Synthesis of 2′,3′-Didehydro-2′,3′-dideoxynucleosides by Reaction of 5′-O-Protected Nucleoside 2′,3′-Dimesylates with Lithium Areneselenolates

Full text of DOI:10.1021/jo962079p

J . Org. Chem. 1997, 62, 3751-3753
3751
Sch em e 1
Syn th esis of
2′,3′-Did eh yd r o-2′,3′-d id eoxyn u cleosid es by
Rea ction of 5′-O-P r otected Nu cleosid e
2′,3′-Dim esyla tes w ith Lith iu m
Ar en eselen ola tes
Derrick L. J . Clive,* Paulo W. M. Sgarbi, and
Philip L. Wickens
Chemistry Department, University of Alberta,
Edmonton, Alberta, Canada T6G 2G2
Sch em e 2
Received November 6, 1996
In tr od u ction
Conversion of nucleosides into their 2′,3′-didehydro-
2′,3′-dideoxy derivatives is currently an important topic
in medicinal chemistry because the deoxygenated com-
pounds or their hydrogenation products (2′,3′-dideoxy-
nucleosides) have been found, in certain cases, to inhibit
the progress of HIV infection.1 We have recently reported
that conversion of 5′-O-protected nucleosides into the
corresponding 2′,3′-dimesylates, followed by treatment
with Te2-, constitutes an effective method for deoxygen-
ation (Scheme 1, 1 f 2 f 3).2 During the course of our
work, we wondered whether the same transformation
could also be accomplished by treating the dimesylates
with ArSe-.3 This possibility was based on the fact that
compounds of partial structure 4 afford olefins when the
hydroxyl function is converted into a good leaving group
(e.g., OMs), as shown in Scheme 2.4 In principle, the
proposed intermediates (5 and 6) should also be acces-
sible by displacement of a single mesyloxy group from a
vicinal dimesylate (Scheme 3). We have now tested the
process summarized by Scheme 3 and describe a number
of examples (see Table 1) where it represents a conve-
nient route to olefins of the nucleoside series.
Sch em e 3
derived dimesylate 12a likewise afforded olefin, but the
primary-secondary dimesylates 13a and 14a behaved
in a different way. The former gave a very low yield
(38%)7 of olefin under our standard conditions with
PhSe-Li+, but reacted efficiently with the aryl selenide
dianion 16, prepared as shown in eq 1. This dianion was
tried in order to determine if a cyclic bis(selenide) would
form and then collapse8 to olefin, but this mode of action
was not verified, since 16 did not prove to be a general
reagent. In the case of the reaction between 13a and 16,
1 mol of the reagent precursor (159) was used per mole
of dimesylate. The other sugar-derived dimesylate 14a
failed to give olefin with PhSe-Li+, and when we tried
the hindered selenide 17,10 both mesyloxy groups of 14a
were displaced by the selenide (1H NMR), with little, if
any, of the desired olefin being formed. This last experi-
ment with 17 was done in an attempt to restrict dis-
Each of the four nucleoside dimesylates examined (see
Table 1) was converted into the corresponding olefin on
treatment with PhSe-Li+ (G2 mol per mole of dimesylate)
in refluxing THF, the selenide anion being generated
from diphenyl diselenide and Et3BHLi.5,6 The sugar-
(1) For a review on AIDS-driven nucleoside chemistry, see: Huryn,
D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
(2) Clive, D. L. J .; Wickens, P. L.; Sgarbi, P. W. M. J . Org. Chem.
1996, 61, 7426.
(3) Simple vicinal dimesylates have been converted into olefins by
the action of an iodide ion, but this method does not appear to be useful
in the nucleoside series, at least, as judged by a test case we examined
(see ref 2).
(4) (a) Reich, H. J .; Chow, F.; Shah, S. K. J . Am. Chem. Soc. 1979,
101, 6638. (b) Clive, D. L. J .; Russell, C. G.; Suri, S. C. J . Org. Chem.
1982, 47, 1632. (c) Re´mion, J .; Dumont, W.; Krief, A. Tetrahedron Lett.
1976, 17, 1385. (d) Re´mion, J .; Krief, A. Tetrahedron Lett. 1976, 17,
3743.
(5) We did not establish whether the liberated Et3B plays any role
in the reaction. cf. Dittmer, D. C.; Zhang, Y.; Discordia, R. P. J . Org.
Chem. 1994, 59, 1004.
(6) Gladysz, J . A.; Hornby, J . L.; Garbe, J . E. J . Org. Chem. 1978,
43, 1204.
(9) Murata, S.; Suzuki, T.; Yanagisawa, A.; Suga, S. J . Heterocycl.
Chem. 1991, 28, 433.
(10) Made from the corresponding diselenide (Kuwajima, I.; Shimizu,
M.; Urabe, H. J . Org. Chem. 1982, 47, 837) by treatment with Et3-
BHLi (cf. ref 6).
(11) Generated from the corresponding ditelluride (ref 12) by
treatment with NaBH4 in EtOH.
(12) Morgan, G. T.; Kellett, R. E. J . Chem. Soc. 1926, 1080.
(13) Generated from the corresponding ditelluride (ref 14) by
treatment with NaBH4 in EtOH.
(14) Morgan, G. T.; Drew, H. D. K. J . Chem. Soc. 1925, 2307.
(15) A THF solution of the selenol acid (Kamiyama, T.; Enomoto,
S.; Inoue, M. Chem. Pharm. Bull. 1985, 33, 5184) was added to a
suspension of NaH (2.1 mole of per mol selenol acid). The suspension
was stirred for 5 min and was then transferred by cannula into a
solution of 13a (1 mol) in THF. No change was detected (TLC) after
24 h.
(7) A significant byproduct was the result of displacement of both
OMs groups by PhSe (see Experimental Section).
(8) For examples of vicinal bis(phenyl selenides) that collapse
spontaneously to olefins, see: Piettre, S.; J anousek, Z.; Merenyi, R.;
Viehe, H. G. Tetrahedron 1985, 41, 2527. In the case of 1,2-bis-
(methylseleno) compounds, chromatography over silica gel causes
decomposition to dimethyl diselenide and the corresponding olefin:
Hermans, B.; Colard, N.; Hevesi, L. Tetrahedron Lett. 1992, 33, 4629.
cf. Gulliver, D. J .; Hope, E. G.; Levason, W.; Murray, S. G.; Potter, D.
M.; Marshall, G. L. J . Chem. Soc., Perkin Trans. 2 1984, 429. Batchelor,
R. J .; Einstein, F. W. B.; Gay, I. D.; Gu, J .-H.; J ohnston, B. D.; Pinto,
B. M. J . Am. Chem. Soc. 1989, 111, 6582.
(16) Bis[2-(hydroxymethyl)phenyl] diselenide was made by reduction
(LiAlH4) of the selenol acid corresponding to 20, followed by aerial
oxidation. The diselenide [FTIR (CH2Cl2 cast) 3310 (broad), 747 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.7-7.1 (m, 16 H), 4.70 (s, 4 H), 2.2-1.8
(br s, 2 H); 13C NMR (CDCl3, 75.5 MHz) δ 137.0 (s′), 133.4 (d′), 131.3
(d′), 130.1 (d′), 128.0 (d′), 124.5 (s′), 33.4 (t′); exact mass m/z calcd for
C14H14O280Se2 373.93243, found 373.93374] was reduced in situ (Et3-
BHLi).
S0022-3263(96)02079-8 CCC: $14.00 © 1997 American Chemical Society

3752 J . Org. Chem., Vol. 62, No. 11, 1997
Notes
Ta ble 1
use of a catalytic amount of the ditelluride corresponding
to 19, with a stoichiometric amount of NaBH4, also led
to olefin in good yield (ca. 89%).
Finally, we made a cursory examination of the selenide
anions 2015 and 2116 in order to see if the intramolecular
processes 22 f 23 (eq 2) might occur and facilitate the
deoxygenation. However, with dimesylate 13a again as
the test case, deoxygenation did not occur, at least to any
noticeable extent with either of these reagents.
In summary, PhSe-Li+ converts secondary-secondary
vicinal dimesylates of the nucleoside series into the
corresponding dideoxy didehydro derivatives.
Exp er im en ta l Section
Gen er a l P r oced u r es. The same general procedures as used
previously2 were followed.
5′-O-[Bis(4-m eth oxyp h en yl)p h en ylm eth yl]-2′,3′-d id eh y-
d r o-2′,3′-d id eoxyin osin e (8b). Gen er a l P r oced u r e. Et3-
BHLi (1 M in THF, 0.52 mL, 0.52 mmol) was added dropwise
by syringe to a stirred solution of PhSeSePh (79.7 mg, 0.255
mmol) in THF (1 mL) (Ar atmosphere). At the end of the
addition a colorless solution had formed, and then 8a 2 (72.6 mg,
0.255 mmol) in THF (1.5 mL) was injected, followed by Et3N
(0.5 mL) and HMPA (40 µL). The solution was refluxed and
stirred for 20 h, and then it was cooled and evaporated at room
temperature. Flash chromatography of the residue over silica
gel (1 × 25 cm), using 5% MeOH-CH2Cl2, gave 8b2 (33.2 mg,
62%), which was identical to an authentic sample and, like that
sample,2 contained slight impurities (1H NMR, 300 MHz).
2′,3′-Did eh yd r o-2′,3′-d id eoxy-5′-O-(tr ip h en ylm eth yl)u r i-
d in e (9b). The general procedure was followed, using Et3BHLi
(1.0 M in THF, 1.1 mL, 1.1 mmol), PhSeSePh (155.5 mg, 0.498
mmol) in THF (2.5 mL), dimesylate 9a 2 (128.2 mg, 0.200 mmol)
in THF (2.5 mL), Et3N (1.0 mL), HMPA (40 µL), and a reflux
period of 12 h. Evaporation of the solvent and flash chroma-
tography of the residue over silica gel (2 × 15 cm), using 1%
MeOH-CH2Cl2 and then 2% MeOH-CH2Cl2, gave 9b2,17 (72.6
mg, 80% yield) as a white solid: mp 190-192 °C (lit.17 mp 188-
191 °C).
placement to just a single mesyloxy function on the basis
of steric factors inherent in the reagent, as opposed to
the substrate.8 It is not clear why the two primary-
secondary dimesylates (13a and 14a ) behave differently
from the others, but all of the secondary-secondary
dimesylates are converted into olefins under our standard
conditions.
N-Acet yl-2′,3′-d id eh yd r o-2′,3′-d id eoxy-5′-O-(t r ip h en yl-
m eth yl)cytid in e (10b) a n d 2′,3′-Did eh yd r o-2′,3′-d id eoxy-5′-
O-(tr ip h en ylm eth yl)cytid in e (10c). Et3BHLi (1.0 M in THF,
0.73 mL, 0.73 mmol) was added dropwise by syringe to a stirred
solution of PhSeSePh (114.3 mg, 0.366 mmol) in THF (1 mL)
(Ar atmosphere). At the end of the addition a colorless solution
had formed. This was taken up into a syringe and added
dropwise to a stirred solution of 10a 2 (104.6 mg, 0.153 mmol) in
We also examined aryl tellurides 1811 and (more
extensively) 19,13 but found that yields (using dimesylate
9a , as a test case) were significantly lower than those
with the selenium reagent; however, treatment of 13a
with 19 afforded olefin 13b in 95% yield, and in this case,
(17) Mansuri, M. M.; Starrett, J . E., J r.; Wos, J . A.; Tortolani, D.
R.; Brodfuehrer, P. R.; Howell, H. G.; Martin, J . C. J . Org. Chem. 1989,
54, 4780.

Notes
J . Org. Chem., Vol. 62, No. 11, 1997 3753
THF (1.5 mL) (Ar atmosphere). Then Et3N (0.5 mL) and HMPA
(ca. 40 µL) were injected, and the solution was stirred and
refluxed for 22 h. Evaporation of the solvent and flash chro-
matography of the residue over silica gel (2 × 18 cm), using 7.5%
MeOH-CH2Cl2, gave 10b2 (15.7 mg, 21%) along with 2′,3′-
dideoxy-2,3-didehydro-5′-O-(triphenylmethyl)cytidine (10c) (30.0
mg, ca. 43%), which was not obtained pure: FTIR (CH2Cl2 cast)
1-(3-Bu ten yl)n a p h th a len e (13b). Use of P h Se-Li+. The
general procedure was followed, using Et3BHLi (1.0 M in THF,
0.2 mL, 0.2 mmol), PhSeSePh (31.2 mg, 0.100 mmol) in THF (1
mL), dimesylate 13a 2 (37.3 mg, 0.100 mmol) in THF (1.5 mL),
Et3N (0.5 mL), HMPA (40 µL), and a reaction time of 12 h at
room temperature. Evaporation of the solvent and flash chro-
matography of the residue over silica gel (1 × 15 cm), using
petroleum ether, gave 13b22 (7.0 mg, 38%). The byproduct of
this reaction was isolated (59%) and identified as the bis(phenyl
selenide) corresponding to displacement of both OMs groups:
1
3500-3100 (broad) cm-1; H NMR (CD2Cl2, 300 MHz) δ 7.6 (d,
J ) 7 Hz, 1 H), 7.4-7.1 (m, 16 H), 6.9 (s, 1 H), 6.2 (d, J ) 6 Hz,
1 H), 5.8 (d, J ) 6 Hz, 1 H), 4.9 (br s, 1 H), 3.4-3.1 (m, 2 H); 13
C
(CD2Cl2, 75.5 MHz) δ 166.31 (s′), 156.39 (s′), 143.90 (s′), 142.38
(d′), 133.53 (d′), 129.08 (d′), 128.28 (d′), 127.73 (d′), 127.59 (d′),
94.85 (d′), 91.01 (d′), 87.43 (s′), 86.03 (d′), 65.48 (t′). The mass
spectrum (EI) was uninformative, as the highest mass peak
corresponded to Ph3C.
FTIR (CH2Cl2, cast) 3067, 3054, 2925, 1476, 1436, 735, 690 cm-1
;
1H NMR (CD2Cl2, 300 MHz) δ 8.09 (m, 1 H), 7.88 (m, 1 H), 7.73
(d, J ) 7.2 Hz, 1 H), 7.09-7.60 (m, 14 H), 3.5-3.0 (m, 5 H), 2.51
(m, 1 H), 1.99 (m, 1 H); 13C NMR (CD2Cl2, 75 MHz) δ 138.01,
135.08, 134.37, 133.56, 132.25, 129.87, 129.51, 129.40, 129.12,
2′,3′-Did eh yd r o-2′,3′-d id eoxy-5-m et h yl-5′-O-(t r ip h en yl-
m eth yl)u r id in e (11b). The general procedure was followed,
using Et3BHLi (1.0 M in THF, 0.49 mL, 0.49 mmol), PhSeSePh
(76.9 mg, 0.246 mmol) in THF (1 mL), dimesylate 11a 2,18 (64.7
mg, 0.0985 mmol) in THF (1.5 mL), Et3N (0.5 mL), HMPA (ca.
20 µL), and a reflux period of 12 h. Evaporation of the solvent
and flash chromatography of the residue over silica gel (2 × 20
cm), using 2% MeOH-CH2Cl2, gave 11b2,19 (34.5 mg, 75%) as a
white solid: mp 105-109 °C (lit.19 mp 107-111 °C).
(E)-3,4-Did eoxy-1,2:5,6-d i-O-isop r op ylid en e-er yth r o-3(E)-
h ex-3-en itol (12b). The general procedure was followed, using
Et3BHLi (1 M in THF, 0.94 mL, 0.94 mmol), PhSeSePh (143.6
mg, 0.460 mmol) in THF (1.5 mL), dimesylate 12a 20 (76.9 mg,
0.184 mmol) in THF (1.5 mL), Et3N (0.92 mL), HMPA (40 µL),
and a reflux period of 17 h. Evaporation of the solvent and flash
chromatography of the residue over silica gel (2.5 × 20 cm), using
25% EtOAc-hexane, gave 12b2,21 (32.3 mg, 77%) as a white
solid: mp 69-70 °C (lit.21 mp 69-71 °C).
1-(3-Bu ten yl)n a p h th a len e (13b). Use of Diselen in 16.
Et3BHLi (1 M in THF, 0.23 mL, 0.23 mmol) was added dropwise
by syringe to a stirred solution of dibenzo[c,e][1,2]diselenin (15)9
(33.3 mg, 0.107 mmol) in THF (5 mL) (Ar atmosphere). At the
end of the addition a colorless solution had formed. Dimesylate
13a 2 (40.0 mg, 0.1074 mmol) in THF (0.82 mL) was then injected
dropwise; the solution was stirred at room temperature for 18
h and then evaporated at room temperature. Flash chromatog-
raphy of the hexane-soluble portion of the residue over silica
gel (2.0 × 15 cm), using hexane, gave 13b22 (19.6 mg, 100%),
spectroscopically identical with an authentic sample,22 and
allowed recovery of dibenzo[c,e][1,2]diselenin (30.4 mg, 91%).
129.05, 128.15, 128.03, 127.41, 127.10, 126.62, 126.20, 125.88,
80
124.27, 45.01, 35.18, 34.94, 31.33; mass (CI) m/z calcd C26H24
Se2 (M + NH3) 513.0, found 513.4.
-
1-(3-Bu ten yl)n a p h th a len e (13b). Use of Tellu r iu m Re-
a gen t 19. (a ) Stoich iom etr ic Rea ction . Bis(2,4-dimethoxy-
phenyl) ditelluride14 (0.278 g, 0.525 mmol) was placed in a three-
neck round-bottomed flask carrying a side arm addition tube
containing NaBH4 (0.182 g, 6.88 mmol). Deoxygenated EtOH
(5 mL) was added, and the mixture was stirred and cooled (0
°C). The NaBH4 was added slowly (H2 evolution) until the
orange solution turned clear (Ar atmosphere). After 1 h, the
cold bath was removed and stirring was continued for 1 h.
Dimesylate 13a 2 (0.163 g, 0.437 mmol) in THF (2 mL) was then
added. After 4 h, CH2Cl2 (20 mL) was added, and the solution
was evaporated. Addition of CH2Cl2 and evaporation was
repeated twice more, and the residue was then adsorbed on silica
gel (0.5 g) from a little CH2Cl2. Flash chromatography over silica
gel (3 × 30 cm), using hexane, gave 13b (0.076 g, 95%),
spectroscopically identical to an authentic sample.22
(b) Ca ta lytic Rea ction . Absolute EtOH (1 mL) was added
to bis(2,4-dimethoxyphenyl) ditelluride14 (0.029 g, 0.056 mmol)
in a three-neck round-bottomed flask fitted with a side arm
addition tube containing NaBH4 (0.173 g, 4.57 mmol). Dimes-
ylate 13a (0.161 g, 0.432 mmol) in THF (2 mL) was added, and
then the NaBH4 was added over 5-6 h (Ar atmosphere). The
mixture was stirred at room temperature for a further 22 h. CH2-
Cl2 (25 mL) was added, and the solvent was evaporated.
Addition of CH2Cl2 (25 mL) and evaporation was repeated twice
more, and the residue was then adsorbed on silica (0.5 g) from
a little CH2Cl2. Flash chromatography over silica gel (2 × 20
cm), using hexane, gave 13b (0.070 g, 89%), as a colorless oil,
spectroscopically identical to an authentic sample.
(18) Huang, J .-T.; Chen, L.-C.; Wang, L.; Kim, M.-H.; Warshaw, J .
A.; Armstrong, D.; Zhu, Q.-Y.; Chou, T.-C.; Watanabe, K. A.; Matulic-
Adamic, J .; Su, T.-L.; Fox, J . J .; Polsky, B.; Baron, P. A.; Gold, J . W.
M.; Hardy, W. D.; Zuckerman, E. J . Med. Chem. 1991, 34, 1640.
(19) Cosford, N. D. P.; Schinazi, R. F. Nucleosides Nucleotides 1993,
12, 149.
(20) Prepared (88% yield) by the reported method (Kuszmann, J .;
Soha´r, P. Carbohydr. Res. 1979, 74, 187). The parent diol was prepared
(36% yield) according to: Chittenden, G. J . F. Carbohydr. Res. 1982,
108, 81.
(21) (a) Kuszmann, J .; Soha´r, P. Carbohydr. Res. 1980, 83, 63. (b)
Ko¨ll, P.; Kopf, J .; Metzger, J . O.; Schwarting, W.; Oelting, M. Liebigs
Ann. 1987, 199.
(22) Lambert, J . B.; Fabricius, D. M. ; Hoard, J . A. J . Org. Chem.
1979, 44, 1480. In preparing the butenylnaphthalene, we used allyl-
lithium, generated (Seyferth, D.; Weiner, M. A. J . Org. Chem. 1961,
26, 4797) from triphenyl(2-propenyl)stannane.
Ack n ow led gm en t. We thank both the Natural
Sciences and Engineering Research Council of Canada
and Health Canada for financial support. P.W.M.S.
held a Graduate Scholarship from CNPq (Brazil).
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for
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