Synthesis of 4′-methyl and 4′-cyano carbocyclic 2′,3′-didehydro nucleoside analogues via 1,4-addition to substituted cyclopentenones

Article abstract of DOI:10.1021/jo040215h

Carbocyclic 4′-methyl and 4′-cyano nucleoside analogues were synthesized using the Michael reaction to introduce the 4′-substituent and Pd-catalyzed allylic substitution to introduce the nucleoside base. Use of both the desired β- and undesired α-1′-carbo

Full text of DOI:10.1021/jo040215h

SCHEME 1
Synthesis of 4′-Methyl and 4′-Cyano
Carbocyclic 2′,3′-Didehydro Nucleoside
Analogues via 1,4-Addition to Substituted
Cyclopentenones
Louis S. Hegedus* and Jeff Cross
Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523
louis.hegedus@colostate.edu
Received June 14, 2004
Approaches to 4′-substituted nucleoside analogues,9 as
well as the synthesis of cyclobut-A,10 neplanocin A,11 and
aristeromycin and carbovir,12 utilizing chromium car-
bene-derived optically active cyclobutanones13 as precur-
sors have recently been reported from these laboratories.
Application of this approach to the synthesis of 4′-
substituted carbocyclic nucleosides is presented below.
The approach taken to 4′-substituted carbocyclic nu-
cleosides (Scheme 1) involved stereoselective conjugate
addition to optically active cyclopentenone 1, followed by
oxazolidinone elimination,14 ketone reduction and esteri-
fication, and introduction of the nucleoside base via well-
established π-allylpalladium chemistry.15 Cyclopentenone
1 was available in three steps in 70% overall yield
utilizing previously developed methodology.12 Conjugate
methylation proved problematic (eq 1).
Abstract: Carbocyclic 4′-methyl and 4′-cyano nucleoside
analogues were synthesized using the Michael reaction to
introduce the 4′-substituent and Pd-catalyzed allylic sub-
stitution to introduce the nucleoside base. Use of both the
desired â- and undesired R-1′-carbonate diastereomers in the
Pd-catalyzed substitution was demonstrated in principle by
epimerization of the R-diastereomer and kinetic diastereo-
differentiation of a 1:1 R/â mixture of 1′-carbonates.
The broad antitumor and antiviral activity displayed
by the naturally occurring carbocyclic nucleosides
neplanocin A and aristeromycin1 coupled with their
greater metabolic stability relative to their glycosidic
relatives2 have made carbocyclic nucleoside analogues the
focus of intensive synthetic studies.3 The observation that
4′-substituted nucleosides also had wide-ranging biologi-
cal activity4 spurred similar interest in their synthesis.5
Substantially less effort has been directed toward the
synthesis of 4′-substituted carbocyclic nucleosides, al-
though cyclopentanoid nucleosides having F,6 OH,6 alkyl,7
and aryl8 substituents at the 4′-position have been
reported.
(1) (a) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi,
M.; Otani, M. J. Antibiot. 1981, 34, 359. (b) Shealy, Y. F.; Clayton, J.
D. J. Am. Chem. Soc. 1969, 91, 3075. (c) DeClercq, E.; Cools, M.;
Balzarini, J.; Marquez, V. E.; Borcherding, D. R.; Borchardt, R. T.;
Drach, J. C.; Kitaoka, S.; Konno, T. Antimicrob. Agents Chemother.
1989, 28, 1291. (d) Borchardt, R. T.; Keller, B. T.; Patel-Thrombre, U.
J. Biol. 1984, 259, 4353. (e) For a review of the chemical and biological
properties of carbocyclic nucleosides, see: Marquez, V. E.; Lim, M. I.
Med. Res. Rev. 1986, 6, 1.
(2) Herdewijn, P.; De Clercq, E.; Balzarini, J.; Vanderhaeghe, H. J.
Med. Chem. 1985, 28, 550.
Typical conjugate alkylation conditions utilizing lithium
dimethylcuprate resulted in no reaction when the mix-
(3) For reviews, see: (a) Rodriguez, J. B.; Comin, M. J. Mini Rev.
Med. Chem. 2003, 3, 95. (b) Schneller, S. W. Curr. Top. Med. Chem.
2002 2, 1087. (c) Crimmins, M. T. Tetrahedron 1998, 54, 9229.
(4) Prisbe, E. J.; Maag, H.; Verheyden, J. P. H.; Rydzewski, R. M.
Structure-Activity Relationships Among HIV Inhibitory 4′-Substituted
Nucleosides. In Nucleosides and Nucleotides as Antitumor and Anti-
viral Agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York,
1993; pp 101-113.
(5) For recent examples, see: (a) Haraguchi, K.; Takeda, S.; Tanaka,
H.; Org. Lett. 2003, 5, 1399. (b) Jung, M. E.; Toyota, A. J. Org. Chem.
2001, 66, 2624. (c) Crich, D.; Hao, X. J. Org. Chem. 1999, 64, 4016. (d)
Crich, D.; Hao, X. J. Org. Chem. 1998, 63, 3796. (e) Maag, H.;
Rydzewski, R. M.; McRoberts, M. J.; Crawford-Ruth, D.; Verheyden,
J. P. H.; Prisbe, E. J. J. Med. Chem. 1992, 35, 1440.
(7) (a) Nieto, M. K.; Blanco, J. M.; Caaman˜o, O.; Fernandez, F.;
Garcia-Mera, X.; Lopez, C.; Balzarini, J.; DeClerq, E. Nucleosides
Nucleotides 1999, 18, 2253. (b) Nieto, M. I.; Blanco, J. M.; Caaman˜o,
O.; Fernandez, F.; Garcia-Mera, X.; Balzarini, J.; Padalko. E.; Neyts,
J.; DeClerq, E. Nucleosides Nucleotides 1998, 17, 1255. (c) Kato, K.;
Suzuki, H.; Tanaka, H.; Miyasaka, T. Tetrahedron: Asymmetry 1998,
9, 911.
(8) Hong, J. H.; Ko, O. H. Bull. Korean Chem. Soc. 2003, 24, 1289.
(9) (a) Hegedus, L. S.; Geisler, L.; Riches, A. G.; Salman, S. S.;
Umbricht, G. J. Org. Chem. 2002, 67, 7649. (b) Hegedus, L. S.; Hervert,
K. L.; Matsui, S. J. Org. Chem. 2002, 67, 4076. (c) Reed, A. D.; Hegedus,
L. S. Organometallics 1997, 16, 2313.
(6) (a) Gumina, G.; Chong, Y.; Choi, Y.; Chu, C. K. Org. Lett. 2000,
2, 1229. (b) Csuk, R.; Do¨rr, P.; Ku¨hn, M.; Krieger, C.; Antipin, M. Y.
Z. Naturforsch. 1999 546, 1068. (c) Csuk, R.; Do¨rr, P.; Ku¨hn, M.;
Krieger, C.; Irngartinger, H.; Oeser, T.; Antipin, M. Y. Z. Naturforsch.
1999, 546, 1079. (d) Wachtmeister, J.; Mu¨hlman, A.; Classon, B.;
Samuelsson, B. Tetrahedron 1999, 55, 10761. (e) Borthwick, A. D.;
Biggadike, K.; Paternoster, I. L.; Coates, J. A. V.; Knight, D. Biorg.
Med. Chem. Lett. 1993, 3, 2577. (f) Biggadike, K.; Borthwick, A. D. J.
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(11) Geisler, L.; Hegedus, L. S. J. Org. Chem. 2000, 65, 4200.
(12) Brown, B.; Hegedus, L. S. J. Org. Chem. 2000, 65, 1865.
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Soc. 1991, 113, 923.
(14) Miller, M.; Hegedus, L. S. J. Org. Chem. 1993, 58, 6779.
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1988, 110, 621. (b) For a review of palladium-catalyzed amination,
see: Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
10.1021/jo040215h CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/30/2004
8492
J. Org. Chem. 2004, 69, 8492-8495

ture was quenched at -78 °C and decomposition (with
free oxazolidinone as the sole identifiable product) when
warmed to room temperature. The use of lithium di-
were considerably less effective and trimethylsilyl cya-
nide failed to react. Enone 1 underwent conjugate addi-
tion with both azide (TMSN3/HOAc/Et3N)24 and PhCH2-
SLi, but the adducts could not be purified or stored since
they underwent spontaneous â-elimination,25 returning
starting material.
16
methylcuprate/BF3‚OEt2 gave modest yields of the
desired conjugate addition, with good selectivity. How-
ever, varying amounts of enone 3, resulting from loss of
the benzyloxy group, were obtained. Dimethyl zinc/nickel-
(II) acetylacetonate17 produced similar yields of conjugate
addition product, but with low stereoselectivity, and
favoring the other diastereomer. Upward of 40% of enone
3 was also observed depending on conditions. The most
effective reagent for conjugate methylation was methyl
copper/BF3‚OEt2,18 which produced good yields of 2 with
modest selectivity and no byproduct 3. The mixed cuprate
MeCuCNLi/BF3‚OEt2 gave similar results.
Treatment of the “natural” D-diastereoisomers 2a and
4b with TBAF in THF produced cyclopentenones 5a and
6b in moderate to good yield (eq 3). The absolute
configurations of these compounds were assigned as
follows. Monophenyl oxazolidinone analogues of cyclo-
pentanones 2 and 4 were synthesized in optically pure
form and their structures were determined by single-
crystal X-ray diffraction. Subjecting these analogues to
TBAF produced enones 5 and 6, respectively, identical
in all respects including the sign and magnitude of
rotation to those produced from the same treatment of 2
and 4.26
The formation of compound 3 warrants comment.
Although electron-transfer pathways are not thought to
be involved in most conjugate additions of copper com-
plexes, they have been observed in special cases.19
Lithium dimethylcuprate reductively cleaved γ-ester20
and γ-carbamate21 groups from R,â-unsaturated esters,
while MeCuCNLi was unreactive.20a A likely path for this
elimination is shown in Scheme 2 and involves single-
electron transfer to give a radical anion intermediate,
followed by ejection of the benzyloxy group, perhaps with
assistance from the Lewis acid present. Reduction and
protonation of the enolate completes the sequence.
SCHEME 2
Reduction of the enones under Luche conditions27 was
virtually nonselective, slightly favoring the â-isomer.28
The resulting alcohols were easily separated by chroma-
tography and converted to their ethyl carbonates under
standard conditions (Scheme 3). With these materials in
hand, palladium-catalyzed coupling was addressed.
SCHEME 3
Nagata’s reagent,22 Et2AlCN, introduced cyanide into
the â-position of 1 in fair yield, but with lower stereo-
selectivity and favoring the opposite diastereoisomer (eq
2), while KCN/Et3N‚HCl and KCN/acetone cyanohydrin23
(16) Smith, A. B.; Jerris, P. J. J. Org. Chem. 1982, 47, 1845.
(17) Petrier, C.; de Souza Barbosa, J. C.; Dupuy, C.; Luche, J.-L. J.
Org. Chem. 1985, 50, 5761.
(18) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.; Maruya-
ma, K. J. Org. Chem. 1982, 47, 119.
Experiments with 9a using sodium dimethyl malonate
and Pd(PPh3)4 gave excellent yields but revealed that the
(19) (a) For a review of mechanistic organocopper chemistry, see:
Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. 2000, 39, 3750. (b)
Chounan, Y.; Ibuka, T.; Yamamoto, Y. J. Chem. Soc., Chem. Commun.
1994, 2003.
(23) Okabe, M.; Sun, R.-C.; Tam, S. Y.-K.; Todaro, L. J.; Coffen, D.
L. J. Org. Chem. 1988, 53, 4780.
(24) Guerin, D. J.; Horstmann, T. E.; Miller, S. J. Org. Lett. 1999,
1, 1107.
(20) (a) Logusch, E. W. Tetrahedron Lett. 1979, 3365. (b) Ruden, R.
A.; Litterer, W. E. Tetrahedron Lett. 1975 2043.
(21) Ibuka, T.; Chu, G.-N.; Yoneda, F. Tetrahedron Lett. 1984, 25,
3247.
(25) Dondoni, A.; Marra, A.; Boscarato, A. Chem. Eur. J. 1999, 5,
3562.
(26) The enantiomer of 5a has been reported: Arrington, M. P.;
Meyers, A. I. Chem. Commun. 1999, 1371.
(22) Nagata, W.; Yoshioka, Y. Org. React. 1977, 25, 255.
J. Org. Chem, Vol. 69, No. 24, 2004 8493

allylic carbonate substrate failed to retain stereochem-
istry during the reaction. Mixing â-9a first with sodium
dimethyl malonate followed by addition of the Pd(PPh3)4
catalyst in DMF gave 11a as a 9:1 â/R mixture of
diastereomers; the same reaction with R-9a gave 11a as
a 1:13 â/R mixture. Adding the catalyst to 9a followed
20 min later by addition of the malonate gave a lower
yield of 11a as a 1.8:1 R/â mixture of diastereoisomers
along with substantial amounts of enone 5a (see below).
Stirring 9a with catalyst in the absence of any nucleo-
phile resulted in near-complete epimerization of the
carbonate29 (with small amounts of 5a and epimerized
7a),30 accounting for the loss of stereochemistry observed
above (Scheme 4).
primarily the N-9 isomer with minor quantities of the
N-7 isomer as a byproduct (eq 5).
Utilization of undesired carbonate R-9a was demon-
strated in principle by epimerization of R-9a with Pd-
(PPh3)4 (see above) and Pd-catalyzed kinetic diastereo-
differentiation of a 1:1 R/â mixture of carbonate 9a with
Trost ligand L2*(S,S). Kinetic diastereodifferentiation
proceeded without incident with thymine as nucleophile,
giving the desired product â-14a in 95% de and returning
carbonate R-9a in moderate yield. Adenine was more
problematic, giving â-15a as a 5:1 R/â mixture and
returning carbonate R-9a, in slightly lower overall yield.
Attempts to run the epimerization and kinetic diaste-
reodifferentiation in the same flask failed, giving sub-
stantial quantities of epimerized alcohol 7a and enone
5a due to extensive carbonate decomposition via hydroly-
sis and oxidation30 (Scheme 5).
SCHEME 4
SCHEME 5
With the less reactive nucleophile adenine and Pd-
(PPh3)4 as catalyst, more extensive epimerization was
observed, â-9a giving a 1.7:1 â/R ratio of products and
R-9a giving a 1:1.7 ratio of the same two products. In
contrast, cyanocarbonate â-10b underwent facile Pd-
(PPh3)4-catalyzed coupling with thymine without loss of
stereochemistry. With adenine, only â-10a underwent
reaction, with R-10a being recovered unchanged (eq 4).
Deprotection of adenine and thymine adducts 12b and
13a-15a proceeded with BCl3 without incident to give
the products 16-19 in fair to excellent yield. The ster-
(29) For studies on the mechanism of palladium-catalyzed epimer-
ization of cyclic allylic substrates, see: (a) Granberg, K. L.; Ba¨ckvall,
J.-E. J. Am. Chem. Soc. 1992, 114, 6858. (b) Amatore, C.; Gamez, S.;
Jutand, A.; Meyer, G.; Moreno-Man˜as, M.; Morral, L.; Pleixats, R.
Chem. Eur. J. 2000, 6, 3372.
(30) Ozawa, F.; Son, T.-Il; Ebina, S.; Osakada, K.; Yamamoto, A
Organometallics 1992, 11, 171.
To prevent loss of stereochemistry in reactions of
methyl adduct â-9a, a Pd(dba)2/dppe catalyst system was
used. Adenine and thymine both coupled with â-9a
stereoretentively under these conditions. Adenine gave
(27) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
(28) The stereochemistry of compounds 7a and 8b was assigned by
single-crystal X-ray crystallography of the derivative alcohols 17 and
19.
(31) Copper iodide was used within 48 h following purification
according to Amareggo, W. L. F.; Perrin, D. D. Purification of
Laboratory Chemicals, 4th ed.; Butterworth-Heinemann: Oxford, 1998;
p 381.
8494 J. Org. Chem., Vol. 69, No. 24, 2004

SCHEME 6
recycled in the synthesis of 4′-methyl-1′-thymine product
16.
Acknowledgment. We thank Angela Bullert and
Jory Wendling for providing single-crystal X-ray analy-
sis and the Williams group for highly purified DMF.
Support for this research was provided by National
Institutes of Health Grant No. GM26178. Mass spectra
were obtained on instruments supported by National
Institutes of Health Grant No. GM49631. X-ray crystal
structures were determined on a Bruker SMART CCD
X-ray diffractometer purchased through the NIH Shared
Instrument Grant Program.
eochemistry of alcohols 17 and 19 was determined by
single-crystal X-ray diffraction (Scheme 6).
A synthesis of four 4′ substituted carbocyclic nucleoside
analogues was developed, allowing different 4′- and 1′-
substituents. An unusual epimerization in conjunction
with kinetic diastereodifferentiation allowed the un-
desired 4′ methyl carbonate R-9a in principle to be
Supporting Information Available: 1H and 13C NMR
spectra of 2-D-â-18; X-ray structural data for 2a, 4b, D-â-17,
and L-â-19 and synthetic procedures and characterization data
for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO040215H
J. Org. Chem, Vol. 69, No. 24, 2004 8495