Efficient and selective removal of methoxy protecting groups in carbohydrates

Article abstract of DOI:10.1021/ol048439+

(Chemical Equation Presented) The selective removal from carbohydrate substrates of methoxy protecting groups next to hydroxy groups is reported. On treatment with Phl(OAc)₂-I₂, the methoxy group is transformed into an easily removable acetal. The mild conditions of this methodology are compatible with many functional groups, and good to excellent yields are usually achieved.

Full text of DOI:10.1021/ol048439+

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3785-3788
Efficient and Selective Removal of
Methoxy Protecting Groups in
Carbohydrates
Alicia Boto,* Da´cil Herna´ndez, Rosendo Herna´ndez,* and Ernesto Sua´rez
Instituto de Productos Naturales y Agrobiolog´ıa del CSIC,
AVda. Astrof´ısico Fco. Sa´nchez 3, 38206-La Laguna, Tenerife, Spain
alicia@ipna.csic.es; rhernandez@ipna.csic.es
Received August 6, 2004
ABSTRACT
The selective removal from carbohydrate substrates of methoxy protecting groups next to hydroxy groups is reported. On treatment with
PhI(OAc)2 I2, the methoxy group is transformed into an easily removable acetal. The mild conditions of this methodology are compatible with
−
many functional groups, and good to excellent yields are usually achieved.
The methoxy group can be readily formed and is stable to a
wide range of reaction conditions. Hence, it has been
frequently used as a protecting group in carbohydrates and
many other substrates.1 On the other hand, the removal of
this robust ether is often difficult, requiring conditions not
compatible with other functional groups. Moreover, if several
methoxy groups are present in the same molecule (as in
product 1, Scheme 1), the selective removal of one of them
is challenging. These problems are especially important in
carbohydrate systems where mild, selective deprotection
conditions are usually required.
We report now on an efficient methodology to selectively
remove methoxy groups next to hydroxy functions (Scheme
1). The methoxy group is transformed, under mild conditions,
into an acetal 2 or 3, which can be hydrolyzed in the presence
of many functional groups, including other acetals.
The transformation is achieved using a tandem radical
hydrogen abstraction-oxidation reaction. Thus, on treatment
with (diacetoxyiodo)benzene (DIB) and iodine, the hydroxy
group generates an alkoxyl radical (as in intermediate 4,
Scheme 1), which abstracts nearby hydrogen atoms within
a suitable distance (2.3-2.8 Å).2,3 The intramolecular H-
abstraction (IHA) from a methoxy group gives a C-radical
5 stabilized by the adjacent oxygen atom. Under the reaction
conditions, the C-radical is oxidized to an oxycarbenium ion
6,4 which is trapped intra- or intermolecularly by nucleophiles
such as hydroxy groups (route a) or acetate ions from the
reagent (route b).
Several carbohydrate substrates were prepared to study the
scope of this methodology. The galactose anomers 7 and 8
(Table 1), the glucose derivatives 9-12, and the rhamnose
derivative 13 were obtained from commercial sugars.5
(2) IHA. Reviews: (a) Cekovic, Z. Tetrahedron 2003, 59, 8073-8090.
(b) Feray, L.; Kuznetsov, N.; Renaud, P. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp
246-278. (c) Robertson, J.; Pillai, J.; Lush, R. K. Chem. Soc. ReV. 2001,
30, 94-103. (d) Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095-
7129, and references therein.
(3) For recent examples of hydrogen abstraction reaction, see: (a)
Jastrzebska, I.; Morzycki, J. W.; Trochimowicz, U. Tetrahedron Lett. 2004,
45, 1929-1932. (b) Sartillo-Piscil, F.; Vargas, M.; Anaya-de-Parrodi, C.;
Quintero, L. Tetrahedron Lett. 2003, 44, 3919-3921. (c) Lee, J. S.; Fuchs,
P. L. Org. Lett. 2003, 5, 2247-2250. (d) Aubele, D. L.; Floreancig, P. E.
Org. Lett. 2002, 4, 3443-3446. (e) Crich, D.; Huang, X.; Newcomb, M. J.
Org. Chem. 2000, 65, 523-529. (f) Chatgilialoglu, C.; Gimisis, T.; Spada,
G. P. Chem.sEur. J. 1999, 2866-2876. (g) Allen, P. A.; Brimble, M. A.;
Prabaharan, H. Synlett 1999, 295-298. (h) Petrovic, G.; Saicic, R. N.;
Cekovic, Z. Synlett 1999, 635-637. (i) Frey, B.; Wells, A. P.; Rogers, D.
H.; Mander, L. N. J. Am. Chem. Soc. 1998, 120, 1914-1915. (j) Tsunoi,
S.; Ryu, I.; Okuda, T.; Tanaka, M.; Komatsu, M.; Sonoda, N. J. Am. Chem.
Soc. 1998, 120, 8692-8701. (k) Allen, P. R.; Brimble, M. A.; Fares, F. A.
J. Chem. Soc., Perkin Trans. 1 1998, 2403-2411. (l) Dorta, R. L.; Mart´ın,
A.; Salazar, J. A.; Sua´rez, E.; Prange´, T. J. Org. Chem. 1998, 63, 2251-
2261.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; John Wiley & Sons: New York, 1991.
10.1021/ol048439+ CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/21/2004

The hydrogen abstraction was then studied with the
glucose substrate 11, which presented a secondary hydroxy
group (entry 5). Although the MM2 calculations7 suggested
that the distance between the oxygen at C-4 and the 3-OMe
hydrogens was suitable for H-abstraction (2.5-2.9 Å), the
â-fragmentation could be an important side-reaction. In fact,
it is known that secondary O-radicals usually give scission
as the main reaction when the resulting C-radical is stabilized
by oxygen functions.4,8
Scheme 1. Selective Methoxy Protecting Group
Transformation
To our satisfaction, the hydrogen abstraction was the main
reaction, and the mixed acetal 20 was obtained in satisfactory
yield. The other expected product, the cyclic acetal 21, could
not be isolated as a pure compound. Observing that it was a
volatile product, the protecting group transformation was
repeated with the 1-O-benzyl analogue 12. In this case, both
the mixed acetal 22 and the cyclic acetal 23 could be isolated,
as the major and minor product, respectively.
The rhamnose substrate 13 also presented a secondary
hydroxy group. As in the previous case, the calculated
distance C2-O‚‚‚H-CH2O-C4 (about 2.4-2.8 Å) was
suitable for the abstraction. According to this, the abstraction
products 24 and 25 were obtained in excellent overall yield
(entry 7). Again, the major product was the O-methyl acetate
24 and not the methylene dioxy acetal 25.
The cleavage of the cyclic and the acetoxy acetals was
then studied via acetolysis. As seen before, the functional-
ization of substrate 8 gave the acetals 16 and 17 (Scheme
2). When the methylenedioxy acetal 16 was treated with
acetic acid and trifluroacetic anhydride (TFAA),9 the mixed
acetals 26 and 27 were obtained in 52 and 45% yield,
respectively (97% global yield). In both compounds, the
oxygen functions on C-4 and C-6 are differently protected,
and hence further selective manipulation of the molecule is
possible.
In case that the 4,6-diol 2810 is required, it can be obtained
in excellent yield by treatment of products 26, 27, or 17 with
methanolic NaOH.
The possibility of obtaining the diol 28 directly from
substrate 8, avoiding the purification of the acetal intermedi-
ates, was tempting. To study the feasibility of the one-pot
H-abstraction-cleavage process, the substrate 8 was treated
under hydrogen abstraction conditions; then, the solvent was
Substrate 7 underwent reaction with DIB and iodine after
irradiation with visible light in CH2Cl2 to give methylene-
dioxy acetal 146 as the major product (entry 1, Table 1),
and the O-methyl acetate 15 as the minor product, in 82%
overall yield. The other galactose anomer 8 gave similar
results (entry 2).
The 1R-benzylglucose derivative 9 yielded a cyclic acetal
18 as the sole product under identical conditions (entry 3).
A similar yield was obtained with the 1â-O-benzyl epimer
10 (entry 4). Interestingly, no hydrogen abstraction was
observed from the benzylic position.4a
(4) (a) It has been reported that the primary alkoxy radicals derived from
carbohydrates in the furanose form gave a mixture of fragmentation and
intramolecular hydrogen abstraction (IHA): Boto, A.; Herna´ndez, D.;
Herna´ndez, R.; Sua´rez, E. J. Org. Chem. 2003, 68, 5310-5319. Under
appropriate conditions, the fragmentation predominated over the IHA. In
contrast, the pyranose substrates described in this communication gave IHA
as the sole reaction. (b) For other related works, see: Francisco, C. G.;
Herrera, A. J.; Sua´rez, E. J. Org. Chem. 2002, 67, 7439-7445. (c) Francisco,
C. G.; Freire, R.; Herrera, A. J.; Pe´rez-Mart´ın, I.; Sua´rez, E. Org. Lett.
2002, 11, 1959-1961. (d) Madsen, J.; Viuf, C.; Bols, M. Chem.sEur. J.
2000, 6, 1140-1146. (e) Francisco, C. G.; Herrera, A. J.; Sua´rez, E.
Tetrahedron Lett. 2000, 41, 7869-7873.
(5) (a) Compound 7: Valangenhove, H.; Reinhold: V. N. Carbohydr.
Res. 1985, 143, 1-20. (b) Compound 8: Vries, N. K.; Buck, H. M.
Carbohydr. Res. 1987, 165, 1-16. (c) Compounds 9 and 10: Francisco,
C. G.; Gonza´lez, C. C.; Sua´rez, E. J. Org. Chem. 1998, 63, 2099-2109.
(d) Compound 11: Reuben, J. Carbohydr. Res. 1986, 157, 201-213. (e)
Compound 12: See Supporting Information. (f) Compound 13: Monneret,
C.; Gagnet, R.; Florent, J. C. Carbohydr. Res. 1987, 6, 221-229.
(6) All compounds were completely characterized by 1H and 13C NMR,
MS, HRMS, IR, and elemental analysis. Two-dimensional COSY, HSQC,
and NOESY experiments were also carried out.
(7) Calculations using a MM2 force field model implanted in ChemBats3D
ultra 6.0 from CambridgeSoft (www.cambridgesoft.com).
(8) For reviews on â-fragmentation, see: (a) Hartung, J.; Gottwald, T.;
Spehar, K. Synthesis 2002, 1469-1498. (b) Zhdankin, V.; Stang, P. J. Chem.
ReV. 2002, 102, 2523-2584. (c) Togo, H.; Katohgi, M. Synlett 2001, 565-
581. (d) Zhang, W. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.
P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 234-245. (e) Sua´rez,
E.; Rodr´ıguez, M. S. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 440-454. (f)
McCarroll, A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224-
2248. (g) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271-1287. (h) Yet, L.
Tetrahedron 1999, 55, 9349-9403. (i) Varvoglis, A. HyperValent Iodine
in Organic Synthesis; Academic Press: New York, 1997. (j) Brun, P.;
Waegell, B. In ReactiVe Intermediates; Abramovitch, R. A., Ed.; Plenum
Press: New York, 1983; Vol. 3, pp 367-426. (k) See also: Wilsey, S.;
Dowd, P.; Houk, K. N. J. Org. Chem. 1999, 64, 8801-8811 and references
therein.
(9) Different deprotection procedures were studied. The best results were
obtained with the AcOH-(CF3CO)2O system: Gras, J. L.; Pellissier, H.;
Nouguier, R. J. Org. Chem. 1989, 54, 5675-5677.
(10) Evtushenko, E. V. Carbohydr. Res. 1999, 316, 187-200.
3786
Org. Lett., Vol. 6, No. 21, 2004

Table 1. Selective Transformation of Methoxy Protecting Groups into Acetals Using Carbohydrate Substrates
a Conditions: DIB (1.5 equiv), I2 (1 equiv), CH2Cl2, 25 °C, irradiation with two 80 W tungsten filament lamps. b Yields are given for products purified
by chromatography on silica gel. c Minor product 15 could not be separated from the major product 14. The product ratio was calculated by NMR. d Product
21 proved to be volatile. e Minor product 25 could not be separated from the major product 24. The product ratio was calculated by NMR.
removed under vacuum, and glacial acetic acid and tri-
fluroacetic anhydride were added at 0 °C. After the mixture
was stirred for 2 h at room temperature, the solvent was
evaporated and 4% NaOH in MeOH-H2O (9:1) was added,
affording the 4,6-diol 28 in good overall yield (77%).
Similarly, treatment of the 1R-benzyl-4,6-methylene glu-
cose derivative 18 (Scheme 3), formed from substrate 9, with
acetic acid and trifluroacetic anhydride afforded the O-methyl
Scheme 2. One-Pot Transformation of Substrate 8 into Diol
28
Scheme 3. One-Pot Transformation of Substrate 9 into Diol
31
Org. Lett., Vol. 6, No. 21, 2004
3787

acetate 29 and the acetate 30 in excellent global yield. It
must be noted that the 1-O-benzyl group was not affected
by the cleavage process conditions. Both products 29 and
30 released the 4,6-diol 31 by saponification.
The sequential H-abstraction-hydrolysis process was also
carried out on 9, under the previously described conditions,
affording the diol 31 in 61% yield (Scheme 3).
As seen in the previous cases, the O-methyl acetates can
be easily removed by basic hydrolysis. Also, as shown in
the Table 1, in the selective deprotection of substrates 11,
12, and 13, the major products were the O-methyl acetates
20, 22, and 24, respectively. To exemplify the hydrolysis of
these substrates, the acetoxy acetal 22 underwent treatment
with methanolic NaOH (Scheme 4), affording the diol 32 in
good yield (88%).
Moreover, when the glucose precursor 12 underwent the
tandem protecting group transformation-cleavage reaction,
the diol 32 was obtained in 50% yield.
In summary, a mild and efficient methodology to selec-
tively cleave methoxy protecting groups next to hydroxy
functions is described. The reaction was carried out with
galactose, glucose, and rhamnose substrates. In the first step,
the methoxy protecting group was transformed into a
methylenedioxy acetal or an O-methyl acetate, using a
tandem radical hydrogen abstraction-oxidation reaction.
These acetal groups were then removed in good to excellent
yields. To simplify this methodology, an efficient one-pot
protecting group transformation-cleavage reaction was
developed. The resulting diols were easily purified, and the
yields were similar to those obtained in the multistep process.
Acknowledgment. This work was supported by the
Investigation Programs PPQ2000-0728 and PPQ2003-01379
of the Plan Nacional de Investigacio´n Cient´ıfica, Ministerio
de Ciencia y Tecnolog´ıa, Spain. We also acknowledge
financial support from FEDER funds. D.H. thanks CSIC-
Gobierno de Canarias, CSIC (I3P) and Ministerio de Edu-
cacio´n y Ciencia (Plan Nacional FPU) for fellowships.
Scheme 4. One-Pot Transformation of Substrate 12 into Diol
32
Supporting Information Available: Synthesis of sub-
strate 12 and General Procedure for the one-pot protecting
group transformation-hydrolysis. 1H and 13C NMR spectra
and spectroscopic data for compounds 12, 14-20, 22-27,
and 29-32. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL048439+
3788
Org. Lett., Vol. 6, No. 21, 2004