Stereoselective route to oxetanocin carbocyclic analogues based on a [2 + 2] photocycloaddition to a chiral 2(5H)-furanone

Article abstract of DOI:10.1021/ol0710616

The synthesis of the trisubstituted cyclobutane 7, which is a suitable precursor for the preparation of oxetanocin carbocyclic analogues, is described. The key step involves a regio- and diastereoselective [2 + 2] photochemical reaction of ketene diethyl

Full text of DOI:10.1021/ol0710616

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2827-2830
Stereoselective Route to Oxetanocin
Carbocyclic Analogues Based on a
[2
+ 2] Photocycloaddition to a Chiral
2(5H)-Furanone
Albert Rustullet, Ramon Alibe´s,* Pedro de March, Marta Figueredo, and
Josep Font
Departament de Qu´ımica, UniVersitat Auto`noma de Barcelona,
08193 Bellaterra, Spain
ramon.alibes@uab.cat
Received May 7, 2007
ABSTRACT
The synthesis of the trisubstituted cyclobutane 7, which is a suitable precursor for the preparation of oxetanocin carbocyclic analogues, is
described. The key step involves regio- and diastereoselective [2 2] photochemical reaction of ketene diethyl acetal with
(S)-5-pivaloyloxymethyl-2(5H)-furanone, 3. As an application of this methodology, ( )-cyclobut-A has been prepared from the intermediate 7.
a
+
−
Oxetanocin-A, 1a, is a naturally occurring oxetane adenine
nucleoside (Figure 1), which was isolated from the fermenta-
varicella zoster virus (VZV), human cytomegalovirus
(HCMV), and human immunodeficiency virus (HIV).2 More
recently, its synthetic analogues oxetanocin-G,3 1b, and
oxetanocin-T,4 1c, have also been described as potent
antiviral agents.
The unique structure of oxetanocin-A coupled with its
biological activity prompted organic chemists to explore the
potential of four-membered carbocyclic nucleosides. Thus,
in 1989, the syntheses of the oxetanocin analogues cyclobut-
A, 2a, and cyclobut-G, 2b, were described.5,6 It was found
that these compounds were active against a broad spectrum
of herpes viruses and HIV.7 Since then, the carbocyclic
analogues of oxetanocin-A have received considerable at-
Figure 1. Oxetanocins and carbocyclic analogues.
(2) Hoshino, H.; Shimizu, N.; Shimada, N.; Takita, T.; Takeuchi, T. J.
Antibiot. 1987, 40, 1077-1078.
tion broth of Bacillus megaterium1 in 1986. This compound
was found to exhibit a broad spectrum of antiviral activity,
including herpes simplex virus 1 and 2 (HSV-1, HSV-2),
(3) Nagahata, T.; Kitagawa, M.; Matsubara, K. Antimicrob. Agents
Chemother. 1994, 38, 707-712.
(4) Alder, J.; Mitten, M.; Norbeck, D.; Marsh, K.; Kern, E. R.; Clement,
J. AntiViral Res. 1994, 23, 93-105.
(1) (a) Shimada, N.; Hasegawa, S.; Harada, T.; Tomisawa, T.; Fujii, A.;
Takita, T. J. Antibiot. 1986, 39, 1623-1625. (b) Nakamura, H.; Hasegawa,
S.; Shimada, N.; Fujii, A.; Takita, T.; Iitaka, Y. J. Antibiot. 1986, 39, 1626-
1629.
(5) Honjo, M.; Maruyama, T.; Sato, Y.; Horii, T. Chem. Pharm. Bull.
1989, 37, 1413-1415.
(6) Ichikawa, Y.-I.; Narita, A.; Shiozawa, A.; Hayashi, Y.; Narasaka,
K. J. Chem. Soc., Chem. Commun. 1989, 1919-1921.
10.1021/ol0710616 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/21/2007

tention that has culminated in different total syntheses.8
Because opposite enantiomers can display different phar-
macological and toxicological properties,9 the synthesis of
enantiomerically pure compounds is required. Nevertheless,
among the reported investigations, only a few synthetic
approaches were devised to provide optically active car-
bocyclic oxetanocins (A and G), including optical resolution10
and stereoselective synthesis.11 Most of these approaches
involve a large number of steps or they present moderate
enantioselectivity, resulting in relatively low overall yields.
Consequently, a further refined synthetic approach to enan-
tiomerically pure oxetanocin carbocyclic analogues is still
awaited.
Scheme 1. Synthetic Strategy to Oxetanocin Cyclobutane
Analogues
As part of our efforts to synthesize novel cyclobutane
nucleosides and evaluate them as antiviral agents, herein we
describe a practical route to a suitably trisubstituted cyclobu-
tane, 7, which can be used as a key common intermediate
for the preparation of oxetanocin carbocyclic analogues. As
an application of this methodology, (-)-cyclobut-A has been
prepared.
(S)-5-Pivaloyloxymethyl-2(5H)-furanone, 3, was visualized
as an appropriate starting material to undertake the synthesis
of the target cyclobutane nucleosides through the strategy
depicted in Scheme 1. Our plan involved four main trans-
formations: (i) cyclobutanone construction by a regio- and
diastereoselective [2 + 2] photocycloaddition of 3 to 1,1-
diethoxyethylene, 4, followed by removal of the acetal group;
(ii) stereoselective reduction of the ketone; (iii) epimerization
at C-1′; and (iv) nucleobase introduction onto the cyclobutane
moiety of 7.
investigated. This photochemical reaction could lead to the
formation of up to four compounds, the head-to-head (HH)
and head-to-tail (HT) anti isomers and the HH and HT syn
isomers (Table 1). It has been reported that the photocy-
Table 1. Photochemical Reaction of Lactone 3 to
1,1-Diethoxyethylene, 4
Accordingly, our initial efforts focused on the preparation
of the key cyclobutanone unit 5. The photochemical reaction
of 5-substituted 2(5H)-furanones to ketene dialkyl acetals
has received little attention,12 and to the best of our
knowledge, a diastereoselective version has not yet been
(7) (a) Norbeck, D. W.; Kern, E.; Hayashi, S.; Rosenbrook, W.; Sham,
H.; Herrin, T.; Plattner, J. J.; Erickson, J.; Clement, J.; Swanson, R.;
Shipkowitz, N.; Hady, D.; Marsh, K.; Arnett, G.; Shannon, W.; Broder, S.;
Mitsuya, H. J. Med. Chem. 1990, 33, 1281-1285. (b) Field, A. K.; Tuomari,
A. V.; McGeever-Rubin, B.; Terry, B. J.; Mazina, K. E.; Haffey, M. L.;
Hagen, M. E.; Clark, J. M.; Braitman, A.; Slusarchyk, W. A.; Young, M.
G.; Zahler, R. AntiViral Res. 1990, 13, 41-52.
solventa
yieldb (%)
8/9/10/11c
HT/HH
anti/syn
acetonitrile
ether
hexane
61
75
72
50:22:21:7
58:34:5:3
52:39:6:3
72:28
92:8
91:9
71:29
63:37
58:42
(8) (a) Ichikawa, E.; Kato, K. Synthesis 2002, 1-28. (b) Ortun˜o, R. M.;
Moglioni, A. G.; Moltrasio, G. Y. Curr. Org. Chem. 2005, 9, 237-259
and references cited therein.
a Irradiation through a quartz filter at -20 °C. b Isolated yield of the
mixture of stereoisomers after column chromatography. c Isomer ratio from
GC analysis of the reaction crude.
(9) (a) Terry, B. J.; Cianci, C. W.; Hagen, M. E. Mol. Pharm. 1991, 40,
591-596. (b) Wang, P.; Gullen, B.; Newton, M. G.; Cheng, Y. C.; Schinazi,
R. F.; Chu, C. K. J. Med. Chem. 1999, 42, 3390-3399.
(10) Chemical resolution: (a) Hsiao, C.-N.; Hannick, S. M. Tetrahedron
Lett. 1990, 31, 6609-6612. (b) Bisacchi, G.; Braitman, A.; Cianci, C. W.;
Clark, J. M.; Field, A. K.; Hagen, M. E.; Hockstein, D. R.; Malley, M. F.;
Mitt, T.; Slusarchyk, W. A.; Sundeen, J. E.; Terry, B. J.; Tuomari, A. V.;
Weaver, E. R.; Young, M. G.; Zahler, R. J. Med. Chem. 1991, 34, 1415-
1421. Enzymatic resolution: (c) Cotterill, I. C.; Roberts, S. M. J. Chem.
Soc., Perkin Trans. 1 1992, 2585-2586.
cloaddition of cyclic enones to electron-rich alkenes occurs
with predictable regioselectivity, giving mainly HT adducts,13
although slight variations of the reaction conditions, par-
ticularly the solvent, can dramatically change the regio-
selectivity.14 Hence, we have examined the effect of the
(11) Enantioselective synthesis: Reference 6. Enzymatic synthesis: (a)
Jung, M. E.; Sledeski, A. W. J. Chem. Soc., Chem. Commun. 1993, 589-
591. Diastereoselective synthesis: (b) Ahmad, S. Tetrahedron Lett. 1991,
32, 6997-7000. (c) Izawa, T.; Ogino, Y.; Nishiyama, S.; Yamamura, S.;
Kato, K.; Takita, T. Tetrahedron 1992, 48, 1573-1580. (d) Brown, B.;
Hegedus, L. S. J. Org. Chem. 1998, 63, 8012-8018. Chiral pool
synthesis: (e) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1993,
34, 7639-7640.
(13) (a) Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am.
Chem. Soc. 1964, 86, 5570-5583. (b) Crimmins, M. T. Chem. ReV. 1988,
88, 1453-1473. (c) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem. ReV.
1993, 93, 3-22. (d) Schuster, D. I. In The Chemistry of Enones; Patai, S.,
Rappoport, Z., Eds.; Wiley: New York, 1989; pp 623-756.
(14) Lange G. L.; Decicco C.; Lee M. Tetrahedron Lett. 1987, 28, 2833-
2836 and references cited therein.
(12) (a) Tada, M.; Kokubo, T.; Sato, T. Tetrahedron 1972, 28, 2121-
2125. (b) Kosugi, H.; Sekiguchi, S.; Sekita, R.; Uda, H. Bull. Chem. Soc.
Jpn. 1976, 520-528.
2828
Org. Lett., Vol. 9, No. 15, 2007

solvent on the regio- and diastereoselectivity of the photo-
cycloaddition of 4 to furanone 3, which has previously shown
good facial selectivity in its photochemical reactions with
ethylene, acetylene, vinylene carbonate, and 1,2-dichloro-
ethylene.15
Scheme 2
Irradiation of a solution of lactone 3 (7.7 mM) and a 10-
fold excess of olefin 4 in acetonitrile with a high-pressure
mercury lamp through a quartz filter for 2 h at -20 °C
afforded the photoadducts 8-11 in 61% global yield and a
ratio 50:22:21:7 (Table 1). Since chromatographic separation
of these adducts was rather cumbersome, NMR analyses of
enriched samples had to be performed. The anti/syn config-
uration of the cycloadducts was determined by the value of
the coupling constant between H-4 and H-515 (∼2 Hz for
the anti isomers 8 and 10 and ∼ 6 Hz for the syn isomers 9
and 11), while the connectivity was established by HMBC
experiments, wherein a correlation between the acetal carbon
atom C-6 and proton H-4 is observed for the HT adducts 8
and 9.
An important solvent effect was noticed when the reaction
was performed in less polar solvents. In ether, after 2.5 h of
irradiation through a quartz filter, both the yield (75%) and
regioselectivity (HT/HH ) 92:8) were remarkably increased,
whereas the stereoselectivity decreased slightly (anti/syn )
63:37). Similar results were found in hexane. When the
reaction was carried out in acetone through a Pyrex filter,
only low yields of the expected cycloadducts were obtained
because the formation of an oxetane by addition of ketene
acetal 4 to acetone competed advantageously.12b
the corresponding aldehyde would epimerize easily.17 Dess-
Martin periodinane (DMP) oxidation of 6 furnished the
aldehyde 17 in 85% yield (Scheme 3), but the initial attempts
Scheme 3
For synthetic purposes, the photocycloaddition was per-
formed in ether and the reaction crude was treated with
p-TsOH in acetone without previous purification. This
protocol afforded a 2:1 mixture of the HT-anti and HT-syn
cyclobutanones, 5 and 12, easily separable by column
chromatography, from which the major isomer 5 could be
isolated in 46% yield for the two steps (Scheme 2).
The stereoselective reduction of ketone 5 from the less
hindered face of the cyclobutane, performed by reaction with
L-Selectride in THF at -78 °C, delivered alcohol 13 in
excellent yield. Subsequent silylation of the hydroxyl group,
followed by LiAlH4 reduction, provided triol 15 in 80% yield
for the two steps. Protection of the vicinal diol as the
isopropylidene acetal 6 was achieved in 82% yield by
reaction of 15 with acetone in the presence of anhydrous
copper sulfate and catalytic HCl.16 Other reaction conditions
such as treatment with 2,2-dimethoxypropane and catalytic
camphorsulfonic acid in acetone, or acetone/catalytic HCl,
furnished variable amounts of the seven-ring acetonide 16.
The next key transformation involved reversing the con-
figuration at C-1′ in 6. In view of the steric congestion
existent at the neighboring carbon atom, it was expected that
to epimerize it using Et3N,18 DBU in CH2Cl2,19 DMAP in
THF, or p-TsOH in CH2Cl2 met with failure, leading only
to recovery of the starting material or poor proportions of
the desired epimer. It was eventually found that treatment
of 17 with Na2CO3 in MeOH20 provided the trans aldehyde,
which was reduced immediately with NaBH4 to the corre-
sponding alcohol. The epimer 18 was isolated in 88% yield
for the two steps, along with a minor amount of 6 (7% yield).
The inversion of configuration at C-1′ of 18 was established
by a NOESY experiment, where cross-peaks between H-1′
and protons H-4′′ and H-4′endo and between H-3′ and
protons H-2′ and H-4′exo were observed.
(15) (a) Alibe´s, R.; Bourdelande, J. L.; Font. J.; Gregori, A.; Parella, T.
Tetrahedron 1996, 52, 1267-1278. (b) Alibe´s, R.; de March, P.; Figueredo,
M.; Font, J.; Fu, X.; Racamonde, M.; Alvarez-Larena, A.; Piniella, J. F.;
Parella, T. J. Org. Chem. 2003, 68, 1283-1289. (c) Alibe´s, R.; Bourdelande,
J. L.; Gregori, A.; Font, J.; Rustullet, A.; Parella, T. J. Carbohydr. Chem.
2003, 22, 501-511. (d) Alibe´s, R.; de March, P.; Figueredo, M.; Font, J.;
Racamonde, M.; Rustullet, A.; Alvarez-Larena, A.; Piniella, J. F.; Parella,
T. Tetrahedron Lett. 2003, 44, 69-71.
(17) Initial attemps to carry out the epimerization by transesterification
of lactone 14 (MeONa/MeOH) met with failure.
(18) Nicolaou, K. C.; Namoto, K.; Ritze´n, A.; Ulven, T.; Shoji, M.; Li,
J.; D’amico, G.; Liotta, D.; French, C. T.; Wartmann, M.; Altmann, K.-H.;
Giannakakou, P. J. Am. Chem. Soc. 2001, 123, 9313-9323.
(19) Pichon, C.; Alexandre, C.; Huet, F. Tetrahedron: Asymmetry 2004,
15, 1103-1111.
(16) Kotecha, N. R.; Ley, S. V.; Mantegani, S. Synlett 1992, 395-399.
(20) Johnson, C. R.; de Jong, R. L. J. Org. Chem. 1992, 57, 594-599.
Org. Lett., Vol. 9, No. 15, 2007
2829

Benzoylation of the primary alcohol of 18 under standard
conditions followed by selective removal of the silyl protect-
ing group with TBAF provided the key intermediate 7 in
84% yield for the two steps.
Once a practical route to 7 had been established, we turned
our attention to the preparation of (-)-cyclobut-A. The
displacement of a mesylate group by adenine was considered
as a plausible methodology to couple the purine base to the
cyclobutane moiety. Accordingly, cyclobutanol 7 was treated
with MsCl and Et3N in CH2Cl2 to afford mesylate 20 in 93%
yield (Scheme 4), which reacted with adenine in the presence
the amine group (NH2) and H-1′ as well as the dioxolane
methyne proton H-4′′, and also between H-8 and H-1′, are
consistent with a N-7 coupled nucleoside. The regiochemistry
of each product was also supported by the higher field
chemical shift value of adenine C-4 carbon of the N-9 isomer
21 (δ 150.2) compared to that of the N-7 isomer 22 (δ 160.6),
due to the larger steric congestion existing in the former.21
Removal of the protecting groups of 21 was accomplished
by sequential treatment with Na2CO3 in methanol and
trifluoroacetic acid-H2O giving 23 in 80% overall yield.
Oxidative cleavage of the vicinal diol of 23 with NaIO4,
followed by reduction of the intermediate aldehyde with
NaBH4, provided the target (-)-cyclobut-A as a crystalline
solid in 84% overall yield. Its NMR spectra and physical
properties matched with those previously reported in the
literature, [R]D -14.3 (c 0.7, H2O) [lit.10b [R]D -13.5 (c 1.0,
H2O)].
Scheme 4
The synthetic intermediate 23 is a cyclobut-A nucleoside
analogue bearing an additional hydroxymethyl group. Hence,
we decided to screen it for antiviral activity. As a preliminary
test, it has been evaluated for anti-HIV activity. This
compound was found to be inactive against HIV-1 NL4-3
strain in MT-4 cells at concentrations up to 25 µg/mL.
In summary, we have reported a practical synthesis of the
trisubstituted cyclobutane 7, which is a versatile precursor
for the preparation of oxetanocin carbocyclic analogues.
From this intermediate, we have completed the synthesis of
(-)-cyclobut-A, 2a, in six steps and 28% overall yield.
Acknowledgment. We acknowledge financial support
from DGES (CTQ2004-02539) and CIRIT (2001SGR00178)
and grant from the Generalitat de Catalunya to (A.R.). We
thank Dr. Jose´ A. Este´ of the Irsicaixa Foundation, Hospital
Universitari Germans Trias i Pujol, for the biological results.
of K2CO3 and 18-crown-6 ether, in DMF at 120 °C for 7 h,
furnishing the expected N-9-coupled product 21 in 45% yield,
along with traces of the N-7 regioisomer 22. Extensive NMR
spectral data, including HMBC and NOESY experiments,
provided strong support for the structures of compounds 21
and 22. The assignment of the attachment site of the purine
base on 21 was established by an HMBC experiment, which
showed correlation between H-1′ and the carbon atoms C-4
and C-8. Its relative stereochemistry was determined by the
NOESY spectrum that shows cross-peaks between H-1′ and
H-4′′. For compound 22, NOE correlations observed between
Supporting Information Available: Experimental de-
1
tails, characterization data, H and 13C NMR spectra of all
new compounds, and anti-HIV activity of compound 23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0710616
(21) Me´vellec, L.; Huet, F. Tetrahedron 1997, 53, 5797-5812.
2830
Org. Lett., Vol. 9, No. 15, 2007