Novel phosphitylating reagents containing a phosphorus-fluorine bond and their application in efficient synthesis of phosphorofluoridates and phosphorofluoridothionates

Article abstract of DOI:10.1039/b103082p

Novel phosphitylating reagents containing a P-F bond are obtained in excellent yield from commercial materials. They react with alcohols at 20 °C in neutral solvents in the presence of tetrazole, chlorotrimethylsilane or benzoyl chloride to give the inter

Full text of DOI:10.1039/b103082p

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Novel phosphitylating reagents containing a phosphorus–fluorine
bond and their application in efficient synthesis of
phosphorofluoridates and phosphorofluoridothionates
1
Wojciech Da˛bkowski* and Izabela Tworowska
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Łódz´,
Sienkiewieza 112, Poland
Received (in Cambridge, UK) 5th April 2001, Accepted 8th August 2001
First published as an Advance Article on the web 11th September 2001
Novel phosphitylating reagents containing a P–F bond are obtained in excellent yield from commercial materials.
They react with alcohols at 20 ЊC in neutral solvents in the presence of tetrazole, chlorotrimethylsilane or benzoyl
chloride to give the intermediate phosphorofluoridites. Subsequent oxidation or sulfurization followed by the
removal of protecting groups gives the phosphorofluoridates and thiophosphorofluoridates in over 90% total yield.
Letsinger and Lunsford revolutionized the chemical synthesis
of oligonucleotides by introduction of the ‘phosphite triester’
methodology.1 This approach became widely accepted when
Fig. 1
Beaucage and Caruthers developed phosphoroamidites as a
new class of preferred phosphitylating intermediates.2 Phos-
The synthetic strategy for the preparation of O-tert-butyl
N,N-diisopropylfluorophosphoramidite is delineated in
Scheme 1. Bis-O,O-(4-nitrophenyl) N,N-diisopropylphos-
phorochloridites are so reactive that their isolation as stable
enantiomers or diastereoisomers is very unlikely. In contrast,
phosphorofluoridites should be chemically and stereochem-
ically considerably more stable due to the strength of the
phosphorus–fluorine bond.3 This higher stability has been
demonstrated by recent work from this laboratory.
3
Known routes to phosphorofluoridites derived from alcohols
of biological interest are of limited value. Recently we discovered
that aryloxy groups attached to a tricoordinate phosphorus
center are readily replaced by fluoride anion (Fig. 1).4,5
Scheme 1 Reagents and conditions: i, Me3SiOAr, THF, 20 ЊC, 1 h;
ii, tBuOH, NaH, THF, 20 ЊC, 5 h; iii, TBAF, THF, 20 ЊC, 10 min.
phoramidite 44 was allowed to react with one equivalent of
tert-butyl alcohol in the presence of sodium hydride to give
O-tert-butyl O-(4-nitrophenyl) N,N-diisopropylphosphor-
amidite 5, which is finally transformed into the phosphitylating
reagent O-tert-butyl N,N-diisopropylphosphorofluoramidite 3
by reaction with TBAFؒ3H2O in 90% overall yield.
Results and discussion
Best results were obtained using the 4-nitrophenyl group.4 This
is a surprisingly easy and efficient nucleophilic displacement
reaction propelled by the high affinity of the fluoride anion for
a phosphorus center. Under favorable structural circumstances
this reaction can compete efficiently with hydrolysis. For
example, in the case of O-nucleosidyl-O-(4-nitrophenyl) phos-
phoroamidites the replacement of the 4-nitrophenoxy group by
fluoride proceeds in very high yield with the aid of commercial
TBAFؒ3H2O. It is most likely that hydrolysis is sterically
inhibited. P compounds containing substituents with less
steric hindrance require water-free fluorinating reagents if
hydrolysis is to be avoided. Another important feature of our
current studies is the demonstration of stereochemical stability
of a number of phosphorofluoridite and other P–F deriv-
atives.6 As part of our search for convenient syntheses of P–F
structures derived from alcohols of biological interest, we
describe in this paper novel efficient phosphitylating reagents
The synthesis of O-(2-cyanoethyl) N,N-diisopropylphos-
phorofluoramidite 7 starts from O-(2-cyanoethyl) N,N,N Ј,NЈ-
tetraisopropylphosphorodiamidite
N,N-diisopropylchlorophosphoramidite
8
or O-(2-cyanoethyl)
and proceeds in
9
overall 95% yield (Scheme 2). Compounds 3 and 7 can be
3
[O-tert-butyl N,N-diisopropylfluorophosphoramidite F-
P(NiPr2)OtBu] and 7 [O-(2-cyanoethyl) N,N-diisopropylfluoro-
phosphoramidite F-P(NiPr2)OCH2CH2CN] in which the P–F
bond is already present.
Scheme 2 Reagents and conditions: i, HOAr, THF, 20 ЊC, 3 h;
ii, Me3SiOAr, THF, 20 ЊC, 1 h; iii, TBAF, THF, 20 ЊC, 10 min.
purified by distillation in vacuo or by silica gel chromatography.
They also can be prepared in a one-flask procedure and used
immediately. They are colorless liquids which can be stored at
ambient temperature. Substrates 6, 8 and 9 are commercially
available. Phosphitylating reagents 3 and 7 react with alcohols
2462
J. Chem. Soc., Perkin Trans. 1, 2001, 2462–2469
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103082p

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Fig. 2
in the presence of activators such as tetrazole, trimethylchloro-
silane (TMSCl) or benzoyl chloride. The phosphorus–fluorine
bond is not affected in this procedure. TMSCl proved to be
a better activator than tetrazole, which must be used in
large excess. The strongly electronegative fluorine does not
affect the use of the activated amino ligand as a leaving group in
phosphitylation procedures. This behavior differs from that of
P amidites containing a CF3 group attached to the phosphorus
center.7 It is noteworthy that examination of the phosphityl-
ation reactions by 31P NMR spectroscopy using fluorophos-
phoramidite 7 in the presence of tetrazole or TMSCl reveals
the formation of intermediates 11 or 12 (Fig. 2) which is in
agreement with the mechanistic scheme we proposed earlier.8
Nucleosidyl phosphorofluoridates 1 have been obtained by
Wittmann9 and used in biological studies. More recent
approaches to the synthesis of this class of compounds come
from several groups of workers.10 The thioanalogues of 1 –
phosphorofluoridothionates 2 – have been prepared for the first
time in this laboratory.11
Scheme 3 Reagents and conditions: i, ROH, tetrazole, THF, 3 h or
ROH, benzoyl chloride, THF, 24 h or ROH, Me3SiCl, THF, 1 h; ii, tert-
butyl hydroperoxide, THF, 1 h or sulfur in (C3H7)2NH, THF, 2 h; iii,
CH3CN, reflux, 2 h; iv, Et3N, THF, 6 h.
Our phosphorylation procedure leading to Wittmann’s type
of compounds is illustrated by the reactions of 5Ј-O-DMTr-
and 3Ј-O-DMTr-protected thymidines with 3 and 7 followed by
oxidation (sulfurization) of the intermediate phosphorofluor-
idites 13a–e and 16a–e. This leads to the corresponding phos-
phorofluoridates 14a–e, 17a–e and phosphorofluoridothionates
15a–e, 18a–e using tert-butyl hydroperoxide or by elemental
sulfur in the presence of triethylamine. In the final step the
tert-butyl group undergoes thermal elimination and the 2-
cyanoethyl group is removed by β-elimination under standard
conditions to give phosphorofluoridates 1a–e or phosphoro-
fluoridothionates 2a–e as final compounds. This sequence of
reactions is shown in Scheme 3. Conversion of 14 and 15 to 1
and 2 involve heating in acetonitrile solution under reflux,
without base being present. The DMTr potective group at the
5Ј-O or 3Ј-O center is not removed under these conditions.
In summary, the procedures we describe are completely
general and very simple. They make phosphorofluoridates
1a–e and phosphorofluoridothionates 2a–e readily available in
excellent yield.
d (doublet), t (triplet) or m (multiplet). Coupling constants (J)
are in Hz.
O-tert-Butyl N,N-diisopropylfluorophosphoramidite 3
To a solution of O-tert-butyl OЈ-(4-nitrophenyl) N,N-diisoprop-
ylphosphoramidite 5 (see below) (10 mmol) in dry THF (50 ml)
was added a solution of TBAF (11 mmol) in THF (5 ml)
at room temperature. After 10 min, tetrabutylammonium
4-nitrophenolate was removed by filtration. The filtrate was
evaporated in vacuo and the residue was purified by column
chromatography using CH2Cl2–CH3C(O)CH3 (10 : 3 v/v, Rf
0.87) as eluent to give pure O-tert-butyl N,N-diisopropyl-
fluorophosphoramidite 3 in 95% yield, δP (80.96 MHz; CDCl3)
148.85 (d, JPF 1096.0); δF (CDCl3) Ϫ69.0 (d, JPF 1096.1); δH
(200.13 MHz; CDCl3), 1.17 {12 H, t, J 6.6, N[CH(CH3)2]2},
1.32 [9 H, s, C(CH3)3], 3.54–3.74 {2 H, m, N[CH(CH3)2]2}.
O,OЈ-Bis-(4-nitrophenyl) N,N-diisopropylphosphoramidite 4
(Route a). A solution of N,N-diisopropylaminodichloro-
phosphine 6 (10 mmol) in dry THF (10 ml) was added dropwise
at room temperature under a nitrogen atmosphere to a stirred
solution of sodium 4-nitrophenolate (25 mmol) in dry THF
(50 ml) during 2 h. Once sodium chloride had been removed
by filtration, the filtrate evaporated to dryness and the residue
was purified by column chromatography (Et2O–n-pentane–
triethylamine 50 : 30 : 5 v/v, Rf 0.75) to give pure O,OЈ-bis-(4-
nitrophenyl) N,N-diisopropylphosphoramidite 4 in 95% yield.
Experimental
The solvents were reagent grade and were distilled and dried
by conventional methods before use. N,N-Diisopropylamino-
dichlorophosphine12 6, O-2-cyanoethyl N,N,N Ј,NЈ-tetra-
isopropylphosphorodiamidite13
8
and O-(2-cyanoethyl)
N,N-diisopropylchlorophosphoramidite14 9 were synthesized
according to published procedures. Tetrazole was purified by
sublimation at 115 ЊC/0.2 mmHg. Chlorotrimethylsilane was
purchased from Fluka. TBAF was purchased from Aldrich.
Thin-layer chromatography (TLC) was performed on silica gel
60F-254 plates (Merck). The products were purified by flash
chromatography on silica gel 60 (Merck; 0.063 mm, 230–400
mesh ASTM). NMR spectra were obtained on Bruker AC 200
and MSL 300 MHz spectrometers. δ-Values are reported in
(Route b). A solution of trimethyl(p-nitrophenoxy)silane
(20 mmol) in dry THF (20 ml) was added to a solution of N,N-
diisopropylaminodichlorophosphine 6 (10 mmol) in dry THF
(20 ml) at room temperature. The mixture was stirred for 1 h,
then chlorotrimethylsilane and solvent were removed under
reduced pressure to give pure phosphorodiamidite 4 in 97%
yield, δP (80.96 MHz; CDCl3) 144.8; δH (200.13 MHz; CDCl3)
1.01 {12 H, d, J 6.8 N[CH(CH3)2]2}, 3.46–3.65 {2 H, m,
N[CH(CH3)2]2}, 6.75 (4 H, d, J 9.13, Ph Hortho), 7.86 (4 H, d,
J 9.12, Ph Hmeta); mp 120–122 ЊC; pale yellow crystals.
1
ppm relative to Me4Si as standard for H NMR (200.13 and
300.13 MHz) and 13C NMR (50.288 and 75.47 MHz), relative
to H3PO4 as external standard for 31P NMR (80.96 and
121.49 MHz), and relative to CFCl3 as external standard for 19
F
NMR (188.15 MHz). The signals are expressed as s (singlet),
J. Chem. Soc., Perkin Trans. 1, 2001, 2462–2469
2463

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O-tert-Butyl OЈ-(4-nitrophenyl) N,N-diisopropylphosphoramidite
5
(Route b). To a solution of 3 (10 mmol) and the required
alcohol (10 mmol) in dry THF (30 ml) was added a solution of
benzoyl chloride (1 eq.) in 10 ml of THF. After 24 h at room
temperature the mixture was evaporated in vacuo and the
residue was purified as above by column chromatography to
obtain pure phosphorofluoridites 13a–e.
To a solution of O,OЈ-bis-(4-nitrophenyl) N,N-diisopropyl-
phosphoramidite 4 (1 mmol) in dry THF (50 ml) were added
tert-butyl alcohol (1 mmol) and NaH (1 mmol) at room tem-
perature. After 5 h sodium 4-nitrophenolate was removed by
filtration. The filtrate was evaporated in vacuo and the residue
was purified by column chromatography using CH2Cl2–
CH3C(O)CH3 (10 : 3 v/v) as eluent to give pure phosphor-
amidite 5 in 90% yield, δP (80.96 MHz; CDCl3) 141.3;
δH (300.13 MHz; CDCl3) 1.03 {6 H, d, J 6.81, N[CH(CH3)2]2},
1.13 {6 H, d, J 6.79, N[CH(CH3)2]2}, 1.24 [9H, s, C(CH3)3],
3.22–3.42 {2 H, m, N[CH(CH3)2]2}, 6.82 (2 H, d, J 9.20,
Ph Hortho), 7.90 (2 H, d, J 9.13, Ph Hmeta).
(Route c). To a solution of 3 (10 mmol) in dry THF (20 ml)
and an alcohol ROH (10 mmol) in dry THF (30 ml) was added
a solution of chlorotrimethylsilane (3 mmol) in THF (10 ml).
After 1 h the mixture was evaporated in vacuo and the residue
was purified by column chromatography, using CH2Cl2–
CH3C(O)CH3 (10 : 1 v/v) as eluent, to give pure phosphoro-
fluoridites 13a–e.
O-[5Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-3Ј-yl] O-tert-butyl
phosphorofluoridite 13a. Yield 90%, δP (121.49 MHz; CDCl3)
131.75 (d, JPF 1210.5), 133.25 (d, JPF 1204.0); δF Ϫ51.35 (d, JPF
1210.5), Ϫ52.00 (d, JPF 1204.8); δH (300.13 MHz; CDCl3) 1.33
[9 H, s, C(CH3)3], 1.41 (3 H, s, 5-CH3), 2.40 (1 H, m, H-2Ј), 2.63
(1 H, m, H-2Љ), 3.45–3.59 (2 H, m, H-5Ј, -5Љ), 3.79 (6 H, s, OCH3
of DMTr), 4.28–4.42 (1 H, m, H-4Ј), 5.24 (1 H, m, H-3Ј), 6.45
(1 H, dd, J 6.4, 6.4, H-1Ј), 6.84, 6.88 (4 H, 2d, J 8.6, 7.7, H-3,
-3Ј, -5, -5Ј of DMTr), 7.18–7.40 (9 H, ArH of DMTr); δC (75.47
MHz; CDCl3) 11.58 (5-CH3), 32.9 [C(CH3)3], 35.88 (C-2Ј),
53.39 (OCH3 of DMTr), 63.26 (C-5Ј), 69.9 [C(CH3)3], 71.37,
72.03 (JPOC 6.1, 6.1, C-3Ј), 84.70 (C-1Ј), 85.14, 85.43 (JPOCC 4.8,
4.9, C-4Ј), 87.30, 87.36 (tert-C of DMTr), 111.57, 111.66 (C-5),
113.39, (C-3, -3Ј, -5, -5Ј of DMTr), 128.06, 128.17, 130.19,
130.50, 131.42 (DMTr), 135.10, 135.19 (C-1, -1Ј of DMTr),
135.27 (C-6), 144.04 (C-1Љ of DMTr), 149.35, 149.45 (C-2),
158.87 (C-4, 4Ј of DMTr).
O-(2-Cyanoethyl) N,N-diisopropylfluorophosphoramidite 7
A solution of O-(2-cyanoethyl) OЈ-(4-nitrophenyl) N,N-diiso-
propylphosphoramidite 10 (see below) (10 mmol) in dry THF
(50 ml) was treated with a solution of TBAF (11 mmol) in THF
(5 ml) at room temperature. After 10 min, tetrabutylammonium
4-nitrophenolate was removed by filtration. The filtrate was
evaporated in vacuo and the residue was purified by column
chromatography using CH2Cl2–CH3C(O)CH3 (10 : 1 v/v, Rf
0 : 9) as eluent to give pure O-(2-cyanoethyl) N,N-diisopropyl-
fluorophosphoramidite 7 in 95% yield, δP (80.96 MHz; CDCl3)
155.85 (d, JPF 1118.1); δF (CDCl3) Ϫ78.1 (d, JPF 1118.4);
δH (200.13 MHz; CDCl3) 1.09 {12 H, d, J 6.82, N[CH(CH3)2]2},
1.56–1.74 (2 H, m, OCH2CH2CN), 3.22–3.42 {2 H, m,
N[CH(CH3)2]2}, 3.46–3.59 (2 H, m, OCH2CH2CN).
O-(2-Cyanoethyl) OЈ-(4-nitrophenyl) N,N-diisopropyl-
phosphoramidite 10
(Route a). To a stirred mixture of O-(2-cyanoethyl) N,N,-
NЈ,NЈ-tetraisopropylphosphorodiamidite 8 (10 mmol) and
tetrazole (11 mmol) in dry THF (50 ml) was added a solution of
4-nitrophenol (10 mmol) in dry THF (10 ml) at room temper-
ature. After 3 h N,N-diisopropylammonium tetrazolide was
removed by filtration. The filtrate was concentrated in vacuo
and the residue was purified by silica gel chromatography,
eluting with CH2Cl2 (Rf 0.97). The fractions containing O-(2-
cyanoethyl) OЈ-(4-nitrophenyl) N,N-diisopropylphosphor-
amidite 10 were collected and evaporated to give a yellow oil in
95% yield.
O-[3Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-5Ј-yl] O-tert-butyl
phosphorofluoridite 13b. Yield 92%, δP (121.49 MHz; CDCl3)
131.8 (d, JPF 1210.1), 133.3 (d, JPF 1205.0); δF (CDCl3) Ϫ51.4,
(d, JPF 1210.5), Ϫ52.0 (d, JPF 1204.8); δH (300.13 MHz; CDCl3)
1.33 [18 H, s, C(CH3)3], 1.90 (3 H, s, CH3), 2.34 (1 H, m, H-2Ј),
2.51 (1 H, m, H-2Љ), 3.33 (1 H, d, H-5Ј), 3.67 (1 H, d, H-5Ј), 3.75
(6 H, s, 2 × OCH3), 4.00 (1 H, s, H-4Ј), 4.30 (1 H, d, H-3Ј), 6.40
(1 H, m, H-1Ј), 6.79 (4 H, d, Ph), 7.20–7.60 (10 H, m, H-6 and
Ph); δC (75.47 MHz, CDCl3) (11.66), 11.70 (5-CH3), 32.61
[C(CH3)3], 39.79 (C-2Ј), 55.29 (CH3 of DMTr), 69.52
[C(CH3)3], 62.98, 63.41 (C-5Ј), 74.35, 75.01 (JPOC = 6.1 and 6.1,
C-3Ј), 84.70 (C-1Ј), 85.14, 85.43 (JPOCC = 4.8 and 4.9 C-4Ј),
87.21, 87.30 (tert-C of DMTr), 111.43, 111.56 (C-5), 113 37
(C-3, -3Ј, -5, -5Ј of DMTr), 128.04, 128.17, 130.15, 130.50,
131.54 (ArC of DMTr except for C-3, -3Ј, -5, -5Ј), 135.25 (C-6),
144.11 (C-1Љ of DMTr), 149.35, 149.41 (C-2), 158.80 (C-4, -4Ј).
(Route b). A solution of trimethyl(p-nitrophenoxy)silane
(10 mmol) in dry THF (10 ml) was added to a solution of O-(2-
cyanoethyl) N,N-diisopropylchlorophosphoramidite
9
(10
mmol) in dry THF (50 ml) at room temperature. The mixture
was stirred for 1 h, then chlorotrimethylsilane and solvent were
removed under reduced pressure to give pure phosphoramidite
10 in 97% yield, δP (80.96 MHz; CDCl3) 147.9; δH (300.13 MHz;
CDCl3) 1.15 {6 H, d, J 6.81, N[CH(CH3)2]2}, 1.23 {6 H, d,
J 6.80, N[CH(CH3)2]2}, 2.70 (2 H, t, J 6.20, OCH2CH2CN),
3.59–3.83 {2 H, m, N[CH(CH3)2]2}, 3.86–4.04 (2 H, m, OCH2-
CH2CN), 7.12 (2 H, d, J 9.21, Ph Hortho), 8.15 (2 H, d, J 6.16, Ph
Hmeta).
O-Citronellyl O-tert-butyl phosphorofluoridite 13c. Yield 90%;
δP (121.49 MHz; CDCl3) 132.2 (d, JPF 1211.0), 131.05 (d, JPF
1211.5); δF (CDCl3) Ϫ58.6 (d, JPF 1211.1), Ϫ58.7 (d, JPF
1211.9); δH (300.13 MHz; CDCl3) 0.81 (3 H, d, J 6.01, CH3CH),
1.09–1.42 (4 H, m), 1.29 [9 H, s, C(CH ) ], 1.53 (3 H, s, CH C᎐),
᎐
3
3
3
1.63 (3 H, s, CH C᎐), 1.82–2.29 (3 H, m, CH CH- and CH CH᎐
᎐
᎐
3
3
2
C), 3.63 (2 H, m, CH O), 5.07 (1 H, t, J 6.01, CH᎐C); δ (75.47
᎐
2
C
MHz; CDCl3) 17.67, 19.54, 25.41, 25.72, 29.11, 32.00,
[C(CH3)3], 37.22, 39.77, 61.21, 69.77 [C(CH3)3] 124.71, 131.29.
General procedure for the synthesis of tert-butyl phosphorofluor-
idites 13a–e
(Route a). To a mixture of O-tert-butyl N,N-diisopropyl-
fluorophosphoramidite 3 (10 mmol) and tetrazole (11 mmol) in
dry THF (50 ml) was added a solution of the required alcohol
(10 mmol) in dry THF (20 ml). The reaction mixture was stirred
for 3 h and monitored by TLC. N,N-Diisopropylammonium
tetrazolide was removed by filtration. The filtrate was concen-
trated in vacuo and the residue was chromatographed on silica
gel, using a gradient of 0–10% CH3C(O)CH3 in CH2Cl2 as
eluent, to give pure phosphorofluoridites 13a–e.
O-(؊)-Menthyl O-tert-butyl phosphorofluoridite 13d. Yield
90%, δP (121.49 MHz; CDCl3) 135.75 (d, JPF 1207.0), 133.85 (d,
JPF 1201.9); δF (CDCl3) Ϫ47.01 (d, JPF 1207.2), Ϫ47.15 (d, JPF
1201.5); δH (300.13 MHz; CDCl3) 0.69 (3 H, d, J 6.93), 0.81
(3 H, d, J 6.52), 0.82 (3 H, d, J 7.03), 1.09 [9 H, s, C(CH3)3],
1.11–2.21 (9 H, m, H of cyclohexanol), 3.26 (1 H, t, J 10.44
OCHCH2); δC (75.47 MHz, CDCl3) 15.74, 20.86, 22.04, 22.85,
25.33, 31.50, 32.71 [C(CH3)3], 34.41, 44.83, 49.76, 70.94, 71.26
[C(CH3)3].
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O-Cholesteryl O-tert-butyl phosphorofluoridite 13e. Yield
95%, δP (121.49 MHz; CDCl3) 130.9 (d, JPF 1212.3), 131.1 (d,
JPF 1220.5); δF Ϫ55.95 (d, JPF 1212.5), Ϫ55.90 (d, JPF 1220.8);
δH (300.13 MHz; CDCl3) 0.61 (3 H, s, CH3-18), 0.69 (3 H, d,
J 6.4, CH3-26), 0.77 (3 H, d, J 6.4, CH3-27), 0.85 (3 H, d, J 6.4,
CH3-21), 0.92 (3 H, s, CH3-19), 1.30 [9 H, s, C(CH3)3], 3.77 (1 H,
d, J 8.0, H-7), 3.91 (1 H, br, H-3), 5.20 (1 H, s, H-6); δC (75.47
MHz; CDCl3) 11.72 (C-18), 18.56 (C-19), 22.44 (C-26), 22.66
(C-27), 32.99 [C(CH3)3] 55.43 (C-14), 55.78 (C-17), 69.71
[C(CH3)3], 72.99 (C-7), 77.43 (C-3), 125.88 (C-6), 142.98 (C-5).
0.85 (3 H, d, J 7.14), 1.09 [9 H, s, C(CH3)3], 1.13–2.26 (9 H, m,
H of cyclohexanol), 3.29 (1 H, t, J 10.39 OCHCH2); δC (75.47
MHz, CDCl3) 15.66, 21.11, 22.15, 22.99, 25.34, 31.48, 32.69
[C(CH3)3], 34.40, 44.91, 49.78, 71.00, 71.37 [C(CH3)3]
O-Cholesteryl O-tert-butyl phosphorofluoridate 14e. Yield
96%, δP (121.49 MHz; CDCl3) Ϫ8.65 (d, JPF 971.8); δF Ϫ72.30
(d, JPF 971.2), Ϫ72.35 (d, JPF 971.0); δH (300.13 MHz; CDCl3)
0.56 (3 H, s, CH3-18), 0.66 (3 H, d, J 6.4, CH3-26), 0.75 (3 H, d,
J 6.4, CH3-27), 0.81 (3 H, d, J 6.4, CH3-21), 0.97 (3 H, s, CH3-
19), 1.34 [9 H, s, C(CH3)3], 3.57 (1 H, d, J 8.0, H-7), 3.89 (1 H,
br, H-3), 5.28 (1 H, s, H-6); δC (75.47 MHz, CDCl3) 11.67
(C-18), 18.46 (C-19), 22.94 (C-26), 23.26 (C-27), 33.09
[C(CH3)3], 55.43 (C-14), 55.38 (C-17), 69.91 [C(CH3)3], 73.01
(C-7), 77.48 (C-3), 125.58 (C-6), 143.18 (C-5).
General procedure for the synthesis of O-tert-butyl phosphoro-
fluoridates 14a–e.
A compound 13a–e (10 mmol) was
dissolved in dry THF (15 ml) and a solution of tert-butyl
hydroperoxide (11 mmol) was added. The mixture was stirred 1
h at rt, concentrated in vacuo, and purified by column chrom-
atography, using CH2Cl2–CH3C(O)CH3 (10 : 1 v/v) as eluent
to give the corresponding O-tert-butyl phosphorofluoridates
14a–e.
General procedure for the synthesis of O-tert-butyl
thiophosphorofluoridates 15a–e
To a solution of phosphorofluoridate 13a–e (10 mmol) in dry
THF (15 ml) was added a saturated solution of sulfur in
(C3H7)2NH (5 ml), with stirring, during 2 h at rt. The crude
product O-tert-butyl thiophosphorofluoridate 15a–e was
chromatographed on silica gel, using a gradient of 0–10%
CH3C(O)CH3 in CH2Cl2 as eluent.
O-[5Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-3Ј-yl] O-tert-butyl
phosphorofluoridate 14a. Yield 98%, δP (121.49 MHz; CDCl3)
Ϫ10.95 (d, JPF 985.2), Ϫ11.3 (d, JPF 985.4); δF (CDCl3) Ϫ77.2,
(d, JPF 985.0), Ϫ77.3 (d, JPF 985.4); δH (300.13 MHz; CDCl3)
1.53 [9 H, s, C(CH3)3], 1.91 (3 H, s, 5-CH3), 2.14 (1 H, m, H-2Ј),
2.36 (1 H, m, H-2Љ), 3.35–3.69 (2 H, m, H-5Ј, -5Љ), 3.87 (6 H, s,
OCH3 of DMTr), 4.18–4.34 (1 H, m, H-4Ј), 5.22 (1 H, m, H-3Ј),
6.55 (1 H, dd, J 6.4, 6.4, H-1Ј), 6.88, 6.99 (4 H, 2d, J 8.6, 7.7,
H-3, -3Ј, -5, -5Ј of DMTr), 7.11–7.41 (9 H, ArH of DMTr);
δC (75.47 MHz; CDCl3) 11.78 (5-CH3), 32.89 [(C(CH3)3]), 35.81
(C-2Ј), 53.43 (OCH3 of DMTr), 63.66 (C-5Ј), 69.19 [C(CH3)3]
71.73, 72.03 (JPOC 6.1, 6.1, C-3Ј), 84.37 (C-1Ј), 85.18, 85.43
(JPOCC 4.8, 4.9, C-4Ј), 87.13, 87.63 (tert-C of DMTr), 111.51,
111.69 (C-5), 113.39 (C-3, -3Ј, -5, -5Ј of DMTr), 128.16, 128.23,
130.21, 130.52, 131.24 (DMTr), 135.14, 135.26 (C-1, -1Ј of
DMTr), 135.71 (C-6), 144.24 (C-1Љ of DMTr), 149.22, 149.56
(C-2), 158.38 (C-4, -4Ј of DMTr).
O-[5Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-3Ј-yl] O-tert-butyl
thiophosphorofluoridate 15a. Yield 97%, δP (121.49 MHz;
CDCl3) 53.45, 53.10 (2d, JPF 1082.2, JPF 1081.9); δF (CDCl3)
Ϫ34.6, Ϫ35.2 (2d, JPF 1082.7, JPF 1085.9); δH (300.13 MHz;
CDCl3) 1.40 [9 H, s, C(CH3)3], 1.51 (3 H, s, 5-CH3), 2.34 (1 H,
m, H-2Ј), 2.63 (1 H, m, H-2Љ), 3.40–3.51 (2 H, m, H-5Ј, -5Љ), 3.71
(6 H, s, OCH3 of DMTr), 4.22–4.44 (1 H, m, H-4Ј), 5.52 (1 H,
m, H-3Ј), 6.14 (1 H, dd, J 6.4, 6.4, H-1Ј), 6.76, 6.98 (4 H, 2d,
J 8.6, 7.7, H-3, -3Ј, -5, -5Ј of DMTr), 7.13–7.39 (9 H, ArH of
DMTr); δC (75.47 MHz; CDCl3) 11.51 (5-CH3), 32.99
[C(CH3)3], 35.58 (C-2Ј), 53.41 (OCH3 of DMTr), 63.31 (C-5Ј),
69.18 [C(CH3)3], 71.31, 72.23 (JPOC 6.1, 6.1, C-3Ј), 84.67 (C-1Ј),
85.21, 85.43 (JPOCC 4.8, 4.9, C-4Ј), 87.13, 87.26 (tert-C of
DMTr), 111.60, 111.76 (C-5), 113.41, (C-3, -3Ј, -5, -5Ј of
DMTr), 128.11, 128.23, 130.20, 130.49, 131.42 (DMTr), 135.09,
135.12 (C-1, -1Ј of DMTr), 135.32 (C-6), 144.12 (C-1Љ of
DMTr), 149.45, 149.55 (C-2), 159.87 (C-4, -4Ј of DMTr).
O-[3Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-5Ј-yl] O-tert-butyl
phosphorofluoridate 14b. Yield 98%, δP (121.49 MHz; CDCl3)
Ϫ9.85 (d, JPF 985.2), Ϫ10.9 (d, JPF 985.4); δF (CDCl3) Ϫ77.9 (d,
JPF 985.0), Ϫ77.0 (d, JPF 985.4); δH (300.13 MHz; CDCl3) 1.50
[9 H, s, C(CH3)3], 1.81 (3 H, s, 5-CH3), 2.00 (1 H, m, H-2Ј), 2.33
(1 H, m, H-2Љ), 3.30–3.71 (2 H, m, H-5Ј, -5Љ), 3.80 (6 H, s, OCH3
of DMTr), 4.11–4.44 (1 H, m, H-4Ј), 5.17 (1 H, m, H-3Ј), 6.33
(1 H, dd, J 6.4, 6.4, H-1Ј), 6.66, 7.11 (4 H, 2d, J 8.6, 7.7, H-3,
-3Ј, -5, -5Ј of DMTr), 7.22–7.49 (9 H, ArH of DMTr); δC (75.47
MHz; CDCl3) 10.99 (5-CH3), 32.98 [C(CH3)3], 34.99 (C-2Ј),
53.49 (OCH3 of DMTr), 64.00 (C-5Ј), 70.09 [C(CH3)3], 72.13,
72.45 (JPOC 6.1, 6.1, C-3Ј), 84.40 (C-1Ј), 85.23, 85.82 (JPOCC 4.8,
4.9, C-4Ј), 87.00, 87.23 (tert-C of DMTr), 111.44, 111.72 (C-5),
113.41 (C-3, -3Ј, -5, -5Ј of DMTr), 128.10, 128.42, 130.01,
130.33, 132.00 (DMTr), 135.14, 135.62 (C-1, -1Ј of DMTr),
135.88 (C-6), 144.44 (C-1Љ of DMTr), 149.82, 150.11 (C-2),
158.27 (C-4, -4Ј of DMTr).
O-[3Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-5Ј-yl] O-tert-butyl
thiophosphorofluoridate 15b. Yield 97%, δP (121.49 MHz;
CDCl3) 52.25, 51.08 (2d, JPF 1082.2, JPF 1081.9); δF (CDCl3)
Ϫ34.2, Ϫ35.0 (2d, JPF 1082.7, JPF 1085.9); δH (300.13 MHz;
CDCl3) 1.37 [9 H, s, C(CH3)3), 1.57 (3 H, s, 5-CH3), 2.33 (1 H,
m, H-2Ј), 2.69 (1 H, m, H-2Љ), 3.33–3.50 (2 H, m, H-5Ј, -5Љ), 3.69
(6 H, s, OCH3 of DMTr), 4.00–4.59 (1 H, m, H-4Ј), 5.55 (1 H,
m, H-3Ј), 6.11 (1 H, dd, J 6.4, 6.4, H-1Ј), 6.66, 7.00 (4 H, 2d,
J 8.6, 7.7, H-3, -3Ј, -5, -5Ј of DMTr), 7.10–7.41 (9 H, ArH of
DMTr); δC (75.47 MHz; CDCl3) 11.49 (5-CH3), 33.04
[C(CH3)3], 35.60 (C-2Ј), 53.53 (OCH3 of DMTr), 63.29 (C-5Ј),
69.76 [C(CH3)3], 71.42, 72.32 (JPOC 6.1, 6.1, C-3Ј), 84.78 (C-1Ј),
85.19, 85.43 (JPOCC 4.8, 4.9, C-4Ј), 87.00, 87.34 (tert-C of
DMTr), 111.78, 111.99 (C-5), 113.57, (C-3, -3Ј, -5, -5Ј of
DMTr), 128.19, 128.30, 130.98, 131.09, 131.78 (DMTr), 135.28,
135.86 (C-1, -1Ј of DMTr), 136.13 (C-6), 144.39 (C-1Љ of
DMTr), 149.71, 149.99 (C-2), 160.01 (C-4, -4Ј of DMTr).
O-Citronellyl O-tert-butyl phosphorofluoridate 14c. Yield
98%, δP (121.49 MHz; CDCl3) Ϫ8.00 (d, JPF 979.01); δF (CDCl3)
Ϫ76.40 (d, JPF 979.00), Ϫ76.95 (d, JPF 973.5); δH (300.13 MHz;
CDCl3) 0.91 (3 H, d, J 6.01, CH3CH), 1.07–1.44 (4 H, m), 1.38
[9 H, s, C(CH ) ], 1.57 (3 H, s, CH C᎐), 1.66 (3 H, s, CH C᎐),
᎐
᎐
3
3
3
3
1.85–2.29 (3 H, m, CH CH and CH CH᎐C), 3.65 (2 H, m,
O-Citronellyl O-tert-butyl thiophosphorofluoridate 15c. Yield
97%, δP (121.49 MHz; CDCl3) 53.85 (d, JPF 1047.19); δF Ϫ29.75
(d, JPF 1047.20), Ϫ30.30 (d, JPF 1050.90); δH (300.13 MHz;
CDCl3) 0.92 (3 H, d, J 6.01, CH3CH), 1.05–1.47 (4 H, m), 1.41
᎐
3
2
CH O), 5.27 (1 H, t, J 6.01, CH᎐C); δ (75.47 MHz; CDCl3)
᎐
2
C
18.12, 19.68, 25.48, 25.77, 30.01, 32.56 [C(CH3)3], 37.45, 39.98,
61.67, 69.89 [C(CH3)3], 124.89, 131.45.
[9 H, s, C(CH ) ], 1.50 (3 H, s, CH C᎐), 1.62 (3 H, s, CH C᎐),
᎐
᎐
3
3
3
3
O-(؊)-Menthyl O-tert-butyl phosphorofluoridate 14d. Yield
95%, δP (121.49 MHz; CDCl3) Ϫ10.25 (d, JPF 982.91); δF
(CDCl3) Ϫ80.30 (d, JPF 982.70), Ϫ79.90 (d, JPF 985.90); δH
(300.13 MHz; CDCl3) 0.67 (3 H, d, J 6.90), 0.80 (3 H, d, J 6.49),
1.83–2.31 (3 H, m, CH CH- and CH CH᎐C), 3.72 (2 H, CH O),
᎐
3 2 2
5.32 (1 H, t, J 6.01, CH᎐C); δ (75.47 MHz; CDCl3) 18.09,
᎐
C
19.83, 25.54, 25.81, 30.43, 32.62 [C(CH3)3], 37.67, 40.04, 61.78,
71.00 [C(CH3)3], 124.94, 131.61.
J. Chem. Soc., Perkin Trans. 1, 2001, 2462–2469
2465

View Article Online
O-(؊)-Menthyl O-tert-butyl thiophosphorofluoridate 15d.
Yield 98%, δP (121.49 MHz; CDCl3) 55.55 (d, JPF 1045.19),
54.45 (d, JPF 1045.70); δF Ϫ28.65 (d, JPF 1045.20), Ϫ32.75 (d,
JPF 1045.70); δH (300.13 MHz; CDCl3) 0.82 (3 H, d, J 6.90), 0.87
(3 H, d, J 6.55), 0.91 (3 H, d, J 7.13), 1.13–2.27 (9 H, m, H of
cyclohexanol), 3.09 (1 H, t, J 11.11, OCHCH2); δC (75.47 MHz;
CDCl3) 15.09, 21.11, 22.32, 23.01, 25.78, 31.52, 34.45, 44.95,
49.81, 70.96.
O-[3Ј-O-(4,4Ј-Dimethoxytrityl]thymidin-5Ј-yl] O-(2-cyano-
ethyl) phosphorofluoridite 16b. Yield 98%, δP (121.49 MHz;
CDCl3) 131.6 (d, JPF 1219.1), 130.85 (d, JPF 1220.0); δF (CDCl3)
Ϫ56.0 (d, JPF 1218.3), Ϫ56.85 (d, JPF 1220.3); δH (300.13 MHz;
CDCl3) 1.90 (3 H, s, 5-CH3), 2.45 (1 H, ddd, J 13.8, 8.9 and 6.0,
H-2Љ), 2.56 (1 H, m, H-2Ј), 2.66 (2 H, t, J 6.6, OCH2CH2CN),
3.25–3.34 (2 H, m, H-5Ј, -5Љ), 3.57 (6 H, s, 2 × OCH3 of DMTr),
4.10 (2 H, q, J 6.5, POCH2CH2CN), 4.26, 4.31 (1 H, m, H-4Ј),
5.19 (1 H, m, H-3Ј), 6.45, 6.50 (1 H, dd, J 8.4 and 7.1, H-1Ј),
6.80 (4 H, 2d, J 8.8 and 7.1, H-3, -3Ј, -5, -5Ј of DMTr), 7.21–
7.49 (2 H, ArH of DMTr except for H-3, -3Ј, -5, -5Ј); δC (50.288
MHz; CDCl3) 11.60, 11.79 (5-CH3), 20.21 (OCH2CH2CN),
39.69 (C-2Ј), 55.38 (OCH3 of DMTr), 60.18 (OCH2CH2CN),
63.00, 63.49 (C-5Ј), 74.43, 75.13 (JPOC 6.7 and 6.9, C-3Ј), 84.74
(C-1Ј), 85.21, 85.44 (JPOC 4.9 and 5.0, C-4Ј), 87.28, 87.37 (tert-C
of DMTr), 111.59, 111.65 (C-5), 113.41 (C-3, -3Ј, -5, -5Ј of
DMTr), 127.53 (OCH2CH2CN), 128.10, 128.22, 130.18, 130.55,
131.51 (ArC of DMTr except for C-3, -3Ј, -5, -5Ј), 135.08,
135.11 (C-1, -1Ј of DMTr), 135.45 (C-6), 144.15 (C-1Љ of
DMTr), 149.46, 149.50 (C-2), 158.87 (C-4, -4Ј of DMTr).
O-Cholesteryl O-tert-butyl thiophosphorofluoridate 15e. Yield
98%, δP (121.49 MHz; CDCl3) 55.0 (d, JPF 1047.9), 53.25 (d, JPF
1052.8); δF Ϫ29,75 (d, JPF 1052.2), Ϫ30.3 (d, JPF 1050.80);
δH (300.13 MHz; CDCl3) 0.51 (3 H, s, CH3-18), 0.66 (3 H, d,
J 6.4, CH3-26), 0.70 (3 H, d, J 6.4, CH3-27), 0.81 (3 H, d, J 6.4,
CH3-21), 0.89 (3 H, s, CH3-19), 1.31 [9 H, s, C(CH3)3], 3.76 (1 H,
d, J 8.0, H-7), 4.01 (1 H, br, H-3), 5.21 (1 H, s, H-6); δC (75.47
MHz; CDCl3) 11.68 (C-18), 18.60 (C-19), 22.32 (C-26), 22.51
(C-27), 33.01 [C(CH3)3], 55.21 (C-14), 55.81 (C-17), 70.01
[C(CH3)3], 73.12 (C-7), 77.39 (C-3), 126.01 (C-6), 142.98
(C-5).
O-Citronellyl O-(2-cyanoethyl) phosphorofluoridite 16c. Yield
95%, δP (121.49 MHz; CDCl3) 131.05 (JPF 1207.3), 132.25
(JPF 1208.5); δF Ϫ56.35 (JPF 1207.3), Ϫ56.75 (JPF 1208.3);
δH (300.13 MHz; CDCl3) 0.80 (3 H, d, J 6.01, CH3CH), 1.11–
General procedure for the synthesis of O-(2-cyanoethyl)
phosphorofluoridites 16a–e
(Route a). To a mixture of O-(2-cyanoethyl) N,N-diisopropyl-
fluorophosphoramidite 7 (10 mmol) and tetrazole (11 mmol) in
dry THF (50 ml) was added a solution of the required alcohol
ROH (10 mmol) in dry THF (20 ml). The reaction mixture was
stirred for 3 h and monitored by TLC. N,N-Diisopropyl-
ammonium tetrazolide was removed by filtration. The filtrate
was concentrated in vacuo and was chromatographed on silica
gel, using a gradient of 0–10% CH3C(O)CH3 in CH2Cl2 as
eluent to give the corresponding pure O-(2-cyanoethyl) phos-
phorofluoridite 16a–e.
1.44 (4 H, m), 1.51 (3 H, s, CH C᎐), 1.60 (3 H, s, CH C᎐),
᎐
᎐
3
3
1.80–2.30 (3 H, m, CH CH and CH CH᎐C), 2.69 (2 H, 2t,
᎐
3
2
J 6.0, OCH2CH2CN), 3.65 (2 H, m, CH2O), 4.20–4.41 (2 H, m,
OCH CH CN) 5.12 (1 H, t, J 6.01, CH᎐C); δ (75.47 MHz;
᎐
2
2
C
CDCl3) 17.62, 19.50, 19.99 (OCH2CH2CN), 25.41, 25.79,
29.83, 37.45, 39.64, 61.30, 63.24 (OCH2CH2CN), 115.48
(OCH2CH2CN), 124.69, 131.31.
O-(؊)Menthyl O-(2-cyanoethyl) phosphorofluoridite 16d.
Yield 93%, δP (121.49 MHz; CDCl3) 132.15 (JPF 1206.3); δF
Ϫ53.15 (JPF 1206.9), Ϫ57.3 (JPF 1209.2); δH (300.13 MHz;
CDCl3) 0.68 (3 H, d, J 6.91), 0.83 (3 H, d, J 6.50), 0.91 (3 H, d,
J 7.03), 1.09–2.30 (9 H, m, of cyclohexanol), 2.32 (2 H, 2t, J 6.0,
OCH2CH2CN), 3.38 (1 H, t, J 10.44, OCHCH2), 4.20–4.47 (2
H, m, OCH2CH2CN); δC (75.47 MHz; CDCl3) 15.09, 20.45
(OCH2CH2CN), 20.74, 22.33, 23.01, 25.53, 31.51, 34.52, 44.98,
49.82, 63.93 (OCH2CH2CN), 70.91, 115.71 (OCH2CH2CN).
(Route b). To a solution of 7 (10 mmol) and an alcohol ROH
(10 mmol) in dry THF (30 ml) was added a solution of benzoyl
chloride (1 eq.) in 10 ml of THF. After 24 h at room temper-
ature the mixture was evaporated in vacuo and the residue was
purified by column chromatography (see route a) to obtain the
pure O-(2-cyanoethyl) phosphorofluoridite 16a–e.
(Route c). To a solution of 7 (10 mmol) in dry THF (20 ml)
and an alcohol (10 mmol) in dry THF (30 ml) was added a
solution of chlorotrimethylsilane (3 mmol) in THF (10 ml).
After 1 h the mixture was evaporated in vacuo and the residue
was purified by column chromatography, using CH2Cl2–
CH3C(O)CH3 (10 : 1 v/v) as eluent, to give the corresponding
pure O-(2-cyanoethyl) phosphorofluoridite 16a–e.
O-Cholesteryl O-(2-cyanoethyl) phosphorofluoridite 16e. Yield
96%, δP (121.49 MHz; CDCl3) 131.1 (JPF 1220.3), 131.4 (JPF
1212.5); δF Ϫ55.9 (JPF 1220.8), Ϫ56.0 (JPF 1212.5); δH (300.13
MHz; CDCl3) 0.63 (3 H, s, CH3-18), 0.73 (3 H, d, J 6.4, CH3-
26), 0.78 (3 H, d, J 6.4, CH3-27), 0.85 (3 H, d, J 6.4, CH3-21),
0.95 (3 H, s, CH3-19), 2.80 (2 H, 2t, J 6.0, OCH2CH2CN), 3.74
(1 H, d, J 8.0, H-7), 3.95 (1 H, br, H-3), 4.23–4.45 (2 H, m,
OCH2CH2CN), 5.19 (1 H, s, H-6); δC (75.47 MHz; CDCl3)
11.67 (C-18), 18.63 (C-19), 19.89 (OCH2CH2CN), 22.44 (C-26),
22.56 (C-27), 55.36 (C-14), 55.82 (C-17), 62.14, (OCH2-
CH2CN), 72.99 (C-7), 77.31 (C-3), 116.50 (OCH2CH2CN),
125.80 (C-6), 142.81 (C-5).
O-[5Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-3Ј-yl] O-(2-cyano-
ethyl) phosphorofluoridite 16a. Yield 99%, δP (121.49 MHz;
CDCl3) 129.65 (d, JPF 1218.5); δF (CDCl3) Ϫ55.9 (d, JPF
1218.3), Ϫ56.05 (d, JPF 1220.3); δH (300.13 MHz; CDCl3) 1.45
(3 H, s, 5-CH3), 2.50 (1 H, m, H-2Ј), 2.61 (1 H, m, H-2Љ), 2.63
(2 H, t, J 6.7, OCH2CH2CN), 3.30–3.49 (2 H, m, H-5Ј, -5Љ), 3.75
(6 H, s, 2 × OCH3 of DMTr), 4.12 (2 H, q, J 6.7, POCH2
CH2CN), 4.26, 4.30 (1 H, m, H-4Ј), 5.14 (1 H, m, H-3Ј), 6.45,
6.48 (1 H, dd, J 8.5 and 7.1, H-1Ј), 6.85 (4 H, 2d, J 8.6 and 7.7,
H-3, -3Ј, -5, -5Ј of DMTr), 7.11–7.44 (2 H, ArH of DMTr
except for H-3, -3Ј, -5, -5Ј); δC (50.288 MHz; CDCl3) 11.63,
11.72 (5-CH3), 20.19 (OCH2CH2CN), 39.77 (C-2Ј), 55.30
(OCH3 of DMTr), 60.11 (OCH2CH2CN), 62.99, 63.46 (C-5Ј),
74.37, 75.03 (JPOC 6.1 and 6.1, C-3Ј), 84.70 (C-1Ј), 85.17, 85.40
(JPOC 4.8 and 4.9, C-4Ј), 87.21, 87.30 (tert-C of DMTr), 111.50,
111.56 (C-5), 113.40, (C-3, -3Ј, -5, -5Ј of DMTr), 127.50
(OCH2CH2CN), 128.00, 128.21, 130.11, 130.54, 131.50 (ArC
of DMTr except for C-3, -3Ј, -5, -5Ј), 135.02, 135.10 (C-1, -1Ј of
DMTr), 135.35 (C-6), 144.10 (C-1Љ of DMTr), 149.43, 149.49
(C-2), 158.80 (C-4, -4Ј of DMTr).
General procedure for the synthesis of O-(2-cyanoethyl) phos-
phorofluoridates 17a–e
To a solution of a compound 16a–e (10 mmol) in dry THF
(15 ml) was added tert-butyl hydroperoxide (11 mmol). The
mixture was stirred 1 h at rt, and then was concentrated in
vacuo. The residue was purified by column chromatography,
using CH2Cl2–CH3C(O)CH3 (10 : 1 v/v) to give the correspond-
ing O-(2-cyanoethyl) phosphorofluoridate 17a–e.
O-[5Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-3Ј-yl] O-(2-cyano-
ethyl) phosphorofluoridate 17a–e. Yield 98%, δP (129.49 MHz;
CDCl3) Ϫ9.85 (d, JPF 979.2); δF (CDCl3) Ϫ78.7 (d, JPF 979.6),
Ϫ78.8 (d, JPF 979.3); δH (300.13 MHz; CDCl3) 1.91 (3 H, s,
5-CH3), 2.58 (1 H, m, H-2Ј), 2.69 (1 H, m, H-2Љ), 2.71 (2 H, t,
2466
J. Chem. Soc., Perkin Trans. 1, 2001, 2462–2469

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J 6.7, OCH2CH2CN), 3.33–3.54 (2 H, m, H-5Ј, -5Љ), 3.77 (6 H, s,
2 × OCH3 of DMTr), 4.11 (2 H, q, J 6.7, POCH2CH2CN),
4.256, 4.33 (1 H, m, H-4Ј), 5.14 (1 H, m, H-3Ј), 6.41, 6.49 (1 H,
dd, J 8.5 and 7.1, H-1Ј), 6.88 (4 H, 2d, J 8.6 and 7.7, H-3, -3Ј, -5,
-5Ј of DMTr), 7.19–7.44 (2 H, ArH of DMTr except for H-3,
-3Ј, -5, -5Ј); δC (50.288 MHz; CDCl3) 11.60, 11.78 (5-CH3),
20.19 (OCH2CH2CN) 39.67 (C-2Ј), 55.43 (OCH3 of DMTr),
60.91 (OCH2CH2CN), 62.88, 63.49 (C-5Ј), 74.32, 75.40 (JPOC
6.1 and 6.1, C-3Ј), 84.75 (C-1Ј), 85.27, 85.48 (JPOC 4.8 and 4.9,
C-4Ј), 87.21, 87.33 (tert-C of DMTr), 111.45, 111.52 (C-5),
113.41 (C-3, -3Ј, -5, -5Ј of DMTr), 127.45 (OCH2CH2CN),
128.09, 128.27, 130.17, 130.53, 131.57 (ArC of DMTr except
for C-3, -3Ј, -5, -5Ј), 135.12, 135.18 (C-1, -1Ј of DMTr), 135.31
(C-6), 144.17 (C-1Љ of DMTr), 149.41, 149.54 (C-2), 158.78
(C-4, -4Ј of DMTr).
General procedure for the synthesis of O-(2-cyanoethyl) thio-
phosphorofluoridates 18a–e
A solution of a phosphorofluoridate 16a–e in dry THF (10 ml)
was treated a saturated solution of sulfur in (C3H7)2NH (5 ml)
and the mixture was stirred for 2 h at rt. Crude product 18a–e
was chromatographed on silica gel, using a gradient of 0–10%
CH3C(O)CH3 in CH2Cl2 as eluent.
O-[5Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-3Ј-yl] O-(2-cyano-
ethyl) thiophosphorofluoridate 18a. Yield 97%, δP (121.49 MHz;
CDCl3) 52.1 (d, JPF 1089.0), 52.75 (d, JPF 1081.0); δF (CDCl3)
Ϫ39.15 (d, JPF 1089.0), Ϫ39.9 (d, JPF 1080.2); δH (300.13 MHz;
CDCl3) 1.51 (3 H, s, CH3-5, 2.45 (1 H, m, H-2Ј), 2.59 (1 H, m,
H-2Љ), 2.61 (2 H, t, J 6.7, OCH2CH2CN), 3.29–3.51 (2 H, m,
H-5Ј, -5Љ), 3.71 (6 H, s, 2 × OCH3 of DMTr), 4.11 (2 H, q, J 6.7,
POCH2CH2CN), 4.26, 4.33 (1 H, m, H-4Ј), 5.09 (1 H, m, H-3Ј),
6.44, 6.49 (1 H, dd, J 8.5 and 7.1, H-1Ј), 6.79 (4 H, 2d, J 8.6 and
7.7, H-3, -3Ј, -5, -5Ј of DMTr), 7.09–7.38 (2 H, ArH of DMTr
except for H-3, -3Ј, -5, -5Ј); δC (50.288 MHz; CDCl3) 11.53,
11.65 (5-CH3), 21.21 (OCH2CH2CN), 39.69 (C-2Ј), 55.09
(OCH3 of DMTr), 59.09 (OCH2CH2CN), 63.07, 63.46 (C-5Ј),
74.29, 75.21 (JPOC 6.1 and 6.1, C-3Ј), 84.68 (C-1Ј), 85.15, 85.75
(JPOC 4.8 and 4.9, C-4Ј), 87.21, 87.51 (tert-C of DMTr), 111.21,
111.43 (C-5), 113.09 (C-3, -3Ј, -5, -5Ј of DMTr), 127.55
(OCH2CH2CN), 128.12, 128.34, 130.09, 130.76, 131.85 (ArC
of DMTr except for C-3, -3Ј, -5, -5Ј), 135.78, 135.86 (C-1, -1Ј of
DMTr), 135.98 (C-6), 144.34 (C-1Љ of DMTr), 149.43, 149.56
(C-2), 158.83 (C-4, -4Ј of DMTr).
O-[3Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-5Ј-yl] O-(2-cyano-
ethyl) phosphorofluoridate 17b. Yield 92%, δP (129.49 MHz;
CDCl3) Ϫ9.09 (d, JPF 979.2); δF (CDCl3) Ϫ77.7 (d, JPF 979.6),
Ϫ79.2 (d, JPF 979.3); δH (300.13 MHz; CDCl3) 1.88 (3 H, s,
5-CH3), 2.47 (1 H, m, H-2Ј), 2.72 (1 H, m, H-2Љ), 2.86 (2 H, t,
J 6.7, OCH2CH2CN), 3.52–3.71 (2 H, m, H-5Ј, -5Љ), 3.99 (6 H,
s, 2 × OCH3 of DMTr), 4.25 (2 H, q, J 6.7, POCH2CH2CN),
4.46, 4.54 (1 H, m, H-4Ј), 5.33 (1 H, m, H-3Ј), 6.43, 6.52 (1 H,
dd, J 8.5 and 7.1, H-1Ј), 6.92 (4 H, 2d, J 8.6 and 7.7, H-3, -3Ј, -5,
-5Ј of DMTr), 7.15–7.50 (2 H, ArH of DMTr except for H-3,
-3Ј, -5, -5Ј); δC (50.288 MHz; CDCl3) 11.66, 11.82 (5-CH3),
20.21 (OCH2CH2CN), 39.69 (C-2Ј), 55.44 (OCH3 of DMTr),
61.00 (OCH2CH2CN), 62.96, 63.57 (C-5Ј), 74.64, 75.84 (JPOC
6.1 and 6.1, C-3Ј), 84.81 (C-1Ј), 85.35, 85.56 (JPOC 4.8 and 4.9,
C-4Ј), 87.09, 87.40 (tert-C of DMTr), 111.33, 111.74 (C-5),
113.56 (C-3, -3Ј, -5, -5Ј of DMTr), 127.49 (OCH2CH2CN),
128.13, 128.27, 130.34, 130.87, 131.37 (ArC of DMTr except
for C-3, -3Ј, -5, -5Ј), 135.20, 135.34 (C-1, -1Ј of DMTr), 135.40
(C-6), 144.24 (C-1Љ of DMTr), 149.89, 149.54 (C-2), 158.81
(C-4, -4Ј of DMTr).
O-[3Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-5Ј-yl] O-(2-cyano-
ethyl) thiophosphorofluoridate 18b. Yield 92%, δP (121.49 MHz;
CDCl3) 51.09 (d, JPF 1089.0), 52.90 (d, JPF 1081.0); δF (CDCl3)
Ϫ39.21 (d, JPF 1089.0), Ϫ39.67 (d, JPF 1080.2); δH (300.13 MHz;
CDCl3) 1.72 (3 H, s, CH3-5), 2.38 (1 H, m, H-2Ј), 2.63 (1 H, m,
H-2Љ), 2.81 (2 H, t, J 6.7, OCH2CH2CN), 3.20–3.47 (2 H, m,
H-5Ј, -5Љ), 3.89 (6 H, s, 2 × OCH3 of DMTr), 4.23 (2 H, q, J 6.7,
POCH2CH2CN), 4.44, 4.56 (1 H, m, H-4Ј), 5.11 (1 H, m, H-3Ј),
6.14, 6.49 (1 H, dd, J 8.5 and 7.1, H-1Ј), 6.81 (4 H, 2d, J 8.6 and
7.7, H-3, -3Ј, -5, -5Ј of DMTr), 7.00–7.28 (2 H, ArH of DMTr
except for H-3, -3Ј, -5, -5Ј); δC (50.288 MHz; CDCl3) 11.19,
11.72 (5-CH3), 21.21 (OCH2CH2CN), 39.79 (C-2Ј), 55.22
(OCH3 of DMTr), 59.35 (OCH2CH2CN), 63.14, 63.87 (C-5Ј),
74.37, 75.89 (JPOC 6.1 and 6.1, C-3Ј), 84.22 (C-1Ј), 85.37, 85.67
(JPOC 4.8 and 4.9, C-4Ј), 87.09, 87.57 (tert-C of DMTr), 111.34,
111.59 (C-5), 113.24 (C-3, -3Ј, -5, -5Ј of DMTr), 127.09
(OCH2CH2CN), 128.09, 128.19, 130.23, 130.82, 131.90 (ArC
of DMTr except for C-3, -3Ј, -5, -5Ј), 135.00, 135.16 (C-1, -1Ј of
DMTr), 135.67 (C-6), 144.99 (C-1Љ of DMTr), 149.53, 149.98
(C-2), 158.02 (C-4, -4Ј of DMTr).
O-Citronellyl O-(2-cyanoethyl) phosphorofluoridate 17c. Yield
94%, δP (121.49 MHz; CDCl3) Ϫ9.45 (d, JPF 978.01); δF (CDCl3)
Ϫ81.55 (d, JPF 974.60), Ϫ81.60 (d, JPF 978.60); δH (300.13 MHz;
CDCl3) 0.97 (3 H, d, J 6.01, CH3CH), 1.18–1.46 (4 H, m), 1.54
(3 H, s, CH C᎐), 1.62 (3 H, s, CH C᎐), 1.82–2.34 (3 H, m,
᎐
᎐
3
3
CH CH and CH CH᎐C), 2.71 (2 H, 2t, J 6.0, OCH CH CN),
᎐
3
2
2
2
3.71 (2 H, m, CH2 O), 4.19–4.42 (2 H, m, OCH2CH2CN), 5.14
(1 H, t, J 6.01, CH᎐C); δ (75.47 MHz; CDCl3) 16.54, 20.19
᎐
C
(OCH2CH2CN), 25.78, 26.01, 29.92, 37.76, 39.80, 61.54, 63.65
(OCH2CH2CN), 115.52 (OCH2CH2CN), 124.78, 131.50.
O-(؊)-Menthyl O-(2-cyanoethyl) phosphorofluoridate 17d.
Yield 96%, δP (121.49 MHz; CDCl3) Ϫ9.45 (d, JPF 978.45),
Ϫ9.40 (d, JPF 974.60); δF (CDCl3) Ϫ78.10 (d, JPF 978.69),
Ϫ80.05 (d, JPF 974.80); δH (300.13 MHz; CDCl3) 0.71 (3 H, d,
J 6.94), 0.84 (3 H, d, J 6.52), 0.87 (3 H, d, J 7.03), 1.10 [9 H,
s, C(CH3)3], 1.14–2.25 (9 H, m, H of cyclohexanol), 3.23 (1 H, t,
J 10.44 OCHCH2); δC (75.47 MHz, CDCl3) 15.63, 20.92, 22.04,
22.91, 25.20, 31.41, 32.71 [C(CH3)3], 34.39, 44.80, 49.62, 70.81,
71.26 [C(CH3)3].
O-Citronellyl O-(2-cyanoethyl) thiophosphorofluoridate 18c.
Yield 92%; δP (129.49 MHz; CDCl3) 53.05 (d, JPF 1047.00);
δF Ϫ28.42 (d, JPF 1047.21), Ϫ29.60 (d, JPF 1053.10); δH (300.13
MHz; CDCl3) 0.92 (3 H, d, J 6.01, CH3CH), 1.15–1.46 (4 H,
m), 1.57 (3 H, s, CH C᎐), 1.65 (3 H, s, CH C᎐), 1.75–2.33 (3 H,
᎐
᎐
3
3
m, CH CH and CH CH᎐C), 2.69 (2 H, 2t, J 6.0, OCH -
᎐
3
2
2
CH2CN), 3.78 (2 H, m, CH2O), 4.19–4.48 (2 H, m, OCH2-
CH CN), 5.18 (1 H, t, J 6.01, CH᎐C); δ (75.47 MHz; CDCl )
᎐
2
C
3
O-Cholesteryl O-(2-cyanoethyl) phosphorofluoridate 17e.
Yield 91%, δP (121.49 MHz; CDCl3) Ϫ10.1 (d, JPF 978.8); δF
Ϫ79.3 (d, JPF 979.4), Ϫ79.75 (d, JPF 980.1); δH (300.13 MHz;
CDCl3) 0.60 (3 H, s, CH3-18), 0.81 (3 H, d, J 6.4, CH3-26), 0.80
(3 H, d, J 6.4, CH3-27), 0.86 (3 H, d, J 6.4, CH3-21), 1.00 (3 H, s,
CH3-19), 2.98 (2 H, t, J 6.2, OCH2CH2CN), 3.74 (1 H, d, J 8.0,
H-7), 4.01 (1 H, br, H-3), 4.23–4.45 (2 H, m, OCH2CH2CN),
5.21 (1 H, s, H-6); δC (75.47 MHz, CDCl3) 11.11 (C-18),
18.26 (C-19), 19.92 (OCH2CH2CN), 22.14 (C-26), 22.76 (C-27),
55.39 (C-14), 55.98 (C-17), 62.04 (OCH2CH2CN), 73.29
(C-7), 77.39 (C-3), 116.65 (OCH2CH2CN), 125.78 (C-6), 142.18
(C-5).
17.09, 20.32 (OCH2CH2CN), 20.56, 25.91, 26.43, 29.99, 37.89,
39.91, 61.77, 63.78 (OCH2CH2CN), 115.61 (OCH2CH2CN),
124.99, 131.76.
O-(؊)-Menthyl O-(2-cyanoethyl) thiophosphorofluoridate 18d.
Yield 95%; δP (129.49 MHz; CDCl3), 53.60 (d, JPF 1049.10),
54.90 (d, JPF 1047.91); δF Ϫ26.75 (d, JPF 1047.90), Ϫ26.90 (d,
JPF 1050.10); δH (300.13 MHz; CDCl3) 0.77 (3 H, d, J 6.91), 0.82
(3 H, d, J 6.50), 0.89 (3 H, d, J 7.03), 1.11–2.23 (9 H, m, H of
cyclohexanol), 2.71 (2 H, 2t, J 6.0, OCH2CH2CN), 3.33 (1 H, t,
J 10.44, OCHCH2), 4.21–4.45 (2 H, m, OCH2CH2CN);
δC (75.47 MHz; CDCl3) 15.33, 20.30 (OCH2CH2CN), 20.45,
J. Chem. Soc., Perkin Trans. 1, 2001, 2462–2469
2467

View Article Online
22.15, 22.99, 25.47, 31.57, 34.48, 44.91, 49.78, 63.91 (OCH2-
CH2CN), 70.89, 115.70 (OCH2CH2CN).
1.09–1.42 (4 H, m), 1.51 (3 H, s, CH C᎐), 1.62 (3 H, s, CH C᎐),
᎐ ᎐
3 3
1.79–2.33 (3 H, m, CH CH and CH CH᎐C), 3.65 (2 H, m,
᎐
3
2
CH -O), 5.16 (1 H, t, J 6.01, CH᎐C); δ (75.47 MHz; CDCl3)
᎐
2
C
17.56, 19.98, 24.98, 25.82, 30.24, 37.87, 39.71, 61.89, 124.91,
131.64.
O-Cholesteryl O-(2-cyanoethyl) phosphorofluoridate 18e.
Yield 95%; δP (129.49 MHz; CDCl3) 53.95 (d, JPF 1050.0); δF
Ϫ30.05 (d, JPF 1050.6), Ϫ30.10 (d, JPF 1051.1); δH (300.13 MHz;
CDCl3) 0.54 (3 H, s, CH3-18), 0.75 (3 H, d, J 6.4, CH3-26), 0.79
(3 H, d, J 6.4, CH3-27), 0.89 (3 H, d, J 6.4, CH3-21), 1.09 (3 H, s,
CH3-19), 2.82 (2 H, 2t, OCH2CH2CN), 3.79 (1 H, d, J 8.0, H-7),
3.95 (1 H, br, H-3), 4.35–4.50 (2 H, m, OCH2CH2CN), 5.31
(1 H, s, 6-H); δC (50.288 MHz; CDCl3) 11.07 (C-18), 18.68
(C-19), 19.11 (OCH2CH2CN), 22.94 (C-26), 22.98 (C-27), 55.73
(C-14), 55.98 (C-17), 72.91 (C-7), 77.73 (C-3), 117.53 (OCH2-
CH2CN), 125.75 (C-6), 143.01 (C-5).
O-(؊)Menthyl hydrogen phosphorofluoridate 1d. Yield 94%,
δP (121.49 MHz; CDCl3) Ϫ8.10 (d, JPF 942.51); δF Ϫ76.80
(d, JPF 942.90); δH (300.13 MHz; CDCl3) 0.98 (3 H, d, J 6.94),
1.01 (3 H, d, J 6.50), 0.12 (3 H, d, J 7.03), 1.14–2.32 (9 H, m,
H of cyclohexanol), 3.43 (1 H, t, J 10.44, OCHCH2); δC (75.47
MHz; CDCl3) 15.45, 21.45, 22.34, 22.91, 25.43, 31.78, 34.44,
44.91, 49.78, 70.95.
O-Cholesteryl hydrogen phosphorofluoridate 1e. Yield 90%,
δP (121.49 MHz; CDCl3) Ϫ7.95 (d, JPF 925.81); δF Ϫ75.45 (d,
JPF 925.80); δH (300.13 MHz; CDCl3) 0.65 (3 H, s, CH3-18), 0.76
(3 H, d, J 6.4, CH3-26), 0.82 (3 H, d, J 6.4, CH3-27), 0.89 (3 H,
d, J 6.4, CH3-21), 1.10 (3 H, s, CH3-19), 3.81 (1 H, d, J 8.0,
H-7), 3.99 (1 H, br, H-3), 5.20 (s, 1 H, H-6); δC (75.47 MHz;
CDCl3) 11.00 (C-18), 18.41 (C-19), 22.09 (C-26), 22.99 (C-27),
55.48 (C-14), 60.00 (C-17), 73.31 (C-7), 77.42 (C-3), 126.01
(C-6), 142.89 (C-5).
General procedure for the synthesis of phosphoromonofluoridates
1a–e
(Route a). A solution of a compound 14a–e in CH3CN was
refluxed for 2 h at 80 ЊC. Thermal elimination of the vinyl
cyanide group gave the desired corresponding compound 1a–e,
which was purified by silica gel column chromatography
[CH2Cl2–CH3C(O)CH3 (10 : 2 v/v)].
(Route b). A solution of a compound 17a–e in dry THF
(10 ml) was treated with Et3N; after a further 6 h, the mixture
was concentrated under reduced pressure and the residue was
purified by silica gel chromatography [CH2Cl2–CH3C(O)CH3
(10 : 2 v/v)] to obtain the corresponding phosphoromono-
fluoridate 1a–e.
General procedure for the synthesis of thiophosphorofluoridates
2a–e
(Route a). A solution of a compound 15a–e in CH3CN was
refluxed 2 h at 80 ЊC. Thermal elimination of the vinyl cyanide
group gave the corresponding compound 2a–e, which was
purified by column chromatography [CH3C(O)CH3–CH2Cl2
(10 : 2)].
O-[5Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-3Ј-yl] hydrogen phos-
phorofluoridate 1a. Yield 94%, δP (121.49 MHz; CDCl3) Ϫ9.4
(d, JPF 929); δF (CDCl3) Ϫ80.05 (d, JPF 929); δH (300.13 MHz;
CDCl3) 1.65 (3 H, s, CH3-5), 2.55 (1 H, m, H-2Ј), 2.63 (1 H, m,
H-2Љ), 3.33–3.54 (2 H, m, H-5Ј, -5Љ), 3.87 (6 H, s, 2 × OCH3 of
DMTr), 4.26, 4.33 (1 H, m, H-4Ј), 5.24 (1 H, m, H-3Ј), 6.14,
6.38 (1 H, dd, J 8.5 and 7.1, H-1Ј), 6.88 (4 H, 2d, J 8.6 and 7.7,
H-3, -3Ј, -5, -5Ј of DMTr), 7.13–7.54 (2 H, ArH of DMTr
except for H-3, -3Ј, -5, -5Ј); δC (75.47 MHz; CDCl3) 11.16, 11.78
(5-CH3), 38.88 (C-2Ј), 55.33 (OCH3 of DMTr), 63.28, 63.57
(C-5Ј), 74.23, 75.10 (JPOC 6.1 and 6.1, C-3Ј), 84.73 (C-1Ј), 85.12,
85.34 (JPOCC 4.8 and 4.9, C-4Ј), 87.21, 87.30 (tert-C of DMTr),
111.05, 111.56 (C-5), 113.49 (C-3, -3Ј, -5, -5Ј of DMTr), 128.11,
128.92, 130.61, 130.89, 131.85 (ArC of DMTr except for C-3,
-3Ј, -5, -5Ј), 134.99, 135.19 (C-1, -1Ј of DMTr), 135.82 (C-6),
144.87 (C-1Љ of DMTr), 149.41, 150.49 (C-2), 158.83 (C-4, -4Ј
of DMTr).
(Route b). The β-elimination of the O-(2-cyanoethyl) group
from a substrate 18a–e gave the desired product thiophosphoro-
fluoridate 2a–e, which was purified by column chromatography,
using the same eluent as for compounds 1a–e.
O-[5Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-3Ј-yl] hydrogen thio-
phosphorofluoridate 2a. Yield 96%; δP (129.49 MHz; CDCl3)
54.35 (d, JPF 1054.0), 54.45 (d, JPF 1054.1); δF (200.13 MHz,
CDCl3) Ϫ30.2 (d, JPF 1054.1), Ϫ30.4 (d, JPF 1054.2); δH (200.13
MHz; CDCl3) 1.71 (3 H, CH3-5), 2.51 (1 H, m, H-2Ј), 2.67 (1 H,
m, H-2Љ), 3.30–3.51 (2 H, m, H-5Ј, -5Љ), 3.78 (6 H, s, OCH3 of
DMTr), 4.22, 4.37 (1 H, m, H-4Ј), 5.19 (1 H, m, H-3Ј), 6.23,
6.50 (1 H, 2d, J 8.1, 7.1, H-1Ј), 6.79 (4 H, 2d, J 8.6, 7.7, H-3, -3Ј,
-5, -5Ј of DMTr), 7.21–7.39 (2 H, ArH of DMTr except for H-3,
-3Ј, -5, -5Ј); δC (50.288 MHz; CDCl3) 10.45, 10.94 (5-CH3),
40.03 (C-2Ј), 55.35 (OCH3 of DMTr), 62.32, 63.03 (C-5Ј),
74.51, 75.29 (JPOC 6.1 6.1, C-3Ј), 84.71 (C-1Ј), 85.09, 85.75
(JPOCC 4.8, 4.9, C-4Ј), 87.33, 87.56 (tert-C of DMTr), 111.26,
111.71 (C-5), 113.48 (C-3, -3Ј, -5, -5Ј of DMTr), 128.11, 128.36,
130.54, 130.87, 131.68 (ArC of DMTr except for C-3, -3Ј, -5,
-5Ј), 135.32, 135.54 (C-1, -1Ј of DMTr), 135.75 (C-6), 144.89
(C-1Љ of DMTr), 149.63, 149.97 (C-2), 158.91 (C-4, -4Ј of
DMTr).
O-[3Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-5Ј-yl]
hydrogen
phosphorofluoridate 1b. Yield 92%, δP (121.49 MHz; CDCl3)
Ϫ6.4 (d, JPF 929); δF (CDCl3) Ϫ80.15 (d, JPF 929); δH (300.13
MHz; CDCl3) 1.75 (3 H, s, CH3-5), 2.50 (1 H, m, H-2Ј), 2.60
(1 H, m, H-2Љ), 3.30–3.58 (2 H, m, H-5Ј, -5Љ), 3.91 (6 H, s, 2 ×
OCH3 of DMTr), 4.36, 4.44 (1 H, m, H-4Ј), 5.77 (1 H, m, H-3Ј),
6.32, 6.47 (1 H, dd, J 8.5 and 7.1, H-1Ј), 6.90 (4 H, 2d, J 8.6 and
7.7, H-3, -3Ј, -5, -5Ј of DMTr), 7.09–7.50 (2 H, ArH of DMTr
except for H-3, -3Ј, -5, -5Ј); δC (75.47 MHz; CDCl3) 11.22, 11.98
(5-CH3), 38.96 (C-2Ј), 55.41 (OCH3 of DMTr), 63.31, 63.50
(C-5Ј), 74.34, 75.90 (JPOC 6.1 and 6.1, 3Ј-C), 84.79 (C-1Ј), 85.21,
85.47 (JPOCC 4.8 and 4.9, C-4Ј), 87.33, 87.42 (tert-C of DMTr),
111.15, 111.50 (C-5), 113.51 (C-3, -3Ј, -5, -5Ј of DMTr), 128.32,
128.99, 130.73, 130.94, 131.92 (ArC of DMTr except for C-3,
-3Ј, -5, -5Ј), 135.00, 135.32 (C-1, -1Ј of DMTr), 135.90 (C-6),
144.93 (C-1Љ of DMTr), 149.49, 150.57 (C-2), 158.90 (C-4, -4Ј
of DMTr).
O-[3Ј-O-(4,4Ј-Dimethoxytrityl)thymidin-5Ј-yl] hydrogen thio-
phosphorofluoridate 2b. Yield 94%; δP (129.49 MHz; CDCl3)
54.00 (d, JPF 1054.0), 54.49 (d, JPF 1054.1); δF (CDCl3) Ϫ30.82
(d, JPF 1054.1), Ϫ30.94 (d, JPF 1054.2); δH (200.13 MHz, CDCl3)
1.77 (3 H, CH3-5), 2.61 (1 H, m, H-2Ј), 2.73 (1 H, m, H-2Љ),
3.26–3.64 (2 H, m, H-5Ј, -5Љ), 3.82 (6 H, s, OCH3 of DMTr),
4.34, 4.41 (1 H, m, H-4Ј), 5.22 (1 H, m, H-3Ј), 6.20, 6.52 (1 H,
2d, J 8.1, 7.1, H-1Ј), 6.81 (4 H, 2d, J 8.6 7.7, H-3, -3Ј, -5, -5Ј of
DMTr), 7.18–7.43 (2 H, ArH of DMTr except for H-3, -3Ј, -5,
-5Ј); δC (50.288 MHz; CDCl3) 10.11, 10.99 (5-CH3), 40.22
(C-2Ј), 55.47 (OCH3 of DMTr), 62.89, 63.56 (C-5Ј), 74.48,
75.00 (JPOC 6.1, 6.1, C-3Ј), 84.93 (C-1Ј), 85.35, 85.98 (JPOCC 4.8,
4.9, C-4Ј), 87.52, 87.88 (tert-C of DMTr), 111.33, 111.99 (C-5),
O-Citronellyl hydrogen phosphorofluoridate 1c. Yield 93%, δP
(121.49 MHz; CDCl3) Ϫ8.85 (d, JPF 974.01); δF Ϫ81.40 (d, JPF
978.40); δH (300.13 MHz; CDCl3) 0.88 (3 H, d, J 6.01, CH3CH),
2468
J. Chem. Soc., Perkin Trans. 1, 2001, 2462–2469

View Article Online
113.56 (C-3, -3Ј, -5, -5Ј of DMTr), 128.34, 128.58, 130.63,
130.90, 131.54 (ArC of DMTr except for C-3, -3Ј, -5, -5Ј),
135.41, 135.67 (C-1, -1Ј of DMTr), 135.84 (C-6), 144.83
(C-1Љ of DMTr), 149.77, 150.00 (C-2), 159.04 (C-4, -4Ј of
DMTr).
155 10 and 3T09A 031 15) and by the German–Polish project
POL-211-96.
References
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O-Citronellyl hydrogen thiophosphorofluoridate 2c. Yield
95%; δP (129.49 MHz; CDCl3) 52.15 (d, JPF 1051.60); δF
(CDCl3) Ϫ31.62 (d, JPF 1051.60), Ϫ31.65 (d, JPF 1050.30); δH
(300.13 MHz; CDCl3) 0.89 (3 H, d, J 6.01, CH3CH), 1.11–1.35
(4 H, m), 1.49 (3 H, s, CH C᎐), 1.73 (3 H, s, CH C᎐), 1.88–2.39
᎐
᎐
3
3
(3 H, m, CH CH and CH CH᎐C), 3.77 (2 H, m, CH O), 5.89
᎐
3
2
2
(1 H, t, J 6.01, CH᎐C); δ (75.47 MHz; CDCl3) 17.04, 21.01,
᎐
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˛
O-(؊)-Menthyl hydrogen thiophosphorofluoridate 2d. Yield
98%; δP (129.49 MHz; CDCl3), 60.20 (d, JPF 1049.11), 60.90 (d,
JPF 1053.65); δF (CDCl3) Ϫ37.30 (d, JPF 1055.80), Ϫ40.70 (d,
JPF 1049.80); δH (300.13 MHz; CDCl3) 0.80 (3 H, d, J 6.95), 0.89
(3 H, d, J 6.50), 0.91 (3 H, d, J 7.13), 1.15–2.23 (9 H, m, H of
cyclohexanol), 3.30 (1 H, t, J 10.00, OCHCH2); δC (75.47 MHz;
CDCl3) 15.29, 20.65, 22.09, 22.30, 25.89, 31.37, 34.48, 44.54,
49.78, 70.80.
7 G. M. Blackburn and M.-J. Guo, Tetrahedron Lett., 1993, 34, 149;
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Cramer, Phosphorus, Sulfur, Silicon, 1999, 144–146, 109.
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Watanabe, A. A. Arzumanov, N. B. Dyatkina and E. A. Shirokova,
Nucleosides, Nucleotides, 1993, 12, 1085; (b) M. D. Percival and
S. G. Withers, J. Org. Chem., 1992, 57, 811; (c) N. Dyatkina,
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O-Cholesteryl hydrogen thiophosphorofluoridate 2e. Yield
96%; δP (129.49 MHz; CDCl3) 53.95 (d, JPF 1050.10); δF
(CDCl3) Ϫ30.05 (d, JPF 1050.60), Ϫ30.10 (d, JPF 1051.10);
δH (300.13 MHz; CDCl3) 0.62 (3 H, s, CH3-18), 0.79 (3 H, d,
J 6.4, CH3-26), 0.88 (3 H, d, J 6.4, CH3-27), 0.94 (3 H, d, J 6.4,
CH3-21), 1.31 (3 H, s, CH3-19), 3.34 (1 H, d, J 8.0, H-7), 4.07
(1 H, br, H-3), 5.09 (1 H, s, H-6); δC (75.47 MHz; CDCl3) 10.94
(C-18), 18.00 (C-19), 22.84 (C-26), 22.99 (C-27), 55.39 (C-14),
56.11 (C-17), 73.39 (C-7), 77.55 (C-3), 125.91 (C-6), 142.33
(C-5).
11 W. Dabkowski and I. Tworowska, Chem. Lett., 1995, 8, 727.
˛
Acknowledgements
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1987, 18, 177.
We are grateful to Professors Jan Michalski and Friedrich
Cramer for interest in this work. This work was supported by
the State Committee for Scientific Research, Poland (No 3T09A
14 N. D. Smiha, J. Biernat, J. McManus and H. Köster, Nucleic Acids
Res., 1984, 12, 4539.
J. Chem. Soc., Perkin Trans. 1, 2001, 2462–2469
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