Synthesis of C-glycosylated compounds with the use of a mild, iodine-catalyzed reaction

The invention concerns C-glycosylated derivatives of soft carbon nucleophile compounds, particularly compounds which contain acid-labile structural units. The invention further concerns a mild, cost-effective, non-hazardous and stereoselective method of general application employing a glycal as a glycosyulating agent and iodine as a catalyst for the preparation of C-glycosylated soft carbon nucleophile compounds.

FIELD OF THE INVENTION 
The invention concerns C-glycosylated derivatives of soft carbon 
nucleophile compounds, particularly compounds which contain acid-labile 
structural units, and more particularly, C-glycosylated derivatives of 
known compounds that are useful pharmacological agents such as 
antibiotics, antineoplastic compounds and antiviral compounds. The 
invention further concerns a mild, cost-effective, non-hazardous and 
stereoselective method of general application employing a glycal as a 
glycosylating agent and iodine as a catalyst for the preparation of 
C-glycosylated soft carbon nucleophile compounds. 
BACKGROUND OF THE INVENTION 
A large number of drugs that exhibit potent antibiotic, antitumor and/or 
antiviral activity belong to the structural class of compounds known as 
C-glycosides, in which a carbohydrate moiety is attached to a carbon atom 
of a typically hydrophobic aglycon unit. Although their glycons are not 
particularly hydrophobic, C-nucleosides are the most representative of 
these C-glycosides both in their abundance and in their biological 
activities. Numerous C-glycosides are currently on the market as medicinal 
drugs. Therefore, development of an improved method for the synthesis of 
such compounds, especially their structural analogs that may possess 
enhanced pharmacological profiles, continues to be an area of intense 
commercial interest in the pharmaceutical and chemical industry (for 
reviews, see: Hacksell, U.; Daves, G. D., Jr. Prog. Med. Chem. 1985, 22, 
1-65 and Daves, G. D., Jr. Acc. Chem. Res. 1990, 23, 201-206 both 
incorporated herewith by reference). 
While several reactions that utilize glycal derivatives as glycosylating 
reagents have been reported employing various Lewis acids as catalysts for 
C-glycosylation, the harsh nature of these Lewis acids has prevented their 
application to the synthesis of the C-glycosylated derivatives of 
acid-labile substrates. These Lewis acids include boron trifluoride 
etherate (Dawe, R. D.; Fraser-Reid, B. J.C.S. Chem. Commun.1981, 
1180-1181; Panek, J. S.; Sparks, M. A. J. Org. Chem. 1982, 47, 3805-3806; 
Sabol, J. S.; Cregge, R. J. Tetrahedron Lett. 1989, 30, 6271-6274), 
ethyldichloroaluminum, and trimethylsilyl trifluoromethanesulfonate (for 
the use of both of these Lewis acids, see: Herscovici, J.; Muleka, K.; 
Antonakis, K. Tetrahedron Lett. 1984, 25, 5653-5656). In addition, since 
most of these strong Lewis acids spontaneously react with air and 
moisture, the use of these Lewis acids presents serious problems in their 
handling, particularly under the large-scale, industrial setting. Another 
approach to C-glycosylation that employs a glycal derivative requires the 
use of expensive metal catalyst whose effects to human health could 
potentially be serious drawbacks (Hacksell, U.; Daves, G. D., Jr. J. Org. 
Chem. 1983, 48, 2870-2876). 
SUMMARY AND DETAILED DESCRIPTION 
In one preferred aspect, the invention concerns C-glycoside compounds, as 
C-1.alpha. and C-1.beta. epimer compounds, obtained by reacting a soft 
carbon nucleophile compound and a glycosylating agent selected from 
3-acylated, carbonated and thionocarbonated five- and six-membered glycals 
in the presence of a catalytic amount of iodine (5-50 mol % with 20 mol % 
being the most representative) to provide a reaction mixture containing 
the corresponding C-1.alpha. and C-1.beta. C-glycoside epimers, isolating 
at least one or both of said .alpha. and .beta. epimers stereoselectively 
from said mixture, and optionally removing one or more acyl groups from 
said epimer products. 
The use of the non-toxic, stable catalyst iodine, which is an extremely 
mild Lewis acid and yet according to the invention retains enough acidity 
to effect C-glycosylation, has virtually solved the heretofore difficult 
problems of the art. 
For glycosylation, glycals of the formulas I-III and Ia-IIIa are preferred: 
##STR1## 
where R.sub.0 is a lower alkyl group and R.sub.1, R.sub.2 and R.sub.3 are 
the same or different and represent an aliphatic acyl group or an aromatic 
acyl group such as a benzoyl group. The glycals are commonly available or 
can be prepared by known methods. 
Preferred soft carbon nucleophiles comprise a compound or a moiety selected 
from members of the group consisting of enolate derivatives having the 
formulas a) to w) 
##STR2## 
and allyl, vinyl, alkynyl and propargyl silanes and stannanes, and MCN; 
wherein M represents 
##STR3## 
R, R.sup.1 and R.sup.2 are independently selected from alkyl, aryl, 
alkenyl and alkynyl, n is from 1 to 5, Hal is a halogen atom, and R', R" 
and R'" are independently selected from lower alkyl groups. Preferred 
nucleophiles are precursors of showdomycin, ravidomycin, formycin, and 
analogs thereof. 
Thus, the soft nucleophiles include derivatives of enolates of ketone, 
aldehyde, ester, lactone, thioester, amides, and lactams, generally 
represented as RO--C(X).dbd.C where X is a substituent and R is a 
trialkyl, dialkylaryl, and alkyldiaryl, or triarylsilyl or tin group, 
ketene acetals, 1,2- and 1,3-dicarbonyl compounds including Meldrum's acid 
and their derivatives, .beta.-ketosulfoxides, .beta.-ketosulfones, and 
.beta.-ketonitro compounds and their derivatives, allyl, vinyl, aryl, 
alkynyl, and propargyl silanes and stannanes, silyl and stannyl cyanides 
(RR'R"SiCN and RR'R"SnCN), 1,3- and 1,3,5-dihydroxybenzene and their anion 
and per-trialkylsilyl and stannyl derivatives and their equivalents. Any 
of various suitable solvents can be used for the glycosylation reaction of 
which THF, acetone, diethyl ether, methylene chloride, chloroform, and 
benzene are preferred. The reaction temperature and time can be varied, 
e.g., ranging from -78.degree. to room temperature for about 0.5 to 12 
hours. 
The following reactions in a preferred embodiment (Table 1) illustrate the 
invention. 
TABLE I 
__________________________________________________________________________ 
C-Glycosylation 
##STR4## 
C-Nucleophile 
Temperature 
Time Products R 
Yield 
.alpha.:.beta. 
__________________________________________________________________________ 
(CH.sub.3).sub.3 SiCH.sub.2 CHCH.sub.2 
-60.degree. C. to RT 
Overnight 
CH.sub.2 CHCH.sub.2 
7-% &gt;20:1 
(CH.sub.3).sub.3 SiC N 
-78.degree. C. 
2 h C N 75% 3:1 
(CH.sub.3).sub.3 SiC N 
-60.degree. C. 
1 h C N 78% 1:3 
##STR5## -78.degree. C. 
2 h CH.sub.2 C(O)Ph 
65% 6:1 
##STR6## -50.degree. C. to RT 
12 h CH.sub.2 C(O)Ph 
78% 2.7:1 
##STR7## 50.degree. C. to 0.degree. C. 
2 h 2-oxocy- clohexyl 
65% 4:1 
__________________________________________________________________________ 
RT = room temperature 
As shown in the table, the epimeric ratio as well as preference for one of 
the two epimers of the C-glycosylated products is dependent on the 
temperature of the reaction (see the cases of trimethylsilyl cyanide and 
acetophenone trimethylsilyl ether). Moreover, quite significantly, the 
thermodynamically more favored .beta.-epimer obtained from ketone enol 
silyl ethers can be obtained as a major product upon treatment of the 
initial .alpha.-epimer enriched product mixture with acid (as described by 
Kende, A. S.; Fujii, Y. Tetrahedron Lett. 1991, 32, 2199-2202) or base (as 
described by Dawe, R. D.; Fraser-Reid, B. J.C.S. Chem. Commun. 1981, 
1180-1181 incorporated by reference) (see Scheme 1 below). The present 
invention in one preferred aspect includes the treatment of the 
.alpha.-epimer enriched product mixture with acid or base thus favoring 
the yield in the present method of the .beta.-epimer, and making the 
present C-glycosylation even more versatile. Many of the present 
C-glycosylated products, particularly those with 1.beta.-carbon chains are 
key intermediates in the synthesis of various C-glycoside antibiotics (as 
described in the two reviews cited above, incorporated herewith by 
reference). 
##STR8## 
In another preferred aspect, the invention concerns partly and completely 
deacylated products having enhanced water-solubility, produced by 
hydrolysis of one or more acyl groups from the acylated product. For 
hydrolysis, acyl group removal can be-achieved for example by refluxing 
the acylated product, under per se commonly used conditions for hydrolysis 
and workup, with an aqueous metal hydroxide (MOH; M=Li, K, Na) in methanol 
or ethanol, or with Zn (OAc).sub.2.2H.sub.2 O in methanol, or with 
LiAlH.sub.4 or diisobutylaluminum hydride in benzene, toluene, ether or 
THF.

The invention and the best mode of carrying out the same are illustrated by 
the following non-limitative examples. 
EXAMPLE I 
Reaction of Triacetyl D-Glucal With Acetophenone Enol Trimethylsilyl Ether 
##STR9## 
Triacetyl D-glucal (1.98 mmol) and iodine (0.398 mmol) were dissolved in 10 
mL of THF and the solution was cooled to -50.degree. C. To this solution 
was added acetophenone enol trimethylsilyl ether (2.00 mmol) and the 
reaction mixture was allowed to warm slowly to room temperature over 12 
hours. The reaction mixture was then diluted with 50 mL of ether and the 
resulting solution was washed with 10 mL of 10% aqueous Na.sub.2 S.sub.2 
O.sub.3. The aqueous layer was back-extracted with ether (3.times.10 mL). 
The combined organic layers were dried over sodium sulfate and the solvent 
was evaporated in vacuo. The crude product thus obtained was purified by 
silica gel flash column chromatography (gradient elution with 9/1 to 2/1 
hexanes/ethyl acetate), providing 1.55 mmol of the C-glycosylated product 
(78%) as a mixture of C-1 epimers (2.7:1.alpha.:.beta.). For the major 
product .alpha.-epimer: .sup.1 H NMR (300 MHz; CDCl.sub.3) .delta.2.03 
(s,3H), 2.09 (s,3H), 3.15 and 3.48 (AB quartet, 2H, J.sub.AB =16.4 Hz; the 
3.15 and 3.48 ppm peaks are further split into doublets with J=6.5 Hz and 
7.1 Hz, respectively), 4.13 and 4.25 (AB quartet, 2H, J.sub.AB =11.9 Hz; 
the 4.13 and 4.25 ppm peaks are further split into doublets with J=3.6 Hz 
and 6.6 Hz, respectively), 4.91-4.97 (m,1H), 5.13-5.17 (m,1H), 5.85 and 
6.08 (AB quartet, 2H, J.sub.AB =10.4 Hz; the 5.85 and 6.08 ppm peaks are 
further split into dd with J=3.0, 2.0 Hz and 2.5, 1.5 Hz, respectively). 
.sup.13 C NMR (75.4 MHz; CDCl.sub.3) .delta.20.70 (q), 21.05 (q), 42.70 
(t), 63.25 (t), 65.51 (d), 68.99 (d), 71.04 (d), 124.84 (d), 128.90 (d), 
129.38 (d), 133.56 (d), 133.96 (d), 137.98 (d), 137.98 (s), 171.03 (s), 
171.42 (s), 197.99 (s). 
EXAMPLE II 
Reaction of Triacetyl D-Glucal With Allyltrimethylsilane 
The procedure of Example I was followed except that the reaction was 
initiated at -60.degree. C. and the reaction mixture was left at room 
temperature overnight. The 1-allyl product was obtained in 70% yield with 
over 20:1 .alpha./.beta. stereoselectivity. For the major .alpha.-epimer: 
.sup.1 H NMR (300 MHz; CDCl.sub.3) .delta.2.08 (s,6H), 2.27-2.36 (m,1H), 
2.41-2.52 (m,1H), 3.93-4.02 (m,1H), 4.15 and 4.23 (AB quartet, 2H, 
J.sub.AB =11.9 Hz; the 4.15 and 4.21 ppm peaks are further split into 
doublets of doublets with J=3.5 and 6.6 Hz, respectively), 4.25-4.31 
(m,1H), 5.09-5.17 (m,3H), 5.76-5.89 (m,1H), 5.79 and 5.93 (AB quartet, 2H, 
J.sub.AB =10.4 Hz; the 5.7 9 and 5.93 ppm peaks are further split into dd 
with J= 2.8, 1.9 and 2.4, 1.6 Hz, respectively); .sup.13 C NMR (75.4 MHz; 
CDCl.sub.3) .delta.20.73, 21.00, 37.96, 62.94, 65.13, 70.00, 71.35, 
117.44, 123.75, 132.83, 133.97, 170.24, 170.55. 
EXAMPLE III 
Reaction of Triacetyl D-Glucal With 1-Trimethylsilyloxy-1 -cyclohexene 
The procedure of Example I was followed except that the reaction was 
performed at -78.degree. C. for 2 hours. The 1-(2-oxocyclohexyl) product 
was obtained in 65% yield with over 4:1 .alpha./.beta. stereoselectivity. 
For the major .alpha.-epimer: .sup.1 H NMR (360 MHz; CDCl.sub.3) 
.delta.2.08 (a,3H), 2.11 (s,3H), 2.30-2.43 (m,3H), 2.61-2.65 (m,1H), 3.86 
(ddd, 1H, J=6.7, 6.7, 3.6 Hz), 4.16 and 4.24 (AB quartet, 2H, J.sub.AB 
=11.9 Hz; the 4.16 and 4.24 ppm peaks are further split into doublets with 
J=3.6 and 6.8 Hz, respectively), 4.46 (ddd, 1H, J=8.8, 4.5, 2.3 Hz), 
5.11-5.16 (m,1H), 5.77 and 6.14 (AB quartet, 2H, J.sub.AB =10.5 Hz; the 
5.77 and 6.14 ppm peaks are further split into doublets of doublets with 
J=2.9, 2.0 and 2.7, 1.5 Hz, respectively); .sup.13 C NMR (75.4 MHz; 
CDCl.sub.3) .delta.20.82, 21.06, 24.67, 27.94, 30.30, 42.74, 53.41, 62.92, 
65.04, 70.15, 70.27, 123.56, 133.06, 170.34, 170.75, 210.95. 
The procedure of Example 1 can be used for preparation of the 
stereoselective 2,3,5-triacetylribosylation of acid-sensitive substrate 
compounds such as precursors of the known compounds showdomycin, 
ravidomycin, formycin and like pharmacologically useful compounds. For 
example, the synthesis of glycosylated showdomycin can be accomplished 
using the commercially available soft carbon nucleophile 1,2 
bis(trimethylsilyl)oxy-1-cyclobutene for stereoselective addition of a 
glycal selected from glycals of formula I-III and Ia-IIIa to produce an 
adduct which is converted to the target compound which can be deacylated 
by per se known procedures to provide showdomycin. A similar synthesis is 
reported in the Hacksell and Daves review article, supra, at page 43. The 
resulting novel triacetylribosylated substrate compounds are contemplated 
to have substantial advantage with respect to greater water solubility and 
yet have substantially the same useful antineoplastic activity and 
posology as the known compounds. 
Having described the invention, the embodiments of the invention in which 
an exclusive property or privilege is claimed are defined as follows.