A Convenient Asymmetric Synthesis of 4′-α-Carboxylated Nucleosides

Full text of DOI:10.1021/jo980301f

3796
J . Org. Chem. 1998, 63, 3796-3797
Communications
bases. Adaptation of the literature synthesis for the thy-
midine derivative to suit each base is not economical, neither
in terms of time nor cost, and we were therefore driven to
develop an asymmetric synthesis capable of providing all
four bases with a minimum of effort. Furthermore, such a
synthesis permits the inclusion of nonstandard bases. Here,
we present such a synthesis in which the chirality is derived
from the commodity chemical, L-tartaric acid.
A Con ven ien t Asym m etr ic Syn th esis of
4′-r-Ca r boxyla ted Nu cleosid es
David Crich* and Xiaolin Hao
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
Received February 20, 1998
C-4′R-Homologated nucleotides, especially esters and
ketones, are molecules of considerable current interest. One
reason for this prominence arises from the ability of certain
C-4′R-ketones to block DNA polymerase and reverse tran-
scriptase enzymes, such as the HIV-1 RT, and so their
potential as antiviral agents.1-3 Alternatively, the C4′-R-
selenol4 and thiol esters5 and the C4′-R-tert-butylcarbonyl
derivative1 serve as convenient and unambiguous precursors
to nucleotide C4′ radicals,6 which are central to the degrada-
tion of oligonucleotides by bleomycin,7 the enediyne antitu-
mor antibiotics,8,9 and ionizing radiation.10 Nucleotide C4′
radicals are also key intermediates in DNA footprinting.11
The vast majority of work with these 2-deoxy-4′R-carbonyl
substituted nucleotides has been conducted with the thy-
midine series. Almost without fail, the synthesis3,5,12,13 of
these ramified thymidines can be traced back to original
work by J ones on the Cannizzaro reaction of aldehyde 1 with
formaldehyde giving the diol 2.14 The reactivity profile of 2
is such that the R-OH is more readily protected than the
â-one,15 which means that selective oxidation of the R-hy-
droxymethyl group to the desired aldehyde or acid is
necessarily preceded by a lengthy three-step selective double-
protection and monodeprotection sequence.3,5,12 Moreover,
the final oxidation of alcohols such as 3 to the ester 4 is
difficult.5 Recently, we have qualitatively demonstrated, by
means of PhS• addition to the corresponding exocyclic
glycals, that the fragmentation of nucleotide C4′ radicals
5-9 is a function of the base.16 Quantification of this
observation requires the synthesis of the C4′ acids of all four
Our synthesis was built on the basis of Seebach’s concept
of self-reproduction of chirality as exemplified by the alky-
lation of tartrate acetals with retention of configuration.17
We began by conversion of dimethyl L-tartrate to the
cyclopentylidene acetal 10 in the standard manner. Depro-
tonation with LDA in a THF/HMPA mixture followed by
quenching with freshly prepared benzyloxymethyl chloride
(BOMCl) provided the adduct 11 in 60% isolated yield as a
single isomer.18 The less substituted ester was then selec-
tively reduced with DIBALH to give alcohol 12 in 75% yield.
Importantly, the hydroxy ester 12 showed no tendency
toward lactonization, so reinforcing the notion that alkyla-
tion of 10 took place with retention of configuration. Swern
oxidation of 12 then gave 80% of the aldehyde 13, which
was converted to the alkene 14, by the usual Wittig
sequence, in 62% yield as a 1:1 mixture of isomers (Scheme
1).
(1) Hess, M. T.; Schwitter, U.; Petretta, M.; Giese, B. Biochemistry 1997,
36, 2332-2337.
(2) Marx, A.; MacWilliams, M. P.; Bickle, T. A.; Schwitter, U.; Giese, B.
J . Am. Chem. Soc. 1997, 119, 1131-1132.
(3) Hrebabecky, H.; Holy, A. Collect. Czech. Chem. Commun. 1997, 62,
1128-1135.
Sch em e 1
(4) Giese, B.; Erdmann, P.; Giraud, L.; Gobel, T.; Petretta, M.; Schafer,
T.; von Raumer, M. Tetrahedron Lett. 1994, 35, 2683-2686.
(5) Crich, D.; Yao, Q. Tetrahedron 1998, 54, 305-318.
(6) Beckwith, A. L. J .; Crich, D.; Duggan, P. J .; Yao, Q. Chem. Rev. 1997,
97, 3273-3312.
(7) Stubbe, J .; Kozarich, J . W.; Wu, W.; Vanderwall, D. E. Acc. Chem.
Res. 1996, 29, 322-330.
(8) Christner, D. F.; Frank, B. L.; Kozarich, J . W.; Stubbe, J .; Golik, J .;
Doyle, T. W.; Rosenberg, I. E.; Krishnan, B. J . Am. Chem. Soc. 1992, 114,
8763-8767.
(9) Hangeland, J . J .; De Voss, J . J .; Heath, J . A.; Townsend, C. A. J .
Am. Chem. Soc. 1992, 114, 9200-9202.
(10) von Sonntag, C. The Chemical Basis of Radiation Biology; Taylor
and Francis: London, 1987.
(11) Pogozelski, W. K.; Mcneese, T. J .; Tullius, T. D. J . Am. Chem. Soc.
1995, 117, 6428-6433.
(12) Marx, A.; Erdmann, P.; Senn, M.; Ko¨rner, S.; J ungo, T.; Petretta,
M.; Imwinkelreid, P.; Dussy, A.; Kulicke, K. J .; Macko, L.; Zehnder, M.;
Giese, B. Helv. Chim. Acta 1996, 79, 1980-1994.
(13) Thrane, H.; Fensholt, J .; Regner, M.; Wengel, J . Tetrahedron 1995,
51, 10389-10402.
Our plan called for the simultaneous hydrolysis of the enol
ether and acetal functions in 14, followed by spontaneous
cyclization to the 2-deoxy-4R-(methoxycarbonyl)-D-ribofura-
(14) J ones, G. H.; Taniguchi, M.; Tegg, D.; Moffatt, J . G. J . Org. Chem.
1979, 44, 1309-1317.
(17) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 2708-2748.
(18) For a related reaction see: Ditrich, K.; Hoffmann, R. W. Liebigs Ann.
Chem. 1990, 15-21.
(15) O-Yang, C.; Wu, Y. H.; Fraser-Smith, E. B.; Walker, K. A. M.
Tetrahedron Lett. 1992, 33, 37-40.
(16) Crich, D.; Mo, X.-S. Tetrahedron Lett. 1997, 38, 8169-8172.
S0022-3263(98)00301-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/20/1998

Communications
J . Org. Chem., Vol. 63, No. 12, 1998 3797
Ta ble 1. Syn th esis of Nu cleosid es fr om 19
Sch em e 2
base
product (% yield)
â:Ra
T
20 (70)
21 (90)
22 (83)
23 (40)
1:1
5:7
1:3
1:1
4-N-Ac-C
2-N-Ac-G
6-N-Bz-A
a
Anomeric ratios were determined by integration of the 1H
NMR spectra of the crude reaction mixtures.
Sch em e 4
Sch em e 3
4). This substance was found to be identical in every respect
to an authentic sample obtained by debenzoylation and
transesterification of 25, which itself had been previously
obtained from 2 via 3.5 This experiment, aside from
establishing anomeric configuration, also nicely serves to
confirm the stereochemical outcome of the initial alkylation
(10 f 11). The anomeric configurations of 21 f 23Râ were
assigned following close parallels in their 1H NMR spectra
with those of 20Râ. Further supporting evidence for the
configurational assignments in 21-23 was gleaned from
specific rotations: at the sodium D line the â-anomers of the
two pyrimidines (20â and 21â) were found to be more
dextrorotatory than their R-epimers, whereas the opposite
was true for the two purines (22â and 23â). This is exactly
the pattern seen with the four natural DNA bases and their
R-anomers.21 Finally, we also noted that all four â-anomers
were faster eluting from silica gel than their R-isomers.
In conclusion, we have developed an efficient asymmetric
synthesis of the 4′-substituted ribofuranoside 19, which is
converted efficiently into any of the desired nucleosides in
high yield. Moreover, the 3′- and 5′-hydroxy groups are
suitably orthogonally protected, enabling selective depro-
tection and elaboration in either direction. Although the
coupling reaction, like most reactions of this type, is not at
present selective, the anomers are readily separable, and
this imperfection is more than offset by the ability to prepare
all four bases from a single precursor and by the potential
for introduction of non-natural bases.
nose skeleton. Unfortunately, direct hydrolysis under a
variety of conditions resulted in elimination and the isolation
of 15 in good yield. After some experimentation, we discov-
ered that 14 could be converted in excellent yield to the
diacetal 16 by treatment with methanolic mercuric acetate,
followed by NaBH4, and that this species readily underwent
the desired conversion to 17 on exposure to 3 N HCl in THF.
Crude 17 was then transformed to the methyl glycosides 18,
which were isolated in 85% overall yield from 16, with
methanolic HCl (Scheme 2).
Silylation of 18 with TBDMSOTf gave 19, which proved
to be a suitable donor for coupling to the various bases. Thus,
treatment of a room-temperature acetonitrile solution of 19
with suitably protected forms of the four standard DNA
19
bases and SnCl4 as promoter provided the nucleosides in
moderate to good yield as R:â mixtures (Scheme 3, Table 1).
In each case, the pairs of anomers were readily separated
by chromatography over silica gel. In the guanosine series,
we also isolated minor amounts of both the R- and â-anomers
of the N7-glycosylated isomers. These were readily distin-
guished from the desired N9 isomers by well-established
spectroscopic methods.20
Ack n ow led gm en t. We thank the NIH (R01 CA60500)
for support of this work.
NOE studies were largely inconclusive, and ultimately,
the configuration of 20â was confirmed by removal of the
benzyl ether by hydrogenolysis over Pd/C, giving 24 (Scheme
Su p p or tin g In for m a tion Ava ila ble: Full experimental and
characterization data for all new compounds (11 pages).
J O980301F
(19) J anardhanam, S.; Nambiar, K. P. Tetrahedron Lett. 1994, 35, 3657-
3660.
(21) R-T: Lemieux, R. U.; Hoffer, M. Can. J . Chem. 1961, 39, 110-115.
â-T: Hoffer, M.; Duschinsky, R.; Fox, J . J .; Yung, N. J . Am. Chem. Soc.
1959, 81, 4112-4113. R-C: Yamaguchi, T.; Saneyoshi, M. Chem. Pharm.
Bull. 1984, 32, 1441-1450. â-C: Pathak, T.; Chattopadhyaya, J . Tetrahe-
dron 1987, 43, 4227-4234. R- and â-G: Robins, M. J .; Robins, R. K. J . Org.
Chem. 1969, 34, 2160-2163. R- and â-A: Ness, R. K.; Fletcher, H. G. J .
Am. Chem. Soc. 1959, 81, 4752-4753.
(20) Kjellberg, J .; J ohansson, N. G. Tetrahedron 1986, 42, 6541-6544.
Chenon, M.-T.; Pugmire, R. J .; Grant, D. M.; Panzica, R. P.; Townsend, L.
B. J . Am. Chem. Soc. 1975, 97, 4627-4635. Garner, P.; Ramakanth, S. J .
Org. Chem. 1988, 53, 1294-1298. Robins, M. J .; Zou, R.; Guo, Z.; Wnuk, S.
F. J . Org. Chem. 1996, 61, 9207-9212.