Facile preparation of protected furanoid glycals from thymidine

Article abstract of DOI:10.1021/jo970947s

The synthesis of O-silyl- and O-acyl-protected furanose glycals from free thymidine was investigated. The method of glycal formation reported by Pedersen et al. was successfully expanded to include 5-ester (toluoyl) protected glycals as well as various combinations of 5'-ester and 3- and 5- tert-butyldimethylsilyl and tert-butyldiphenylsilyl protection. Gram quantities of furanoid glycals can be prepared in a few days in two-four steps in overall yields ranging from 17 to 80%.

Full text of DOI:10.1021/jo970947s

J . Org. Chem. 1997, 62, 9065-9069
9065
F a cile P r ep a r a tion of P r otected F u r a n oid Glyca ls fr om Th ym id in e
Melissa A. Cameron, Sarah B. Cush, and Robert P. Hammer*
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803
Received May 29, 1997X
The synthesis of O-silyl- and O-acyl-protected furanose glycals from free thymidine was investigated.
The method of glycal formation reported by Pedersen et al. was successfully expanded to include
5-ester (toluoyl) protected glycals as well as various combinations of 5′-ester and 3- and 5-tert-
butyldimethylsilyl and tert-butyldiphenylsilyl protection. Gram quantities of furanoid glycals can
be prepared in a few days in two-four synthetic steps in overall yields ranging from 17 to 80%.
Sch em e 1
The preparation of aryl C-glycosides and C-nucleosides
is of intense interest because of their potential antiviral
and antitumor activity1 and their use as novel base-
pairing moieties in oligonucleotides.2 Several approaches
have been developed for the preparation of C-glycosides
and C-nucleosides including multistep assembly of the
aryl unit de novo on the sugar moiety (Scheme 1, path
A),3 multistep assembly of the sugar de novo on the
aromatic aglycon (Scheme 1, path B),4 electrophilic
aromatic substitution with a glycosyl cation (Scheme 1,
path C),5 and nucleophilic attack of aryl organometallics
directly onto lactones (Scheme 1, path D)2e,6 or glycosyl
halides (Scheme 1, path E).2a-d An alternative strategy
for preparation of C-nucleosides has been developed by
Daves et al.7,8 which utilizes a Pd-catalyzed Heck-type
coupling of aryl halides to cyclic enol ethers, either
pyranoid or furanoid glycals (Scheme 1, path F).
A limitation of this latter approach has been poor
accessibility of the furanoid glycals, which in contrast to
pyranose glycals are highly acid labile. For example,
reduction of pyranosyl halides by elemental zinc in acetic
acid produces good yields of pyranose glycals;9 this
method fails for furanosyl glycals.10 Ireland et al.11
demonstrated a synthesis of 5-O-protected glycals in four
steps from 2,3-isopropylidene-protected ribonolactone.
The overall yield was 60%, but the 5-O-protection pos-
sibilities were limited and scale-up was difficult because
of the aluminum hydride reduction, chlorination, and
dissolving metal reduction required in this route.
A
modified approach was developed by Daves et al.12 to
allow for differential protection of the 3- and 5-hydroxyl
groups. The method required six steps with an overall
yield of 25%. The protecting group choices were in-
creased to include silyl-protecting groups, but the chem-
istry was still limited because of the need for DIBAl-H
reduction, chlorination, and Na/NH3 reduction. More
recently, two groups have developed methods to prepare
glycals from 2-deoxyribose. Kassou and Castillo´n13 have
used a selenoxide elimination approach to access glycals
(three-five steps, e 40-65% yield) that is compatible
with 3- and 5-acyl protection. Townsend and co-work-
ers14 utilized the elimination of a 1-O-mesylate on a
protected 2-deoxyribose to prepare mono- or bis-silyl-
protected glycals (four-five steps, 20-82% yields).
* Dr. Robert P. Hammer, Department of Chemistry, 232 Choppin
Hall, Louisiana State University, Baton Rouge, LA 70803,
Telephone:
(504)
388-4025,
Facsimile:
(504)
388-3458,
Internet: chammer@chrs1.chem.lsu.edu
X Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) (a) Daves, G. D., J r.; Cheng, C. C. Prog. Med. Chem. 1976, 13,
303-349. (b) Hacksell, U.; Daves, G. D., J r. Prog. Med. Chem. 1985,
22, 1-65.
(2) (a) Schweitzer, B. A.; Kool, E. T. J . Org. Chem. 1994, 59, 7238-
7242. (b) Schweitzer, B. A.; Kool, E. T. J . Am. Chem. Soc. 1995, 117,
1863-1872. (c) Ren, R. X.-F.; Chaudhuri, N. C.; Paris, P. L.; Rumney,
S.; Kool, E. T. J . Am. Chem. Soc. 1996, 118, 7671-7678. (d) Moran,
S.; Ren, R. X.-F.; Rumney, S.; Kool, E. T. J . Am. Chem. Soc. 1997,
119, 2056-2057. (e) Hildbrand, S.; Leumann, C. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1968-1970.
(3) Watanabe, K. A. Chemistry of Nucleosides and Nucleotides, Vol.
3, Plenum Press: New York, 1994; pp 438-477.
(4) Solomon, M. S.; Hopkins, P. B. Tetrahedron Lett. 1991, 32, 3297-
3300.
Pedersen et al.15 reported that furanose erythro-glycals
can be produced easily from free thymidine or 5′-O-(tert-
butyldiphenylsilyl)thymidine (1c) by using typical base
silylation conditions: refluxing 1,1,1,3,3,3-hexamethyl-
disilazane (HMDS) and (NH4)2SO4 (eq 1). This approach
(5) J aramillo, C.; Knapp, S. Synthesis 1994, 1-20.
(6) Kraus, G. A.; Molina, M. T. J . Org. Chem. 1988, 53, 752-753.
(7) (a) Arai, I.; Daves, G. D., J r. J . Org. Chem. 1978, 43, 4110-
4112. (b) Arai, I.; Daves, G. D., J r. J . Org. Chem. 1979, 44, 21-22. (c)
Daves, G. D., J r. Acc. Chem. Res 1990, 23, 201-206. (d) Kwok, D.-I.;
Farr, R. N.; Daves, G. D., J r. J . Org. Chem. 1991, 56, 3711-3713. (e)
Zhang, H.; Brakta, M.; Daves, G. D., J r. Nucleosides Nucleotides 1995,
14, 105-116.
(8) For more recent examples by other groups, see: (a) Chen, J . J .;
Walker, J . A.; Liu, W.; Wise, D. S.; Townsend, L. B. Tetrahedron Lett.
1995, 36, 8363-8366. (b) Erion, M. D.; Rydzewski, R. M. Nucleosides
Nucleotides 1997, 16, 315-337.
(9) Sharma, M.; Brown, R. K. Can. J . Chem. 1966, 44, 2825-2835.
(10) Ferrier, R. J . Adv. Carbohydr. Chem. 1969, 24, 199-266.
(11) Ireland, R. E.; Thairisvongs, S., Vanier, D.; Wilcox, C. S. J . Org.
Chem. 1980, 45, 48-61.
(12) Cheng, J . C.; Hacksell, U.; Daves, G. D., J r. J . Org. Chem. 1985,
50, 2778-2780.
(13) Kassou, M.; Castillo´n, S. Tetrahedron Lett. 1994, 35, 5513-
5516.
(14) Walker, J . A.; Chen, J . J .; Wise, D. S.; Townsend, L. B. J . Org.
Chem. 1996, 61, 2219-2221.
(15) Larsen, E.; J orgensen, P. T.; Sofan, M. A.; Pedersen, E. B.
Synthesis 1994, 1037-1038.
S0022-3263(97)00947-X CCC: $14.00 © 1997 American Chemical Society

9066 J . Org. Chem., Vol. 62, No. 26, 1997
Cameron et al.
Ta ble 1. P r od u ct Yield s for Glyca ls
yield
(%)b,c
yield (%)
thymidine
glycal
R
R′
from 1a d
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
2a e
2be
2ce
2d
2ee
2fe
2g
2h
2i
2j
2k
2l
2m
2n
2o
H
H
H
H
H
80
74
91
52
69
80
a
79
a
59
a
80 (1)
53 (2)
70 (2)
38 (2)
47 (2)
76 (2)
a
55 (3)
a
40 (3)
a
TBDMS
TBDPS
Tol
TBDMS
TBDPS
Tol
TBDMS
TBDMS
TBDPS
TBDPS
Tol
TBDMS
TBDPS
Tol
TBDPS
Tol
TBDMS
Tol
TBDMS
TBDPS
TBDMS
TBDPS
has the advantage of readily available starting materials,
potential compatibility with a wide range of protecting
groups, and very straightforward experimental proce-
dures. Thus, we envisioned this as an ideal method for
making up to gram amounts of glycals rapidly and
efficiently, as it avoids the experimental diffculties of
previous glycal preparations (e.g., large scale dissolving
metal reductions,11,12 large scale aluminum hydride
reductions11-13). Herein we show that this method works
very well for preparation of furanose glycals with a wide
range of O-silyl protection. Additionally, 5-O-acyl-pro-
tected glycals, previously only accessible by a selenoxide
elimination method,13 can also be prepared in good to
excellent yields with this straighforward chemistry.
Protected thymidines 1a -o were prepared according
to known procedures in one (1b-g), two (1h -m ), or at
most three (1n -o) steps (see Scheme 2, Experimental
Section, and Supporting Information). The protection
groups on the thymidines were introduced by silylation
with either tert-butyldimethylsilyl chloride (TBDMSCl)
or tert-butyldiphenylsilyl chloride (TBDPSCl) and imi-
dazole in DMF or by toluoylation with p-toluoyl chloride
in pyridine. Where 5′-toluoyl groups were used as
temporary protection, they were removed by treatment
with ammonia in methanol.
On ∼0.2-3 mmol scales, the thymidines were treated
under Pedersen’s conditons (excess HMDS, (NH4)2SO4,
reflux) and all, except for the 3′-O-toluoyl-protected
thymidines (1g, 1i, 1k ), were converted to the corre-
sponding protected glycals (Table 1). In the cases where
a free hydroxyl group was present (2b-d , 2n , 2o), the
initial product formed was the O-trimethylsilyl (TMS)
derivative, but under the workup conditions the TMS
group was cleaved and the free hydroxyl compound was
isolated. For optimal glycal yields, heating should be
discontinued as soon as all the nucleoside is consumed
(TLC). In general, the crude products from extraction
are pure enough for further reactions, though we report
here yields after flash chromatographic purification
(Table 1).
74
94
36
79
39 (3)
64 (3)
18 (4)
53 (4)
Tol
H
H
a
b
No glycal product obtained. Isolated yield after chromatog-
raphy. c Purified silyl-protected glycals decompose readily at room
temperature, though they may be stored in the freezer up to
several weeks. In contrast, the 5-O-toluoylglycals (2d , 2l, 2m ) are
stable at room temperature for several days and appear to be
d
indefinetely stable in the freezer. The number in parentheses
indicates the number of steps required to prepare the glycal from
commercially available free thymidine 1a . e A separate time course
experiment was run to determine the rate of glycal formation for
several of the protected thymidines: Thymidine (1a -c, 1e, 1f; 0.1
mmol), (NH4)2SO4 (0.5 g, 3.8 mmol) in HMDS (5 mL). Reaction
mixtures were lowered simultaneously into preheated oil baths
and all started refluxing within 30 s. Disappearance of starting
material (TLC, GC) was considered as the end of the reaction.
Reaction times: 2a , 170 min; 2b, 125 min; 2c, 145 min; 2e, 180
min; 2f, 180 min.
Using Pedersen’s method, we have prepared furanoid
glycals having both O-silyl and, for the first time, 5-O-
acyl protection. The advantages of this method are the
greater generality of protecting groups that can be used
and the speed and experimental ease with which glycals
can be made. Previous methods for preparing furanose
glycals starting from ribonolactone11,12 require at least
six steps and are difficult to scale-up because of the
required sequential DIBAl-H reduction, low-temperature
chlorination, and Na/NH3 reduction. The more recent
approaches to glycals from 2-deoxyribose13,14 are much
improved, but still have some disadvantages relative to
the Pedersen route from thymidine. The Castillo´n
method requires use of the toxic, pungent, and expensive
reagent benzeneselenol. Townsend’s approach requires
a low-temperature reduction step that is incompatible
with 5-O-ester protection (e.g., 2d , 2j, 2l, 2m ). Yields of
glycals made herein under Pedersen conditions, including
the four previously unknown glycals 2d , 2j, 2l, 2m , are
comparable to those acheived by Townsend. Also, pro-
duction of glycals by the Pedersen method is always one
less step from commercially available material than the
Townsend Route: bis-O-TBDMS glycal 2e, two steps
from thymidine (1a ), 47% yield, or three steps from
2-deoxyribose, 63% yield; bis-O-TBDPS glycal 2f, two
steps from 1a , 76% yield, or three steps from 2-deoxyri-
bose, 80% yield; 3-O-TBDPS glycal 2o, four steps from
1a , 53% yield, or five steps from 2-deoxyribose, 20% yield.
Gram quantities of furanoid glycals can now be prepared
in a few days using standard nucleoside protection
chemistry and typical HMDS silylation conditions. Im-
Yields of glycal products with O-TBDMS protection
were always lower than analogous TBDPS derivatives
[e.g., 2b (74%) vs 2c (91%); 2e (69%), 2j (59%) vs 2f (80%);
2l (74%) vs 2m (94%); 2n (36%) vs 2o (79%)]. This
suggests some cleavage of TBDMS ethers under the
slightly acidic conditions of the reaction or overall lower
stability of the TBDMS glycals. As previously noted by
Pedersen,15 thymidines in which a 3′-ester group was
included (1g, 1i, 1k ) produced no isolable glycal products
though starting material was consumed slowly16 to form
furfuryl alcohol derivatives.17 The 5′-O-toluoylthymi-
dines (1d , 1l, 1m ) were successfully converted to the
corresponding glycals and were found to be much more
stable to storage than those with only silyl protection
(Table 1, footnote c).
(17) For example, attempted preparation of 2k by method D resulted
in formation of the TBDPS ether of furfuryl alcohol: 1H NMR (200
MHz, CDCl3) δ 7.65-7.61 (m, 4H, Ar), 7.38-7.26 (m, 6H, Ar), 6.21 (m,
1H, H2), 6.06 (d, 1H, H3), 2.18 (s, 2H, H5), 0.99 (s, 9H, C(CH3)3). 13C
NMR (50 MHz, CDCl3) δ 142.1 (C1), 110.2 (C2), 107.4 (C3), 58.9 (C5),
26.8 (C(CH3)3), 14.2 (C(CH3)3).
(16) Free thymidine (1a ) and toluoyl-protected thymidines (1d , 1g,
1i, 1k -m ) are much less soluble in HMDS and dissolve slowly in the
refluxing HMDS.

Protected Furanoid Glycals from Thymidine
J . Org. Chem., Vol. 62, No. 26, 1997 9067
Meth od B. Gen er a l Con d ition s for Tolu oyla tion . 5′-
O-(ter t-Bu tyldim eth ylsilyl)-3′-O-(p-tolu oyl)th ym idin e (1i).
5′-O-(tert-Butyldimethylsilyl)thymidine (1b) (0.207 g, 0.58
mmol) was introduced to a dried flask under Ar. Pyridine (5
mL) was added, and the solution was cooled to 0 °C. The
p-toluoyl chloride (0.15 mL, 1.13 mmol) was added slowly over
15 min. The solution was allowed to warm to room temper-
ature followed by heating to 50-55 °C for 4 h. Then, it was
cooled to room temperature and poured onto ice followed by
an extraction with CH2Cl2. The organic layer was washed with
aqueous NaHCO3 and then distilled water. The washed layer
was dried with Na2SO4 and concentrated under reduced
pressure. It was recrystallized from CH2Cl2 to yield a white
solid (0.219 g, 80%): TLC Rf 0.84 (1:2 CH2Cl2-EtOAc); mp
173 °C; FABMS (MNBA) 475.2 (M + H)+; 1H NMR (300 MHz,
CDCl3) δ 8.84 (s, 1H, H3), 7.95-7.92 (m, 2H, Ar), 7.61 (app d,
Sch em e 2
J Me ) 1.2 Hz, 1H, H6), 7.28-7.25 (m, 2H, Ar), 6.48 (dd, J H2′
)
5.3, J H2′ ) 9.3 Hz, 1H, H1′), 5.49 (d, J ) 6.1 Hz, 1H, H3′), 4.25
(s, 1H, H4′), 4.04 (dd, J H4′ ) 2.0, J H5′ ) 11.3 Hz, 1H, H5′), 3.97
(dd, J H4′ ) 1.9, J H5′ ) 11.3 Hz, 1H, H5′), 2.58 (dd, J H1′ ) 5.3,
J H2′ ) 13.8 Hz, 1H, H2′), 2.42 (s, 3H, C5-CH3), 2.27-2.19 (m,
1H, H2′), 1.95 (d, J H6 ) 1.0 Hz, 3H, Ar-CH3), 0.96 (s, 9H,
C(CH3)3), 0.17 (s, 6H, Si-CH3); 13C NMR (75 MHz,CDCl3) δ
166.3 (C(O)-Ar), 163.6 (C4), 150.4 (C2), 144.4 (C(O)-Ar), 135.1
(C6), 129.8, 129.3 (Ar), 126.6 (Ar-CH3), 111.3 (C5), 85.7 (C4′),
84.9 (C1′), 75.8 (C3′), 63.7 (C5′), 38.2 (C2′), 25.9 (C(CH3)3), 21.7
(Ar-CH3), 18.4 (C(CH3)3), 12.5 (C5-CH3), -5.3, -5.4 (Si-CH3).
Anal. Calcd for C24H34N2O6Si‚H2O: C, 58.51; H, 7.37; N, 5.69.
Found: C, 58.38; H, 6.72; N, 5.78.
Meth od C. Gen er a l Con d ition s for Detolu oyla tion . 3′-
O-(ter t-Bu tyld im eth ylsilyl)th ym id in e (1n ).20 3′-O-(tert-
Butyldimethylsilyl)-5′-O-(p-toluoyl)thymidine (1l) (0.062 g, 0.13
mmol) was introduced into a dried flask under N2. NH3-
saturated CH3OH (10 mL) was added. Additional NH3(g) was
bubbled through the solution for 5 min, and the reaction was
left to stir for 24 h. It was evaporated under reduced pressure
to an oil that was purified by flash chromatography (EtOAc)
to yield a white solid (0.044 g, 95%): TLC Rf 0.72 (EtOAc);
mp 90 °C (lit. mp 83-84 °C);20 FABMS (glycerol) 357.2 (M +
H)+; 1H NMR (200 MHz, CDCl3) δ 8.88 (br, 1H, H3′), 7.37 (app
d, J Me )1.1 Hz, 1H, H6′), 6.14 (t, J ) 6.7, 1H, H1′), 4.49 (m,
1H, H3′), 3.96-3.89 (m, 2H, H4′ and H5′), 3.76 (m, 1H, H5′),
2.72 (br, OH), 2.43-2.15 (m, 2H, H2′), 1.91 (d, J H6 ) 0.9 Hz,
3H, C5-CH3), 0.89 (s, 9H, C(CH3)3), 0.09 (s, 6H, Si-CH3); 13C
NMR (62.9 MHz, CDCl3) δ 163.7 (C4), 150.3 (C2), 137.0 (C6),
111.0 (C5), 87.6 (C4′), 86.9 (C1′), 71.6 (C3′), 62.0 (C5′), 40.5
(C2′) 25.7 (C(CH3)3), 17.9 (C(CH3)3), 12.5 (C5-CH3), -4.7, -4.9
(Si-CH3).
proved access to differentially protected five-member
glycals should greatly increase their potential as inter-
mediates in organic synthesis, especially for preparation
of aryl- and heteroaryl-2-deoxy-C-furanosides.8
Exp er im en ta l Section
General methods of synthesis, purification, and character-
ization have been described previously.18 The protected thy-
midine derivatives 1a -o were prepared according to Scheme
2 and methods A, B, and C below. Glycal formation from
thymidines 1 was accomplished using method D with varia-
tions detailed for each specific compound.
Meth od A. Gen er a l Con d ition s for Silyla tion . 5′-O-
(ter t-Bu tyld im eth yl)-3′-O-(ter t-bu tyld ip h en ylsilyl)th ym i-
d in e (1h ).19 5′-O-(tert-Butyldimethylsilyl)thymidine (1b) (3.37
g, 9.46 mmol) was introduced to a dried flask under Ar. DMF
(40 mL) was added, and the solution was stirred until 1b
dissolved. Imidazole (2.07 g, 30.40 mmol) was added followed
by TBDPSCl (3.17 g, 11.54 mmol). The solution was stirred
for 24 h. It was poured into water (500 mL) and extracted with
ether (3 × 250 mL). The ether layer was then washed with
aqueous NaHCO3 (200 mL) followed by distilled water (200
mL). It was dried with Na2SO4 and evaporated under reduced
pressure to give a clear oil. This was purified by flash
chromatography (hexanes and then ether) to yield a white solid
(5.5 g, 98%): TLC Rf 0.91 (9:1 CHCl3-CH3OH); mp 56 °C;
FABMS (MNBA) 596.5 (M + H)+; 1H NMR (250 MHz, CDCl3)
δ 9.62 (s, 1H, H3), 7.67-7.63 (m, 4H, Ar and H6), 7.47-7.37
(m, 7H, Ar), 6.53 (dd, J H2′ ) 5.5, J H2′ ) 8.9 Hz, 1H, H1′), 4.34
(d, J ) 5.2 Hz, 1H, H3′), 4.00 (s, 1H, H4′), 3.63 (dd, J H4′ ) 1.3,
J H5′ ) 11.0 Hz, 1H, H5′), 3.14 (dd, J H4′ ) 1.8, J H5′ ) 10.9 Hz,
1H, H5′), 2.34 (dd, J ) 5.3, 13.0 Hz, 1H, H2′), 1.87 (s, 3H, C5-
CH3) 1.85-1.82 (m, 1H, H2′), 1.09 (s, 9H, C(CH3)3), 0.78 (s,
9H, C(CH3)3), -0.07 (s, 3H, Si-CH3), -0.11 (s, 3H, Si-CH3);
13C NMR (62.9 MHz, CDCl3) δ 164.0 (C4), 150.5 (C2), 135.6
(C6), 135.4, 133.3, 133.0, 129.9, 127.8 (Ar), 110.7 (C5), 88.0
(C4′), 85.0 (C1′), 74.2 (C3′), 63.1 (C5′), 41.3 (C2′), 26.8 (C(CH3)3),
25.7 (C(CH3)3), 18.9 (C(CH3)3), 18.1 (C(CH3)3), 12.3 (CH3), -5.6
(Si-CH3), -5.8 (Si-CH3).
Meth od D. Gen er a l Con d ition s for Glyca l F or m a -
tion .21 1,4-An h yd r o-3,5-bis-O-(ter t-bu tyld ip h en ylsilyl)-2-
d eoxy-D-er yth r o-p en t -1-en it ol (2f).14
3′,5′-Bis-O-(tert-
butyldiphenylsilyl)thymidine (1f) (0.99 g, 1.38 mmol) was
introduced to a dried flask under Ar. HMDS (10.0 mL, 47.3
mmol) was added, and the solution was stirred until dissolved.
After the addition of the (NH4)2SO4 (0.29 g, 2.19 mmol), the
solution was refluxed for 4 h. The HMDS was evaporated
under reduced pressure and the residue was partitioned
between water and cyclohexane. The organic layer was
washed with aqueous NaHCO3 and then distilled water. It
was dried with Na2SO4 and evaporated under reduced pressure
to give a yellow oil that was purified by alumina flash
chromatography (1:2 ether-hexanes) (0.648 g, 79%): TLC Rf
0.65 (1:2 ether-hexanes); FABMS (MNBA) 591.3 (M - H)+;
1H NMR (200 MHz, CDCl3) δ 7.79-7.62 (m, 9H, Ar), 7.48-
7.36 (m, 11H, Ar), 6.51 (d, J H2 ) 2.3 Hz, 1H, H1), 4.99 (t, J )
2.0 Hz, 1H, H2), 4.92 (m, 1H, H3), 4.59-4.53 (m, 1H, H4),
3.49-3.45 (m, 2H, H5), 1.12, 1.03 (2s, 18H, C(CH3)3); 13C NMR
(50 MHz, CDCl3) δ 149.3 (C1), 135.8, 135.6, 135.0, 134.9, 134.2,
134.0, 129.7, 129.3, 127.7, 127.5 (Ar), 103.4 (C2), 89.2 (C3),
77.0 (C4), 63.8 (C5), 26.9, 26.8 (C(CH3)3), 19.2, 19.1 (C(CH3)3).
(18) (a) Fernandez, M. d. F.; Vlaar, C. P.; Fan, H.; Hammer, R. P.
J . Org. Chem. 1995, 60, 7390-7391. (b) Flanagan, J . H., J r.; Khan, S.
H.; Menchen, S.; Soper, S. A.; Hammer, R. P. Bioconjugate Chem. 1997,
8, 751-756.
(19) Perbost, M.; Hoshiko, T.; Morvan, F.; Swayze, E.; Griffey, R.
H.; Sanghvi, Y. S. J . Org. Chem. 1995, 60, 5150-5156.
(20) Ogilvie, K. K. Can. J . Chem. 1973, 51, 3799-3807.
(21) Reaction times vary with starting glycal and with the scale;
larger scales require longer times. Molar amount of (NH4)2SO4 does
not appear to be critical to success of the reaction, though more than
1 equiv is preferred to get reasonable reaction rates.

9068 J . Org. Chem., Vol. 62, No. 26, 1997
Cameron et al.
1,4-An h yd r o-2-d eoxy-D-er yth r o-p en t-1-en itol (2a )15 was
prepared according to method D from 1a (96 mg, 0.40 mmol)
and (NH4)2SO4 (0.157 g, 1.19 mmol) in 5 mL of HMDS. No
extraction was performed, and the product was isolated by
alumina flash chromatography (1:2 ether-hexanes) to yield a
yellow oil (0.0367 g, 80%): TLC Rf 0.24 (1:2 ether-hexanes);
CIMS (isobutane) 117.1 (M + H)+; 1H NMR (250 MHz, CDCl3)
δ 6.49 (d, J H2 ) 2.3 Hz, 1H, H1), 5.02 (t, J ) 2.4 Hz, 1H, H2),
4.81 (m, 1H, H3), 4.31 (dt, J ) 2.5, 6.5 Hz, 1H, H4), 3.65 (dd,
J ) 5.9, 10.7 Hz, 1H, H5), 3.43 (dd, J ) 6.8, 10.7 Hz, 1H, H5);
13C NMR (50 MHz, CD3OD) δ 150.6 (C1), 104.3 (C2), 90.6 (C3),
76.1 (C4), 63.3 (C5).
1,4-An h yd r o-5-O-(ter t-b u t yld im et h ylsilyl)-2-d eoxy-D-
er yth r o-pen t-1-en itol (2b)12 was prepared according to method
D from 1b (0.502 g, 1.41 mmol), HMDS (7 mL, 33.2 mmol),
and (NH4)2SO4 (0.196 g, 1.48 mmol). The product was purified
by alumina flash chromatography (1:2 ether-hexanes) to yield
a yellow oil (0.24 g, 74%): TLC Rf 0.98 (9:1 CH2Cl2-EtOAc);
CIMS (NH3) 230.2 (M + H)+, 247.2 (M + NH4)+; 1H NMR (250
MHz, CDCl3) δ 6.53 (d, J H2 ) 2.4 Hz, 1H, H1), 5.14 (t, J ) 2.9
Hz, 1H, H2), 4.78 (br, 1H, H3), 4.33 (dt, J H5 ) 5.8, J H3 ) 2.9
Hz, 1H, H4), 3.71 (dd, J H5 ) 10.7, J H4 ) 5.8 Hz, 1H, H5), 3.51
(m, 1H, H5), 1.60 (br, 1H, OH), 0.89 (s, 9H, C)CH3)3), 0.07,
0.06 (2s, 6H, Si-CH3); 13C NMR (62.9 MHz, CDCl3) δ 150.1
(C1), 103.1 (C2), 89.3 (C3), 75.7 (C4), 62.9 (C5), 25.8 (C(CH3)3),
18.3 (C(CH3)3), -5.4 (Si-CH3).
purified by alumina flash chromatography (1:1 ether-hexanes)
to yield a yellow oil (1.12 g, 79%): TLC Rf 0.72 (1:2 ether-
hexanes); CIMS (NH3) 469.3 (M + H)+, 486.3 (M + NH4)+; 1H
NMR (200 MHz, CDCl3) δ 7.57-7.49 (m, 4H, Ar), 7.23-7.19
(m, 6H, Ar), 6.30 (br, 1H, H1), 4.86 (m, 2H, H2 and H3), 4.23
(br, 1H, H4), 3.61 (dd, J H4 ) 5.2, J H5 ) 10.9 Hz, 1H, H5), 3.51
(dd, J H4 ) 5.2, J H5 ) 10.9 Hz, 1H, H5), 0.94, 0.76 (2s, 18H,
C(CH3)3), -0.07 (s, 6H, Si-CH3); 13C NMR (50 MHz, CDCl3) δ
149.2 (C1), 135.6, 135.0, 133.3, 129.8, 127.8, 127.5 (Ar), 103.5
(C2), 89.0 (C3), 76.1 (C4), 63.7 (C5), 26.9, 26.0 (C(CH3)3), 19.3,
18.1 (C(CH3)3), -4.1 (Si-CH3), -4.3 (Si-CH3).
1,4-An h yd r o-3-O-(ter t-bu tyld im eth ylsilyl)-5-O-(ter t-bu -
tyld ip h en ylsilyl)-2-d eoxy-D-er yth r o-p en t-1-en itol (2j) was
prepared according to method D from 1j (0.72 g, 1.21 mmol)
and (NH4)2SO4 (0.60 g, 4.54 mmol). The product was purified
by alumina flash chromatography to yield a yellow oil (0.337
g, 59%): TLC Rf 0.79 (1:2 EtOAc-hexanes); HR-FABMS
1
(MNBA) theoretical (M - H)+ 467.2438, found 467.2430; H
NMR (250 MHz, CDCl3) δ 7.72-7.66 (m, 4H, Ar), 7.46-7.37
(m, 6H, Ar), 6.52 (d, J H2 ) 2.6 Hz, 1H, H1), 5.06 (m, 1H, H2),
4.99 (m, 1H, H3), 4.38 (dt, J H3 ) 3.1, J H5 ) 5.1 Hz, 1H, H4),
3.74 (dd, J H4 ) 5.5, J H5 ) 10.9 Hz, 1H, H5), 3.67 (dd, J H4
)
5.2, J H5 ) 10.8 Hz, 1H, H5), 1.09, 0.91 (2s, 18H, C(CH3)3), 0.01
(s, 6H, Si-CH3); 13C NMR (50 MHz, CDCl3) δ 149.1 (C1), 135.6,
129.66, 127.65 (Ar), 103.5 (C2), 89.0 (C3), 76.0 (C4), 63.7 (C5),
25.8, 25.7 (C(CH3)3), 19.2 (C(CH3)3), -4.2, -4.4 (Si-CH3). Anal.
Calcd for C27H40O3Si2: C, 69.18; H, 8.60. Found: C 68.91; H,
8.77.
1,4-An h yd r o-5-O-(ter t-b u t yld ip h en ylsilyl)-2-d eoxy-D-
er yth r o-pen t-1-en itol (2c)14 was prepared according to method
D from 1c (0.302 g, 0.63 mmol), HMDS (1 mL, 4.74 mmol),
and (NH4)2SO4 (0.350 g, 2.65 mmol). The product was purified
by alumina flash chromatography (1:2 ether-hexanes) to yield
a yellow oil (0.204 g, 91%): TLC Rf 0.79 (1:2 ether-hexanes);
1H NMR (250 MHz, CDCl3) δ 7.77-7.74 (m, 4H, Ar), 7.51-
7.40 (m, 7H, Ar), 6.56 (d, J H2 ) 2.6 Hz, 1H, H1), 5.10 (t, J )
1,4-An h yd r o-3-O-(ter t-bu tyld im eth ylsilyl)-5-O-(p-tolu -
oyl)-2-d eoxy-D-er yth r o-p en t-1-en itol (2l) was prepared ac-
cording to method D from 1l (0.114 g, 0.24 mmol) and
(NH4)2SO4 (0.210 g, 1.59 mmol). A yellow oil (0.062 g, 74%)
was obtained after purification by alumina flash chroma-
tography: TLC Rf 0.87 (1:2 EtOAc-hexanes); HR-FABMS
2.8 Hz, 1H, H2), 5.04 (m, 1H, H3), 4.45 (dt, J H3 ) 2.4, J H5
)
1
(MNBA) theoretical (M + H)+ 349.1835, found 349.1830; H
5.2 Hz, 1H, H4), 3.80 (dd, J H4 ) 5.0, J H5 ) 10.8 Hz, 1H, H5),
3.70 (dd, J H4 ) 5.8, J H5 ) 10.7 Hz, 1H, H5), 1.11 (s, 9H, C-
(CH3)3); 13C NMR (62.9 MHz, CDCl3) δ 149.4 (C1), 135.6, 134.0,
133.3, 129.7, 127.7 (Ar), 103.3 (C2), 88.8 (C3), 75.7 (C4), 63.7
(C5), 26.8 (C(CH3)3), 19.3 (C(CH3)3).
NMR (250 MHz, CDCl3) δ 7.97, (d, J Ar ) 8.1 Hz, 2H, Ar), 7.28
(d, J Ar ) 9.6 Hz, 2H, Ar), 6.58 (d, J H2 ) 2.6 Hz, 1H, H1), 5.25
(t, J ) 2.5 Hz, 1H, H2), 5.05 (m, 1H, H3), 4.74 (dt, J ) 2.9, 5.9
Hz, 1H, H4), 4.48 (d, J H4 ) 5.9 Hz, 2H, H5), 2.44 (s, 3H, Ar-
CH3), 0.92 (s, 9H, C(CH3)3), 0.08 (s, 6H, Si-CH3); 13C NMR (50
MHz CDCl3) δ 166.4 (C(O)-Ar), 149.1 (C1), 143.8 (C(O)-Ar),
129.7, 129.0 (Ar), 127.0 (Ar-CH3), 103.6 (C2), 86.3 (C3), 76.4
(C4), 64.1 (C5), 25.8 (C(CH3)3), 21.6 (tol-CH3), 18.0 (C(CH3)3),
-4.3, -4.5 (Si-CH3). Anal. Calcd for C19H28O4Si: C, 65.48;
H, 8.10. Found: C, 65.63; H, 8.23.
1,4-An h yd r o-5-O-(p-tolu oyl)-2-d eoxy-D-er yth r o-p en t-1-
en itol (2d ) was prepared according to method D from 1d
(0.0369 g, 0.102 mmol), HMDS (1 mL, 4.74 mmol), and (NH4)2-
SO4 (0.3 g, 2.3 mmol). The product was purified by alumina
flash chromatography (1:2 ether-hexanes) to yield a clear oil
(0.012 g, 52%): TLC Rf 0.67 (1:2 ether-hexanes); HR-FABMS
1,4-An h yd r o-2-d eoxy-3′-O-(ter t-bu tyld ip h en ylsilyl)-5′-
O-(p-tolu oyl)-D-er yth r o-p en t-1-en itol (2m ) was prepared
according to method D from 1m (1.26 g, 2.10 mmol) and (NH4)2-
SO4 (0.708 g, 5.36 mmol). A yellow oil (0.93 g, 94%) was
obtained after purification by alumina flash chromatography
(EtOAc): TLC Rf 0.88 (1:2 EtOAc-hexanes); HR-FABMS
1
(MNBA) theoretical (M + H)+ 235.0970, found 234.0948; H
NMR (250 MHz, CDCl3) δ 7.96, (d, J Ar ) 8.5 Hz, 2H, Ar), 7.20
(d, J Ar ) 8.2 Hz, 2H, Ar), 6.49 (d, J H2 ) 2.0 Hz, 1H, H1), 4.95
(t, J ) 2.7 Hz, 1H, H2), 4.87 (m, 1H, H3), 4.70 (m, 1H, H4),
3.99 (m, 2H, H5), 2.41 (s, 3H, Ar-CH3); 13C NMR (50 MHz
CDCl3) δ 165.9 (C(O)-Ar), 149.1 (C1), 143.3 (C(O)-Ar), 129.4,
128.7 (Ar), 127.4 (Ar-CH3), 103.1 (C2), 86.0 (C3), 76.8 (C4),
63.7 (C5), 21.3 (tol-CH3). Anal. Calcd for C13H14O4: C, 66.66;
H, 6.02. Found: C, 66.58, H, 6.05.
1
(MNBA) theoretical (M + H)+ 473.2148, found: 473.2148; H
NMR (200 MHz, CDCl3) δ 7.83 (d, J Ar ) 7.9 Hz, 2H, Ar), 7.68-
7.65 (m, 4H, Ar), 7.41-7.34 (m, 6H, Ar), (7.20 (d, J Ar ) 7.9,
2H, Ar), 6.46 (d, J H2 ) 2.9 Hz, 1H, H1), 4.93 (t, J ) 2.6 Hz,
1H, H2), 4.85 (br, 1H, H3), 4.68 (br, 1H, H4), 3.99-3.94 (m,
2H, H5), 2.40 (s, 3H, Ar-CH3), 1.05 (s, 9H, C(CH3)3); 13C NMR
(50 MHz, CDCl3) δ 165.3 (C(O)-Ar), 149.1 (C1), 143.7 (C(O)-
Ar), 135.7, 134.9, 129.9, 129.8, 129.3, 129.0, 127.8, 127.7 (Ar),
127.0 (Ar-CH3), 103.5 (C2), 86.4 (C3) 77.2 (C4), 64.1 (C5), 26.9
(C(CH3)3), 19.0 (C(CH3)3). Anal. Calcd for C29H32O4Si: C,
73.70; H, 6.83. Found: C, 73.82, H, 6.63.
1,4-An h ydr o-3,5-bis-O-(ter t-bu tyldim eth ylsilyl)-2-deoxy-
D-er yth r o-p en t-1-en itol (2e)14 was prepared according to
method D from 1e (1.055 g, 2.24 mmol) and (NH4)2SO4 (0.61
g, 4.62 mmol) in 10 mL of HMDS and yielded a yellow oil
(0.534 g, 69%) after purification by alumina flash chromatog-
raphy (1:2 ether-hexanes): TLC Rf 0.86 (1:2 CH2Cl2-EtOAc);
1H NMR (300 MHz, CDCl3) δ 6.45 (d, J H2 ) 2.6 Hz, 1H, H1),
5.00 (t, J ) 2.50 Hz, 1H, H2), 4.87 (br, 1H, H3), 4.28 (dt, J H3
) 2.7, J H5 ) 5.9 Hz, 1H, H4), 3.69 (dd, J H4 ) 5.6, J H5 ) 10.6
Hz, 1H, H5), 3.50 (dd, J H4 ) 6.4, J H5 ) 10.6 Hz, 1H, H5), 0.90,
0.89 (2s, 18H, C(CH3)3), 0.08, 0.06 (2s, 12H, Si-CH3); 13C NMR
(75 MHz, CDCl3) δ 149.2 (C1), 103.6 (C2), 89.1 (C3), 76.2 (C4),
63.0 (C5), 26.1, 25.9 (C(CH3)3), 18.6, 18.3 (C(CH3)3), -4.1 (Si-
CH3), -4.2 (Si-CH3), -5.1 (Si-CH3).
1,4-An h yd r o-3-O-(ter t-b u t yld im et h ylsilyl)-2-d eoxy-D-
er yth r o-p en t-1-en itol (2n )23 was repared according to method
D from 1n (0.1607 g, 0.45 mmol) and (NH4)2SO4 (0.304 g, 2.30
mmol). Alumina flash chromatography yielded a yellow oil
(0.0375 g, 36%): TLC Rf 0.76 (1:2 EtOAc-hexanes); 1H NMR
(200 MHz, CDCl3) δ 6.47 (dd, J H2 ) 2.5 Hz, 1H, H1), 5.01 (t, J
) 2.5 Hz, 1H, H2), 4.81 (t, J ) 2.3, 1H, H3), 4.30 (dt, J ) 2.7,
9.1 Hz, 1H, H4), 3.65 (dd, J H4 ) 6.3, J H5 ) 10.7 Hz, 1H, H5),
3.44 (dd, J H4 ) 6.6, J H5 ) 10.7 Hz, 1H, H5), 0.89 (s, 9H,
C(CH3)3), 0.13 (s, 6H, Si-CH3); 13C NMR (50 MHz, CDCl3) δ
1,4-An h yd r o-5-O-(ter t-bu tyld im eth ylsilyl)-3-O-(ter t-bu -
tyld ip h en ylsilyl)-2-d eoxy-D-er yth r o-p en t-1-en itol (2h )22
was prepared according to method D from 1h (1.80 g, 3.03
mmol) and (NH4)2SO4 (0.55 g, 4.16 mmol). The product was
(22) Farr, R. N.; Daves, G. D. J . Carbohydr. Chem. 1990, 9, 653-
660.
(23) Gold, B. I. PCT Int. Appl. WO9623777 Aug 8, 1996; Chem.
Abstr. 1996, 125, 248328.

Protected Furanoid Glycals from Thymidine
J . Org. Chem., Vol. 62, No. 26, 1997 9069
148.9 (C1), 103.4 (C2), 88.8 (C3), 76.1 (C4), 62.2 (C5), 25.9
(C(CH3)3), 18.1 (C(CH3)3), -4.3 (Si-CH3).
Health (CA65930) for support of this research. We are
also grateful to the Louisiana Educational Quality
Support Fund (LEQSF) for a Board of Regents Fellow-
ship to M.A.C. Grants to LSU from the NSF REU
program (CHE-9424021) and the Howard Hughes Medi-
cal Institute (HHMI 71195-520302) provided stipends
to S.B.C. We give special thanks to Dr. Tracy McCarley
at Louisiana State University and Dr. Edward Larka
at the University of Minnesota for expert assistance
with mass spectrometric measurements.
1,4-An h yd r o-3-O-(ter t-b u t yld ip h en ylsilyl)-2-d eoxy-D-
er yth r o-p en t-1-en itol (2o)14,22 was prepared according to
method D from 1o (0.180 g, 0.37 mmol) and (NH4)2SO4 (0.245
g, 1.86 mmol). The product was purified using alumina flash
chromatography to yield a yellow oil (0.105 g, 79%): TLC Rf
0.90 (1:2 EtOAc-hexanes); 1H NMR (250 MHz, CDCl3) δ 7.76-
7.66 (m, 4H, Ar), 7.46-7.38 (m, 6H, Ar), 6.45 (d, J H2 ) 2.5 Hz,
1H, H1), 4.87 (t, J ) 2.7 Hz, 1H, H2), 4.78 (t, J ) 2.5, 1H,
H3), 4.53-4.47 (m, 1H, H4), 3.41 (dd, J H4 ) 7.0, J H5 ) 10.8
Hz, 1H, H5), 3.26 (dd, J H4 ) 5.1, J H5 ) 10.8 Hz, 1H, H5), 1.10
(s, 9H, C(CH3)3); 13C NMR (50 MHz, CDCl3) δ 149.0 (C1), 135.8,
135.2, 134.2, 129.6, 127.7 (Ar), 103.3 (C2), 89.1 (C3), 76.4 (C4),
62.4 (C5), 26.6 (C(CH3)3), 19.0 (C(CH3)3).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and 1H and 13C NMR spectra of compounds 1b -g,
1j-m , and 1o (5 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.
Ack n ow led gm en t. We thank the Petroleum Re-
search Fund of the American Chemical Society and the
National Cancer Institute of the National Institutes of
J O970947S