Modulation of photodeprotection by the sunscreen protocol

Article abstract of DOI:10.1021/acs.orglett.5b00019

A protocol for the selective photoremoval of alcohol protecting groups modulated by the presence of auxiliary light absorbing molecules is presented. Thus, by this method, a single light source was used to selectively remove a specific protecting group in the presence of another chromophore with a lower molar absorption coefficient. The use of a molecular sunscreen, either internal or external, was found to be crucial to achieve high selectivities.

Full text of DOI:10.1021/acs.orglett.5b00019

Letter
pubs.acs.org/OrgLett
Modulation of Photodeprotection by the Sunscreen Protocol
Or Eivgi, Efrat Levin, and N. Gabriel Lemcoff*
Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel, 84105
*
S Supporting Information
ABSTRACT: A protocol for the selective photoremoval of
alcohol protecting groups modulated by the presence of
auxiliary light absorbing molecules is presented. Thus, by this
method, a single light source was used to selectively remove a
specific protecting group in the presence of another
chromophore with a lower molar absorption coefficient. The
use of a molecular sunscreen, either internal or external, was
found to be crucial to achieve high selectivities.
he development of novel methods for selective removal of
protecting groups in organic synthesis has been of
T
paramount importance for the achievement of great feats in
1
the construction of complex molecules. Naturally, an ideal
2
synthesis would be rid of protection−deprotection steps;
unfortunately, in most cases this is not possible and in order to
acquire the desired scaffolds, chemical protective groups must
be added. When more than two protective groups are needed,
these must be removed in a selective or even orthogonal
3
manner; for example, under the right conditions, the popular
tert-butyldimethylsilyl (TBS) or tert-butyl diphenyl silyl
(
TBDPS) ether will remain while the trimethylsilyl (TMS)
4
ether group is hydrolyzed completely. Harsher conditions can
then remove TBS or TBDPS when it is no longer needed.
The use of light as a deprotection tool has the advantage that
it is usually harmless toward other chemical functionalities
found in the molecule. Thus, the development of several
5
−10
Figure 1. Photodeprotection of tris(trimethylsilyl)silyloxy octane in
the presence of light absorbing molecules. Reaction conditions: 0.03 M
protected alcohol, 0.1 M sunscreen (unless otherwise indicated), 0.3
M methanol-d (10 equiv), in 1 mL of CD Cl irradiated by 254 nm
photoremovable protecting groups (PPG) and photocages
has been well received by expert practitioners of the art of
organic synthesis. More recently, Bochet et al. have put forth
4
2
2
3,11−14
1
the chromatic orthogonality concept
where two different
light. Deprotection conversions measured by H NMR.
protecting groups may be removed with light of a different
wavelength, a concept that was then developed and modified by
1
5−17
254 nm) compared to the other molecules tested (see
Supporting Information).
others.
Herein, we present a new method, by which
protecting groups with different absorption coefficients may be
selectively removed with a single light source in the presence of
either an internal or external “sunscreen” accessory.
Having determined this, the efficacy of photocleavage
protection by phenanthrene was also examined at different
concentrations and also the use of an external solution of
The photodeprotection of tris(trimethylsilyl)silyl (sisyl)
protected alcohols by 254 nm UV light is a quite useful and
19
phenanthrene surrounding the vial with 1a (Table 1).
Next, the effect of using the same sunscreen on the
photodeprotection of 2-nitrobenzyl-pentanol (2a) was exam-
ined. The 2-nitrobenzyl group family is a well-known and
18
well-studied reaction. Taking into account the low molar
absorption coefficients of silyl ethers at shortwave UV, we
deemed it a good starting point to look into the photo-
deprotection of tris(trimethylsilyl)silyloxy octane (1a) in the
presence of several light absorbing molecules that would act as
molecular sunscreens. As shown in Figure 1, phenanthrene was
found as the most efficient sunscreen to prevent silyl
deprotection, consistent with the fact that phenanthrene has
20−23
common PPG for alcohols and other functional groups.
2-
Nitrobenzyl protected alcohols have molar absorption co-
efficients of about 4 times higher at 254 nm than those of
Received: January 4, 2015
Published: January 21, 2015
the largest molar absorption coefficient (∼35 000 M− cm at
1
−1
©
2015 American Chemical Society
740
DOI: 10.1021/acs.orglett.5b00019
Org. Lett. 2015, 17, 740−743

Organic Letters
Letter
Table 1. External Sunscreen Effect on Photodeprotection of
a
Tris(Trimethylsilyl)Silyloxy Octane in 254 nm UV Light
external sunscreen
0.1 M phenanthrene)
internal sunscreen
(0.1 M phenanthrene)
no
sunscreen
(
time
(
min)
1a:1b
0
5
100:0
100:0
100:0
100:0
100:0
100:0
100:0
95:5
100:0
66:34
0:100
0:100
0:100
1
3
6
5
0
0
89:11
81:19
a
Reaction conditions: 0.03 M protected alcohol, methanol-d4 (10
equiv), in 1 mL of CD Cl , irradiated by 254 nm UV light in quartz
2
2
1
NMR tube. Deprotection conversion measured by H NMR.
tris(trimethylsilyl)silyl (sisyl) protected alcohols (Figure 2).
Indeed, although the deprotection was slowed in the presence
of phenanthrene, the reaction still proceeded at an appreciable
rate (see Supporting Information).
Figure 3. Selective photodeprotection of o-nitro [(pentyloxy)methyl]
benzene and tris(trimethylsilyl) silyloxy octane. Reaction conditions:
0
.03 M of protected alcohol, methanol-d (5 equiv), and specified
4
concentration of sunscreen in 1 mL of CD Cl irradiated by 254 nm
2
2
1
UV light. Deprotection conversion measured by H NMR. Internal
standard: 1 equiv of 1,3,5 trioxane.
Figure 2. Measured molar absorption coefficients at 254 nm
(
CH Cl ).
2 2
Encouraged by the significant difference in the photocleavage
sequences for both PPGs, an experiment was set up with both
sisyl and 2-nitrobenzyl ethers present in solution. Thus,
pentanol and octanol were protected with 2-nitrobenzyl and
sisyl respectively and irradiated with 254 nm light in a CH Cl2
2
solution in the presence and absence of phenanthrene (both
internal and external). The results are illustrated in Figure 3.
The scope of the reaction was probed also for secondary
alcohols with very similar results as shown in Figure 4.
Having shown that indeed sisyl and 2-nitrobenzyl protecting
groups may be selectively photocleaved by the judicious use of
a sunscreen, two diol scaffolds were protected with both
protecting groups to afford compounds 5a and 6a. A selective
deprotection sequence in these molecules would mimic
challenges that may arise within complex organic mole-
2
4,25
cules.
Once again, as shown in Figures 5 and 6, even
within the same molecular scaffold, the use of the sunscreen
method afforded the selective photocleavage of the more
sensitive protecting group. Notably, compound 6a is a
bisphenol molecule, expanding the sunscreen deprotection
method to this type of alcohols as well. The selective
deprotection of 5a to afford 5b was carried out in a preparative
scale using the internal protection protocol and afforded 82%
isolated yields, providing an attractive alternative methodology
for selective cleavage of protecting groups with light from a
single source. As a control experiment the photocleavage
reactions were conducted with lower power light sources to
determine whether selectivity could be achieved by this fashion.
Even though the 2-nitrobenzyl ether was cleaved at a higher
rate, the selectivity produced by the sunscreen protocol could
Figure 4. Selective photodeprotection of o-nitro [(cyclopentyloxy)-
methyl] benzene and 2-tris(trimethylsilyl)silyloxy pentane in the
presence of phenanthrene. Reaction conditions: 0.03 M of protected
alcohol, methanol-d4 (5 equiv), and specified concentration of
sunscreen in 1 mL of CD Cl , irradiated by 254 nm UV light.
2 2
1
Deprotection conversions measured by H NMR.
not be reproduced (see Supporting Information). In addition,
while the intensity of the light is very difficult to tune, it is quite
simple to change the concentration of the sunscreen to achieve
optimal results.
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DOI: 10.1021/acs.orglett.5b00019
Org. Lett. 2015, 17, 740−743

Organic Letters
Letter
wavelength was shown to efficiently modulate the photo-
cleavage and achieve high selectivities with several protected
alcohols. Moreover, the use of an external peripheral sunscreen,
such as an external phenanthrene solution or even a simple
PET bottle, allows for a straightforward method that does not
necessitate additional purification schemes to remove the
absorbing molecule added. Thus, a new concept that expands
protecting group methodology is presented, where with a single
light source selective deprotection may be achieved by choosing
the appropriate protecting groups. The expansion of this
concise methodology to improve existing chromatic orthogonal
methods is currently being studied in our laboratories.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Additional data, experimental procedures, full characterization,
and NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Figure 5. Selective intramolecular photodeprotection of 5a. Reaction
conditions: 0.015 M of protected diol, 2 equiv of methanol-d4,
specified concentration of sunscreen in 1 mL of CD Cl , irradiated by
■
2
2
*E-mail: lemcoff@bgu.ac.il.
Notes
1
254 nm UV light. Deprotection conversions measured by H NMR.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The Israel Science Foundation is gratefully acknowledged for
financial support.
■
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26
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DOI: 10.1021/acs.orglett.5b00019
Org. Lett. 2015, 17, 740−743