Short synthesis of octosyl nucleosides

Article abstract of DOI:10.1021/ol0600382

Commercial 1,2:5,6-di-O-isopropylidene-α-D-allofuranose was converted to a protected bicyclic octosyl acid thioglycoside donor by a 10-step sequence that features an intramolecular ester enolate alkylation. Glycosylation of N-benzoyladenine and methyl uri

Full text of DOI:10.1021/ol0600382

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1335-1337
Short Synthesis of Octosyl Nucleosides
Spencer Knapp,*,† Vinay V. Thakur,† Machender R. Madduru,†
Krishnan Malolanarasimhan,† Gregori J. Morriello,‡ and George A. Doss‡
Department of Chemistry & Chemical Biology, Rutgers - The State UniVersity of New
Jersey, 610 Taylor Road, Piscataway, New Jersey 08854, and Merck & Co., P.O. Box
2000, Rahway, New Jersey 07065-0900
knapp@rutchem.rutgers.edu
Received January 6, 2006 (Revised Manuscript Received February 13, 2006)
ABSTRACT
Commercial 1,2:5,6-di-O-isopropylidene-r-D-allofuranose was converted to a protected bicyclic octosyl acid thioglycoside donor by a 10-step
sequence that features an intramolecular ester enolate alkylation. Glycosylation of N-benzoyladenine and methyl uridine-5-carboxylate followed
by deprotection gave the respective nucleosides “octosyl adenine” and octosyl acid A.
Complex nucleoside antibiotics are diversely polyfunctional
targets.1 A synthetic strategy can either feature (a) “early
glycosylation,” which requires chain, ring, and functional
group elaboration of a commercially available or early-route
nucleoside, or (b) “late glycosylation,” in which N-glycosyla-
tion of a purine/pyrimidine acceptor with a higher sugar
donor occurs toward the end of the route. The challenges
have been successfully met in a variety of instances, but other
attractive synthetic approaches have foundered because
seemingly basic steps such as glycosylation, C-C bond for-
mation, and protecting group removal are more troublesome
in these complex molecular settings than in simpler furano-
side or nucleoside frameworks. The various approaches2-11
to the synthesis of octosyl acid A (1, Figure 1)12 illustrate
the difficulties, particularly with respect to the timing of the
introduction of the pyrimidine vs formation of the strained
trans-fused 1,5-dioxabicyclo[4.3.0]nonane ring system. The
three pioneering syntheses2-4 of 1 made use of the chain
extension at C-5′ and then intramolecular Williamson ether
formation,2,4 or an oxymercuration,3 to fuse the tetrahydro-
pyran ring onto an existing nucleoside. In no case was the
pyrimidine introduced after formation of the bicyclic glycon,
even though this might be considered a more convergent and
versatile strategy.13 A promising approach5 to 1 described
the prior assembly of a bicyclic glycon, but standard
activation at C-1′ for Vorbru¨ggen coupling14 to a pyrimidine
was unsuccessful (Scheme 1), the failure being “attributed
to the susceptibility of the 3,7-anhydrooctose skeleton to
† Rutgers - The State University of New Jersey.
‡ Merck & Co.
(1) (a) Hanessian, S.; Dixit, D. M.; Liak, T. J. Pure Appl. Chem. 1981,
53, 129-148. (b) Knapp, S. Chem. ReV. 1995, 95, 1859-1876. (c) Ichikawa,
S.; Matsuda, A. Nucleosides Nucleotides Nucleic Acids 2005, 24, 319-
329.
(2) (a) Danishefsky, S.; Hungate, R. J. Am. Chem. Soc. 1986, 108, 2486-
2487. (b) Danishefsky, S. J.; Hungate, R.; Schulte, G. J. Am. Chem. Soc.
1988, 110, 7434-7440.
(3) Hanessian, S.; Kloss, J.; Sugawara, T. J. Am. Chem. Soc. 1986, 108,
2758-2759.
(4) Kozaki, S.; Sakanaka, O.; Yasuda, T.; Shimizu, T.; Ogawa, S.; Suami,
T. J. Org. Chem. 1988, 53, 281-286.
(5) Anzai, K.; Saita, T. Bull. Chem. Soc. Jpn. 1977, 50, 169-174.
(6) Kim, K. S.; Szarek, W. A. Carbohydr. Res. 1982, 100, 169-176.
(7) Kim, K. S.; Szarek, W. A. Can. J. Chem. 1981, 59, 878-888.
(8) Kim, K. S.; Kang, C. M.; Kim, S. J.; Jung, K. S.; Hahn, C. S. Bull.
Kor. Chem. Soc. 1985, 6, 350-354.
(9) Araki, Y.; Endo, T.; Arai, Y.; Tanji, M.; Ishido, Y. Tetrahedron Lett.
1989, 30, 2829-2832.
Figure 1. Octosyl nucleoside targets.
10.1021/ol0600382 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/09/2006

Scheme 1. Attempted Preparation of Octosyl Anomeric
Scheme 2. Synthesis of the 3,7-Anhydroocturonate
Acetate
acids”.5 Given that the adenine analogue of 1, “octosyl
adenine” (2) shows more pronounced biological activity than
1 (2 competes with cAMP for cyclic AMP phosphodi-
esterases15), a late glycosylation approach to this class of
complex nucleosides, in which the pyrimidine or purine could
be varied, might have value.13b Furthermore, synthetic steps
would be saved if commercially available 1,2:5,6-di-O-
isopropylidene-R-D-allofuranose (5, Scheme 2), which al-
ready matches at C-5 the C-5′ stereochemistry of 1 and 2,
could be used as the starting material. We are pleased to
report the syntheses of 1 and 2 by successful implementation
of this late glycosylation strategy.
Alkylation of 5 at O-3 with isopropyl bromoacetate
occurred smoothly in the presence of the strong soluble base
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-
diazaphosphorine16 (BEMP, Scheme 2). Selective hydrolysis
of the 5,6-O-isopropylidene of 6 was followed by conversion
of the primary hydroxyl to an iodide (8) and then protection
of O-5 as the THP ether (9). Intramolecular alkylation of
the ester lithium enolate17 of 9 was successful in dilute
solution (2.6 mM), whereas at higher concentrations inter-
molecular Claisen condensation siphoned away the starting
material. The product was obtained as a mixture of two
stereoisomers at C-7, 10 and 11 (each a mixture of THP
diastereomers), along with recovered 9. The stereochemical
picture became clearer after conversion of 10/11 by hydroly-
sis and acetylation to the desired C-7 isomer 12 (54% yield
from 10/11) and the C-7 epimer 13 (30% from 10/11), each
of which was isolated and characterized. The hindered C-5
hydroxyl of 13 had not acetylated, but the acetyl group could
be added in a followup step to provide 14. First-order vicinal
coupling constants, particularly those of the H-6 and H-7
protons, allow assignment of the configuration and confor-
mation of 12 and 14, as shown in Scheme 2. For example,
H-7 for 12 appears as a dd (J ) 2.7, 12.3 Hz), reflecting
respective ax-eq and ax-ax couplings with the H-6’s, whereas
H-7 for 14 is a d (J ) 6.8 Hz; < 1 Hz coupling to the trans
H-6).
The modest stereoselectivity (10/11 ) 1.8:1) for the
intramolecular ester enolate alkylation may be attributed to
the availability of reasonably uncongested transition states
A (chairlike) and B (boatlike) for the respective modes of
cyclization (Figure 2). Fortunately, the undesired epimer 11
(10) Haraguchi, K.; Hosoe, M.; Tanaka, H.; Tsuruoka, S.; Kanmuri, K.;
Miyasaka, T. Tetrahedron Lett. 1998, 39, 5517-520.
(11) Malolanarasimhan, K. Ph.D. Dissertation, Rutgers - The State
University of New Jersey, New Brunswick, NJ, 2001.
(12) Isono, K.; Crain, P. F.; McCloskey, J. A. J. Am. Chem. Soc. 1975,
97, 943-945.
(13) See also the synthesis of malayamycin A and analogues: (a)
Hanessian, S.; Marcotte, S.; Machaalani, R.; Huang, G. Org. Lett. 2003, 5,
4277-4280. (b) Hanessian, S.; Huang, G.; Chenel, C.; Machaalani, R.;
Loiseleur, O. J. Org. Chem. 2005, 70, 6721-6734.
(14) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234-1255.
Figure 2. Stylized transition states for intramolecular alkylation.
(15) Suhadolnik, R. J. Nucleosides as Biological Probes; Wiley: New
York, 1979; p 297.
(16) Grotli, M.; Douglas, M.; Beijer, B.; Eritja, R.; Sproat, B. Bioorg.
Med. Chem. Lett. 1997, 7, 425-428.
(17) Burke, S. D.; Fobare, W. F.; Pacofsky, G. J. J. Org. Chem. 1983,
48, 5221-5228.
in the 10/11 mixture could be converted to the desired isomer
12 by an epimerization sequence (Scheme 2) that consists
1336
Org. Lett., Vol. 8, No. 7, 2006

of treatment of the mixture with tert-butoxide, replacement
of any isopropyl lost to hydrolysis by carboxylate O-
alkylation, hydrolysis of the O-THP at C-5, and then
acetylation. In this way, 12 could be produced from 10/11
in 74% overall yield, 48% from 9 (64% based on recovered
9). The synthetic route to 3,7-anhydroocturonic ester 12 is
relatively short and efficient, but of little use if C-1 cannot
be activated for nucleosidation.
of either stereochemistry are effective donors for N-glyco-
sylation,21,22 17 ought to serve as a precursor to a variety of
octosyl nucleosides, including 1 and 2, differing only in the
identity of the nucleobase.
Both glycosylations proved successful (Scheme 3). Treat-
ment of a mixture of 17 and silylated N6-benzoyladenine with
N-iodosuccinimide and triflic acid22 led to the protected
nucleoside 18 along with a small amount of an isomer,
probably N-7 glycosylated. Deprotection with aqueous
lithium hydroxide removed the acetyl and pivaloyl groups
and hydrolyzed the isopropyl ester, but not the N-benzoyl,
which promotes deprotonation at N-6 under these condi-
tions.23 Subsequent ammonolysis, however, removed the
remaining protecting group, and the product 2 was isolated
and characterized by its mass spectrum and fully assigned
proton and carbon NMR spectra. In particular, the singlet
for H-1′ of 2 is diagnostic for octosyl nucleosides of the
desired stereochemistry, and the respective chemical shifts
for C-4 and C-5 (148.5 and 119.1 ppm) match those of
adenosine (149.2 and 119.5) but not 7-(â-D-ribofuranosyl)-
adenine (160.7 and 110.2).24 A literature description of 2
(which was prepared by a nucleoside transglycosylation
sequence starting with 1)25 includes chemical shifts for H-1′,
H-2, and H-8 that match our values.
In converting 12 to a donor for N-glycosylation, we
employed the Lewis acid mediated acetal exchange reaction
of acetonides with mercaptans.18 Thus, 12 was converted to
the ring-opened bis(phenylthio)acetal 15 (Scheme 3), and
Scheme 3. Donor Preparation, Glycosylations, and
Deprotection
The option to activate the anomeric center of 12 for
N-glycosylation as a thioglycoside, rather than the more usual
anomeric acetate, was crucial to the success of this route.
The question26 has been posed: “Why not use the protected
1-O-acyl or 1-O-alkyl sugars for nucleoside synthesis instead
of the corresponding 1-phenylthio sugars, which entail
additional reaction steps and bad smelling thiophenols?” The
syntheses of 1 and 2 and several additional targets13b,21,27,28
provide the answer: In a complex synthetic undertaking, the
thioglycoside is often a more effective way to prepare the
anomeric center for late N-glycosylation.
Acknowledgment. We are grateful to Merck & Co. and
SynChem Research, Inc., for financial support and to Prof.
1
Stephen Hanessian for supplying the H NMR spectrum of
1.
Supporting Information Available: Experimental details
and spectral characterization of new compounds, including
copies of 13C and 1H NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0600382
then 15 was closed to the thioglycoside 16 with promotion
by Ag(I)19 and participation of O-4. Although the anomeric
stereochemistry was not determined with certainty, 16 was
obtained as a single isomer. Subsequent pivaloylation at O-2
to give 17 proceeded very slowly, suggesting that the nearby
(cis?) phenylthio substituent hinders acylation, as had been
observed with a related thioglycoside.20 As thioglycosides
(20) Knapp, S.; Shieh, W.-C.; Jaramillo, C.; Trilles, R. V.; Nandan, S.
R. J. Org. Chem. 1994, 59, 946-948.
(21) Hanessian, S.; Sato, K.; Liak, T. J.; Dahn, N.; Dixit, D. J. Am. Chem.
Soc. 1984, 106, 6114-6115.
(22) Knapp, S.; Shieh, W.-C. Tetrahedron Lett. 1991, 32, 3627-3630.
(23) Knapp, S.; Madduru, M. R.; Lu, Z.; Morriello, G. J.; Emge, T. J.;
Doss, G. A. Org. Lett. 2001, 3, 3583-3585
(24) Chenon, M.-T.; Pugmire, R. J.; Grant, D. M.; Panzica, R. P.;
Townsend, L. B. J. Am. Chem. Soc. 1975, 97, 4627-4636.
(25) (a) Azuma, T.; Isono, K. Tetrahedron Lett. 1976, 20, 1687-1690.
(b) Azuma, T.; Isono, K. Chem. Pharm. Bull. 1977, 25, 3347-3353.
(26) Vorbru¨ggen, H.; Ruh-Pohlenz, C. Handbook of Nucleoside Synthesis;
Wiley: New York, 2001; p 69.
(18) Liang, D.; Schuda, A. D.; Fraser-Reid, B. Carbohydr. Res. 1987,
164, 229-240.
(19) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.;
Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321-5330.
(27) Knapp, S.; Nandan, S. R. J. Org. Chem. 1994, 59, 281-283.
(28) Knapp, S.; Gore, V. K. Org. Lett. 2000, 2, 1391-1393.
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