
Compound
α-14a
β-14a
β-14b
α-14c
β-14c
α/β-14d
73
22
13
15
6
455
61
18
23
10
769
192
27
28
18
Fig. 2 First-order plot of the conversion of β-14b to FU in 90%
RPMI-1640 and 10% FBS at 37 °C, pH 7.4, where x is the percent of
β-14b remaining, molar values for the two compounds are assumed
equal, and the sum of the two HPLC signals is taken as 100% at each
point.
52
139
400
Measurement of the small amount of 5-fluoro-2′-deoxyuridine
(FUdR) is highly dependent on the ratio of extinction coeffi-
cients of β-14b and FU. If the molar ε ratio for β-14b–FU is
1 : 1, there appears to be a small increase from ∼3% to 7.7%
during the course of the reaction. If it is 2 : 1, FUdR begins near
2.9%, rises to 4.9% in 4 h, and falls to 4.0% in 63 h. However,
that appears to be beyond the limit, since such a low assumed ε
results in an apparent decrease in the amount of FUdR present
after the initial rise, and FUdR is stable under the solvolysis
conditions.
in all samples from the beginning and their HPLC integrals in
proportion to those of the total mixture increased slowly over the
course of three days.
Approximate first-order rates of fragmentation of 14 were
observed in the cell growth media used, RPMI-1640 and foetal
bovine serum (FBS) and mixtures of the two, pH 7.4, 37 °C.
Approximate half-lives based on HPLC data are summarized in
Table 1.
No reference standard was included in these studies, and the
data are therefore only semiquantitative. It was assumed that the
integrals of the HPLC peaks of all of the compounds in a given
mixture are proportional to their molar concentrations. However,
published ultraviolet spectral curves show a slightly higher ε for
thymidine than for thymine.31 Taking the molecular weights into
account, the thymine–thymidine molarity ratio 2 : 1 would
produce approximately equal HPLC peaks, and the actual half-
lives may be somewhat shorter than those tabulated. It appears
unlikely that ε for FU would be higher than that of β-14b.
In spite of the limitations of the data, first-order kinetic plots
can be obtained. If the sum of the HPLC integrals for β-14b and
5-fluorouracil (FU) is taken as 100% and it is assumed that the
molar extinction coefficients are equal, a first-order plot of the
conversion of β-14b to FU in 90% RPMI-1640 and 10% FBS at
37 °C, pH 7.4, yields k1 = 9.35 ( 0.10) × 10−6 sec−1 (Fig. 2).
An erroneous assumption about the relative extinction coeffi-
cients of β-14b and FU will alter k1 but not change the rate law
from first-order. For example, if it is assumed that the extinction
coefficient of FU is half that of β-14b, then k1 = 12.3 ( 0.23) ×
10−6 sec−1, a 28% increase.
In human liver extract, the ratio of β-14b/FU after 12 h was
∼60/40, in the same range as found in the various buffers. There
is no measurable enzymatic degradation of β-14b.
Discussion
Instability of 14 under physiological conditions
The fragmentation of 14 had not been anticipated, in as much as
β-alkoxy-substituted boronic esters are generally stable at room
temperature. There is precedent for β-elimination of boron and
oxygen in the partial decomposition of pinacol [1-chloro-2-(ben-
zyloxy)hexyl]boronate during distillation at 125–130 °C, though
the distillate yielded an analytically pure residue of the β-alkoxy
compound after the volatile by-products were removed by short
path vacuum distillation at 50–65 °C.32 The mechanism of the
facile β-elimination of boron and halide from (β-bromoalkyl)-
boronic esters has been studied in detail.33 A plausible mechan-
ism for the fragmentation of 14 to a pyrimidine base and
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β,γ-unsaturated aldehyde 21 via a borate complex 20 is illus-
trated. Since 21 would not be very stable under the reaction con-
ditions, definitive evidence was not obtained, though the
appearance of ill-defined NMR signals in the region expected for
olefinic protons is in accord.
3. None of the boron-substituted deoxyribonucleoside ana-
logues synthesized has any significant cytotoxicity toward the
Hep G2 cell line.
4. All of the boron-substituted deoxyribonucleoside analogues
undergo gradual hydrolytic cleavage under physiological con-
ditions, liberating the pyrimidine base.
5. The hydrolytic cleavages are pseudo-first-order, apparently
base-catalysed, with half-lives on the order of several hours to
days at 37 °C, pH 7.4.
6. The boronic acids oxidize slowly in air to produce small
amounts of the corresponding deoxyribonucleosides.
7. No evidence of any enzymatic cleavage or oxidation was
observed.
Experimental
(4S,5S)-2-[(1S)-2-[(tert-Butyldimethylsilyl)oxy]-1-(benzyloxy)-
ethyl]-4,5-dicyclohexyl-1,3,2-dioxaborolane (5)
The preparation of (S,S)-1,2-dicyclohexyl-1,2-ethanediol
[DICHED] from 1,2-diphenyl-1,2-ethanediol (84 g, 0.39 mol)
by the reported procedure34 was modified during workup by
addition of acetonitrile (300 mL) and potassium bifluoride
(100 g, 1.28 mol) in water (500 mL), resulting in immediate pre-
cipitation of (S,S)-DICHED. (S,S)-DICHED (tert-butyldimethyl-
silyl)boronate (3c) was prepared by the published method.11
(Dichloromethyl)lithium was prepared by addition of n-butyl-
lithium (1.6 M in hexanes, 37 mL, 59 mmol) to dichloromethane
(12 mL, 180 mmol) in THF (350 mL) at −100 °C under argon.
The differing rates of degradation in different buffers suggest
general base catalysis. The measured half-life of β-14b, 15–27 h
in the various buffers at pH 7.4, increases to 54 h at pH 5, much
too small a change to be consistent with specific hydroxide ion
catalysis. No measurable degradation was observed at pH 3. The
faster fragmentation of the β-isomers at pH 7.4 contrasts with
greater loss of the α-isomers during chromatography on silica.
Error evaluation
A solution of (silyloxymethyl)boronic ester 3c (19.5 g,
51.3 mmol) in THF (300 mL) was added, followed by the
addition of anhydrous zinc chloride (1 M in ether, 100 mL,
100 mmol). The resulting solution was allowed to warm to room
temperature and stirred overnight. The solution was concentrated
and diluted with 10% ether in pentane (500 mL). The organic
layer was washed with saturated aqueous ammonium chloride,
dried over magnesium sulphate, and concentrated under vacuum.
Flash chromatography yielded the pure product 4 (21.8 g,
50.8 mmol). (Sometimes the reaction was not completed. The
resulting materials (3 and 4) were purified on silica gel with
pentane–ether (30 : 1 to 20 : 1), yield <50%.) A solution of
sodium benzyl oxide in THF was prepared by treatment of
benzyl alcohol (6.4 mL, 62 mmol) with sodium hydride (60%
dispersed in mineral oil, 2.5 g, 62 mmol, washed twice with
pentane) in THF (200 mL) overnight at room temperature. The
sodium benzyl oxide solution was transferred to a solution of
chloro boronic ester 4 (21.8 g, 50.8 mmol) in THF (100 mL) via
cannula at room temperature. The resulting mixture was refluxed
overnight. The progress of the reaction was monitored with TLC
and NMR. The reaction was quenched with water at 0 °C, then
diluted with ether and saturated aqueous ammonium chloride.
The resulting solution was extracted with ether. The combined
organic layer was dried over magnesium sulphate, filtered, and
concentrated. The concentrate was quickly purified on silica gel
eluting with pentane–ether (20 : 1) to give the pure liquid 5
(25 g, 97%): [α]2D2 −17.7° (c 0.04, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.40–7.20 (m, 5H), 4.66 (s, 2H), 3.94–3.80 (m, 4H),
3.46 (dd, J = 6.0, 5.7 Hz, 1H), 1.82–1.54 (m, 11H), 1.41–0.85
(m, 11H + s, 9H at δ 0.90), 0.06 (s, 6H); 13C NMR (75 MHz,
The identification of decomposition products of β-14b and
β-14c and the rates of their formation were investigated in order
to understand whether the cytotoxicities of β-14b and β-14c
were properties of the compounds themselves or resulted from
decomposition products. The data obtained are accurate enough
for this purpose. Radical catalysed air oxidation of boronic acids
is often encountered, and it is not surprising that a variable few
per cent of the corresponding deoxyribonucleosides were found
in the samples of 14.
The assumption that the UV detector of the HPLC instrument
responds equally to equal molar concentrations of β-14b, FUdR,
and FU is likely a good approximation for β-14b and FUdR, in
which the chromophore is remote from the structural difference.
Accordingly, estimates of the relative concentrations of FUdR
and β-14b in freshly prepared solutions of the latter are accurate
enough for the conclusion that the FUdR accounts for the
cytotoxicity.
Conclusions
1. A series of nucleoside analogues having a boronic acid func-
tion in place of the 3′-hydroxyl group has been synthesized via
asymmetric boronic ester homologation with (dichloromethyl)-
lithium.
2. The required change of chiral directors has been accom-
plished efficiently by direct displacement of (S,S)-1,2-dicyclo-
hexyl-1,2-ethanediol from boron with (+)-(1S,2S,3R,5S)-
pinanediol.
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CDCl3) δ 139.5, 128.3, 127.9, 127.4, 83.9, 72.9, 70.3 (br, C-B),
64.8, 43.1, 28.4, 27.6, 26.6, 26.2, 26.16, 26.1, 18.6, −5.1;
HRMS (ESI-Q/ICR) m/z: [M + Na]+ Calcd for C29H49BNaO4Si
523.3385; Found 523.3375; Calcd for C29H49BKO4Si 539.3125;
Found 539.3112.
temperature and stirred overnight. After it was quenched with
water at 0 °C, the mixture was extracted with ether. The organic
layer was dried, filtered, and concentrated. Flash chromatography
yielded liquid 8 (9.7 g, 86% from 7); [α]2D2 8.5° (c 0.03, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.40–7.20 (m, 5H), 5.83 (m,
1H), 5.10–4.90 (m, 2H), 4.80 (d, J = 11.7, 1H), 4.57 (d, J =
11.1 Hz, 1H), 4.26 (dd, J = 9.0, 2.1 Hz, 1H), 3.82–3.60 (m, 3H),
2.48–2.10 (m, 3H), 2.05 (t, J = 5.4 Hz, 1H), 1.93–1.77 (m, 2H),
1.56–1.46 (m, 1H), 1.35 (s, 3H0, 1.29 (s, 3H), 1.19 (d, J =
10.5 Hz, 1H), 0.90 (s, 9H), 0.83 (s, 3H), 0.06 (s, 3H). 0.05 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 139.5, 138.6, 128.4, 128.0,
127.5, 115.4, 85.8, 81.4, 77.9, 73.1, 66.7, 51.4, 39.7, 38.4, 35.8,
32.0, 29.0, 27.3, 26.7, 26.4 (bs, C-B), 24.3, 18.5, −5.12, −5.08;
HRMS (ESI-Q/ICR) m/z: [M + Na]+ Calcd for C29H47BNaO4Si
521.3229; Found 521.3218.
[(1S,2S,3R,5S)-Pinanediol (S)-[1-benzyloxy-2-(tert-butyl-
dimethylsilyloxy)ethyl]boronate] (6)
The DICHED boronic ester 5 (28 g, 56 mmol) was transester-
ified with (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-
2,3-diol (pinanediol from (+)-α-pinene) (9.5 g, 56 mmol) in
ether (100 mL) in the presence of water (10 mL). An hour later,
DICHED had precipitated. The solution was concentrated under
vacuum. Pentane was added and the precipitated DICHED was
filtered, 9.7 g (77%). The filtrate was concentrated under reduced
pressure, then 6 was quickly purified on silica gel with pentane–
ether (30 : 1 to 20 : 1), liquid, 24 g (96%), [α]2D2 +9.5° (c 0.093,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.40–7.20 (m, 5H), 4.66
(s, 2H), 4.31 (dd, J = 8.7, 1.5 Hz, 1H), 3.96–3.80 (m, 2H), 3.45
(dd, J = 5.7, 3.3 Hz, 1H), 2.38–2.28 (m, 1H), 2.24–2.14 (m,
1H), 2.07 (t, J = 4.8 Hz, 1H), 1.95–1.85 (m, 2H), 1.40 (s, 3H),
1.29 (s, 3H), 1.20 (d, J = 10.5 Hz, 1H), 0.90 (s, 9H), 0.84 (s,
3H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 139.4, 128.4,
127.9, 127.4, 86.6, 78.3, 72.8, 70.3 (br, C-B), 64.7, 51.3, 39.6,
38.2, 35.6, 28.8, 27.3, 26.7, 26.2, 24.2, 18.6, −5.09, −5.1;
HRMS (ESI-Q/ICR) m/z: [M + Na]+ Calcd for C25H41BNaO4Si
467.2759; Found 467.2744; [M + K]+ Calcd for C25H41BKO4Si
483.2499; Found 483.2489.
(1S,2S,3R,5S)-Pinanediol (1S,2S)-[2-benzyloxy-3-(tert-butyl-
dimethylsilyloxy)-1-(2-oxyethyl)-propyl]boronate (9)
The boronate 8 (0.8 g, 1.60 mmol, 1 eq.) was dissolved in 1,4-
dioxane (15 mL) and water (5 mL). Potassium osmate dihydrate
(11.82 mg, 0.032 mmol, 0.02 eq.), sodium periodate (1.373 g,
6.42 mmol, 4 eq.) and 2,6-lutidine (343.9 mg, 3.2 mmol,
375 μL, 2 eq.) were added and the mixture was stirred at room
temperature and checked by TLC. The reaction was finished
within 1 h. Water (30 mL) was added, followed by saturated
ammonium chloride (15 mL) and ethyl acetate (50 mL). The
water phase was extracted with ethyl acetate (3 × 50 mL). The
combined organic phase was washed with brine, dried over
Na2SO4, filtered and concentrated to a black oily residue.
Chromatography on silica gel with 2–4% ethyl acetate in
hexanes yielded colourless oily 9 (0.490 g, 63%), 1H NMR
(300 MHz, CDCl3) δ 9.7 (t, J = 1.5 Hz, 1H), 7.40–7.20 (m, 5H),
4.74 (d, J = 11.4 Hz, 1H), 4.50 (d, J = 11.4, Hz, 1H), 4.27 (dd,
J = 8.7, 1.8 Hz, 1H), 3.86–3.66 (m, 2H), 2.66 (ddd, J = 6.9, 3.6,
1.2 Hz, 1H), 2.32 (ddt, J = 13.8, 9.0, 2.7 Hz, 1H), 2.21–2.11 (m,
1H), 2.03 (t, J = 5.4 Hz, 1H), 2.42–2.32 (m, 2H), 1.36 (s, 3H),
1.28 (s, 3H), 1.16 (d, J = 11.1 Hz, 1H), 0.90 (s, 9H), 0.83 (s,
3H). 0.054 (s, 3H), 0.049 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
203.2, 139.1, 128.4, 128.1, 127.6, 86.1, 80.4, 78.1, 73.0, 65.8,
51.4, 42.0, 39.6, 38.4, 35.6, 28.7, 27.3, 26.5, 26.2, 24.2, 20.5
(bs, C-B), 18.5, −5.2; HRMS (ESI-Q/ICR) m/z: [M + Na]+
Calcd for C28H45BNaO5Si 523.3022; Found 523.3019.
(1S,2S,3R,5S)-Pinanediol (1S,2S)-[1-allyl-2-benzyloxy-3-
(t-butyldimethylsilyloxy)propyl]boronate (8)
The boronic ester 6 (12 g, 27 mmol) was dissolved in anhydrous
THF (270 mL) under argon. Dibromomethane (5.7 mL,
81 mmol) was added by syringe. The solution was cooled to
−78 °C and lithium diisopropylamide (2 M, 20 mL, 40.5 mmol)
was added dropwise, followed by ZnCl2 (1 M in diethyl ether,
135 mL). After overnight stirring, the mixture was quenched
with water and diluted with pentane (500 mL). The organic layer
was washed with ammonium chloride (3 × 100 mL), then dried
over magnesium sulphate, filtered, and concentrated. Flash
chromatography on silica with n-pentane–diethyl ether (30 : 1)
yielded liquid (1S,2S,3R,5S)-pinanediol (1S,2R)-[2-benzyloxy-l-
bromo-3-(t-butyldimethylsilyloxy)propyl]boronate (7) (12.1 g,
(1S,2S,3R,5S)-Pinanediol (3S,4S)-5-O-tert-Butyldimethylsilyl-2,3-
dideoxyribosyl-3-boronate (10)
1
83%), H NMR (300 MHz, CDCl3) δ 7.38–7.22 (m, 5H), 4.73
(AB, J = 21.0, 11.1 (11.4) Hz, 2H), 4.34 (dd, J = 8.7, 2.1 Hz,
1H), 4.00–3.78 (m, 3H), 3.52 (d, J = 7.8 Hz, 1H), 2.40–2.28 (m,
1H), 2.19–2.09 (m, 1H), 2.08 (t, J = 6.0 Hz, 1H), 1.94–1.84 (m,
2H), 1.36 (s, 3H), 1.27 (s, 3H), 1.26 (d, J = 10.8 Hz, 1H), 0.9 (s,
9H), 0.83 (s, 3H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 138.8, 128.4, 127.9, 127.6, 86.8, 81.8, 78.6, 73.3, 63.9, 51.5,
39.5, 38.5, 35.4, 29.7 (bs, C-B), 28.5, 27.2, 26.4, 26.2, 24.2,
18.6, −5.2; LRMS (ESI) Calcd for C26H42 11B78BrNaO4Si
559.2026; Found 558.2 (20%), 559.2 (97%), 560.2 (50%), 561.2
(100%), 562.2 (30%), 563.2 (10%). Bromo boronic ester 7 in
THF at −70 °C was treated with allylmagnesium bromide
(1.7 M, 16 mL, 27 mmol). The solution was warmed to room
The aldehyde boronate 9 (600 mg, 1.2 mmol) was treated with
10% palladium on charcoal (300 mg) in ethyl acetate (30 mL)
under hydrogen. The mixture was stirred overnight, then moni-
tored by TLC. If debenzylation of 9 was incomplete, 20% palla-
dium hydroxide (50 mg) was added and hydrogenolysis
continued. The mixture was filtered through a celite pad and the
filtrate was concentrated. The residue was purified on silica gel
with 5 : 1 pentane–ether to yield pure liquid mixture of dideoxy-
ribosyl boronate anomers 10 (α and β); 81% (400 mg) to quanti-
tative. The ratio of anomers α/β was ∼0.5, based on NMR data:
[α]2D2 +19.3° (c 0.035, CHCl3); 1H NMR (300 MHz, CDCl3)
9354 | Org. Biomol. Chem., 2012, 10, 9349–9358
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δ [5.51 (m, 0.33) + 5.38 (dd, J = 8.4, 3.0 Hz, 0.67) = 1H],
4.34–4.24 (m, 2H), 3.84 (dd, J = 10.8, 2.7 Hz, 1H), 3.70–3.40
(m, 2H), 2.39–2.17 (m, 2.5H), 2.10–2.00 (m, 2H), 1.97–1.78
(m, 4H), 1.61 (m, 0.5H), [1.39 (s, 1) + 1.38 (s, 2) = 3H], 1.29 (s,
3H), [1.11 (d, J = 11.1 Hz, 0.33H + 1.03 (d, J = 10.8 Hz, 0.67)
= 1H], 0.93 (s, 9H), 0.89 (s, 3H), 0.84 (s, 3H), [0.113 (s, 2) +
0.111 (s, 2) + 0.06 (s, 2) = 6H]; 13C NMR (75 MHz, CDCl3) δ
99.6, 86.4, 86.1, 83.0, 81.4, 78.3, 78.2, 66.0, 64.8, 51.4, 39.61,
39.57, 38.34, 38.32, 36.2, 35.65, 35.57, 28.77, 28.74, 27.2,
26.65, 26.60, 26.17, 24.2, 18.66, 18.62, −5.05, −5.12, −5.24,
−5.35; HRMS (EI-Q-TOF) m/z: [M]+ Calcd for C21H38BO4Si
393.2637; Found 393.2643.
acetone (2 : 1 : 1), then chloroform–acetone (9 : 1) to give the
pure liquid mixture of isomers (ratio of α–β = 1 : 2, 140 mg,
61%): 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 1.2 Hz,
0.67H), 7.27 (d, J = 1.2 Hz, 0.33 H), 0.97 (d, J = 11.1 Hz);
HRMS (ESI-Q/ICR) m/z: [M + K]+ Calcd for C26H43BKN2O6Si
557.2615; Found 557.2602.
(1S,2S,3R,5S)-Pinanediol 3′-deoxythymidine-3′-boronate
(α/β-13a)
The boronate 12 (80 mg, 0.154 mmol) was treated with HCl
(4 M in dioxane, 0.1 mL) in THF (0.5 mL) at room temperature.
After 1 h the reaction was complete. The solution was treated
with water and extracted with ethyl acetate (3 × 10 mL). The
organic layer was dried over magnesium sulphate, filtered, and
concentrated. The concentrates were purified by thin layer
chromatography. Useful eluting solvents for chromatography
were n-pentane–ether–acetone (2 : 1 : 1), chloroform–ether–
acetone (4 : 1 : 1), and chloroform–acetone (3 : 1). The liquid
(1S,2S,3R,5S)-Pinanediol (3S,4S)-1-acetyl-5-O-tert-
butyldimethylsilyl-2,3-dideoxyribosyl-3′-boronate (11)
The dideoxyribose boronate 10 (300 mg, 0.73 mmol) was dis-
solved in dichloromethane (10 mL), then the solution was
cooled to 0 °C, followed by the addition of a solution of acetic
anhydride (0.21 mL, 2.19 mmol) and N,N-dimethylamino-4-
pyridine (13 mg, 0.11 mmol) in methylene chloride (5 mL). The
solution was stirred overnight. Water (10 mL) was added. The
mixture was extracted with chloroform (3 × 100 mL). The
chloroform solution was dried over magnesium sulphate, filtered,
and concentrated. Chromatography on silica with 3 : 1 pentane–
ether yielded liquid 11 (325 mg, 98%, α/β mixture); [α]2D2 +17.0°
1
β-isomer eluted first: β-13a 36 mg (58%); H NMR (300 MHz,
CDCl3) δ 8.8 (s, 1H), 7.65 (d, 0.9 Hz, 1H), 6.11 (dd, J = 6.9,
1.8 Hz, 1H), 4.30 (dd, J = 8.7, 2.1 Hz, 1H), 4.13 (dt, J = 11.4,
3.3 Hz, 1H), 4.10–4.00 (m, 1H), 3.88–3.78 (m, 1H), 2.56–2.18
(m, 4H, 2.05 (t, J = 4.5 Hz, 1H), 1.96–1.88 (m, 1H), 1.89 (d, J =
0.9 Hz, 3H), 1.86–1.78 (m, 1H), 1.39 (s, 1H), 1.29 (s, 1H), 1.00
(d, J = 10.8, 1H), 0.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
164.1, 150.5, 136.5, 110.2, 86.7, 86.0, 85.0, 78.4, 63.1, 51.2,
39.6, 38.3, 36.5, 35.5, 28.7, 27.2, 26.7, 24.1, 21.7 (bs, C-B),
12.8; 11B NMR (160 MHz, CDCl3) δ 31.4; HRMS (ESI-Q/ICR)
m/z: [M + Na]+ Calcd for C20H29BN2NaO6 427.2011; Found
1
(c 0.03, CHCl3); H NMR (300 MHz, CDCl3) δ [6.30 (dd, J =
5.1, 1.8 Hz, 0.33) + 6.26 (d, J = 4.5 Hz, 0.67) = 1H], 4.38–4.15
(m, 2H = [4.35 (m, 0.33) + 4.29 (dd, J = 8.4, 2.1 Hz, 0.33) +
4.27 (dd, J = 8.7, 1.8 Hz, 0.66) + 4.20 (m, 0.66)]), 3.76–3.62
(m, 2H), 2.28–2.45 (m, 1.5H), 2.27–2.14 (m, 2H), 2.11–2.03 (m,
1.5H), 1.39 + 1.38 (s, 3H), 1.293 + 1.289 (s, 3H), [1.14 (d, J =
11.1 Hz, 0.33) + 1.03 (d, J = 11.1 Hz, 0.67) = 1H], [0.91 (s, 6) +
0.88 (s, 3) = 9H], [0.85 + 0.84 (s, 3H)], [0.067 (s, 2) + 0.062 (2)
+ 0.053 (1) + 0.050 (1) = 6H]; 13C NMR (75 MHz, CDCl3) δ
170.72, 170.68, 100.0, 99.2, 86.2, 85.6, 83.1, 78.2, 78.23,
78.19, 66.5, 65.2, 51.42, 51.37, 39.61, 39.58, 38.37, 38.31,
36.2, 35.63, 35.56, 35.1, 28.83, 28.76, 27.2, 26.65, 26.59,
26.22, 26.15, 24.15, 21.69, 21.34, 18.7, 18.6, −5.04, −5.10.
−5.11, −5.14; LRMS (ESI) Calcd for C23H41BNaO6Si 475.3;
Found 475.5; HRMS (EI-Q-TOF) m/z: [M − C2H3O2]+ Calcd
for C21H38BO4Si 393.2637; Found 393.260.
1
427.1999. The presumed α-13a 10 mg (16%) (liquid): H NMR
(300 MHz, CDCl3) δ 8.54 (s, 1H), 7.25 (d, J = 1.5 Hz, 1H), 6.12
(dd, J = 5.7 Hz, 1H), 4.39 (m, 1H), 4.30 (dd, J = 9.7, 1.8 Hz,
1H), 4.87–3.77 (m, 1H), 3.70–3.60 (m, 1H), 2.71–2.61 (m, 1H),
2.40–2.18 (m, 2H), 2.05 (t, J = 5.1 Hz, 1H), 2.02–1.70 (m, 2H),
[1.95 (d, J = 0.9 Hz, 3H)], 1.39 (s, 3H), 1.29 (s, 3H), 1.01 (d,
J = 10.8 Hz, 1H), 0.842 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
163.9, 150.5, 135.5, 110.9, 87.0, 86.8, 84.0, 78.5, 65.0, 51.3,
39.6, 38.4, 35.8, 35.5, [31.2, 30.5, 29.9], 28.8, 27.2, 26.7, 24.2,
12.9.
Oxidation of deoxythymidine-3′-boronic ester β-13a
The boronic ester β-13a (20 mg, 0.05 mmol) was treated with
sodium hydroxide (1 M aq. solution, 25 μL) and hydrogen per-
oxide (30% aq. solution, 7 μL) in THF at 0 °C, and warmed to
room temperature. The reaction mixture was stirred for 4 h, then
diluted with water (1 mL). The solution was extracted with ether
(3 × 1 mL). The water layer was concentrated under vacuum to
yield thymidine, identical with a purchased authentic sample by
proton NMR.
(1S,2S,3R,5S)-Pinanediol 5′-(t-butyldimethylsilyl)-3′-
deoxythymidine-3′-boronate (α/β-12a)
To a mixture of the boronate 11 (200 mg, 0.442 mmol) and O,
O′-bis(trimethylsilyl)-thymine (125 mg, 0.46 mmol) in dichloro-
methane (10 mL) was added bromotrimethylsilane (60 μL,
0.46 mmol) at 0–25 °C. O,O′-Bis(trimethylsilyl)thymine was
dissolved at room temperature in the dichloromethane solution
(5–30 min required). At this point, the reaction was completed.
Tetrabutylammonium fluoride (1 M in THF, 0.9 mL, 0.9 mmol)
was added and the mixture was stirred for an hour. After the
reaction was quenched with water, the solution was extracted
with chloroform (20 mL), then ethyl acetate (2 × 20 mL). The
extracts were dried over magnesium sulphate, filtered, and con-
centrated. The residue was purified on silica with pentane–ether–
β-3′-Deoxythymidine-3′-boronic acid (β-14a)
The deoxythymidine boronate β-13a (25 mg, 0.062 mmol) was
stirred overnight with phenylboronic acid (7 mg, 0.056 mmol) in
pentane (0.3 mL)–water (0.3 mL)–methanol (0.1 mL). The solu-
tion was diluted with 0.5 mL of water, then extracted with ether
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2′,3′-Dideoxy-5-fluorouridine-3′-boronic acid (β-14b)
(3 × 1 mL). Concentration of the aqueous phase yielded amor-
phous solid boronic acid β-14a (12.5 mg, 75%); 1H NMR
(300 MHz, D2O) δ 7.78 (s, 1H), 6.08 (d, J = 7.2 Hz, 1H), 4.17
(m, 1H), 3.92 (dd, J = 12.3, 2.7 Hz, 1H), 3.77 (dd, J = 12.3,
4.2 Hz, 1H), 2.52–2.40 (m, 1H), 2.40–2.20 (m, 1H), 1.87 (s,
3H), 1.61 (m, 1H); 1H NMR (300 MHz, CD3OD) δ 8.1 (bs, 1H),
5.98 (dd, J = 6.3, 1.8 Hz, 1H), 4.10 (dt, J = 11.1 Hz, 1H), 3.94
(dd, J = 12.3, 2.4, 1H), 2.40–2.20 (m, 2H), 1.88 (d, J = 1.2 Hz,
3H); 13C NMR (75 MHz, CD3OD) δ 166.9, 152.5, 138.8, 110.3,
87.6, 87.5, 62.9, 37.6, 23.2 (broad s, C-B), 12.7; 11B NMR
(160 MHz, D2O) δ 29.8; HRMS (MALDI-TOF) m/z: [M + Na]+
Calcd for C10H15BN2NaO6 293.0915; Found 293.0907.
2′,3′-Dideoxy-5-fluorouridine-3′-boronic ester (α/β-13b) (36 mg,
0.0875 mmol) and phenylboronic acid (10 mg, 0.083 mmol)
were dissolved in water–ether–acetone (1.3 mL, 5 : 5 : 3). The
solution was stirred overnight, then diluted with ether (2 mL)
and water (1 mL). The water layer was separated and concen-
1
trated to give amorphous solid β-14b (19.5 mg, 82%); H NMR
(300 MHz, D2O) δ 8.14 (d, J = 6.6 Hz, 1H), 6.01 (d(m), J =
6.6 Hz, 1H), 4.22–4.13 (m, 1H), 3.93 (dd, J = 12.6, 3.3 Hz, 1H),
3.77 (dd, J = 12.6, 4.8 Hz, 1H), 2.50–2.24 (m, 2H), 1.52 (m,
1H); 19F NMR (282 MHz, D2O) δ −167.98 (d, J = 5.9 Hz); H
1
NMR (300 MHz, CD3OD) δ 8.55 (d, J = 6.9 Hz, 1H), 5.94 (d, J
= 5.7 Hz, 1H), 4.11 (d, J = 10.8 Hz, 1H), 3.97 (dd, J = 12.3,
2.7 Hz, 1H), 3.69 (d, J = 12.0, 1H), 2.40–2.24 (m, 2H),
1.95–1.80 (m, 1H); 13C NMR (75 MHz, CD3OD) δ 158.6 (d, J
= 26.0 Hz, 158.8, 158.4), 149.5, 141.7, 138.6, 125.8 (d, J = 53.2
Hz, 126.0, 125.6), 86.6, 61.1, 36.5, 21.5 (bs, C-B); 19F NMR
(282 MHz, CD3OD) δ −171.14 (d, J = 6.8 Hz); 11B NMR
α-3′-Deoxythymidine-3′-boronic acid (α-14a)
Amorphous α-deoxythymidine boronic acid α-14a was obtained
by a similar procedure to the preparation of 3-deoxythymidine
1
boronic acid β-14a; 74%; H NMR (300 MHz, D2O) δ 7.61 (d,
J = 1.2 Hz, 1H), 6.07 (AB, J = 6.0 Hz, 1H), 4.45 (m, 1H) 3.76
(dd, J = 12.3, 3.3 Hz, 1H), 3.61 (dd, J = 12.0, 5.4 Hz, 1H), 2.61
(m, 1H), 2.09 (m, 1H), 1.88 (s, [d, J = 0.9], 3H), [1.71 (m, 1H)];
1H NMR (500 MHz, CD3OD) δ 7.54 (s, 1H), 6.08 (t, J = 6 Hz,
1H), 4.40 (m, 1H), 3.68 (dd, J = 12.0, 3.5 Hz, 1H), 3.55 (dd, J =
12.0, 5.0 Hz, 1H), 2.63 (m, 1H), 1.98–1.80 (m, 1H), 1.91 (d, J =
1.5 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 166.7, 152.6,
137.9, 111.4, 88.5, 86.2, 65.1, 36.8, 26.8 (bs, C-B), 12.6; 11B
NMR (160 MHz, D2O) δ 30.2.
(160 MHz, CD3OD)
δ 29.7; HRMS (ESI-Q/ICR) m/z:
[M + Na]+ Calcd for C9H12BFN2NaO6 297.0665, Found
297.0665. The sample in methanol apparently formed the mono-
methyl boronic ester: HRMS (ESI-Q/ICR) m/z: [M + Na]+ Calcd
for C10H14BFN2NaO6 311.0821; Found 311.0819; and the
dimethyl ester: Calcd for C11H16BFN2NaO6 325.0978; Found
325.0977.
(1S,2S,3R,5S)-Pinanediol 2′,3′-dideoxy-5-iodouridine-3′-
boronate (α/β-13c)
(1S,2S,3R,5S)-Pinanediol 2′,3′-dideoxy-5-fluorouridine-3′-
boronate (α/β-13b)
Iodouracil (714 mg, 3 mmol) was treated with hexamethyldisila-
zane (7 mL) followed by chlorotrimethylsilane (0.03 mL). The
mixture was refluxed overnight, the hexamethyldisilazane was
distilled, and the residue of the bis(trimethylsilyl)-5-iodouracil
was kept under vacuum overnight. A solution of acylated
dideoxyribosylboronate 11c (180 mg, 0.4 mmol) and the disily-
lated 5-iodouracil (161 mg, 0.42 mmol) in dichloromethane
(8 mL was treated with bromotrimethylsilane (0.06 mL,
0.42 mmol). After stirring for 1 h, the solvent was completely
removed in vacuo overnight. The residue of silylated 12c was re-
dissolved in anhydrous acetonitrile (3 mL) followed by the
addition of a solution of caesium fluoride (1.5 mL, 1 M). The
solutions were stirred for 1 h, followed by the addition of 10%
HCl (1 mL). The solutions were stirred for an additional 1 h,
then extracted with ethyl acetate (3 × 20 mL). Solutions were
concentrated under reduced pressure. After thin layer chromato-
graphy on silica with pentane–ether–acetone (1 : 1 : 1) liquid
anomers of the deoxy-5-iodouridine boronic ester 13c were
obtained. Isolated yield, α-13c 99 mg (48%), β-13c, 52 mg
(25%); α-13c, 1H NMR (300 MHz, CDCl3) δ 9.64 (br, 1H),
7.89 (s, 1H), 6.06 (t, J = 6.0 Hz, 1H), 4.43 (m, 1H), 4.31 (dd, J
= 9.0, 2.1 Hz, 1H), 3.83 (dd, J = 11.7, 3.0 Hz, 1H), 3.64 (dd, J =
12.0, 5.1 Hz, 1H), 2.74 (m, 1H), 2.40–2.18 (m, 2H), 2.05 (t, J =
5.1 Hz, 1H), 2.02–1.72 (m, 3H), 1.39 (s, 3H), 1.29 (s, 3H), 0.98
(d, J = 10.8 Hz, 1H), 0.84 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 160.6, 150.4, 144.6, 88.0, 86.8, 84.5, 78.4, 68.2, 64.7, 51.2,
39.5, 38.3, 36.2, 35.4, 28.7, 27.1, 26.7, 24.1, 23.4 (bs, C-B);
To a mixture of the boronic ester 11 (400 mg, 0.84 mmol) and
O,O′-bis(trimethylsilyl)-5-fluorouridine (255 mg, 0.93 mmol) in
dichloromethane (18 mL) was added bromotrimethylsilane
(0.13 mL, 0.93 mmol) at 20–25 °C. The mixture was stirred for
50 min, tetrabutylammonium fluoride (1 M in THF, 0.9 mL,
0.9 mmol) was added, and stirring was continued for 1 h. After
the reaction was treated with 10% HCl (1.5 mL), the solution
was extracted with chloroform (20 mL), then ethyl acetate (2 ×
20 mL). The extracts were dried over magnesium sulphate,
filtered, and concentrated. The residue was purified on silica gel
with pentane–acetone (5 : 1 to 3 : 1) to give a liquid mixture of
anomers (α–β ratio ∼1 : 2 by 1H NMR). The resulting compound
in methanol was treated with aq. 10% HCl (1.5 mL), then
extracted with ethyl acetate (3 × 20 mL), dried, filtered, and con-
centrated. Thin layer chromatography yielded the liquid
1
β-anomer, 60 mg (17.5%): H NMR (300 MHz, CDCl3) δ 8.89
(bs, 1H), 8.23 (d, J = 6.6 Hz, 1H), 6.03 (d, J = 6.6 Hz, 1H), 4.30
(dd, J = 9.0, 2.1 Hz, 1H), 4.13 (m, 1H), 3.86 (dd, J = 12.0, 2.7 Hz,
1H), 2.54–2.16 (m, 4H), 2.04 (t, J = 5.1 Hz, 1H), 1.97–1.70
(m, 2H), 1.39 (s, 3H), 1.29 (s, 3H), 0.98 (d, J = 11.1 Hz, 1H),
0.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.4 (d, J =
26.6 Hz, 157.6, 157.2), 149.1, 141.8, 138.7, 125.4 (d, J =
34.6 Hz), 86.72 (86.68), 85.6, 78.4, 62.4, 51.2, 39.6, 38.3, 37.0,
35.5, 31.1, 28.7, 27.1, 26.7, 24.1, 20.6 (bs, C-B); 19F NMR
(282 MHz, CDCl3) δ −166.76 (d, J = 4.5 Hz); 11B NMR
(160 MHz, CDCl3) δ 31.3; HRMS (ESI-Q/ICR) m/z: [M + Na]+
Calcd for C19H26BFN2NaO6 431.1760; Found 431.1758.
HRMS (ESI-Q/ICR) m/z: [M
+
Na]+ Calcd for
C19H26BINaN2O6 539.0821; Found 539.0816; m/z: [M + K]+
9356 | Org. Biomol. Chem., 2012, 10, 9349–9358
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Calcd for C19H26BIKN2O6 555.0560; found 555.0557. β-13c,
1H NMR (300 MHz, CDCl3) δ 9.26 (bs, 1H), 8.58 (s, 1H), 6.03
(d, J = 5.4 Hz, 1H), 4.30 (dd, J = 8.4, 1.5 Hz, 1H), 4.18 (dt,
J = 11.7, 2.7 Hz, 1H), 4.12 (dd, J = 12.3, 2.1 Hz, 1H), 3.85 (dd,
J = 12.3, 3.0 Hz, 1H), 2.76 (bs, 1H), 2.53–2.18 (m, 4H), 2.05 (t,
J = 5.4 Hz, 1H), 1.93 (m, 1H), 1.86–1.74 (m, 2H), 1.39 (s, 3H),
1.29 (s, 3H), 0.98 (d, J = 11.1 Hz, 1H), 0.84 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 160.6, 150.2, 145.9, 87.1, 86.7, 85.9, 78.4,
66.8, 62.3, 51.2, 39.6, 38.3, 37.2, 35.5, 28.7, 27.2, 26.7, 24.1,
20.5 (bs, C-B); HRMS (ESI-Q/ICR) m/z: [M + Na]+ Calcd for
C19H26BIN2NaO6 539.0821; Found 539.0823.
0.15 + 0.14 + 0.10 (s + s + s, 1 : 1 : 0.7, 6H); HRMS (ESI-Q/
ICR) m/z: [M + H]+ Calcd for C25H43BN3O5Si 504.3065, Found
504.3057; (ESI-Q/ICR) m/z: [M
+
Na]+ Calcd for
C25H42BN3NaO5Si 526.2885; Found 526.2879. Desilylation of
α/β-12d (250 mg, 0.5 mmol) in the usual manner, with some
decomposition during chromatography, yielded (α/β-13d)
1
(120 mg, 62%); H NMR (300 MHz, CD3OD) δ 8.63 + 8.06 (d,
J = 7.8 Hz + d, J = 7.5 Hz, 3 : 1, 1H), 7.75 (d, J = 7.2 Hz, impur-
ity), 6.12 + 6.05 (d, J = 7.5 Hz + d, J = 7.8 Hz, 1H), 6.03 (d, J =
7.2 Hz, impurity), 5.96 (m, 1H), 4.34 + 4.33 (dd + dd, J = 8.4,
1.8 Hz, 1H), [4.42 (m) + 4.16 (dt, J = 11 Hz, 2.7 Hz) + 4.00 (dd,
J = 12.5 Hz, 2.3 Hz) + 3.76 (dd, J = 12.5 Hz, 2.9 Hz),
3.75–3.45 (m), 0.3 : 1 : 1 : 1 : 0.6, 3H], 2.7 (m, weak), 2.5–1.7
(m, 8H), 1.39, 1.37, 1.36 (s, s, s, ratio 2 : 0.3: 0.7, 3H), 1.302 +
1.296 (s, s, 3H) 1.07 (d, 0.7H, J = 10.8 Hz), 1.06 (d, ∼0.3H, J =
10.8 Hz), 0.87, 0.86 (s, s, ratio 3 : 1, 3H) HRMS (ESI-Q/ICR)
β-2,′3′-Dideoxy-5-iodouridine-3′-boronic acid (β-14c)
The boronic ester β-13c (99 mg, 0.19 mmol) in pentane–water–
ether–methanol (2 : 2 : 1 : 1, 2 mL) was treated with phenylboro-
nic acid (22 mg, 0.18 mmol). After overnight stirring, 3 mL of
diethyl ether and 1 mL of water were added, the phases were
separated, and the aqueous phase was extracted with two more
3 mL portions of ether. Crude pinanediol phenylboronate
(47 mg, 98%) containing a small amount of unchanged β-13c
was recovered from the organic phase, and concentration of the
aqueous phase yielded the amorphous solid boronic acid β-14c
+
m/z: [M + H]+ Calcd for C19H29BN3O5 390.2200; Found
390.2188; HRMS (ESI-Q/ICR) m/z: [M + Na]+ calcd for
C19H28BN3NaO5 412.2020; Found 412.2014.
2,′3′-Dideoxycytidine-3′-boronic acid (a/β-14d)
Dideoxycytidine boronic ester (30 mg, 0.077 mmol) was trans-
esterified with phenylboronic acid (9 mg, 0.073 mol) in the
usual manner, and concentration of the aqueous phase yielded
1
(48 mg, 66%); H NMR (300 MHz, CD3OD) δ 8.84 (s, 1H),
5.93 (dd, J = 5.4, 1.8 Hz, 1H), 4.14 (dt, J = 11.1, 3.0 Hz, 1H),
3.97 (dd, J = 12.3, 2.7 Hz, 1H), 3.67 (dd, J = 12.0, 2.4 Hz, 1H),
2.40–2.20 (m, 2H), 1.85 (m, 1H); 13C NMR (75 MHz, CD3OD)
δ 163.3, 152.2, 147.8, 88.4, 88.2, 66.8, 62.2, 38.1, 22.5 (bs,
1
impure amorphous α/β-14d (66%, 13 mg); H NMR (300 MHz,
CD3OD) δ 8.52 (s, impurity), 8.22 + 7.74 (d + d, J = 7.2 Hz,
7.8 Hz, 1H), 7.76 (s, impurity), 7.65 (br, 2H, merged with HDO
in other fractions), 7.38 (m, absent in fractions that contain
pinanediol), 6.30–5.80 (m, 2H), [4.38 (m) + 4.12 (dt, J = 11.4,
2.7 Hz) + 3.92 (dd, J = 12.3, 3.0 Hz) + 3.71 (dd, J = 12.0,
3.6 Hz, 1H) + 3.63–3.53 (m), 1 : 3 : 3 : 3 : 2, 3H], 2.73 +
2.40–2.16 (m, 2H), 1.82 + 1.70 (br, 1H); HRMS (ESI-Q/ICR)
m/z: [M + Na]+ Calcd for C9H15BN3O5 256.1105; Found
256.1094; Calcd for C9H14BN3NaO5 278.0924, Found 278.0920.
C-B); HRMS (ESI-Q/ICR) m/z: [M
C9H12BIN2NaO6 404.9725; Found 404.9731.
+
Na]+ Calcd for
α-2′,3′-Dideoxy-5-iodouridine-3′-boronic acid (α-14c)
By the procedure used with β-13c, α-13c (52 mg, 0.1 mmol)
was converted to crude pinanediol phenylboronate (25 mg, 98%)
and amorphous boronic acid α-14c (28 mg, 73%); 1H NMR
(300 MHz, CD3OD) δ 8.09 (s, 1H), 6.03 (t, J = 6.0 Hz, 1H),
4.12 (m, 1H), 3.68 (dd, J = 12.3, 3.6 Hz, 1H), 3.54 (dd, J =
12.0, 5.4 Hz, 1H), 2.69 (m, 1H), 2.02–1.98 (m, 2H); 13C NMR
(75 MHz, CD3OD) δ 163.1, 152.2, 146.9, 89.4, 86.4, 67.9, 65.3,
36.9, 26.3 (bs, C-B); HRMS (ESI-Q/ICR) m/z: [M + Na]+ Calcd
for C9H12BIN2NaO6 404.9725; Found 404.9726.
Caesium (1S)-[2-benzyloxy-1-(p-methoxybenzyloxy)ethyl]-
trifluoroborate (18)
Pinanediol (1R)-(2-benzyloxy-1-chloroethyl)boronate (16) was
prepared by the method described previously.10 Crude 16 was
added to lithium p-methoxybenzyl oxide in THF, the mixture
treated with anhydrous DMSO as previously described,10 and
the product extracted and concentrated to yield crude
(1R,2R,3S,5R)-pinanediol (1S)-(2-benzyloxy-1-p-methoxybenzyl-
oxyethyl)boronate (17) (72.8 g, 90% from 3a), which was used
directly in the next step; 1H NMR (300 MHz, CDCl3) δ 0.832 (s,
3), 1.22 (d, J = 10.8 Hz, 1), 1.28 (s, 3), 1.38 (s, 3), 1.6 (m, ∼1,
impurity?) 1.9–2.4 (m, 5), 3.57 (m, 1), 3.69–3.80 (m, 2), 3.79
(s, 3), 3.81 (s, ∼2, impurity?), 4.32 (dd, J = 2 Hz, J = 9 Hz, 1),
4.57 and 4.62 (AB, J = 6 Hz, 2), 4.59 (s, 2), 6.84 (m, 2), 6.89
(m, ∼1.5 impurity?), 7.3 (m, 7 (+∼1.5, impurity?)). Impurities
consistent with the data include chloro boronic ester 16 and
p-methoxybenzyl alcohol. A stock solution of caesium bifluoride
in hydrofluoric acid was prepared by adding caesium fluoride
(37 g, 0.244 mol) in small portions to well stirred 48% hydro-
fluoric acid (16.8 mL, 0.488 mol) in a 500 mL polyethylene
bottle cooled with an ice bath [CAUTION: Highly exothermic.],
(1S,2S,3R,5S)-Pinanediol 2,′3′-dideoxycytidine-3′-boronate
(α/β-13d)
Reaction of acetylated deoxyriboseboronic acid 11 (320 mg,
0.71 mol) with bis(trimethylsilyl)cytosine (189 mg, 0.74 mol)
by a procedure similar to that used with 5-iodouridine for the c
series yielded the liquid silylated boronic ester α/β-12d (310 mg,
87%); 1H NMR (300 MHz, CD3OD) δ 8.34 + 7.70 (d, J =
7.5 Hz + d, J = 7.2 Hz, ratio 2 : 1, 1H], 5.95 (m, possibly d, J =
6.3 Hz, obscuring δ 5.98, t, J ∼ 6 Hz, 2 : 1, 1H), 5.90 + 5.81 (d,
J = 7.5 Hz + d, J = 7.2 Hz, 1 : 2, 1H), 4.42 (m, weak), 4.33 +
4.31 (dd + dd, 3 : 1, J = 8.7, 1.8 Hz, 1H), 4.3–4.1 + 3.9–3.7 (m
+ m, 3H), 2.7–1.7 (m, 8H), 1.38 +1.34 (s + s, 3 : 1, 3H), 1.30 +
1.29 (s + s, 3 : 1, 3H), 1.05 + 1.01 (d + d, J = 10.8 Hz, 3 : 1,
1H), 0.96 + 0.93 (s + s, 3 : 1, 9H), 0.87 + 0.85 (s + s, 3 : 1, 3H),
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25.0 mL, 9.75 M in CsHF2, 19.5 M in HF.8 A portion of this
solution (17.7 mL, 0.173 mol of CsHF2) was added to a stirred
solution of all of the 17 (72.8 g, 0.16 mol) in diethyl ether
(250 mL) in a polyethylene bottle cooled with ice. No precipitate
formed. After overnight, addition of pentane (150 mL) resulted
in formation of 3 phases. The ether/pentane phase was decanted
and concentrated to crude (1R,2R,3S,5R)-pinanediol (19.5 g,
∼70%). The remainder was treated with water (180 mL) and
3 : 1 pentane–diethyl ether, again resulting in 3 liquid phases.
The densest phase froze in the freezer (−19 °C) overnight.
Further treatment of this phase with diethyl ether and cooling in
the freezer led to solid crude 18 (25.6 g, ∼30%). Evaporation of
the aqueous (middle) phase led to a mixture of pinanediol and
18 (23 g), which was discarded. Two recrystallizations of crude
18 from acetonitrile by addition of diethyl ether yielded an
Acknowledgements
We thank the William H. Prusoff Foundation for a gift to
Washington State University, and NIH grants RR0631401
and RR12948, NSF grants CHE-9115282 and DBI-9604689,
and the Murdock Charitable Trust for support of the WSU NMR
Centre.
Notes and references
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1
analytical sample, mp > 275 °C: H NMR (300 MHz, CD3OD)
δ 3.14 (unresolved m, J ∼ 4 Hz, 1), 3.70 (s, 1), 3.72 (d, J ∼
2 Hz, 1), 3.76 (s, 3), 4.482 and 4.486 (AB, J = 12 Hz, 2), 4.58 +
4.62 (AB, J = 11 Hz, 2), 6.85 (d of m’s, J ∼ 2 Hz, J = 7 Hz, 2),
7.3 (m, 7); 13C NMR (75 MHz, CD3OD) δ 54.4, 72.5, 74.3,
113.3, 127.2, 127.7, 128.1, 129.6, 132.3 (w, poor S/N ratio
obscured weaker peaks); 19F NMR (282 MHz, CD3OD) δ
−147.0 (unresolved m). Anal. Calcd for C17H19BCsF3O3: C,
43.25; H, 4.06; B, 2.29; Cs, 28.16; F, 12.07. Found: C, 43.11; H,
3.83; B, 2.31; Cs, 30.3; F, 11.3. The unexplained deviations of
the Cs and F values from those expected are typical of results
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(1S,2S,3R,5S)-Pinanediol (1S)-(2-benzyloxy-1-p-methoxy-
benzyloxyethyl)boronate (19)
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Caesium (1S)-[2-benzyloxy-1-(p-methoxybenzyloxy)ethyl]tri-
fluoroborate (18) (24.6 g, 0.052 mol), (1S,2S,3R,5S)-pinanediol
(8.95 g, 0.53 mol), and sodium bicarbonate (10 g, 0.12 mol) in a
two-phase system of water (500 mL) and diethyl ether (200 ml)
were stirred at 22 °C under argon. Reaction progress was moni-
1
tored by comparison of the H NMR signals of free pinanediol
(δ 3.95, dd, J ∼ 6 Hz, J ∼ 9 Hz) and boronic ester 19 (δ 4.31,
dd, J = 1.9 Hz, J = 8.9 Hz) in aliquots from the ether phase.
Completion required ∼8 days. The ether phase was separated,
washed with water (100 mL), and concentrated on a rotary evap-
orator. The residue was dissolved in pentane (200 mL) and
passed through a silica gel column with additional pentane. The
solution was concentrated and stirred overnight under vacuum
(0.24 torr), 16.3 g (69%) of liquid 19; 1H NMR (300 MHz,
CDCl3) δ 0.82 (s, 3), 1.20 (d, J = 10.8 Hz, 1), 1.27 (s, 3), 1.40
(s, 3) 1.83–1.9 (m, 2), 2.06 (m, 1), 2.15 (m, 1), 2.31 (m, 1), 3.56
(m, 1), 3.73 (m, 2), 3.77 (s, 3), 4.31 (dd, J = 1.9 Hz, J = 8.9 Hz),
4.52 and 4.61 (AB, 2, d + d, J = 12 Hz), 4.59 (s, 2), 6.84 (m, 2),
7.30 (m, 7); 13C NMR (75 MHz, CDCl3) δ 24.3, 26.7, 27.3,
28.9, 35.6, 38.3, 39.6, 51.3, 55.5, 68.2 (broad, CB), 71.8, 72.4,
73.4, 78.4, 86.8, 113.9, 127.6, 127.9, 128.4, 129.7, 131.3, 138.8,
159.3. HRMS (EI-double focusing magnetic sector) m/z: [M]+
Calcd for C27H35BO5 450.2583; Found 450.2597; m/z: [M −
C7H7]+ Calcd for C20H28BO5 359.2034, Found 359.2039; m/z:
[M − C8H9O]+ Calcd for C19H26BO4, 329.1928; Found
329.1932.
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9358 | Org. Biomol. Chem., 2012, 10, 9349–9358
This journal is © The Royal Society of Chemistry 2012