Umpolung strategy for the synthesis of 2-deoxy-C-aryl glycosides: A serendipitous, efficient route for C-furanoside analogues

Article abstract of DOI:10.1021/ol025794w

Matrix presented 2-Deoxy-C-aryl glycosides are potential synthetic targets as they form a very vital moiety of several biologically active natural products. This paper describes a synthetic route using an umpolung strategy, which has not been explored til

Full text of DOI:10.1021/ol025794w

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1739-1742
Umpolung Strategy for the Synthesis of
2-Deoxy-C-aryl Glycosides: A
Serendipitous, Efficient Route for
C-Furanoside Analogues†
S. Vijayasaradhi and Indrapal Singh Aidhen*
Department of Chemistry, Indian Institute of Technology,
Madras, Chennai-600 036, India
isingh@iitm.ac.in
Received February 28, 2002
ABSTRACT
2-Deoxy-C-aryl glycosides are potential synthetic targets as they form a very vital moiety of several biologically active natural products. This
paper describes a synthetic route using an umpolung strategy, which has not been explored till date. Our synthetic endeavor led to a versatile
intermediate aryl ketone 10, which has paved the way for two important classes of C-glycosides, viz., C-alkyl furanosides 12 and methyl
2-deoxy-C-aryl pyranosides 14.
The C-aryl glycosides, part of the general C-glycoside1
family, are carbohydrates with an aromatic ring directly
attached to the anomeric carbon. Due to a strong C-C bond
at the anomeric center, they are endowed with an inherent
ability to withstand enzymatic and chemical hydrolysis.2
These compounds therefore constitute an important class of
biologically active natural products.3 The class 2-deoxy-C-
aryl glycosides, in particular, constitutes a common structural
feature of several groups of antitumor antibiotics such as
the angucyclines,4 pluramycin,5 gilvocarcins,6 and the vineo-
mycins.7 Hence, they have become a vital subject of synthetic
interest8 to practicing carbohydrate chemists. The synthesis
of C-aryl glycosides can be broadly classified as (1)
activation of the anomeric center either as an electrophilic
oxonium ion or as a nucleophilic carbanion followed by
reaction with the corresponding aromatic equivalents,8,9 (2)
transition metal mediated cross-coupling between suitably
functionalized glycosyl and aromatic coupling partners,10 (3)
cycloaddition between aromatic aldehydes and activated
dienes,11 and (4) benzannulation strategies based on as-
(6) Takahashi, K.; Yoshida, M.; Tomita, F.; Shirahata, K. J. Antibiot.
1981, 34, 271-275. (b) Hirayama, N.; Takahashi, K.; Shirahata, K.; Ohashi,
Y.; Sasada, Y. Bull. Chem. Soc. Jpn. 1981, 54, 1338-1342. (c) Horii, S.;
Fukase, H.; Mizuta, E.; Hatano, K.; Mizuno, K. Chem. Pharm. Bull. 1980,
28, 3601-3020.
(7) Imamura, N.; Kakinuma, K.; Ikekawa, N.; Tanaka, H.; Omura, S. J.
Antibiot. 1981, 34, 1517-1518.
(8) Kaelin, D. E., Jr.; Lopez, O. D.; Martin, S. F. J. Am. Chem. Soc.
2001, 123, 6937-6938 and references therein.
(9) Suzuki, K.; Matsumoto, T. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel-Decker: New York, 1997; pp 527-542.
(10) For a review, see: Frappa, I.; Sinou, D. J. Carbohydr. Chem. 1997,
16, 255.
† Dedicated to Professor K. K. Balasubramanian and Professor B.
Viswanathan (both from IIT-M, Chennai).
(1) Du, Y.; Linhardt, R. J. Tetrahedron 1998, 54, 9913.
(2) Kuribayashi, T.; Ohkawa, N.; Satoh, S. Bioorg. Med. Chem. Lett.
1998, 8, 3307-3310.
(3) Hansen, M. R.; Hurley, L. H. Acc. Chem. Res. 1996, 29, 249 and
references therein.
(4) Krohn, K.; Rohr, J. Top. Curr. Chem. 1997, 188, 127-195.
(5) Nadig, H.; Sequin, U. HelV. Chim. Acta 1987, 70, 1217-1228. (b)
Sequin, U. Fortschr. Chem. Org. Naturst. 1986, 50, 58-122.
10.1021/ol025794w CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/17/2002

sembling the glycosylated aromatic ring from suitably
functionalized carbohydrate precursors.12
X should be available from a suitably protected D-arabinose
derivative.
The retrosynthetic analysis depicted in Scheme 1 invokes
the use of an umpolung strategy. The route based on the
The ready accessibility of the differentially protected sugar
aldehyde 616 (Scheme 2) from D-arabinose paved the way
Scheme 2. Synthesis of Electrophile 5a
Scheme 1. Retrosynthetic Approach for 2-Deoxy-C-aryl
Glycoside
a Reagents: (a) NaBH4, CH3OH, 0 °C, 15 min, 83%. (b) para-
TsCl, Et3N, CHCl3, catalytic DMAP, 24 h, 27 °C, 80%. (c) NaI,
NaHCO3, (CH3)2CO, 60 °C, 75%.
for the required iodo derivative 5 as a synthetic equivalent
for the five-carbon electrophilic synthon X. Reduction of the
aldehyde 6 with sodium borohydride afforded the alcohol 7
in 70% yield, which was activated as the tosylate 8 and
converted to the iodide 5 in 75% yield by reaction with NaI
in acetone.
The R-aminonitriles 4a-g underwent clean alkylation with
the iodo compound 5, affording the alkylated products 9a-g
as diastereoisomeric mixtures in 75-77% yields (Scheme
3). The progress of the reaction could be easily seen by the
Scheme 3. Successful Alkylation of Aryl Acyl Anion
Equivalenta
umpolung strategy has never been explored in the literature
for the synthesis of 2-deoxy-C-aryl glycosides 1. The
hemiketal 2, a potential precursor for 1 should be readily
amenable from the aryl ketones 3. The strategy appeared to
be extremely attractive, as there is no dearth of acyl anion
equivalents in the literature.13 From the plethora of reagents
available for the acyl anion synthon Y, we were attracted
by the less frequently used R-aminonitriles 4, due to the
simplicity and convenience involved in their preparation on
a multigram scale.14 Also, unlike alkylations of other acyl
anion equivalents, which require much stronger bases,
stringent dry conditions, and low temperatures, alkylation
of R-aminonitriles are conveniently carried out at room
temperature.15 The arabino-configured electrophilic synthon
(11) (a) Danishefsky, S. J.; Uang, B. J.; Quallich, G. J. Am. Chem. Soc.
1985, 107, 1285. (b) Schmidt, R. R.; Frick, W.; Haag-Zeino, B.; Appara,
S. Tetrahedron Lett. 1987, 28, 4045. (c) Hart, D. J.; Leroy, V.; Merriman,
G. H.; Young, D. G. J. J. Org. Chem. 1992, 57, 5670. (d) Schmidt, B.;
Sattelkau, T. Tetrahedron. 1997, 53, 12991.
a Reagents: (a) NaH, Dry DMF, 1 h, 27 °C. (b) CuSO4‚5H2O,
CH3OH:H2O, 5-6 h, 60 °C.
(12) (a) Yamaguchi, M.; Hasebe, K.; Higashi, H.; Uchida, M.; Irie, A.;
Minami, T. J. Org. Chem. 1990, 55, 1611. (b) Yamaguchi, M.; Horiguchi,
A.; Ikeura, C.; Minami, T. J. Chem. Soc., Chem. Commun. 1992, 434.
(13) Ager, D. J. In Umpoled Synthons: A SurVey of Sources and Uses
in Synthesis; Hase, T. A., Ed.; John Wiley & Sons: New York, 1987; pp
19-72.
gradual decrease of the deep yellow color of the carbanion
after addition of the electrophile. Without any purification,
the alkylated products 9a-g were directly subjected to
hydrolysis using CuSO4‚5H2O in aqueous methanol at 60
(14) Dyke, S. F.; Tiley, E. P.; White, A. W. C.; Gale, D. P. Tetrahedron
1975, 31, 1219-1222.
1740
Org. Lett., Vol. 4, No. 10, 2002

°C.17 Clean unmasking of the keto functionality occurred to
furnish the aryl ketones18 10a-g in 68-70% yields.
Since hydrolysis of the terminal isopropylidene ketal
protection in aryl ketones 10a-g, under mild aqueous acidic
conditions, should in principle give the 2-deoxy-C-aryl
glycosides as hemiketals 11 (Scheme 4), compound 10a as
the proton signals in the molecule were perfomed by double-
quantum-filtered correlation spectroscopy (DQF-COSY). All
the carbons in the molecule were unambiguously correlated
to the proton signals by performing a heteronuclear multiple-
quantum coherence (HMQC) experiment. The presence of
an ether bridge between C-3 and C-6 was confirmed from a
heteronuclear multiple-bond correlation (HMBC) spectrum,
3
which clearly indicated a J correlation between C-3 and
H-6a, H-6b as well as between C-6 and H-3 (Figure 1, A).
Finally, rotating frame Overhauser spectroscopy (ROESY)
revealed a strong NOE for H-C (3)/H-C(5) and H-C(3)/
H-C(4), thereby locating all the substituents on the same
side of the molecule. Since the stereochemistry at C-4 and
C-5 is fixed, the orientation of the alkyl chain at C-3 must
be â.
Scheme 4. Serendipity Leading to the Formation of C-Alkyl
Furanosidesa
The mechanistic rationale for the formation of 12a is also
easily discernible (Scheme 5). Effective chelation of a proton
a Reagent: (a) 0.02 N H2SO4 in CH3CN.
Scheme 5. Mechanism for the Formation of 12a
a representative example was subjected to reaction with 0.02
N sulfuric acid in acetonitrile. Interestingly, the isolated
compound in 77% yield, strikingly revealed a characteristic
carbonyl functionality (δC ) 197.25 ppm in 13C NMR and
1
a strong band at ν ) 1680 cm-1 in IR spectrum). H NMR
further indicated the presence of only one benzyloxy group
(δH ) 4.41 and 4.76 ppm, each d, 2H, J ) 11.72 Hz). On
the basis of the spectral evidence, the isolated compound
was found to be 12a19 (Scheme 4).
The structure and the absolute configuration of the various
stereogenic centers in compound 12a were confirmed by
performing extensive NMR experiments. Assignment of all
between the oxygen atoms of the carbonyl group and
â-benzyloxy group promotes a facile â-elimination leading
to a potential Michael acceptor 13a. A facile intramolecular
Michael reaction from the more exposed face of the double
bond explains the formation of the product 12a with
dominant â-selectivity. The generality for the formation of
C-alkyl furanosides 12a-g from 10a-g, under 0.02 N H2SO4
in acetonitrile, was reproduced in good yields and â-selectiv-
ity as shown in Table 1.
To exclude the formation of the Michael acceptor 13a
either prior to or after the ketal hydrolysis, it became
imperative to use nonacidic conditions for the removal of
the isopropylidene ketal protection in 10a. With the prece-
dence that a dilute solution of iodine in methanol20 has been
(15) Selvamurugan, V.; Aidhen, I. S. Tetrahedron 2001, 57, 6065-6069.
(16) Babirad, S. A.; Wang, Y.; Kishi, Y. J. Org. Chem. 1987, 52, 1370-
1372.
(17) Buchi, G.; Liang, P. H.; Wuest, H. Tetrahedron Lett. 1978, 31,
2763-2764.
(18) These aryl ketones were not stable; therefore, they were immediately
used for subsequent reactions.
Figure 1. (A) Significant HMBC (f) and NOE observed in
ROESY (s) for 12a. (B) Significant NOE observed in the ROESY
for 14a.
Org. Lett., Vol. 4, No. 10, 2002
1741

carbons in the molecule were unambiguously correlated to
the proton signals by performing HMQC experiments. A
ROESY correlation (Figure 1, B) revealed an Overhauser
enhancement peak for OCH3-C(1)/H-C(3) and OCH3-
C(1)/H-C(5), clearly placing all these substituents on the
same side of the ring. Since the OCH3 is located R, the
orientation of the aryl moiety at C-1 was confirmed to be â.
The formation of the pyranoside product21 under 1% I2/
methanol solution conditions was further confirmed and
generalized by two more examples, 14b and 14c, as depicted
in Scheme 6.
Table 1. Formation of C-Alkyl Furanosides from 10a-g with
a Solution of 0.02 N H2SO4 in Acetonitrile in 1.5 h
entry
product
% yielda
R:â ratiob
1
2
3
4
5
6
7
12a
12b
12c
12d
12e
12f
12g
77
78
76
75
72
80
70
1:10
1:10.3
1:8
1:5.7
1:10
1:10
1:1
In conclusion, our synthetic studies toward 2-deoxy-C-
aryl glycosides, by an umpolung strategy that has not been
reported to date, has led to versatile intermediate, aromatic
ketones. These ketones provide both the pyranoside and
furanoside analogues in good yields and stereoselectivity by
a mere change in the deisopropylidenation conditions.
1
a Isolated yields. b Calculated from H NMR spectra.
used for deprotection of isopropylidene ketals, ketone 10a
was treated with a 1% solution of I2 in methanol (Scheme
6). To our satisfaction, a clean reaction ensued furnishing
Acknowledgment. We thank DST, New Delhi for
sponsoring this project [SP/S1/G-06/2000], RSIC, Chennai
for spectral studies, and Dr. Armin Geyer (University of
Regensburg, Germany) for performing some special NMR
experiments.
Scheme 6. Synthesis of Methyl 2-Deoxy-C-aryl
Glucopyranosidesa
Supporting Information Available: Characterization
data for compounds 5, 7, 12a-g, and 14a-c. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL025794W
a Reagents: (a) 1% I2 in CH3OH, 8 h, 27 °C, 76-80%.
(19) There is only one report for synthesis of this furanoside analogue
by a Claisen condensation of methyl ketones with sugar lactones. Both the
yields and stereoselectivity are poor in this work; see: Csuk, R.; Kuhn,
M.; Strohl, D. Tetrahedron 1997, 53, 1311-1322.
the required 2-deoxy-C-aryl glucopyranoside as the methyl
R-D-glucopyranoside derivative 14a in 76% yield. Un-
ambiguous assignments of all the proton signals in compound
14a were performed by a DQF-COSY experiment. All the
(20) Szarek, W. A.; Zamojski, A.; Tiwari, K. A.; Ison, E. R. Tetrahedron
Lett. 1986, 27, 3827-3830.
(21) Methyl ketosides have been conveniently deoxygenated to aryl
glycosides: Shiozaki, M. J. Org. Chem. 1991, 56, 528-532.
1742
Org. Lett., Vol. 4, No. 10, 2002