De novo synthesis of 4′-ethoxy nucleoside analogues

Article abstract of DOI:10.1021/jo020151f

Butenolides 5a and 13 were used as optically active templates in the de novo synthesis of 4′-disubstituted nucleoside analogues. The butenolides were reduced and acylated in situ to give acetates 10 and 14. Vorbrueggen coupling gave the protected nucleoside analogues 11 and 15. Reduction of 11 gave 4′-ethoxy-2′,3′-dideoxythymidine (6) and deprotection of 15 gave 4′-ethoxy-2′,3′-dideoxydidehydrothymidine (7). The cis-dihydroxylation of a variety of butenolides occurred with the major product formed from oxidation of the β-face.

Full text of DOI:10.1021/jo020151f

De Novo Syn th esis of 4′-Eth oxy Nu cleosid e An a logu es
Louis S. Hegedus,* Lisa Geisler, Andrew G. Riches, Sarri S. Salman, and Gisela Umbricht
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
hegedus@lamar.colostate.edu
Received March 6, 2002
Butenolides 5a and 13 were used as optically active templates in the de novo synthesis of
4′-disubstituted nucleoside analogues. The butenolides were reduced and acylated in situ to give
acetates 10 and 14. Vorbru¨ggen coupling gave the protected nucleoside analogues 11 and 15.
Reduction of 11 gave 4′-ethoxy-2′,3′-dideoxythymidine (6) and deprotection of 15 gave 4′-ethoxy-
2′,3′-dideoxydidehydrothymidine (7). The cis-dihydroxylation of a variety of butenolides occurred
with the major product formed from oxidation of the â-face.
In tr od u ction
substitution,8 or from open-chain, ribose-derived 4′-keto
carbohydrates.9 The recent availability of L-ribose from
L-xylose7 should provide access to the unnatural L-series
of nucleosides, of current interest both as antivirals
having reduced toxicity,10 and precursors to stable L-RNA
building blocks.11
De novo syntheses of 4′-disubstituted nucleoside ana-
logues provide the most flexibility, both with respect to
functionality and stereochemistry.12 An efficient synthe-
sis of an optically active template for nucleoside analogue
synthesis has recently been reported from these labora-
tories.13 The conversion of this key intermediate into 4′-
disubstituted nucleoside analogues is reported below.
Since the initial discovery of nucleocidin, a 4′-fluorori-
bonucleoside having potent antibiotic activity,1 members
of this unusual class of compounds have been shown to
have anticancer activity,2 agonistic activity toward ad-
enosine receptors,3 and more recently, anti-HIV activity.4
In contrast to other nucleoside analogues having anti-
HIV activity, which must lack the 3′-hydroxy group, the
anti-HIV active 4′-azidonucleosides required a 3′-hydroxy
group for activity,5 indicating a fundamentally different
mode of action for this class.
Many syntheses of 4′-disubstituted nucleosides involve
functionalization of existing nucleosides.1b,2,5a,6 Control of
stereochemistry is often the difficult aspect of these
syntheses, and this approach is restricted to the naturally
occurring D-nucleosides.7 4′-Disubstituted nucleosides
have also been synthesized from carbohydrates, convert-
ing the 4′-hydroxymethyl group to an aldehyde and using
enolate chemistry to introduce the other 4′(carbon)-
Resu lts a n d Discu ssion
The starting point for these synthetic studies was the
synthesis of optically active butenolides via chromium
carbene photochemistry (Scheme 1).13 Photolysis of opti-
cally active ene carbamates 2 with chromium carbene
complex 1 produced optically active cyclobutanones 3 in
good yield. The absolute configuration of the two new
stereogenic centers was determined by the absolute
configuration of the chiral auxiliary, making both enan-
tiomers of 3 equally available. Baeyer-Villiger oxidation
proceeded with retention of configuration of the migrating
group, and in high yield giving lactones 4. Treatment
(1) (a) Hewitt, R. I.; Gumble, A. R.; Taylor, L. H.; Wallace, W. S.
Antibiot. Annu. 1956-1957, 722. (b) J enkins, I. D.; Verheyden, J . P.
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Melman, N.; Tiwari, K. N.; Secrist, J . A.; Schneller, S. W.; Cristalli,
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101-113.
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Chem. 1992, 267, 257.
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97, 4386. (b) J ones, G. H.; Yaniguchi, M.; Tegg, D.; Moffatt, J . G. J .
Org. Chem. 1979, 44, 1309. (c) O-Yang, C.; Wu, H. Y.; Fraser-Smith,
E. B.; Walker, K. A. M. Tetrahedron Lett. 1992, 33, 37. (d) O-Yang,
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33, 2841. (f) Haraguchi, K.; Tanaka, H.; Itoh, Y.; Yamaguchi, K.;
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Synthesis 1992, 191. (b) J ohnson, C. R.; Esker, J . L.; Van Zandt, M. C.
J . Org. Chem. 1994, 59, 5854. (c) Siddiqi, S. M.; Schneller, S. W.; Ikeda,
S.; Snoeck, R.; Andrei, G.; Balzarini, J .; DeClerq, E. Nucleosides
Nucleotides 1993, 12, 185.
(7) L-Ribonucleosides have recently been synthesized from L-
xylose: Moyroud, E.; Strazewski, P. Tetrahedron 1999, 55, 1277.
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10.1021/jo020151f CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/27/2002
J . Org. Chem. 2002, 67, 7649-7655
7649

Hegedus et al.
SCHEME 2
F IGURE 1.
SCHEME 1
SCHEME 3
with TBAF eliminated the oxazolidinone giving buteno-
lides 5 in excellent yield.
systems. Reduction (Pearlman’s catalyst/H2) both deben-
zylated the 5′ position and reduced the double bond, giv-
ing 4′-ethoxy-2′,3′-dideoxythymidine (6) in excellent yield,
again as an inseparable 1:1 mixture of C-1 anomers.
Synthesis of 4′-ethoxy-2′,3′-dideoxydidehydrothymidine
(7) from 11 proved to be difficult. All attempts to remove
the benzyl group from 11 while keeping the double bond
intact failed. Oxidative methods, dissolving metals, and
Lewis acidic conditions gave no reaction or caused
decomposition.
The benzyl group can be removed from butenolide 5a
with BCl3 to give alcohol 12 and other protecting groups
were surveyed. TES-protected alcohol 13 could withstand
the reduction/acylation conditions to give acetate 14 as
a 1:1 mixture of diastereomers. Vorbru¨ggen coupling gave
the protected 4′-ethoxy-2′,3′-dideoxydidehydrothymidine
15 in good yields. The TES group was removed with
TBAF at 0 °C to give 4′-ethoxy-2′,3′-dideoxydidehy-
drothymidine (7) in 60% yield, as a 1:1 mixture of C-1
anomers, which could be separated by preparative TLC
(Scheme 3).
The photochemical step produces the thermodynami-
cally less-stable cyclobutanone, with the two large groups
syn, and this relationship carries through to the lactones
4. Surprisingly, treatment of less-stable lactone 4a with
Lewis acids such as BF3‚OEt2 resulted in equilibration
to a 9:1 mixture of epimers, favoring the more stable anti
epimer. Replacement of the O-benzyl group by the larger
O-TBS group at the cyclobutanone stage resulted in
production of the corresponding lactone which epimerized
completely to the more stable anti isomer when treated
with stannic chloride. This facile epimerization makes
both enantiomers of butenolide 5 available from a single
enantiomer of the chosen chiral auxiliary. Conversion of
butenolide 5a to 4′-ethoxy nucleoside analogues (6-9)
was next addressed.
Previous studies had shown that attempts to reduce
5-ethoxylactones to free lactols resulted in facile ring
opening with ejection of ethoxide to give the correspond-
ing 4-keto-aldehyde. To prevent this, the lactol aluminate
was trapped in situ with acetic anhydride in the presence
of pyridine and DMAP,14 giving acetate 10 in excellent
yield as a 1:1 mixture of C-1 anomers (Scheme 2).
Vorbru¨ggen coupling15 with silylated thymine produced
protected 4′-ethoxy-2′,3′-dideoxydidehydrothymidine de-
rivative 11 in good yield, but with no stereoselectivity,
as expected for Vorbru¨ggen couplings of 2′-deoxyribose
Synthesis of 4′-ethoxy- and 4′-ethoxy-2′-deoxythymi-
dine (8 and 9) would require the cis-dihydroxylation of
butenolide 5a from the R-face of the butenolide, the same
face as the ethoxy substituent. Studies directed toward
the total synthesis of neplanocin A16 revealed that the
17
oxidation with RuCl3/NaIO4 or OsO4 produced 16-â as
(15) Vorbru¨ggen, H.; Ruh-Pohlenz, C. Handbook of Nucleoside
Synthesis; J ohn Wiley & Sons: New York, 2001.
(14) Dahanukar, V.; Rychnovsky, S. J . Org. Chem. 1996, 61, 8317.
7650 J . Org. Chem., Vol. 67, No. 22, 2002

Synthesis of 4′-Ethoxy Nucleoside Analogues
TABLE 1. Cis-d ih yd r oxyla tion of Bu ten olid e (-)-5
moiety anti to the CH2OBn group). Epimerization of the
5′-position was successful with 19 and Et2AlCl but only
to 20% conversion (eq 1). Other protecting groups, such
as the boronate ester18 or benzylidene acetal as well as
other Lewis acids (Sc(OTf)3, SnCl4, TiCl4, Et2OBF3,
Y(OTf)3) did not improve the yield or conversion for the
epimerization, making this approach to the desired R-diol
impractical.
TABLE 2. Cis-d ih yd r oxyla tion Stu d ies
Since the inability to cis-dihydroxylation from the
â-face precluded the syntheses of the “natural” diaster-
eomers of nucleoside analogues 8 and 9, synthetic ap-
proaches to “unnatural” (at C-2 and C-3) diastereomers
were examined. Reduction of 16-â with Dibal/Pyr/DMAP
produced lactol triacetate 23 in modest yield, as a 1:1
mixture of C-1 anomers (Scheme 4). The major byproduct
of this process was the 2′,3′-diacetate of 16-â, from
acetylation of unreduced 16-â, and it was formed even
when a large excess of Dibal was used. In an attempt to
suppress this reaction, 16-â was protected as acetonide
21. This completely suppressed formation of the undes-
ired byproduct and gave an excellent yield of the one
diastereomer of 22.
Vorbru¨ggen coupling of acetates 22 and 23 proved
problematic, with most Lewis acids (SnCl4, Me2AlCl, Et2-
AlCl, Sr(OAc)3, TMSOTF) causing extensive ring opening
and decomposition. Acetate 22 epimerized completely
under the coupling conditions, but no coupled product
could be observed.
a
Percent yield based on recovered starting material.
the major diol, and with KMnO4, 16-â was the only diol
formed (Table 1).
In an attempt to synthesize the “unnatural” (at C-3)
4′-ethoxy-2′-deoxynucleoside analogue, intermediate 21
was treated with samarium iodide and ethylene glycol19
to produce R-deoxygenated lactone 24 in good overall
yield (Scheme 5). Reduction/acylation as above gave lactol
diacetate 25 in fair yield, as a 5:1 mixture of anomers.
With this substrate, small amounts of ring opened,
reduced material was always observed and easily re-
moved. R-Deoxygenated lactone 24 could also be reduced
with Pd/C and H2 to give a quantitative yield of diol 26.
Conversion to acetonide 27 occurred in an unoptimized
59% yield. Reduction/acylation conditions gave acetate
28 in fair yield, as a 1:1 mixture of diastereomers.
Vorbru¨ggen coupling was unsuccessful with both acetates
under a variety of conditions. Starting material was
recovered with mild conditions (5 equiv of Lewis acid, 0
°C to rt) or ring opening was seen when a larger excess
of the Lewis Acid and higher temperatures were used.
In an attempt to increase the diastereoselectivity to
favor the R-diol, studies were performed on a range of
butenolides and dideoxydidehydronucleoside analogues
(Table 2). The hydroxymethyl group was protected with
larger protecting groups in attempts to increase the steric
bias for the R-diol. With KMnO4 or OsO4 as the oxidant,
low conversions of the butenolides were obtained. With
RuCl3 and NaIO4 as the oxidant, the best diastereose-
lectivity and conversion (1.3:1 mixture and 54% yield)
was obtained with the tert-butyldiphenyl silyl ether
butenolide 18. Unfortunately, the tert-butyldiphenyl silyl
protecting group was not compatible with the remaining
synthetic transformations. In an attempt to increase the
steric bias even further and change the electronic proper-
ties of the alkene, the cis-dihydroxylation was attempted
on dideoxydidehydronucleoside analogues (15 and 7). No
reaction was observed with KMnO4 or OsO4 and RuCl3/
NaIO4 gave a very low conversion. Therefore, increasing
the steric bulk on the â-face and changing the electronic
properties of the butenolide did not improve the diaste-
reoselectivity to favor the R-diol, but inhibited the oxida-
tion reaction. In addition, the use of AD mix R and AD
mix â gave no conversion with 5a .
Con clu sion
Using chromium carbene chemistry, either enantiomer
of butenolide 5 was synthesized and used as an optically
(17) Shing, T. K. M.; Tai, V. W-F.; Tam, E. K. W. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2312.
(18) Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura,
N.; Kusama, H.; Kuwajima, I. J . Am. Chem. Soc. 1998, 120 (49),
12980-12981.
(19) (a) Hanessian, S.; Girard, C.; Chiara, J . L. Tetrahedron Lett.
1992, 33, 573. (b) Molander, G. A. Org. React., 1994, 46, 211.
Epimerization of the 5′-position on the undesired â-diol
would lead to the correct relative stereochemistry (diol
(16) Hegedus, L. S.; Geisler, L. J . Org. Chem. 2000, 65, 4200-4203.
J . Org. Chem, Vol. 67, No. 22, 2002 7651

Hegedus et al.
SCHEME 4
SCHEME 5
(4R,5R)-5-(Ben zyloxym et h yl)-5-et h oxy-4-(4′R-p h en yl-
oxa zolid in -2′-on e)-d ih yd r ofu r a n -2-on e (4c). (4R,5S)-Lac-
tone 4a (44 mg, 0.11 mmol) was dissolved in 3 mL of freshly
distilled CH2Cl2. BF3OEt2 (16 µL, 0.13 mmol) was then added,
and the reaction was allowed to stir at room temperature for
4 h. The reaction was poured into NaHCO3 (aq) and stirred.
Separation of the organic layer followed by concentration in
vacuo yielded an oil. Purification by SiO2 column chromatog-
raphy using 3:1 hexane:EtOAc as eluent provided a clear oil
(30 mg, 0.073 mmol, 68%) containing a 9:1 mixture of 4c:4a .
4c: 1H NMR δ 7.4-7.25 (m, 10H), 5.19 (dd, J ) 9.1 Hz, J )
4.4 Hz, 1H), 5.01 (dd, J ) 8.8 Hz, J ) 9.8 Hz, 1H), 4.58 (m,
3H), 4.11 (dd, J ) 4.4 Hz, J ) 8.4 Hz, 1H), 3.77 (d, J ) 10.2
Hz, 1H), 3.84-3.7 (m, 2H), 3.71 (d, J ) 10.2 Hz, 1H), 2.33 (dd,
J ) 17.5 Hz, J ) 8.7 Hz, 1H), 2.23 (dd, J ) 17.5 Hz, J ) 8.9
Hz, 1H), 1.28 (t, J ) 6.9 Hz, 3H), 1.18 (t, 3H). 13C NMR δ 172.2,
140.4, 137.2, 129.5, 129.1, 128.4, 127.9, 127.8, 126.3, 107.4,
73.9, 70.8, 69.1, 59.9, 58.6, 53.9, 31.4, 15.7. IR (neat) 2978,
active template for the de novo synthesis of 4′-disubsti-
tuted nucleoside analogues. 4′-Ethoxy-2′,3′-dideoxythy-
midine (6) and 4′-ethoxy-2′,3′-dideoxydidehydrothymidine
(7) were synthesized. Unfortunately, 4′-ethoxy and 4′-
ethoxy-2′-deoxythymidine (8 and 9) could not be synthe-
sized by a variety of methods from the butenolide
template because of the lack of stereochemical control of
the diol formation. In addition, “unnatural” diastereomers
could not be synthesized because of the increased insta-
bility of the intermediates caused by the 4′-ethoxy
substituent.
Exp er im en ta l Section
Gen er a l Meth od s. THF was distilled from sodium-ben-
zophenone ketyl, DMF was distilled from MgSO4, and CH2-
Cl2, benzene, and Et3N were distilled from CaH2. Commercially
available reagents were used as received except as indicated.
1H NMR, NOE, COSY (300 MHz), 13C NMR (75 MHz), and
HSQC (400 1H MHz) spectra were recorded in CDCl3 unless
otherwise noted and chemical shifts are given in ppm relative
to CDCl3 (7.27 ppm). Column chromatography was performed
with ICN 32-66 nm, 60 Å silica gel using flash column
techniques. Elemental analyses were performed by M-H-W
Laboratories, Phoenix, AZ. FAB high-resolution mass spec-
trometry (HRMS) was obtained with a Fisons VG AutoSpec
mass spectrometer with a Cs ion gun, m-nitrobenzyl alcohol
was used for the matrix, and the resolution was set to 10000.
All reactions were performed in flame-dried glassware under
an atmosphere of Ar unless otherwise noted. Compounds 3a ,
4a , 5a , and 5b were made by published procedures,13a as were
3b and 4b.20
2359, 1790, 1753 cm-1
.
Gen er a l P r oced u r e for Diba l Red u ction s. The starting
material was dissolved in CH2Cl2 and dried with MgSO4. The
mixture is filtered through Celite into a flame-dried flask. The
solution was purged with Ar and then cooled to -78 °C. A 1.3
equiv amount of Dibal was added dropwise via syringe. The
reaction was stirred at -78 °C for 1 h. The reaction was
monitored by TLC and more Dibal was added, as needed, in
portions of 0.5 equiv until there is no starting material present
by TLC. 3 equiv of pyridine, 2 equiv of DMAP, and 4 equiv of
Ac2O were added, respectively, and the reaction was warmed
to 0 °C. The ice bath was allowed to warm to room-temperature
overnight, and then the solution was quenched with Rochelle’s
salt, extracted with CH2Cl2, dried, and concentrated. The crude
mixture was purified by flash column chromatography (hex-
ane/EtOAc).
(5S)-2-Acetoxy-5-(ben zyloxym eth yl)-5-eth oxy-2,5-d ih y-
d r ofu r a n (10). Acetate 10 was prepared by using the general
(20) Brown, B.; Hegedus, L. S. J . Org. Chem. 2000, 65, 1865-1872.
7652 J . Org. Chem., Vol. 67, No. 22, 2002

Synthesis of 4′-Ethoxy Nucleoside Analogues
procedure to give 66 mg (0.23 mmol, 85%) as a 1:1 mixture of
diastereomers and as a yellow oil: 1H NMR δ 7.38-7.26 (m,
5H), 6.89 (s, 0.5H), 6.75 (s, 0.5H), 6.23-6.11 (m, 2H), 4.64 (s,
1H), 4.6 (s, 1H), 3.77 (d, J ) 12.5 Hz, 0.5H), 3.73 (d, J ) 12.3
Hz, 0.5H), 3.56 (d, J ) 15.9 Hz, 0.5H), 3.53 (d, J ) 16.2 Hz,
0.5H), 3.65-3.3 (m, 2H), 2.1 (s, 1.5H), 2.03 (s, 1.5H), 1.19 (t, J
) 7 Hz, 3H); 13C NMR δ 170.5, 170.1, 138.4, 138.2, 134.5, 133.7,
130.3, 130.2, 128.5, 128.4, 127.8, 127.6, 115.2, 114.2, 100.7,
99, 74.1, 73.8, 73.7, 73.6, 58.8, 58.4, 21.3, 21.2, 15.5, 15.4; IR
(neat) 2975, 2932, 2866, 2358, 2336, 1748 cm-1; FAB-LRMS
calcd for C14H17O3 (M - OAc): 233.13, found 233.13.
65.4, 60.0, 15.1; IR (neat) 3432, 1765 cm-1; FAB-HRMS calcd
for C7H10O4 (M + 1): 159.0657, found 159.0653.
(5S)-5-Eth oxy-5-(tr ieth ylsila n yloxym eth yl)-5H-fu r a n -
2-on e (13). Alcohol 12 (20.5 mg, 0.130 mmol) was dissolved
in 2 mL of DMF. DMAP (15.8 mg, 0.130 mmol), imidazole (21.2
mg, 0.311 mmol), and TESCl (0.030 mL, 0.16 mmol) were
added, and the mixture was stirred at room temperature for
12 h. The reaction was quenched with saturated aqueous NH4-
Cl, extracted with CH2Cl2, washed with brine, dried with
MgSO4, and concentrated. The crude oil was purified by flash
column chromatography (10:1 hexane/EtOAc) to yield TES
protected alcohol 13 (34.9 mg, 0.128 mmol, 99%) as a yellow
(4′S)-5′-O-Ben zyl-4′-eth oxy-2′,3′-d id eoxyd id eh yd r oth y-
m id in e (11). A two-necked flask was charged with thymine
(16.6 mg, 0.132 mmol) and 2.5 mL CH3CN. N,O-Bis(trimeth-
ylsilyl)acetamide (0.065 mL, 0.26 mmol) was added via syringe,
and the mixture was stirred for 30 min. The solution went
from a cloudy white suspension to a clear solution. Acetate 10
(35 mg, 0.12 mmol) was added dissolved in 1 mL of CH3CN
and the solution was cooled to 0 °C. SnCl4 (15 µL, 0.13 mmol)
was added via syringe down the sidearm of the flask to precool
the solution. The solution was stirred at 0 °C for ∼20 min until
no starting material was present by TLC (silica gel, 4:1 hexane/
EtOAc). The reaction was quenched cold with saturated
aqueous NaHCO3, extracted with CH2Cl2, dried with MgSO4,
and concentrated. The crude residue was purified by flash
column chromatography (100% EtOAc f 100% MeOH gradient
elution). The fractions were collected, concentrated, dissolved
in CH2Cl2, and filtered to removed any silica particles. Coupled
11 (27 mg, 0.075 mmol, 63%) was obtained as a separable
mixture of anomers: R-Anomer: 1H NMR δ 9.74 (s, 1H), 7.4-
7.25 (m, 5H), 6.93 (s, 1H), 6.38 (dd, J ) 1.1 Hz, 5.6 Hz, 1H),
6.02 (dd, J ) 0.8 Hz, 5.8 Hz, 1H), 4.61 (d, J ) 12 Hz, 1H), 4.56
(d, J ) 12 Hz, 1H), 3.83 (d, J ) 10.5 Hz, 1H), 3.7-3.35 (m,
2H), 3.48 (d, J ) 10.5 Hz, 1H), 1.9 (s, 3H), 1.18 (t, J ) 7.1 Hz,
3H); 13C NMR δ 164.2, 151.3, 137.7, 136.1, 133.9, 129, 128.6,
128, 127.8, 112.5, 111.4, 87.86, 73.69, 70.71, 58.86, 15.53,
12.57. â-Anomer: 1H NMR δ 9.69 (s, 1H), 7.53 (s, 1H), 7.4-
7.25 (m, 5H), 7.13 (s, 1H), 6.12 (s, 2H), 4.56 (s, 2H), 3.73 (s,
2H), 3.7-3.35 (m, 2H), 1.47 (s, 3H), 1.16 (t, J ) 7.1 Hz, 3H);
13C NMR δ 164.2, 151.1, 137.4, 136.4, 135.5, 131.3, 128.7,
128.2, 127.9, 114.2, 111.2, 88.67, 73.74, 72.9, 57.85, 15.33,
11.93. IR (neat) 1695 cm-1. Anal. Calcd for C19H22N2O5: C,
63.67; H, 6.18; N, 7.82. Found: C, 63.62; H, 6.07; N, 7.58.
(4′S)-4′-Eth oxy-2′,3′-d id eoxyth ym id in e (6). A solution of
coupled 11 (11 mg, 0.030 mmol) in MeOH (2 mL) was stirred
over 20% Pd(OH)2/C (4 mg) under an H2 atmosphere (1 atm)
for 1 h. Argon was bubbled through the solution. Filtration of
the reaction mixture through Celite and removal of solvent
afforded 6 as a white solid and as a 1:1 mixture of diastere-
omers (7.0 mg, 0.047 mmol, 88%): 1H NMR δ 9.1 (s, 1H), 9.05
(s, 1H), 7.43 (d, J ) 1.1 Hz, 1H), 7.34 (d, J ) 1.1 Hz, 1H), 6.45
(t, J ) 6.6 Hz, 1H), 6.26 (d, J ) 4.2 Hz, 0.5H), 6.24 (d, J ) 3.8
Hz, 0.5H), 3.9-3.5 (m, 8H), 2.7-2 (m, 8H), 1.95 (s, 1.5H), 1.9
(s, 1.5H), 1.24 (t, J ) 6.9 Hz, 1.5H), 1.17 (t, J ) 7 Hz, 1.5H));
13C NMR (400 MHz) δ 163.8, 163.7, 150.8, 150.4, 136.0, 135.8,
111.4, 109.9, 109.8, 86.3, 86.1, 63.0, 62.6, 57.7, 57.6, 33.1, 31.6,
30.8, 30.0, 15.7, 15.6, 12.6; IR (neat) 3430, 1692 cm-1; FAB-
HRMS calcd for C12H18N2O5 (M + 1): 271.1294, found 271.1289.
oil: [R]25 -55o (c ) 0.74, CH2Cl2); 1H NMR δ 7.16 (d, J ) 6.0
D
Hz, 1H), 6.21 (d, J ) 5.4 Hz, 1H), 3.89 (d, J ) 10.8 Hz, 1H),
3.77 (d, J ) 10.8 Hz, 1H), 3.52, (m, 1H), 3.38 (m, 1H), 1.17 (t,
J ) 6.9 Hz, 3H), 0.90 (t, J ) 3.7 Hz, 9H), 0.55 (q, J ) 7.7 Hz,
6H); 13C NMR δ 169.8, 152.4, 125.5, 110.1, 65.1, 59.9, 15.2,
6.7, 4.4; IR (neat) 1772, 1082 cm-1; FAB-HRMS calcd for
C
13H24O4Si (M + 1): 273.1522, found 273.1518.
(5S)-2-Acetoxy-5-eth oxy-5-(tr ieth ylsila n yloxym eth yl)-
2,5-d ih yd r ofu r a n (14). Acetate 14 (12.9 mg, 0.0408 mmol,
68%) was prepared by using the general procedure. The yellow
oil was a 1:1 mixture of diastereomers: 1H NMR δ 6.84 (s,
1H), 6.63 (s, 1H), 6.10 (m, 4H), 3.80 (m, 2H), 3.61, (m, 3H),
3.37 (m, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 1.16 (t, J ) 6.9 Hz,
3H), 1.15 (t, J ) 6.9 Hz, 3H), 0.92 (m, 18H), 0.58 (m, 12H);
13C NMR δ 170.5, 170.1, 134.4, 133.6, 130.1, 129.9, 115.8,
114.8, 100.6, 99.0, 67.3, 66.5, 58.7, 58.2, 53.9, 21.2, 15.3, 15.2,
6.7, 4.4, 4.4.; IR (neat) 1751 cm-1; FAB-LRMS calcd for
C
13H26O3Si (M-OAc): 257.17, found 257.15.
(5′S)-5′-E t h oxy-5′-O-t r iet h ylsila n yl-2′,3′-d id eoxyd id e-
h yd r oth ym id in e (15). Protected nucleoside analogue 15 (80.8
mg, 0.211 mmol, 67%) was prepared by using the procedure
for protected nucleoside analogue 11. The anomers were
separated by preparative TLC (2:1 hexane/EtOAc × 2). high
Rf anomer: 1H NMR δ 8.24 (bs, 1H), 7.27 (s, 1H), 6.87 (s, 1H)
6.33 (dd, J ) 1.2 Hz, J ) 5.7 Hz, 1H), 6.04 (dd, J ) 0.9 Hz, J
) 5.4 Hz 1H), 3.93 (d, J ) 10.5 Hz, 1H), 3.65 (m, 3H), 1.91 (s,
3H), 1.12 (t, J ) 6.9 Hz, 3H), 0.96 (t, J ) 7.8 Hz, 9H), 0.62 (q,
J ) 7.8 Hz, 6H); low rf anomer: 1H NMR δ 8.70 (bs, 1H), 7.50
(s, 1H), 7.06 (s, 1H) 6.14 (d, J ) 6.0 Hz, 1H), 6.06 (d, J ) 6.3
Hz, 1H), 3.84 (s, 2H), 3.50 (m, 1H), 3.39 (m, 1H), 1.91 (s, 3H),
1.19 (t, J ) 6.9 Hz, 3H), 0.96 (t, J ) 8.1 Hz, 9H), 0.63 (q, J )
7.8 Hz, 6H); 13C NMR δ 163.5, 150.6, 135.8, 133.7, 130.8, 115.2,
110.7, 88.7, 65.8, 57.9, 15.3, 12.6, 6.8, 4.3; both anomers 13C
NMR δ 163.9, 150.9, 150.7, 135.9, 135.8, 135.0, 133.5, 130.9,
128.9, 115.1, 113.3, 111.1, 110.7, 88.7, 87.7, 65.8, 64.1, 58.7,
57.8, 15.5, 15.3, 12.5, 6.8, 6.7, 4.4, 4.3; IR (neat) 3187, 3058,
1699 cm-1; FAB-HRMS calcd for C18H31N2O5Si (M + H):
383.2002, found 383.2004.
(4′S)-4′-E t h oxy-2′,3′-d id eoxyd id eh yd r ot h ym id in e (7).
Protected nucleoside analogue 15 (42.8 mg, 0.112 mmol) was
dissolved in 4 mL of THF and then cooled to 0 °C. TBAF (1
M) in THF (0.12 mL, 0.12 mmol) was added via syringe. The
reaction was stirred at 0 °C until no starting material was
present (∼10 min) by TLC (silica gel, EtOAc). The reaction
was concentrated and purified by preparative TLC (100%
EtOAc) to yield both anomers of 7 as clear oils. The stereo-
chemistry of the anomers was determined by 2D spectroscopy
and NOE studies (see Supporting Information). (1R,4S) ano-
mer: (8.7 mg, 0.032 mmol, 29%): [R]25D +88° (c ) 0.35, CHCl3);
1H NMR δ 8.30 (bs, 1H), 7.35 (s, 1H), 7.12 (s, 1H), 6.23 (dd, J
) 6.0 Hz, J ) 1.8 Hz, 1H), 6.16 (d, J ) 5.7 Hz, 1H), 3.87 (d, J
) 11.7 Hz, 1H), 3.78 (d, J ) 12.9 Hz, 1H), 3.52 (m, 1H), 3.41
(m, 1H), 2.29 (bs, 1H), 1.88 (s, 3H), 1.20 (t, J ) 7.5 Hz, 3H);
13C NMR δ 163.4, 150.6, 135.8, 134.4, 130.8, 114.7, 111.2, 89.0,
(5S)-5-Eth oxy-5-(h yd r oxym eth yl)-5H-fu r a n -2-on e (12).
(-)-5-(Benzyloxymethyl)-5-ethoxy-5H-furan-2-one (5) (16 mg,
0.064 mmol) was dissolved in 1.5 mL of CH2Cl2 and cooled to
-78 °C. BCl3 (0.2 mL, 0.2 mmol) was added via syringe, and
the solution was stirred for 20 min. The reaction was quenched
cold with MeOH, and saturated aqueous Na2S2O3 was added.
The mixture was extracted with CH2Cl2, dried, and concen-
trated. The crude residue was purified by flash column
chromatography (2:1 hexane/EtOAc) to yield alcohol 12 (8.4
mg, 0.053 mmol, 82%): [R]25D -59o (c ) 1.13, CHCl3); 1H NMR
δ_7.27 (d, J ) 6.8 Hz, 1H), 6.27 (d, J ) 5.6 Hz, 1H), 3.87 (dd,
J ) 6.4 Hz, J ) 11.6 Hz, 1H), 3.73 (dd, J ) 7.2 Hz, J ) 11.6
Hz, 1H), 3.54, (m, 1H), 3.39 (m, 1H), 2.02 (t, J ) 7.2 Hz, 1H),
1.19 (t, J ) 6.8 Hz, 3H); 13C NMR δ 169.6, 152.4, 125.8, 109.5,
65.9, 58.2, 15.2, 12.4; IR (neat) 3447, 3177, 3057, 1695 cm-1
;
FAB-HRMS calcd for C12H17N2O5 (M + H): 269.1137, found
269.1138. (1S,4S) anomer: (9.2 mg, 0.034 mmol, 30%): [R]25
D
1
-66° (c ) 0.31, CHCl3); H NMR (400 MHz) δ 8.92 (bs, 1H),
7.21 (d, J ) 1.2 Hz, 1H), 6.94 (d, J ) 1.6 Hz, 1H), 6.37 (dd, J
) 6.0 Hz, J ) 2.0 Hz, 1H), 6.11 (dd, J ) 5.6 Hz, J ) 1.6 Hz,
J . Org. Chem, Vol. 67, No. 22, 2002 7653

Hegedus et al.
1H), 3.84 (dd, J ) 5.6 Hz, J ) 11.6 Hz, 1H), 3.75 (dd, J ) 5.2
Hz, J ) 11.6 Hz, 1H), 3.62 (q, J ) 7.2 Hz, 2H), 2.35 (t, J ) 5.6
2H), 2.05 (s, 3H), 2.02 (s, 3H), 1.97 (s, 3H), 1.18 (t, J ) 7.1 Hz,
3H); IR (thin film) νmax 2933, 1753 cm-1. Anal. Calcd for
C20H26O9; C, 58.53; H, 6.39. Found; C, 58.35; H, 6.15. Also
Hz, 1H), 1.92 (d, J ) 1.2 Hz, 3H), 1.20 (t, J ) 6.8 Hz, 3H); 13
C
NMR δ 163.6, 150.8, 135.7, 135.2, 129.3, 113.4, 111.4, 87.7,
64.2, 59.0, 15.5, 12.5; IR (neat) 3421, 1696 cm-1; FAB-HRMS
calcd for C12H17N2O5 (M + H): 269.1137, found 269.1135; Anal.
Calcd for C19H16N2O5: C, 53.73; H, 6.01; N, 10.44. Found: C,
53.96; H, 6.07; N, 10.21.
obtained was 2,3-diacetoxy lactone (6.0 mg, 0.016 mmol, 15%)
as a colorless oil: 1H NMR δ 7.37-7.27 (m, 5H), 5.94 (d, J )
4.9 Hz, 1H), 5.53 (d, J ) 4.9 Hz, 1H), 4.60 (d, J ) 12.1 Hz,
1H), 4.46 (d, J ) 12.1 Hz, 1H), 3.83 (d, J ) 10.8 Hz, 1H), 3.71
(m, 2H), 3.65 (d, J ) 10.8 HZ, 1H), 2.11 (s, 3H), 1.93 (s, 3H),
1.22 (t, J ) 7.1 Hz, 3H).
(3S,4R,5S)-5-(Ben zyloxym et h yl)-3,4-d iol-5-et h oxy-d i-
h yd r ofu r a n -2-on e cycloh exa n on id e (20). Dry (3S,4R,5S)-
lactone 1916(4.3 mg, 0.012 mmol) was dissolved in 0.5 mL of
CH2Cl2 and cooled to -78 °C. Et2AlCl (0.02 mL, 0.024 mmol)
was added via syringe. The solution was stirred at -78 °C for
2 h. The reaction was quenched with cold saturated aqueous
NaHCO3, extracted with CH2Cl2, dried, and concentrated.
Purification by preparative TLC (10:1 hexane:EtOAc × 2) gave
19 (3.3 mg, 0.0090 mmol) and epimerized 20 (1.0 mg, 0.0027
mmol). 1H NMR spectrum matches the spectrum for its
enantiomer synthesized by a known method:16 1H NMR δ 7.40
(m, 3H), 7.25 (m, 2H), 4.90 (d, J ) 6.0 Hz, 1H), 4.71 (d, J )
5.7 Hz, 1H), 4.60 (d, J ) 11.7 Hz, 1H), 4.50 (d, J ) 11.7 Hz,
1H), 4.00 (m, 1H), 3.85 (m, 1H), 3.72 (d, J ) 9.9 Hz, 1H), 3.69
(d, J ) 9.6 Hz, 1H), 1.70 (m, 10H), 1.23 (t, J ) 6.9 Hz, 3H).
(4R,5R)-5-(Ben zyloxym eth yl)-5-eth oxy-4-h yd r oxyd ih y-
d r ofu r a n -2-on e (24). Acetonide 21 (50 mg, 0.16 mmol) was
dissolved in THF (2 mL), and dry ethylene glycol (0.1 mL) was
added. This solution was degassed by freeze-pump-thaw (3
cycles). A degassed solution of SmI2 (9 mL, 0.17 M in THF)19
was added via cannula, and the resulting mixture was stirred
at room temperature for 0.5 h before quenching by addition of
saturated aqueous NaHCO3. The mixture was extracted with
Et2O (2 × 40 mL). The organic phase was washed with 10%
Na2S2O3 solution, washed with brine, dried, and evaporated
to give a pale brown oil. Flash column chromatography of the
crude product (1:4 EtOAc/hexane) gave lactone 24 (38.1 mg,
0.143 mmol, 92%) as a colorless oil: [R]25 -20° (c ) 0.44,
D
1
CHCl3); H NMR δ 7.39 (m, 5H), 4.64 (d, J ) 12.1 Hz, 1H),
4.58 (d, J ) 11.8 Hz, 1H), 4.37 (ddd, J ) 1.5 Hz, J ) 3.7 Hz,
J ) 6.2 Hz, 1H), 3.95 (d, J ) 10.6 Hz, 1H), 3.76 (d, J ) 10.6
Hz, 1H), 3.60 (m, 2H), 2.96 (ddd, J ) 1.1, J ) 6.2 Hz, J ) 18.0
Hz, 1H), 2.67 (dd, J ) 1.1 Hz, J ) 3.7 Hz, 1H), 2.46 (dd, J )
1.5 Hz, J ) 18.3 Hz, 1H), 1.18 (t, J ) 7.0 Hz, 3H); 13C NMR δ
174.6, 136.8, 128.7, 128.4, 128.0, 109.4, 73.7, 72.6, 65.2, 58.7,
36.6, 15.3; IR (neat) νmax 3455, 1795 cm-1; FAB-HRMS calcd
for C14H18O5 (M + H): 267.1232, found 267.1239.
(3S,4R,5R)-5-(Ben zyloxym eth yl)-3,4-d iol-5-eth oxyd ih y-
d r ofu r a n -2-on e a ceton id e (21). A flask, equipped with
reflux condenser and Soxhlett extractor containing 4 Å mo-
lecular sieves, was charged with diol 16-â (32.3 mg, 0.114
mmol), 2,2-dimethoxypropane (0.25 mL, 2.9 mmol), and 15 mL
of benzene. The solution was warmed to reflux, and a few
crystals of TsOH were added. The reaction was kept at reflux
for 30 min and then cooled to room temperature. The organic
layer was washed with saturated aqueous NaCO3 (×2) and
DI H2O (×2), dried, and concentrated to give pure acetonide
(4R,5R)-5-(Ben zyloxym et h yl)-2,4-d ia cet oxy-5-et h oxy-
tetr a h yd r ofu r a n (25). Acetate 25 was prepared by using the
general procedure except Dibal (2.3 equiv) was only added at
the beginning of the reaction, the reaction stirred at -78 °C
for 3 h, and then 4 equiv of pyridine, 2 equiv of DMAP, and 8
equiv of Ac2O were added. Flash column chromatography of
the crude product (1:8 EtOAc/hexane) gave the impure diac-
etate 25 (14 mg, 0.040 mmol, 39%) as a colorless oil (5:1
mixture of anomers): 1H NMR major anomer δ 7.33 (m, 5H),
6.27 (d, J ) 5.9 Hz, 1H), 5.18 (d, J ) 5.1 Hz, 1H), 4.61 (d, J )
12.1 Hz, 1H), 4.50 (d, J ) 12.4 Hz, 1H), 3.72 (d, J ) 10.3 Hz,
1H), 3.64 (d, J ) 10.6 Hz, 1H), 3.60 (m, 2H), 2.75 (dt, J ) 5.5
Hz, J ) 15.0 Hz, 1H), 2.05 (s, 3H), 1.96 (s, 3H), 1.17 (t, J )
7.0 Hz, 3H); minor anomer 6.38 (dd, J ) 6.3 Hz, J ) 4.5 Hz,
1H), 5.33 (dd, J ) 5.7 Hz, J ) 1.7 Hz, 1H), 2.56 (ddd, J ) 14.7
Hz, J ) 5.7 Hz, J ) 4.5 Hz, 1H), 2.31 (ddd, J ) 14.7 Hz, J )
6.3 Hz, J ) 1.7 Hz, 1H), 2.07 (s, 3H), 1.91 (s, 3H); both anomers
13C NMR δ 169.8, 169.4, 137.7, 127.9, 127.7, 127.6, 109.6,
109.1, 97.5, 97.3, 74.7, 74.5, 73.5, 65.4, 65.1, 57.1, 57.0, 37.9,
37.3, 21.2, 21.0, 21.0, 20.8, 15.4, 15.2; IR (thin film) νmax 1749
cm-1; FAB-LRMS calcd for C16H21O5 (M - OAc): 293.15, found
293.14.
21 (35.5 mg, 0.110 mmol, 96%) as a colorless oil: [R]25 +12°
D
(c ) 0.72, CHCl3); IR (thin film) νmax 1799 cm-1
;
1H NMR δ
7.37 (m, 5H), 4.90 (d, J ) 5.1 Hz, 1H), 4.70 (d, J ) 12.1 Hz,
1H), 4.61 (d, J ) 4.8 Hz, 1H), 4.60 (d, J ) 12.5 Hz, 1H), 3.85
(d, J ) 11.0 Hz, 1H), 3.72 (d, J ) 11.0 Hz, 1H), 3.69 (q, J )
7.0 Hz, 2H), 1.44 (s, 3H), 1.41 (s, 3H), 1.18 (t, J ) 7.0 Hz, 3H);
13C NMR δ 173.6, 137.3, 127.9, 127.8, 114.5, 106.3, 79.3, 75.8,
73.6, 64.1, 59.0, 26.8, 26.1, 15.1; Anal. Calcd for C16H22O6: C,
63.34; H, 6.88. Found: C, 63.16; H, 7.00.
(2S,3S,4R,5R)-2-Acetoxy-5-(ben zyloxym eth yl)-3,4-d iol-
5-eth oxytetr a h yd r ofu r a n Aceton id e (22). Acetate 22 (37.8
mg, 0.103 mmol, 94% yield) was prepared by using the general
procedure: [R]25D +19° (c ) 0.655, CHCl3); 1H NMR δ 7.34 (m,
5H), 5.94 (d, J ) 4.0 Hz, 1H), 4.92 (dd, J ) 3.4 Hz, J ) 5.4 Hz,
1H), 4.68 (d, J ) 12.3 Hz, 1H), 4.59 (d, J ) 5.4 Hz, 1H), 4.58
(d, J ) 12.9 Hz, 1H), 3.74 (d, J ) 10.8 Hz, 1H), 3.68 (d, J )
10.5 Hz, 1H), 3.58 (m, 2H), 2.15 (s, 3H), 1.49 (s, 3H), 1.38 (s,
3H), 1.18 (t, J ) 6.9 Hz, 3H); 13C NMR δ 168.9, 137.7, 128.2,
127.9, 127.6, 113.8, 105.6, 96.6, 82.5, 78.5, 73.4, 65.0, 57.1, 26.0,
25.7, 20.9, 15.4; IR (neat) 1748.5 cm-1; FAB-HRMS calcd for
C
19H26O7 (M + H): 367.1757, found 367.1758.
(4R,5R)-5-E t h oxy-4-h yd r oxy-5-(h yd r oxym et h yl)d ih y-
d r ofu r a n -2-on e (26). Lactone 25 (30.3 mg, 0.114 mmol) was
dissolved in 2.5 mL of EtOH and stirred over 10% Pd/C (15
mg) under a H2 atmosphere (1 atm) until no starting material
was present (∼1 h) by TLC (silica gel, 1:1 hexane:EtOAc).
Argon was bubbled through the solution. The solution was
filtered through Celite and then concentrated to give dialcohol
(3S,4R,5R)-5-(Ben zyloxym et h yl)-5-et h oxy-2,3,4-t r ia c-
etoxytetr a h yd r ofu r a n (23). Acetate 23 was prepared by
using the general procedure except 3.3 equiv of Dibal was
added at the beginning of the reaction and then 6 equiv of
pyridine, 2.2 equiv of DMAP, and 8 equiv of Ac2O were used.
1
The H NMR spectrum of the crude material indicated a 0.6:1
26 (20 mg, 0.11 mmol) in quantitative yield as a colorless oil:
mixture of anomeric acetates which were separated by flash
chromatography on SiO2, eluting with 2:5 EtOAc/hexane to
give 23: anomer 1 of 23 (14 mg, 0.034 mmol, 22%): 1H NMR
δ 7.30 (m, 5H), 6.18 (d, J ) 4.1 Hz, 1H), 5.71 (dd, J ) 4.9, J )
4.1 Hz, 1H), 5.43 (d, J ) 4.9 Hz, 1H), 4.58 (d, J ) 12.2 Hz,
1H), 4.43 (d, J ) 12.2 Hz, 1H), 3.63 (d, J ) 10.7 Hz, 1H), 3.60
(m, 2H), 3.54 (d, J ) 10.7 Hz, 1H), 2.09 (s, 3H), 2.01 (s, 3H),
1.93 (s, 3H), 1.20 (t, J ) 7.1 Hz, 3H); anomer 2 of 23 (20 mg,
0.049 mmol, 31%): 1H NMR δ 7.27-7.38 (m, 6H), 6.34 (d, J )
5.0 Hz, 1H), 5.55 (t, J ) 5.0 Hz, 1H), 5.42 (d, J ) 5.0 Hz, 1H),
4.58 (d, J ) 12.2 Hz, 1H), 4.45 (d, J ) 12.2 Hz, 1H), 3.68 (d,
J ) 10.6 Hz, 1H), 3.59 (d, J ) 10.6 Hz, 1H), 3.54-3.65 (m,
1
[R]25 -3° (c ) 0.5, CHCl3); H NMR δ 4.44 (ddd, J ) 1.6 Hz,
D
J ) 3.6 Hz, J ) 5.6 Hz, 1H), 4.11 (dd, J ) 4.0 Hz, J ) 12.0
Hz, 1H), 3.97 (dd, J ) 7.6 Hz, J ) 12.0 Hz, 1H), 3.70 (m, 2H),
3.01 (dd, J ) 6.4 Hz, J ) 18.0 Hz, 1H), 2.83 (d, J ) 3.6 Hz,
1H), 2.52 (dd, J ) 1.6 Hz, J ) 18.4 Hz, 1H), 1.97 (t, J ) 4.9
Hz, 1H), 1.22 (t, J ) 7.0 Hz, 3H); 13C NMR δ 174.9, 109.7, 72.5,
59.0, 58.8, 37.1, 15.4 cm-1; IR (neat) 3421, 1772; FAB-HRMS
calcd for C7H12O5 (M + H): 177.0763, found 177.0756.
(4R,5R)-4,6-Diol-5-eth oxydih ydr ofu r an -2-on e Aceton ide
(27). Lactone 27 was prepared by using the procedure for
acetonide 21. Lactone 27 (11.4 mg, 0.0527 mmol, 59%) was
7654 J . Org. Chem., Vol. 67, No. 22, 2002

Synthesis of 4′-Ethoxy Nucleoside Analogues
obtained as a clear oil: [R]25D +5° (c ) 0.57, CH2Cl2); 1H NMR
δ 4.27 (d, J ) 5.4 Hz, 1H), 4.07 (d, J ) 12.9 Hz, 1H), 3.99 (d,
J ) 12.3 Hz, 1H), 3.65 (m, 2H), 2.94 (dd, J ) 5.4 Hz, J ) 18.0
Hz, 1H), 2.46 (d, J ) 18.0 Hz, 1H), 1.48 (s, 3H), 1.38 (s, 3H),
1.20 (t, J ) 7.2 Hz, 3H); 13C NMR δ 175.0, 103.7, 99.2, 70.8,
61.6, 58.6, 35.2, 26.4, 21.0, 15.5; IR (neat) 1799 cm-1; FAB-
HRMS calcd for C10H16O5 (M + H): 217.1076, found 217.1073.
(4R,5R)-2-Acet oxy-4,6-d iol-5-et h oxyd ih yd r ofu r a n -2-
on e Aceton id e (28). Acetate 28 (20.7 mg, 0.0795 mmol, 54%
yield) was prepared by using the general procedure and
obtained as a 1:1 mixture of diastereomers and as a clear oil:
1H NMR δ 6.53 (dd, J ) 4.8 Hz, J ) 6.2 Hz, 1H), 6.35 (d, J )
5.7 Hz, 1H), 4.24 (d, J ) 5.1 Hz, 1H), 4.15 (d, J ) 5.4 Hz, 1H),
3.97 (d, J ) 12.5 Hz, 1H), 3.97 (s, 2H), 3.91 (d, J ) 12.5 Hz,
1H), 3.63 (m, 2H), 3.48 (m, 2H), 2.58 (dt, J ) 5.5 Hz, J ) 20.1
Hz, 1H), 2.38 (m, 3H), 2.13 (s, 3H), 2.10 (s, 3H), 1.47 (s, 3H),
1.46 (s, 3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.18 (t, J ) 6.0 Hz, 3H),
1.16 (t, J ) 7.0 Hz, 3H); 13C NMR δ 170.1, 104.9, 103.5, 99.0,
98.7, 98.4, 98.3, 74.7, 73.1, 63.2, 62.5, 57.3, 56.9, 38.0, 37.3,
FAB-HRMS calcd for C10H17O4 (M - OAc): 201.1127, found
201.1127.
Ack n ow led gm en t. Support for this research under
Grant No. GM26178 from the National Institutes of
General Medical Sciences (Public Health Service) is
gratefully acknowledged. Mass spectra were obtained
on instruments supported by the National Institutes of
Health shared instrumentation grant GM49631.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 20 and 23; 1H and 13C NMR spectra for compounds
4c, 6, (1S,4S)-7, (1R,4S)-7, 10, 12, 13, 14, 15, 21, 22, 24, 26,
27, and 28; NOE spectra for compounds (1S,4S)-7 and (1R,4S)-
7; 1H-1H 2D (COSY) spectra for compounds (1S,4S)-7 and
(1R,4S)-7. This material is available free of charge via the
Internet at http://pubs.acs.org.
27.5, 27.0, 21.4, 21.2, 20.7, 20.1, 15.7, 15.5; IR (neat) 1749 cm-1
;
J O020151F
J . Org. Chem, Vol. 67, No. 22, 2002 7655