Development of a photolabile carbonyl-protecting group toolbox

Article abstract of DOI:10.1021/jo102429g

New salicyl alcohol derived photolabile carbonyl protecting groups have been developed, and the effect of substituents on the photochemical properties of photolabile protecting groups (PPGs) has been studied. The 3-(dimethylamino)phenyl groups at the α position prove to be important to the efficiency of the deprotection reactions, as shown in the photo reactions of the acetal 9. On the other hand, expansion of the salicyl alcohol's benzene skeleton to naphthalene does not improve the photochemical properties of PPGs. A neutral protecting protocol has been generalized to new PPGs with α,α-diaryl salicyl alcohol backbone. Thus, installation of PPGs onto aldehydes is readily achieved at 140 °C without using any other chemical reagents. These PPGs are stable under acidic conditions typical for hydrolyzing acetals and constitute orthogonal protecting groups with traditional 1,3-dioxane/1,3-dioxolane for carbonyl compounds. Highly efficient release of carbohydrate molecules is demonstrated, which can be potentially useful in site-specific release and immobilization of carbohydrates for preparation of high-density microarrays. With the enriched PPG toolbox, PPGs are divided into three subgroups based on their UV absorption profiles. PPGs from different subgroups can be sequentially removed by using different UV irradiation wavelengths. For PPGs absorbing UVA (λ >315 nm), photochemical deprotection can be carried out with sunlight in high yields.

Full text of DOI:10.1021/jo102429g

ARTICLE
pubs.acs.org/joc
Development of a Photolabile Carbonyl-Protecting Group Toolbox†
Haishen Yang, Xin Zhang, Lei Zhou, and Pengfei Wang*
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, Alabama 35294, United States
S Supporting Information
b
ABSTRACT: New salicyl alcohol derived photolabile carbonyl
protecting groups have been developed, and the effect of
substituents on the photochemical properties of photolabile
protecting groups (PPGs) has been studied. The 3-
(dimethylamino)phenyl groups at the R position prove to be
important to the efficiency of the deprotection reactions, as
shown in the photo reactions of the acetal 9. On the other hand,
expansion of the salicyl alcohol’s benzene skeleton to naphtha-
lene does not improve the photochemical properties of PPGs. A
neutral protecting protocol has been generalized to new PPGs
with R,R-diaryl salicyl alcohol backbone. Thus, installation of PPGs onto aldehydes is readily achieved at 140 °C without using any
other chemical reagents. These PPGs are stable under acidic conditions typical for hydrolyzing acetals and constitute orthogonal
protecting groups with traditional 1,3-dioxane/1,3-dioxolane for carbonyl compounds. Highly efficient release of carbohydrate
molecules is demonstrated, which can be potentially useful in site-specific release and immobilization of carbohydrates for
preparation of high-density microarrays. With the enriched PPG toolbox, PPGs are divided into three subgroups based on their UV
absorption profiles. PPGs from different subgroups can be sequentially removed by using different UV irradiation wavelengths. For
PPGs absorbing UVA (λ >315 nm), photochemical deprotection can be carried out with sunlight in high yields.
hotolabile protecting groups (PPGs) are protecting groups
that can be removed with photo irradiation under neutral and
R-diphenyl-5-methoxysalicyl alcohol,5a R,R-diphenyl-3,5-di-
methoxysalicyl alcohol, and R,R-diphenyl-5-(dimethylamino)-
salicyl alcohol were examined as the PPG reagents.5c Indeed,
meta electron-donating substitution improved the efficiency of
deprotection reactions. However, the intermediate IV was not
observed in the reaction mixture. Instead, in the presence of
water, the PPG reagent V has been recovered to different extents
depending on the structure of PPGs and reaction conditions.5c,7
These new PPGs have some advantageous features. For
example, they are easily synthesized from commercially available
inexpensive materials, they have high protection/deprotection
efficiencies, and they possess remarkable dark stability. In
particular, mindful of the unique structural features of these
PPGs, we have developed a neutral protecting protocol and
demonstrated for the first time that both protection and depro-
tection reactions can be conducted under neutral conditions
without using any other chemical reagents.8 These PPGs have
found applications in controlled release of anticancer agents9 and
synthesis.10 Herein we report our effort in further enriching the
PPG tool box and applications of PPGs in releasing carbohy-
drates, selective deprotection, and deprotection with sunlight.
P
reagent-free conditions. In addition, photochemical deprotection
reactions can be carried out with precise spatial and temporal
control. These features are important to a broad spectrum of
applications ranging from dynamic studies in biology to surface
patterning and photolithographic preparation of high density
biochips.1,2 The past two decades have witnessed continuous
emergence of new PPGs and their creative applications.3
Among various functional groups, we are particularly interested
in developing PPGs for carbonyl groups. Carbonyl groups are
important functional groups in organic chemistry and often need
protection in the course of multistep syntheses.1 Moreover, many
biologically important molecules have a carbonyl moiety; deactivat-
ing these molecules through modifying carbonyl groups with PPGs
and subsequent release in a desired environment upon irradiation is
an appealing approach to controlled release of molecules.
Research in developing photolabile carbonyl protecting
groups dates back several decades, and much progress has been
made.4 We recently reported a series of new PPGs for carbonyl
groups featuring the salicyl alcohol skeleton (Scheme 1).5 We
hypothesize that irradiation of the acetal I results in cleavage of
the benzylic C-O bond to produce the intermediate II. The
depicted electron movement in II leads to release of the carbonyl
compound III and formation of the intermediate IV. According
to the excited state meta effect,6 introducing an electron-donating
group at the meta position(s) of the salicyl alcohol skeleton
should facilitate the benzylic C-O bond cleavage. Therefore R,
’ RESULTS AND DISCUSSION
In the search for more salicyl alcohol derived PPGs of different
properties, we pursued structural modification of the salicyl
Received: November 9, 2010
Published: March 03, 2011
r
2011 American Chemical Society
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Scheme 1. Proposed Mechanism of Photochemical
Deprotection
Figure 1. UV spectra of acetals 2-6.
Scheme 2. Synthesis of Acetals 2-6
alcohol along two directions: (1) changing its R-substituents and
(2) expanding the aromatic chromophore.
Figure 2. UV spectra of acetals 7-9.
Changing r-Substituents. Because of ready access to the
methyl salicylate 1 and known properties of the PPG in 2,5a we
designed various PPGs in the acetals 3-6 to study the R-
substituent effect (Scheme 2). The acetals 2-6 were synthesized
in two steps. First, the salicyl alcohols were prepared from
reaction of the corresponding Grignard reagents with the ester
1. Then the PPGs were installed onto 3-phenylpropanal. The
known acetal 2 was used as a reference compound.
The UV spectrum of 2 resembles that of 3 (Figure 1), and both
have an absorption peak centering at 297 nm with similar
magnitude (i.e., ε = 4.4 Â 103 M-1 cm-1 for 2 and ε = 3.6 Â
103 M-1 cm-1 for 3, respectively, Figure 1). We assume this
absorption peak originates from the 5-methoxysalicyl chromo-
phore. For the acetal 4, in addition to the 297 nm absorption (ε =
8.4 Â 103 M-1 cm-1), there are two overlapping peaks at 277 nm
(ε = 10.4 Â 103 M-1 cm-1) and 283 nm (ε = 11.4 Â 103
M-1 cm-1) that probably originate from the two R groups (i.e.,
3-methoxyphenyl group). The high absorption of 4 at 297 nm
relative to that of 2 and 3 can be attributed to its overlap with the
long wavelength tail of the two 3-methoxyphenyl groups. For the
acetal 5, in addition to the shoulder peak at 297 nm, there is an
absorption peak at 286 nm (ε = 7.1 Â 103 M-1 cm-1) that is
probably from the two 3,5-dimethoxyphenyl groups at the R
position. The acetal 6 has a slightly longer absorption maximum
at around 302 nm (ε = 8.5 Â 103 M-1 cm-1) with the long
wavelength end extending to 350 nm. We attribute the red-shift
to the two R groups (i.e., 3-(dimethylamino)phenyl group).
The acetals 7-9 (Figure 2) were also synthesized by using the
same method depicted in Scheme 2. Comparison of the UV
profiles between 3 and 7 (ε283 nm = 1.9 Â 103 M-1 cm-1, Φ =
0.1)11,12 revealed that the absorption peak at 297 nm should be of
the 5-methoxysalicyl chromophore, which was also confirmed by
the comparison between 4 and 8. The UV spectrum of 8 also
lacks the peak at 297 nm, but similar to 4, it has the two
overlapping peaks at 276 nm (ε = 8.2 Â 103 M-1 cm-1) and
283 nm (ε = 7.8 Â 103 M-1 cm-1), which were assigned to the
two R 3-methoxyphenyl groups. The UV spectrum of 9 shows
that the two 3-(dimethylamino)phenyl groups actually absorb at
309 nm (ε = 4.9 Â 103 M-1 cm-1); that should also be the case
in 6 where absorption of the R groups and the salicyl skeleton are
overlapping.
Photoreactions of 2-6 were carried out with a 450 W medium
mercury lamp in a Hanovia photoreactor. The acetals 2-6 (5 mM
in CD3CN/D2O 9:1) were irradiated with Pyrex-filtered light for 8
min. Although the acetals 2-5 have different UV profiles, they all
showed similar photochemical efficiency in releasing the aldehyde,
withthechemical yieldsranging from 54% to 68% (Table1, entries
1-4). The photochemicalresults combined with the common UV
absorption at 297 nm suggest that UV absorption of the
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Table 1. Properties of Photocleavable Acetals
entry acetal ε (λ) of acetal (M-1 cm-1)/103 deprotection yield (%)a,b,c
1
2
3
2
3
4
4.4 (297 nm)
3.6 (297 nm)
8.4 (297 nm)
11.5 (283 nm)
10.4 (277 nm)
7.1 (286 nm)
8.5 (302 nm)
54d
68d
57d
4
5
5
6
54d
83d
87e
26f
32f
6
7
7
8
1.9 (283 nm)
7.8 (283 nm)
8.2 (276 nm)
4.9 (309 nm)
8
9
87d
94e
92d
92e
84d
80e
9
10
11
3.4 (327 nm)
7.7 (314 nm)
Figure 3. UV spectra of acetals 9-11.
10
a Irradiated with a 450 W medium mercury lamp in a Hanovia photo-
reactor without excluding air. b The acetal (5 mM in CD3CN/D2O 9:1)
was irradiated in a NMR tube unless indicated otherwise. c Yields
1
determined by H NMR analysis. d 8 min of irradiation with a Pyrex
filter sleeve. e 5 min of irradiation without a filter. f The acetal (5 mM in
CD3CN/D2O 9:1) was irradiated for 5 min in a quartz UV cell behind
another UV cell containing a filter solution (centring at 283 nm in the
useful UV region) prepared from BiCl3 (0.264 mM) in conc HCl/H2O
(2:3).
5-methoxysalicyl chromophore at 297 nm should account for
benzylic bond cleavage in the series of 2-5.
However, the acetal 6 was apparently more efficient in
releasing the aldehyde than 3-5, with a yield of 83% (Table 1,
entry 5). It seemed that the R substituents (i.e., two 3-
(dimethylamino)phenyl groups) not only led to a bathochromic
shift of the PPGs UV absorption but also notably facilitated the
benzylic C-O bond breakage. To examine to what extent the R
groups influence the photolysis, we compared the photochemical
reactions of 6 and 9. Under the same irradiation conditions with
Figure 4. MO computations of 12 and 13.
electron-donating substituent at C5 and/or C7 would increase
electron density at C2 in the first excited state and was anticipated
to facilitate heterolysis of the C-O bond.5,6 Mindful of this favorable
electronic effect, we synthesized the acetals 14-18 (Figure5).Among
them, the acetals 15 and 16 resembled the computation model
compounds 12 and 13, bearing a 5-OMe and 7-OMe, respectively.
As expected, spectral red-shifts of these acetals were observed
with the expanded aromatic skeletons compared with methoxyl-
substituted salicyl alcohol based PPGs (see Supporting In-
formation). However, photochemical efficiencies were not im-
proved. In fact, upon irradiation in CD3CN/D2O (9:1) (2.5 mM
solution) with Pyrex-filtered light for 15 min, none of the acetals
14-18 had a higher conversion and released more 3-phenyl-
propanal than the reference acetal 2 did. The methoxyl group in
15 and 16 only slightly improved reaction yields. For example,
NMR analysis showed that the aldehyde was released from 15
and 16 in 19% and 8% yields, respectively, whereas the yield from
14 was about 6%. Among the acetals 14-18, the highest yield of
releasing propanal was 44% from 18, which was still lower than
93% from 2 under the same reaction conditions.
light from a Pyrex-filtered mercury lamp, the acetal 9 (ε309 nm
=
4.9 Â 103 M-1 cm-1, Φ = 0.23)11,12 released the aldehyde in
87% yield. Given the fact that the unsubstituted salicyl chromo-
phore does not absorb above 280 nm, the high yield of the
benzylic C-O bond cleavage should be attributed to absorption
by the two 3-(dimethylamino)phenyl groups. This chemical
yield was also comparable to the yield of 92% obtained from
the photoreaction of 10 (Figure 3, ε327 nm = 3.4 Â 103 M-1 cm-1
,
Φ = 0.13)5c when 9 and 10 were irradiated side by side for 8 min
(Table 1, entries 8 and 9). When both 9 and 10 were irradiated for
5 min with the medium-pressure lamp without a filter, they
released the aldehyde in 94% and 92% yields, respectively.
However, irradiation of 11 (Figure 3), with the PPG combining
the effective absorptions of both 9 and 10, resulted in 84% yield
after 8 min irradiation with Pyrex-filtered light or 80% yield after 5
min irradiation without a filter (Table 1, entry 10). In both cases,
the yields were inferior to that of either 9 or 10.
Selectively Removing Carbonyl Protecting Groups. Struc-
tural variation led to useful new PPGs. For instance, the acetal 9
released the aldehyde in similar yield as 10, but the photoreaction
was cleaner and more PPG reagent was recovered after deprotec-
tion. In addition, the particular PPG reagent was readily prepared
in high yield from commercially available methyl salicylate in just
one step.
Expanding Salicyl Chromophore. To examine the effects of
an expanded salicyl chromophore, we studied PPGs with naphtha-
lene backbones. Molecular orbital calculations13 on the model
compounds 12 and 13 (Figure 4) demonstrated that an
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Figure 5. Acetals 14-18.
The salicyl alcohol derived carbonyl PPGs can be divided into
three subgroups A-C on the basis of their UV absorptions
(Figure 6). Group A PPGs (e.g., PPGs in 195c and 20) can be
removed with long wavelength UV irradiation, e.g., by 350 nm
lamps in a Rayonet reactor, by filtered light (λ > 320 nm) in a
Honovia reactor setting,14 or by sunlight. Group B PPGs (e.g.,
PPGs in 21 and 22)5a,c have to be removed with UV of
wavelength shorter than 320 nm. Removal of Group C PPGs
(e.g., PPGs in 23,5c 24, and 25) requires light wavelength shorter
than 280 nm, i.e., they are inert to Pyrex-filtered light. The PPGs
in 24 and 25 had good photochemical efficiency (vide infra). The
low yields of the acetal 7 and 8 (possessing the same PPGs) in
Table 1 were due to low conversion of 7 and 8 caused by low
intensity of the filtered light. In general, these PPGs are more
stable toward acid treatment than the traditional dioxane or
dioxolane protection of carbonyls.
To demonstrate selective deprotection with carbonyl protecting
groups, we synthesized acetals from the aldehydes 26 and 27
(eq 1). Notably, the acetals 28-31 were prepared by generalizing
the neutral protection protocol we recently developed.7 Thus,
heating a neat mixture of an aldehyde and the corresponding PPG
reagent at 140 °C led to 28-31 in 82%, 75%, 88%, and 73% yields,
respectively. This protection procedure does not require any other
chemical reagents, even solvent. We also converted the aldehyde
32 to the dioxolane 33 (eq 2). Under the typical conditions of
releasing carbonyls from dioxolanes, e.g., treatment of the acetals
28-31 and 33 with HCl (2 N) in THF at 40 °C for over 24 h, the
acetal33 released the aldehyde 32 cleanly withonlya trace amount
of 33 left. In contrast, the acetals 28-31 showed no sign of
reaction based on NMR and TLC analysis.
Figure 6. PPGs respond to different UV wavelength.
Table 2. Photoreactions of Acetals 28-31
entryacetala irradiation λ (nm)b reaction time (min)deprotection yield (%)f
1
2
3
4
28
31
29
30
>320c
>320c
>280d
>210e
50
50
40
10
94
91
91
75
a [acetal] = 0.8 mM in 250 mL of MeCN/H2O (9:1). b Irradiated with a
450 W medium mercury lamp in a Hanovia photoreactor without
c
excluding air. Filtered with a Pyrex sleeve and 10% NaNO3 solution.
d Filtered with a Pyrex sleeve. e Filtered with a Vycor sleeve.
f Isolated yield.
on NMR analysis. In a preparative run, the aldehyde 27 was
released from 28 in 94% yield (Table 2, entry 1). The PPG
reagent (i.e., R,R-di(dimethylamino)phenyl salicyl alcohol) was
isolated in 82% yield, in agreement with the proposed mecha-
nism in Scheme 1. Under the same conditions, the aldehyde 27 was
obtained in 91% yield from 31. However, the PPG portion in this
case had a different fate and benzophenone instead of the corre-
sponding PPG reagent (i.e., R,R-diphenyl-5-(dimethylamino)salicyl
alcohol) was observed in more than 80% yield based on NMR
analysis. It was presumably formed through a secondary photoreac-
tion of the PPG reagent. Irradiation of 29 and 30 in two separate
reaction vessels with Pyrex-filtered light (λ > 280 nm) removed the
PPG from 29 only while the acetal 30 remained unchanged based
on NMR analysis. The photoreaction of 29 was confirmed in a
preparative run and the aldehyde 26 was isolated in 91% yield
(Table 2, entry 2). Finally, a solution of 30 was irradiated with
Vycor-filtered UV light (λ > 210 nm), and the reaction produced
the aldehyde 26 in 75% yield (Table 2, entry 3). The lower yield of
the isolated aldehyde was due to side reactions of the released
aldehyde under low-wavelength UV irradiation, and the yield is
aldehyde-structure-dependent. For example, with Vycor-filtered
irradiation, the aldehyde 27 cleanly generated allyl rhamnoside via
a Norrish type II pathway. On the other hand, 3-phenylpropanal was
relatively more stable than the aldehyde 26.5c
When the acetals 28-31 (in CD3CN/D2O 9:1) were irra-
diated individually in separate reaction vessels under the same
conditions with UV (λ > 320 nm),14 only the PPG in 28 and 31
was removed, whereas the acetal 29 and 30 remain intact based
Deprotection with Sunlight. As with other PPGs shown in
Figure 6, Group A protecting groups are stable under indoor
lighting. As such, they do not require special precautions to
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prepare and handle the PPG-protected compounds. However,
they can be conveniently removed with sunlight in high effi-
ciency. For instance, a solution of 28 (5 mM in MeCN/H2O 9:1)
in a Pyrex test tube was kept in a water bath and placed outdoors
under sunlight in clear weather. The reaction temperature varied
between 20 to 30 °C during the reaction course. After 2 h, the
reaction was complete, and the aldehyde was isolated in 81%
yield. Prolonged irradiation did not significantly influence the
yield of released aldehyde. For example, irradiation of 28 for 3 h
led to 79% yield of 27. Similarly, irradiation of 31 for 3 h led to
82% yield of 27. However, the PPG reagents decomposed during
extended irradiation in both cases. The reaction time could be
affected by the shape of reaction vessels owing to their different
efficiency in absorbing sunlight.
2-[Bis(3-dimethylamino-phenyl)-hydroxy-methyl]-phe-
nol (PPG of 9). To a solution of salicylic acid methyl ester (192 mg,
1.26 mmol, 1 equiv) in THF was added dropwise the solution of PhLi
(2 M in n-Bu2O, 0.63 mL, 1 equiv) at -78 °C under argon, and the
mixture was stirred for a further 5 min. Then the resultant solution was
transferred to the stirred solution of 3-dimethylaminophenyl magne-
sium bromide (2 equiv), prepared from (3-bromophenyl)-dimethyl-
amine (0.50 g, 2.5 mmol, 0.36 mL) and magnesium (73 mg, 2.4 equiv) in
8 mL THF, and the resultant solution was stirred overnight. Workup as
usual followed by flash chromatography (petroleum ether/ethyl acetate =
3/1, Rf 0.4) to afford the title compound (323 mg, 71%). 1H NMR (400
MHz, CDCl3) δ 8.28 (s, 1 H), 7.15-7.21 (m, 3 H), 6.89 (dd, J = 1.2, 8.1
Hz, 1 H), 6.61-6.74 (m, 6 H), 6.50 (dd, J = 0.7, 7.7 Hz, 2 H), 3.50 (s, 1
H), 2.86 (s, 12 H); 13C NMR (75 MHz, CDCl3) δ 156.1, 150.3, 145.9,
130.5, 130.1, 129.1, 128.5, 118.7, 117.2, 116.7, 112.5, 112.0, 84.8, 40.6;
IR(neat) 3228, 3073, 2885, 2803, 1600, 1495, 1351, 1236, 758; HRMS
(ESI) m/e calcd for C23H27N2O2, 363.2073, found 363.2073.
’ CONCLUSIONS
General Procedure for Preparing Aetals 3-9 and 11 and
Their Corresponding PPG. 4-Methoxysalicylic acid methyl ester
(for PPGs in 2-6), salicylic acid methyl ester (for PPGs in 7-9 and 11),
or 4-dimethylamino salicylic acid methyl ester (for PPG in 10) and
ArMgBr or ArLi were stirred at room temperature overnight. Workup as
usual followed by recrystallization or flash chromatography afforded the
corresponding PPGs. The PPG reagent and the aldehyde (PPG/
aldehyde = 1: 2) were stirred at 140 °C under argon for 2 h. Upon
completion, the reaction mixtures were purified by flash column
chromatography to afford the desired acetals.
4,4-Bis(4-fluoro-phenyl)-6-methoxy-2-phenethyl-4H-benzo-
[1,3]dioxine (3). Yield 73%; Rf 0.5 (petroleum ether/ethyl acetate =
7/1); 1H NMR (400 MHz, CDCl3) δ 7.33-7.36 (m, 2 H), 7.25-7.29
(m, 2 H), 7.18-7.22 (m, 2 H), 7.10-7.15 (m, 3 H), 7.01-7.08 (m, 3
H), 6.85 (dd, J = 0.4, 9.0 Hz, 1 H), 6.80 (dd, J = 2.9, 9.0 Hz, 1 H), 6.33
(dd, J = 0.3, 2.9 Hz, 1 H), 4.87 (dd, J = 4.2, 6.1 Hz, 1 H), 3.59 (s, 3 H),
2.77 (ddd, J = 6.0, 9.2, 14.6 Hz, 1 H), 2.62 (ddd, J = 7.2, 9.0, 14.0 Hz, 1
H), 2.04-2.18 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 162.4 (d, J =
248.1 Hz), 162.0 (d, 1H, J = 246.9 Hz), 153.0, 146.3, 141.7 (d, J = 3.1
Hz), 141.2, 139.9 (d, J = 3.2 Hz), 131.1 (d, J = 8.1 Hz), 129.8 (d, J = 8.1
Hz), 128.28, 128.27, 125.8, 125.5, 117.8, 115.1, 114.9 (d, J = 3.4 Hz),
114.6 (d, J = 2.9 Hz), 114.2, 94.3, 83.3, 55.5, 35.9, 29.6; IR(neat) 3062,
3027, 2932, 2835, 1602, 1506, 1497, 1465, 1455, 1407, 1272, 1227, 1158,
1041, 831; HRMS (ESI) m/e calcd for C29H24F2O3Na, 481.1591, found
481.1593.
6-Methoxy-4,4-bis(3-methoxy-phenyl)-2-phenethyl-4H-
benzo[1,3]dioxine (4). Yield 82%; Rf 0.3 (petroleum ether/ethyl
acetate = 7/1); 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 8.0 Hz, 1
H), 7.18-7.24 (m, 3 H), 7.11-7.15 (m, 1 H), 7.07-7.09 (m, 2 H),
6.91-6.96 (m, 2 H), 6.78-6.86 (m, 6 H), 6.41 (d, J = 2.8 Hz, 1 H),
4.92 (dd, J = 4.1, 6.0 Hz, 1 H), 3.72 (s, 3 H), 3.70 (s, 3 H), 3.60 (s, 3 H),
2.80 (ddd, J = 5.8, 9.8, 14.1 Hz, 1 H), 2.64 (ddd, J = 7.2, 9.3, 14.0 Hz, 1
H), 2.04-2.21 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 159.3, 159.1,
152.8, 147.3, 146.3, 145.7, 141.4, 128.9, 128.7, 128.27, 128.23, 125.7,
125.6, 121.8, 120.6, 117.5, 115.0, 114.8, 114.2, 114.0, 113.2, 112.4,
94.5, 84.0, 55.5, 55.1, 55.1, 36.1, 29.6; IR(neat) 3000, 2936, 2833,
1598, 1493, 1256, 1225, 1196, 1126, 814, 700; HRMS (ESI) m/e calcd
for C31H30O5Na, 505.1991, found 505.1999.
4,4-Bis(3,5-dimethoxy-phenyl)-6-methoxy-2-phenethyl-
4H-benzo[1,3]dioxine (5). Yield 69%; Rf 0.1 (petroleum ether/ethyl
acetate = 15/1); 1H NMR (400 MHz, CDCl3) δ 7.22-7.25 (m, 2 H),
7.15-7.28 (m, 1 H), 7.11-7.14 (m, 2 H), 6.82 (d, J = 8.9 Hz, 1 H), 6.74
(dd, J = 3.0, 8.9 Hz, 1 H), 6.54 (d, J = 2.3 Hz, 2 H), 6.47 (d, J = 2.3 Hz, 2
H), 6.44 (d, J = 2.9 Hz, 1 H), 6.42 (t, J = 2.3 Hz, 1 H), 6.34 (t, J = 2.3 Hz, 1
H), 5.03 (dd, J = 4.2, 5.8 Hz, 1 H), 3.73 (s, 6 H), 3.72 (s, 6 H), 3.65 (s, 3
H), 2.85 (ddd, J = 5.7, 10.3, 14.2 Hz, 1 H), 2.73 (ddd, J = 6.5, 10.1, 13.8
Hz, 1 H), 2.08-2.24 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 160.3,
We studied the structure-property relationship of salicyl
alcohol based photolabile carbonyl protecting groups. The 3-
(dimethylamino)phenyl groups at the R position appear to be
important to deprotection efficiency, while enlarging the aro-
matic backbone in salicyl alcohols from benzene to naphthalene
does not improve photochemical efficiency. Furthermore, a
group of new PPGs for carbonyl protection has been developed.
These PPGs are divided into three subgroups based on their UV
absorption profiles. PPGs from different subgroups can be
removed sequentially with different UV irradiation, which is
anticipated to be potentially useful in many applications. For
PPGs absorbing long wavelength UV, photochemical deprotec-
tion can be carried out with sunlight in high yields. PPGs in the
new toolbox share some important features, e.g., they all are
structurally simple, chemically stable, and easy to prepare. They
all can be installed and removed with high chemical efficiencies.
Moreover, due to their common structural feature, the reagent-
free green chemistry PPG-installation protocol can be readily
generalized to new PPGs. For the first time, a group of PPGs that
can be installed and removed under reagent-free conditions have
been developed. In addition, our new PPGs constitute orthogo-
nal protecting groups with traditional acid-labile 1,3-dioxane/
1,3-dioxolane for carbonyl compounds. We have also demon-
strated release of monosaccharides having an anomeric aldehyde
moiety, which can be potentially useful in site-specific release and
immobilization of carbohydrates to solid surfaces for preparation
of high-density carbohydrate microchips.
’ EXPERIMENTAL SECTION
2-[Bis(4-fluoro-phenyl)-hydroxy-methyl]-phenol (PPG in
7). A solution of salicylic acid methyl ester (1.20 g, 7.89 mmol, 1 equiv)
in THF was added to the solution of 4-fluorophenyl magnesium
bromide (3.5 equiv), prepared from 4-bromofluorobenzene (4.83 g,
3.03 mL) and magnesium (0.80 g, 4.2 equiv) in 15 mL THF, and the
resultant solution was stirred overnight. Workup as usual followed by
flash chromatography (petroleum ether/ethyl acetate = 8/1, Rf 0.3) to
afford the title compound (2.21 g, 90%). 1H NMR (400 MHz, CDCl3) δ
7.75 (s, 1 H), 7.15-7.23 (m, 5 H), 7.01-7.06 (m, 4 H), 6.90 (dd, J = 1.1,
8.1 Hz, 1 H), 6.76 (dt, J = 1.2, 7.6 Hz, 1 H), 6.49 (dd, J = 1.6, 7.8 Hz, 1 H),
3.72 (s, 1 H); 13C NMR (101 MHz, CDCl3) δ 162.3 (d, J = 247.7 Hz),
155.4, 140.6 (d, J = 3.2 Hz), 130.0, 129.8, 129.7, 129.5 (d, J = 8.2 Hz),
119.4, 117.6, 115.1 (d, J = 21.5 Hz), 83.4; IR(neat) 3228, 1602, 1584,
1507, 1227, 1159, 838, 740; HRMS (ESI) m/e calcd for C19H14F2O2Na,
335.0860, found 335.0868.
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ARTICLE
160.1, 152.8, 147.8, 146.3, 146.2, 141.4, 128.3, 125.8, 125.4, 117.4, 114.6,
114.1, 107.7, 106.7, 99.5, 98.9, 94.6, 84.2, 55.5, 55.3, 55.2, 36.2,
29.7; IR(neat) 3000, 2937, 2835, 1595, 1495, 1456, 1425, 1205, 1155,
1041; HRMS (ESI) m/e calcd for C33H35O7, 543.2383, found
543.2374.
6-Methoxy-4,4-bis(3-dimethylamino)-2-phenethyl-4H-
benzo[1,3]dioxine (6). Yield 71%; Rf 0.2 (petroleum ether/ethyl
acetate = 12/1); 1H NMR (400 MHz, CDCl3) δ 7.08-7.24 (m, 7 H),
6.81-6.84 (m, 3 H), 6.73 (dd, J = 2.9, 9.0 Hz, 3 H), 6.61 (dd, J = 2.7, 8.0
Hz, 1 H), 6.56 (d, J = 8.0 Hz, 1 H), 6.48 (d, J = 2.9 Hz, 1 H), 5.08 (dd, 1H,
J = 4.0, 5.9 Hz), 3.63 (s, 3 H), 2.88 (s, 6 H), 2.86 (s, 6 H), 2.69-2.93 (m, 2
H), 2.06-2.24 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 152.6, 150.3,
150.1, 146.8, 146.4, 145.0, 141.7, 128.34, 128.29, 128.24, 128.19, 126.5,
125.7, 118.3, 117.2, 114.8, 113.9, 113.5, 112.6, 112.1, 111.7, 94.5, 84.8,
55.5, 40.63, 40.58, 36.3, 29. 7; IR(neat) 3026, 2928, 2803, 1600, 1494,
1434, 1352, 1272, 1229, 1041, 759, 700; HRMS (ESI) m/e calcd for
C33H37N2O3, 509.2804, found 509.2805.
4,4-Bis(4-fluoro-phenyl)-2-phenethyl-4H-benzo[1,3]-
dioxine (7). Yield 71%; Rf 0.6 (petroleum ether/ethyl acetate = 15/1);
1H NMR (400 MHz, CDCl3) δ 7.29-7.32 (m, 2 H), 7.01-7.25 (m, 10
H), 6.90-6.96 (m, 3 H), 6.82 (dt, J = 1.1, 7.8 Hz, 1 H), 6.75 (dd, J = 1.5,
7.8 Hz, 1 H), 4.99(dd, J =4.4, 5.6 Hz, 1 H), 2.82 (ddd, J =6.0, 9.6, 15.3 Hz,
1 H), 2.66-2.74 (m, 1 H), 2.10-2.24 (m, 2 H); 13C NMR (101 MHz,
CDCl3) δ 162.4 (d, J =248.0Hz), 162.0 (d, J =246.9Hz), 152.3, 141.8 (d,
J = 3.0 Hz) 141.1, 139.9 (d, J = 3.2 Hz), 131.1 (d, J = 8.2 Hz), 129.8 (d, J =
8.1 Hz), 129.5, 128.6, 128.31, 128.28, 125.9, 125.0, 120.4, 117.2, 115.0 (d,
J = 21.4 Hz), 114.7 (d, J = 21.4 Hz), 94.4, 83.3, 35.9, 29.5; IR(neat) 3063,
3028, 2929, 1603, 1584, 1506, 1485, 1457, 1407, 1228, 1158, 1038, 987,
836, 755, 700; HRMS (ESI) m/e calcd for C28H22F2O2Na, 451.1486,
found 451.1499.
4,4-Bis(3-methoxy-phenyl)-2-phenethyl-4H-benzo[1,3]-
dioxine (8). Yield 71%; Rf 0.5 (petroleum ether/ethyl acetate = 15/1);
1H NMR (400 MHz, CDCl3) δ 7.09-7.29 (m, 8 H), 6.77-6.95 (m, 9
H), 5.07 (dd, J = 4.1, 5.8 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 2.85 (ddd,
J = 5.7, 9.9, 13.7 Hz, 1 H), 2.74 (ddd, J = 6.6, 10.1, 14.7 Hz, 1 H), 2.18 (m,
2 H); 13C NMR (101 MHz, CDCl3) δ 159.4, 159.1, 152.2, 147.5, 145.8,
141.4, 129.6, 129.0, 128.7, 128.31, 128.27, 125.8, 125.1, 121.9, 120.7,
120.2, 117.0, 115.0, 114.3, 113.3, 112.4, 94.6, 84.0, 55.2, 55.1, 36.2, 29.6;
IR(neat) 3061, 3028, 3002, 2957, 2936, 2834, 1598, 1583, 1485, 1455,
1433, 1403, 1290, 1257, 1124, 1040, 995, 780, 757, 737, 700; HRMS
(ESI) m/e calcd for C30H28O4Na, 475.1885, found 475.1890.
4,4-Bis(3-dimethylamino)-2-phenethyl-4H-benzo[1,3]-
dioxine (9). Yield 69%; Rf 0.3 (petroleum ether/ethyl acetate = 9/1);
1H NMR (300 MHz, CDCl3) δ 7.19-7.24 (m, 3 H), 7.08-7.17 (m, 5
H), 6.86-6.93 (m, 2 H), 6.78-6.83 (m, 3 H), 6.69-6.73(m, 2 H),
6.56-6.63 (m, 2 H), 5.15 (dd, J = 4.1, 5.7 Hz, 1 H), 2.86 (s, 6 H), 2.84 (s,
6 H), 2.71-2.93 (m, 2 H), 2.07-2.27 (m, 2 H); 13C NMR (101 MHz,
CDCl3) δ 152.3, 150.3, 150.1, 146.9, 145.1, 141.7, 129.8, 128.4, 128.3,
128.2, 128.0, 126.1, 125.7, 119.9, 118.3, 117.4, 116.7, 113.6, 112.8, 112.1,
111.7, 94.6, 84.8, 40.6, 40.6, 36.3, 29.6; IR(neat) 3062, 3027, 2927, 2803,
1681, 1600, 1581, 1496, 1485, 1455, 1434, 1352, 1236, 1126, 1038, 988,
930, 858, 756, 735, 700; HRMS (ESI) m/e calcd for C32H35N2O2,
479.2699, found 479.2697.
987, 934, 857, 756, 700; HRMS (ESI) m/e calcd for C34H40N3O2,
522.3121, found 522.3124.
Representative Procedure to Prepare the PPGs of 14, 15,
16, 17, and 18. Method A: Synthesis of 3-(Hydroxydiphenyl-
methyl)naphthalen-2-ol (PPG of 14). To a solution of 3-hydroxy-2-
naphthoic acid (0.94 g, 5 mmol) in methanol (6 mL) was added sulfuric
acid (4 drops). The reaction mixture was refluxed at 80 °C for 8.5 h. The
solvent was then removed, and the reaction mixture was neutralized with
saturated sodium bicarbonate until pH = 7 and washed with brine. The
product was extracted with dichloromethane, and the organic layers
were combined, dried over anhydrous Na2SO4, and concentrated to
provide methyl 3-hydroxy-2-naphthoate (0.71 g, 70%) as a light
yellow solid.
To a solution of methyl 3-hydroxy-2-naphthoate (0.71 g, 3.5 mmol)
in freshly distilled tetrahydrofuran (35 mL) was slowly added phenyl
lithium (14 mL, 7 mmol, 2.0 M solution in dibutylether) at -78 °C
under argon protection. The reaction temperature was raised to room
temperature over 6 h. The reaction was then quenched with saturated
ammonium chloride until pH = 7. The aqueous layer was extracted with
dichloromethane, and the organic layers were combined and concen-
trated. The residue was purified with flash column chromatography
(petroleum ether/ethyl acetate = 4/1) to provide 3-(hydroxy-
diphenylmethyl) naphthalen-2-ol (0.85 g, 74%) as a pale yellow solid.
R f 0.4 (petroleum ether/ethyl acetate = 4/1).
Method B: Synthesis of Methyl 2-Hydroxy-1-naphthoate (Ester
Precursor of 17). To a solution of iodomethane (0.568 g, 14 mmol)
in acetone (1 mL) were added 2-hydroxy-1-naphthoic acid (0.188 g, 1
mmol) and potassium carbonate (0.276 g, 2 mmol). The reaction
mixture was stirred at 60 °C overnight. The crude product was washed
with dichloromethane through Celite and concentrated. The residue
was purified with flash column chromatography (petroleum ether/ethyl
acetate = 9/1) to provide methyl 2-hydroxy-1-naphthoate (0.137 g,
68%). Rf 0.5 (petroleum ether/ethyl acetate = 9/1).
Representative Procedure of Installing the PPG: 2-Phe-
nethyl-4,4-diphenyl-4H-naphtho[2,3-d][1,3]dioxine (14). To
3-(hydroxydiphenylmethyl) naphthalen-2-ol (32.6 mg, 0.10 mmol) and
p-toluenesulfonic acid (1.9 mg, 0.01 mmol) in benzene (0.1 mL) was
added 3-phenylpropionaldehyde (7 μL, 0.05 mmol). Upon completion,
the reaction mixture was directly purified with flash column chroma-
tography (petroleum ether/ethyl acetate = 7/1) to provide 14 (27 mg,
1
61%). Rf 0.6 (petroleum ether/ethyl acetate = 7/1); H NMR (300
MHz, CDCl3) δ 7.69 (d, J = 8.3 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 1 H),
7.41-7.10 (m, 19 H), 5.16 (dd, J = 4.3, 5.6 Hz, 1 H), 2.82 (m, 2 H), 2.23
(m, 2 H); 13C NMR (75 MHz, CDCl3) δ 150.9, 146.3, 143.8, 141.5,
133.7, 129.6, 129.4, 128.3, 128.3, 128.2, 127.9, 127.6, 126.8, 126.5, 126.3,
125.8, 123.8, 111.8, 94.7, 84.7, 36.3, 29.6; IR (neat) 3058, 3027, 2958,
2928, 1637, 1603, 1501, 1462, 1256, 1170, 800, 748; HRMS (ESI) m/z
calcd for C32H26O2Na, 465.1830, found 465.1833.
9-Methoxy-2-phenethyl-4,4-diphenyl-4H-naphtho[2,3-
d][1,3]dioxine (15). Yield 93%; Rf 0.5 (petroleum ether/ethyl acetate
= 9/1); 1H NMR (300 MHz, CDCl3) δ 7.72 (s, 1 H), 7.35-7.11 (d, 18
H), 6.72 (m, J = 4.3 Hz, 1 H), 5.15 (t, J = 4.9 Hz, 1 H), 3.97 (s, 1 H), 2.81
(ms, 2 H) 2.22 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 154.5, 150.6,
146.3, 143.9, 141.5, 129.4, 129.1, 128.3, 128.2, 127.9, 127.6, 127.1, 126.1,
125.8, 123.7, 120.2, 107.0, 103.9, 94.7, 84.7, 55.6, 36.4, 29.6; IR (neat)
3059, 3026, 2929, 1600, 1446, 1398, 1123, 807, 757, 700; HRMS (ESI)
m/z calcd for C33H28O3Na, 495.1936, found 495.1942.
7-Methoxy-2-phenethyl-4,4-diphenyl-4H-naphtho[2,3-
d][1,3]dioxine (16). Yield 64%; Rf 0.6 (petroleum ether/ethyl
acetate = 9/1); 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J = 9.1 Hz, 1
H), 7.39-7.05 (m, 20 H), 6.89 (d, J = 2.5 Hz, 1 H), 5.13 (dd, J = 4.3, 5.6
Hz, 1 H), 3.81 (s, 1 H), 2.81 (m, 2 H), 2.21 (m, 2 H); 13C NMR (75
MHz, CDCl3) δ 156.2, 149.2, 146.4, 144.0, 141.5, 129.4, 129.1, 128.8,
128.4, 128.3, 128.1, 127.9, 127.5, 127.0, 125.8, 119.8, 112.0, 105.5, 94.6,
[4,4-Bis(3-dimethylamino-phenyl)-2-phenethyl-4H-benzo-
[1,3]dioxin-6-yl]-dimethyl-amine (11). Yield 69%; Rf 0.2
1
(petroleum ether/ethyl acetate = 5/1); H NMR (400 MHz, CDCl3)
δ 7.08-7.23 (m, 8 H), 6.85-6.88 (m, 2 H), 6.78-6.81 (m, 2 H), 6.72
(dd, J = 2.5, 8.2 Hz, 1 H), 6.66 (dd, J = 2.9, 8.9 Hz, 1 H), 6.60 (dd, J = 2.6,
8.2 Hz, 1 H), 6.57 (d, J = 7.7 Hz, 1 H), 6.36 (d, J = 2.9 Hz, 1 H), 5.07 (dd,
J = 4.0, 5.9 Hz, 1 H), 2.69-2.93 (m, 20 H), 2.06-2.23 (m, 2 H); 13C
NMR (101 MHz, CDCl3) δ 150.22, 150.18, 147.1, 145.4, 144.8, 144.6,
141.8, 128.4, 128.3, 128.2, 128.1, 126.1, 125.7, 118.4, 117.4, 116.8, 115.3,
114.4, 113.7, 112.8, 112.0, 111.7, 94.4, 84.9, 41.7, 40.7, 36.4, 29.7;
IR(neat) 3026, 2927, 2883, 2800, 1600, 1498, 1434, 1239, 1134, 1060,
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ARTICLE
84.7, 55.2, 36.3, 29.6; IR (neat) 3060, 3026, 2932, 1612, 1507, 1251,
1214, 1033, 886, 700; HRMS (ESI) m/z calcd for C33H28O3Na,
495.1936, found 495.1940.
75.0, 72.8, 72.1, 68.0, 66.8, 43.5, 28.8, 18.8, 18.0; IR(neat) 3088, 3063,
3031, 2919, 1725, 1603, 1497, 1454, 1363, 1115, 1064, 913, 737, 698;
HRMS (ESI) m/e calcd for C32H38O6Na, 541.2566, found 541.2567.
General Procedure for Preparation of Aetals 28-31. The
PPG reagent and the aldehyde (PPG/aldehyde = 1.1:1) were stirred at
140 °C under argon for 2 h. Upon completion, the reaction mixtures
were purified by flash column chromatography to afford the desired
acetals.
4,4-Bis(3-dimethylamino-phenyl)-2-[4-(3,4,5-tris-benzy-
loxy-6-methyl-tetrahydro-pyran-2-yloxy)-butyl]-4H-benzo-
[1,3]dioxine (28). Yield 82% (Mixture of two diastereomers), Rf 0.4
(petroleum ether/ethyl acetate = 5/1); 1H NMR (400 MHz, CDCl3) δ
7.28-7.37 (m, 15 H), 7.17 (t, J = 7.9 Hz, 1 H), 7.10 (dd, J = 8.1, 19.0 Hz,
2 H), 6.87 (t, J = 7.5 Hz, 2 H), 6.79 (t, J = 7.8 Hz, 1 H), 6.73 (s, 1 H), 6.67
(t, J = 7.5 Hz, 2 H), 6.59 (d, J = 8.0 Hz, 1 H), 6.53 (d, J = 7.5 Hz, 1 H),
5.07 (t, J = 5.1 Hz, 1 H), 4.94 (d, J = 10.8 Hz, 1 H), 4.68-4.77 (m, 3 H),
4.61-4.65 (m, 3 H), 3.84 (dd, J = 3.1, 9.0 Hz, 1 H), 3.73-3.75 (m, 1 H),
3.58-3.69 (m, 3 H), 3.25-3.32 (m, 1 H), 2.83-2.84 (m, 12 H), 1.83-
1.85 (m, 2 H), 1.48-1.53 (m, 4 H), 1.32 (d, J = 5.8 Hz, 3 H); 13C NMR
(101 MHz, CDCl3) δ 152.19, 150.20, 150.1, 146.9, 145.0, 138.6, 138.6,
138.3, 129.8, 128.4, 128.3, 128.2, 128.03, 128.01, 128.0, 127.9, 127.6,
127. 5, 126.1, 119.8, 118.08, 118.05, 117.3, 116.68, 116.67, 113.5, 112.8,
112.0, 111.7, 97.9, 97.8, 95.0, 84.7, 80.52, 80.50, 80.2, 80.1, 75.4, 75.4,
75.0, 74.9, 72.74, 72.70, 72.2, 72.1, 67.9, 67.20, 67.16, 40.6, 34.3, 29.3,
29.2, 20.2, 18.0; IR(neat) 3063, 3030, 2916, 2804, 1600, 1579, 1496,
1454, 1352, 1279, 1238, 1118, 1064, 736, 699; HRMS (ESI) m/e calcd
for C55H63N2O7, 863.4635, found 863.4636.
6-Methoxy-4,4-diphenyl-2-[2-(3,4,5-tris-benzyloxy-6-meth-
yl-tetrahydro-pyran-2-yloxy)-ethyl]-4H-benzo[1,3]dioxine
(29). Yield 75% (mixture of two diastereomers), Rf 0.6 (petroleum
ether/ethyl acetate = 3/1); 1H NMR (400 MHz, CDCl3) δ 7.17-7.38
(m, 25 H), 6.854 (d, J = 8.9 Hz, 0.5 H), 6.852 (d, J = 8.9 Hz, 0.5 H), 6.76
(dd, J = 3.0, 4.4 Hz, 0.5 H), 6.73 (dd, J = 3.1, 4.5 Hz, 0.5 H), 6.351 (d, J =
2.9 Hz, 0.5 H), 6.348 (d, J = 2.9 Hz, 0.5 H), 5.05 (t, J = 5.2 Hz, 0.5 H),
5.01 (t, J = 5.2 Hz, 0.5 H), 4.92 (d, J = 17.9 Hz, 1 H), 4.89 (d, J = 18.0 Hz,
1 H), 4.42-4.72 (m, 6 H), 3.72-3.84 (m, 1 H), 3.46-3.68 (m, 9 H),
2.04-2.08 (m, 2 H), 1.299 (d, J = 5.7 Hz, 1.5 H), 1.294 (d, J = 5.8 Hz, 1.5
H); 13C NMR (101 MHz, CDCl3) δ 152.8, 152.77, 146.3, 146.1, 145.73,
145.69, 144.1, 143.8, 138.6, 138.54, 138.47, 138.42, 138.37, 138.2, 129.1,
128.9, 128.23, 128.19, 128.16, 128.03, 127.95, 127.83, 127.76, 127.73,
127.70, 127.45, 127.38, 125.7, 117.6, 117.5, 114.9, 114.8, 113.9, 97.8,
97.5, 92.9, 92.7, 84.2, 84.1, 80.3, 80.2, 80.0, 79.9, 75.2, 75.0, 74.7, 74.65,
72.6, 72.5, 72.0, 71.9, 67.89, 67.85, 62.4, 61.8, 55.38, 55.36, 34.6, 34.4,
17.9; IR(neat) 3062, 3030, 2908, 1494, 1453, 1225, 1115, 1066, 755,
737, 699; HRMS (ESI) m/e calcd for C50H50O8Na, 801.3403, found
801.3394.
3-Phenethyl-1,1-diphenyl-1H-naphtho[2,1-d][1,3]dioxine
(17). Yield 90%; Rf 0.6 (petroleum ether/ethyl acetate = 7/1); 1H NMR
(300 MHz, CDCl3) δ 7.75 (d, J = 8.9 Hz, 1 H), 7.68 (d, J = 8.1 Hz, 1 H),
7.54 (dd, J = 3.1, 6.4 Hz, 2 H), 7.40-7.3 (m, 5 H), 7.30 (d, J = 8.6 Hz, 1
H), 7.24-7.09 (m, 8 H), 7.04-6.99 (m, 3 H), 5.00 (dd, J = 4.2, 6.1 Hz, 1
H), 2.68 (m, 2 H), 2.14 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 151.9,
144.8, 141.8, 141.4, 131.8, 130.8, 130.3, 129.6, 128.4, 128.3, 128.2, 127.9,
127.7, 126.3, 125.8, 125.6, 123.0, 118.9, 94.3, 85.0, 35.9, 29.7; IR (neat)
3058, 3027, 2929, 1402, 1237, 817, 747, 701; HRMS (ESI) m/z calcd for
C32H26O2Na, 465.1830, found 465.1837.
2-Phenethyl-4,4-diphenyl-4H-naphtho[1,2-d][1,3]dioxine
(18). Yield 92%; Rf 0.5 (petroleum ether/ethyl acetate = 7/1); 1H NMR
(300 MHz, CDCl3) δ 8.19 (m, 1 H), 7.73 (m, 1 H), 7.52-7.10 (m, 18
H), 6.93 (d, J = 8.6 Hz, 1 H), 5.21 (t, J = 5.0 Hz, 1 H), 2.87 (m, 2 H), 2.33
(m, 2 H); 13C NMR (75 MHz, CDCl3) δ 147.7, 145.8, 144.5, 141.5,
133.2, 129.6, 128.4, 128.1, 127.6, 127.5, 127.4, 126.6, 126.5, 125.8, 125.6,
124.8, 121.8, 119.5, 95.0, 84.3, 36.2, 29.8; IR (neat) 3060, 3026, 2928,
1604, 1575, 1463, 1266, 909, 734, 700; HRMS (ESI) m/z calcd for
C32H26O2Na, 465.1830, found 465.1842.
3-(3,4,5-Tris-benzyloxy-6-methyl-tetrahydro-pyran-2-
yloxy)-propionaldehyde (26). The procedure for preparation of 26
was similar to the preparation of 27 from 2-allyloxy-3,4,5-tris-benzyloxy-
6-methyl-tetrahydro-pyran. The yields of hydroboration-oxidation and
Swern oxidation were 86% and 79%, respectively. Rf 0.6 (petroleum
ether/ethyl acetate = 3/1); 1H NMR (400 MHz, CDCl3) δ 9.71 (t, J =
1.6 Hz, 1 H), 7.25-7.38 (m, 15 H), 4.93 (d, J = 10.8 Hz, 1 H), 4.68-
4.77 (m, 3 H), 4.60-4.64 (m, 3 H), 3.95 (td, J = 5.9, 10.3 Hz, 1 H), 3.79
(dd, J = 3.1, 8.8 Hz, 1 H), 3.73 (dd, J = 2.0, 2.9 Hz, 1 H), 3.59-3.70 (m, 3
H), 2.60 (t, J = 6.0 Hz, 2 H), 1.34 (d, J = 5.8 Hz, 3 H); 13C NMR (101
MHz, CDCl3) δ 200.4, 138.4, 138.1, 128.3, 128.0, 127.8, 127.6, 127.58,
127.5, 127.46, 98.1, 80.2, 79.8, 75.3, 74.6, 72.8, 72.1, 68.2, 61.0, 43.3,
17.9; IR(neat) 3088, 3063, 3030, 2973, 2916, 1725, 1496, 1453, 1362,
1116, 1063, 1028, 737, 697; HRMS (ESI) m/e calcd for C30H34O6Na,
513.2253, found 513.2257.
5-(3,4,5-Tris-benzyloxy-6-methyl-tetrahydro-pyran-2-
yloxy)-pentanal (27). BH3 Me2S (2 M, 0.3 mL) was added dropwise
3
at 0 °C to a stirred solution of 3,4,5-tris-benzyloxy-2-methyl-6-pent-4-
enyloxy-tetrahydro-pyran (0.608 g, 1.2 mmol). Following the addition
of the hydride, the cooling bath was removed and the solution was stirred
for 1.5 h at rt. Ethanol (0.4 mL) was then added followed by 0.18 mL of 3
N sodium hydroxide. After cooling to 0-5 °C in an ice-water bath,
hydrogen peroxide (35%, 0.2 mL) was added dropwise, following the
addition of the peroxide, the cooling bath was then removed and the
reaction mixture was stirred overnight. After being heated at 80 °C for an
hour, the cooled solution was extracted with ether (10 mL Â 4). The
combined extracts were washed with water and brine, dried (Na2SO4),
concentrated. Flash column chromatography on silica gel, eluted with
petroleum ether/ethyl acetate = 3/1, afforded 5-(3,4,5-tris-benzyloxy-6-
methyl-tetrahydro-pyran-2-yloxy)-pentan-1-ol (0.557 g, 88%, Rf 0.3
(petroleum ether/ethyl acetate = 3/1)) as a colorless oil.
4,4-Bis(4-fluoro-phenyl)-2-[2-(3,4,5-tris-benzyloxy-6-
methyl-tetrahydro-pyran-2-yloxy)-ethyl]-4H-benzo[1,3]-
dioxine (30). Yield 88% (mixture of two diastereomers), Rf 0.6
1
(petroleum ether/ethyl acetate = 5/1); H NMR (400 MHz, CDCl3)
δ 7.15-7.38 (m, 21 H), 7.01-7.05 (m, 1 H), 6.89-6.96 (m, 3 H),
6.83-6.87 (m, 1 H), 6.74 (d, J = 7.8 Hz, 0.5 H), 6.73 (d, J = 7.8 Hz, 0.5
H), 5.05 (t, J = 5.3 Hz, 0.5 H), 5.02 (t, J = 5.2 Hz, 0.5 H), 4.93 (d, J = 10.8
Hz, 0.5 H), 4.89 (d, J = 10.8 Hz, 0.5 H), 4.44-4.74 (m, 6 H), 3.83 (td, J =
5.9, 10.0 Hz, 0.5 H), 3.76 (td, J = 6.7, 10.3 Hz, 0.5 H), 3.68 (dd, J = 3.0,
9.1 Hz, 0.5 H), 3.45-3.62 (m, 4.5 H), 2.01-2.13 (m, 2 H), 1.300 (d, J =
5.7 Hz, 1 H), 1.296 (d, J = 5.7 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ
162.3 (d, J = 248.2 Hz), 162.2 (d, J = 248.1 Hz), 162.0 (d, J = 247.1 Hz),
152.1, 152.0, 141.6 (d, J = 3.1 Hz), 139.9 (d, J = 3.2 Hz), 139.62 (d, J =
3.2 Hz), 138.59, 138.57, 138.51, 138.43, 138.41, 138.3, 131.1 (d, J = 8.1
Hz), 130.9 (d, J = 8.2 Hz), 129.8 (d, J = 8.1 Hz), 129.43, 129.40, 128.6,
128.28, 128.3, 128.24, 128.23, 128.00 127.8, 127.7, 127.6, 127.53,
127.49, 127.41, 124.95, 124.94, 120.43, 120.38, 117.3, 117.2, 115.1 (d,
J = 21.4 Hz), 114.9 (d, J = 21.3 Hz), 114.7 (d, J = 21.4 Hz), 98.0, 97.7,
The above obtained alcohol (0.557 g, 1.07 mmol) was oxidized to
aldehyde via Swern oxidation method. The general procedure and flash
column chromatography on silica gel, eluted with petroleum ether/ethyl
acetate = 4/1, afforded the title aldehyde 27 (0.39 g, 70%) as a colorless
oil. Rf 0.6 (petroleum ether/ethyl acetate = 3/1); 1H NMR (400 MHz,
CDCl3) δ 9.74 (t, J = 1.6 Hz, 1 H), 7.27-7.38 (m, 15 H), 4.95 (d, J =
10.8 Hz, 1 H), 4.70-4.79(m, 3 H), 4.63-4.65 (m, 3 H), 3.83 (dd, J =
3.1, 8.9 Hz, 1 H), 3.75 (dd, J = 1.9, 2.8 Hz, 1 H), 3.59-3.69 (m, 3 H),
3.32 (td, J = 6.2, 9.8 Hz, 1 H), 2.42 (dt, J = 1.4, 7.2 Hz, 2 H), 1.55-1.68
(m, 6 H), 1.33 (d, J = 5.8 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 202.2,
138.5, 138.33, 128.31, 128.28, 128.0, 127.8, 127.6, 127.5, 97.9, 80.5, 75.4,
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ARTICLE
92.9, 92.8, 83.4, 83.3, 80.4, 80.3, 80.1, 80.1, 75.4, 75.1, 74.8, 74.7, 72.7,
72.1, 72.0, 68.1, 67.99, 62.3, 61.8, 34.6, 34.5, 18.0, 17.98; IR(neat) 3064,
3032, 2971, 2915, 1734, 1603, 1584, 1486, 1455, 1281, 1227, 1159, 1117,
1067, 839, 737, 698; HRMS (ESI) m/e calcd for C49H46F2O7Na,
807.3109, found 807.3109.
450 W medium pressure mercury lamp with different filters without
excluding air. The reaction mixture was then concentrated directly, and
the residue was subjected to flash column chromatography. For 28 and
31, acetonitrile was removed, and the residue was extracted with
dichloromethane. The combined organic layers were dried over
Na2SO4, filtered, and concentrated, and then the residue was subjected
to flash column chromatography.
For acetals 28 (172.9 mg, 0.200 mmol) and 31 (159.7 mg, 0.195
mmol), the solutions were irradiated for 50 min with a Pyrex sleeve and a
10% NaNO3 solution (λ > 320 nm) to provide the aldehyde 27 (98 mg,
94% from 28 and 92 mg, 91% from 31, respectively). Rf 0.6 (petroleum
ether/ethyl acetate = 3/1); 1H NMR (400 MHz, CDCl3) δ 9.74 (t, J =
1.6 Hz, 1 H), 7.27-7.38 (m, 15 H), 4.95 (d, J = 10.8 Hz, 1 H), 4.70-
4.79(m, 3 H), 4.63-4.65 (m, 3 H), 3.83 (dd, J = 3.1, 8.9 Hz, 1 H), 3.75
(dd, J = 1.9, 2.8 Hz, 1 H), 3.59-3.69 (m, 3 H), 3.32 (td, J = 6.2, 9.8 Hz, 1
H), 2.42 (dt, J = 1.4, 7.2 Hz, 2 H), 1.55-1.68 (m, 6 H), 1.33 (d, J = 5.8
Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 202.2, 138.5, 138.33, 128.31,
128.28, 128.0, 127.8, 127.6, 127.5, 97.9, 80.5, 75.4, 75.0, 72.8, 72.1, 68.0,
66.8, 43.5, 28.8, 18.8, 18.0; IR(neat) 3088, 3063, 3031, 2919, 1725, 1603,
1497, 1454, 1363, 1115, 1064, 913, 737, 698; HRMS (ESI) m/e calcd for
C32H38O6Na, 541.2566, found 541.2567.
{4,4-Diphenyl-2-[4-(3,4,5-tris-benzyloxy-6-methyl-tetra-
hydro-pyran-2-yloxy)-butyl]-4H-benzo[1,3]dioxin-6-yl}-di-
methyl-amine (31). Yield 73% (mixture of two diastereomers), Rf 0.5
(petroleum ether/ethyl acetate = 5/1); 1H NMR (400 MHz, CDCl3) δ
7.16-7.41 (m, 25 H), 6.82 (d, J = 8.9 Hz, 1 H), 6.63 (dd, J = 2.9, 9.0 Hz,
1 H), 6.20 (d, J = 2.9 Hz), 1H, 4.91-4.96 (m, 2 H), 4.68-4.77 (m, 3 H),
4.56-4.65 (m, 3 H), 3.84 (td, J = 3.4, 9.0 Hz, 1 H), 3.74 (td, J = 1.6, 3.1
Hz, 1 H), 3.54-3.70 (m, 3 H), 3.25-3.29 (m, 1 H), 2.69 (s, 6 H), 1.76-
1.86 (m, 2 H), 1.36-1.50 (m, 4 H), 1.32 (d, J = 5.9 Hz, 3 H); 13C NMR
(101 MHz, CDCl3) δ 146.27, 146.26, 144.64, 144.58, 144.4, 138.57,
138.52, 138.50, 138.3, 129.21, 129.19, 128.25, 128.23, 128.04, 127.98,
127.96, 127.87, 127.82, 127.80, 127.69, 127.56, 127.55, 127.51, 127.4,
127.2, 125.4, 117.2, 114.8, 114.4, 97.8, 97.7, 94.7, 84.2, 80.5, 80.1, 80.1,
75.34, 75.33, 74.92, 74.89, 72.7, 72.11, 72.06, 67.9, 67.14, 67.09, 41.5,
34.2, 29.1, 29.0, 20.1, 20.1, 18.0; IR(neat) 3087, 3062, 3031, 2920, 2796,
1601, 1505, 1453, 1447, 1400, 1362, 1241, 1117, 1066, 1028, 736, 699;
HRMS (ESI) m/e calcd for C53H58NO7, 820.4213, found 820.4216.
3-(3,4,5-Tris-benzyloxy-6-benzyloxymethyl-tetrahydro-
For acetal 29 (156.8 mg, 0.201 mmol) the wolution was irradiated for
40 min with a Pyrex sleeve as filter (λ > 280 nm) to provide the aldehyde
1
26 (90 mg, 91%). Rf 0.6 (petroleum ether/ethyl acetate = 3/1); H
pyran-2-yloxy)-propionaldehyde (32). BH3 Me2S (0.35 mL, 1.7
3
NMR (400 MHz, CDCl3) δ 9.71 (t, J = 1.6 Hz, 1 H), 7.25-7.38 (m, 15
H), 4.93 (d, J = 10.8 Hz, 1 H), 4.68-4.77 (m, 3 H), 4.60-4.64 (m, 3 H),
3.95 (td, J = 5.9, 10.3 Hz, 1 H), 3.79 (dd, J = 3.1, 8.8 Hz, 1 H), 3.73 (dd,
J = 2.0, 2.9 Hz, 1 H), 3.59-3.70 (m, 3 H), 2.60 (t, J = 6.0 Hz, 2 H), 1.34
(d, J = 5.8 Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ 200.4, 138.4, 138.1,
128.3, 128.0, 127.8, 127.6, 127.58, 127.52, 127.46, 98.1, 80.2, 79.8, 75.3,
74.6, 72.8, 72.1, 68.2, 61.0, 43.3, 17.9; IR(neat) 3088, 3063, 3030, 2973,
2916, 1725, 1496, 1453, 1362, 1116, 1063, 1028, 737, 697; HRMS (ESI)
m/e calcd for C30H34O6Na, 513.2253, found 513.2257.
For acetal 30 (157.6 mg, 0.200 mmol), the solution was irradiated for
10 min with a Vycor sleeve (λ > 210 nm) to provide the aldehyde 26
(73.5 mg, 75%).
Representative Procedure of Deprotection with Sunlight.
A Pyrex test tube (16 mm  150 mm) containing 15 mL solution of 28
(5 mM in MeCN/H2O = 9/1) was kept in a water bath and placed
outdoor under sunlight in clear weather. After 2 h, the mixture was
concentrated directly, and the obtained residue was purified by flash
column chromatography (petroleum ether/ethyl acetate = 4/1) to
provide the aldehyde 27 (31.4 mg, 81%).
mmol) was added dropwise at 0 °C under argon to a solution of
2-allyloxy-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran
(1.0 g, 1.7 mmol) in THF (8 mL), and the resultant solution was stirred
at room temperature for 15 h. Then hydrogen peroxide (35%, 2.0 mL)
and sodium hydroxide (3 N, 20 mL) were added at room temperature,
and the reaction mixture was stirred for further 6 h. Workup as usual
followed by flash column chromatography (petroleum ether/ethyl
acetate = 3/1, Rf 0.3) afforded 5-(3,4,5-tris-benzyloxy-6-methyl-tetra-
hydro-pyran-2-yloxy)-pentan-1-ol (0.829 g, 80%) as a colorless oil.
The mixture of the above obtained alcohol (0.50 g, 0.835 mmol) and
PCC (0.287 g, 1.25 mmol) in dichloromethane (10 mL) was stirred at
room temperature for 13 h. Workup as usual followed by flash chromatog-
raphy (petroleum ether/ethyl acetate = 3/1, Rf 0.5) afforded the title
compound 32 (0.35g, 70%). 1H NMR (400 MHz, CDCl3) δ9.73(t,J=1.3
Hz, 1 H), 7.21-7.35 (m, 18 H), 7.12 (dd, J = 1.9, 7.2 Hz, 1 H), 4.96 (d, J =
10.8 Hz, 1 H), 4.73-4.83 (m, 4 H), 4.62 (d, J= 9.1 Hz, 1 H), 4.59 (d, J= 9.3
Hz, 1 H), 4.46 (d, J = 10.7 Hz, 1 H), 4.45 (d, J = 12.1 Hz, 1 H), 3.91-4.00
(m, 2 H), 3.61-3.77 (m, 5 H), 3.56 (dd, J = 3.6, 9.7 Hz, 1 H), 2.61-2.77
(m, 2 H); 13C NMR (101 MHz, CDCl3) δ 200.2, 138.5, 137.9, 137.6,
128.24, 128.16, 128.14, 127.9, 127.70, 127.68, 127.5, 127.4, 97.1, 81.7, 79.7,
77.3, 75.5, 74.8, 73.2, 73.0, 70.1, 68.1, 61.4, 43.2; IR(neat) 3088, 3063, 3030,
2920, 2730, 1725, 1497, 1454, 1360, 1158, 1072, 738, 698; HRMS (ESI) m/
e calcd for C37H40O7Na, 619.2672, found 619.2669.
Stability of Acetals 28-31 and 33 toward Acid Treatment.
Acetals 33 and 28-31 (0.01 mmol) in THF (0.3 mL) and HCl (2 N,
0.1 mL) were stirred at 40 °C. After 18 h, 1H NMR showed that there
was almost no 33 left, whereas no aldehyde release from acetals 28-31
was detected.
3,4,5-Tris-benzyloxy-2-benzyloxymethyl-6-(2-[1,3]dioxolan-
2-yl-ethoxy)-tetrahydro-pyran (33). The mixture of aldehyde 32
’ ASSOCIATED CONTENT
(100 mg, 0.168 mmol), p-TsOH H2O (3 mg, 0.017 mmol), and DMF
3
(0.5 mL) was placed into the 60 °C bath on rotary evaporator for 5 h under
vacuum. Workup as usual followed by flash chromatography (petroleum
ether/ethyl acetate = 3/1, Rf 0.4) afforded the title compound 33 (98 mg,
92%). 1H NMR (400 MHz, CDCl3) δ 7.25-7.36 (m, 18 H), 7.11-7.14
(m, 2 H), 4.97-5.01 (m, 2 H), 4.75-4.84 (m, 4 H), 4.60-4.66 (m, 2 H),
4.46 (d, J = 11.7 Hz, 2 H), 3.89-3.40 (m, 3 H), 3.72-3.87 (m, 5 H), 3.62-
3.67 (m, 2 H), 3.53-3.59 (m, 2 H), 1.95-2.06 (m, 2 H); 13C NMR (101
MHz, CDCl3) δ 138.8, 138.3, 138.2, 137. 9, 128.39, 128.35, 128.34, 128.31,
127.94, 127.90, 127.8, 127.7, 127.6, 127.5, 102.1, 97.0, 82.0, 80.00, 77.6,
75.7, 75.1, 73.4, 73.0, 70.1, 68.4, 64.8, 63.7, 33.9; IR(neat) 3088, 3063, 3030,
2883, 1497, 1454, 1361, 1142, 1072, 1028, 737, 697; HRMS (ESI) m/e
calcd for C39H44O8Na, 663.2934, found 663.2935.
S
Supporting Information. General procedure, UV spec-
b
tra of 14-18, and 1H NMR and 13C NMR spectra of 3-9, 11,
14-18, and 26-33. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: wangp@uab.edu.
’ ACKNOWLEDGMENT
General Procedure of Photolysis. Acetals 28-31 (0.20 mmol)
in 225 mL of acetonitrile and 25 mL of water were irradiated with a
We thank NSF for support (CHE-0848489).
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The Journal of Organic Chemistry
ARTICLE
DEDICATION
†Dedicated to Professor Howard E. Zimmerman.
detected in methanol. Reactions in other solvent systems were pre-
viously discussed.5a,c
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73, 9497.
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(7) The photoreactions became cleaner and more PPG reagent V
could be obtained with more water as the cosolvent, albeit the yields of
released carbonyl compounds were not affected. Taking into considera-
tion of the poor solubility of the studied acetals in highly polar solvent
systems, we conducted most of the photoreactions in acetonitrile/water
(9:1). Photo deprotection reactions carried out in methanol did not
provide cleaner reactions and better yields of released aldehydes than in
acetonitrile/water (9:1). Instead some dimethyl acetal byproducts were
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