A flexible, efficient synthesis of (±)-carbocyclic phosphonic acid nucleoside derivatives

Article abstract of DOI:10.1055/s-2005-863745

An efficient and flexible synthesis of cyclopentane and hydroxylated cyclopentane phosphonic acid analogues is described. The key step involves the opening of an epoxide with either a nucleoside base or a selenyl anion to access the target molecules.

Full text of DOI:10.1055/s-2005-863745

LETTER
765
A Flexible, Efficient Synthesis of ( )-Carbocyclic Phosphonic Acid Nucleoside
Derivatives
Synthesis of
(
h)-Carbocycl
i
ic Phos
l
phonic
l
A
cid N
i
ucleos
p
ide
D
erivatives Wainwright,a Adrian Maddaford,a Richard Bissell,a Ray Fisher,a David Leese,a Andrew Lund,a
Karen Runcie,a Peter S. Dragovich,c Javier Gonzalez,c Pei-Pei Kung,c Donald S. Middleton,b David C. Pryde,*b
Peter T. Stephenson,b Scott C. Suttonc
a
Peakdale Molecular Ltd., Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak, SK23 0PG, UK
b
Pfizer Global Research and Development, Ramsgate Road, Sandwich, CT13 9NJ, UK
E-mail: David.Pryde@pfizer.com
c
Pfizer Global Research and Development, 10777 Science Centre Drive, San Diego, California 92121, USA
Received 9 December 2004
ative.6 Such routes could be adapted to access phosphonic
Abstract: An efficient and flexible synthesis of cyclopentane and
acids, however, we wished to maximise the flexibility of
our route, and chose to synthesise all targets via the readi-
hydroxylated cyclopentane phosphonic acid analogues is described.
The key step involves the opening of an epoxide with either a nu-
ly prepared epoxy-alcohol 4. In this strategy, nucleoside
bases can be added to the meso-trans-epoxy-phosphonyl-
methyl cyclopentane 5 to generate directly 3¢-deoxy-
carbocyclic nucleosides 7. Conversely, the cis-epoxy-
phosphonylmethyl cyclopentane 6 could be converted to
an allyl species onto which bases could be appended using
Pd-p-allylation chemistry,7 providing access to a range of
ribose 10, arabinose 11, cyclopentane 9 and cyclopentene
8 analogues. This article describes how this strategy was
put into practice.
cleoside base or a selenyl anion to access the target molecules.
Key words: phosphonic acids, ribose analogues, nucleosides,
epoxide
Chemotherapies based on the administration of analogues
of nucleosides and deoxynucleosides 1 have proved suc-
cessful against a range of cancers and viral infections such
as HIV, cytomegalovirus, and herpes virus.1 In each case,
intracellular processing of the nucleoside to its triphos-
phate 2 generates the active form of the nucleoside.2 This
phosphorylation sequence is often stepwise, and per-
formed by more than one cellular kinase, and the initial
formation of the nucleoside monophosphate is often the
most difficult step in the sequence. Strategies to facilitate
or bypass this first phosphorylation step have included the
use of prodrugs of the pre-formed monophosphate.3 Phos-
phonic acids 3 are rather more chemically stable ana-
logues of the monophosphate which in some cases can
still undergo phosphorylation and generate effective mim-
ics of a nucleoside triphosphate (Figure 1).4
O
Base
OH
O
O
P
P
O
R
O
OH
OH
O
R
5
4
OH
7
Base
Base
O
O
O
P
O
R
P
OH
OH
P
O
OH
O
R
8
OH
9
6
Base
OH
O
P
OH
OH
Base
OH
O
HO
P
OH
O
P
O
P
O
P
O
11
Base
HO
O
Base
OH
Base
O
HO
HO
P
O
O
O
OH
OH
OH OH OH
10
OH
OH
OH
3
2
1
Scheme 1 An epoxide-opening strategy to access cyclopentene 8,
cyclopentane 9, hydroxycyclopentane 7, cis-dihydroxycyclopentane
10 and trans-dihydroxycyclopentane 11 phosphonic acid nucleoside
mimics.
Figure 1 Nucleosides, nucleoside triphosphates, and carbocyclic
phosphonic acid nucleoside mimics.
We have been investigating synthetic procedures which
would allow us to access a range of phosphonic acid ana-
logues of carbocyclic nucleosides.5 Herein, we wish to re-
port a flexible synthesis of hydroxy, dihydroxy and
dideoxy versions using an efficient epoxide-opening strat-
egy outlined in Scheme 1. Carbocyclic ribose analogues
have been synthesised in a variety of ways, usually start-
ing with ribose itself or a substituted cyclopentane deriv-
The trans-epoxy-alcohol 4a8 was synthesised in six
straightforward steps (Scheme 2) from dimethyl mal-
onate, by a sequence of allylation, RCM,8a saponification,
reduction, alcohol silyl-protection and a trans-selective
epoxidation.9 The latter process afforded a 3:1 mixture of
trans:cis epoxides from which the trans-isomer was iso-
lated in 40% yield following silica gel column chromatog-
raphy. Compound 4a was converted to the corresponding
iodide10 and then to the diisopropyl phosphonate ester in a
standard Arbuzov reaction. We have found throughout
this work that diisopropyl phosphonates give generally
cleaner reactions than the corresponding ethyl or methyl
SYNLETT 2005, No. 5, pp 0765–0768
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863745; Art ID: D36004ST
© Georg Thieme Verlag Stuttgart · New York

766
P. Wainwright et al.
LETTER
O
phosphonate esters. Reaction of this epoxide with adenine
and Cs2CO3 gave a 41% yield of the racemic carbocyclic
nucleoside mimic. The epoxide-opening reaction did
prove to be quite sluggish and required extended reaction
times in hot DMF to give the desired alcohol product.
Standard TMSBr-mediated deprotection of the phospho-
nate ester provided the corresponding phosphonic acid
1915 in 40% yield.
PhSe OAc
b,c
a
OH
OH
OTBDMS
16
4b
20
d,e
OAc
O
OAc
a
b
MeO2C
CO2Me
NH
i,j
f,g,h
N
O
MeO2C
CO2Me
MeO2C
CO2Me
13
P
12
O
O
P
O
14
OH
O
OH
OH
c
21
23
22
O
e,f
d
Scheme 3 a. VO(acac)2, TBHP, CH2Cl2, 48 h, r.t., 89%; b. TB-
DMSCl, imidazole, CH2Cl2, 2 h, r.t., 100%; c. (PhSe)2, NaBH4,
EtOH, 1 h, 0 °C to r.t., then 1 h, reflux, then Ac2O, Et3N, DMAP,
CH2Cl2, 16 h, 0 °C to r.t., 100%; d. H2O2, Hünigs base, 1-butanol,
CH2Cl2, 1 h, 50 °C, 79%; e. TBAF, THF, 1 h, r.t., 40%; f. TsCl, Et3N,
DMAP, 48 h, 0 °C, 98%; g and h. NaI, butanone, 5 h, reflux, then
P(Oi-Pr)3, 65 h, 120 °C, 36%; i. uracil, Pd(PPh3)4, THF, DMSO, LiH,
0.5 h, 50 °C, 47%; j. TMSBr, MeCN, 16 h, r.t., 54%.
CO2Me
OH
16
OTBDMS
g, h
17
15
O
NH2
N
O
l,m
i, j, k
O
P
N
N
O
N
P
Phosphonate ester 24 could be simply hydrogenated under
Pd catalysis and deprotected to give the analogous cyclo-
pentane 25 (Scheme 4). Phosphonate ester 24 also served
as an ideal material to introduce a cis-dihydroxyl func-
tionality through simple cis-hydroxylation. When 24 was
treated with OsO4 and NMO in a mixture of acetone and
water, two major products were formed. When these were
isolated by silica gel chromatography, we were surprised
to discover that both the cis- (27) and trans-dihydroxy
(30) cyclopentanes had formed in the osmylation reac-
tion.14 We rationalised this finding through the intermedi-
ate cyclic osmate 26 undergoing competitive hydrolysis
by water to give the cis isomer 27 (path x), or being cap-
tured by the phosphonyl group through an intermediate
such as 29, followed by hydrolysis (path y) leading to the
trans-isomer 30. Deprotection of each isomer separately
gave the final phosphonic acids. The cis to trans ratio of
the osmylation step always favoured the trans-isomer by
an approximately 3:1 ratio. It was found that during the
TMSBr-mediated deprotection step, the separated cis-di-
hydroxy phosphonate 27 underwent further 2¢-isomerisa-
tion to give a 2:1 ratio of diol phosphonic acids in favour
of the trans-isomer. This latter isomerisation presumably
proceeds by activation of the 2¢-OH by either a proton or
TMS, followed by SN2 displacement by the phosphonate
ester, similar to path y described in Scheme 4.17
OH
OH
O
O
18
OH
4a
OH
19
Scheme 2 a. NaOMe, allyl bromide, MeOH, 3 h, 0 °C to r.t., 87%;
b. Grubbs’ catalyst, CH2Cl2, 72 h, reflux, 93%; c. LiCl, DMSO, 150
°C, 3 h, 78%; d. LiAlH4, THF, 1 h, 0 °C to r.t., 72%; e. TBDMSCl,
imidazole, DMF, 16 h, r.t., 96%; f. MCPBA, CH2Cl2, 1 h, 0 °C to r.t.,
97%; g and h. TBAF, THF, 1 h, r.t., then silica gel chromatography,
40% (for trans-isomer); i. TsCl, Et3N, DMAP, CH2Cl2, 16 h, 0 °C,
93%; j. NaI, butanone, 5 h, reflux, 91%; k. P(Oi-Pr)3, 30 h, 120 °C,
58%; l. adenine, Cs2CO3, DMF, Kryptofix, 9 d, 120 °C, 41%; m.
TMSBr, MeCN, 16 h, r.t., 40%.
Several other carbocyclic phosphonic acids were synthe-
sised according to Scheme 3 and Scheme 4. The cis-ep-
oxy-alcohol 4b was produced exclusively from the
hydroxymethyl cyclopentene 16 using vanadyl(acac)
promoted epoxidation11 and then reacted with NaSePh,
generated in situ with diphenyldiselenide and NaBH4,12
and the intermediate seleno-alcohol protected as its ace-
tate ester.
Hydrogen peroxide-mediated selenide oxidation and
elimination provided the allyl acetate 2116 in excellent
yield. Deprotection of the silyl ether and conversion of the
resulting alcohol to its phosphonate ester 22 was carried
out according to the sequence described above. The allyl
acetate was activated with tetrakis-triphenylphosphine
palladium, and the resulting p-allyl palladium species
alkylated with uracil.7 This resulted in a single regioiso-
mer of a diastereoisomerically pure product,13 which
when deprotected under standard TMSBr conditions gave
the cyclopentene phosphonic acid 23.
Above is described a flexible synthesis of a range of cy-
clopentane phosphonic acid analogues, all based on an ep-
oxide ring-opening strategy. Application of this chemistry
to further examples of racemic nucleoside mimics, and
asymmetric versions thereof, will be reported in due
course.
Synlett 2005, No. 5, 765–768 © Thieme Stuttgart · New York

LETTER
Synthesis of (±)-Carbocyclic Phosphonic Acid Nucleoside Derivatives
767
O
O
NH
N
NH
a,b
N
O
P
O
O
O
P
O
OH
O
OH
25
24
c
O
O
O
NH
N
O
P
NH
NH
O
N
b
N
O
P
O
OH
P
y
O
HO
O
Path x
O
O
O
O
x
O
O
Os
OH
HO
OH
HO
O
O
27
H2O
28 (+31)
26
Path y
O
H
O
O
O
Os
O-
O
O
NH
NH
P+ O
N
H
OH
P
b
N
O
HO
H2O
U
O
O
O
P
O
O
O
29
OH
HO
OH
HO
31
30
Scheme 4 a. H2 (1 atm.), Pd/C (20%), EtOH, 18 h, r.t., 100%; b. TMSBr, MeCN, 16 h, r.t., 20% for compound 25; 12% for compound 31,
29% for compound 28; c. OsO4, NMO, acetone, H2O, 16 h, 50 °C, 66% overall (22% of 27, 44% of 30).
(13) Assumed to be the diastereoisomer shown by direct analogy
References
to literature reports for such p-allyl Pd-mediated base
attachments.7.
(1) (a) de Clercq, E. J. Clin. Virol. 2001, 22, 73. (b) de Clercq,
E. J. Clin. Virol. 2004, 30, 115. (c) Johnson, S. A. Expert
Opin. Pharmacother. 2001, 2, 929.
(2) See for example: el Kouni, M. H. Curr. Pharm. Des. 2002,
8, 581; and references therein.
(14) Assignment of facial selectivity for the initial osmylation,
and cis- and trans-diols was made by proton NMR methods
(Figure 2), by firstly rigorously assigning each proton using
COSY, followed by NOE experiments (vide infra).
(3) (a) See for example: Kukhanova, M.; Krayevsky, A.;
Prusoff, W.; Cheng, Y. C. Curr. Pharm. Design 2000, 6,
585; and references therein. (b) Erion, M. D.; Raja Reddy,
K.; Boyer, S. H.; Matelich, M. C.; Gomez-Galeno, J.;
Lemus, R. H.; Ugarkar, B. G.; Colby, T. J.; Schanzer, J.; van
Poelje, P. D. J. Am. Chem. Soc. 2004, 126, 5154.
(4) Dando, T.; Plosker, G. Drugs 2003, 63, 2215.
(5) For a recent review of ribose-modified nucleosides, see:
Ichikawa, E.; Kato, K. Synthesis 2002, 1.
(6) Ravenscroft, P.; Newton, R. F.; Scopes, D. I. C. Tetrahedron
Lett. 1986, 27, 747.
Figure 2 NOE assignments for the cis-diol 27 and the trans-diol 30.
(7) (a) Ogawa, A.; Shuto, S.; Tanaka, M.; Sasaki, T.; Mori, S.;
Shigeta, S.; Matsuda, A. Chem. Pharm. Bull. 1999, 47,
1000. (b) Shi, J.; Schinazi, R. F. Nucleosides, Nucleotides
Nucleic Acids 2001, 20, 1367. (c) Hong, J. H.; Shim, M. J.;
Ro, B. O.; Ko, O. H. J. Org. Chem. 2002, 67, 6837.
(d) Crimmins, M. T.; King, B. W.; Zuercher, W. J.; Choy, A.
L. J. Org. Chem. 2000, 65, 8499.
(8) (a) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 11312. (b) Depres, J.-P.; Greene, A. E. J.
Org. Chem. 1984, 49, 928.
(9) Agrofoglio, L.; Condom, R.; Guedj, R. Tetrahedron Lett.
1992, 33, 5503.
(10) Cremer, S. E.; Blankenship, C. J. Org. Chem. 1982, 47,
1626.
(11) Asami, M.; Takahashi, J.; Inoue, S. Tetrahedron:
Asymmetry 1994, 5, 1649.
(12) Shi, J.; McAtee, J.; Wirtz, S.; Tharnish, P.; Juodawlkis, A.;
Liotta, D. C.; Schinazi, R. F. J. Med. Chem. 1999, 42, 859.
(15) Experimental Procedure, Preparation of 19.
To a solution of 6-amino-purine (1 g, 7.4 mmol) in N,N-
dimethylformamide (160 mL) was added Cs2CO3 (4.82 g,
14.8 mmol, 2 equiv), Kryptofix 2.2.2 (279 mg, 0.74 mmol,
0.1 equiv) and 4a (4.27 g, 16.3 mmol, 2.2 equiv). The
reaction mixture was stirred under argon at 120 °C for 4 d.
After this time, HPLC analysis indicated that the reaction
was 20% complete, therefore a further 1.94 g (1 equiv) 4a
were added and stirring continued at 120 °C for a further 5
d. The reaction mixture was then cooled, concentrated in
vacuo purified by flash chromatography (silica, 5–20%
MeOH in CH2Cl2) to give 1.2 g (41%) of the phosphonate
ester as a yellow solid; mp 157–159 °C. 1H NMR (CD3OD):
d = 1.31 (d, 12 H), 1.90–2.20 (m, 5 H), 2.60–2.80 (m, 2 H),
4.65 (m, 2 H), 8.16 (2 × s, 2 H); LRMS (ES+): m/z (rel.
int.) = 398.24 [M + H]+. Chemical purity by HPLC, Synergy
Synlett 2005, No. 5, 765–768 © Thieme Stuttgart · New York

768
P. Wainwright et al.
LETTER
Hydro RP18 4.6 × 150 mm, 0–40% MeCN over 20 min then
held for 5 min, aq phase 20 mM NaH2PO4, pH 2, 93.7% (260
nm). Bromotrimethylsilane (4.9 mL, 3.7 mmol, 3.3 equiv)
was added to a portion of this ester (450 mg, 1.13 mmol) in
MeCN (10 mL) and then stirred overnight at r.t. The reaction
mixture was concentrated in vacuo, added to H2O (10 mL)
and adjusted to pH 4.5 with 1 M NaOH solution. After
removing the solvent in vacuo the residue was added to H2O
(3 mL). Then, 5 drops of TFA were added and the resultant
solution purified by preparative HPLC. Freeze drying gave
260 mg (74%) of 19 as a white solid. 1H NMR (18% DCl in
D2O): d = 0.15–0.40 (m, 5 H), 0.75–0.90 (m, 2 H), 2.90 (m,
1 H), 3.25 (m, 1 H), 6.85 (s, 1 H), 7.85 (s, 1 H). Rf = 0.6
(1:1:1:1:1 toluene–acetone–BuOH–H2O–HOAc). LRMS
(ES+): m/z (rel. int.) = 314.10 [M + H]+. Chemical purity by
HPLC, Synergy Hydro RP18 4.6 × 150 mm, 0–20% MeCN
over 20 min then held for 5 min, aq phase 20 mM NaH2PO4,
pH 7, 96.97% (261 nm).
mixture was then allowed to cool to r.t. and 1 M citric acid
(200 mL) was added. The organic layer was washed with sat.
NaHCO3 (200 mL) and brine (200 mL), and was then
concentrated in vacuo. The residue was dissolved in hexane
(500 mL) and washed with H2O (2 × 500 mL). The organic
phase was filtered and concentrated under vacuum to give 21
(10 g, 79%) as a brown oil. 1H NMR (CDCl3): d = 0.06 (s, 6
H), 0.85 (s, 9 H), 1.49 (dt, 1 H), 2.02 (s, 3 H), 2.39 (dt, 1 H),
2.80 (m, 1 H), 3.52 (d, 2 H), 5.62 (m, 1 H), 5.84 (m, 1 H),
6.02 (m, 1 H).
(17) Experimental Procedure, Preparation of 31.
The cyclopentene 24 (1.63 g, 4.60 mmol) was dissolved in
acetone (5 mL) and to this NMO (539 mg, 9.2 mmol) was
added followed by 1% OsO4 in H2O (2.5 mL). This mixture
was heated at 50 °C overnight. More NMO (50 mg, 0.85
mmol) was added and stirred for a further 2 h at 50 °C. The
solution was then concentrated by evaporation and purified
by flash chromatography (85:15 CH2Cl2–MeOH) to give 27
(220 mg, 0.56 mmol, 12%) and 30 (530 mg, 1.36 mmol,
29%). Analytical data for 27: Rf = 0.3 (10% MeOH in
CH2Cl2). 1H NMR (CD3OD): d = 1.30 (d, 12 H), 1.70 (m, 1
H), 1.90 (m, 1 H), 2.15 (m, 2 H), 2.30 (m, 1 H), 4.05 (t, 1 H),
4.20 (dd, 1 H), 4.65 (m, 2 H), 5.10 (m, 1 H), 5.65 (d, 1 H),
7.90 (d, 1 H). Analytical data for 30: Rf = 0.2 (10% MeOH
in CH2Cl2). 1H NMR (CD3OD): d = 1.30 (d, 12 H), 1.60 (m,
1 H), 1.80 (m, 1 H), 2.15 (m, 2 H), 2.35 (m, 1 H), 3.80 (t, 1
H), 4.20 (t, 1 H), 4.45 (m, 1 H), 4.65 (m, 2 H), 5.65 (d, 1 H),
7.60 (d, 1 H). Trimethylsilylbromide (1.8 mL, 13.6 mmol)
was added to a stirred solution of 30 (530 mg, 1.36 mmol) in
MeCN (20 mL) under an atmosphere of nitrogen, the
reaction mixture was stirred overnight at r.t. The reaction
was not complete and therefore more trimethylsilylbromide
(2 mL) was added. This mixture was left at r.t. for a further
2 d. The solvent was then removed under vacuum. Then,
H2O (10 mL) was added to the reaction mixture, which was
basified with 1 M aq NaOH and subsequently acidified with
TFA. The solvent was removed under reduced pressure and
H2O (10 mL) was added. The crude product was purified by
HPLC (0.1% TFA in H2O 10 min, then 10% MeCN,
Atlantis) and freeze dried to give 31 (245 mg, 0.80 mmol,
59%). Rf = 0.30 (1:1:1:1:1 toluene–acetone–butan-1-ol–
H2O–HOAc). 1H NMR (D2O): d = 1.30–1.60 (m, 2 H), 1.70–
2.00 (m, 2 H), 2.15 (m, 1 H), 3.80 (m, 1 H), 4.00 (dd, 1 H),
4.90 (q, 1 H), 5.50 (d, 1 H), 7.80 (d, 1 H), 11.10 (s, 1 H).
LRMS (ES+): m/z (rel. int.) = 307.12 [M + H]+. Chemical
purity by HPLC, Synergy Hydro 4.6 × 150 mm, 1.0 mL/min,
0– 40% MeCN over 20 min then to 70% over 5 min, held at
70% for 5 min, aq phase 20 mM NaH2PO4, pH 2.5, 97.82%
(270 nm).
(16) Experimental Procedure, Preparation of 21.
To a stirred solution of diphenyl diselenide (180 g, 0.58 mol,
1 equiv) in EtOH (8 L) at 0 °C was slowly added in small
portions NaBH4 over 70 min. Compound 4b (262 g, 1.15
mol, 2 equiv) was then added dropwise to the reaction
mixture over 15min and the solution was allowed to warm to
r.t. The reaction mixture was subsequently heated at reflux
for 1 h, air was blown over the cooled solution, and the
solvent was removed in vacuo. The residue was dissolved in
CH2Cl2 (2 L), the organic fraction was washed with H2O
(2 × 300 mL) and brine (300 mL), dried over MgSO4, and
the solvent was removed in vacuo. The crude hydroxy-
selenide (39 g, 88.7 mmol, 1 equiv) was subsequently
dissolved in CH2Cl2 (400 mL) and Et3N (12.7 mL, 90.9
mmol, 1 equiv) and 4-(dimethylamino)pyridine (4 mg, 0.033
mmol) were added. The reaction mixture was then cooled to
0 °C and acetic anhydride (8.5 mL, 90.1 mmol, 1 equiv) was
added dropwise over 15 min. The reaction mixture was then
stirred at r.t. overnight. Then, CH2Cl2 (1 L) and H2O (1 L)
were added, the organic layer was separated, washed with
H2O and brine, and the solvent was removed in vacuo to give
crude 20 (450 g, 100%) as an oil. 1H NMR (CDCl3): d = 0.02
(s, 6 H), 0.87 (s, 9 H), 1.43 (m, 1 H), 1.83 (m, 1 H), 1.92 (s,
3 H), 2.02 (m, 1 H), 2.26–2.39 (m, 2 H), 3.51 (d, 2 H), 3.64
(m, 1 H), 5.11 (m, 1 H), 7.22–7.29 (m, 3 H), 7.51–7.62 (m,
2 H). A portion of crude 20 (20 g, 48.2 mmol, 1 equiv) was
taken up and stirred in CH2Cl2 (150 mL) at 0 °C and to this
was added 35% aq H2O2 (50 mL) and N,N-diisopropyl-
ethylamine (18.5 mL, 106 mmol, 2.2 equiv). After stirring
for 15 min, 1-BuOH (75 mL) was added and the reaction
mixture was heated at 50 °C for 40 min. The reaction
Synlett 2005, No. 5, 765–768 © Thieme Stuttgart · New York