A facile, multigram synthesis of ribofuranoid glycals

Full text of DOI:10.1021/jo951376b

J . Org. Chem. 1996, 61, 2219-2221
2219
Sch em e 1
A F a cile, Mu ltigr a m Syn th esis of
Ribofu r a n oid Glyca ls
J ohn A. Walker, II, J iong J . Chen, Dean S. Wise, and
Leroy B. Townsend*
Department of Medicinal Chemistry, College of Pharmacy,
and Department of Chemistry, College of Literature, Arts,
and Sciences, University of Michigan,
Ann Arbor, Michigan 48109
Received J uly 27, 1995
In tr od u ction
elimination process in a basic environment to give the
desired glycal. We now report a procedure developed in
our laboratories that is suitable for a multigram synthesis
of bis-silylated ribofuranoid glycals from 2-deoxy-D-ribose.
Our research group has been interested in the synthe-
sis of nucleoside analogs for a number of years. Recently,
we have taken an interest in the preparation of various
2′-deoxy-C-nucleoside analogs.1 The synthetic approaches
to these compounds can be grouped into four categories.
These categories are (1) total synthesis from noncarbo-
hydrate and nonheterocyclic precursors, (2) chemical
interconversion of preformed C-nucleosides, (3) introduc-
tion of a functional group at the anomeric position of a
carbohydrate followed by a construction of the heterocy-
clic moiety, and (4) condensation of sugar derivatives with
preformed heterocycles.1a Employing the fourth meth-
odology, Daves and co-workers have developed the use
of palladium-catalyzed cross-coupling reactions using
iodoheterocycles and ribofuranoid glycals (2,3-dihydro-
furans) to afford 2′-deoxy-C-nucleosides in a direct, two-
step procedure.2,3
We envisaged this route as being synthetically compat-
ible for our specific purposes and initiated research using
this approach. In the course of our research, we devel-
oped a need for multigram quantities of various silylated
glycals. Although the Ireland procedure,4 used by Daves5a
and Chmielewski,5b is an elegant method to provide
ribofuranoid glycals, the scale-up of the reaction is limited
due to a lithium/liquid ammonia-promoted fragmenta-
tion.4 This prompted us to initiate studies designed to
provide a route for the synthesis of ribofuranoid glycals
from readily available starting materials that could easily
be scaled-up to multigram quantities.
Resu lts a n d Discu ssion s
Protection of 2-deoxy-D-ribono-1,4-lactone (1, synthe-
sized in 90-95% yields via bromine oxidation of 2-deoxy-
D-ribose7 ) at the 3- and 5-positions with the appropriate
silyl chloride in dimethylformamide in the presence of
imidazole gave the 3,5-bis-O-silylated products 2a -c.
These compounds, after simple aqueous extractions, were
very pure based on TLC and NMR analysis and were
used without further purification. Also, while 2a and 2b
were isolated as syrups, 2c is a solid and thus easier to
handle. Reduction of the lactones 2a -c using diisobu-
tylaluminum hydride at -78 °C gave the requisite
2-deoxy-D-erythro-pentofuranose derivatives 3a -c as 1:1
mixtures of anomers. Again, these compounds were
sufficiently pure, after 0.5 M disodium tartrate washes,
to be used in the subsequent step.
At this point, the syrupy compounds 3a -c were
dissolved in dry dichloromethane and cooled to -50 °C.
To this solution was added 4 equiv of triethylamine
followed by methanesulfonyl chloride. The temperature
of the reaction was maintained at -40 to -50 °C until
TLC showed a complete consumption of 3a -c (and
presumed formation of the intermediate mesylate). The
reactions were then warmed to reflux, and the elimina-
tion was allowed to occur at reflux temperature over a
period of 15-18 h. After column chromatography, the
title compounds 4a -c were isolated in 53-86% yields
on a multigram scale. We have found that chromatog-
raphy of these compounds on silica gel using ethyl
acetate/hexane as the eluent leads to the formation of
the aromatic furans. However, a solvent system of
diethyl ether/petroleum ether5a,8 does not lead to aroma-
tization. Finally, compound 4a was selectively desily-
lated at the 5-position using tetrabutylammonium fluo-
ride to give 5a . This compound was spectrometrically
identical to the compound as synthesized by Farr and
Daves.8
It is known that, under basic conditions, sulfonate
esters undergo elimination reactions via an E2 process
involving â-hydrogen extraction to give the unrearranged,
unsaturated product.6 As shown in Scheme 1, we pre-
dicted that an appropriately 3,5-bisprotected-2-deoxy-D-
ribofuranose could be mesylated and then undergo the
(1) For a review of the chemistry and biology of C-glycosides, see:
(a) Watanabe, K. A. In Chemistry of Nucleosides and Nucleotides 3;
Townsend. L. B., Ed.; Plenum Press: New York, 1994; Chapter 5. (b)
Hacksell, U.; Daves, G. D., J r. Prog. Med. Chem. 1985, 22, 1-65. (c)
Buchanan, J . G. Prog. Chem. Org. Nat. Prod. 1983, 44, 243-299. (d)
Goodchild, J . Top. Antibiot. Chem. 1982, 6, 99-227.
(2) Daves, G. D., J r. Acc. Chem. Res. 1990, 23, 201-206.
(3) Daves, G. D., J r. In Carbohydrates: Synthetic Methods and
Applications in Medicinal Chemistry; Ogura, H., Hasegawa, A., Suami,
T., Eds.; Kodansha: Tokyo; VCH Verlagsgesellschaft: Weinheim; VCH
Publishers: New York, 1992; Chapter 3.
We have found that 4c is the easiest compound to work
with due to its surprising stability. Whereas 4b decom-
poses to the furan, as determined by 1H NMR, in 24 h at
(4) Ireland, R. E.; Thaisrivongs, S.; Vanier, N.; Wilcox, C. S. J . Org.
Chem. 1980, 45, 48-61.
(5) (a) Cheng, J . C.-Y.; Hacksell, U.; Daves, G. D. J r. J . Org. Chem.
1985, 50, 2778-2780. (b) Abramski, W.; Chmielewski, M. J . Carbohydr.
Chem. 1994, 13, 125-128.
(7) Deriaz, R. E.; Overend, W. G.; Stacey, M; Teece, E. G.; Wiggins,
L. F. J . Chem. Soc. 1949, 1879-1883.
(8) Farr, R. N.; Daves, G. D. J r. J . Carbohydr. Chem. 1990, 9, 653-
660.
(6) Hamrick, P. J ., J r.; Hauser, C. R. J . Org. Chem. 1961, 26, 4199-
4203.
0022-3263/96/1961-2219$12.00/0 © 1996 American Chemical Society

2220 J . Org. Chem., Vol. 61, No. 6, 1996
Notes
luminum hydride (1.5 M solution in toluene, 22.5 mL, 33.8 mmol)
was added dropwise over the course of 10 min. The reaction
was stirred at -78 °C for 5 h, and then methanol (20 mL) was
added to quench the reaction. The solution was warmed to 0
°C and poured into 1000 mL of diethyl ether. At room temper-
ature, the ethereal solution was washed with a 0.5 M disodium
tartrate solution (2 × 500 mL) and water (500 mL), dried over
magnesium sulfate, and evaporated in vacuo to give 3a as a
clear, colorless syrup which was not purified any further: 1H
NMR (300 MHz, DMSO-d6) δ 6.26 and 6.20 (d, 1, J ) 5.4 Hz,
1-OH R and â).
A flame-dried, evacuated 200 mL round-bottom flask equipped
with a reflux condenser was charged with a portion of 3a (4.19
g, 6.85 mmol), as obtained above, under argon. Dry dichlo-
romethane (50 mL) was added, and the resulting solution was
cooled to -50 °C. To this solution was added triethylamine (3.62
mL, 26 mmol) followed by methanesulfonyl chloride (0.66 mL,
8.56 mmol). Stirring was continued, maintaining the temper-
ature between -40 °C and -50 °C, for 2.5 h. At this time, 3a
had been entirely consumed as determined by tlc (5% diethyl
ether/petroleum ether). The reaction was warmed to room
temperature and then heated at reflux temperature for 15 h.
The reaction was then cooled to room temperature and filtered
through a short silica gel bed (90 × 100 mm). The filtrate was
evaporated to afford a clear oil that was subjected to silica gel
chromatography (40 × 150 mm, 5% diethyl ether/petroleum
ether, Rf ) 0.79) to give, after solvent evaporation, 3.54 g (86%
from 1) of 4a as a clear, colorless syrup: [R]22D +119.5° (c 0.255,
CH2Cl2) 1H NMR (360 MHz, CDCl3) δ 7.60 (m, 10), 7.34 (m, 10),
6.41 (dd, 1, J ) 0.8 Hz, 2.7 Hz), 4.90 (ddt, 1, J ) 0.9 Hz, 2.7 Hz,
2.7 Hz), 4.82 (dd, 1, J ) 2.6 Hz, 2.6 Hz), 4.46 (m, 1), 3.38 (m, 2),
1.04 (s, 9), 0.94 (s, 9). 13C NMR (90 MHz, CDCl3) δ 149.5, 136.0,
134.2, 133.5, 129.8, 127.8, 103.6, 89.4, 77.0, 64.0, 26.9, 19.4, 19.3.
HRMS calcd for C37H44Si2O3H: 593.2907. Found 593.2851.
room temperature and 4a was stable under similar
conditions for less than two days, 4c was found to be
stable for at least one week.9 We have also found that,10
as reported,3 these bis-protected glycals still retain regio-
and stereospecificity in the palladium-catalyzed cross-
couplings.
In conclusion, we have developed a preparation of bis-
protected ribofuranoid glycals that is not only high
yielding(53-86%), but also very amenable to multigram
scale-up. The glycals prepared in our laboratory have
been successfully utilized for the synthesis of a novel class
of 2′-deoxy-â-D-ribofuranos-1′-yl pyrazine C-nucleosides
in high yields.10
Exp er im en ta l Section
Unless otherwise noted, materials were obtained from com-
mercial suppliers and were used as provided. Dimethylforma-
mide (calcium oxide), dichloromethane (phosphorus pentoxide),
and tetrahydrofuran (sodium/benzophenone) were distilled from
the indicated drying agent and stored over activated 4 Å
molecular sieves under a positive pressure of argon prior to use.
2-Deoxy-D-ribono-1,4-lactone was synthesized via the method of
Deriaz et al.7 The phrase “evaporated in vacuo” is meant to
imply the use of a rotary evaporator with a bath temperature
not exceeding 40 °C using a water aspirator. Thin-layer chro-
matography (TLC) was accomplished on Analtech 60F-254 silica
gel plates, and the detection of components on TLC was made
via a methanolic sulfuric acid spray followed by heat. Solvent
systems are expressed as a percentage of the more polar
component with respect to total volume (v/v%). Mallinckrodt
SilicAR 230-400 mesh (40-63 µm) was used for chromatogra-
phy, which was carried out by using the flash technique.11
Melting points are uncorrected. Mass spectroscopy and elemen-
tal analyses were performed by the University of Michigan
Chemistry Department. The presence of solvent as indicated
by elemental analysis was verified by 1H NMR spectroscopy.
Note: The reactions described below are general for all of the
compounds in Scheme 1 and will be illustrated by the synthesis
of 4a .
1,4-An h yd r o-3,5-O-bis[(1,1-d im eth yleth yl)d ip h en ylsilyl]-
2-d eoxy-D-er yth r o-p en t-1-en itol (4a ). A flame-dried, evacu-
ated 1000 mL round-bottom flask equipped with a Claisen arm
and an addition funnel was charged with 17 (9.53 g, 72.1 mmol)
under argon. To this was added imidazole (24.54 g, 360 mmol),
and the mixture was dissolved in 100 mL of dry DMF. The
solution was cooled to 0 °C, and tert-butylchlorodiphenylsilane
(39.4 mL, 151.4 mmol) was added dropwise over the course of
45 min while maintaining the temperature at 0 °C. The reaction
was warmed to room temperature and then stirred under argon
for 18 h. At this time, the reaction was poured into 1500 mL of
ethyl acetate, and the precipitated imidazole hydrochloride was
removed by filtration through a bed of Celite/silica gel/sand (90
× 120 mm; equal parts). The filtration bed was washed
thoroughly with ethyl acetate. The ethyl acetate layer was
extracted with 0.5 N HCl (400 mL), water (2 × 500 mL), and
brine (150 mL), dried over magnesium sulfate, and filtered, and
the filtrate was evaporated in vacuo to give crude 2a as an off-
white syrup: 1H NMR (300 MHz; DMSO-d6) δ 7.34-7.70 (m,
20), 4.49 (m, 1), 4.46 (m, 1), 3.54 (dd, 1, J ) 2.9 Hz, 11.7 Hz),
3.26 (dd, 1, J ) 2.9 Hz, 11.7 Hz), 2.40-2.80 (m, 2).
Anal. Calcd for
Found: C, 73.95; H, 7.87.
C37H44Si2O3‚0.5 H2O: C, 73.91; H, 7.54.
1,4-An h yd r o-3,5-O-b is(t r iet h ylsilyl)-2-d eoxy-D-er yth r o-
p en t-1-en itol (4b): via 2b [clear syrup. 1H NMR (270 MHz,
CDCl3) δ 4.48 (d, 1, J ) 6.7 Hz), 4.32 (m, 1), 3.75 (m, 2), 2.80
(dd, 1, J ) 6.6 Hz, 17.6 Hz), 2.36 (d, 1, J ) 17.6 Hz), 0.91(m,
12), 0.53 (m, 15)].
Without purification, this was reduced to 3b which subse-
quently gave, as described above, 7.73 g (53% from 1) of 4b as
a clear syrup. Rf ) 0.67 in 5% diethyl ether/petroleum ether.
1H NMR (270 MHz; CDCl3) δ 6.49 (dd, 1, J ) 0.6 Hz, 2.6 Hz),
5.03 (t, 1, J ) 2.6 Hz), 4.83 (m, 1), 4.32 (ddt, 1, J ) 0.6 Hz, 2.5
Hz, 6.3 Hz), 3.69 (dd, 1, J ) 6.1 Hz, 10.5 Hz), 3.46 (dd, 1, J )
6.1 Hz, 10.5 Hz). 13C NMR (67.5 MHz; CDCl3) δ 149.1, 103.6,
89.4, 76.1, 62.9, 6.6, 5.3, 4.7.
1,4-An h yd r o-3,5-O-bis[(1,1-d im eth yleth yl)d im eth ylsilyl]-
2-d eoxy-D-er yth r o-p en t-1-en itol (4c): via 2c [white solid. Mp
72-74 °C. 1H NMR (360 MHz, CDCl3) δ 4.44 (m, 1), 4.28 (m,
1), 3.73 (m, 2), 2.76 (dd, 1, J ) 6.7 Hz, 17.6 Hz), 2.33 (dd, 1, J )
2.6 Hz, 17.6 Hz), 0.82(s, 18), 0.09 (s, 12). 13C NMR (90 MHz,
CDCl3) δ 176.8, 88.3, 69.8, 62.6, 39.2, 26.0, 25.8, 18.4, 18.1, -4.5,
-5.4].
Without purification, this was reduced to 3c which subse-
quently gave, as described above, 11.26 g (66% from 1) of 4c as
a clear syrup: Rf ) 0.91 in 5% diethyl ether/petroleum ether.
[R]22 +79.5° (c 0.247; CH2Cl2). 1H NMR (360 MHz, CDCl3) δ
D
6.47 (dd, 1, J ) 0.8 Hz, 2.6 Hz), 5.01 (t, 1, J ) 2.6 Hz), 4.87 (m,
1), 4.29 (m, 1), 3.69 (dd, 1, J ) 5.7 Hz, 10.7 Hz), 3.51 (dd, 1, J )
5.7 Hz, 10.7 Hz). 13C NMR (90 MHz, CDCl3) δ 149.2, 103.6, 89.1,
A flame-dried, evacuated 500 mL round-bottom flask equipped
with a Claisen arm and an addition funnel was charged with a
portion of 2a (13.73 g, 22.5 mmol), as obtained above, under
argon. Anhydrous diethyl ether (100 mL) was added and the
resulting solution cooled to -78 °C. At this time, diisobutyla-
76.2, 63.0, 26.1, 18.6, 18.3, -4.1, -5.1. HRMS calcd for C17H36
Si2O3H: 345.2275. Found 345.2281. Anal. Calcd for C17H36
-
-
Si2O3‚0.1CH2Cl2: C, 57.89; H, 10.29. Found: C, 58.11; H, 10.20.
1,4-An h yd r o-2-d eoxy-3-O-[(1,1-d im eth yleth yl)d ip h en yl-
silyl]-D-er yth r o-p en t-1-en itol (5a ). A 200 mL round-bottom
flask was charged with 4a (3.50 g, 5.9 mmol). Diethyl ether (80
mL) was added, and to the resulting solution was added a 1.0
M solution of tetrabutylammonium fluoride in tetrahydrofuran
(5.9 mmol). The reaction was continued at room temperature
until TLC showed the complete consumption of 4a (approxi-
mately 90 min). The reaction was quenched with 1,2-dichloro-
ethane, and the solvent was evaporated in vacuo. The resultant
(9) The decomposition of 4a -c were followed by observing the 1H
NMR spectra of samples in CDCl3 kept at room temperature. While
4a and 4b were fully decomposed after 48 h, 4c showed no decomposi-
tion even after 150 h.
(10) Chen, J . J .; Walker, J . A., II; Liu, W.; Wise, D. S.; Townsend,
L. B. Tetrahedron Lett. 1995, 36, 8363-8366.
(11) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

Notes
J . Org. Chem., Vol. 61, No. 6, 1996 2221
oil was subjected to silica gel chromatography (45 × 200 mm,
50% diethyl ether/petroleum ether) to give, after solvent evapo-
ration of the appropriate fractions, 502 mg of 5a (24%) as a clear
oil. The proton NMR was identical to the glycal as synthesized
by Farr and Daves.8
Ack n ow led gm en t . This investigation was sup-
ported by Grant ROI-CA56842 from the National In-
stitutes of Health.
J O951376B