1-(o-Nitrophenyl)-2,2,2-trifluoroethyl ether derivatives as stable and efficient photoremovable alcohol-protecting groups.

Full text of DOI:10.1002/anie.200353247

Communications
Protecting Groups
1-(o-Nitrophenyl)-2,2,2-trifluoroethyl Ether
Derivatives as Stable and Efficient
Photoremovable Alcohol-ProtectingGroups**
Alexandre Specht and Maurice Goeldner*
The photochemical unmasking of chemical functional groups
has been used extensively in organic synthesis.[1] Even though
photochemical methods may not be suitable for larger-scale
reactions, they nevertheless display remarkable selectivity
during the unmasking step and are therefore orthogonal to
most organic reactions. An interesting application is found in
the preparation of caged compounds, which requires the
chemical modification of biomolecules by photoremovable
protecting groups.[2] Such protecting groups are designed first
to mask the biological function and second to permit the
liberation of the biomolecule by the action of light, thus
triggering the biological function in a controlled way. The
caged biomolecule must be stable in neutral buffered
solutions, and the photochemical reaction must be efficient
at wavelengths greater than 300 nm (high quantum yields)
and rapid with respect to the kinetics of biological processes.
A series of photoremoveable alcohol-protecting groups
have been described in the literature, including carbonates,[3]
carbamates,[4] acetals,[5] and esters,[6] which each have their
own photochemical properties but also represent chemical
functionalities of restricted hydrolytic stability. There have
been several examples of ether linkages formed with alcohol-
containing biomolecules to ensure better chemical stability,
including 9-phenylthioxanthyl-protected dRNAs[7] and o-
nitrobenzyl derivatives of carbohydrates[8] and choline.[9]
Alternatively, a-hydroxy-b-alkoxypivaloyl derivatives have
been used for solid-phase photochemical ether cleavage to
release alcohols,[10] but these reagents might not be ideal for
the caging of water-soluble molecules. The synthesis of ether
derivatives in the o-nitrobenzyl series required the design of
an individual methodology for each compound. 2-O-(2-
Nitrobenzyl)-d-glucose was synthesized by alkylating a dibu-
tylstannylidene glucose derivative with o-nitrobenzyl bro-
mide in moderate yield,[8a] whereas in two other examples a
Lewis acid catalyzed reductive ring opening of a cyclic
acetal[8b] or ketal[9] was used to generate 6-O-(2-nitrobenzyl)
methylglucoside or o-nitrobenzyl choline ether derivatives,
respectively. As for their photochemical properties, product
quantum yields were 0.63 and 0.27 for the 2-O-(2-nitro-
benzyl)-d-glucose[8a] and the O-[1-(2-nitrophenyl)ethyl]cho-
[*] Dr. A. Specht, Prof. M. Goeldner
Laboratoire de Chimie Bioorganique, UMR 7514 CNRS
FacultØ de Pharmacie, UniversitØ Louis Pasteur Strasbourg
BP24, 67401 Illkirch Cedex (France)
Fax: (+33)390-244-306
E-mail: goeldner@bioorga.u-strasbg.fr
[**] The authors thank Dr. Luc Lebeau for useful discussions. This work
was supported by the CNRS, the UniversitØ Louis Pasteur
Strasbourg, and the RØgion Alsace.
2008 ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200353247
Angew. Chem. Int. Ed. 2004, 43, 2008 –2012

Angewandte
Chemie
line[9] ether derivatives, respectively. The
photofragmentation kinetics of o-nitroben-
zyl ether derivatives were recently rein-
vestigated.[11] These studies demonstrated
the decay of long-lived hemiketal inter-
mediates to be the major fragmentation
pathway, rather than the decay of the usual
aci-nitro intermediates, thus resulting in a
much slower fragmentation rate.
Table 1: Ether synthesis with 1-(o-nitrophenyl)-2,2,2-trifluoroethanol derivatives 1a and 1b: Mitsunobu
reactions in benzene in the presence of A: DIAD/PPh3 (1.5 equiv) or B: TMAD/PBu3 (1.5 equiv).[a]
Alcohols
Ether derivative
A/B
t [h]
T [8C][b]
Yield [%]
(Conv. [%])[c]
A
A
A
B
A
A
1
120
24
2.5
240
48
0
18
40
70
83 (>95)
31 (85)
43 (73)
RT
70
70
RT
70
1a
2a
1a
1b
3a
3b
Herein we describe new o-nitrobenzyl
ether derivatives, substituted with a trifluoro-
methyl group at the benzylic position: NPT
(1-(2-nitrophenyl)-2,2,2-trifluoroethyl) and
DMNPT (1-(4,5-dimethoxy-2-nitrophenyl)-
2,2,2-trifluoroethyl) ethers. The presence of
the trifluoromethyl substituent makes gen-
eral synthetic pathways for the ether deriv-
atives from alcohols possible through a
Mitsunobu coupling reaction (Scheme 1).
The NPT and DMNPT ether derivatives
synthesized displayed remarkable photo-
chemical properties. They released alcohols
1a
1b
7a
7b
B
B
24
24
70
70
8 (28)
7 (35)
1a
10a
B
24
70
18 (60)
[a] DIAD=diisopropyl azodicarboxylate, TMAD=tetramethyl azodicarboxamide, Ar=p-MeC6H4.
[b] RT=reaction was carried out at room temperature. [c] Conv.=conversion.
were converted into their corresponding NPT or DMNPT
ether derivatives. Caged choline and[9] arsenocholine[17] were
selected for the potential photochemical regulation of chol-
inesterases[18] and a-tolylgalactosides[19] for that of lactose
permease transporter.[20] Neither processes require fast time
resolution, with the cholinesterases investigated under cry-
ophotolytic conditions and subsequent controlled temper-
ature increase,[21] whereas the turnover rate of the transporter
is about 15 sÀ1. The synthesis of the NPT and DMNPT ether
Scheme 1. 1-(o-Nitrophenyl)-2,2,2-trifluoroethanol derivatives as photo-
derivatives required for the photochemical study is outlined
in Scheme 2. The direct synthesis of the galactosides through
selective opening of cyclic 4,6-acetals, previously described
for the modification of glycosides at C4 by an o-nitrobenzyl
group,[8b] failed in our hands in this series. The synthesis of the
4-substituted galactoside derivative required the use of a
removable alcohol-protecting groups.
with high quantum yields (0.4 < F < 0.7), thus conferring to
the DMNPT derivatives excellent photolytic efficiencies
above 300 nm.
The strong basic reaction conditions of the ether Wil-
liamson synthesis do not accommodate the halogenated o-
nitrobenzyl derivatives, which polymerize or decompose
under such conditions.[8a,9] Therefore, we considered the
possibility of using a Mitsunobu coupling reaction[12] to
synthesize the NPT and DMNPT ether derivatives. The 1-
(o-nitrophenyl)-2,2,2-trifluoroethanol derivatives 1a and 1b
were synthesized by nitration of trifluoroacetophenone[13] or
of the corresponding 3,4-dimethoxy derivative with nitric acid
at 08C, and subsequent reduction with NaBH4. The presence
of the trifluoromethyl group at the benzylic position[14] does
sufficiently increase the acidity of the alcohols 1a and 1b to
permit their successful conversion into a series of ether
derivatives by using a Mitsunobu coupling reaction with
different alcohols (Table 1). Benzyl alcohol was used to assess
experimental improvement of the coupling reaction with the
derivative 1a.[15,16] However, low yields were obtained for the
coupling reaction with secondary alcohols (7a and 7b), which
is probably a result of steric factors (Table 1).
Scheme 2. Synthesis of caged choline, arsenocholine, and 4-substituted a-tol-
ylgalactosides: a) NaI, acetone, reflux, 22 h, 90%; b) NMe3, toluene, 258C,
40 h, 75%; c) AsMe3, acetonitrile, reflux, 20 h, 74%; d) MeONa (cat.), MeOH,
08C, 20 h, 92%.
By using these coupling reactions a variety of alcohol-
containing molecules with a potential biological function
Angew. Chem. Int. Ed. 2004, 43, 2008 –2012
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2009

Communications
glucoside[22] corresponding to the epimer of 8 at C4 to take
into account the inversion of configuration that occurs during
Mitsunobu coupling.
Table 2: Photofragmentation parameters of NPT (4a, 8a) and DMNPT
(5b, 8b) ether derivatives.[a]
Compound
k [sÀ1] (aci-nitro decay)
f
Figure 1 shows the photolytic reactions of compounds 4a
and 5b in terms of their UV difference spectra (hn: l =
364 nm, in a phosphate buffer at pH 7.2). A clean photolytic
4a
5b
8a
8b
k1 =3.2”105, k2 =1.4”104
0.70
0.43
0.62
0.52
[a] All details for the determination of the aci-nitro decay can be found in
reference [9]. The determination of the quantum yield for the photo-
conversion of compounds 4a, 5b, 8a, and 8b is described in the
Experimental Section.
was described for a DMNPE–NAD (1-(4,5-dimethoxy-2-
nitrophenyl)diazoethyl b-nicotinamide adenine dinucleotide)
analogue[23] (F = 0.19), whereas 4,5-dimethoxy-2-nitrobenzyl
ether derivatives displayed values as lowas 0.006. [24] We have
no explanation for these discrepancies, but with the observed
high quantum yields together with the favorable evolution of
the photolytic reaction above 320 nm, the DMNPT caging
group demonstrated unprecedented photolytic efficiencies at
these wavelengths. With such photolytic properties, DMNPT
ethers should find application in biphoton excitation proc-
esses.
Figure 1. Difference UV spectra showing the reaction progress during
photolysis at 364 nm of a) NPT choline (4a) and b) DMNPT arseno-
choline (5b) at 258C in a phosphate buffer (0.1m, pH 7.2).
The rate-limiting step of the photolytic reaction is
presumably the fragmentation of the nitroso hemiketal
intermediate,[11] rather than the decay of the aci-nitro
intermediate (Scheme 3). Rate constants of 3.2 ” 105 sÀ1 and
reaction (Figure 1a) is depicted for the NPT derivative 4a,
which leads to the quantitative formation of choline, as
demonstrated by NMR spectroscopic analysis (not shown),
together with, presumably, (o-nitroso)trifluoroacetophenone
hydrate. The structure of the proposed nitroso compound is in
agreement with spectroscopic data (UV: lmax = 313 nm; IR:
n˜(NO) = 1510 cmÀ1). Its formation was demonstrated by
HPLC to be concomitant with the disappearance of the
starting compound (not shown). The photolytic reaction in
the DMNPT series was more complex as a result of the
photolytic instability of the corresponding nitroso derivative
during the time course of the photolysis. The absorbance of
the nitroso derivative (lmax = 311 and 378 nm) is observed
initially, but this compound is subsequently converted into
two unidentified compounds that absorb at wavelengths
above 380 nm. The quantitative photolytic release of arseno-
choline was established by using an enzymatic assay[9] (not
shown). The main point of interest of the dimethoxy-
substituted derivatives is their absorbance above 300 nm
(lmax = 340 nm; e = 3650). Independent of the DMNPT ether
derivative tested, favorable photolytic evolution of the
reaction was observed between 320 and 380 nm, as depicted
for 5b (Figure 1b).
The photochemical properties of compounds 4a, 5b, 8a,
and 8b are summarized in Table 2. The quantum yields for the
photoconversion of these compounds were very high: up to
0.7 for the NPT-substituted derivatives, and also above 0.4 for
the DMNPT derivatives. The o-nitroveratryl group has been
tested as a photoremovable protecting group on numerous
biomolecules as a chromophoric substitute for the weakly
absorbing o-nitrobenzyl derivatives at l > 300 nm. In most
cases this modification led to a dramatic decrease in the
photolytic quantum yield. To our knowledge the highest value
Scheme 3. Postulated intermediates in the photofragmentation
reaction of NPT (R’=H) and DMNPT (R’=OCH3) ether derivatives.
1.4 ” 104 sÀ1 at pH 7.2 were determined for the decay of the
aci-nitro intermediate derived from compound 4a (Table 2).
Preliminary results indicate that the formation of the nitroso
hemiketal intermediate (Scheme 3) is fast (sub-millisecond
time range), which suggests that the final release of the
alcohol together with the formation of the trifluoromethyl
ketone derivative is rate-limiting. Partial deprotonation of the
hemiketal intermediate at neutral pH (a value of 9.1[25] has
been reported for the pKa of related hemiketals) could
accelerate such a decomposition process. The details of the
kinetics of the photochemical decomposition of such o-
nitrobenzyl ether derivatives are currently under investiga-
tion.[26]
NPT and DMNPT ether derivatives are stable and
efficient photoremovable alcohol-protecting groups. As in
the case of related nitrobenzyl alcohol-protecting groups, the
NPT or DMNPT caging groups are not suitable for the
investigation of fast biological processes. Nevertheless, the
use of NPT and DMNPT caging groups might be extended to
the masking of other chemical functional groups, such as
2010
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 2008 –2012

Angewandte
Chemie
used for both 4a or 8a and the 1-(2-nitrophenyl)ethyl (NPE) ether
carboxylic and phosphoric acids, for which a faster release is
expected.[11b] The caging of relevant neurotransmitters and
second messengers is presently under investigation.
reference (identical extinction coefficients at 364 nm), whereas for
the DMNPT ether derivatives a mixture of 0.1 mm of 5b or 8b and
1 mm of the NPE ether reference was used. The mixtures of substrate
and reference were photolyzed by continuous irradiation at 364 nm,
and aliquots were subjected to reversed-phase HPLC to determine
the extent of the photolytic conversions. HPLC analysis was carried
out on a Zorbax C18 column (4.6 ” 250 nm); elution was performed at
Experimental Section
General procedure for Mitsunobu coupling: A mixture of triphenyl-
phosphane/diisopropyl azodicarboxylate (DIAD) or tributylphos-
phane/tetramethyl azodicarboxamide (TMAD) (1:1, 1.5 equiv) was
added as a solution in benzene to a solution in benzene of 1a or 1b
(1 equiv) and benzyl alcohol or 2-bromoethanol (1.2–2 equiv). The
resulting mixture was stirred under an argon atmosphere (see Table 1
for reaction conditions). The solvent was removed after the time
indicated, and the crude product was purified by flash chromatog-
raphy or reversed-phase HPLC.
À1
a flowrate of 1 mLmin with a linear gradient of acetonitrile in an
aqueous solution of TFA (0.1%) from 0 to 100% (v/v) over 30 min.
The retention times for 4a, 5b, 8a, 8b, (o-nitroso)trifluoroacetophe-
none, and (4,5-dimethoxy-1-nitroso)trifluoroacetophenone were 20.7,
22.4, 25.7, 24.9, 22.5, and 21.2 min, respectively. Quantum yields were
estimated by considering the conversions at ꢀ 30% to limit errors
due to undesired light absorption during photolysis as much as
possible.
1a: 1H NMR (200 MHz, CDCl3, 258C, TMS): d = 4.51 (br s, 1H),
6.16 (q, 3J(H,F) = 6.0 Hz, 1H), 7.57–7.62 (m, 1H), 7.68–7.77 (m, 1H),
7.98 (d, 3J(H,H) = 7.9 Hz, 1H), 8.01 ppm (dd, 3J(H,H) = 9.0 Hz,
4J(H,H) = 1.1 Hz, 1H); 13C NMR (300 MHz, CDCl3, 258C, TMS):
d = 67.0 (q, 2J(C,F) = 33 Hz), 124.3 (q, 1J(C,F) = 283 Hz), 125.3, 129.6,
129.9, 130.5, 133.9, 148.9 ppm.
Received: November 4, 2003 [Z53247]
Keywords: caging groups · Mitsunobu reaction ·
.
1b: 1H NMR (300 MHz, CDCl3, 258C, TMS): d = 3.99 (s, 3H),
4.03 (s, 3H), 6.32–6.38 (m, 1H), 7.36 (s, 1H), 7.66 ppm (s, 1H);
13C NMR (300 MHz, CDCl3, 258C, TMS): d = 56.7, 56.9, 66.7 (q,
2J(C,F) = 32 Hz), 108.4, 110.9, 122.8 (q, 1J(C,F) = 210 Hz), 127.4,
141.3, 149.4, 153.7 ppm.
photochemistry · photolysis · protecting groups
[1] a) V. N. R. Pillai, Synthesis 1980, 1 – 26; b) C. G. Bochet, J. Chem.
Soc. Perkin Trans. 1 2002, 123 – 142.
2a: 1H NMR (200 MHz, CDCl3, 258C, TMS): d = 4.67 (d,
3J(H,H) = 11.4 Hz, 1H), 4.72 (d, 3J(H,H) = 11.4 Hz, 1H), 5.94 (q,
3J(H,F) = 3.0 Hz, 1H), 7.30–7.42 (m, 5H), 7.56–7.63 (m, 1H), 7.74
(dd, 3J(H,H) = 7.9 Hz, 3J(H,H) = 7.5 Hz, 1H), 7.99 (d, 3J(H,H) =
7.9 Hz, 1H), 8.03 ppm (d, 3J(H,H) = 8.3 Hz, 1H); 13C NMR
(300 MHz, CDCl3, 258C, TMS): d = 73.4 (q, 2J(C,F) = 32 Hz), 73.5,
123.9 (q, 1J(C,F) = 281 Hz), 125.3, 128.5, 128.9, 129.0, 130.4, 130.7,
133.9, 136.3, 149.7 ppm.
[2] a) S. R. Adams, R. Y. Tsien, Annu. Rev. Physiol. 2000, 18, 755 –
784; b) G. Marriott, Methods Enzymol. 1998, 291, “Caged
Compounds” (special issue).
[3] a) M. C. Pirrung, J.-C. Bradley, J. Org. Chem. 1995, 60, 1116 –
1117; b) A. Hasan, K.-P. Stengele, H. Giegrich, P. Cornwell,
K. R. Isham, R. A. Sachleben, W. Pfleiderer, R. S. Foote,
Tetrahedron 1997, 53, 4247 – 4264; c) T. Furuta, Hirayama,
Y. M. Iwamura, Org. Lett. 2001, 3, 1809 – 1812; d) M. C. Pirrung,
L. Wang, M. P. Montague-Smith, Org. Lett. 2001, 3, 1105 – 1108.
[4] S. Loudwig, M. Goeldner, Tetrahedron Lett. 2001, 42, 7957 –
7959.
[5] a) U. Zehavi, B. Amit, A. Patchornik, J. Org. Chem. 1972, 37,
2281 – 2285; b) K. C. Nicolaou, N. Winssinger, J. Pastor, F.
DeRoose, J. Am. Chem. Soc. 1997, 119, 449 – 450; c) S. Wana-
tabe, R. Hiroikawa, M. Iwamura, Bioorg. Med. Chem. Lett. 1998,
8, 3375 – 3378; d) S. Pitsch, P. A. Weiss, X. Wu, D. Ackermann, T.
Honegger, Helv. Chim. Acta 1999, 82, 1753 – 1761.
[6] a) P. B. Jones, M. P. Pollastri, N. A. Porter, J. Org. Chem. 1996,
61, 9455 – 9461; b) M. C. Pirrung, W. H. Pieper, K. P. Kaliappan,
M. R. Dhananjeyan, Proc. Natl. Acad. Sci. USA 2003, 100,
12548 – 12553.
[7] M. P. Coleman, M. K. Boyd, Tetrahedron Lett. 1999, 40, 7911 –
7915.
[8] a) J. E. T. Corrie, J. Chem. Soc. Perkin Trans. 1 1993, 2161 – 2166;
b) S. Watanabe, T. Sueyoshi, M. Ichihara, C. Uehara, M.
Iwamura, Org. Lett. 2001, 3, 255 – 257.
[9] L. Peng, M. Goeldner, J. Org. Chem. 1996, 61, 185 – 191.
[10] R. Glatthar, B. Giese, Org. Lett. 2000, 2, 2315 – 2317.
[11] a) A. P. Pelliccioli, J. Wirz, Photochem. Photobiol. Sci. 2002, 1,
441 – 458; b) J. E. T. Corrie, A. Barth, V. R. N. Munasinghe,
D. R. Trentham, M. C. Hutter, J. Am. Chem. Soc. 2003, 125,
8546 – 8554.
1
4a: H NMR (300 MHz, CD3CN, 258C, TMS): d = 3.16 (s, 9H),
3.55–3.67 (m, 2H), 4.00–4.14 (m, 2H), 5.99 (q, 3J(H,F) = 9.6 Hz, 1H),
7.78 (m, 1H), 7.86–7.95 (m, 2H), 8.18 ppm (d, 3J(H,H) = 9.0 Hz, 1H).
1
5b: H NMR (300 MHz, CD3CN, 258C, TMS): d = 2.30 (s, 9H),
2.71–2.79 (m, 2H), 3.88–4.01 (m, 2H), 3.93 (s, 3H), 3.98 (s, 3H), 6.03
3
(q, J(H,F) = 6.1 Hz, 1H), 7.18 (s, 1H), 7.72 ppm (s, 1H); 13C NMR
(300 MHz, CD3CN, 258C, TMS): d = 8.4, 26.3, 56.6, 56.9, 65.1, 74.2 (q,
2J(C,F) = 31 Hz), 109.9, 110.4, 124.9 (q, 1J(C,F) = 281 Hz), 142.1,
150.2, 154.2 ppm.
6: 1H NMR (200 MHz, CDCl3, 258C, TMS): d = 2.07 (s, 3H), 2.13
(s, 3H), 2.15 (s, 3H), 2.31 (s, 3H), 3.05 (d, 3J(H,H) = 5.4 Hz, 1H), 3.63
(td, 3J(H,H) = 5.4 Hz, 3J(H,H) = 9.3 Hz, 1H), 3.98 (m, 1H), 4.19–4.54
(m, 2H), 4.98 (dd, 3J(H,H) = 3.7 Hz, 3J(H,H) = 10.3 Hz, 1H), 5.54 (t,
3J(H,H) = 9.0 Hz, 1H), 5.65 (d, 3J(H,H) = 3.4 Hz, 1H), 6.97 (d,
3J(H,H) = 8.8 Hz, 2H), 7.10 ppm (d, 3J(H,H) = 8.8 Hz, 2H);
13C NMR (300 MHz, CDCl3, 258C, TMS): d = 21.1, 21.2, 21.3, 21.4,
69.6, 70.7, 70.8, 73.1, 86.9, 95.1, 117.0, 130.4, 132.8, 154.1, 170.8 ppm.
1
8a: H NMR (300 MHz, CD3OD, 258C, TMS): d = 2.27 (s, 3H),
3.01–4.07 (m, 6H), 5.26 (d, 3J(H,H) = 3.4 Hz, 0.5H), 5.40 (d,
3J(H,H) = 3.4 Hz, 0.5H), 5.83 (q, 3J(H,F) = 6.0 Hz, 0.5H), 6.02 (q,
3J(H,F) = 6.1 Hz, 0.5H), 6.96–7.10 (m, 4H), 7.67 (m, 1H), 7.76 (dd,
3
3J(H,H) = 6.6 Hz, J(H,H) = 7.0 Hz, 1H), 7.86 (m, 1H), 8.05 ppm (d,
3J(H,H) = 8.3 Hz, 1H).
1
8b: H NMR (300 MHz, CD3OD, 258C, TMS): d = 2.30 (s, 3H),
3.15–4.53 (m, 6H), 3.95 (s, 3H), 3.99 (s, 3H), 5.49 (d, 3J(H,H) =
[12] a) O. Mitsunobu, Synthesis, 1981, 1, 1 – 28; b) D. L. Hughes, Org.
React. 1992, 42, 335 – 656.
3
3.6 Hz, 1H), 6.20 (d, J(H,F) = 6.4 Hz, 1H), 7.04–7.12 (m, 4H), 7.47
(s, 1H), 7.70 ppm (s, 1H).
[13] E. E. Smissman, J. P. Li, Z. H. Israili, J. Org. Chem. 1968, 33,
4231 – 4236.
The quantum yields for the photoconversion of compounds 4a,
5b, 8a, and 8b were determined by comparison with the photolysis of
1-(2-nitrophenyl)ethyl choline[9] (f= 0.27) or 1-(2-nitrophenyl)ethyl
arsenocholine[16] (f= 0.26), which were taken as references in a
phosphate buffer (0.1m, pH 7.2) at 258C. Identical absorbances for
the reference and the compound tested were used during the
photolyses. For the NPT derivatives concentrations of 1 mm were
[14] R. Stewart, R. Van der Linden, Can. J. Chem. 1960, 38, 399 – 406.
[15] a) H.-S. Cho, J. Yu, J. R. Falck, J. Am. Chem. Soc. 1994, 116,
8354 – 8355; b) J. R. Falck, J. Yu, H.-S. Cho, Tetrahedron Lett.
1994, 35, 5997 – 6000; c) D. P. Sebesta, S. S. O'Rourke, W. A.
Pieken, J. Org. Chem. 1996, 61, 361 – 362.
[16] S. Ito, T. Tsunoda, Pure Appl. Chem. 1999, 71, 1053 – 1057.
Angew. Chem. Int. Ed. 2004, 43, 2008 –2012
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2011

Communications
[17] L. Peng, J. Wirz, M. Goeldner, Angew. Chem. 1998, 110, 2838 –
2840; Angew. Chem. Int. Ed. 1998, 37, 2691 – 2693.
[18] L. Peng, I. Silman, J. Sussman, M. Goeldner, Biochemistry 1996,
35, 10854 – 10861.
[19] M. Sahin-Toth, P. Gunawan, M. C. Lawrence, T. Toyokuni, H. R.
Kaback, Biochemistry 2002, 41, 13039 – 13045.
[20] J. Abramson, I. Smirnova, V. Kasho, G. Verner, H. R. Kaback, S.
Iwata, Science 2003, 301, 60 – 615.
[21] a) A. Specht, T. Ursby, M. Weik, L. Peng, J. Kroon, D. Bourgeois,
M. Goeldner, ChemBioChem 2001, 2, 845 – 848; b) T. Ursby, M.
Weik, E. Fioravanti, M. Goeldner, D. Bourgeois, Acta Crystal-
logr. Sect. D 2002, 58, 607 – 614.
[22] The p-methylphenyl-2,3,6-tri-O-acetyl-a-d-glucopyranoside
6
was synthesized by using strategy of transient and selective
protection of the hydroxy groups at C4 and C6 as a benzylidene
acetal of p-methylphenyl-a-d-glucopyranoside.[17] Acetylation of
the remaining hydroxy groups at C2 and C3, followed by
hydrogenolysis of the benzylidene acetal and controlled acetyl-
ation of the primary hydroxy group at C6, gave the desired
triacetate derivative 6 in 48% overall yield.
[23] B. E. Cohen, B. L. Stoddard, D. E. Koshland, Jr., Biochemistry
1997, 36, 9035 – 9044.
[24] Y. Hirayama, M. Iwamura, T. Furuta, Bioorg. Med. Chem. Lett.
2003, 13, 905 – 908.
[25] K. Brady, T.-C. Liang, R. H. Abeles, Biochemistry 1989, 28,
9066 – 9070.
[26] J. Wirz, personal communication.
2012
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 2008 –2012