Organosulfur- or organoselenium-induced intramolecular cycloaddition of β-allenic α-difluoromethylenephosphonic acid monoesters: Synthesis of novel cyclic phosphate mimics

Article abstract of DOI:10.1055/s-2006-948204

Novel cyclic phosphate mimics, γ-organosulfur or organoselenium substituted α-difluoromethylenephostones were synthesized in good yields with high regioselectivity under mild conditions by the electrophilic cyclization of β-allenic α-difluoromethylenephos

Full text of DOI:10.1055/s-2006-948204

LETTER
2227
Organosulfur- or Organoselenium-Induced Intramolecular Cycloaddition of
b-Allenic a-Difluoromethylenephosphonic Acid Monoesters: Synthesis of
Novel Cyclic Phosphate Mimics
S
Y
ynthesis of
N
ove
u
l
Cyclic Phos
n
phate Mimics Lin,a,b Jin-Tao Liu*a
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, P. R. of China
b
College of Chemistry and Environment Science, Nanjing Normal University, 122 Ninghai Road, Nanjing 210097, P. R. of China
Fax +86(21)64166128; E-mail: jtliu@mail.sioc.ac.cn
Received 1 May 2006
7
8
ester, cyclic lysophosphatidic acid, and cyclic glycero-
Abstract: Novel cyclic phosphate mimics, g-organosulfur or orga-
noselenium substituted a-difluoromethylenephostones were syn-
thesized in good yields with high regioselectivity under mild
conditions by the electrophilic cyclization of b-allenic a-difluoro-
9
phosphates. Recently much attention has focused on the
role of cyclic phosphates in cellular signal transition.10
Therefore, it is of great significance to develop efficient
methylenephosphonic acid monoesters induced by ArSCl or Ar- methods for the synthesis of cyclic a-difluoromethylene-
SeCl. The reaction represents the first example of an intramolecular
phosphonates which might have potential biological ac-
addition of phosphonic acid monoesters to b-allenic carbon–carbon
double bonds.
tivities.
An electrophile-promoted heteroannulation process in-
volving unsaturated compounds bearing a tethered nu-
Key words: b-allenic a-difluoromethylenephosphonic acid mo-
noester, phosphate mimic, a-difluoromethylenephostone, orga-
cleophilic substituent has proven to be an efficient
synthetic method toward a large variety of heterocyclic
noselenium, organosulfur, cyclization
1
1
systems. Among them an organosulfur- or organoseleni-
12
um-induced ring-closure protocol received much atten-
tion due to the convenience of the process and the
existence of a sulfur/selenium moiety in the product as a
potential reaction center for further synthetic transforma-
tions.13
The history of a-difluoromethylenephosphonates as hy-
drolytically stable natural phosphate mimics dates back to
1
the late 20th century. In 1981, Blackburn first reported
that the isoelectronic and isosteric replacement of oxygen
by difluoromethylene in phosphate analogues conferred
metabolic stability and imparted important features for re- In this communication, we disclose the first example of
ceptor binding. Since then interest has been growing in the organosulfur/organoselenium induced intramolecular ad-
development of general methods for the synthesis of com- dition of phosphonic acid monoesters to b-allenic carbon–
pounds in which the difluoromethylenephosphonate carbon double bonds as a convenient method for the syn-
group is borne within a functionalized array. Numerous thesis of novel cyclic phosphate mimics, a-difluorometh-
structurally novel and biologically interesting acyclic a- ylenephostones.
difluoromethylenephosphonate derivatives have been
prepared and studied as potential enzyme inhibitors and
b-Allenic a-difluoromethylenephosphonic acid mono-
esters 1 were readily prepared from the corresponding di-
useful probes for the elucidation of the biochemical pro-
ethyl phosphonates by hydrolysis in aqueous sodium
hydroxide solution.
2
cess. In contrast, evaluation of cyclic a-difluoromethy-
lenephosphonates (phostones) as biological phosphate
mimics has never been performed because there are few
synthetic methods available to construct such kind of het-
The cyclization reaction of 1a with p-MeC H SCl was
6
4
first carried out in CH Cl at room temperature with a mo-
2
2
3
lar ratio of 1:1.5. It was found that the reaction proceeded
very fast, giving a white solid after workup. Spectral and
elemental analysis showed that it was the desired cyclic
product 2a, but the yield was only 37%. Then the reaction
conditions were optimized and the best result was ob-
tained when the reaction was carried out at –30 °C using
MeCN as the solvent.
erocycles.
On the other hand, a series of compounds bearing a cyclic
phosphate moiety play vital roles in diverse biological
processes. Cyclic phosphates (cPIP) of foremost biologi-
cal importance are the universal second messenger cyclic
AMP and cyclic GMP. Other cyclic phosphates detected
in biological systems include glucose cyclic phosphodi-
4
5
Under the optimized conditions, the reaction of other b-al-
ester, 2¢,3¢-cyclic phosphodiester nucleotides, riboflavin
6
lenic phosphonic acid monoesters with p-CH C H SCl
3 6 4
4
¢,5¢-cyclic phosphodiester, myo-inositol 1,2-phosphodi-
was investigated.14 As shown in Table 2, both d-mono-
substituted and d,d-disubstituted b-allenic phosphonic
acid monoesters gave the cyclization products in moder-
ate to excellent yields. In the cases of allenic phosphonic
acid monoesters with different terminal substituents, the
SYNLETT 2006, No. 14, pp 2227–2230
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Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-948204; Art ID: W09006ST
©
Georg Thieme Verlag Stuttgart · New York

2
228
Y. Lin, J.-T. Liu
LETTER
a
Table 1 Cyclization of 1a with p-MeC H SCl under Different Conditions
6
4
H
O
F
+
SCl
S
CF2POEt
OH
F
OEt
P
O
O
1a
2a
Temperature
r.t.
Entry
Solvent
CH Cl
Additive (1 equiv)
Isolated yield (%)
1
2
3
4
5
6
–
–
37
77
73
74
77
78
84
2
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
r.t.
Et N
r.t.
3
K CO
r.t.
2
3
–
–
–
0 °C
–10 °C
–30 °C
7
a
The reaction was carried out with 1a (0.5 mmol) and p-MePhSCl (0.75 mmol).
a
Table 2 Cyclization of 1 with p-MeC H SCl
6
4
R1
R2
H
MeCN
O
F
+
SCl
S
F
CF2POEt
OH
N2, –30 °C
OEt
R1
R
P
2
O
O
1
2
Entry
R1
Me
Et
R2
Me
Et
Product
2a
Isolated yield (%)
1
2
3
4
5
6
7
8
84
78
49
62
79
59
94
89
95
2b
-(CH ) -
2c
2
5
-(CH ) -
2d
2
4
Me
Me
Et
Et
t-Bu
H
2e
2f
2g
n-Pr
i-Pr
H
2h
9
H
2i
a
The reaction was carried out using 1 (0.5 mmol) and p-MeC H SCl (0.75 mmol).
6
4
reaction gave cyclic products as a mixture of two diaste- products, which might be formed by exo ring closure were
reoisomers. The ratios of the two isomers were approxi- not detected. Based on the above results a plausible mech-
1
mately 1:1 (Table 3, entries 5–9) as indicated by H NMR anism is proposed for the formation of 2 or 3 as illustrated
spectroscopy.
in Scheme 1. The reaction of 1 with ArSCl or ArSeCl
gave cyclic intermediate A and released a chloride ion.
With the assistance of the chloride ion, intramolecular nu-
cleophilic attack of oxygen in the phosphonyl group on
the terminal carbon of allene in the favored endo mode af-
forded the corresponding cyclization product.
Under similar conditions, this protocol could also be suc-
cessfully applied to the cyclization of 1 with PhSeCl, giv-
ing g-phenylselenium substituted cyclic phosphonates 3.
The results are summarized in Table 3.
The reaction was regioselective. In all cases, only six-
membered phostones were obtained and five-membered
In conclusion, regioselective organosulfur- or organosele-
nium-induced intramolecular cycloaddition of b-allenic
Synlett 2006, No. 14, 2227–2230 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Cyclic Phosphate Mimics
2229
Table 3 Cyclization of 1 with PhSeCl a
R1
H
O
MeCN
N2, –30 °C
F
Se
R2
+
SeCl
F
CF2POEt
OH
OEt
R1
R
P
2
O
O
3
1
Entry
R1
Me
Et
R2
Me
Et
Product
3a
Isolated yield (%)
1
2
3
4
5
6
7
8
85
82
47
87
86
71
95
94
93
3b
-(CH ) -
3c
2
5
-(CH ) -
3d
2
4
Me
Me
Et
Et
t-Bu
H
3e
3f
3g
n-Pr
i-Pr
H
3h
9
H
3i
a
The reaction was carried out using 1 (0.5 mmol) and PhSeCl (0.75 mmol).
a-difluoromethylenephosphonic acid monoesters was may have interesting biological importance in the con-
achieved under mild conditions, providing a convenient struction of cyclic phosphate mimics. Further investiga-
method for the synthesis of novel cyclic a-difluorometh- tions of this reaction and the properties of those novel
ylenephosphonates. The unique combination of selenium fluorine-containing phostones are in progress.
or sulfur with cyclic a-difluoromethylenephosphonates
Acknowledgment
R1
R2
H
O
We thank the National Natural Science Foundation of China for fi-
nancial support (No. 20572124).
CF2POEt
OH
ArXCl
References and Notes
Ar
X
(
1) (a) Blackburn, G. M.; Brown, D.; Martin, S. J.; Parratt, M. J.
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R1
R2
H
CF2
OEt
O
P
HO
(
A
Campbell, M. M. J. Chem. Soc., Perkin Trans. 1 1997,
Ar
X
Ar
X
1
249. (c) Caplan, N. A.; Pogson, C. I.; Hayes, D. J.;
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21. (d) Yokomatsu, T.; Hayakawa, Y.; Kihara, T.;
R1
R2
H
R1
R2
H
4
CF2
OEt
CF2
OEt
Koyanagi, S.; Soeda, S.; Shimeno, H.; Shibuya, S. Bioorg.
Med. Chem. 2000, 8, 2571. (e) Xu, Y.; Prestwich, G. D.
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H.; Yokomatsu, T.; Shibuya, S. Tetrahedron 2003, 59,
10223. (j) Li, X. F.; Bhandari, A.; Holmes, C. P.;
O
O
P
P
O
O
Cl–
Cl–
H
H
HCl
F
XAr
HCl
1
R
ArX
R2
F
F
OEt
R1
R
P
O
X = S, Se
P
O
F
2
O
OEt
O
Szardenings, A. K. Bioorg. Med. Chem. Lett. 2004, 14,
4
301. (k) Gautier, A.; Garipova, G.; Salcedo, C.; Balieu, S.;
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Synlett 2006, No. 14, 2227–2230 © Thieme Stuttgart · New York

2
230
Y. Lin, J.-T. Liu
LETTER
(13) (a) Paulmier, C. Selenium Reagents and Intermediates in
(3) (a) Thatcher, G. R.; Campbell, A. S. J. Org. Chem. 1993, 58,
2
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(
(
(
(
(14) Cyclic Products 2 or 3; Typical Procedure: To a solution
of 1 (0.5 mmol) in MeCN (6 mL) in a dry Schlenk tube was
slowly added p-MeC H SCl or PhSeCl (0.75 mmol) in
(
8) Shinitzky, M.; Friedman, P.; Haimovitz, R. J. Biol. Chem.
6
4
1993, 268, 14109.
MeCN (2 mL) at –30 °C under a N atmosphere. After the
2
(
9) Friedman, P.; Haimovitz, R.; Markman, O.; Roberts, M. F.;
reaction was complete (monitored by TLC, ca. 30 min), the
reaction mixture was concentrated and the residue was
purified by flash chromatography on silica gel to give
product 2 or 3.
Shinitzky, M. J. Biol. Chem. 1996, 271, 953.
(
10) For recent references, see: (a) Meier, C.; Lorey, M.; Clercq,
E. D.; Balzarini, J. Bioorg. Med. Chem. Lett. 1997, 7, 99.
(b) Gypakis, A.; Wasner, H. K. Biol. Chem. 2000, 381,
Compound 2a
1
139. (c) Kaur, K.; Lan, M. J. K.; Pratt, R. F. J. Am. Chem.
Mp 54–55 °C. IR (KBr): 1616, 1285, 1116, 1037, 1005
–
1 1
Soc. 2001, 123, 10436. (d) Liu, Y.; Bruzik, K. S.;
Ananthanarayanan, B.; Cho, W. Bioorg. Med. Chem. 2003,
cm . H NMR (300 MHz, CDCl ): d = 7.40–7.38 (m, 2 H),
3
7.28–7.25 (m, 2 H), 5.05–4.92 (m, 1 H), 4.35–4.29 (m, 2 H),
1
1, 2471. (e) Wang, P.; Wu, P.; Egan, R. W.; Billah, M. M.
2.40 (s, 3 H), 1.85 (s, 3 H), 1.74 (s, 3 H), 1.38 (t, J = 6.6 Hz,
1
9
Gene 2003, 314, 15. (f) Fujiwara, Y.; Seboek, A.; Meakin,
S.; Kobayashi, T. J. Neurochem. 2003, 87, 1272.
3 H). F NMR (282 MHz, CDCl ): d = –101.08 (AB, dd,
3
J
= 308.7 Hz, JP-F = 95.6 Hz, J = 11.6, 10.1, 7.9 Hz).
H-F
F-F
3
1
(
g) Pelash, A.; Shinitzky, M. Biochem. Biophys. Res.
P NMR (121 MHz, CDCl ): d = –0.58 to –2.54 (m). EIMS:
3
+
Commun. 2004, 315, 1045.
m/z (%) = 348 (M , 29.56), 225 (35.63), 189 (100.00), 117
(56.26), 107 (27.57), 97 (56.06), 77 (58.91). Anal. Calcd for
C H F O PS: C, 51.72; H, 5.50. Found: C, 51.92; H, 5.49.
(
(
11) Frederickson, M.; Grigg, R. Org. Prep. Proced. Int. 1997,
29, 33.
1
5
19
2
3
12) (a) Ihara, M.; Hags, Y.; Yonekura, M.; Ohsawa, T.;
Compound 3a
Mp 56–57 °C. IR (KBr): 1621, 1285, 1027, 1001 cm . H
–
1 1
Fukumoto, K. J. Am. Chem. Soc. 1983, 105, 7345.
(
b) Mühlstädt, M.; Schubert, C.; Kleinpeter, E. J. Prakt.
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3
Chem. 1985, 2, 270. (c) Berthe, B.; Outurquin, F.; Paulmier,
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Outurquin, M.; Paulmier, C. J. Chem. Soc., Perkin Trans. 1
(m, 3 H), 5.41–5.29 (m, 1 H), 4.37–4.32 (m, 2 H), 1.85 (s, 3
1
9
H), 1.75 (s, 3 H), 1.40 (t, J = 7.2 Hz, 3 H). F NMR (282
MHz, CDCl ): d = –102.16 (AB, dd, J = 311.8 Hz,
3
F-F
3
1
2
001, 1, 37. (e) Jana, G.; Viso, A.; Diaz, Y.; Castillon, S.
JP-F = 95.6 Hz, JH-F = 10.2, 8.5, 7.9 Hz). P NMR (121
Eur. J. Org. Chem. 2003, 209. (f) Bugarcic, Z. M.;
Gavrilovic, M. Monatsh. Chem. 2003, 134, 1359.
MHz, CDCl ): d = –0.71 to –2.64 (m). EIMS: m/z (%) = 382
3
+
(M , 2.47), 381 (14.23), 223 (17.00), 133 (10.31), 117
(g) Marshall, J.; Wang, X. J. Org. Chem. 1990, 55, 2995.
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(100.00), 97 (35.47), 77 (50.49), 65 (10.49), 51 (18.10).
Anal. Calcd for C H F O PSe: C, 44.11; H, 4.49. Found:
C, 44.12; H, 4.60.
1
4
17
2
3
Synlett 2006, No. 14, 2227–2230 © Thieme Stuttgart · New York