From Furan to Nucleosides

Full text of DOI:10.1021/ja9537336

J. Am. Chem. Soc. 1996, 118, 3037-3038
3037
Scheme 1.a Alkylation with a Purine Base: a Synthesis of
ent-Adenosine Acetonide
From Furan to Nucleosides
Barry M. Trost* and Zhongping Shi
Department of Chemistry, Stanford UniVersity
Stanford, California 94305-5080
ReceiVed NoVember 6, 1995
The potential therapeutic applications of nucleosides provide
an ever increasing need for simple synthetic entries to them.1,2
Almost without exception, their synthesis involves starting from
a carbohydrate precursor for the furanose ring which raises the
issue of chemoselectivity as well as diastereoselectivity of
glycosylation. For some applications, significant deoxygenation
may be required. A potentially useful new paradigm begins
with cis-2,5-diacyloxy-2,5-dihydrofuran3 which possesses dis-
placeable substituents in the 2,5-positions with the correct
stereochemistry for entry into the nucleoside family using
palladium catalysis. While elimination leading to aromatization
is one obvious concern, the major issue to be resolved is
asymmetric induction. Our recent successes in desymmetriza-
tion of carbocycles,4 which has led to an asymmetric synthesis
of carbanucleosides, led us to examine whether heterocycles
also could be efficiently desymmetrized which may lead to an
asymmetric nucleoside synthesis from cis-diester 1, available
in 76% yield as a crystalline solid, mp 174-5 °C, by the
oxidation of furan with lead tetrabenzoate.3
While alkylation of these diacyloxydihydrofurans with 6-chlo-
ropurine (2) using achiral 1,2-diphenylphosphinoethane (dppe)
as a ligand and (dba)3Pd2‚CHCl3 (3, dba ) dibenzylideneac-
etone) is not productive, the chiral 4 with the same Pd(0) source
effects smooth alkylation as shown in Scheme 1 to give 55
whose ee is established to be 93% by mandelate analysis of the
cis-dihydroxylated product.6 Recrystallization of 5 from ethyl
acetate-hexane gives enantiomerically pure 5,5 mp 132-3 °C,
[R]D -135.6° (c ) 2.6, CH2Cl2).
a
(a) 1.1:1 ratio of 1:2, (C2H5)3N, THF, 2% 3, 6% 4 or ent-4, rt. (b)
1.7% 3, 12% Ph3P, Cs2CO3, 1:1 THF:CH3CN, rt. (c) 4% OsO4, NMO,
CH2Cl2, H2O, rt. (d) (CH3)2C(OCH3)2, CH3COCH3, PPTS, CH2Cl2,
35 °C. (e) 1 atm H2, 5% Pd/BaSO4, 1:1 C2H5OAc:CH3OH, rt. (f)
(C2H5)3N, o-O2NC6H4SO2Cl, CH2Cl2, -78 °C then moist C2H5OAc,
rt. (g) HOBT, DCC, THF, rt then -10 °C, NaBH4. (h) NH4OH,
CH3CN, H2O, rt.
initially investigated our use of (phenylsulfonyl)nitromethanes8
in a second Pd(0)-catalyzed reaction unsuccessfully. We
attributed the failure to the presence of an acidic hydrogen in
the initial alkylation product that triggered decomposition. Thus,
we devised a new -CO2H equivalent as illustrated in eq 1 and
The advantage of this methodology is the simplicity of access
to either enantiomer. Thus, the L-nucleosides7 may be accessed
simply by performing the reaction with the enantiomeric ligand
ent-5 as shown in Scheme 1 to give ent-5, mp 132-3 °C, [R]D
+136.0° (c ) 2.6, CH2Cl2). To introduce the C-5 carbon, we
explored its use in a synthesis of ent-adenosine and an ent-
NECA9 intermediate as illustrated in Scheme 1. Dibenzyl
benzyloxycarboxymalonate (6) participates extremely well in
the second Pd(0)-catalyzed substitution with complete regio-
and diastereoselectively to give 75 virtually quantitatively.
Dihydroxylation to give 85 after acetonide formation is com-
pletely diastereoselective and anti as suggested by the 1H NMR
coupling constants (J1,2 ) 2.2 Hz and J3,4 ) 1.7 Hz) and proved
by correlation to a known compound (Vide infra). Catalytic
hydrogenolysis generates the hydroxy diacid 9 which is directly
subjected to o-nitrobenzenesulfonyl chloride and triethylamine.
At -78 °C, the bis mixed anhydride forms and, upon warming
to room temperature, decarbonylates to the R-keto mixed
anhydride. At this point, ethyl acetate saturated with water is
added to effect hydration and subsequent second decarbonylation
to the desired acid 10. Comparison of the spectral properties
of the obtained acid 10 to those recorded for the D-isomer10
shows their identity except for absolute configuration. Such
carboxylic acids are frequently of interest. For example, the
N-ethylcarboxamide in the D-series has proven to be one of the
most interesting metabolically stable analogs of adenosine.10
This new route provides either enantiomer of this series.
(1) For a few recent reviews, see: Chu, C. K., Baker, D. C., Eds.
Nucleosides and Nucleotides as Antitumor and AntiViral Agents; Plenum
Press: New York, 1993. Adams, J., Merluzzi, V. J., Eds. The Search for
AntiViral Drugs: Case Histories from Concept to Clinic; Birkhauser:
Boston, MA, 1993. Lukevics, E. I.; Zablocka, A. Nucleoside Synthesis:
Organosilicon Methods; Ellis Horwood: New York, 1991. Townsend, L.
B., Ed. Chemistry of Nucleosides and Nucleotides; Plenum Press: New
York, 1988.
(2) Also see: Huryn, D. M.; Okabe, M. Chem. ReV. 1992, 92, 1745.
Bonnet, P. A.; Robins, R. K. J. Med. Chem. 1993, 36, 635. Jacobson, K.
A.; van Galen, P. J. M.; Williams, M. J. Med. Chem. 1992, 35, 407. Nair,
V.; Fasbender, A. J. Tetrahedron 1993, 49, 2169. Erion, M. D.; Niwas, S.;
Rose, J. D.; Ananthan, S.; Allen, M.; Secrist, J. A., III; Babu, Y. S.; Bugg,
C. E.; Guida, W. C.; Ealick, S. E.; Montgomery, J. A. J. Med. Chem. 1993,
36, 3771. DeMesmaeker, A.; Ha¨ner, R.; Martin, P.; Moser, H. E. Acc. Chem.
Res. 1995, 28, 366. Uhlmann, E. P.; Peyman, A. Chem. ReV. 1990, 90,
544. Garner, P. P. In Studies in Natural Products Chemistry; Atta-Ur-
Rahman, Ed.; Elsevier: Amsterdam, 1988; Vol. 1.
(3) Elming, N.; Claason-Kaas, N. Acta Chem. Scand. 1952, 6, 535.
(4) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc.
1992, 114, 9327. Trost, B. M.; Li, L.; Guile, S. D. J. Am. Chem. Soc. 1992,
114, 8745.
(5) This compound has been satisfactorily characterized.
(6) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S.
L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370.
(8) Trost, B. M.; Kuo, G. H.; Benneche, T. J. Am. Chem. Soc. 1988,
110, 621.
(9) Siddiqi, S. M.; Jacobson, K. A.; Esker, J. L.; Olah, M. E.; Ji, X.;
Melman, N.; Tiwari, K. N.; Secrist, J. A., III; Schneller, S. W.; Cristalli,
G.; Stiles, G. L.; Johnson, C. R.; Ijgerman, A. P. J. Med. Chem. 1995, 38,
1174. Holy, A.; Sorm, F. Coll. Czech. Chem. Commun. 1969, 34, 3383.
(7) Cf Urat, H.; Ogura, E.; Shinohara, K.; Ueda, Y.; Akagi, M. Nucleic
Acids Res. 1992, 20, 3325. Blommers, M. J. J.; Tondelli, L.; Garbesi, A.
Biochemistry 1994, 33, 7886. For L-dideoxy analogues as antiviral agents,
see: Lin, T.-S.; Cheng, Y.-C. PCT Int. Appl. WO 9427616A1 941208;
Chem. Abstr. 1995, 122, 123093.
0002-7863/96/1518-3037$12.00/0 © 1996 American Chemical Society

3038 J. Am. Chem. Soc., Vol. 118, No. 12, 1996
Communications to the Editor
Scheme 2.b Synthesis of the Polyoxin-Nikkomycin
Nucleoside Core
(17,16a mp 237-240 °C, [R]D +17.4° (c ) 0.50, H2O)) and
talo (18,16a mp 214-7 °C, [R]D +9.6° (c ) 0.5, H2O)) isomers,
whose structures are confirmed by comparison to authentic
samples,16a are obtained in nearly equal amounts.
The ability to effect Pd(0)-catalyzed alkylations without
eliminations to the aromatic furans with 2,5-diacyloxy-2,5-
dihydrofurans17 and the advantage of chiral vs achiral ligands
in just effecting such alkylations are noteworthy. Sequential
Pd(0)-catalyzed reactions first with chiral then with achiral
ligands provide in three steps from furan appropriately alkylated
and enantiomerically pure cis-2,5-disubstituted-2,5-dihydro-
furans suitable for further elaboration to nucleoside analogues.
The prospect of performing the two Pd(0)-catalyzed steps in a
single pot may further simplify the synthesis. Furthermore, the
nature of either the 2- or 5-substituent can be readily varied by
choice of nucleophiles as illustrated by the two applications
outlined. This route provides the dihydrofurans initially: a
highly desireable feature since (1) they are frequently the desired
target and therefore their cumbersome syntheses from sugars
may be avoided and (2) the absence of extra hydroxyl groups
as in the case of the normal strategies from sugars diminishes
chemoselectivity problems. Thus, 2,3-dideoxy, 2- or 3-deoxy,
and the normal nucleosides and their analogues should be readily
available by this methodology. It also provides the uronic acids
directly, thereby circumventing the frequently troublesome
oxidation of C-5.11,18 The effectiveness of this chemistry is
illustrated by the availability of L-nucleosides in nine steps from
furan in 18% overall yield and of the polyoxin-nikkomycin
core in only six steps and 39% overall yield. The development
of acyloxymalonates as a hydroxycarbonyl anion equivalent in
Pd(0) reactions also should prove generally useful for stereospe-
cific introduction of this versatile functional group.
a
(a) 1.25:1 ratio of 12:1, 2% 3, 7% 4, (C2H5)3N‚HCl, (C2H5)3N,
THF, 0 °C. (b) 2% 3, 10% Ph3P, Cs2CO3, CH3CN, rt. (c) 6% OsO4,
NMO, PhCH3:H2O:CH2Cl2 (1:1.7:50), rt. (d) CF3CO2H, 1:9 H2O:THF,
reflux. (e) (i) H2 (1 atm), (C2H5)3N, 5% Pd/BaSO4, CH3OH, rt; (ii)
(C2H5)3NH SO3R (R ) camphor), DMF:dioxane, rt.
Chemoselective reduction of the acid followed by aminoloysis
generates the acetonide of ent-adenosine 115,9,11 whose hydroly-
sis to ent-adenosine is well documented in the D-series.12
Use of a uracil equivalent as the nucleophile in the enantio-
discriminating step proved to be extraordinarily sensitive to the
choice of heterocycle and the reaction conditions. Focusing
on 4-methoxypyrimidin-2-one (12)13 as the pronucleophile, the
best conditions involve chloroform containing a 1:5 ratio of
triethylamine hydrochloride to triethylamine at 0 °C to room
temperature with 2% of palladium catalyst 3 and 7% of ligand
4 to produce 13,5 mp 182-3 °C, [R]D -103.9° (c ) 2.4, CH2-
Cl2) (65% yield, 85% yield brsm14 ), whose ee is determined to
be >98% by the mandelate analysis of the cis-dihydroxylated
product.6 Availability of enantiomerically pure 13 provides a
simple entry into the basic nucleoside skeleton of the polyoxin-
nikkomycin complexes15,16 as shown in Scheme 2. The allo
Acknowledgment. We thank the National Institutes of Health and
Institute of General Medical Sciences for their generous support of our
programs. We are especially indebted to Dr. Masahiro Miyazawa who
performed some of the initial studies in this area. Mass spectra were
provided by the Mass Spectrometry Center of the UCSF supported by
the Division of Research Resources of the National Institutes of Health.
Palladium salts were generously loaned to us by Johnson Matthey Alfa
Aesar. We thank Dr. Arthur Kluge for providing the comparison
spectra and samples of 17 and 18.
(10) For NECA, see: Daly, J. W.; Ukena, D.; Olsson, R. A. Can. J.
Physiol. Pharmacol. 1987, 65, 365. Daly, J. W. J. Med. Chem. 1982, 25,
197. Prasad, R. N.; Bariana, D. S.; Fung, A.; Savic, M.; Tietje, K.; Stein,
H. H.; Brondyk, H.; Egan, R. S. J. Med. Chem. 1980, 23, 313.
(11) Bridges, A. J. Nucleic Acid Chem. 1991, 4, 230.
(12) Poppe, L.; Hull, W. E.; Retey, J. HelV. Chim. Acta 1993, 76, 2367.
Hampton, A. J. Am. Chem. Soc. 1961, 83, 3640.
(13) Holy, A.; Ivanova, C. S. Nucleic Acid Res. 1974, 1, 19.
(14) brsm ) based upon recovered starting material.
(15) For a review, see: Isono, K. J. Antibiotics 1988, 41, 1711. Also
see: Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333. Konig, W. A.; Hahn,
H.; Rathmann, R.; Haas, W.; Keckeisen, A.; Hagenmaier, H.; Bormann,
C.; Deheler, W.; Kurth, R.; Zahner, H. Ann. 1986, 407.
(16) (a) Damodaran, N. P.; Jones, G. H.; Moffatt, J. G. J. Am. Chem.
Soc. 1971, 93, 3812. (b) Tabusa, F.; Yamada, T.; Suzuki, K.; Mukaiyama,
T. Chem. Lett. 1984, 405. (c) Saksena, A. K.; Lovey, R. G.; McPhail, A.
T. J. Org. Chem. 1986, 51, 5024. (d) Garner, P.; Park, J. M. J. Org. Chem.
1990, 55, 3772. (e) Dondoni, A.; Junquera, F.; Mercha´n, F. L.; Merino, P.;
Tejero, T. Tetrahedron Lett. 1994, 35, 9439.
Supporting Information Available: Characterization data for
compounds 5, 7, 8, 10, 11, and 13-16 (3 pages). This material is
contained in many libraries on microfiche, immediately follows this
article in the microfilm version of the journal, can be ordered from the
ACS, and can be downloaded from the Internet; see any current
masthead page for ordering information and Internet access instructions.
JA9537336
(17) During the course of this work, Pd(0)-catalyzed reactions of 2,5-
diacetoxy-2,5-dihydrofuran have been reported, see: Holzapfel, C. S.;
Williams, D. B. G. Tetrahedron 1995, 51, 8555.
(18) However, see: Singh, A. K.; Varma, R. Tetrahedron Lett. 1992,
33, 2307.