p-Methoxybenzyl ether cleavage by polymer-supported sulfonamides.

Article abstract of DOI:10.1021/ol025514c

[reaction: see text] p-Methoxybenzyl ethers have been found to transfer from alcohols to sulfonamides in the presence of catalytic trifluoromethanesulfonic acid. This process for protecting group removal can be performed in solution with yields >94%. Through the use of sulfonamide-functionalized ("safety-catch") resins, p-methoxybenzyl ethers can be cleaved in excellent yields with minimal purification.

Full text of DOI:10.1021/ol025514c

ORGANIC
LETTERS
2
002
Vol. 4, No. 7
131-1133
p-Methoxybenzyl Ether Cleavage by
Polymer-Supported Sulfonamides
1
Ronald J. Hinklin and Laura L. Kiessling*,†,‡
†
Departments of Chemistry and Biochemistry, UniVersity of Wisconsin-Madison,
Madison, Wisconsin 53706
kiessling@chem.wisc.edu
Received January 5, 2002
ABSTRACT
p-Methoxybenzyl ethers have been found to transfer from alcohols to sulfonamides in the presence of catalytic trifluoromethanesulfonic acid.
This process for protecting group removal can be performed in solution with yields >94%. Through the use of sulfonamide-functionalized
(“safety-catch”) resins, p-methoxybenzyl ethers can be cleaved in excellent yields with minimal purification.
The p-methoxybenzyl (PMB) protecting group is used
widely. Its utility stems, in part, from its propensity to
undergo cleavage under conditions orthogonal to those
employed for benzyl group removal. PMB groups are
generally removed through the use of oxidizing agents such
as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or
promoter (Figure 1). Upon isolation of the byproducts, it was
found that the PMB group had been transferred to the
sulfonamide intermediate to yield 3 in 94%. We hypothesized
1
ceric ammonium nitrate (CAN). PMB groups may also be
cleaved in the presence of strong acids, but they are stable
2
to many acidic conditions. For example, PMB ethers are
used as protecting groups in many glycosylation reactions
3
promoted by catalytic acids. Consequently, we were sur-
prised to observe quantitative removal of a PMB ether group
during the attempted glycosylation of 1, in which catalytic
4
trifluoromethanesulfonic acid (TfOH) was employed as a
†
Department of Chemistry.
Department of Biochemistry.
‡
Figure 1. Initial observation of PMB ether cleavage in the presence
of catalytic triflic acid.
(
1) (a) Green, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; John Wiley & Sons: New York, 1999. (b) Oikawa, Y.; Yoshioka,
T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885-888. (c) Classon, B.;
Garegg, P. J.; Samuelsson, B. Acta Chem. Scand., Ser. B 1984, B38, 419-
4
22.
that this process might constitute a new method for the
selective removal of PMB ethers.
(
2) (a) Hodgetts, K. J.; Wallace, T. W. Synth. Commun. 1994, 24, 1151-
1
6
155. (b) Jenkins, D. J.; Riley, A. M.; Potter, B. V. L. J. Org. Chem. 1996,
1, 7719-7726. (c) Yan, L.; Kahne, D. Synlett 1995, 523-524. (d) De
5
To determine if the process is general, compound 4 was
Medeiros, E. F.; Herbert, J. M.; Taylor, R. J. K. J. Chem. Soc., Perkin
Trans. 1 1991, 2725.
treated with 0.1 equiv of TfOH in the presence of N-methyl-
(
3) For examples, see: (a) Sanders, W. J.; Manning, D. D.; Koeller, K.
M.; Kiessling, L. L. Tetrahedron 1997, 53, 16391-16422. (b) Zhang, Z.;
Ollmann, I.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem.
Soc. 1999, 121, 734-753. (c) Morales, J.; Zurita, D.; Penades, S. J. Org.
Chem. 1998, 63, 9212-9222.
(4) Hinklin, R. J.; Kiessling, L. L. J. Am. Chem. Soc. 2001, 123, 3379-
3380.
(5) Sharma, G. V. M.; Mahahngam, A. K. J. Org. Chem. 1999, 64, 8943-
8944.
1
0.1021/ol025514c CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/05/2002

6
p-toluenesulfonamide (5) (Figure 2). Complete removal of
the PMB group was observed, and sulfonamide 3 and
menthol (6) were generated. Importantly, PMB removal was
Table 1. Deprotection of PMB Ethers Using Catalytic TfOH in
the Presence of a Sulfonamidea
Figure 2. The effect of sulfonamide structure on the deprotection
of PMB ether 4. (a) 0.1 equiv of TfOH in Et O.
2
not observed when sulfonamide 5 was omitted from the
reaction. Silver triflate also promoted PMB group cleavage;
however, >1 equiv was required to obtain cleavage kinetics
similar to those observed with 0.1 equiv of triflic acid.
Attempts to effect PMB removal using weaker acids have
not been successful.
a
0
.1 M substrate in Et2O, 0.55 equiv of TsNH2 and 0.1 equiv of TfOH.
2
b
c
Low yield due to formation of TsNdCHAr. 1.1 equiv of TsNHMe instead
of TsNH2.
With this initial success, we explored the effect of
sulfonamide structure on the reaction. A primary sulfonamide
was tested in place of 5 to determine whether two PMB
groups could be transferred to one sulfonamide. The reaction
of 4 in the presence of 0.1 equiv of TfOH with 0.55 equiv
of p-toluenesulfonamide (7) resulted in complete removal
of the PMB group. Two sulfonamide byproducts (8 and 9)
were generated. The utility of an alkyl sulfonamide, ethane-
sulfonamide (10), also was explored. It, too, was effective,
generating 6 in high yield along with the expected sulfona-
mides 11 and 12. The rate of the reaction with the more
nucleophilic alkyl sulfonamide was not enhanced signifi-
cantly; consequently, we employed aryl sulfonamides in
subsequent studies.
Sulfonamide substitution also can influence the outcome
of the deprotection reaction for some substrates. For example,
treatment of benzylidene acetal 15 with tosylsulfonamide (7)
and TfOH resulted in a mixture of products; the desired
alcohol was produced in very low yield (<10%). Under these
conditions, the benzylidene acetal is labile, and competitive
8
sulfonimine formation occurs. In contrast, when secondary
sulfonamide 5 was employed, compound 15 was transformed
into the desired alcohol in high yield (94%). The use of the
secondary sulfonamide eliminates the possibility of sulfon-
imine formation, thereby allowing for PMB group release
from substrates that contain acid-sensitive functional groups.
The method we have developed for PMB ether cleavage
is complementary to others. For example, it can be applied
to substrates sensitive to oxidation, as the reaction of
compound 16 illustrates (Table 1). Hydroquinone derivatives
are oxidized by either DDQ or CAN; treatment of 16 with
The scope of the deprotection process was evaluated using
7
several PMB ethers, 13-16 (Table 1). These were generated
from the corresponding alcohols via standard transformations.
Compounds 4, 13, and 14 all can be cleaved to afford very
high isolated yields of the product alcohols (Table 1). Most
reactions can be performed with the commercially available
p-toluenesulfonamide 7. When the N-methyl derivative 5 is
the acceptor, however, chromatographic separation is more
facile because only one sulfonamide is produced (3 vs. 8
and 9).
9
CAN yielded the quinone product exclusively. In contrast,
2
the reaction of 16 in the presence of TsNH and TfOH
afforded the phenol in high yield. No unwanted quinone
byproducts were observed.
A key objective to be met in the development of new
10
methods is to streamline product isolation and purification.
To this end, solid-supported reagents and scavenging resins
are valuable. Our finding that sulfonamide groups can
(
(
6) Townsend, C. A.; Theis, A. B. J. Org. Chem. 1980, 45, 1697-1699.
7) (a) Mulard, L. A.; Kovac, P.; Glaudemans, C. P. J. Carbohydr. Res.
1
994, 251, 213-232. (b) Srikrishna, A.; Viswajanani, R.; Sattigeri, J. A.;
Vijaykumar, D. J. Org. Chem. 1995, 60, 5961-5962. (c) Wennerberg, J.;
Olofsson, C.; Frejd, T. J. Org. Chem. 1998, 63, 3595-3598.
(8) Wunsch, B.; Nerdinger, S. Chem. Lett. 1998, 799-800.
(9) Amsberry, K. L.; Borchardt, R. T. Pharm. Res. 1991, 8, 323-330.
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Org. Lett., Vol. 4, No. 7, 2002

function as scavengers in PMB ether cleavage reactions
prompted us to examine the utility of immobilized sulfona-
mides. Sulfonamide-functionalized resins are used widely in
solid-phase organic synthesis.11 We envisioned that these
could facilitate PMB ether removal by trapping the PMB
cation (Figure 3). Purification of the desired alcohol would
Table 2. Deprotection of Various PMB Ethers in the Presence
of Sulfonamide-Substituted Resins
Figure 3. Example illustrating the strategy for PMB ether removal
using safety-catch resins as scavengers.
involve neutralization of the triflic acid and filtration.
PMB ether cleavage occurred with a resin-bound sulfon-
amide group under conditions similar to those used for
reactions in solution. The yield, however, was optimal when
dioxane solvent was used instead of diethyl ether. Because
the commercially available resins contain primary sulfona-
mide groups, only 0.5 equiv of resin is required, in principle.
The loading levels can vary, however, and some reaction
sites may be inaccessible; consequently, 0.7 equiv was used.
These conditions gave reproducible results. After the mixture
was neutralized, filtered, and concentrated, the desired
alcohol could be recovered in high yield and purity without
chromatography (Table 2). As anticipated, when substrate
a
0
.1 M substrate in dioxane, 0.7 equiv of p-toluenesulfonamide safety-
b
catch resin and 0.1 equiv of TfOH. Reduced yield due to volatility of
product. c Low yield due to competitive sulfonimine formation.
1
5 was treated with resin 18 competitive sulfonimine
formation led to low yields (<10%) of the target alcohol
Table 2, entry 4). The use of an immobilized secondary
sulfonamide should circumvent this difficulty.
A typical procedure for the deprotection of PMB ethers
using safety-catch resin 18 has been developed. The resin
Our studies demonstrate that sulfonamides function as
excellent scavengers in the acid-catalyzed cleavage of PMB
ethers. Additionally, commercially available safety-catch
resins can be used to effect PMB protecting group removal
to afford target alcohols in high yields with minimal
purification. This protocol is convenient, and it can be used
with substrates sensitive to oxidation. Finally, our studies
suggest that sulfonamide-containing compounds, either in
solution or immobilized, may act to effectively capture
carbocation byproducts in a wide range of reactions.
(
18 (0.07 mmol) is allowed to swell in 1 mL of dioxane, 0.01
mmol of TfOH is added, and the mixture is agitated. The
resin is filtered, rinsed with dioxane, and resuspended in 1
mL of dioxane. The PMB ether (0.1 mmol) is added,
followed by TfOH (0.01 mmol). After 4-6 h, the reaction
is quenched by the addition of aqueous sodium bicarbonate.
The mixture is filtered through a small plug of silica gel to
remove water and salts, and the resulting solution is
concentrated. This procedure affords the desired alcohols in
excellent yields.
Acknowledgment. This research was supported by the
NIH (GM49975), the Mizutani Foundation for Glycoscience,
and the NSF. We thank R. M. Owen (UW-Madison) for
supplying the precursor to compound 15.
(
10) For a review, see: (a) Eames, J.; Watkinson, M. Eur. J. Org. Chem.
001, 1213-1224. For recent examples, see: (b) Kaldor, S. W.; Siegel,
M. G.; Fritz, J. E.; Dressman, B. A.; Hahn, P. J. Tetrahedron Lett. 1996,
7, 7193-7196. (c) Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman,
S. L.; Parlow, J. J.; South, M. S.; Woodard, W. J. Am. Chem. Soc. 1997,
2
Supporting Information Available: Experimental pro-
cedures and NMR spectral data of aromatic and aliphatic
sulfonamide products (3, 8, 9, 11, and 12). This material is
available free of charge via the Internet at http://pubs.acs.org.
3
1
19, 4874-4881. (d) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997,
1
19, 4882-4886.
(11) (a) Backes, B. J.; Virgilio, A. A.; Ellman, J. A. J. Am. Chem. Soc.
1
996, 118, 3055-3056. (b) Kenner, G. W.; McDermott, J. R.; Sheppard,
R. C. Chem. Commun. 1971, 636-637.
OL025514C
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