Synthesis of purine and pyrimidine isodideoxynucleosides from (S)- glycydol using iodoetherification as key step. Synthesis of (S,S)-iso-ddA

Full text of DOI:10.1021/jo990495e

6508
J . Org. Chem. 1999, 64, 6508-6511
Syn th esis of P u r in e a n d P yr im id in e
Isod id eoxyn u cleosid es fr om (S)-Glycyd ol
Usin g Iod oeth er ifica tion a s Key Step .
Syn th esis of (S,S)-iso-d d A1
Yolanda D´ıaz, Fernando Bravo, and Sergio Castillo´n*
Departament de Quı´mica, Universitat Rovira i Virgili,
Pc¸a. Imperial Tarraco 1, 43005 Tarragona, Spain
F igu r e 1.
Sch em e 1
Received March 22, 1999
Analogues of natural nucleosides have proved to be
efficient antiviral agents. The chemistry of nucleosides
is a field that is being actively investigated in the search
for new antiviral drugs with improved biological proper-
ties and minimun toxic effects. Consequently, many
different families of nucleoside analogues have been
synthesized. Of these, 2′,3′-dideoxynucleosides have been
extensively studied,2 and some of them have been ap-
proved for treating AIDS. Nevertheless, dideoxynucleo-
sides degrade rapidly because the glycosidic link hydro-
lyzes under acidic conditions, such as those in the gastric
environment, and becasuse of the action of enzymes.3 To
overcome these limitations, several modifications have
been made to the structure of nucleosides (fluoronucleo-
sides, C-nucleosides and carbocyclic analogues, etc).
Isonucleosides constitute a novel class of nucleosides that
have attracted great interest.4 They are highly stable
toward acids and enzymatic deamination and show
strong and selective anti-HIV and anti-HSV activity. Iso-
ddA4a,c is a good example (Figure 1); its anti-HIV activity
is similar to that of ddA, and it has no apparent toxicity.
Likewise, some isopyranosyl nucleosides also have potent
antiviral activity4e (Figure 1).
Sch em e 2
Isonucleosides are usually prepared from carbohy-
drates through multistep sequences. The most common
strategy reduces methyl glycosides by treating them with
triethylsilane in the presence of a Lewis acid (Scheme
1).4f The tetrahydrofurans are also synthesized through
protocols of ring opening-ring closing of sugar precursors4a
or through asymmetric synthesis from prochiral starting
materials5 (Scheme 1). Furthermore, the discovery that
some L-nucleosides are anti-AIDS agents refutes the idea
that the D-configuration is a requirement for biological
activity. Thus, the antiviral activities of nucleosides such
as L-3TC6 and L-FTC6a,7 are similar to, or better than,
the activities of D-enantiomers and also have a more
favorable toxicity profile.
* To whom correspondence should be addressed. Email: castillon@
quimica.urv.es.
(1) Presented in part at the XIII International Round Table on
Nucleosides and Nucleotides and Their Biological Applications, Mont-
pellier, France, September 1998, P27.
In this paper, we describe the asymmetric synthesis
of purine and pyrimidine isodideoxynucleosides with S,S
absolute stereochemistry, which may be regarded as
L-related dideoxynucleosides4g (Figure 1). It is based on
the synthesis of the key intermediate A (Scheme 2) from
a 4-pentene-1,2-diol through iodine-induced cyclization.
The intermediate A can be coupled to the base under
(2) (a) Mitsuya, H.; Yarchoan, R.; Broder, S. Science 1990, 249, 1533.
(b) Nasr, M.; Turk, S. R. Nucleosides and Nucleotides as Antitumoral
and Antiviral Agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press:
New York, 1993; p 227. (c) Broder, S. Med. Res. Rev. 1990, 10, 419.
(3) (a) York, J . L. J . Org. Chem. 1981, 46, 2171. (b) Marquez, V. E.;
Lim, M.-I. Med. Res. Rev. 1986, 6, 1. (c) Marquez, V. E.; Tseng, C.
K.-H.; Kelley, J . A.; Mitsuya, H.; Broder, S.; Roth, J . S.; Driscoll, J . S.
Biochem. Pharmacol. 1987, 36, 2719. (d) Kawaguchi, T.; Fukushima,
S.; Ohmura, M.; Mishima, M.; Nakano, M. Chem. Pharm. Bull. 1989,
37, 1944. (e) Nair, V.; Buenger, G. S. J . Org. Chem. 1990, 55, 3695.
(4) (a) Huryn, D. M.; Sluboski, B. C.; Tam, S. Y.; Todaro, L. J .;
Weigele, M. Tetrahedron Lett. 1989, 30, 6259. (b) J ones M. F.; Noble,
S. A.; Robertson, C. A.; Storer, R.; Highcock, R. M.; Lamont, R. B. J .
Chem. Soc., Perkin Trans. 1992, 1, 1427. (c) Nair, V.; Nuesca, Z. M. J .
Am. Chem. Soc. 1992, 114, 7951. (d) Nair, V. Nucleosides and
Nucleotides as Antitumor and Antiviral Agents; Chu, C. K., Baker, D.
C., Eds.; Plenum Press: New York, 1993; p 127. (e) Verheggen, I.; Van
Aerschot, A.; Toppet, S.; Snoeck, R.; J anssen, G.; Balzarini, J .; De
Clercq, E.; Herdewijn, P. J . Med. Chem. 1993, 36, 2033. (f) Bolon, P.
J .; Sells, T. B.; Nuesca, Z. M.; Purdy, D. F.; Nair, V. Tetrahedron 1994,
50, 7747. (g) Nair, V.; J ahnke, T. S. Antimicrob. Agents Chemother.
1995, 39, 1017. (h) Prevost, N.; Rouessac, F. Synth. Commun. 1997,
27, 2325.
(5) J ung, M. E.; Kretschik, O. J . Org. Chem. 1998, 63, 2975.
(6) (a) Beach, J . W.; J eong, L. S.; Alves, A. J .; Pohl, D.; Kim, H. O.;
Chang, C.-N.; Doong, S.-L.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K.
J . Org. Chem. 1992, 57, 2217. (b) Coates, J . A. V.; Cammack, N.;
J enkinson, H. J .; Mutton, I. M.; Pearson, B. A.; Storer, R.; Cameron,
J . M.; Penn, C. R. Antimicrob. Agents Chemother. 1992, 36, 202. (c)
Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.; Cannon,
D.; J eong, L.-S.; Beach, J . W.; Choi, W.-B.; Yeola, S.; Liotta, D. C.
Antimicrob. Agents Chemother. 1992, 36, 672.
(7) (a) Hoong, L. K.; Strange, L. E.; Liotta, D. C.; Koszalka, G. W.
Burns, C. L.; Schinazi, R. F. J . Org. Chem. 1992, 57, 5563. (b) Furman,
P. A.; Davis, M.; Liotta, D. C.; Paff, M.; Frick, L. W.; Nelson, D. J .;
Dornsife, R. E.; Wurster, J . A.; Wilson, L. J .; Fyfe, J . A.; Tuttle, J . V.;
Miller, W. H.; Conderay, L.; Averett, D. R.; Schinazi, R. F.; Painter,
G. R. Antimicrob. Agents Chemother. 1992, 36, 2686.
10.1021/jo990495e CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/27/1999

Notes
J . Org. Chem., Vol. 64, No. 17, 1999 6509
Sch em e 3
Sch em e 4
Mitsunobu conditions or by nucleophilic displacement
from the corresponding sulfonates.
Resu lts a n d Discu ssion
Tetrahydrofuran synthesis based on electrophilically
induced cyclization has been extensively discussed in the
literature.8 According to Baldwin’s rules,9 the exo mode
of cyclization is often preferred for small rings, but
exceptions to these rules are common, particularly when
the endo product is preferred for electronic factors.10
Previous reports on the cyclization of related systems
show that cyclization is often in the exo mode,11 even
when the alcohol is protected.12 In particular, J ung
observed this in a recently reported synthesis of branched
isonucleosides.13 However, it has been described that the
iodine-induced cyclization of compound 2a , whose pri-
mary hydroxyl group is protected, proportionates the
5-endo-trig product.14 Because both 5-exo-trig and 5-endo-
trig products are appropriate starting materials for the
synthesis of isonucleosides (see Scheme 3), we decided
to explore first the iodoetherification of alkenol 2b
(Schemes 3 and 4) using the more stable TBDPS as the
protecting group.
(S)-Glycydol (1) was treated with an ethereal solution
of the higher-order organocuprate reagent (CH2CH)2Cu-
(CN)(MgCl)2 to afford the key homoallyl alcohol 2b in a
98% yield (Scheme 4).
Iodoetherification was initially tested with compound
2b in the conditions previously reported,14 and a diaste-
reoisomeric mixture of 3,5-trans-tetrahydrofuran 4 and
3,5-cis-tetrahydrofuran 12 was obtained in an 83% yield,
after a 5-exo-trig cyclization. No silylated products were
obtained. However, when the reaction was left to stand
for longer reaction times, the silyl derivatives 10 and 13
were isolated alongside the unprotected products 4 and
12. This may be due to the in situ silylation of products
4 and 12 that initially formed with the tert-butyldiphen-
ylsilyl iodide present in the reaction medium. No traces
of 5-endo-trig products were recovered in any of the
conditions tested.
Compounds 4 and 12 were subjected to NOE experi-
ments to determine their configuration, but the results
were unclear, probably because of their conformational
mobility. Therefore, compound 4 was transformed into
the 3,5-dinitrobenzoate 11, and NOE experiments in this
case enabled the stereochemistry to be determined:
(8) (a) Bartlett, P. A.; Richardson, D. P.; Myerson, J . Tetrahedron
1984, 40, 2317. (b) Bartlett, P. A. Asymmetric Synthesis; Morrison, J .
D., Ed.; Academic Press: London, 1984; Vol. 3, pp 411-454. (c) Boivin,
T. L. B. Tetrahedron 1987, 43, 3309. (d) Cardillo, G.; Orena, M.
Tetrahedron 1990, 46, 3321. (e) Orena, M. Houben-Weyl; Helmchen,
G., Hoffmann, R. W., Mulzer, J ., Schumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, New York, 1995; Vol. 21e, pp 4760-4817.
(9) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
(10) For some representative examples of iodoetherification see: (a)
Kang, S. H.; Lee, S. B. Tetrahedron Lett. 1993, 34, 7579. (b) Lipshutz,
B. H.; Tirado, R. J . Org. Chem. 1994, 59, 8307. (c) Barks, J . M.; Knight,
D. W.; Seaman, C. J .; Weingarten, G. G. Tetrahedron Lett. 1994, 35,
7259. (d) Galatsis, P.; Manwell, J . J . Tetrahedron Lett. 1995, 36, 8179.
(e) Knight, D. W.; Redfern, A. L.; Gilmore, J . Tetrahedron Lett. 1998,
39, 8909.
(11) (a) Williams, D. R.; Grote, J .; Harigaya, Y. Tetrahedron Lett.
1984, 25, 5231. (b) Reitz, A. B.; Nortey, S. O.; Maryanoff, B. E.; Liotta,
D.; Monahan, R., III. J . Org. Chem. 1987, 52, 4191.
(12) (a) Nicotra, F.; Panza, L.; Ronchetti, F.; Russo, G.; Toma, L.
Carbohydr. Res. 1987, 103, 49. (b) Hatakeyama, S.; Sakurai, K.;
Takano, S. Heterocycles 1986, 24, 633.
(13) J ung, M. E.; Nichols, C. J . J . Org. Chem. 1998, 63, 347.
(14) Bedford, S. B.; Bell, K. E.; Fenton, G.; Hayes, C. J .; Knight, D.
W.; Shaw, D. Tetrahedron Lett. 1992, 33, 6511.
After these results we decided to explore the reaction
of the fully deprotected 3 with iodine in dry acetonitrile
under the kinetic conditions described by Bartlett.8a The
reaction proceeded readily to give compound 4 in a 71%
yield, together with a minor amount of the 3,5-cis-
tetrahydrofuran 12, as a result of a 5-exo-trig cyclization.

6510 J . Org. Chem., Vol. 64, No. 17, 1999
Notes
heterogeneous mixture was warmed to -20 °C until the CuCN
completely dissolved, and it was then cooled again to -78 °C. A
solution of 1 (10 g, 32 mmol) in 100 mL of dry ether was added
dropwise. The resulting mixture was warmed to -60 °C and
stirred for 5 h. The reaction was monitored by TLC in EtOAc/
Hex 1:10, quenched by addition of an aqueous solution (10%
concentrated NH4OH/90% saturated NH4Cl), and warmed to
ambient temperature with vigorous stirring until the solids
dissolved. The mixture was extracted with ether, and the
combination of extracts was washed with water and then with
brine. The ethereal solution was dried, filtered, and concentrated
It was the gauche effect between both hydroxyls that
determined the stereoselectivity.15
It has been observed in compounds related to 4 that
acetate displaces iodine only with difficulty.13 We used
potassium p-nitrobenzoate to reduce the basicity of the
reagent. The reaction of compound 4 with potassium
p-nitrobenzoate in DMF at 60 °C was unsuccessful.
However, when the reaction was carried out in DMSO
at 90 °C using 18-crown-6, compound 5 was obtained in
a 73% yield.
to dryness to afford 10.70 g (98%) of alcohol 2b as a syrup. [R]25
D
) +3.0 (c 0.986, CHCl3). 1H NMR (CDCl3) δ 7.70-7.35 (m, 10H),
5.79 (ddt, 1H, J ) 17.1, 10.1, 6.5, 6.5), 5.11-5.02 (m, 2H), 3.79
(dddd, 1H, J ) 6.5, 6.0, 6.0, 3.8), 3.67 (dd, 1H, J ) 10.1, 3.8),
3.53 (dd, 1H, J ) 10.1, 6.0), 2.51 (bs, 1H), 2.24 (tt, 2H, J ) 6.5,
6.5, 1.4, 1.4), 1.08 (s, 9H). 13C NMR (CDCl3) δ 135.5, 134.3, 133.0,
129.8, 127.7, 117.4, 71.2, 67.2, 37.5, 26.8, 19.2. Anal. Calcd for
C21H28O2Si: C, 74.07; H, 8.29. Found: C, 74.32; H, 8.32.
(R)-4-P en ten -1,2-d iol (3). A solution of 10 g (29.4 mmol) of
2b in 300 mL of dry THF was treated with 32 mL (32 mmol) of
a 1 M tetrabutylammonium fluoride solution in THF at 0 °C
under an argon atmosphere. The reaction was monitored by TLC
in ethyl ether/petroleum ether 1:1. The mixture was left to warm
to room temperature, poured into a water/ice mixture, and
extracted with ether. The combination of extracts was concen-
trated and chromatographed with ethyl ether/petroleum ether
20:1 to give 2.94 g (98%) of 3 as an oil. [R]25D +3.3 (c 0.25, CHCl3).
1H NMR (CDCl3) δ 5.79 (m, 1H, J ) 17.1, 10.2, 5.7, 5.7), 5.10-
5.01 (m, 2H), 3.88 (bs, 2H), 3.68 (dddd, 1H, J ) 7.5, 6.5, 6.5,
2.8), 3.56 (dd, 1H, J ) 11.5, 2.8), 3.37 (dd, 1H, J ) 11.5, 7.5),
2.18-2.12 (m, 2H). 13C NMR (CDCl3) δ 134.2, 117.8, 71.4, 66.0,
37.6. Anal. Calcd for C5H10O2: C, 58.80; H, 9.87. Found: C,
59.15; H, 9.96.
To synthesize iso-ddA, compound 5 was transformed
into the tosyl derivative, which was then treated with
adenine, potassium carbonate, and 18-crown-6, according
to the reported procedure,4f to give 42% of compound 6
and a mixture of the unprotected product 7 and crown
ether potassium salt. This mixture proved to be insepa-
rable.
Treatment of 5 with adenine in dioxane under Mit-
sunobu16 conditions led to a complex inseparable mixture.
However, when DMF was used as the solvent, compound
6 was obtained in a 62% yield, without deprotection. The
treatment of compound 6 with sodium methoxide in
methanol led to compound 74a,c in quantitative yield.
Thus, isonucleoside 7 was obtained in 6 steps from 1 in
an overall yield of 31%.
Alcohol 5 was also coupled with N3-benzoylthymine17
under Mitsunobu conditions (Scheme 4). The reaction
was carried out in dioxane18 to give the isonucleoside 8
in a 63% yield, together with 15% of the O2-derivative
14. Isonucleoside 8 was fully deprotected by treatment
with NH3/MeOH to give 94f in a 65% yield.
In summary, isodideoxynucleosides with S,S absolute
stereochemistry were synthesized from the readily ava-
laible glycydol 1 using a 5-exo-trig iodocyclization as the
key step. The method enables both enantiomeric iso-
nucleosides to be prepared.
(3R,5S)-5-Iodom eth yltetr ah ydr ofu r an -3-ol (4)an d (3R,5R)-
5-Iod om eth yltetr a h yd r ofu r a n -3-ol (12). In a flask fitted with
a magnetic bar, 2.05 g (20.07 mmol) of 3 was dissolved in 130
mL of dry acetonitrile under an argon atmosphere, and 5.06 g
(60.21 mmol) of NaHCO3 was added. The resulting mixture was
stirred at room temperature for 5 min and cooled to 0 °C, and
15.28 g (60.21 mmol) of I2 was added. The reaction mixture was
left to warm to room temperature for 2 h. The evolution of the
reaction was monitored by TLC in ether/petroleum ether 1:1.
The mixture was diluted with ether and washed with 10%
sodium thiosulfate solution until the color disappeared. The
aqueous layer was extracted several times with ether. The
combination of extracts was dried, filtered, and concentrated.
The residue was purified by column chromatography in ether/
petroleum ether 1:1 to afford 3.23 g (71%) of 4 (lower Rf) and
1.20 g (26%) of 12.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected. Opti-
cal rotations were measured at 25 °C in 10 cm cells. 1H and 13C
NMR spectra were recorded in a 300 MHz (300 and 75.4 MHz,
respectively) apparatus with CDCl3 as solvent, unless otherwise
specified. Coupling constants are given in hertz (Hz). Elemental
analyses were determined at the Servei de Recursos Cientifics
(Universitat Rovira i Virgili). Flash column chromatography was
performed using silica gel 60 A CC (40-63 microns). Radial
chromatography was performed on 1, 2, or 4 mm plates of silica
gel, depending on the amount of product. Medium-pressure
chromatography (MPLC) was performed using silica gel 60 A
CC (6-35 microns). Band separation was monitored by UV. TLC
plates were prepared by using Kieselgel 60 PF254. Solvents for
chromatography were distilled at atmospheric pressure prior to
use. Reaction solvents were purified and dried by using standard
procedures.
(R)-1-O-(ter t-Bu tyld ip h en ylsilyl)-4-p en ten -1,2-d iol (2b).
CuCN (6.61 g, 73.6‚mmol) was placed in a flask under argon
and dried by gentle heating with a flame under vacuum. It was
then allowed to cool under a positive pressure of argon. This
process was repeated three times, and then ether (100 mL) was
added. The resulting mixture was stirred to form a slurry and
cooled to -78 °C, and then vinylmagnesium chloride (87 mL,
147.2 mmol) was added dropwise over a period of 15 min. The
(4): [R]25 -12.6 (c 1.005, CHCl3). 1H NMR (CDCl3) δ 4.57
D
(dddd, 1H, J ) 5.3, 3.9, 1.7, 1.7), 4.22 (dddd, 1H, J ) 9.2, 5.6,
5.6, 5.6), 4.08 (dd, 1H, J ) 9.9, 3.9), 3.84 (dt, 1H, J ) 9.9, 1.3,
1.3), 3.30 (d, 2H, J ) 5.6), 2.17 (m, 1H, J ) 13.5, 5.6, 1.3, 1.3),
2.06 (bs, 1H), 1.80 (ddd, 1H, J ) 13.5, 9.2, 5.3). 13C NMR (CDCl3)
δ 77.0, 76.1, 72.8, 41.9, 10.1. Anal. Calcd for C5H9O2I: C, 26.34;
H, 3.98. Found: C, 26.41; H, 4.03.
(12): [R]25 +7.2 (c 1.349, CHCl3). 1H NMR (CDCl3) δ 4.53
D
(dddd, 1H, J ) 6.1, 4.1, 1.7, 1.7), 4.06 (dddd, 1H, J ) 8.1, 6.4,
5.4, 5.4), 3.98 (dt, 1H, J ) 9.9, 1.7, 1.7), 3.81 (dd, 1H, J ) 9.9,
3.9), 3.45 (dd, 1H, J ) 10.0, 6.4), 3.37 (dd, 1H, J ) 10.0, 5.4),
2.36 (ddd, 1H, J ) 14.0, 8.1, 6.1), 2.15 (bs, 1H), 1.81 (dddd, 1H,
J ) 14.0, 5.4, 1.7, 1.7). 13C NMR (CDCl3) δ 78.2, 76.3, 72.2, 40.7,
10.7. Anal. Calcd for C5H9O2I: C, 26.34; H, 3.98. Found: C,
26.45; H, 3.93.
[(2S,4R)-4-H yd r oxyt et r a h yd r ofu r a n -2-yl]m et h yl p -Ni-
tr oben zoa te (5). Compound 4 (1.1 g, 4.82 mmol) was dissolved
in 55 mL of DMSO and 7.9 g (38.54 mmol) of potassium
p-nitrobenzoate. Then, 0.13 g (0.49 mmol) of 18-crown-6 was
added. The heterogeneous mixture was heated to 90 °C for 16
h. The reaction was monitored by TLC in ethyl acetate/hexane
1:1. The reaction mixture was poured into ice/water and stirred
for 15 min. The aqueous solution was extracted several times
with ether. The combination of extracts was washed with 10%
sodium thiosulfate and then with water. The ethereal extracts
were dried, filtered, and concentrated. The resulting residue was
purified by radial chromatography over aluminum oxide in ethyl
(15) Labelle, M.; Morton, H. E.; Guindon, Y.; Springer, J . P. J . Am.
Chem. Soc. 1988, 110, 4533.
(16) Mitsunobu, O. Synthesis 1981, 1.
(17) Cruickshank, K. A.; J iricny, J .; Reese, C. B. Tetrahedron Lett.
1984, 681.
(18) Hossain, N.; Rozenski, J .; De Clercq, E.; Herdewijn, P. Tetra-
hedron 1996, 52, 13655.

Notes
J . Org. Chem., Vol. 64, No. 17, 1999 6511
acetate/hexane 1:1 to furnish 0.94 g (73%) of 5 as crystalline
) 10.8, 4.0), 2.46 (m, 1H, J ) 14.7, 8.1, 6.3), 2.23-2.17 (m, 1H),
2.18 (s, 3H). 13C NMR (CDCl3) δ 164.4, 162.8, 161.9, 157.2, 149.5,
135.5-123.6, 119.1, 78.9, 76.0, 73.0, 66.8, 34.5, 12.4.
solid. Mp 103-106 °C. [R]25 +18.7 (c 0.910, CHCl3). 1H NMR
D
(CDCl3) δ 8.37-8.18 (m, 4H), 4.64-4.58 (m, 1H), 4.59 (m, 1H, J
) 9.8, 6.7, 6.1, 3.1), 4.52 (dd, 1H, J ) 11.8, 3.1), 4.32 (dd, 1H, J
) 11.8, 6.7), 4.05 (dd, 1H, J ) 9.8, 4.0), 3.85 (dt, 1H, J ) 9.8,
1.3, 1.0), 2.15 (bs, 1H), 2.13 (m, 1H, J ) 13.3, 6.1, 1.3, 1.3), 1.90
(ddd, 1H, J ) 13.3, 9.4, 5.1). 13C NMR (CDCl3) δ 164.7, 135.3,
1-[(3S ,5S )-5-(H yd r oxym e t h yl)t e t r a h yd r ofu r a n -3-yl]-
th ym in e (9). Compound 8 (0.225 g, 0.47 mmol) was treated with
2.5 mL of ammonium hydroxide in 9 mL of methanol at room
temperature for 8 h. The course of the reaction was monitored
by TLC in ethyl acetate. The solvent was removed in vacuo, and
the residue was chromatographed to afford 0.069 g (65%) of 9.
UV (MeOH) λmax 268 nm (lit.4f 271). [R]25D +25.5 (c 0.945, MeOH)
130.9, 123.6, 75.8, 75.5, 72.1, 67.2, 37.6. Anal. Calcd for C12H13
-
NO6: C, 53.93; H, 4.90; N, 5.24. Found: C, 53.85; H, 4.89; N,
5.27.
1
1-[(3S,5S)-5-(p-Nitr oben zoyloxym eth yl)tetr ah ydr ofu r an -
3-yl]a d en in e (6). A total of 0.150 g of 5 (0.56 mmol) was
dissolved in 10 mL of DMF and added to a flask containing
adenine (0.305 g, 2.26 mmol) and triphenylphosphine (0.295 g,
1.12 mmol). Then, DEAD (0.175 mL, 1.13 mmol) diluted in 2
mL of DMF was added dropwise. The reaction mixture was
stirred for 5 days at 75 °C, and the reaction was monitored by
TLC in dichloromethane/methanol 10:1. The solvent was re-
moved in vacuo, and the residue was purified by MPLC using a
linear gradient (dichloromethane to dichloromethane/methanol
(lit.4f +26.0). H NMR (CDCl3) δ 9.86 (bs, 1H), 7.53 (d, 1H, J )
1.2), 5.40-5.31 (m, 1H), 4.06 (dd, 1H, J ) 10.6, 2.2), 4.06-4.01
(m, 1H), 4.00 (dd, 1H, J ) 12.6, 2.7), 3.94 (dd, 1H, J ) 10.6,
6.7), 3.72 (dd, 1H, J ) 12.6, 4.8), 2.83 (bs, 1H), 2.58-2.43 (m,
1H), 1.98-1.88 (m, 1H), 1.89 (s, 3H). 13C NMR (CDCl3) δ 162.8,
151.3, 137.3, 111.7, 80.1, 72.5, 62.6, 54.7, 33.5, 12.3.
(3R,5S)-3-O-(ter t-Bu t yld ip h en ylsilyl)-5-iod om et h ylt et -
r a h yd r ofu r a n -3-ol (10) a n d (3R,5R)-3-O-(ter t-Bu tyld ip h en -
ylsilyl)-5-iod om eth yltetr a h yd r ofu r a n -3-ol (13). NaHCO3
(0.694 g, 8.28 mmol) was added under argon to a solution of 0.94
g (2.76 mmol) of 2b in 20 mL of dry acetonitrile. The mixture
was stirred at room temperature for 5 min and cooled to 0 °C.
Then, 2.10 g (8.28 mmol) of I2 was added. The resulting mixture
was warmed to room temperature and maintained at this
temperature for 9 h. The reaction was monitored by TLC in ethyl
ether/petroleum ether 1:1. The mixture was diluted with ether
and washed with a 10% solution of sodium thiosulfate until the
color disappeared. The combination of extracts was dried,
filtered, and concentrated. The resulting residue was chromato-
graphed over silica gel in ethyl ether/petroleum ether 1:1 to
furnish 0.150 g (12%) of a silyl derivative 10/13 mixture and
0.39 g (62%) of a mixture of the alcohols 4 and 12 as syrups.
Data for the diastereoisomeric mixture follows. (10): 1H NMR
(CDCl3) δ 7.76-7.35 (m, 10H), 4.54-4.46 (m, 1H), 4.24 (m, 1H,
J ) 9.3, 5.7, 5.4, 5.1), 3.88 (dd, 1H, J ) 9.3, 4.2), 3.80 (ddd, 1H,
J ) 9.3, 2.1, 1.0), 3.27 (dd, 1H, J ) 10.2, 5.7), 3.23 (dd, 1H, J )
10.2, 5.1), 2.15-2.04 (m, 1H), 1.64-1.53 (m, 1H), 1.06 (s, 9H).
13C NMR (CDCl3) δ 135.7, 133.7, 129.9, 127.8, 79.0, 76.4, 74.0,
42.1, 26.7, 18.9, 10.3. (13): 1H NMR (CDCl3) δ 7.76-7.35 (m,
10H), 4.47-4.41 (m, 1H), 4.15 (m, 1H, J ) 7.6, 7.6, 6.0, 4.9),
3.90 (ddd, 1H, J ) 9.5, 1.2, 0.9), 3.68 (dd, 1H, J ) 9.5, 4.8), 3.46
(dd, 1H, J ) 9.7, 7.6), 3.39 (dd, 1H, J ) 9.7, 6.0), 2.04-1.94 (m,
1H), 1.64-1.53 (m, 1H), 1.08 (s, 9H). 13C NMR (CDCl3) δ 135.8,
133.4, 129.9, 127.8, 77.3, 76.1, 73.5, 40.3, 26.7, 18.9, 10.1. Anal.
Calcd for C21H27IO2Si: C, 54.08; H, 5.83. Found: C, 54.23; H,
5.86.
20:1) to furnish 0.133 g (62%) of 6. Mp 190-193 °C (dec). UV
1
(CHCl3) λmax 262 nm. [R]25 +17.8 (c 0.256, (CHCl2)2). H NMR
D
(CDCl3) δ 8.24 (d, 2H, J ) 8.6), 8.22 (s, 1H), 8.10 (d, 2H, J )
8.6), 8.04 (s, 1H), 5.26 (m, 1H), 4.61 (dd, 1H, J ) 2.6, 11.8), 4.5-
4.4 (m, 2H), 4.32 (d, 1H, J ) 2.8, 10.4), 4.11 (dd, 1H, J ) 5.7,
10.4), 3.81 (dt, 1H, J ) 8.0, 13.9), 2.12 (ddd, 1H, J ) 4.2, 8.4,
13.9). 13C NMR (CDCl3) δ 152.7, 138.2, 130.7, 123.5, 76.6, 72.2,
65.9, 54.3, 35.2. Anal. Calcd for C17H16N6O5: C, 53.13; H, 4.20;
N, 21.87. Found: C, 53.05; H, 4.30; N, 21.65.
1-[(3S,5S)-5-(H yd r oxym et h yl)t et r a h yd r ofu r a n -3-yl]a d -
en in e (7). A suspension of 0.130 g (0.34 mmol) of compound 6
was debenzoylated by treatment with sodium methoxide (0.030
g, 0.56 mmol) in methanol (16 mL). After 30 min the mixture
became clear. Then, a few milliliters of methanol were added,
and the solvent was evaporated in vacuo. The crude was purified
by MPLC using a linear gradient (dichloromethane to dichlo-
romethane/methanol 8:1) to give 0.079 g (99%) of iso-ddA (7).
UV (H2O) λmax 262 nm (lit.4f 260 nm). [R]25 -30.3 (c 0.840,
D
MeOH) (lit.4f -26.6, c 1.0; for enantiomer4b +31.9, c 1.05). 1H
NMR (DMSO) δ 8.26 (s, 1H), 8.14 (s, 1H), 7.24 (bs, 2H), 5.17
(dtd, 1H, J ) 8.7, 5.3, 5.3, 3.6), 4.98 (t, 1H, J ) 5.6), 4.01 (dd,
1H, J ) 9.7, 3.6), 3.99 (m, 1H), 3.95 (dd, 1H, J ) 9.7, 6.0), 3.62
(ddd, 1H, J ) 11.8, 4.8, 3.9), 3.52 (ddd, 11.8, 5.6, 4.6), 2.57 (dt,
1H, J ) 13.2, 8.1, 8.1), 2.08 (ddd, 1H, J ) 13.2, 8.2, 5.1). 13C
NMR (DMSO) δ 156.2, 152.6, 139.1, 118.8, 79.7, 71.9, 62.5, 53.9,
33.9. Anal. Calcd for C10H13N5O2: C, 51.06; H, 5.57; N, 29.77.
Found: C, 50.95; H, 5.63; N, 29.65.
(3R,5S)-5-Iodom eth yltetr ah ydr ofu r an -2-yl 3,5-Din itr oben -
zoa te (11). A solution of 0.030 g (0.131 mmol) of 4 in 2 mL of
pyridine at 0 °C was treated with 0.034 g (0.145 mmol) of 3,5-
dinitrobenzoyl chloride for 16 h. The mixture was poured into
water/ice and was extracted several times with ethyl acetate.
The organic layer was dried, filtered, and concentrated in vacuo.
The residue was chromatographed by radial chromatography in
ethyl acetate/hexane 1:7 to give 0.047 g (85%) of 11 as a
1-[(3S,5S)-5-(p-Nitr oben zoyloxym eth yl)tetr ah ydr ofu r an -
3-yl]-3-b en zoylt h ym in e (8) a n d 2-[(3S,5S)-5-(p -Nit r ob en -
zoyloxym et h yl)t et r a h yd r ofu r a n -3-yl]-3-b en zoylt h ym in e
(14). To a solution of 5 (0.2 g, 0.75 mmol), N3-benzoylthymine
(0.344 g, 1.50 mmol), and triphenylphosphine (0.393 g, 1.50
mmol) in dioxane (7 mL) was added DEAD (0.250 mL, 1.50
mmol) dissolved in 4 mL of dioxane over a period of 30 min.
The reaction mixture was stirred for 5 days, and the reaction
was monitored by TLC in ethyl acetate/hexane 1:1. The solvent
was removed in vacuo, and the residue was purified by column
chromatography to furnish 0.225 g (63%) of 8 and 0.054 g (15%)
of 14. They were contaminated with impurities which were
removed in the next deprotection step.
crystalline solid. Mp 91-93 °C. [R]25 -3.9 (c 0.21, CHCl3). 1H
D
NMR (CDCl3) δ 9.21-9.07 (m, 3H), 5.64 (m, 1H), 4.28 (dd, 1H,
J ) 10.8, 4.8), 4.27-4.18 (m, 1H), 4.04 (dt, 1H, J ) 10.8, 1.2,
1.2), 3.30 (d, 2H, J ) 4.5), 2.42 (m, 1H, J ) 14.2, 5.9, 1.2, 1.2),
2.05 (ddd, 1H, J ) 14.2, 9.4, 5.9). 13C NMR (CDCl3) δ 162.3,
133.5, 129.5, 122.8, 78.2, 78.0, 73.3, 39.0, 8.9. Anal. Calcd for
C12H11IN2O7: C, 34.14; H, 2.63; N, 6.64. Found: C, 34.16; H,
2.64; N, 6.55.
1
(8): UV (CHCl3) λmax 268 nm. H NMR (CDCl3) δ 8.28-7.15
(m, 10H), 5.35-5.26 (m, 1H), 4.68 (dd, 1H, J ) 12.3, 2.8), 4.51
(dd, 1H, J )12.3, 6.9), 4.30-4.19 (m, 1H), 4.13 (dd, 1H, J ) 11.1,
2.0), 3.95 (dd, 1H, J ) 11.1, 6.9), 2.70 (ddd, 1H, J ) 13.9, 9.0,
7.3), 1.87-1.76 (m, 1H), 1.82 (s, 3H). 13C NMR (CDCl3) δ 164.0,
163.4, 162.4, 150.2, 137.3, 135.6-128.0, 112.0, 76.9, 71.8, 65.6,
55.1, 35.0, 12.3.
Ack n ow led gm en t. Financial support by DGICYT
PB95-521-A (Ministerio de Educacion y Cultura, Spain)
is acknowledged. F.B. thanks CIRIT (Generalitat de
Catalunya) for a grant. Technical assistance by the
Servei de Recursos Cientifics (URV) is acknowledged.
(14): 1H NMR (CDCl3) δ 8.41-7.43 (m, 10H), 5.61-5.55 (m,
1H), 4.33-4.23 (m, 1H), 4.16 (dd, 1H, J ) 11.8, 4.0), 4.14 (dd,
1H, J ) 10.8, 6.9), 3.98 (dd, 1H, J ) 11.8, 7.5), 3.93 (dd, 1H, J
J O990495E