Stereoselective synthesis of protected thymine polyoxin C via [2,3]- Wittig-Still rearrangement of ribose-derived allylic stannyl ethers

Full text of DOI:10.1021/jo9808066

J . Org. Chem. 1998, 63, 6735-6738
6735
Sch em e 1a
Ster eoselective Syn th esis of P r otected
Th ym in e P olyoxin C via [2,3]-Wittig-Still
Rea r r a n gem en t of Ribose-Der ived Allylic
Sta n n yl Eth er s
Arun K. Ghosh* and Yong Wang
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607
Received April 29, 1998
The [2,3]-Wittig rearrangement leading to stereocon-
trolled carbon-carbon bond formation has been increas-
ingly utilized in organic synthesis.1 The synthetic po-
tential of this reaction is extended even further in Still’s
variant of the [2,3]-Wittig rearrangement (Wittig-Still
rearrangement) where unstable oxymethyllithium is
generated at low temperature by a tin-lithium exchange
reaction.2 Recently, we reported a stereoselective syn-
thesis of an antifungal nucleoside, sinefungin.3 In our
continuing interest in the development of synthetic
methodologies for bioactive amino acid nucleosides, we
have investigated the [2,3]-Wittig rearrangement of E-
and Z-allylic stannyl ethers derived from an isopropy-
lidene D-ribose derivative. Herein we report that the
[2,3]-rearrangement of Z-allylic stannyl ether proceeded
with nearly complete syn selectivity and excellent iso-
lated yield. The resulting [2,3]-rearranged product was
converted to the protected thymine polyoxin C, which is
a basic component of many bioactive polyoxins, including
polyoxin J (1). Polyoxins are important antifungal agents
with chitin synthetase inhibitory properties.4 Synthesis
and biological evaluation of polyoxins and their variants
have been the subject of immense interest over the
years.5,6 Early syntheses of polyoxin nucleosides via
cyanohydrin formation at the C-5′ aldehyde of uridine
have been reported.5g,h A very useful strategy to polyoxin
C and other glycosyl R-amino acids has been developed
from D-serinal.5c Protected ribose-derived nitro olefin and
nitrone-based strategies have also been utilized in the
synthesis of polyoxin C.5b,d Thymine polyoxin has been
synthesized from myoinositol and other noncarbohydrate
a
Key: (a) DIBAL, CH2Cl2, -78 °C, 2-3 h (92-95%); (b) KH,
Bu4N+I-, Bu3SnCH2I, THF, 23 °C, 4 h; (c) nBuLi, THF, -78 °C, 2
h (74-84%).
precursors as well.5a,e,6c Our approach to polyoxin C
synthesis is based upon the chain lengthening of sugars
by a highly stereoselective [2,3]-Wittig rearrangement.
(1) (a) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105. (b) Marshall,
J . A. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 3, p 975 and references therein.
(2) (a) Still, W. C.; Mitra, A. J . Am. Chem. Soc. 1978, 100, 1927. (b)
Bruckner, R.; Priepke, H. Angew. Chem., Int. Ed. Engl. 1988, 27, 278.
(3) Ghosh, A. K.; Liu, W. J . Org. Chem. 1996, 61, 6175.
(4) (a) Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333. (b) Gooday,
G. W. Abh. Dtsch. Akad. Wiss. DDR, Abt. Math. Naturwiss.; Tech.,
Issue 2N; 1979; p 159. (c) Mori, M.; Kakiki, K.; Misato, T. Agric. Biol.
Chem. 1974, 38, 699.
(5) For synthesis of polyoxin nucleotides, see: (a) Dehoux, C.;
Fontaine, E.; Escudier, J .-M.; Baltas, M.; Gorrichon, L. J . Org. Chem.
1998, 63, 2601. (b) Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino,
P.; Tejero, T. Tetrahedron Lett. 1994, 35, 9439. (c) Garner, P.; Park, J .
M. J . Org. Chem. 1990, 55, 3772. (d) Barrett, A. G. M.; Lebold, S. A.
J . Org. Chem. 1990, 55, 3853. (e) Auberson, Y.; Vogel, P. Tetrahedron
1990, 46, 7019. (f) Tabusa, F.; Yamada, T.; Suzuki, K.; Mukaiyama,
T. Chem. Lett. 1984, 405. (g) Damodaran, N. P.; J ones, G. H.; Moffatt,
J . G. J . Am. Chem. Soc. 1971, 93, 3812. (h) Naka, T.; Hashizume, T.;
Nishimura, M. Tetrahedron Lett. 1971, 95.
The known7 methyl glycoside 2 was readily converted
to trans-R,â-unsaturated ester 3 by Swern oxidation
followed by Horner-Emmons olefination with sodium
hydride and triethyl phosphonoacetate as described
previously.3 The cis-R,â-unsaturated ester 4 was pre-
pared selectively by Still’s variant of Horner-Emmons
olefination with bis(2,2,2-trifluoroethyl)methoxycarbon-
ylmethyl phosphonate.8 Reduction of these esters with
DIBAL in CH2Cl2 at -78 °C for 2 h provided the
respective trans- and cis-allylic alcohols 5 and 6 in
excellent yields (Scheme 1). Etherification of alcohols 5
and 6 with potassium hydride and Bu3SnCH2I in the
presence of catalytic amounts of Bu4N+I- afforded the
respective E- and Z-stannylated ethers 7 and 8. Tin-
n
(6) For the total synthesis of polyoxins, see: (a) Akita, H.; Uchida,
K.; Kato, K. Heterocycles 1998, 47, 157. (b) Dondoni, A.; J unquera, F.;
Merchan, F. L.; Merino, P.; Tejero, T. J . Org. Chem. 1997, 62, 5497.
(c) Chida, N.; Koizumi, K.; Kitada, Y.; Yokoyama, C.; Ogawa, S. J .
Chem. Soc. Chem. Commun. 1994, 111. (d) Mukaiyama, T.; Suzuki,
K.; Yamada, T.; Tabusa, F. Tetrahedron 1990, 46, 265. (e) Kazuhara,
H.; Ohrui, H.; Emoto, S. Tetrahedron Lett. 1973, 5055 and references
therein.
(7) (a) Ghosh, A. K.; McKee, S. P.; Sanders, W. M.; Darke, P. L.;
Zugay, J . A.; Emini, E. A.; Schleif, W. A.; Quintero, J . C.; Huff, J . R.;
Anderson, P. S. Drug Des. Discovery 1993, 10, 77. (b) Levene, P. A.;
Stiller, E. T. J . Biol. Chem. 1934, 299.
(8) (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(b) Spada, M. R.; Ubukata, M.; Isono, K. Heterocycles 1992, 34, 1147.
S0022-3263(98)00806-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/29/1998

6736 J . Org. Chem., Vol. 63, No. 19, 1998
Notes
n
Sch em e 2a
lithium exchange of E-stannyl ether 7 with BuLi at -78
°C in THF resulted in a syn/anti mixture (4.4:1 by 400-
MHz H NMR) of rearranged product 9 and its epimer
1
in 84% yield after silica gel chromatography. On the
n
other hand, the reaction of Z-stannyl ether 8 with BuLi
provided exclusively the syn product 9 in 74% isolated
yield. 1H NMR (400 MHz) revealed the presence of a
single isomer.
The initial stereochemical assignment of the [2,3]-
rearranged syn product 9 has been made on the basis of
previous stereochemical studies of [2,3]-Wittig-Still
rearrangement by Bru¨ckner and co-workers.9 Further
evidence of this stereochemical assignment was provided
after the syn-rearranged product 9 was converted to
thymine polyoxin C. The stereochemical assignment is
also consistent with “Houk-like” transition-state models
as shown in Figure 1.10 In these models, the allylic C-O
bond is orthogonal to the plane of the allylic CdC and is
antiperiplanar with respect to the impending carbanion.
Consistent with these models, both compounds 7 (E-
isomer) and 8 (Z-isomer) provided the same major
rearranged product 9 through the more favorable transi-
tion states A and C, respectively. Between the corre-
sponding diastereomeric transition states B (E-isomer)
and D (Z-isomer), transition state D is highly disfavored
because of severe developing allylic [1,3] strain. This may
explain why compound 8 (Z-isomer) provided exclusively
syn-rearranged product 9 compared to compound 7 (E-
isomer), which has exhibited a syn/anti product ratio of
4.4:1.
a
Key: (a) Swern oxidation; (b) NaClO2, Me2CdCHMe, tBuOH,
23 °C, 12 h; (c) MeOCOCl, iPr2NEt, NaN3 then PhCH2OH, PhMe,
100 °C, 12 h (68% from 9); (d) O3, NaOH, CH2Cl2, MeOH, -78 to
23 °C, 2 h (94%); (e) Dowex 50W, MeOH, 65 °C, 12 h; (f) Ac2O, Py,
23 °C, 4 h; (g) Ac2O, AcOH, CH2Cl2, cat. H2SO4, 23 °C, 2 h (70%
from 13); (h) Thymine-bis-TMS, Cl (CH2)2Cl, TMSOTf, 45 °C, 2 h
(80%).
use of diisopropylethylamine instead of triethylamine.
The above acid 10 without further purification was
exposed to diisopropylethylamine, methyl chloroformate,
and sodium azide at 0 °C. The resulting acyl azide was
dissolved in toluene and heated at 100 °C for 1 h. After
this period, benzyl alcohol was added and the mixture
was heated at reflux for 12 h to furnish the Cbz derivative
11 in 68% yield (from 9) after silica gel chromatography.
Since the Curtius rearrangement proceeds with retention
of configuration of the migrating carbon atom, the
stereochemistry of the urethane-bearing chiral center in
11 was assigned accordingly.11 Of particular note, the
attempted Curtius rearrangement of 10 with diphe-
nylphosphoryl azide and triethylamine followed by treat-
ment with benzyl alcohol and subsequent heating at
reflux for 10 h resulted in R,â-unsaturated ester 12 as
the major product, along with a small amount of Cbz
derivative 11.12 For conversion of the vinyl group in 11
F igu r e 1.
As shown in Scheme 2, alcohol 9 was converted to Cbz-
protected amine derivative 11 by oxidation followed by
Curtius rearrangement of the resulting carboxylic acid.
Thus, Swern oxidation of 9 provided the corresponding
aldehyde which, upon exposure to sodium chlorite in tert-
butyl alcohol, afforded the acid 10. It is important to note
that the use of triethylamine in the standard Swern
oxidation protocol resulted in a substantial amount of
epimerization of the resulting â,γ-unsaturated carbox-
aldehyde. This epimerization was circumvented by the
(9) (a) Priepke, H.; Bru¨ckner, R. Chem. Ber. 1990, 123, 153. (b)
Priepke, H.; Bru¨ckner, R.; Harms, K. Chem. Ber. 1990, 123, 555. (c)
Scheuplein, S. W.; Kusche, A.; Bru¨ckner, R.; Harms, K. Chem. Ber.
1990, 123, 917 and references therein.
(10) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y.-D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J . T.; Li, Y.; Loncharich, R. J .
Science 1986, 231, 1108.
(11) (a) Ghosh, A. K.; Hussain, K. A.; Fidanze, S. J . Org. Chem. 1997,
62, 6080. (b) Grunewald, G. L.; Ye, Q. J . Org. Chem. 1988, 53, 4021.
(c) Ninomiya, K.; Shiori, T.; Yamada, S. Tetrahedron 1974, 30, 2151
and references therein.

Notes
J . Org. Chem., Vol. 63, No. 19, 1998 6737
Na2SO4. Evaporation of the solvent gave a residue which was
purified on a silica gel column (50% ethyl acetate/hexane) to
to methyl ester 13, ozonolytic cleavage was carried out
in methanolic sodium hydroxide solution to afford 13 in
94% yield after chromatography.13
afford 5 as a colorless oil (1.335 g, 92%): [R]23 -42.2 (c 0.83,
D
1
CHCl3); IR (neat) 3423, 2950, 2930, 1630, 1374, 1088 cm-1; H
To install thymine at the anomeric center, the protect-
ing group interconversion of 13 to triacetate 14 was
carried out in a three-step sequence: (1) removal of the
isopropylidene group with Dowex 50W H+ in methanol,
(2) acetylation of the resulting diol with acetic anhydride
in pyridine, and (3) acetal exchange by treatment with
acetic anhydride and a catalytic amount of concentrated
sulfuric acid in a mixture of glacial acetic acid and CH2-
Cl2 at 23 °C for 2 h (70%, 2:1 mixture of anomers).
Triacetate 14 was exposed to Vorbru¨ggen reaction condi-
tions14 with 5-methyl-2,4-bis(trimethylsilyloxy)pyrimi-
dine in the presence of TMSOTf in dichloroethane at 45
°C for 2 h to afford the protected â-nucleoside 15 (mp
81-83 °C) in 80% yield after silica gel chromatography.
NMR (400 MHz, CDCl3 ) δ 5.82 (m, 2H), 4.98 (s, 1H), 4.66 (d,
1H, J ) 8.2 Hz), 4.61 (s, 2H), 4.15 (t, 1H, J ) 5.4 Hz), 3.34 (s,
3H), 1.49 (s, 3H), 1.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
24.9, 26.4, 54.7, 62.6, 84.5, 85.4, 87.4, 109.3, 112.3, 130.4, 132.4;
MS (EI) m/z 230 (M+), 215 (M+ - Me), 198, 155. Anal. Calcd
for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.22; H, 7.94.
Met h yl (Z)-5,6-Did eoxy-2,3-O-isop r op ylid en e-â-D-r ib o-
h ep t -5-en ofu r a n osid e (6). To a stirred solution of ester 48
(1.07 g, 4.15 mmol) in CH2Cl2 (15 mL) at -78 °C was added
DIBAL (1.0 M in hexane, 12.4 mL, 12.4 mmol) solution, and the
resulting mixture was stirred for 3 h at -78 °C. After this
period, the reaction was worked up as described for 5 to furnish
the allyl alcohol 6 as a colorless oil (930 mg, 95%): 1H NMR
(400 MHz, CDCl3) δ 5.74 (m, 1H), 5.61 (m, 1H), 4.97 (s, 1H),
4.95 (d, 1H, J ) 9.5 Hz), 4.62 (d, 1H, J ) 5.9 Hz), 4.58 (d, 1H,
J ) 5.9 Hz),4.33 (m, 1H), 4.24 (m, 1H), 3.31 (s, 3H), 1.49 (s, 3H),
1.30 (s, 3H); MS (EI) m/z 230 (M+), 215 (M+ - Me), 198, 155.
Met h yl 5-(S)-Deoxy-5-vin yl-2,3-O-isop r op ylid en e-â-D-
r ibo-h exa n ofu r a n osid e (9). To a suspension of KH (418 mg,
10.4 mmol, prewashed with hexane) and tetrabutylammonium
iodide (25 mg) in dry THF (10 mL) at 0 °C was added dropwise
a solution of alcohol 5 (1.2 g, 5.23 mmol) in THF (2 mL). The
resulting red suspension was allowed to warm to 23 °C, and the
mixture was stirred for 1 h. The reaction was cooled to 0 °C,
and Bu3SnCH2I (2.1 g, 6.8 mmol) in THF (2 mL) was added
dropwise over a period of 2 min. The mixture was stirred at
0-23 °C for 4 h. After this period, the reaction was quenched
with a saturated NH4Cl solution (10 mL). The layers were
separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were dried over anhydrous
Na2SO4. Evaporation of the solvents provided the allyl stan-
nylmethyl ether 7 as a colorless oil. This material was used for
the next reaction without further purification. An analytical
sample of 7 was obtained by flash chromatography over silica
gel (5% ethyl acetate/hexane): 1H NMR (400 MHz, CDCl3) δ
5.71-5.74 (m, 2H), 4.98 (s, 1H), 4.65 (d, 1H, J ) 10.9 Hz), 4.61
(s, 2H), 3.85 (d, 2H, J ) 6.8 Hz), 3.69 (s, 2H), 3.32 (s, 3H), 1.49
(s, 3H), 1.35 (s, 3H), 1.20-1.62 (m, 12H), 0.85-0.94 (m, 15H).
The spectral properties (1H and 13C NMR) of 15 ([R]23
D
+17.1, c 0.45, CHCl3; lit.5a [R]23 +19.8, c 0.56, CHCl3)
D
are in full agreement with the reported values.
In conclusion, a stereoselective synthesis of protected
thymine polyoxin C has been accomplished starting from
D-ribose. The key steps in the synthesis are a highly
diastereoselective [2,3]-sigmatropic reaction of Z-allylic
stannyl ethers, followed by conversion of the resulting
hydroxymethyl group to the Cbz-protected amine deriva-
tive by a Curtius rearrangement. The stereoelectronic
effects of the [2,3]-Wittig rearrangement of the ribose-
derived E- and Z-stannyl ethers are noteworthy. Further
application of this stereoselective [2,3]-Wittig-Still rear-
rangement in synthesis is in progress.
Exp er im en ta l Section
All melting points were recorded and uncorrected. Anhydrous
solvents were obtained as follows: 1,2-dichloroethane was first
refluxed for 2 h over P2O5 and then distilled, tetrahydrofuran
was distilled from sodium and benzophenone, methylene chloride
was distilled from CaH2 and trimethylchlorosilane and pyridine
were distilled from CaH2. All other solvents were HPLC grade.
Column chromatography was performed with Whatman 240-
400 mesh silica gel under a low pressure of 5-10 psi. Thin-
layer chromatography (TLC) was carried out with Merck silica
gel 60 F-254 plates.
Met h yl (E)-5,6-Did eoxy-2,3-O-isop r op ylid en e-â-D-r ibo-
h ep t-5- en ofu r a n osid e (5). To a stirred solution of ester 33
(1.7 g, 6.62 mmol) in CH2Cl2 (10 mL) at -78 °C was added
DIBAL (1 M in hexane, 19 mL, 19 mmol) solution, and the
resulting mixture was stirred at -78 °C for 2 h. After this
period, the reaction was carefully quenched with water (3 mL)
and the mixture was allowed to warm to 23 °C. The mixture
was filtered through a glass wool plug, and the solid was rinsed
several times with CH2Cl2 and water. The combined filtrate was
transferred to a separatory funnel, and the layers were sepa-
rated. The aqueous layer was extracted with CH2Cl2 (2 × 20
mL), and the combined organic layers were dried over anhydrous
To a stirred solution of above crude stannyl ether 7 in THF
(10 mL) at -78 °C, was added nBuLi (2.5 M in hexane, 3.2 mL,
8 mmol) dropwise by a syringe pump over a period of 1 h. The
resulting mixture was stirred for 2 h at -78 °C. After this
period, the reaction was quenched with saturated NH4Cl solution
and the resulting mixture was warmed to 23 °C. The layers
were separated, and the aqueous layer was extracted with ethyl
acetate (2 × 20 mL). The combined organic layers were dried
over anhydrous Na2SO4. Evaporation of the solvents gave a
residue which was chromatographed over silica gel (25% ethyl
1
acetate/hexane) to furnish an inseparable mixture (4.4:1 by H
NMR) of 9 and its epimer (1.07 g, 84% from 5) as a colorless oil.
Major isomer 9: IR (neat) 3454, 2988, 2936, 1643, 1374, 1090
1
cm-1; H NMR (400 MHz, CDCl3) δ 5.81 (m, 1H), 5.27 (dd, 1H,
J ) 1.1, 10 Hz), 5.21 (dd, 1H, J ) 1.1, 18 Hz), 4.95 (s, 1H), 4.71
(dd, 1H, J ) 1.5, 6.2 Hz), 4.53 (d, 1H, J ) 6.2 Hz), 4.25 (dd, 1H,
J ) 1.5, 8 Hz), 3.72 (m, 1H), 3.59 (m, 1H), 3.35 (s, 3H), 2.46 (m,
1H), 1.49 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
136, 135.4, 118.9, 112.6, 109.4, 87.3, 85.3, 82.2, 64.1, 63.2, 55.6;
MS (EI) m/z 213 (M+ - OMe), 197, 173, 59. Anal. Calcd for
C12H20O5: C, 59.0; H, 8.25. Found: C, 58.90; H, 8.40. Minor
isomer: 1H NMR (400 MHz, CDCl3) δ 5.15 (m, 1H), 5.29 (m,
2H), 4.99 (s, 1H), 4.68 (dd, 1H, J ) 1, 5.9 Hz), 4.57 (d, 1H, J )
5.9 Hz), 4.14 (d, 1H, J ) 11.2 Hz), 3.81 (m, 1H), 3.66 (m, 1H),
3.40 (s, 3H), 2.46 (m, 1H), 1.48 (s, 3H), 1.31 (s, 3H).
(12) The tentative R,â-unsaturated ester 12 was formed as a major
product (50% yield).
Met h yl 5-(S)-Deoxy-5-vin yl-2,3-O-isop r op ylid en e-â-D-
r ibo-h exa n ofu r a n osid e (9). (prepared from Z-alcohol 6). The
Z-alcohol 6 (672.8 mg, 2.92 mmol) was converted to Z-stannyl
ether 8 as a colorless oil by following the procedure described
for E-stannyl ether 7. This material was used for the next
reaction without further purification. An analytical sample of
8 was obtained by flash chromatography over silica gel (5% ethyl
acetate/hexane). 1H NMR for 8: (400 MHz, CDCl3) δ 5.61 (dd,
2H, J ) 4.2, 5 Hz), 4.96 (s, 1H), 4.92 (d, 1H, J ) 6.7 Hz), 4.62
(d, 1H, J ) 5.8 Hz), 4.56 (d, 1H, J ) 5.6 Hz), 4.0 (d, 1H, J ) 4.1
Compound 11 was isolated in a small amount (<10% yield): 1H NMR
(200 MHz, CDCl3) δ 7.35 (m, 5H), 6.16 (q, 1H, J ) 7.4 Hz), 5.23 (brs,
1H), 5.12 (d, 2H, J ) 4.7 Hz), 5.03 (s, 1H), 4.65 (dd, 1H, J ) 1.0, 6.0
Hz), 4.59 (d, 1H, J ) 6.0 Hz), 3.43 (s, 3H), 1.77 (d, 3H, J ) 7.4 Hz),
1.52 (s, 3H), 1.30 (s, 3 H).
(13) Marshall, J . A.; Garofalo, A. W.; Sedrani, R. Synlett 1992, 643.
(14) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234.

6738 J . Org. Chem., Vol. 63, No. 19, 1998
Notes
Hz), 3.72 (s, 2H), 3.31 (s, 3H), 1.43 (s, 3H), 1.29 (s, 3H), 1.24-
1.63 (m, 12H), 0.86-0.98 (m, 15H). Wittig-Still rearrangement
of Z-stannyl ether 8 as described above (for stannyl ether 7)
provided the alcohol 9 (528 mg, 74% from 6) exclusively as a
colorless oil: [R]23D-29 (c 0.13, CHCl3 ).
8.3 Hz), 5.11 (brs, 2H), 4.96 (s, 1H), 4.93 (d, 1H, J ) 5.8 Hz),
4.57 (d, 1H, J ) 5.8 Hz), 4.49 (t, 1H, J ) 8 Hz), 4.33 (d, 1H, J )
7.6 Hz), 3.75 (s, 3H), 3.32 (s, 3H), 1.51 (s, 3H), 1.30 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 25.0, 26.4, 52.5, 55.8, 56.4, 67.3, 81.3,
85.0, 87.6, 110.1, 112.6, 128.2, 128.5, 135.9, 155.7, 170.5; MS
(EI) m/z 396 (M+ + H), 395 (M+), 173, 91. Anal. Calcd for
C19H25NO8: C, 57.71; H, 6.31; N, 3.54. Found: C, 57.53; H, 6.36;
N, 3.75.
Meth yl 5-(R)-N-[(P h en ylm eth oxy)ca r bon yl]-5,6-d id eoxy-
2,3-O-isop r op ylid en e-â-D-r ibo-h ep t-6-en fu r a n osid e (11). To
a stirred solution of DMSO (0.18 mL, 2.54 mmol) in CH2Cl2 (5
mL) at -78 °C was added dropwise oxalyl chloride (0.13 mL,
1.52 mmol). The resulting mixture was stirred for 2 min, and
then a solution of alcohol 9 (248 mg, 1.02 mmol) in CH2Cl2 (2
mL) was added dropwise over a period of 1 min. The mixture
was stirred at -78 °C for an additional hour. The reaction was
quenched with diisopropylethylamine (0.9 mL, 5.08 mmol), and
the mixture was allowed to warm to 0 °C for 30 min. Ethyl
acetate (20 mL) was added to the reaction mixture, and the
mixture was successively washed with a 1 M aqueous NaHSO4
solution (20 mL) and pH 7 buffered solution (20 mL). The
organic layer was dried over anhydrous Na2SO4. Evaporation
of the solvent gave the crude aldehyde, which was used for the
next reaction immediately without further purification.
To a stirred solution of the above aldehyde in a mixture of
tert-butyl alcohol (10 mL) and 2-methyl-2-butene (3 mL) at 23
°C were added sodium chlorite (900 mg, 10 mmol) in water (1
mL) and NaH2PO4 (1.38 g, 10 mmol) in water (1 mL) sequen-
tially. The resulting mixture was stirred at 23 °C for 12 h. After
this period, the reaction mixture was diluted with saturated
NH4Cl (10 mL) and the mixture was extracted with ethyl acetate
(3 × 20 mL). The combined organic layers were dried over
anhydrous Na2SO4. Evaporation of the solvent provided the
acid, which was directly used for the next reaction.
To a stirred solution of the above acid in acetone (4 mL) was
added diisopropylethylamine (0.21 mL, 1.22 mmol) at 0 °C. The
resulting mixture was stirred for 10 min, and ClCO2Me (0.1 mL,
1.32 mmol) was added dropwise over a period of 1 min. The
reaction mixture was stirred at 0 °C for 30 min, and then sodium
azide (132 mg, 2.03 mmol) in water (2 mL) was added. The
mixture was stirred for an additional 30 min at 0 °C. After this
period, CH2Cl2 (20 mL) and water (20 mL) were added and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (2 × 20 mL). The combined organic layers were
successively washed with 1 M NaHSO4 (20 mL) and pH 7 buffer
(20 mL) and dried over anhydrous Na2SO4. Evaporation of the
solvent under reduced pressure gave a colorless oil, which was
dissolved in toluene (5 mL). The resulting mixture was heated
at 100 °C for 1 h. After this period, benzyl alcohol (0.21 mL, 2
mmol) was added and the resulting mixture was refluxed for
12 h. The reaction was cooled to 23 °C, and the solvent was
evaporated to give a yellow residue, which was chromatographed
over silica gel (5% ethyl acetate/benzene) to furnish the Cbz
derivative 11 (249 mg, 68% from 9) as a white solid: mp 80-82
°C; [R]23D -11 (c 0.18, CHCl3 ); IR (neat) 3447, 2925, 1643, 1239,
1092 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.26-7.37 (m, 5H), 5.95
(m, 1H), 5.28 (d, 1H, J ) 11.4 Hz), 5.25 (dd, 1H, J ) 1, 4.7 Hz)
5.12 (dd, 1H, J ) 4.7, 17 Hz), 4.98 (s, 1H), 4.97 (br s, 1H), 4.74
(d, 1H, J ) 4.9 Hz), 4.59 (d, 1H, J ) 4.9 Hz), 4.29 (dd, 1H, J )
5.6, 9.9 Hz), 3.98 (dd, 1H, J ) 1.1, 9.4 Hz), 3.34 (s, 3H), 1.46 (s,
3H), 1.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 25.0, 26.5, 55.0,
55.5, 66.9, 88.9, 109.7, 112.5, 116.8, 126.9, 127.5, 128.0, 128.1,
128.4, 135.3, 136.2, 155.9; MS (EI) m/z 363 (M+), 331, 173, 146,
115, 91. Anal. Calcd for C19H25NO6: C, 62.80; H, 6.93; N, 3.86.
Found: C, 62.19; H, 7.14; N, 3.58.
Meth yl 5-Deoxy-5-[(p h en ylm eth oxy)ca r bon yl]a m in o]-â-
D-a llofu r a n u r on a te-1,2,3-tr ia ceta te (14). To a stirred solu-
tion of 13 (446.5 mg, 1.14 mmol) in MeOH (20 mL) was added
Dowex 50W H+ resin (600 mg), and the mixture was heated at
65 °C for 12 h. After this period, the resin was filtered off and
the solvent was removed under reduced pressure. The residue
was dissolved in pyridine (4 mL), Ac2O (1 mL) was added, and
the resulting mixture was stirred at 23 °C for 4 h. The reaction
mixture was poured into ice, stirred for 30 min, and extracted
with ethyl acetate (2 × 20 mL). The combined organic layers
were successively washed with saturated aqueous CuSO4 solu-
tion and brine and then dried over anhydrous Na2SO4. Evapo-
ration of the solvent gave a residue, which was dissolved in a
mixture of CH2Cl2 (2 mL) and AcOH (2 mL). To this mixture
at 0 °C was added Ac2O (0.5 mL), followed by a drop of
concentrated H2SO4. The resulting mixture was stirred at 0 °C
for 1 h and then at 23 °C for 2 h. The reaction mixture was
poured onto ice and stirred for 30 min. The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (2
× 10 mL). The combined organic layer was successively washed
with saturated NaHCO3 and brine and dried over anhydrous
Na2SO4. Evaporation of the solvent provided a residue, which
was chromatographed on silica gel (33% ethyl acetate/hexane)
to furnish the triacetate 14 (373 mg, 70% from 13) as a colorless
oil: IR (neat) 3420, 1750, 1720 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.35 (s, 5H), 6.36 (d, 0.33H, J ) 8.9 Hz, R-anomer), 6.09 (s,
0.67H, â-anomer), 5.54 (m, 1H), 5.29 (d, 1H, J ) 4.7 Hz), 5.11
(s, 2H), 4.67 (dd, 1H, J ) 4.4, 8.7 Hz), 4.45 (dd, 1H, J ) 4.4, 7.6
Hz), 3.76 (s, 3H), 2.10 (s, 3H), 2.01 (s, 6H).
Meth yl 1,5-Did eoxy-1-(3,4-d ih yd r o-5-m eth yl-2,4-d ioxo-
1(2H)-p yr im id in yl)-5-[[(p h en ylm eth oxy)ca r bon yl]a m in o]-
â-D-a llofu r a n u r on a te-2,3-d ia ceta te (15). To a stirred sus-
pension of thymine (17 mg, 0.13 mmol) in hexamethyl disilazane
(2 mL) was added trimethylchlorosilane (0.1 mL), and the
resulting mixture was heated at 120 °C for 5 h. The mixture
was cooled to 23 °C, and the solvent was removed under reduced
pressure to give the crude bis-silylated thymine. The residue
was dissolved in dichloroethane (2 mL), and a solution of
triacetate 14 (20 mg, 0.043 mmol) in dichloroethane (1 mL)
followed by TMSOTf (46 µL, 0.126 mmol) was added at 23 °C.
The resulting mixture was heated at 45 °C for 2 h, cooled to 23
°C, and quenched with saturated sodium bicarbonate solution.
The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were
dried over anhydrous Na2SO4, and the solvents were evaporated
under reduced pressure. The resulting residue was chromato-
graphed on silica gel (40% ethyl acetate/benzene) to give the title
nucleoside 15 (18.4 mg, 80%) as a pale yellow solid: mp 81-83
°C; [R]23D +17.1 (c 0.45, CHCl3); IR (neat), 3380, 1750, 1715 cm-1
;
1H NMR (200 MHz, CDCl3) δ 8.15 (s, 1H), 7.35 (s, 5H), 7.05 (d,
1H, J ) 0.7 Hz), 5.93 (d, 1H, J ) 5.6 Hz), 5.79 (d, 1H, J ) 8.1
Hz), 5.51 (t, 1H, J ) 5.9 Hz), 5.26 (t, 1H, J ) 5.9 Hz), 5.14 (s,
2H), 4.81 (dd, 1H, J ) 3.7, 8.5 Hz), 4.39 (dd, 1H, J ) 3.7, 4.7
Hz), 3.81 (s, 3H), 2.09 (s, 6H), 1.87 (d, 3H, J ) 0.7 Hz); 13C NMR
(100 MHz, CD3COCD3) δ 12.3, 20.3, 52.8, 56.1, 67.1, 70.6, 72.9,
81.8, 89.3, 111.6, 128.5, 128.6, 129.1, 137.3, 137.7, 151.4, 157.4,
164.0, 169.9, 170.0, 170.1; MS (EI) m/z 534 (M+ + H), 408, 91.
Meth yl (Meth yl-5-N-[(ph en ylm eth oxy)car bon yl]-5-deoxy-
2,3-O-isop r op ylid en e-â-D-a llofu r a n osid e)u r on a te (13). To
a stirred solution of 11 (36.5 mg, 0.1 mmol) in a mixture of CH2-
Cl2 (3 mL) and MeOH (1 mL) was added solid NaOH (20 mg),
and a stream of ozonized oxygen was bubbled through this
stirred mixture at -78 °C until the color of the solution changed
from yellow to blue. The reaction mixture was diluted with
water and allowed to warm to 23 °C. The layers were separated,
and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layers were dried over anhydrous Na2SO4. Evapo-
ration of the solvent gave a residue, which was chromatographed
over silica gel (15% ethyl acetate/hexane) to provide the methyl
Ack n ow led gm en t. Financial support of our work
by the National Institutes of Health (GM 55600) is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 6-8, 12, and 14-15 and 13C NMR spectra for 10
and 15 (8 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
ester 13 (37.1 mg, 94%) as a white solid: mp 66-68 °C; [R]23
D
-14 (c 2.81, CHCl3); IR (neat) 3428, 1720, 1643, 1109 cm-1; H
1
NMR (400 MHz, CDCl3) δ 7.32-7.41 (m, 5H), 5.52 (d, 1H, J )
J O9808066