Efficient synthesis of fluorophosphonylated alkyles by ring-opening reaction of cyclic sulfates

Article abstract of DOI:10.1021/ol801443s

(Figure Presented) Ring-opening reactions of functionalized 1,2-cyclic sulfates and oxetanes with the phosphonodifluoromethyl carbanion are reported. This approach allows an easy access to fluorinated βhydroxyphosphonates that are building blocks in the s

Full text of DOI:10.1021/ol801443s

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3895-3898
Efficient Synthesis of
Fluorophosphonylated Alkyles by
Ring-Opening Reaction of Cyclic
Sulfates
Sonia Amel Diab, Aboubacary Sene, Emmanuel Pfund, and Thierry Lequeux*
Laboratoire de Chimie Mole´culaire et Thio-organique, ENSICAEN, UniVersite´ de Caen
Basse-Normandie, UMR-CNRS 6507, 6 Bd du Mare´chal Juin, 14050 Caen Cedex, France
thierry.lequeux@ensicaen.fr
Received June 26, 2008
ABSTRACT
Ring-opening reactions of functionalized 1,2-cyclic sulfates and oxetanes with the phosphonodifluoromethyl carbanion are reported. This
approach allows an easy access to fluorinated ꢀ-hydroxyphosphonates that are building blocks in the synthesis of acyclic nucleosides.
Synthesis of precursors of nucleoside phosphorylase inhibitors from these alcohols is described.
Due to the importance of the phosphate moiety in the living
world, a variety of stable phosphate mimics have been
developed and used to either assign its exact role in biological
pathways or inhibit enzymes responsible for several dis-
eases.1 Since the pioneering work of Blackburn2 and Cham-
bers,3 difluoromethylphosphonates are known as the best
isosteric and isoacidic phosphate analogues. Thus, many
derivatives containing a difluoromethylphosphonate function
were designed as potential enzyme inhibitors4 and as useful
probes for the elucidation of biochemical processes.5 Among
the different preparation methods of phosphonodifluorom-
ethyl derivatives described in the literature, the carbanionic
method starting from the diethyl difluoromethylphosphonate
is the most common.6 However, since Montreal’s protocol,
this approach is compromised due to the regulation of HCFC
and CFC needed to synthesize the starting materials. To
overcome this major limitation, we developed an alternative
route to form this fluorinated carbanion from the diisopropyl
(5) (a) Burton, D. J.; Yang, Z. Y.; Qiu, W. Chem. ReV. 1996, 96, 1641.
(b) Halazy, S.; Ehrhard, A.; Eggenspiller, A.; Gerges-Gross, V.; Danzin,
C. Tetrahedron 1996, 52, 177. (c) Kawamoto, A. M.; Campbell, M. M.
J. Chem. Soc., Perkin Trans. 1 1997, 1249. (d) Caplan, N. A.; Pogson,
C. I.; Hayes, D. J.; Blackburn, G. M. J. Chem. Soc., Perkin Trans. 1 2000,
n/a, 421. (e) Yokomatsu, T.; Hayakawa, Y.; Kihara, T.; Koyanagi, S.; Soeda,
S.; Shimeno, H.; Shibuya, S. Bioorg. Med. Chem. 2000, 8, 2571. (f) Pfund,
E.; Lequeux, T.; Masson, S.; Vazeux, M.; Cordi, A.; Pierre, A.; Serre, V.;
Herve´, G. Bioorg. Med. Chem. 2005, 13, 4921.
(1) (a) Romanenko, V. D.; Kukhar, V. P. Chem. ReV. 2006, 106, 3868.
(b) Romanenko, V. D.; Kukhar, V. P. Tetrahedron 2008, 64, 6153.
(2) (a) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J. Chem. Soc.,
Chem. Commun. 1981, 930. (b) Blackburn, G. M.; Eckstein, F.; Kent, D. E.;
Pere´e, T. D. Nucleosides Nucleotides 1985, 4, 165.
(6) (a) Burton, D. J.; Sprague, L. G. J. Org. Chem. 1988, 53, 1523. (b)
Obayashi, M.; Kondo, K. Tetrahedron Lett. 1982, 31, 5571. (c) Obayashi,
M.; Ito, E.; Matsui, K.; Kondo, K. Tetrahedron Lett. 1982, 23, 2323. (d)
Berkowitz, D. B.; Shen, Q.; Maeng, J. Tetrahedron Lett. 1994, 35, 6445.
(e) Lequeux, T.; Percy, J. M. J. Chem. Soc., Chem. Commun. 1995, 2111.
(f) Blades, K.; Lequeux, T.; Percy, J. M. Chem. Commun. 1996, 1457. (g)
Pfund, E.; Lequeux, T.; Vazeux, M.; Masson, S. Tetrahedon Lett. 2002,
43, 2033. (h) Pfund, E.; Lequeux, T.; Masson, S.; Vazeux, M. Org. Lett.
2002, 4, 843. (i) Pfund, E.; Masson, S.; Vazeux, M.; Lequeux, T. J. Org.
Chem. 2004, 69, 4670.
(3) Chambers, R. D.; O’Hagan, D.; Lamont, R. B.; Jain, S. C. J. Chem.
Soc., Chem. Commun. 1990, 1053.
(4) (a) Halazy, S.; Ehrhard, A.; Danzin, C. J. Am. Chem. Soc. 1991,
113, 315. (b) Berkowitz, D. B.; Bose, M. J. Fluorine Chem. 2001, 112, 13.
(c) Chambers, R. D.; Jaouhari, R.; O’Hagan, D. Tetrahedron 1989, 45, 16–
5101. (d) Berkowitz, D. B.; Bose, M.; Pfannenstiel, T. J.; Doukov, T. J.
Org. Chem. 2000, 65, 4498. (e) Matulic-Adamic, J.; Haeberli, P.; and
Usman, N. J. Org. Chem. 1995, 60, 2563.
10.1021/ol801443s CCC: $40.75
Published on Web 07/31/2008
2008 American Chemical Society

phosphonodifluoromethyl sulfide 1 prepared by nucleophilic
fluorination.7 In contrast, this new method allowed the use
of Lewis acid, and we showed that the anion reacted with a
weaker electrophile such as THF, trimethylene oxide, and
epoxides to produce hydroxydifluoromethylphosphonates in
moderate to good yields.8
Scheme 1. Ring-Opening Reaction of Ethane 1,2-Cyclic Sulfate
As resulting alcohols are known to be of great interest for
the preparation of highly sophisticated difluoromethylphos-
phonates by C-C bond formation,9 other ring-opening
reactions of functionalized cyclic sulfates and oxetanes were
explored and are reported in this paper. Derivation of the
obtained alcohols in acyclic nucleoside precursors is also
described.
We previously showed that the phosphonodifluoromethyl
anion could react with epoxides in the presence of Lewis
acid (BF3-Et2O) to afford ꢀ-hydroxydifluoromethylphospho-
nates in moderate to good yields.8 However, this reaction
was limited due to a retro-reaction, and an excess of anion
or epoxide was needed to obtain the desired products in good
yields. To circumvent this limitation, we focused our study
on the more reactive 1,2-cyclic sulfates. These synthetic
equivalents of epoxides are known to be more electrophilic.10
Up to date, only three successful examples dealing with the
preparation of fluorinated alcohols from 1,2-cyclic sulfates
have been reported. These include their ring-opening reac-
tions with fluoride (TBAF),10a trifluoromethyl (CF3I/
hydrolysis step and did not result from a proton transfer via
a cyclic sulfate rearrangement.
This preliminary result contrasts with Hu’s data concerning
the ring-opening reaction of cyclic sulfates with
PhSO2CF2 .12 Such a difference of reactivity between both
-
phosphonyl and sulfonyl fluorinated carbanions was unex-
pected and difficult to rationalize since completely opposite
reactivity profiles have been reported in ring-opening reaction
of epoxides.8,14 To explore the scope and limitation of the
phosphonodifluoromethyl anion reactivity toward cyclic
sulfates, our study was extended to constrained substituted
1,2-cyclic sulfates. Ring-opening reactions were realized
following this scheme. The carbanion formed by addition
of 1 to a solution of tert-butyllithium in THF at -78 °C
was trapped by addition of neat 1,2-cyclic sulfate (1.3 equiv).
After 15 min of stirring and acidic workup, ꢀ-hydroxydif-
luoromethylphosphonates 5-10 were isolated after flash
chromatography in moderate to good yields (Table 1). Ring-
opening reactions of functionalized 1,2-cyclic sulfates are
relatively fast and do not require any Lewis acid. Unlike
epoxides, a low amount of hydrolysis product 3 was observed
even by using 1.3 equiv of cyclic sulfate. This reaction was
regioselective and occurred on the less substituted carbon
atom.15 From the halogenated cyclic sulfate, no substitution
reaction of the chlorine atom was observed. However, in this
case, about 25% of product 3 was detected in the crude
mixture. The ꢀ-hydroxydifluoromethylphosphonate 6 was
isolated in 53% yield (Table 1). HMPA addition did not
improve the rate and the yield of the reaction. As mentioned
by Hu,12 we also found the reaction supported other
functional groups (OBn, OAr) and was efficient with alkyl-
or aryl-substituted cyclic sulfates (Table 1, compounds
7-10). Contrary to epoxides, the absence of Lewis acid
allowed the anion formed by LDA deprotonation of
HCF2P(O)(OEt)2 to react in a similar manner with cyclic
sulfates (Table 1, note a).
12
TDAE),11 and sulfonodifluoromethyl (PhSO2CF2 ) anions.
-
To the best of our knowledge, no attempt using the
phosphonodifluoromethyl anion has been described. First,
ethane 1,2-cyclic sulfate, easily prepared from ethylenegly-
col,13 was tested. The fluorinated carbanion was reacted at
-78 °C with ethane 1,2-cyclic sulfate (1.2 equiv) over 2 h.
After acidic treatment with H2SO4, the corresponding
fluorinated ꢀ-hydroxyphosphonate 2 was isolated in 22%
yield, while about 70% of diisopropyl difluoromethylphos-
phonate 3 was recovered (Scheme 1). Attempts to optimize
the ring-opening reaction by changing the reaction time or
the temperature or by adding a Lewis acid8 or HMPA12 were
unsuccessful. In each case, phosphonate 3 was obtained as
the major compound after acidic hydrolysis. On the other
hand, workup with methyl iodide instead of H2SO4 resulted
in the formation of diisopropyl 1,1-difluoroethylphosphonate
4 as the main product. This result suggested that the
formation of the hydrolysis product 3 occurred during the
(7) Henry-dit-Quesnel, A.; Toupet, L.; Pommelet, J. C.; Lequeux, T.
Org. Biomol. Chem. 2003, 1, 2486.
(8) Ozouf, P.; Binot, G.; Pommelet, J. C.; Lequeux, T. Org. Lett. 2004,
6, 3747.
(9) (a) Xu, Y.; Prestwich, G. D. Org. Lett. 2002, 4, 4021. (b) Vino,
T. K.; Griffith, O. H.; Keana, J. F. W. Tetrahedron Lett. 1994, 35, 7193.
(c) Matulic-Adamic, J.; Haeberli, P.; Usman, N. J. Org. Chem. 1995, 60,
2563. (d) Ladame, S.; Willson, M.; Pe´rie´, J. Eur. J. Org. Chem. 2002, n/a,
2640. (e) Butt, A. H.; Percy, J. M.; Spencer, N. S. Chem. Commun. 2000,
1691. (f) Lopin, C.; Gautier, A.; Gouhier, G.; Piettre, S. R. J. Am. Chem.
Soc. 2002, 124, 14668.
The ring-opening reaction was attempted with the 1,2-
cyclic sulfamidate derived from benzyl phenylalaninol. After
(10) (a) Byun, H-S.; He, L.; Bittman, R. Tetrahedron 2000, 56, 7051.
(b) Lohray, B. B. Synthesis 1992, 1035.
(11) Takechi, N.; Ait-Mohand, S.; Medebielle, M.; Dolbier, W. R., Jr.
Org. Lett. 2002, 4, 4671.
(14) Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829.
(15) Structures of the obtained regioisomers have been easily assigned
by 19F NMR analysis. In these spectra, each fluorine atom exhibits a
multiplet (dddd) indicating the presence of a methylene group adjacent to
the difluoromethylphosphonate function and an asymmetric carbon.
(12) Ni, C.; Liu, J.; Zhang, L.; Hu, J. Angew. Chem., Int. Ed. 2007, 46,
786.
(13) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538.
3896
Org. Lett., Vol. 10, No. 17, 2008

Table 1. Ring-Opening Reactions of Functionalized 1,2-Cyclic
Sulfates and Sulfamidate
Scheme 2. Ring-Opening Reaction with Substituted Oxetanes
nucleoside analogues. Derivation of alcohols 14 and 158 was
realized by introduction of nucleic bases. Alkylation of
6-chloropurine was conducted from their corresponding
tosylates 16 and 17 in the presence of K2CO3 in DMF.4a
Nucleoside precursors 18 and 19 were isolated in good yields
(Scheme 3).
Scheme 3
.
6-Chloropurine Introduction onto Fluorinated
Hydroxyphosphonates
a From HCF2P(O)(OEt)2 and LDA, the desired product was isolated in
48% yield under the same experimental conditions.
workup and flash chromatography, the corresponding pro-
tected ꢀ-amino-difluoromethylphosphonate 11 was isolated
in 69% yield.
Alkylation of the N3-benzoylthymine,17 under these condi-
tions, was not successful due to a weaker nucleophilicity of
pyrimidine rings. In the presence of PPh3 and DEAD,
fluorinated alcohols 14 and 15 were converted to their
corresponding thymine derivatives 20 and 21 in moderate
yields. However, partial deprotection of the thymine oc-
curred, and the residual triphenylphosphine oxide was
difficult to remove. Other experimental conditions were
explored to optimize the thymine base coupling reaction
(Scheme 4 and Table 2).
Thymine alkylation via its sodium salts was limited, and
from tosylate 17 derivative 21 was isolated in 35% yield
(Table 2, entry 1). The use of a nonmetallic base such as
1,1,3,3-tetramethylguanidine (TMG), known to enhance the
yield of nucleophilic substitution reactions,18 was then tested.
To cover the scope of the synthesis of functionalized
alcohols, we focused our study on the ring-opening reaction
of oxetane derivatives. As mentioned, these reactions were
realized in the presence of BF3·Et2O, and diethyl ether was
used as solvent. Reactions reached completion after 5 min
under stirring at -78 °C. From 2- and 3,3-substituted
oxetanes, corresponding fluorinated hydroxyphosphonates 12
and 13 were obtained in 57% and 65% yields, respectively,
with traces of 3 (Scheme 2).16 Due to a lack of general
methods for the preparation of functionalized oxetanes, the
ring-opening reaction of 1,3-cyclic sulfates was attempted.
Unfortunately, only traces (<10%) of γ-hydroxydifluoro-
phosphonates were detected from 1,3-dimethyl 1,3-cyclic
sulfate, even in the presence of Lewis acid or HMPA.
As previously mentioned, the use of ꢀ-hydroxydifluoro-
(17) Cruickshank, K. A.; Jiricny, J.; Reese, C. B. Tetrahedron Lett. 1984,
25, 681.
phosphonates was illustrated by the synthesis of acyclic
(18) (a) Dowd, P.; Wilk, B. K.; Wlostowski, M. Synth. Commun. 1993,
23, 2323. (b) Schwans, J. P.; Cortez, C. N.; Olveraz, J. M.; Piccirilli, J. A.
J. Am. Chem. Soc. 2003, 125, 10012.
(16) Partial degradation of alcohols 12 and 13 was observed during their
purifications by flash chromatography.
Org. Lett., Vol. 10, No. 17, 2008
3897

desired compound 22 was isolated in 69% yield (Table 2,
entry 4). Although this is the first reported example of nucleic
base introduction using the nucleophilic property of TMG,
this reaction occurred without increased regioselectivity.
Finally, these new coupling conditions have also been applied
to the N3-benzoylthymine (Table 2, entry 5). In this case,
tosylates 16 and 17 were converted into their corresponding
thymine derivatives 20 and 21 in good yields with excellent
regioselectivities when treated in the presence of TMG.
Finally, thymine derivatives 22 and 23 were obtained in 67
and 71% yield, respectively, after treatment of 20 and 21
with methylamine in ethanol. This first room-temperature
alkylation of protected thymine with primary alkylsulfonate
is highly competitive with previous known methods.
In summary, we reported the synthesis of functionalized
hydroxyphosphonates by new ring-opening reactions of 1,2-
cyclic sulfates and oxetanes. From monosubstituted cyclic
sulfates, the products were obtained in high yields, while
from ethane 1,2-cyclic sulfate low yield was observed. The
decreasing torsional strain ingoing to the transition state could
be attributed to this high difference of reactivity. Oxetanes
reacted as well as 1,2-cyclic sulfates to produce the expected
alcohols in good yields. The synthetic interest of hydroxy-
difluorophosphonates was illustrated by their derivation into
precursors of acyclonucleotides by using mild nucleic base
coupling reactions. The biological evaluation of the fully
deprotected acyclic nucleoside is under investigation and will
be reported in due course.
Scheme 4
.
Thymine Alkylation with Fluorophosphonylated
Tosylates
A mixture of tosylate 17 and thymine was treated with TMG
in DMSO or acetonitrile at room temperature (Table 2, entry
2). After 15 h of stirring, the corresponding fluorophospho-
nylated thymine 22 was isolated in 86% yield as a mixture
of two regioisomers (77/23) in favor of the N1-isomer.
Table 2. Different Conditions for Thymine Alkylation
product
(yield) N1/N3
entries
condition
isomers
N3-benzoylthymine, NaH,
DMF, 80 °C, 4 h
thymine, TMG, DMSO, rt,
15 h
bis(trimethylsilyl)thymine,
TBAF, THF, rt, 22 h
bis(trimethylsilyl)thymine,
TMG, DMSO, rt, 15 h
N3-benzoylthymine, TMG,
DMSO, rt, 15 h
1
2
3
4
5
21 (35%), nd
Acknowledgment. This work has been performed within
the Institut Normand de Chimie Mole´culaire Me´dicinale et
Macromole´culaire (INC3M) and the CRUNCh network. Le
Ministe`re de la Recherche, the CNRS, the Re´gion Basse-
Normandie, and the Agence Universitaire de la Francophonie
(A. S. grant) are gratefully thanked for their financial support.
22 (86%), 77/23
22 (71%), 68/32
22 (69%), 60/40
Supporting Information Available: Experimental pro-
cedures for the preparation of 2 and 5-23 and NMR spectra
for compounds 5-9, 11-13, and 23. This material is
available free of charge via the Internet at http://pubs.acs.org.
20 (75%), 21 (81%), 100/0
From the bis(trimethylsilyl)thymine and tosylate 17 in the
presence of tetrabutylammonium fluoride (TBAF),19 deriva-
tive 22 was obtained in 71% yield, also as a mixture of
regioisomers (Table 2, entry 3).
On the basis of few reports describing the nucleophilic
properties of TMG toward strong electrophiles,20 tosylate
17 was treated by the silylated thymine in the presence of
TMG (1.5 equiv). As for TBAF, TMG reacted on the silicon
center, and after 15 h of stirring at room temperature, the
OL801443S
(20) (a) Terry, P. H.; Borkovec, A. B. J. Med. Chem. 1967, 10, 118. (b)
Fanshawe, W. J.; Bauer, V. J. J. Med. Chem. 1967, 10, 273. (c) Stearns,
J. F.; Rapoport, H. J. Org. Chem. 1977, 42, 3608. (d) Chaudhry, S. C.;
Kummer, D. J. Organomet. Chem. 1988, 339, 241. (e) Kolomeitsev, A. A.;
Koppel, L; A.; Rodima, T.; Barten, J.; Lork, E.; Ro¨schenthaler, G.-V.;
Kalijurand, I.; Ku¨tt, A.; Koppel, I.; Ma¨emets, V.; Leito, I. J. Am. Chem.
Soc. 2005, 127, 17656. (f) Mo¨llers, C.; Prigge, J.; Wibbeling, B.; Fro¨hlich,
R.; Brockmeyer, A.; Scha¨fer, H. J.; Schma¨lzlin, E.; Bra¨uchle, C.; Meerholz,
K.; Wu¨rthwein, E-U. Eur. J. Org. Chem. 2003, 1198. (g) Qi, Y.; Gao, H.;
Yang, M.; Xia, C.-G.; Suo, J. Synth. Commun. 2003, 33, 1073. (h) Ramirez,
F.; Ricci, J. S.; Okazaki, H.; Marecek, J. F.; Lewy, M. Phosphorus Sulfur
1984, 20, 279.
(19) Esteban-Gamboa, A.; Balzarini, J.; Esnouf, R.; De Clercq, E.;
Camarasa, M-J.; Pe´rez-Pe´rez, M-J. J. Med. Chem. 2000, 43, 971.
3898
Org. Lett., Vol. 10, No. 17, 2008