Synthesis of griseolic acid analogues: Regioselective α-facial [1,2]-migration in the rhodium acetate catalyzed reaction of D-glucose derived α-diazo-β-keto ester

Article abstract of DOI:10.1021/jo026858j

This paper describes an efficient route for the synthesis of known and novel griseolic acid analogues 1d and 1e, respectively. The key intermediate dioxabicyclo derivative 6, with the required stereochemical orientation at C6, was obtained by rhodium acet

Full text of DOI:10.1021/jo026858j

pounds have been found to show greater activity and
selectivity.3,4
Syn th esis of Gr iseolic Acid An a logu es:
Regioselective r-F a cia l [1,2]-Migr a tion in
th e Rh od iu m Aceta te Ca ta lyzed Rea ction
of D-Glu cose Der ived r-Dia zo-â-k eto Ester
The total synthesis of griseolic acid and analogues is
restricted due to the stereochemical and structural chal-
lenges that include key steps such as preparation of a
strained 1,5-dioxabicyclo[3.3.0]oct-3-ene ring system and
the distereoselective formation of a quaternary carbon
with -COOH and -CH2COOH substituents. In general,
the known strategies first involve construction of the
dioxabicyclic ring skeleton with -OR and -COOR groups
and then the stereoselective introduction of two carbon
acid units using carbanion chemistry.5Recently, Knapp
and co-workers reported π-face-dependent radical cy-
clization to achieve the bicyclic system with required
substituents at C6.6 We thought of exploring the applica-
tion of rhodium carbenoid chemistry toward the synthesis
of griseolic acid analogues. In this direction, we have
investigated the reaction of D-glucose-derived R-diazo-â-
keto ester 5 with rhodium(II) acetate, which directly led
to the key intermediate needed for the synthesis of
griseolic acid analogues 1d and 1e.
Reaction of diacetone-D-glucose with ethyl bromoac-
etate in the presence of NaH in THF afforded 3-O-
carbethoxymethylene-D-glucose derivative 2 (Scheme 1).
Selective deprotection of the 5,6-O-isopropylidene group
in 2 and sodium periodate oxidation gave 3-O-carb-
ethoxymethylene-R-D-xylo-pentodialdo-1,4-furanose (3).
Treatment of 3 with ethyl diazoacetate and BF3-OEt2
in dichloromethane afforded sugar â-keto ester 4,7 which
on reaction with mesyl azide and triethylamine provided
the R-diazo-â-keto ester 5. The rhodium(II) acetate
catalyzed reaction of 5 (benzene reflux) afforded 6 in
which formation of the dioxabicyclic skeleton, with both
substituents (-COOR and -CH2COOR) in the required
(R) absolute configuration at C6, was achieved in one
step.
Navnath P. Karche, Santosh M. J achak, and
Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre,
University of Pune, Pune-411 007, India
ddd@chem.unipune.ernet.in
Received December 17, 2002
Abstr a ct: This paper describes an efficient route for the
synthesis of known and novel griseolic acid analogues 1d
and 1e, respectively. The key intermediate dioxabicyclo
derivative 6, with the required stereochemical orientation
at C6, was obtained by rhodium acetate catalyzed reaction
of D-glucose derived R-diazo-â-keto ester 5 in a novel high-
yielding methodology.
In rhodium(II)-catalyzed oxonium-ylide formation re-
actions of R-diazo-â-keto esters, the product derived from
either [2,3]-sigmatropic rearrangement or [1,2]-migration
is routinely observed;1 however, [1,4]-migration as a
prominent process has been demonstrated by us only
recently.2 During this study, we have noticed an interest-
ing observation that the reactions of D-glucose derived
R-diazo-â-keto esters follow selective R-facial [1,2]-migra-
tion of the substituent along with the formation of a 1,5-
dioxabicyclo[3.3.0]octane ring skeletonsthe core struc-
tural component of griseolic acids. Griseolic acids A, B,
and C (1a , 1b, and 1c), isolated from the cultural broths
We assumed that the reaction involves generation of
a rhodium carbenoid species A (Scheme 2) followed by a
metal-bound five-membered oxonium ylide B as the first
step. As the reaction proceeds, the migration of the -CH2-
COOEt group from oxygen to rhodium is completed, via
the intermediacy of four-centered oxabicyclo[3.2.0]heptane
transition state (TS) C, to afford TS D. Subsequently,
the cleavage of the Rh-CH2COOEt bond followed by
formation of a new carbon-carbon bond (between C6 and
-CH2COOEt) and rupture of the Rh-C6 bond with the
loss of Rh(II) acetate in a three-membered TS E, by a
concerted process, afforded [1,2]-rearranged product 6.2b
of Streptomyces griseoaurantiacus,3 have been shown to
have inhibitory activity against cyclic nucleotide-phos-
phodiesterase and structural analogues of these com-
(4) (a) Murofushi, Y.; Kimura, M.; Kuwano, H.; Iijima, H.; Yamazaji,
M.; Kaneko, M. Chem. Pharm Bull. 1988, 36, 3760-3763. (b) Miya-
koshi, S.; Haruyama, H.; Shioiri, T.; Takahashi, S.; Torikata, A.;
Yamazaki, M. J . Antibiot. 1992, 45, 395-399. (c) Kaneko, M.; Kimura,
M.; Murofushi, Y.; Yasumoto, T.; Iijima, Y.; Yamazaki, M. Nucleosides
Nucleotides 1992, 11, 865-887. (d) Pickering, L.; Nair, V. Nucleosides
Nucleotides 1996, 15, 1751-1769.
(1) For general reviews of rhodium-carbenoids see: (a) Adams, J .;
Spero, D. M. Tetrahedron 1991, 47, 1765-1795. (b) Padwa, A.; Krumpe,
K. E. Tetrahedron 1992, 48, 5385-5402. (c) Ye, T.; McKervey, M. A.
Chem. Rev. 1994, 94, 1091-1112. (d) Padwa, A.; Weingarten, M. D.
Chem. Rev. 1996, 96, 223-269. (e) Doyle, M. P.; Forbes, D. C. Chem.
Rev. 1998, 98, 911-935. (f) Sulikowski, G. A.; Cha, K. L.; Sulikowski,
M. M. Tetrahedron: Asymmetry 1998, 9, 3145-3169.
(2) The selectivity in [1,2]- versus [1,4]-migration is controlled by
the electronic factor associated with the migratory group, see: (a)
Dhavale, D. D.; Desai, V. N.; Saha, N. N. J . Chem. Soc., Perkin Trans.
1 2000, 147-151. (b) Dhavale, D. D.; Karche, N. P.; J achak, S. M. J .
Org. Chem. 2001, 66, 6323-6332.
(3) Nakagawa, F.; Okazaki, T.; Naito, A.; Iijima, Y.; Yamazaki, M.
J . Antibiot. 1985, 38, 823-829.
(5) (a) Tulshian, D.; Doll, R. J .; Stansberry, M. F. J . Org. Chem.
1991, 56, 6819-6822. (b) Tulshian, D.; Czarniecki, M.; Doll, R. J .; Ahn,
H. S. J . Med. Chem. 1993, 36, 1210-1220. (c) Tulshian, D. B.;
Czarniecki, M. J . Am. Chem. Soc. 1995, 117, 7009-7010. (d) Pickering,
L.; Nair, V. Nucleosides Nucleotides 1997, 16, 1435-1438.
(6) Knapp, S.; Madduru, M. R.; Lu, Z.; Morriello, G. J .; Emge, T. J .;
Doss, G. A. Org. Lett. 2001, 3, 3583-3585.
(7) Dhavale, D.; Bhujbal, N.; J oshi, P.; Desai, S. Carbohydr. Res.
1994, 263, 303-307.
10.1021/jo026858j CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/24/2003
J . Org. Chem. 2003, 68, 4531-4534
4531

SCHEME 1. Syn th esis of 1d a
a
Reagents and conditions: (a) [i] Acetone, I2 (0.2 equiv), 25 °C, 6 h, 72%; [ii] NaH (1.5 equiv), BrCH2COOEt (1.2 equiv), TBAI (0.03
equiv), THF, 25 °C, 12 h, 78%. (b) [i] 10% H2SO4, EtOH, 25 °C, 6 h, 89%; [ii] NaIO4 (1.5 equiv), acetone, H2O, 0 °C, 2 h, 86%. (c) Ethyl
diazoacetate (1.5 equiv), BF3-etherate (0.6 equiv), CH2Cl2, 0 °C, 2 h, 76%. (d) MsN3 (1.1 equiv), Et3N (2.0 equiv), CH3CN, 25 °C, 2.5 h,
83%. (e) Rh2(OAc)4 (0.002 equiv), C6H6, 80 °C, 10 min, 74%. (f) NaBH4 (0.5 equiv), CH3OH, 0 °C, 2 h, 89%. (g) Pyridine (19.0 equiv),
(CH3CO)2O (10.0 equiv), DMAP (0.05 equiv), 25 °C, 12 h, 94%. (h) NaH (1.5 equiv), CS2 (8.0 equiv), imidazole (0.005 equiv), CH3I (1.8
equiv), THF, 25 °C, 1 h, 86%. (i) nBu3SnH (2.2 equiv), AIBN (0.05 equiv), toluene, 110 °C, 4 h, 69%. (j) Reference 5a.
SCHEME 2. Mech a n ism for th e F or m u la tion of 6
The absolute configuration at the newly generated
stereocenter C6 was established by NOEDIF studies
wherein irradiation of C7 methylene protons showed
NOE with H3 and H4 ring protons. This requires the
-CH2COOEt group to have a cis relationship with H3
and H4 resulting in (R) absolute configuration at C6. In
the subsequent step, sodium borohydride reduction of the
keto group in 6 afforded only D-gluco-isomer 7 wherein
the addition of hydride has taken place from the lower
face of 6 (Re face attack at the carbonyl group). Acylation
of 7 with acetic anhydride/pyridine produced 8 in almost
quantitative yields. The relative configuration at C5 in
8 was established by NOEDIF studies which revealed an
NOE between H5 and H4 and one of the H7 protons
(methylene protons) thus indicating â-orientation of the
-OAc group at C5 and confirming D-gluco-configuration
for 8. Therefore, (S) absolute configuration was assigned
at C5 in 7 and 8.
deprotection of the 1,2-acetonide group followed by
guaninylation, is reported. Therefore, our route consti-
tutes the formal synthesis of 1d . In an attempt to
synthesize a new analogue of griseolic acid 1e, the acetyl
derivative 8 was subjected to acetolysis (AcOH-Ac2O and
catalytic H2SO4) to afford triacetate derivative 11 as an
anomeric mixture. Vorbru¨ggen glycosylation with bis-
(trimethylsilyl)-N6-benzoyladenine and tert-butyldimeth-
ylsilyl triflate in refluxing acetonitrile afforded 12.8
Deprotection of 12 with 1 N NaOH-ethanol gave griseol-
ic acid analogue 1e (Scheme 3).
In summary, we have demonstrated the applicability
of rhodium carbenoid chemistry in the formation of the
otherwise difficult to obtain oxa-bicyclo ring system and
providing the R-facial selectivity in a [1,2]-migration that
allows a novel approach to access griseolic acid analogues.
Exp er im en ta l Section
Protection of the -OH group in 7 with carbon disulfide
and methyl iodide in the presence of NaH gave the
S-methyl dithiocarbonate 9. Reduction of the dithiocar-
bonate group in 9 with tributyltin hydride and AIBN
Gen er a l. Melting points were recorded with melting point
apparatus and are uncorrected. IR spectra were recorded with
an FTIR spectrophotometer as a thin film or in Nujol mull
1
(8) Vorbru¨ggen, H.; Ruh-polenz, C. Org. React. 2000, 55, 1-630. In
this reaction, small amounts (<10%) of unwanted anomeric R-nucleo-
side and N-7 alkylated product were also formed. An analogous
observation was also noticed by others.4a,5c
afforded the reduced product 10. The H NMR spectrum
of 10 was found to be in consonance with that reported.5a
The conversion of 10 to griseolic acid analogue 1d , via
4532 J . Org. Chem., Vol. 68, No. 11, 2003

SCHEME 3. Syn th esis of 1ea
CDCl3) δ 9.70 (s, 1H), 6.11 (d, J ) 3.6 Hz, 1H), 4.74 (d, J ) 3.6
Hz, 1H), 4.61 (d, J ) 3.6 Hz, 1H), 4.35 (d, J ) 3.6 Hz, 1H), 4.21
(q, J ) 7.2 Hz, 2H), 4.10 (s, 2H), 1,48 (s, 3H), 1.34 (s, 3H), 1.28
(t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 199.0, 169.4,
112.6, 105.9, 85.1, 84.5, 82.6, 67.8, 61.3, 27.0, 26.4, 14.2. Anal.
Calcd for C12H18O7: C, 52.52; H, 6.61. Found: C, 52.76; H, 6.36.
E t h yl 6-Deoxy-1,2-O-isop r op ylid en e-3-O-ca r b et h oxy-
m eth ylen e-R-D-xylo-h ep t-5-u lo-1,4-fu r a n u r on a te (4). To a 0
°C cooled solution of 3 (500 mg, 1.82 mmol) and ethyl diazoac-
etate (0.29 mL, 2.73 mmol) in dry CH2Cl2 (15 mL) under N2 was
added dropwise BF3-etherate (0.10 mL, 1.08 mmol) in dry CH2-
Cl2 (2 mL) with control of the evolution of N2 (20 min). The
mixture was stirred at 0 °C for 2 h and quenched with a
saturated solution of sodium bicarbonate (5 mL). The organic
layer was separated and the aqueous layer was extracted with
dichloromethane (3 × 10 mL). After workup, the residue thus
obtained was purified with column chromatography (PE/ethyl
acetate 9:1) to give 4 as thick oil (498 mg, 76% yield); Rf 0.41
(40% EtOAc in hexanes); [R]D -52.00 (c 0.50, CHCl3); IR (neat)
a
Reagents and conditions: (a) CH3COOH, (CH3CO)2O, CH2Cl2,
H2SO4 (0.01 equiv), 25 °C, 4 h, 74%. (b) Bis(trimethysilyl)-N-
benzoyladenine (1.5 equiv), TBDMSOTf (1.5 equiv), CH3CN, 75
°C, 3 h, 73%. (c) 1 N NaOH (8.0 equiv) in aq EtOH, 25 °C, 24 h,
63%.
1
1747, 1733, 1717 cm-1; H NMR (300 MHz, CDCl3) δ 6.08 (d, J
) 3.6 Hz, 1H), 4.76 (d, J ) 3.6 Hz, 1H), 4.74 (d, J ) 3.5 Hz, 1H),
4.28 (d, J ) 3.5 Hz, 1H), 4.26-4.14 (m, 4H), 4.10 (AB quartet,
J ) 12.3 Hz, 2H), 3.70 (AB quartet, J ) 16.2 Hz, 2H), 1.47 (s,
3H), 1.33 (s, 3H), 1.32-1.23 (m, 6H); 13C NMR (75 MHz, CDCl3)
δ 201.2, 169.6, 167.0, 112.5, 105.8, 85.3, 84.9, 82.4, 68.2, 61.1
(strong), 47.3, 26.9, 26.3, 14.1, 14.0. Anal. Calcd for C16H24O9:
C, 53.30; H, 6.71. Found: C, 53.16; H, 6.76. (The 1H and 13C
NMR spectrum showed ∼5% enol contribution.)
(expressed in cm-1). 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded in CDCl3 as a solvent unless otherwise
noted. NMR chemical shifts are reported in δ (ppm) downfield
from TMS. Elemental analyses were carried out with an
elemental analyzer. Optical rotations were measured with a
polarimeter, using sodium light (D line 589.3 nm) at 25 °C. TLC
was performed on precoated plates (0.25 mm, silica gel 60 F254).
Flash chromatography was performed on 200-400-mesh silica
gel and column chromatography was carried out with 100-200-
mesh silica gel. The reactions were carried out in oven-dried
glassware under dry N2. Acetonitrile, benzene, dichloromethane,
and THF were purified and dried before use. Petroleum ether
(PE) is a distillation fraction between 40 and 60 °C. Rhodium
acetate dimer was purchased from Aldrich and was activated
by heating at 100 °C under reduced pressure (3 mm of Hg) for
3 h prior to use. After workup, the organic layer was washed
with water and brine, dried over anhydrous sodium sulfate, and
evaporated at reduced pressure.
E t h yl 6-Deoxy-6-d ia zo-1,2-O-isop r op ylid en e-3-O-ca r b -
eth oxym eth ylen e-r-D-xylo-h ep t-5-u lo-1,4-fu r a n u r on a te (5).
To a stirred solution of â-keto ester 4 (300 mg, 0.83 mmol) in
dry acetonitrile (30 mL) was added methanesulfonyl azide (111
mg, 0.91 mmol) and triethylamine (0.23 mL, 1.65 mmol). The
reaction mixture was stirred at room temperature for 2.5 h and
quenched with aqueous 2 N NaOH (1 mL). The organic layer
was separated and the aqueous layer was extracted with ethyl
acetate (3 × 20 mL). The combined organic layer after workup
and purification by column chromatography (PE/ethyl acetate
8.5:1.5) afforded 5 as a pale yellow solid; mp 106-108 °C (266
mg, 83% yield); Rf 0.38 (40% EtOAc in hexanes); [R]D +15.64 (c
0.20, CHCl3); IR (Nujol) 2150, 1751, 1712 cm-1 1H NMR (300
;
3-O-Ca r beth oxym eth ylen e-1,2:5,6-d i-O-isop r op ylid en e-
r-D-glu co-1,4-fu r a n ose (2). To a 0 °C cooled solution of 1,2:
5,6-di-O-isopropylidene-R-D-gluco-1,4-furanose (1000 mg, 3.85
mmol) in dry THF was added NaH (230 mg, 5.77 mmol) and
the reaction mixture was allowed to attain room temperature
and stirred for 6 h. Ethyl bromoacetate (0.51 mL, 4.62 mmol) in
THF was added dropwise followed by addition of TBAI (45 mg,
0.12 mmol). The reaction mixture was stirred for an additional
12 h. Workup and purification by column chromatography (PE/
ethyl acetate 9.5:0.5) afforded 2 as a white solid: mp 65-67 °C
MHz, CDCl3) δ 6.11 (d, J ) 3.6 Hz, 1H), 5.54 (d, J ) 3.6 Hz,
1H), 4.65 (d, J ) 3.5 Hz, 1H), 4.53 (d, J ) 3.5 Hz, 1H), 4.39-
4.28 (m, 2H), 4.27-3.90 (m, 4H), 1.51 (s, 3H), 1.34 (s, 3H), 1.32-
1.28 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 185.0, 169.3, 161.3,
112.5, 105.3, 83.9, 83.3, 82.3, 77.3, 66.8, 61.5, 60.9, 27.0, 26.5,
14.2, 14.1. Anal. Calcd for C16H22N2O9: C, 49.72; H, 5.74.
Found: C, 49.96; H, 5.56.
Eth yl 3,6-An h yd r o-6-(R)-ca r beth oxy-7-d eoxy-1,2-O-iso-
p r op ylid en e-r-D-glu co-oct-5-u lo-1,4 -fu r a n u r on a te (6). A
solution of 5 (250 mg, 0.65 mmol) and rhodium(II) acetate (3
mg, 0.013 mmol) in benzene (10 mL) was refluxed for 10 min
under N2. On cooling, the reaction mixture was directly loaded
on a silica gel (100-200 mesh) column and eluted (PE/ethyl
acetate 9:1) to afford 6 as an oil (172 mg, 74% yield); Rf 0.43
(40% EtOAc in hexanes); [R]D +32.63 (c 0.25, CHCl3); IR (neat)
(1038 mg, 78% yield); Rf 0.46 (40% EtOAc in hexanes); [R]D
-
48.00 (c 0.30, CHCl3); IR (Nujol) 1749, 1160, 1134 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.88 (d, J ) 3.6 Hz, 1H), 4.70 (d, J ) 3.6
Hz, 1H), 4.32 (t, J ) 4.2 Hz, 1H), 4.22 (s, 2H), 4.20 (m, 2H), 4.12
(m, 2H), 4.09 (m, 2H), 1.48 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H),
1.31 (s, 3H), 1.28 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 170.0, 111.7, 108.9, 105.0, 83.5, 83.1, 80.9, 72.5, 68.3, 67.1,
61.0, 26.8 (strong), 26.2, 25.4, 14.2. Anal. Calcd for C16H26O8:
C, 55.46; H, 7.56. Found: C, 55.58; H, 7.37.
1
1778, 1747, 1724 cm-1; H NMR (300 MHz, CDCl3) δ 6.04 (d, J
) 3.6 Hz, 1H), 4.97 (d, J ) 3.6 Hz, 1H), 4.90 (d, J ) 3.9 Hz, 1H),
4.83 (d, J ) 3.9 Hz, 1H), 4.28-4.18 (m, 2H), 4.14 (q, J ) 7.5 Hz,
2H), 3.49-2.98 (AB quartet, J ) 18.0 Hz, 2H), 1.50 (s, 3H), 1.38
(s, 3H), 1.33-1.23 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 202.0,
170.2, 166.8, 113.4, 107.9, 85.7, 84.9, 83.5, 79.8, 62.8, 61.6, 41.7,
27.6, 26.9, 14.0, 13.9. Anal. Calcd for C16H22O9: C, 53.60; H, 6.19.
Found: C, 53.46; H, 6.36.
3-O-Car beth oxym eth ylen e-1,2-O-isopr opyliden e-r-D-xylo-
p en tod ia ld o-1,4-fu r a n ose (3). A solution of 2 (1000 mg, 2.88
mmol) in 10% H2SO4 (5 mL) in ethanol (15 mL) was stirred at
25 °C for 6 h. The reaction mixture was neutralized with a
saturated solution of potassium carbonate, ethanol was evapo-
rated, and residue was extracted with chloroform. Purification
by column chromatography (PE/ethyl acetate 6.5:3.5) gave diol
as a thick oil (776 mg, 89% yield). The diol (700 mg, 2.31 mmol)
was treated with sodium metaperiodate (744 mg, 3.46 mmol) in
acetone-water (7:3, 10 mL) at 0 °C. After 2 h, ethylene glycol
(0.5 mL) was added, acetone was evaporated, and the residue
was extracted with CHCl3 (3 × 20 mL). Purification by column
chromatography (PE/ethyl acetate 9:1) afforded 3 as a thick oil
(546 mg, 86% yield); Rf 0.36 (40% EtOAc in hexanes); [R]D -32.00
(c 0.50, CHCl3); IR (neat) 1735, 1717 cm-1; 1H NMR (300 MHz,
Eth yl 3,6-An h yd r o-6-(R)-ca r beth oxy-7-d eoxy-1,2-O-iso-
p r op ylid en e-r-D-glu co-oct-1,4-fu r a n u r on a te (7). To a cooled
solution of 6 (500 mg, 1.40 mmol) in methanol (20 mL) was added
sodium borohydride (28 mg, 0.70 mmol) and the reaction mixture
was stirred at 0 °C. After 2 h 1 N HCl (3 mL) was added,
methanol was evaporated, and the residue was extracted with
ethyl acetate (10 mL × 3). Workup and purification by column
chromatography (PE/ethyl acetate 8:2) gave 7 as a white solid;
mp 68 °C (445 mg, 89% yield); Rf 0.33 (40% EtOAc in hexanes);
[R]D )+30.26 (c 0.40, CHCl3); IR (Nujol) 3468, 1746, 1720 cm-1
;
J . Org. Chem, Vol. 68, No. 11, 2003 4533

1H NMR (300 MHz, CDCl3) δ 5.90 (d, J ) 3.6 Hz, 1H), 4.92 (d,
J ) 4.2 Hz, 1H), 4.81 (t, J ) 4.2 Hz, 1H), 4.64 (d, J ) 3.6 Hz,
1H), 4.30 (d, J ) 4.2 Hz, 1H), 4.28-4.20 (m, 2H), 4.14 (q, J )
7.2 Hz, 2H), 3.10 (d, J ) 16.0 Hz, 1H), 2.71 (d, J ) 16.0 Hz, 1H),
1.75-1.60 (br, 1H, exchanges with D2O), 1.47 (s, 3H), 1.33-1.22
(m, 9H); 13C NMR (75 MHz, CDCl3) δ 171.1, 169.0 113.4, 107.9,
85.7, 84.9, 84.5, 83.5, 79.8, 62.8, 61.6, 41.7, 27.6, 26.9, 14.0, 13.9.
Anal. Calcd for C16H24O9: C, 53.30; H, 6.71. Found: C, 53.66;
H, 6.36.
reaction mixture was allowed to attain room temperature. After
4 h, dichloromethane (100 mL) was added. The organic layer on
workup and evaporation of solvent afforded 11 as an anomeric
mixture. Separation by column chromatography (PE/ethyl ac-
etate 8:2) gave R-anomer as thick oil (164 mg; 59% yield); Rf
0.38 (40% EtOAc in hexanes); IR (neat) 1751, 1732 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 6.52 (d, J ) 4.8 Hz, 1H), 5.63 (dd, J
) 4.8 and 2.4 Hz, 1H), 5.41 (d, J ) 5.1 Hz, 1H), 4.98 (t, J ) 5.1
Hz, 1H), 4.92 (dd, J ) 5.1 and 2.4 Hz, 1H), 4.28-420 (dq, J )
7.2 and 3.0 Hz, 2H), 4.13 (q, J ) 7.2 Hz, 2H), 3.14 (d, J ) 16.0
Hz, 1H), 2.79 (d, J ) 16.0 Hz, 1H), 2.10 (s, 3H), 2.06 (s, 3H),
2.03 (s, 3H), 1.31 (t, J ) 7.2 Hz, 3H), 1.22. (t, J ) 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 169.5, 169.2, 169.1, 169.0, 168.7,
96.4, 85.7, 85.6, 79.6, 77.6, 76.0, 61.8, 60.8, 41.5, 20.7, 20.4, 20.2,
14.0, 13.9. Anal. Calcd for C19H26O12: C, 51.09; H, 5.87. Found:
C, 51.26; H, 5.76. Further elution gave a mixture of R- and
â-anomer (41 mg, 15% yield).
E t h yl 1,7-Did eoxy-6-c-ca r b et h oxy-3,6-a n h yd r o-1-(6-N-
ben zoyl-a m in o-9-H-p u r in -9-yl)-2,5-d ia cetoxy-r-D-glu co-oct-
1,4-fu r a n u r on a te (12). To a stirred solution of 11 (100 mg, 0.23
mmol) in acetonitrile (5 mL) was added bis(trimethylsilyl)-N-
benzoyladenine (130 mg, 0.345 mmol) followed by tert-butyl
dimethylsilyl triflate (0.05 mL, 0.345 mmol) and the reaction
mixture was refluxed. After 3 h, ethyl acetate was added and
the organic layer was washed with a cold solution of NaHCO3
and evaporated. The crude product was purified by column
chromatography (PE/ethyl acetate 5:4) to give 12 as a semisolid
(102 mg, 73% yield); Rf 0.45 (80% EtOAc in hexane); [R]D +77.80
(c 0.65, CHCl3); IR (neat) 3346, 1745, 1610, 1587; 1H NMR (300
MHz, CDCl3) δ 9.05 (br s, 1H), 8.79 (s, 1H), 8.01 (s, 1H), 7.97 (d,
J ) 7.2 Hz, 2H), 7.58 (d, J ) 7.2 Hz, 1H), 7.50 (t, J ) 7.2 Hz,
2H), 6.95 (d, J ) 5.1 Hz, 1H), 5.83 (dd, J ) 5.1 and 1.2 Hz, 1H),
5.58 (d, J ) 5.7 Hz, 1H), 5.45 (dd, J ) 5.7 and 4.5 Hz, 1H), 5.12
(dd, J ) 4.5 and 1.2 Hz, 1H), 4.34 (dq, J ) 6.9 and 2.5 Hz, 2H),
4.17 (q, J ) 6.9 Hz, 2H), 3.21 (d, J ) 16.8 Hz, 1H), 2.92 (d, J )
16.8 Hz, 1H), 2.09 (s, 3H), 2.04 (s, 3H), 1.38 (t, J ) 6.9 Hz, 3H),
1.28 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.9,
169.3, 169.1, 169.0, 168.6, 152.7, 149.2, 142.4, 133.4, 132.7, 128.8
(strong), 127.7 (strong), 122.3, 86.4, 86.0, 85.8, 81.5, 77.3, 77.2,
Eth yl 3,6-An h yd r o-6-(R)-ca r beth oxy-7-d eoxy-1,2-O-iso-
pr opyliden e-5-O-acetoxy-r-D-glu co-oct-1,4-fu r an u r on ate (8).
To a stirred solution of 7 (300 mg, 0.83 mmol) in pyridine (1.3
mL, 15.7 mmol) at 0 °C was added acetic anhydride (0.78 mL,
8.3 mmol) and DMAP (5 mg, 0.04 mmol). The reaction mixture
was allowed to attain room temperature. After 12 h ethyl acetate
(10 mL) was added and the organic layer separated and worked
up. Evaporation of solvent and purification by column chroma-
tography (PE/ethyl acetate 8.5:1.5) afforded 8 as thick oil (314
mg, 94% yield); Rf 0.42 (40% EtOAc in hexanes); [R]D +8.60 (c
0.30, CHCl3); IR (neat) 1747, 1722 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 6.01 (d, J ) 3.5 Hz, 1H), 5.42 (d, J ) 4.4 Hz, 1H), 4.93
(m, 2H), 4.73 (d, J ) 3.7 Hz, 1H), 4.24 (q, J ) 7.2 Hz, 2H), 4.12
(q, J ) 7.2 Hz, 2H), 3.20-2.77 (AB quartet, J ) 16.5 Hz, 2H),
2.12 (s,3H), 1.46 (s, 3H), 1.33 (s, 3H), 1.30 (t, J ) 7.2 Hz, 3H),
1,0.24 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.8,
169.4, 169.2, 112.3, 107.8, 86.2, 84.9, 83.9, 80.9, 77.3, 61.7, 60.9,
42.2, 27.4, 26.8, 20.7, 14.3, 14.2. Anal. Calcd for C18H26O10: C,
53.70; H, 6.51. Found: C, 53.46; H, 6.76.
Eth yl 3,6-An h yd r o-6-(R)-ca r beth oxy-7-d eoxy-1,2-O-iso-
p r op ylid en e-5-O-(S-m eth yld ith ioca r bon a te)-r-D-glu co-oct-
1,4-fu r a n u r on a te (9). To a solution of 7 (100 mg, 0.28 mmol)
in dry THF was added NaH (17 mg, 0.42 mmol) and imidazole
(1 mg, 0.0056 mmol) and the reaction mixture was stirred for 1
h at room temperature. Carbon disulfide (0.13 mL, 2.24 mmol)
was added, the solution was stirred 1 h, and then methyl iodide
(0.03 mL, 0.50 mmol) was added. After an additional 20 min of
stirring dichloromethane (40 mL) was added and the organic
layer was worked up. Purification by column chromatography
(PE/ethyl acetate 9.5:0.5) gave 9 as a thick oil (109 mg, 86%
yield); Rf 0.40 (40% EtOAc in hexanes); [R]D +21.17 (c 0.15,
CHCl3); IR (neat) 1745, 1723 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.30 (d, J ) 4.5 Hz, 1H), 6.03 (d, J ) 4.2 Hz, 1H), 5.08 (t, J )
4.2, 3.9 Hz, 1H), 4.96 (d, J ) 3.9 Hz, 1H), 4.78 (d, J ) 4.5 Hz,
1H), 4.24 (q, J ) 7.2 Hz, 2H), 4.14 (q, J ) 7.2 Hz, 2H), 3.18 (d,
J ) 16.2 Hz, 1H), 2.83 (d, J ) 16.2 Hz, 1H), 2.57 (s, 3H), 1.46 (s,
3H), 1.33-1.22 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 215.1,
169.2, 169.1, 112.4, 108.1, 86.9, 86.3, 83.9, 83.4, 83.2, 61.8, 60.9,
41.8, 27.4, 27.1, 26.8, 14.2, 13.9. Anal. Calcd for C18H26S2O9: C,
46.54; H, 5.97. Found: C, 46.26; H, 5.56.
Eth yl 3,6-An h yd r o-6-(R)-ca r beth oxy-7,5-d id eoxy-1,2-O-
isop r op ylid en e-r-D-glu co-oct-1,4-fu r a n u r on a te (10). A solu-
tion of 9 (100 mg, 0.22 mmol) in dry toluene (5 mL) was added
to a refluxing solution of tributyltin hydride (69 mg, 0.48 mmol)
and AIBN (2 mg, 0.011 mmol) in toluene under N2. The solution
was refluxed for 4 h, toluene was evaporated, and residue was
dissolved in ethyl acetate (30 mL). Workup and purification by
column chromatography (PE/ethyl acetate 8.5:1.5) afforded 10
as a thick oil (52 mg, 69% yield); Rf 0.38 (40% EtOAc in hexanes);
[R]D +15.60 (c 0.65, CHCl3); IR (neat) 1742 1729 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.78 (d, J ) 3.9 Hz, 1H), 4.92-4.88 (m, 2H),
4.63 (d, J ) 3.9 Hz, 1H), 4.28-4.08 (m, 4H), 2.97 (d, J ) 15.3
Hz, 1H), 2.68 (d, J ) 14.1 Hz, 1H), 2.64 (d, J ) 15.3 Hz, 1H),
2.22 (dd, J ) 14.1, 4.2 Hz, 1H), 1.45 (s, 3H), 1.30 (s, 3H), 1.28 (t,
J ) 7.2 Hz, 3H), 1.25 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 172.4, 168.9, 111.5, 106.9, 89.0, 84.8, 84.5, 82.8, 61.4,
60.8, 42.8, 42.3, 27.2, 26.6,14.2 (strong). Anal. Calcd for
C16H24O8: C, 55.78; H, 7.02. Found: C, 55.96; H, 6.76.
62.2, 61.1, 41.5, 20.6, 20.2, 14.3, 14.2. Anal. Calcd for C29H31
N5O11: C, 55.65; H, 4.99. Found: C, 55.76; H, 4.76.
-
1,7-Did eoxy-6-c-ca r boxy-3,6-a n h yd r o-1-(6-a m in o-9-H-p u -
r in -9-yl)-r-D-glu co-oct-1,4-fu r a n u r on ic Acid (1e). A solution
of 12 (100 mg, 0.16 mmol) in ethanol-water (7:3, 2 mL) and
NaOH (51 mg, 1.28 mmol) was stirred at room temperature.
After 24 h, the reaction mixture was neutralized with 1 N HCl
and the volume of the reaction mixture was reduced to half by
evaporation at reduced pressure. The solution was loaded on a
Chromabond C18 ec (Macherey-Nagel) column and eluted first
with water to remove all inorganic salt and then with 10%
acetone in water. Evaporation of solvent gave a semisolid that
was repeatedly washed with chloroform (3 × 2 mL) to give 1e
as a solid (38 mg, 63% yield); mp 232-235 °C; [R]D +32.30 (c
0.15, CH3OH); IR (KBr) 3442, 1737, 1627 cm-1 1H NMR (300
;
MHz, D2O) δ 8.30 (s, 1H), 7.92 (s, 1H), 5.85 (d, J ) 6.0 Hz, 1H),
4.83 (m, 2H), 4.22 (d, J ) 5.1 Hz, 1H), 3.52 (s, 1H), 2.66-2.44.
(AB quartet, J ) 15.3 Hz, 2H); 13C NMR (75 MHz, D2O) δ 172.3,
172.2, 155.2, 152.4, 149.0, 140.8, 118.8, 89.6, 86.3, 81.7, 79.5,
76.0, 75.1, 42.6. Anal. Calcd for C14H15N5O8: C, 44.08; H, 3.96.
Found: C, 44.32; H, 3.77.
Ack n ow led gm en t. We thank the Department of
Science and Technology (SP/S1/G-23/2000) and the
University Grants Commission for financial support and
for procuring the high field NMR facility.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of all new compounds 2-12 and 1e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Eth yl 3,6-An h yd r o-6-(R)-ca r beth oxy-7-d eoxy-1,2,5-O-tr i-
a cetoxy-r- a n d â-D-glu co-oct-1,4-fu r a n u r on a te (11). To a
stirred solution of compound 8 (250 mg, 0.62 mmol) in dichlo-
rometane (20 mL) at 0 °C was added a mixture of acetic acid
and acetic anhydride (1:1.5, 20 mL) and H2SO4 (0.01 mL). The
J O026858J
4534 J . Org. Chem., Vol. 68, No. 11, 2003