A new access to C-arylglycosides related to the gilvocarcins

Article abstract of DOI:10.1016/j.tetlet.2004.08.009

A new strategy has been developed for the synthesis of C-aryl glycosides based on a xanthate-mediated free radical addition-cyclization sequence of an acetophenone xanthate to a vinylic carbohydrate followed by aromatization.

Full text of DOI:10.1016/j.tetlet.2004.08.009

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7335–7338
A new access to C-arylglycosides related to the gilvocarcins
*
´
Alejandro Cordero-Vargas, Beatrice Quiclet-Sire and Samir Z. Zard
` ´
Laboratoire de Synthese Organique associe au CNRS, Ecole Polytechnique, 91128Palaiseau, France
Received 28 May 2004; revised 17 July 2004; accepted 2 August 2004
Available online 23 August 2004
Abstract—A new strategy has been developed for the synthesis of C-aryl glycosides based on a xanthate-mediated free radical addi-
tion–cyclization sequence of an acetophenone xanthate to a vinylic carbohydrate followed by aromatization.
Ó 2004 Elsevier Ltd. All rights reserved.
C-Aryl glycosides or glycosylarenes represent an impor-
tant class of natural products in which carbohydrates
are directly bound to an aromatic moiety through a
C–C bond and which have been shown to be specially
resistant to enzymatic hydrolysis.1 These compounds
constitute interesting synthetic targets in the light of
their biological activities and unique structures. The
anticancer gilvocarcins (1a and 1b) belong to one of four
classes of naturally occurring C-arylglycosides, in which
the sugar is located para to a phenolic hydroxyl group
(Fig. 1).2
selectivity. This method was successfully applied for
the total synthesis of the gilvocarcins and their ana-
logues.2 However, because this is a Lewis acid promoted
process, the aromatic moieties that take part in the reac-
tion are required to be electron-rich and the carbohy-
drate unit solidly protected.
It is known that a-tetralones can be converted into the
corresponding naphthols by different means.4 Although
this transformation is very effective, the main problem
lies in the preparation of appropriately substituted tetra-
lones. A few years ago, we reported a new method for
the preparation of a-tetralones using a xanthate-medi-
ated free radical addition–cyclization sequence.5,6 This
process allows the synthesis of a wide variety of substi-
tuted tetralones under mild and neutral conditions. We
have now found that this approach can indeed be
extended to the synthesis of group I C-aryl glycosides
(in which the sugar is located para to a phenolic hyd-
roxyl group) by combining the radical sequence with
an efficient aromatization protocol. This opens a poten-
tially short route to the gilvocarcins.
Figure 1.
As shown in Scheme 1, we initially chose starting mate-
rials bearing electron withdrawing groups in order to
show the applicability of our method. Thus, our path
to the C-aryl glycosides initially involved the radical
addition of xanthates 2a–b5,7 onto known olefin 38 using
dilauroyl peroxide (DLP) as initiator in 1,2-dichloro-
ethane (DCE) as solvent, yielding 4a and 4b in 93%
and 84% yields, respectively.9 When a refluxing solution
of 4a and 4b in DCE was treated with 1.4equiv of DLP
(added portionwise), tetralones 5a (57%), and 5b (53%)
were obtained,10 together with a small amount of the
corresponding reduced products 6a (15%) and 6b
(21%), respectively.
Over the past few years, several methods for the con-
struction of these compounds have been developed.
The O ! C-glycoside rearrangement reported by Suzuki
and co-workers3 is probably the most useful because it
has several advantages in terms of regio- and stereo-
Keywords: C-Arylglycosides; Gilvocarcins; Xanthate; Addition;
Cyclization; Aromatisation.
*
Corresponding author. Tel.: +33 169334867; fax: +33 169333851;
e-mail: cordero@dcso.polytechnique.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.009

7336
A. Cordero-Vargas et al. / Tetrahedron Letters 45 (2004) 7335–7338
Table 1. Addition products
Starting xanthate
Olefin
Product (yield %)
8, R1 = OM e,
3
16, R1 = OM e,
R2 = H, R3 = OM e
9, R1 = OPiv,
R2 = H, R3 = OMe (77%)
17, R1 = OPiv,
R2 = OMe, R3 = H
R2 = OMe, R3 = H (95%)
1013
18
(64%)
Scheme 1.
11
14
19 (58%)a
With tetralones 5a–b in hand, completion of the synthe-
sis required only the aromatization step. It was antici-
pated that oxidation of the C5–C6 bond would induce
enolization of the ketone moiety yielding the completely
aromatized product possessing an appropriately located
phenolic hydroxyl. After some experimentation, we
found that treatment of 5a–b with Br2 and a catalytic
amount of AlCl3 in Et2O followed by elimination under
basic conditions furnished C-aryl glycosides 7a and 7b in
good yields11 (Scheme 2).
12
15
20 (42%)b
a Along with 27% recovered starting material.
b 44% recovered starting material.
Adducts 16–20 were then treated with a stoichiometric
amount of DLP in DCE to give the corresponding tetra-
lones 21–23 in variable yields (Table 2). Compounds 19
and 20 did not afford the expected tetralones, producing
a complex mixture of products instead. The reasons for
the failures with these two compounds are still unclear.
It is possible that intramolecular hydrogen abstraction
followed by an uncontrolled sequence competed success-
fully with the desired ring-closure to the tetralone.
Table 2. Cyclization products
Adduct
Tetralone (yield %)
Scheme 2.
16, R1 = OM e,
21, R1 = OMe, R2 = H,
R3 = OMe (41%)
22, R1 = OPiv, R2 = OM e,
R3 = H (26%)
We have thus been able to assemble in a few steps com-
plex structures, which would otherwise be only tediously
accessible by conventional routes.
R2 = H, R3 = OM e
17, R1 = OPiv,
R2 = OMe, R3 = H
Having developed an effective and regioselective strategy
for preparing group I C-aryl glycosides, it remained to
extend this approach to different starting xanthates
and carbohydrates. Thus, acetophenone xanthates 8–
12 were subjected to the same reaction conditions
depicted below in the presence of known olefins 3,8
13,12 14,13 and 1514 to afford the corresponding adducts
16–20 in good to excellent yields (Table 1).
18
19
20
23 (65%)
Degradation
Degradation

A. Cordero-Vargas et al. / Tetrahedron Letters 45 (2004) 7335–7338
7337
9. Synthesis of ( )-S-[4-(4-chlorophenyl)-1-(1,2-O-isopropyl-
idene-3-O-methyl-a-D-glucofuranosyl)-4-oxobutyl] O-ethyl-
dithiocarbonate 4a. A solution of 2a (0.5g, 1.81mmol)
and 3 (0.73g, 3.63mmol) in 1,2-dichloroethane (1.8mL)
was refluxed for 15min under argon. Lauroyl peroxide
(DLP) was then added (5mol%) to the refluxing solution,
followed by additional portions (2mol% every 90min).
When starting material was completely consumed (after
addition of 17mol% of DLP), the crude mixture was
cooled to room temperature, concentrated under reduced
pressure, and the residue was purified by flash column
chromatography (silica gel, petroleum ether–ethyl acetate,
9:1) to give adduct 4a (0.801g, 93%) as a separable mixture
of diastereoisomers (ratio 2:1). Diastereoisomer I (white
crystals, recrystallized from petroleum ether, mp = 95–
96°C): 1H NMR (CDCl3, 400MHz) d 7.88 (d, 2H, CH
arom, J = 8.0Hz), 7.42 (d, 2H, CH arom, J = 8.8Hz), 5.92
(d, 1H, O–CH–O, J = 4.0Hz), 4.6 (q, 2H, OCH2,
J = 7.1Hz), 4.55 (d, 1H, O2CH–CH, J = 4.4Hz), 4.34
(dd, 1H, S–CH–CH, J = 9.4, 3Hz), 4.18 (dt, 1H, CH–S,
J = 9.4, 4.3Hz), 3.79 (d, 1H, CH–OMe, J = 2.8Hz), 3.36
(s, 3H, OCH3), 3.10–3.24 (m, 2H, CO–CH2), 2.46–2.53 (m,
1H, CO–CH2–CH2), 2.05–2.14 (m, 1H, CO–CH2–CH2),
1.50 (s, 3H, C–CH3), 1.39 (t, 3H, CH2–CH3, J = 7.0Hz),
1.32 (s, 3H, C–CH3); 13C NMR (CDCl3, 100MHz) d 213.1
(C@S), 198.1 (CO), 139.4 (C–CO), 135.2 (C–Cl), 129.5
(CH arom), 128.9 (CH arom), 111.8 (O–C–O), 105.3 (O–
CH–O), 84.1 (O2CH–CH), 81.2 (S–CH–CH), 81.1 (CH–
S), 70.3 (OCH2), 57.9 (OCH3), 48.4 (CH–OMe), 35.8
(CO–CH2), 27.0 (CO–CH2–CH2), 26.9 (C–CH3), 26.3 (C–
CH3), 13.8 (CH2–CH3); IR (CCl4) 1691 (C@O), 1217
These preliminary studies indicate that this approach
could indeed be used to construct the gilvocarcins (1a–
b). The conditions are mild and many substituents are
tolerated. The successful synthesis of differentially pro-
tected dihydroxy derivatives 21 and 22 is particularly
relevant in this context. Furthermore, because this
approach allows the use of a great variety of substituents
(including electron withdrawing groups) on the aromatic
ring and on the sugar moiety, it should be useful for the
expedient preparation of a broad variety of analogues of
the natural products.
Acknowledgements
We would like to thank CONACYT (Mexico) for gener-
ous financial support (A.C.V.).
Supplementary data
Supplementary material associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2004.08.009. This contains detailed description of experi-
mental procedures and spectral information and analy-
ses for new compounds.
(C@S), 1052 (S–C) cmÀ1
;
MS (CI+NH3) m/z
References and notes
494 (MH++NH3), 492 (MH++NH3), 477 (MH+), 475
25
1. For reviews see: (a) Jaramillo, C.; Knapp, S. Synthesis
1994, 1; (b) Suzuki, K.; Matsumoto, T. In Preparative
Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel-
Dekker: New York, 1997; pp 527–542; (c) Posteme, M.
H. D. Tetrahedron 1992, 48, 8545.
2. (a) Matsumoto, T.; Hosya, T.; Suzuki, K. J. Am. Chem.
Soc. 1992, 114, 3568; (b) Hosoya, T.; Takashiro, E.;
Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116,
1004.
(MH+); ½aꢀD +15.4 (c 1, CHCl3). Diastereoisomer II
(colorless oil): 1H NMR (CDCl3, 400MHz) d 7.88 (d,
2H, CH arom, J = 8.8Hz), 7.47 (d, 2H, CH arom,
J = 8.8Hz), 5.91 (d, 1H, O–CH–O, J = 3.6Hz), 4.58–4.65
(m, 3H, OCH2 and O2CH–CH),4.34 (dd, 1H, S–CH–CH,
J = 8.8, 2.8Hz), 4.24 (dt, 1H, CH–S, J = 9.4, 3.4Hz), 3.78
(d, 1H, CH–OMe, J = 3.6Hz), 3.42 (s, 3H, OCH3), 3.16 (t,
2H, CO–CH2, J = 7.6Hz), 2.33 (dddd, 1H, CO–CH2–
CH2, J = 15.0, 7.6, 7.4, 3.5Hz), 1.98–2.07 (m, 1H, CO–
CH2–CH2), 1.48 (s, 3H, C–CH3), 1.39 (t, 3H, CH2–CH3,
J = 7.4Hz), 1.32 (s, 3H, C–CH3); 13C NMR (CDCl3,
100MHz) d 213.8 (C@S), 198.2 (CO), 139.5 (C–CO), 135.1
(C–Cl), 129.6 (CH arom), 128.9 (CH arom), 111.7 (O–C–
O), 104.9 (O–CH–O), 84.5 (O2CH–CH), 81.3 (S–CH–
CH), 80.6 (CH–S), 70.3 (OCH2), 57.7 (OCH3), 49.8 (CH–
OMe), 36.0 (CO–CH2), 26.9 (C–CH3), 26.3 (C–CH3), 25.1
(CO–CH2–CH2), 13.8 (CH2–CH3); IR (CCl4) 1690
(C@O), 1217 (C@S), 1052 (S–C) cmÀ1; MS (CI+NH3)
m/z 494 (MH++NH3), 492 (MH++NH3), 477 (MH+), 475
3. Matsumoto, T.; Hosoya, T.; Suzuki, K. Tetrahedron Lett.
1990, 31, 4629.
4. (a) Manitto, P.; Speranza, G.; Monti, D.; Fontana, G.;
Panosetti, E. Tetrahedron 1995, 51, 11531; (b) Hulme, A.
N.; Henry, S. S.; Meyers, A. I. J. Org. Chem. 1995, 60,
1265; (c) Schoepfer, J.; Gay, B.; End, N.; Muller, E.;
Scheffel, G.; Cravatti, G.; Furet, P. Bioorg. Med. Chem.
Lett. 2001, 11, 1201.
5. (a) Liard, A.; Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z.
Tetrahedron Lett. 1997, 38, 1759; (b) Cordero-Vargas, A.;
Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2003, 5, 3717.
6. For some recent publications involving cyclization of
carbon-centered radicals to aromatic ring systems, see: (a)
Kaoudi, T.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem.,
Int. Ed. 2000, 39, 731; (b) Ohno, H.; Wakayama, R.;
Maeda, S.; Iwasaki, H.; Okumura, M.; Iwata, C.; Mika-
miyama, H.; Tanaka, T. J. Org. Chem. 2003, 68, 5909; (c)
Clive, D. L.; Fletcher, S. P.; Liu, D. J. Org. Chem. 2004,
69, 3282; (d) Menes-Arzate, M.; Martinez, R.; Cruz-
Almanza, R.; Muchowski, J. M.; Osornio, Y. M.;
Miranda, L. D. J. Org. Chem. 2004, 69, 4001.
7. (a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672;
(b) Zard, S. Z. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M., Eds.; Wiley VCH: Weinheim,
2001; p 90.
25
(MH+); ½aꢀD À35.1 (c 1, CHCl3).
10. Synthesis of ( )-6-chloro-4-(1,2-O-isopropylidene-3-O-
methyl-a-D-glucofuranosyl)-3,4-dihydro-2H-naphthalen-
1-one 5a. A solution of 4a (0.67g, 1.43mmol) in 1,2-
dichloroethane (14mL) was refluxed for 15min under
argon. Lauroyl peroxide (DLP) was then added portion-
wise (20mol% per hour) to the refluxing solution. When
starting material was completely consumed (after addition
of 1.4equiv of DLP), the crude mixture was cooled to
room temperature, concentrated under reduced pressure,
and purified by flash column chromatography (silica gel,
petroleum ether–ethyl acetate, 9:1 to 2:1) to give tetralone
5a (0.283g in 57%) as a separable mixture of diastereo-
isomers. Diastereoisomer I (white needles, recrystallized
from petroleum ether, mp = 129–132°C): 1H NM
(CDCl3, 400MHz) d 8.0 (d, 1H, CH arom, J = 8.8Hz),
7.35 (d, 1H, CH arom, J = 8.8Hz), 7.35 (s, 1H, CH arom),
R
8. Josan, J. S.; Eastwood, F. W. Carbohydr. Res. 1968, 7,
161.

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A. Cordero-Vargas et al. / Tetrahedron Letters 45 (2004) 7335–7338
5.93 (d, 1H, O–CH–O, J = 4.0Hz), 4.62 (d, 1H, O2CH–
Br2 (0.027g, 0.008mL, 0.17mmol). The cooling bath was
then removed and the mixture was stirred at room
temperature for a further 1h. When starting material
was completely consumed, the solvent was removed under
reduced pressure and the resulting mass decolorized with a
1:1 mixture of CH2Cl2/water and extracted with CH2Cl2.
The combined organic extracts were dried and evaporated
and the residue was then dissolved in 1mL of DMF and
0.025g (3.4mmol) of Li2CO3 and 0.03g (3.4mmol) of LiBr
were added to the reaction mixture. The solution was
heated for 30min at 140°C, cooled to room temperature,
extracted with diethyl ether, and the combined organic
extracts were dried and concentrated in vacuo. The residue
was purified by flash column chromatography (silica gel,
petroleum ether–ethyl acetate, 8:2) and recrystallized with
CH2Cl2/petroleum ether to give C-aryl glycoside 7a
(0.037g, 61% overall yield from 5a) as pale-brown crystals
(mp = 184–187°C): 1H NMR (CDCl3, 400MHz) d 8.22 (d,
1H, CH arom, J = 8.8Hz), 7.83 (d, 1H, CH arom,
J = 2.0Hz), 7.63 (d, 1H, CH arom, J = 7.6Hz), 7.43 (dd,
1H, CH arom, J = 9.0, 7.6Hz), 6.79 (d, 1H, CH arom,
J = 8.0Hz), 6.15 (d, 1H, O–CH–O, J = 4.0Hz), 5.79 (d,
1H, Ar–CH, J = 2.8Hz), 4.75 (d, 1H, O2CH–CH,
J = 3.6Hz), 4.05 (d, 1H, CH–OMe, J = 3.2Hz), 2.89 (s,
3H, OCH3), 1.67 (s, 3H, C–CH3), 1.43 (s, 3H, C–CH3);
13C NMR (CDCl3, 100MHz) d 151.4 (C–OH), 132.9 (C–
Cl), 132.2 (C–COH), 126.8 (CH arom), 125.6 (CH arom),
124.8 (CH arom), 122.6 (C–CH), 122.3 (C–CCH), 121.2
(CH arom), 111.9 (O–C–O), 108.7 (CH arom), 104.1 (O–
CH–O), 84.9 (O2CH–CH), 83.2 (Ar–CH), 78.5 (CH–
OMe), 58.6 (OCH3), 27.0 (C–CH3), 26.4 (C–CH3); IR
CH, J = 4.0Hz), 4.17 (dd, 1H, Ar–CH–CH, J = 10.8,
2.8Hz), 3.51 (s, 3H, OCH3), 3.45–3.56 (m, 1H, Ar–CH),
3.36 (d, 1H, CH–OMe, J = 2.8Hz), 2.78 (ddd, 1H, CO–
CH2, J = 19.2, 14.2, 5.2Hz), 2.64 (ddd, 1H, CO–CH2–
CH2, J = 18.6, 4.8, 2.0Hz), 2.51 (dddd, 1H, CO–CH2–
CH2, J = 14.4, 5.2, 2.4, 2.4Hz), 2.18 (tt, 1H, CO–CH2,
J = 14.0, 4.8Hz), 1.40 (s, 3H, C–CH3), 1.30 (s, 3H, C–
CH3); 13C NMR (CDCl3, 100MHz) d 197.1 (CO), 145.5
(C–CO), 139.8 (C–Cl), 131.2 (C–CH), 129.4 (CH arom),
129.2 (CH arom), 128.1 (CH arom), 111.7 (O–C–O), 104.9
(O–CH–O), 83.0 (O2CH–CH), 80.8 (Ar–CH–CH), 79.9
(CH–OMe), 56.8 (OCH3), 35.7 (Ar–CH), 33.6 (CO–CH2),
26.9 (C–CH3), 26.2 (C–CH3), 24.2 (CO–CH2–CH2); IR
(CCl4) 1691 (C@O) cmÀ1
;
MS (CI+NH3) m/z
372 (MH++NH3), 370 (MH++NH3), 355 (MH+), 353
25
(MH+); ½aꢀD À53.9 (c 1, CHCl3). Diastereoisomer II (white
powder, recrystallized from petroleum ether, mp = 108–
1
110°C): H NMR (CDCl3, 400MHz) d 7.96 (d, 1H, CH
arom, J = 8.4Hz), 7.58 (d, 1H, CH arom, J = 1.6Hz), 7.29
(dd, 1H, CH arom, J = 8.0, 1.6Hz), 5.96 (d, 1H, O–CH–O,
J = 4Hz), 4.63 (d, 1H, O2CH–CH, J = 4.0Hz), 4.25 (dd,
1H, Ar–CH–CH, J = 10.0, 2.8Hz), 3.75 (d, 1H, CH–OMe,
J = 2.8Hz), 3.48 (s, 3H, OCH3), 3.30 (ddd, 1H, Ar–CH,
J = 10.0, 5.0, 4.8Hz), 2.60–2.75 (m, 2H, CO–CH2), 2.20–
2.29 (m, 1H, CO–CH2–CH2), 1.96–2.02 (m, 1H, CO–CH2–
CH2), 1.40 (s, 3H, C–CH3), 1.31 (s, 3H, C–CH3); 13C
NMR (CDCl3, 100MHz) d 196.8 (CO), 146.8 (C–CO),
139.8 (C–Cl), 130.6 (CH arom), 130.5 (C–CH), 128.8 (CH
arom), 127.8 (CH arom), 111.5 (O–C–O), 104.9 (O–CH–
O), 84.1 (O2CH–CH), 81.1 (Ar–CH–CH), 80.7 (CH–
OMe), 57.6 (OCH3), 37.2 (Ar–CH), 35.4 (CO–CH2), 26.6
(C–CH3), 26.1 (C–CH3), 25.1 (CO–CH2–CH2); IR (CCl4)
1690 (C@O) cmÀ1; MS (CI+NH3) m/z 372 (MH++NH3),
(CCl4) 3603 (OH) cmÀ1
; MS (CI+NH3) m/z 370
(MH++NH3), 368 (MH++NH3), (MH+), 353 (MH+),
25
351 (MH+); ½aꢀD À67.83 (c , CHCl3); Anal. Calcd for
25
370 (MH++NH3), 355 (MH+), 353 (MH+); ½aꢀD À23.15
C18H19ClO5: C, 61.63; H, 5.46. Found: C, 61.92; H, 5.63.
12. May, J. A.; Sartorelli, A. C. J. Med. Chem. 1979, 22, 971.
13. Giannis, A.; Sandhoff, K. Tetrahedron Lett. 1985, 26,
1479.
(c 1, CHCl3).
11. Synthesis of 6-chloro-4-(1,2-O-isopropylidene-3-O-meth-
yl-a-D-glucofuranosyl)-naphthalen-1-ol 6a. To a stirred
solution of 5a (0.06g, 0.17mmol) and AlCl3 (0.002g,
0.017mmol) in Et2O (1.7mL) at 0°C was added dropwise
14. Haudrechy, A.; Sina, P. J. Org. Chem. 1992, 57,
4142.