Zinc-mediated synthesis of α-C-glycosides from 1,2-anhydroglycosides

Article abstract of DOI:10.1055/s-2003-38751

α-C-Glycosides have been prepared by the addition of organozinc reagents to glycal epoxides. Dialkyl and diaryl zinc reagents in the presence of CF₃COOH provide the corresponding α-glycosides in 53-82% yields. Organozinc chlorides RZnC1 formed

Full text of DOI:10.1055/s-2003-38751

870
LETTER
Zinc-Mediated Synthesis of a-C-Glycosides from 1,2-Anhydroglycosides
Z
inc-Mediated
o
Synthesis of
n
α
-
C
-Glyco
g
s
Xue,* Kai-Zhen Han, Lin He, Qing-Xiang Guo
Department of Chemistry, University of Science and Technology of China, Hefei, 230026, P.R.China
E-mail: xuesong@ustc.edu.cn
Received 24 February 2003
Abstract: α-C-Glycosides have been prepared by the addition of
O
O
organozinc reagents to glycal epoxides. Dialkyl and diaryl zinc re-
agents in the presence of CF3COOH provide the corresponding
α-glycosides in 53–82% yields. Organozinc chlorides RZnCl
formed by the reaction RLi with zinc chloride can also be success-
fully applied to this coupling reaction with high α-selectivity.
O
O
BnO
BnO
BnO
BnO
O
OBn
OBn
2
1
Key words: α-C-glycosides, epoxide, organozinc reagents, stereo-
selectivity, trifluoroacetic acid
RZnX
R
O
R
O
BnO
BnO
BnO
BnO
C-Glycosides are conformationly stable glycoside ana-
logues, which have received a great deal of attention from
the synthesis and medicinal chemistry.1 Due to the impor-
tance of the stereochemical outcome of the C-glycosides,
which must be at least highly stereoselective, if not ste-
reospecific, great effort has been made to develop a num-
ber of elegant approaches to their synthesis.2 The addition
of organometallic reagents to glycal epoxides is a funda-
mental preparation of these compounds. Grignard re-
agents,3 copper reagents,4 and organostannanes5,4b
generally prefer to give β-C-glycosides, which have a
trans relationship between the C-2 hydroxy group and the
formed C-1 carbon-carbon bond. While the addition of
aluminum and boron reagents6 to glycal epoxides has
been reported to provide α-C-glycosides with good
yields. Another synthetic approach to α-C-glycosides
from epoxides concerns the reductive ring opening of ep-
oxides with titanocene(III) chloride in the presence of
trapping reagents.7
+
OH
OH
OBn
OBn
3
4
Scheme 1
stant (J2,3 = 8.8 Hz) and a smaller coupling constant
(J1,2 = 5.5 Hz) at δ = 5.05 ppm. These data are consistent
with prediction for α-C-glycoside.11 The choice of Et2O
as solvent affords a 45% yield of 3a after stirring for 16
hours. Reaction performed in THF provides only small
amount of 3a after lengthy reaction time (24 h).
The reaction is applicable to a variety of zinc reagents.12
Dimethylzinc in the presence of CF3COOH behaves iden-
tically to give α-C-glycoside 3b in 81% yield. Aryl zinc
compounds, such as diphenylzinc and difurylzinc, can
Here, we wish to report our preliminary results regarding
the addition of organozinc species to glycal epoxides
(Scheme 1). The cis addition products previously ob-
tained in the addition of organozinc reagents to cyclo-1,3-
diene monoepoxide prompted us to verify the possibility
of zinc-mediated synthesis of α-C-Glycosides from 1,2-
anhydroglycosides.8
Table 1 Addition of ZnR2 to Epoxide 2 in the Presence of CF3CO2H
Entry ZnR2
Solvent
Time Product Yield
(h)
(%)a
1
2
3
4
5
ZnEt2
ZnEt2
ZnMe2
ZnPh2
CH2Cl2
Et2O
3
3a
3a
3b
3c
3d
65
16
4
45
The epoxidation of tribenzyl-D-glucal 1 according to
Danishefsky’s protocol9 followed by the addition of
CF3CO2ZnEt, which is in situ formed by the reaction of
ZnEt2 with CF3COOH in CH2Cl2, gives α-C-glycoside 3a
with complete stereoselectivity in a 65% yield (entry 1 in
Table 1).10 The stereochemical elucidation of the addition
CH2Cl2
CH2Cl2
CH2Cl2
81
5
64
5
82
O
Zn
2
1
product is based on the analysis of H NMR spectra. In-
1
6
7
CH2Cl2
CH2Cl2
3
5
3e
3f
58
53
Zn
Zn
deed, the H NMR spectrum of the corresponding O-2-
Cl
2
acetylated derivative of 3a shows a large coupling con-
Synlett 2003, No. 6, Print: 05 05 2003.
Art Id.1437-2096,E;2003,0,06,0870,0872,ftx,en;U03403ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
2
OAc
a Isolated yields.

LETTER
Zinc-Mediated Synthesis of α-C-Glycosides from 1,2-Anhydroglycosides
871
also be added to the epoxide 2 and afford the correspond- The mechanism is closely related to that proposed by J. D.
ing addition products in 64% and 82% yields respectively. Rainier in his work.6b The transfer of R group from RZnX,
which can act as a Lewis acid system as well as being nu-
Importantly, functionalized zinc reagents proceed
cleophilic in character, occurs from the same face as the
smoothly, and the reaction is able to withstand the inclu-
oxygen of epoxide and results in a cis addition product.
sion of halide and ester (entries 6 and 7 in Table 1).
In conclusion, we have demonstrated a new method for
Encouraged by this initial result, we wish to extend further
the organozinc reagents ZnR2 to zinc halide RZnX, since
it is atom efficient. Treatment of n-BuZnCl, which is eas-
ily prepared by the reaction of n-butyllithium with anhy-
drous zinc chloride in diethyl ether, with the glycal
epoxide 2 affords the corresponding addition product with
high α selectivity in 69% yield (entry 2 in Table 2). Use
of higher concentration of organozinc specie n-BuZnCl
the synthesis of α-C-glycosides using organozinc species.
CF3CO2ZnR affords α-glycosides with completely stereo-
control, whereas organozinc chloride RZnCl provides ad-
dition products with different degree of stereoselectivity,
depending upon the organometallic reagent used. Addi-
tional studies of the scope are in progress.
could improve the reaction efficiency (entry 1 vs. entry 2
in Table 2). According to the conditions optimized for or-
ganozinc halide addition reaction, phenyl and furyl lithi-
um in this manner also give the desired α-C-glycoside in
78% and 72% yields, respectively. Similarly, the reaction
of acetylenic lithium with ZnCl2 and epoxide 2 give only
the products of α-C-glycosides in good yields.13,14
Acknowledgment
We thank the National Natural Science Foundation of China
(20202009) and the Natural Science Foundation of Anhui province
for financial support.
References
(1) (a) Levy, D. E. Tang, C. The Chemistry of C-Glycosides;
Elsevier Science: Tarrytown New York, 1995. (b) Postema,
M. H. D. C-Glycoside Synthesis; CRC Press: Boca Raton,
1995.
(2) For recent review of C-glycosides see: (a) Postema, M. H.
D. In Glycochemistry Principles, Synthesis and
Table 2 Addition of RLi or Grignard Reagents to Epoxide 2 in Pres-
ence of ZnCl2
a
Entry RM
Time
(h)
Product Yield α/βc
(%)b
1d
2
n-BuLi
16
5
3g
3g
3c
3d
41
69
78
72
>95/5
>95/5
>95/5
>95/5
Applications; Bertozzi, C.; Wang, P. G., Eds.; Marcel
Dekker: New York, 2000, 77–131. (b) Du, Y.; Lindhart, R.
J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913.
n-BuLi
(3) (a) Klein, L. L.; McWhorter, W. W. Jr.; Ko, K. P.; Kishi, Y.;
Uemura, D.; Hirata, Y. J. Am. Chem. Soc. 1982, 104, 7362.
(b) Best, W. M.; Ferro, V.; Harle, J.; Stick, R. V.; Tilbrook,
D. M. G. Aust. J. Chem. 1997, 50, 463. (c) Rainier, J. D.;
Allwein, S. P. J. Org. Chem. 1998, 63, 5310. (d) Rainier, J.
D.; Allwein, S. P. Tetrahedron Lett. 1998, 39, 9601.
(e) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W.
B.; Rainier, J. D. Tetrahedron 2002, 58, 1997.
(4) (a) Bellosta, V.; Czernecki, S. J. Chem. Soc., Chem.
Commun. 1989, 199. (b) Evans, D. A.; Trotter, B. W.; Cote,
B. Tetrahedron Lett. 1998, 39, 1709.
(5) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Cote, B.; Dias,
L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55,
8671.
3
PhLi
5
4
5
O
Li
5
6
7
8
Ph–C≡C–Li
5
5
4
4
3h
3i
86
80
41
74
100/0
100/0
66/34
0/100
Li
n-BuMgCl
3g
4a
MgCl
a Reaction condition: epoxide is added to 4.0 equiv of preformed re-
agent (RM, ZnCl2), CH2Cl2, 0 °C to r.t.
b Isolated yields.
(6) (a) Bailey, J. M.; Craig, D.; Gallagher, P. T. Synlett 1999,
132. (b) Rainier, J. D.; Cox, J. M. Org. Lett. 2000, 2, 2707.
(7) Parrish, J. D.; Little, R. D. Org. Lett. 2002, 4, 1439.
(8) Xue, S.; Li, Y. L.; Han, K. Z.; Yin, W.; Wang, M.; Guo, Q.
X. Org. Lett. 2002, 4, 905.
c Determined by 1H NMR.
d 2.0 Equiv of reagent is used.
(9) Halcomb, R. L.; Danishefsky, S. J. J Am. Chem. Soc. 1989,
111, 6661.
Of note are attempted coupling reactions with Grignard
reagents in the presence of anhydrous zinc chloride.
Treatment of n-butylmagnesium chloride with ZnCl2, fol-
lowed by epoxide 2, provides a 66:34 mixture of α- and β-
C-glycosides (entry 7 in Table 2).15 On the other hand, the
reaction of allylmagnesium chloride with ZnCl2 and ep-
oxide 2 affords exclusively the β-C-glycoside (entry 8 in
Table 2). Essentially the same result was obtained when
the above reaction was carried out in the absence of anhy-
drous zinc chloride.3 We intend to further study these re-
actions to improve both yield and stereochemical control.
(10) General Procedure for Preparation of α-C-Glycosides.
To a solution of tri-O-benzyl-D-glucal (42 mg, 0.1 mmol)
and 1.5 mL of CH2Cl2 at 0 °C was added a solution of
dimethyldioxirane (0.15 mmol) in actone dropwise. After
stirring for 30 min, the reaction mixture was concentrated in
vacuum. The resulting white solid was taken up in CH2Cl2
(1.0 mL). To another solution of ZnR2 (0.2 mmol, 2 equiv)
in 1 mL of CH2Cl2 at 0 °C was added CF3COOH (15 µL, 0.2
mmol, 2 equiv) very slowly via syringe under N2. After
stirring for 30 min, to this solution was added the solution of
epoxide dropwise via syringe. The mixture was stirred for 3–
5 h from 0 °C to r.t. The reaction was quenched with sat. aq
NH4Cl and extracted with CH2Cl2 (3 × 10 mL). The
Synlett 2003, No. 6, 870–872 ISSN 0936-5214 © Thieme Stuttgart · New York

872
S. Xue et al.
LETTER
combined organic solution was washed with brine, dried
(MgSO4), and concentrated. Then, the product was isolated
by silica gel column chromatography. Acetylated 3a: Mp
55–56 °C. 1H NMR (400 MHz, CDCl3): δ = 7.33–7.27 (m,
13 H), 7.16 (m, 2 H), 5.05 (dd, J = 8.8, 5.5 Hz, 1 H), 4.77 (d,
J = 11.5 Hz, 1 H), 4.74 (d, J = 9.5 Hz, 1 H), 4.71 (d, J = 11.2
Hz, 1 H), 4.63 (d, J = 12.2 Hz, 1 H), 4.52 (d, J = 10.3 Hz, 1
H), 4.50 (d, J = 10.9 Hz, 1 H), 4.02 (m, 1 H), 3.82 (m, 1 H),
3.71–3.65 (m, 4 H), 1.99 (s, 3 H), 1.70 (m, 1 H), 1.48 (m, 1
H), 0.94 (t, J = 7.4 Hz, 3 H). 13C NMR (400 MHz, CDCl3):
δ = 170.1, 138.4, 138.2, 138.0, 128.4, 128.3, 128.0, 127.8,
127.7, 127.6, 80.2, 77.7, 74.7, 74.6, 73.7, 73.5, 73.1, 71.6,
69.0, 20.9, 19.1, 9.6. HRMS (FAB+) calcd for C31H36O6:
505.2590 [MH+]. Found: 505.2585. Acetylated 3e: Mp 62–
63 °C. 1H NMR (400 MHz, CDCl3): δ = 7.33–7.26 (m, 13
H), 7.15 (m, 2 H), 5.05 (dd, J = 8.6, 5.3 Hz, 1 H), 4.76 (d,
J = 11.5 Hz, 1 H), 4.74 (d, J = 10.4 Hz, 1 H), 4.71 (d, J = 9.8
Hz, 1 H), 4.61 (d, J = 12.1 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1
H), 4.49 (d, J = 10.8 Hz, 1 H), 4.11 (m, 1 H), 3.82 (m, 1 H),
3.72–3.65 (m, 4 H), 3.51 (t, J = 6.6 Hz, 2 H), 1.99 (s, 3 H),
127.9, 127.8, 127.7, 127.6, 80.1, 77.6, 74.8, 74.7, 73.6, 73.1,
72.1, 72.0, 69.0, 64.3, 29.8, 28.4, 25.7, 21.8, 21.0. HRMS
(FAB+) calcd for C35H42O8: 591.2958 [MH+]. Found:
591.2952. Acetylated 3h: Mp 70–71 °C. 1H NMR (300
MHz, CDCl3): δ = 7.38 (m, 2 H), 7.29–7.19 (m, 16 H), 7.08
(m, 2 H), 5.13 (d, J = 5.7 Hz, 1 H), 4.91 (dd, J = 9.9, 5.7 Hz,
1 H), 4.81–4.71 (m, 3 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.48 (d,
J = 10.8 Hz, 1 H), 4.46 (d, J = 12.3 Hz, 1 H), 3.98 (m, 2 H),
3.71–3.63 (m, 3 H), 1.96 (s, 3 H). 13C NMR (300 MHz,
CDCl3): δ = 170.2, 138.7, 138.2, 138.1, 132.1, 128.6, 128.5,
128.2, 128.1, 127.9, 127.8, 122.3, 89.6, 83.2, 81.4, 77.9,
75.5, 75.4, 74.2, 73.7, 72.8, 68.8, 66.3, 21.1. IR (KBr): ν =
2909, 2228, 1741, 1454, 1238, 1099, 1041 cm–1. HRMS
(FAB+) calcd for C37H36O6: 599.2409 [MNa+]. Found:
599.2408.
(11) (a) The stereochemistry of α-C-glycosides was assigned
from the coupling constants, which J1,2 value ranged from
4.2 to 5.9 Hz. (b) Leeuwenburgh, M. A.; Timmers, C. M.;
van der Marel, G. A.; van Boom, J. H.; Mallet, J. M.; Sinay,
P. G. Tetrahedron Lett. 1997, 38, 6251. (c) See ref.6b
(12) For trifluoracetic acid accelerated the cyclopropanation of
olefins, see: (a) Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron
Lett. 1998, 39, 8621. (b) Charette, A. B.; Lacasse, M. C.
Org. Lett. 2002, 4, 3351.
(13) For ZnCl2 mediated sodium malonate addition to glycal
epoxides with β-selectivity, see: Timmers, C. M.; Dekker,
M.; Buijsman, R. C.; van der Marel, G. A.; Ethell, B.;
Anderson, G.; Burchell, B.; Mulder, G. J.; van Boom, J. H.
Bioorg. Med. Chem. Lett. 1997, 7, 1501.
1.80–1.77 (m, 3 H), 1.55 (m, 1 H), 1.43–1.40 (m, 2 H). 13
C
NMR (400 MHz, CDCl3): δ = 170.1, 138.4, 138.1, 137.9,
129.7, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 80.0, 77.5,
74.7, 74.6, 73.5, 72.9, 71.9, 68.9, 44.8, 32.2, 25.4, 22.6, 20.9.
HRMS (FAB+) calcd for C33H39O6Cl: 567.2513 [MH+].
Found: 567.2500. Acetylated 3f: Mp 77–78 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.27–7.10 (m, 13 H), 7.10 (m, 2 H),
4.98 (dd, J = 8.7, 5.4 Hz, 1 H), 4.71 (d, J = 11.8 Hz, 1 H),
4.67 (d, J = 10.7 Hz, 1 H), 4.65 (d, J = 11.1 Hz, 1 H), 4.55
(d, J = 12.1 Hz, 1 H), 4.46 (d, J = 11.9 Hz, 1 H), 4.44 (d,
J = 10.9 Hz, 1 H), 4.09–3.94 (m, 3 H), 3.74 (m, 1 H), 3.66–
3.59 (m, 4 H), 1.96 (s, 3 H), 1.93 (s, 3 H), 1.71–1.51 (m, 4
H), 1.47–1.26 (m, 2 H). 13C NMR (400 MHz, CDCl3): δ =
171.2, 170.1, 138.4, 138.2, 138.1, 128.5, 128.4, 128.1,
(14) For ZnCl2 mediated acetylide anion additions to glycal
epoxides with α-selectivity, see ref.11a
(15) For comparison, the reaction of n-butylmagnesium chloride
with epoxide 2 in THF from –78 °C to 0 °C gave a 45:55
mixture of α- and β-C-glycoside.
Synlett 2003, No. 6, 870–872 ISSN 0936-5214 © Thieme Stuttgart · New York