Ring enlargement of cyclic acetals and ketals: A way to seven-membered nucleoside phostones

Article abstract of DOI:10.1021/ol7023899

Novel seven-membered nucleoside phostones were prepared by the reaction of chlorodiethyl phosphite with 3′,5′-acetals or ketals derived from xylo-dT. A mechanism for the ring enlargement was proposed, and support for it was provided by ab initio calculations.

Full text of DOI:10.1021/ol7023899

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5469-5472
Ring Enlargement of Cyclic Acetals and
Ketals: A Way to Seven-Membered
Nucleoside Phostones
Ondrˇej Pa´v,† Ivan Barv´ık,‡ Milosˇ Budeˇsˇ´ınsky´,† Milena Masoj´ıdkova´,† and
Ivan Rosenberg*,†
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech
Republic, FlemingoVo n. 2, 166 10 Prague 6, Czech Republic, and Institute of Physics,
Charles UniVersity, Ke KarloVu 5, 121 16 Prague 2, Czech Republic
iVan@uochb.cas.cz
Received October 1, 2007
ABSTRACT
Novel seven-membered nucleoside phostones were prepared by the reaction of chlorodiethyl phosphite with 3
′
,5′
-acetals or ketals derived
from xylo-dT. A mechanism for the ring enlargement was proposed, and support for it was provided by ab initio calculations.
Cyclic nucleoside phosphates (cNMP) are biologically
significant compounds that play a key regulatory role in cell
signaling and metabolism.1 Since these compounds have been
observed to modulate protein kinase activity, the search for
active analoguessagonists or antagonistssis highly desir-
able. Interest in these compounds is evident from the number
of commercially available modified 3′,5′-cyclic nucleotides
used for various biochemical and biological studies.2 Typical
modifications of cyclic nucleotides comprise either a change
of configuration of the sugar hydroxyls3,4 or a replacement
of both the bridging and nonbridging oxygen atoms of the
six-membered cyclic phosphodiester moiety with another
heteroatom. Thus, compounds with the modified phosphodi-
ester moiety, e.g., 5′C-SP(dO)O-3′C,5,6 5′C-OP(dO)S-3′C,7
5′C-N(R)P(dO)O-3′C,8 5′C-N(R)P(dS)O-3′C,9 5′C-OP(d
O)N(R)-3′C,10,11 5′C-OP(dS)N(R)-3′C,12 5′C-NH-P(dS)-
NH-3′C,12 5′C-CH2P(dO)O-3′C,13 5′C-CF2P(dO)O-3′C,14
and 5′C-OP(dO)CH2-3′C,15,16 have been prepared and
biologically evaluated. In contrast to nucleoside cyclothio-
phosphates and cyclophosphoamides, the three latter com-
pounds, i.e., six-membered cyclic nucleoside phosphonates
(nucleoside phostones) with the bridging P-C linkage,
exhibited extraordinary chemical and nuclease stabilities.13-16
A direct synthesis of simple, seven-membered phostones
via ring enlargement of six-membered acetals in their reaction
with 2-chloro[1,3,2]dioxaphospholane under Lewis acid
catalysis has already been described in the literature.17
(8) Murayama, A.; Jastorff, B.; Cramer, F.; Hettler, H. J. Org. Chem.
1971, 36, 3029.
(9) Jastorff, B.; Krebs, T. Chem. Ber. 1972, 105, 3192.
(10) Morr, M.; Kula, M. R.; Roesler, G.; Jastorff, B. Angew. Chem., Int.
Ed. Engl. 1974, 86, 308.
(11) Morr, M.; Kula, M. R.; Ernst, L. Tetrahedron 1975, 31, 1619.
(12) Morr, M.; Ernst, L. Chem. Ber. 1978, 111, 2152.
(13) Koh, Y.-H.; Shim, J. H.; Wu, J. Z.; Zhong, W.; Hong, Z.; Girardet,
J.-L. J. Med. Chem. 2005, 48, 2867.
† Academy of Sciences of the Czech Republic.
‡ Charles University.
(1) Alberts, B.; Bray, D.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.;
Walter, P. Essential Cell Biology; Garland Publishing, Inc.: New York,
1997; p 481.
(2) http://www.biolog.de.
(3) Hubert-Habart, M.; Goodman, L. J. Chem. Soc. [Sect. D], Chem.
Commun. 1969, 13, 740.
(4) Miller, J. P. AdV. Cycl. Nucleotide Res. 1981, 14, 335.
(5) Chladek, S.; Nagyvary, J. J. Am. Chem. Soc. 1972, 94, 2079.
(6) Shuman, D. A.; Miller, J. B.; Scholten, L. N.; Simon, L. N.; Robins,
R. K. Biochemistry 1973, 12, 2781.
(7) Morr, M.; Kula, M. R.; Roesler, G.; Jastorff, B. Angew. Chem., Int.
Ed. Engl. 1974, 13, 280.
(14) Matulic-Adamic, J.; Haeberli, P.; Usman, N. J. Org. Chem. 1995,
60, 2563.
(15) Jones, G. H.; Albrecht, H. P.; Damodaran, N. P.; Moffatt, J. G. J.
Am. Chem. Soc. 1970, 92, 5510.
(16) Morr, M.; Kakoschke, Ch.; Ernst, L. Tetrahedron Lett. 2001, 42,
8841.
10.1021/ol7023899 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

Moreover, a seven-membered carbohydrate 4,6-phostone was
obtained as an unexpected product from methyl 4,6-O-
benzylidene-D-galactopyranoside and triethyl phosphite under
TMSOTf catalysis.18 Our systematic study on the synthesis
and biological properties of the nucleoside phosphonic acids
and related compounds provided a number of structurally
diverse isopolar nucleotide analogues.19 Among them, a
seven-membered nucleoside phostone was prepared by
intramolecular esterification of adenosine-5′-O-methylphos-
phonic acid.20
furanose ring indicate that it adopts a 3E (C3′-endo)
conformation, while the annealed 1,3-dioxane ring is in a
chair form (Figure 1, form A).
In continuation of our research on the reactivity of alkyl
phosphites,21,22 we report here a synthetic route to a new
class of analogues of nucleoside-3′,5′-cyclophosphates 4
with a substituted seven-membered phostone ring. These
compounds were prepared by the reaction of cyclic 3′,5′-
acetals and ketals 2 with chlorodiethyl phosphite (Scheme
1). This reaction resulted in enlargement of the six-membered
Figure 1. Preferred conformations and selected observed NOE
contacts in compounds 2b and 2c (A) and 4b and 4c (B).
Scheme 1. Preparation of Nucleoside Phostones 4
Because the initially employed experimental conditions
for the reaction of acetals and ketals with triethyl phos-
phite in the presence of TMSOTf, which we took from the
recently published work,18 led to N-ethylthymine as a
product of cleavage of the glycosidic bond, we modified the
earlier established protocol.17 Using chlorodiethyl phos-
phite and SnCl4 catalysis, we transformed compounds 2a-c
into the appropriate phostones 3a-c in good yields. Under
these conditions, we did not observe the formation of
regioisomer 5 (Scheme 1). In the case of acetals 2b and 2c,
the reaction proceeded diastereoselectively (>95% de) with
retention of configuration on the acetal carbon atom. The R
configuration was again determined by 2D-ROESY NMR
experiments from the observed NOE contacts of proton
P-CHR-O to H-3′ and H-5′a in compounds 4b and 4c. The
vicinal couplings in furanose rings are very similar to those
found in 2b and 2c and indicate their 3E (C3′-endo)
conformation. Although the obtainable vicinal coupling con-
stants do not form a sufficient set for detailed conformation
analysis of the seven-membered ring, the above-discussed
NOE contacts strongly support a chair form B shown in
Figure 1.
acetal or ketal ring to that of a seven-membered phostone.
The starting compounds 2a-c were prepared by the
reaction of xylo-dT 1 with 2,2′-dimethoxypropane, benzal-
dehyde dimethyl acetal, and cyclohexylcarbaldehyde di-
methyl acetal, respectively, in the presence of p-toluene-
sulfonic acid (Scheme 1). In the case of acetals 2b and 2c,
the S epimer was the only isolated product. Its configuration
was determined by 2D-ROESY NMR experiments from the
observed NOE contacts of the O-CHR-O proton to H-3′ and
H-5′a in compounds 2b and 2c. The vicinal couplings in
In the case of 3′,5′-O-isopropylidene derivative 2a, we
examined the influence of several Lewis acids (SnCl4,
TMSOTf, BF3‚Et2O) and solvents (CH3CN, CH2Cl2) on the
course of the phosphonylation reaction in more detail. We
found that the reaction catalyzed by 0.1 equiv of SnCl4 or
TMSOTf proceeded very rapidly to afford the desired product
3a. On the other hand, the use of BF3‚Et2O resulted only in
the anomerization of the isopropylidene nucleoside 2a to
R-2a and in a partial hydrolysis of the thymine nucleobase.
Furthermore, the presence of 1.0 equiv of SnCl4 or TMSOTf
resulted in the anomerization of 2a and 3a and, thus, in the
isolation of 4a and R-4a in an equimolar ratio. Regardless
of the Lewis acid used, or its concentration, the phospho-
nylation reaction proceeded regioselectively and with reten-
tion of configuration at the acetal carbon atom. In contrast
to CH3CN, the use of CH2Cl2 as a solvent favored anomer-
ization (see part 5 in the Supporting Information).
(17) Krutskii, L. N.; Safiulina, O. Z.; Krutskaya, L. V.; Chernyak, E. I.;
Tsivunin, V. S. Zh. Obshch. Khim. 1983, 53, 1525.
(18) Moravcova, J.; Heissigerova, H.; Kocalka, P.; Imberty, A.; Sykora,
D.; Fris, M. Tetrahedron Lett. 2003, 44, 8797.
(19) Rosenberg, I. In Frontiers in Nucleosides and Nucleic Acids;
Schinazi, R. F., Liotta, D. C., Eds.; IHL Press: Tucker, GA, 2004; pp 519-
548.
(20) Holy, A.; Rosenberg, I. Metab. Enzymol. Nucleic Acids, Proc. Int.
Symp., 4th 1982, Meeting Date 1981, 119.
(21) Rosenberg, I.; Kralikova, S. Collect. Czech. Chem. Commun., Symp.
Ser. 1996, 61, S81.
(22) Endova, M.; Masojidkova, M.; Budesinsky, M.; Rosenberg, I.
Tetrahedron 1998, 54, 11187.
5470
Org. Lett., Vol. 9, No. 26, 2007

Scheme 2. Proposed Mechanism of Ring Enlargement (Im ) Intermediate)
On the basis of our observation that the phosphonylation
further research. Thus, we studied the hydrolysis of phostones
3 to the free phosphonic acids and monomethyl esters using
aqueous 1 M sodium hydroxide and methanolic 1 M sodium
methoxide, respectively. Suprisingly, the expected products
of the ring opening were not observed, and phostonic acids
4 were found as the only products even at elevated temper-
ature. Under the same experimental conditions, the seven-
membered carbohydrate phostone18 was readily cleaved in
1 M aqueous sodium hydroxide to the corresponding
phosphonic acid.
To support the proposed reaction mechanism, we at-
tempted to obtain some relevant data from the ab initio
calculations. The analysis of conformational energies, transi-
tion states, IRC, and electrostatic potential distributions of
model systems representing compounds 2 and 4 supported
the reaction mechanism depicted in Scheme 2.
reaction also proceeded, though very slowly, under heating
and in the absence of Lewis acid, we proposed the reaction
mechanism depicted in Scheme 2. We reasoned that the
(EtO)2P+ cation23 (in fact, Lewis acid) formed via heterolysis
of (EtO)2PCl coordinated to the 5′-oxygen atom, and as a
consequence, a partial positive charge was induced on the
acetal carbon atom. Ring opening of this “activated” acetal
Im1 followed by the intramolecular Arbuzov reaction of Im2
could lead to the cyclic phosphonium intermediate Im3,
which in turn could split off the ethyl ester group with the
assistance of chloride anion to afford product 3. Very
probably, chloride anion participates both in the acetal ring
opening (Im1) preventing racemization on the acetal carbon
atom and in the stabilization of the phosphonium intermediate
Im3. In order to check a possible influence of traces of HCl
as a Lewis acid present in (EtO)2PCl on the course of the
phosphonylation reaction, we added 0.1 equiv of HCl
(anhydrous solution in DMF) to the reaction mixture. Cyclic
phosphonates 3a-c were not formed, and we observed only
the cleavage of the nucleoside bond of 2a-c.
The regioselectivity of the phosphonylation reaction could
be explained on the basis of the electrostatic potential
map of compound 2b (Figure 2). The possible attack on
In order to explain the accelerating effect of the used Lewis
acids (SnCl4 and TMSOTf) on the phosphonylation reaction,
we examined the 31P NMR spectra of an equimolar mixture
of (EtO)2PCl and the appropriate Lewis acid in two solvents
(CH3CN, CH2Cl2), expecting the formation of (EtO)2P+
cation (shift from ∼160 to ∼300 ppm) as it was described
for the (EtO)2PCl-AlCl3 system.23 However, no signal at
300 ppm was detected in any case. In contrast to SnCl4,
AlCl3 is a much stronger Lewis acid providing, in the
reaction with (EtO)2PCl, the [(EtO)2P]+[AlCl4]- speciessa
source of the strong (EtO)2P+ electrophile. In summary,
the results obtained suggest that a mechanism involving
activation of the acetal ring with Lewis acid as the first
reaction step should indeed be considered if Lewis acids
are employed as catalysts (see part 8 in the Supporting
Information).
Figure 2. Electrostatic potential distribution in compound 2b:
positive, blue; negative, red (for XYZ coordinates, see the Supporting
Information).
the acetal carbon atom by chloride anion is allowed from
the front side only, as to attack the acetal from the back
side is shielded by the electronegative 4′- and 5′-oxygen
atoms.
Ab initio calculations also revealed a tendency of chloride
anion to attack acetal carbon from the front side whereas
(EtO)2P+ was attracted to the 5′-hydroxyl (Figure 3).
Having obtained the phostones 3, we attempted to open
their seven-membered ring to obtain substituted 3′-O-
methylphosphonates with defined chirality on the carbon
atom of the P-C bond, a feature of importance for our
(23) Baenziger, N. C.; Wiemer, D. F. J. Heterocycl. Chem.1996, 33, 979.
Org. Lett., Vol. 9, No. 26, 2007
5471

of six-membered xylo-dT 3′,5′-acetals and ketals with
chlorodiethyl phosphite in the presence of catalytic amount
of SnCl4. We found that this reaction proceeded in a regio-
and diastereoselective manner. Proposed reaction mechanism
was supported by a series of ab initio calculations. The
elaborated methodology is currently being applied to the
acetals and ketals of other nucleosides.
Acknowledgment. Support by Grant Nos. 203/05/0827
and 202/05/0628 (Czech Sci. Found.), Res. Centres LC06061
and LC06077, and Grant No. MSM 0021620835 (Czech M.
of Educ.) under research project Z40550506 is gratefully
acknowledged. We are indebted to the staff of the Depart-
ment of Mass Spectrometry (IOCB) for measurements of
HR-MS spectra and Dr. Z. Tocik for valuable discussions.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
Details of the phosphonylation reaction and coordinates
obtained from ab initio calculations. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 3. Structures of intermediates Im1 and Im2 obtained from
ab initio calculations (Scheme 2, the reaction of acetal 2b with
(EtO)2PCl).
In conclusion, we have synthesized novel seven-membered
nucleoside phostones branched in R-position to the phos-
phorus atom, using a simple method based on the reaction
OL7023899
5472
Org. Lett., Vol. 9, No. 26, 2007