Development of the carboxamide protecting group, 4-(tert -butyldimethylsiloxy)-2-methoxybenzyl

Article abstract of DOI:10.1021/jo201495w

The new carboxamide protecting group, 4-(tert-butyldimethylsiloxy)-2- methoxybenzyl (SiMB), has been developed. While this SiMB group can be removed using mild basic desilylation methods, it can also be deprotected under strongly acidic or oxidative conditions. An application of this group to simple carboxamide groups, as well as to more complex and acid-sensitive adenosine derivatives containing a cyclophane scaffold, was also demonstrated.

Full text of DOI:10.1021/jo201495w

Article
pubs.acs.org/joc
Development of the Carboxamide Protecting Group,
4-(tert-Butyldimethylsiloxy)-2-methoxybenzyl
Kazuhiro Muranaka, Satoshi Ichikawa,* and Akira Matsuda*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: The new carboxamide protecting group, 4-(tert-
butyldimethylsiloxy)-2-methoxybenzyl (SiMB), has been
developed. While this SiMB group can be removed using
mild basic desilylation methods, it can also be deprotected
under strongly acidic or oxidative conditions. An application of
this group to simple carboxamide groups, as well as to more
complex and acid-sensitive adenosine derivatives containing a
cyclophane scaffold, was also demonstrated.
group to a more complex system was also demonstrated by an
improved synthesis of 4 and its derivative 46.
INTRODUCTION
■
The essential role of protecting groups is to prevent functional
groups from unwanted reactions during a synthesis.1 Therefore,
it is preferable if these protecting groups possess additional
functions, such as the ability to induce selectivity in reactions, a
conformational change of the molecules, or functionalization
of neighboring chemical entities.2 Consequently, their con-
tribution in organic synthesis is considerable. N-Protection
of a carboxamide to induce a conformational change is an
established strategy to improve the yields of certain intra-
molecular cyclization reactions, especially those providing
highly strained macrocycles.3 We have recently reported the
synthesis of an adenosine analogue containing a 14-membered
cyclophane as a potential Hsp90 inhibitor (4, Scheme 1).4 A
key reaction in the synthesis of 4 is the highly efficient ring-
closing metathesis (RCM) assisted by the 2,4-dimethoxybenzyl
(DMB) group. The conversion to the highly strained 14-
membered cyclophane 2 containing two olefins within the
macrocycle was nearly quantitative, indicating that the impact
of the newly introduced DMB group on the RCM was
considerable, since no cyclization products were obtained when
the nitrogen atom of the carboxamide moiety was unprotected.
However, it turned out that the DMB group was relatively
stable under the acidic deprotection conditions (TFA, Et3SiH,
CH2Cl2, room temperature, 24 h), during the course of which
the 14-membered cyclophane derivatives gradually decom-
posed partly because of depurination. As a result, the chemical
yields of 4 were low. Protection of a carboxamide is an area of
protecting group chemistry that has received little attention
compared to that of other functional groups, and as a
consequence, few good methods exist.1 Herein, we describe
the development of a new carboxamide protecting group, the
4-(tert-butyldimethylsiloxy)-2-methoxybenzyl (SiMB) group,
which helps cyclization reactions and can be removed under
conditions other than strong acid. An application of the SiMB
Several substituted N-benzylcarboxamide protecting groups5
have been reported in the literature; however, most of them are
ultimately removed by strongly acidic or oxidative conditions.6
Less attention has been paid to developing substituted N-
benzylcarboxamide protecting groups cleavable under mildly
basic conditions. Recently, the 4-(tert-butyldimethylsiloxy)-3-
fluorobenzyl group has been developed as a sugar hydroxyl
protecting group by Crich’s group.7 This protecting group was
removed by tetrabutylamonium fluoride (TBAF) under micro-
wave irradiation or conventional heating. We simply designed the
4-siloxy-2-methoxybenzyl group 6 as a carboxamide protective
group by replacing one of the methoxy substituents of the DMB
group with a siloxy group (Scheme 2). Upon treatment of 6 under
typical desilylation conditions, the liberated 4-hydroxy-2-methoxy-
benzyl group could be removed to give the secondary carboxamide
8 in addition to the 3-methoxy-p-quinonemethide (9). To ensure
chemical stability during the synthesis, we chose a TBS group as
the capping group at the 4-position.8
RESULTS AND DISCUSSION
■
The model carboxamides protected with an SiMB group were
prepared as shown in Scheme 3.9 Reductive amination of 4-
(tert-butyldimethylsiloxy)-2-methoxybenzaldehyde (11), which
was prepared by conventional TBS protection of commercially
available 4-hydroxy-2-methoxybenzaldehyde (10), with p-
anisidine gave the N-SiMB-protected amine 12. The amine
was acylated with benzoyl chloride in the presence of Et3N in
CH2Cl2 to give the corresponding carboxamide 13 in 94%.
First, we attempted to optimize the conditions to deprotect the
SiMB group (Table 1). Exposure of 13 to TBAF in THF at
room temperature resulted only in removal of the TBS group
Received: July 18, 2011
Published: October 12, 2011
© 2011 American Chemical Society
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Scheme 1. Previous Study for the Synthesis of Cyclophane-Type Adenosine Derivatives
Scheme 2. 4-(tert-Butyldimethylsiloxy)-2-methoxybenzyl
Table 1. Deprotection of SiMB Group
(SiMB) Group
a
entry
conditions
TBAF, THF, rt
time
24 h
yield (%)
b
1
2
3
4
5
6
7
8
trace (98)
TBAF, THF, MW, 150 °C
CsF, aq 1,4-dioxane, reflux
CsF, aq 1,4-dioxane, MW, 150 °C
K2CO3, MeOH, reflux
10 min
12 h
97
93
95
90
93
84
83
95
29
Scheme 3. Preparation of N-SiMB Carboxamides
20 min
9 h
K2CO3, MeOH, MW, 100 °C
80% aq TFA, rt
10 min
30 min
30 h
DDQ, CH2Cl2−H2O, rt
DDQ, CH2Cl2−H2O, rt
c
9
20 min
1 h
10
CAN, MeCN−H2O, rt
a
b
Isolated yield. TLC analysis. The yield shown in parentheses is an
isolated yield of 16 to which the removal of the TBS group occurred.
c
16 was used as a substrate.
gave 15 in 93% yield (entry 3). When a microwave reactor with
a higher temperature was used, the reaction time was
dramatically shortened to 20 min (entry 4). Since the
deprotection is an oxidative process, the deprotection under
O2 atmosphere was also investigated. However, promotion of
the reaction time was not observed, and 15 was obtained in
90% in entry 3 and 91% in entry 4 under O2 atmosphere
(1 atm), respectively. Treatment of 13 with K2CO3 in MeOH
under thermal and microwave conditions afforded 15 in
90% and 93% yield, respectively (entries 5 and 6). Compared
to the 4-(tert-butyldimethylsiloxy)-3-fluorobenzyl group as a
protective group of the alcohol,7 the SiMB group was easily
removed from the carboxamide in high chemical conversion
under these conditions. Acidic and oxidative conditions, which
are generally used to remove an N-DMB group,1 were also
to give N-(4-hydroxy-2-methoxybenzyl)-p-benzanisidide (16)
in 98% yield (entry 1). Since a careful TLC analysis indicated
that a trace amount of the desired p-benzanisidide (15) was
formed in this reaction, we then examined the reaction using
higher temperatures. When the reaction was conducted at
150 °C under microwave irradiation (70 W, 5 bar), further
cleavage of the resulting 4-hydroxy-2-methoxybenzyl group
proceeded within 10 min to afford 15 in 97% yield (entry 2).
From these results, we confirmed the feasibility of the
deprotection of the SiMB group under basic conditions.
Next, other basic desilylation conditions were tested. Treat-
ment of 13 with CsF in refluxing aqueous 1,4-dioxane for 12 h
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examined (entries 7 and 8). In the case of oxidative conditions
using DDQ in wet CH2Cl2, a long reaction time was required
to complete the reaction (entry 8). However, the oxidation of
the free phenol 16, which was obtained by TBAF treatment
(entry 1), with DDQ proceeded very smoothly to provide 15 in
95% yield (entry 9). This two-step procedure provides an
opportunity to deprotect the SiMB group without having to
deal with high temperature. In addition, the 4-(tert-
butyldimethylsiloxy)-3-fluorobenzyl group was resistant to
DDQ oxidation.7 On the other hands, the SiMB group can
be removed by DDQ by modulating the susceptibility to the
oxidative conditions. Although not fitting into our stated goal of
finding a carboxamide protecting group which is not removed
with strong acid or oxidative conditions, the feasibility of using
such a two-step approach as a room temperature method for
deprotection would expand the scope of this new protecting
group. When 13 was treated with CAN, 13 completely
consumed within 1 h. However, the yield of 15 was poor
(29%) because of further removal of the N-4-methoxy-
phenyl group (entry 10).
Since it is likely that electron-donating substituents increase
the rate of formation of the p-quinonemethide, the
deprotection efficiency of the 4-siloxybenzyl group might be
enhanced by increasing the number of methoxy substituents.
Therefore, we next compared the reactivity of the 4-tert-
butyldimethylsiloxybenzyl (SiB) group and the 4-(tert-butyldi-
methylsiloxy)-2,6-dimethoxybenzyl (SiDMB) group, which
possess two electron-donating methoxy substituents at the
o-positions or none. The SiB- and SiDMB-protected substrates
23 and 24 were prepared from the corresponding 4-
hydroxybenzaldehydes 17 and 18 in a manner similar to the
synthesis of 13 (Scheme 4). The deprotection conditions using
Table 2. Comparison of the Reactivity of Substituted N-Benzyl
Group under Basic Conditions
a
entry
substrates
conditions
reflux
time
72 h
yield (%)
b
1
2
3
4
23 (R = H)
23 (R = H)
24 (R = OMe)
31 (57)
MW, 150 °C
reflux
9 h
88
94
97
8 h
24 (R = OMe)
MW, 150 °C
15 min
a
b
Isolated yield. The yield shown in parentheses is an isolated yield of
N-(4-hydroxybenzyl)-p-benzanisidide to which the removal of the TBS
group occurs.
conditions proceeded very smoothly to give 15 in excellent
yields (entries 3 and 4). The deprotection of the SiDMB group
was slightly faster than that of the SiMB group, and increasing
the number of the electron-donating methoxy group resulted in
an increase rate of deprotection. Considering the cost of 4-
hydroxybenzaldehyde derivatives (4-hydroxy-2-methoxybenzal-
dehyde, Wako Chemicals, 5 g, ¥19500 vs 4-hydroxy-2,6-
dimethoxybenzaldehyde, Aldrich, 1 g, ¥25700), the SiMB group
would be the best choice as the carboxamide protecting group
since there was very little difference between the two groups
with regard to the ease of deprotection.
Next, the orthogonality of the SiMB group with other
protecting groups, which are labile under acidic, basic, or
oxidative conditions, was examined (Table 3). We prepared the
Scheme 4. Preparation of 23 and 24
Table 3. Selective Deprotection of the SiMB Group in the
Presence of Other Protective Groups
a
entry
substrates
methods products
time
yield (%)
1
2
3
4
5
6
7
8
14a (R = NHBoc)
14a (R = NHBoc)
14b (R = NHFmoc)
14b (R = NHFmoc)
14c (R = OBz)
A
C
B
C
A
B
C
A
25a
25a
25b
25b
25c
25c
25c
25d
30 min
21 h
93
54
95
43
1.5 h
35 h
b
20 min
22 h
14
14c (R = OBz)
87
96
91
CsF were selected to compare the reactivity of the different N-
4-siloxybenzyl groups, and the results are summarized in Table 2.
When the N-SiB-protected carboxamide 23 was treated with
CsF under thermal conditions (entry 1), the deprotection was
not complete even after 72 h and gave the secondary
carboxamide 15 in only 31% yield along with N-(4-
hydroxybenzyl)-p-benzanisidide in 57% yield. In order to
accelerate this reaction, we next used a microwave reactor
(entry 2). However, the time to obtain 15 was much longer
than that for the SiMB deprotection (20 min for 13 vs 9 h for
23). On the other hand, deprotection of the SiDMB-protected
carboxamide 24 under thermal or microwave irradiation
14c (R = OBz)
12 h
14d (R = OPMB)
30 min
a
b
Isolated yield. Besides 25c, compounds 26 and 27 were obtained in
31% and 49% yield, respectively.
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Scheme 5. Orthogonality between the SiMB and the DMB Groups and Reversible Modification of the SiMB Group
N-protected p-glycylanisidide derivatives (14a and 14b) and
the O-protected p-glycolanisidide derivatives (14c and 14d) by
the simple condensation of the amine 12 with the
corresponding carboxylic acid derivatives (EDCI, DMAP,
CH2Cl2, 94% to quantitative yield) as shown in Scheme 3.
When CsF-promoted deprotection conditions (method A)
were applied to 14a, which possesses an acid-labile N-Boc
protecting group, the N-Boc-p-glycylanisidide (25a) was cleanly
obtained in 93% yield (entry 1), while DDQ oxidation in wet
CH2Cl2 (method C) resulted in a moderate yield of 25a due to
incomplete reaction with concomitant byproducts (entry 2).
When the base-sensitive N-Fmoc-protected carboxamide 14b
was treated with aqueous 80% TFA (method B), the
deprotected 25b was obtained in 95% yield (entry 3). Under
the oxidative conditions, a byproduct, which might have
occurred by oxidation of the Fmoc group, was observed, and
the isolated yield of 25b was moderate (entry 4). Next, the
glycolamide 14c containing an O-benzoyl substituent was
treated with method A. The desired 25c was obtained in 14%
yield along with the des-TBS product 26 and the fully
deprotected compound 27 in 31% and 49% yield, respectively
(entry 5). Treatment of 14c with method B or C proceeded to
give 25c in high yield (entries 6 and 7). The most remarkable
example is the O-p-methoxybenzyl-N-SiMB-p-glycolanisidide
(14d). Deprotection of the SiMB group of 14d with method A
proceeded smoothly to give 25d without cleavage of the PMB
ether. If the carboxamide nitrogen atom had been protected
with a DMB group, 25d could not have been obtained because
the PMB ether would be easily cleaved under acidic and
oxidative conditions, which are generally used for the removal
of an N-DMB group.1 As discussed above, the SiMB group is
very useful for the protection of a carboxamide nitrogen atom
when the target molecules contain acid- or oxidation-labile
moieties and is the first example of an N-benzyl-type protective
group cleavable under mildly basic conditions.
N-benzyl-type protecting groups as the substrate (Scheme 5).
Reductive alkylation of the glycyl-p-anisidide hydrochloride
(28)10 with 11 gave the N-SiMB-protected amine 29. The
resulting amine 29 was acylated with the carboxylic acid 31,
which was prepared from 3011 by catalytic hydrogenation, using
EDCI and DMAP in CH2Cl2 to give 32 in 74% over two steps
from 28. First, treatment of 32 with CsF in aqueous 1,4-
dioxane under microwave irradiation, in order to effect selective
deprotection of the SiMB group, proceeded to give 33 in 96%
yield. When 32 was treated with 80% aqueous TFA, the
removal of both the SiMB and the DMB groups proceeded
cleanly to provide 34 in 88% yield. We also planned to remove
the DMB group of 32 selectively in the presence of the SiMB
group. This was accomplished by substituent manipulation
from a TBS group to an electron-withdrawing acetyl group
prior to treatment with 80% aqueous TFA. Namely, the
electron-withdrawing substituent was intended to enhance
stability under acidic and oxidative conditions, in much the
same way that a 2-acetoxy substituent enhances the stability of
N-(4-methoxybenzyl)carboxamide under acidic conditions.6e
Removal of the TBS group of 32 by brief treatment with TBAF
at room temperature followed by acylation of the resulting
hydroxyl moiety with acetic anhydride afforded the N-(4-
acetoxy-2-methoxybenzyl)-protected carboxamide 35 in nearly
quantitative yield over two steps. When 35 was treated with
TFA or DDQ, selective cleavage of the DMB group proceeded
to give the desired carboxamide 36 in 85% and 70% yield,
respectively. Thus, stability to acidic and oxidative conditions
could be imparted to the SiMB group by facile conversion of
the TBS capping group to the electron-withdrawing acetyl
group. In addition, simple deprotection of the 4-acetoxy-2-
methoxybenzyl group by treatment with CsF gave 34 in 88%
yield.
Having developed the SiMB group, we next evaluated its
potency in the synthesis of 4 (Scheme 6). The N-SiMB-
protected RCM precursor 41a was prepared in a manner
similar to the synthesis of 1.4 The SiMB group was introduced
We further verified the orthogonality of the SiMB group with
a DMB group with a glycylglycine derivative 32 bearing both
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into 37 by reductive alkylation of 11 to give an N-SiMB amine
in 92% yield. Bromoacetylation of the amine followed by
the Arbuzov reaction with triethyl phosphite provided the
N-SiMB-N-arylphosphonoacetamide 38. The mild Horner−
Wadsworth−Emmons (HWE) olefination12 of 38 with the
adenosine 5′-aldehyde derivative 40a, which was prepared
by the oxidation of the alcohol of 39a4 with Dess−Martin
periodinane,13 was conducted, and the N-SiMB-protected
unsaturated E-carboxamide 41a was obtained in 93% yield
over two steps. The RCM precursor 41a existed in an
approximate 4:3 mixture of rotamers in CDCl3 observed by
1H NMR at room temperature. A similar observation was
noted in the case of the N-DMB-protected carboxamide 1.4
Treatment of 41a with the first-generation Grubbs’ catalyst
4214 in CH2Cl2 gave the desired 14-membered cyclophane 43a
in nearly quantitative yield as a mixture of trans- and cis-
isomers.15 As expected, the efficiency of the SiMB group in the
RCM was similar to that of the DMB group. In addition, it was
found that this RCM was scalable because the reaction
proceeded smoothly even with low catalyst loading (0.5 mol
% of 42) and high concentration (0.1 M). After removal of TBS
groups of trans-43a at both the SiMB moiety and the
2′-hydroxyl group, treatment of the resulting trans-44a with
CsF afforded the secondary carboxamide trans-45a in 91%
yield. Although direct conversion of trans-43a to trans-45a by
the treatment with CsF should be straightforward, it turned out
to be difficult to distinguish by TLC analysis between the
desired product trans-45a and the compound, in which only the
TBS group on the SiMB moiety of trans-43a had been removed.
Since monitoring of the progress of the deprotection reaction
was difficult, the stepwise deprotection method worked well.
Finally, brief treatment of trans-45a with TFA to deprotect the
Tr and the two MOM groups followed by air oxidation of the
resulting hydroquinone moiety successfully afforded trans-4 in
84% yield over two steps. Similarly, cis-4 was synthesized in
satisfactory yield (83% over two steps). In order to demonstrate
further applicability, the synthesis of the more rigid derivative
46, which consisted of a 13-membered cyclophane framework,
was conducted. The synthesis of 46 started from the 3′-deoxy-
3′-α-allyladenosine derivative 39b, the preparation of which is
described in Scheme 7. Stereoselective radical allylation of
adenosine 3′-phenoxy thionocarbonate derivative 4816 afforded
49 in good yield.17 We prepared 39b by protection of 49 with a
Tr group followed by selective removal of the TBS-protecting
group at the 5′-hydroxy group with TBAF in the presence of
acetic acid in THF at low temperature. Dess−Martin oxidation
of 39b gave the aldehyde 40b, and the subsequent HWE
olefination of 40b with 38 afforded the N-SiMB carboxamide
41b, which is the RCM precursor, in 90% yield over two steps
(Scheme 6). Compound 41b existed as a 1:1 mixture of
rotamers in CDCl3. Treatment of 41b with the RCM catalyst
42 in CH2Cl2 under reflux afforded the desired 13-membered
Scheme 6. Improved Synthesis of 4 and 13-Membered
Cyclophane Derivatives 46
Scheme 7. Preparation of 39b
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ESIMS-LR m/z = 289 [(M + Na)+]; ESIMS-HR calcd for
C14H22O3NaSi 289.1236, found 289.1232.
cyclophane 43b in 98% yield. The cyclophane 43b was
obtained as trans- and cis-isomers (trans/cis = 13.8:1),15 and the
geometric selectivity of this RCM reaction was rather high
compared with the case of the synthesis of the 14-membered
derivative 43a (2.2:1). After successfully constructing the
desired 13-membered cyclophane, we carried out the stepwise
conversion of 43b to 46, including desilylation, removal of the
N-(4-hydroxy-2-methoxybenzyl) group, deprotection of the Tr
and the two MOM groups, followed by air oxidation of the
hydroquinone moiety, as in the synthesis of 4. All of the
reactions proceeded smoothly, and the desired trans- and cis-46
were obtained in good yields (90% for trans-46, 79% for cis-46).
As discussed above, this synthetic strategy using the N-SiMB
group as the carboxamide protecting group, which helps the
cyclization, is quite effective and enabled us to prepare 4 and 46
in 65−68% and 59−73% yields over seven steps from the
corresponding adenosine derivatives 39a and 39b, respectively.
N-(4-tert-Butyldimethylsiloxy-2-methoxybenzyl)-p-anisidine
(12). A mixture of p-anisidine (250 mg, 2.0 mmol), 11 (590 mg, 2.2
mmol), and AcOH (0.57 mL, 10 mmol) in CH2Cl2 (10 mL) was
stirred at room temperature for 10 min. The mixture was treated with
NaBH(OAc)3 (1.7 g, 8.0 mmol) at 0 °C, and the resulting mixture was
stirred at room temperature for 20 min. The reaction was quenched
with saturated aqueous NaHCO3 (50 mL), and the mixture was
extracted with AcOEt (80 mL). The organic layers were washed with
saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified by silica
gel column chromatography (2 × 10 cm, hexane/AcOEt = 9/1) to
give 12 (730 mg, 98%) as a slightly yellow syrup: 1H NMR (500 MHz,
CDCl3) δ 7.11 (d, 1H, SiMB-6, J = 8.0 Hz), 6.77 (d, 2H, H-2, J = 8.6
Hz), 6.63 (d, 2H, H-3, J = 8.6 Hz), 6.37 (m, 2H, SiMB-3 and SiMB-5),
4.18 (s, 2H, SiMB-CH2), 3.81 (s, 3H, OMe), 3.80 (br s, 1H, NH), 3.74
(s, 3H, OMe), 0.99 (s, 9H, tBu), 0.20 (s, 6H, Me × 2); 13C NMR (125
MHz, CDCl3) δ 158.4, 156.2, 152.2, 143.0, 129.8, 120.5, 114.9, 114.6,
111.5, 103.6, 55.9, 55.5, 44.5, 25.8, 18.3, −4.2; ESIMS-LR m/z = 396
[(M + Na)+]; ESIMS-HR calcd for C21H31O3NNaSi 396.1971, found
396.1971.
CONCLUSION
■
A new carboxamide protecting group, the 4-(tert-butyldime-
thylsiloxy)-2-methoxybenzyl (SiMB) group, has been devel-
oped. The SiMB group can be removed under conditions other
than strong acid. An application of the SiMB group to a
complex and acid-sensitive molecule was also demonstrated.
The SiMB group is very useful for the protection of the
carboxamide nitrogen atom when the target molecules contain
acid- or oxidation-labile moieties and is the first example of an
N-benzyl-type protective group cleavable under mildly basic
conditions. In this study, we have investigated the deprotection
of the SiMB group with only two types of N-substituted
carboxamides, which are N-p-methoxyphenyl and N-carba-
moylmethyl carboxamides. Further study will be necessary to
determine the versatility of this protecting group, and its
application of the SiMB group is underway.
N-(4-tert-Butyldimethylsiloxy-2-methoxybenzyl)-p-benzani-
sidide (13). A solution of 12 (110 mg, 0.30 mmol) in CH2Cl2 (3
mL) was treated with benzoyl chloride (45 μL, 0.36 mmol) and Et3N
(0.10 mL, 0.72 mmol) at 0 °C, and the resulting mixture was stirred at
room temperature for 10 min. The reaction was quenched with H2O,
and the mixture was extracted with AcOEt (30 mL). The organic
layers were washed with 0.1 N aqueous HCl (20 mL), saturated
aqueous NaHCO3 (20 mL), and brine (20 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified by silica gel
column chromatography (2 × 5 cm, hexane/AcOEt = 5/1) to give 13
(135 mg, 94%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.32
(m, 2H, Bz), 7.23−7.10 (m, 4H, Bz and SiMB-6), 6.79 (d, 2H, H-2′,
J = 8.0 Hz), 6.59 (d, 2H, H-3′, J = 8.0 Hz), 6.39 (dd, 1H, SiMB-5, J =
1.8, 8.0 Hz), 6.29 (d, 1H, SiMB-3, J = 1.8 Hz), 5.05 (s, 2H, SiMB-
t
CH2), 3.65 (s, 3H, OMe), 3.60 (s, 3H, OMe), 0.98 (s, 9H, Bu), 0.19
(s, 6H, Me × 2); 13C NMR (125 MHz, CDCl3) δ 170.7, 158.3, 157.8,
156.1, 136.6, 130.4, 129.2, 129.1, 128.6, 128.3, 127.7, 18.5, 113.7,
111.6, 103.3, 55.2, 55.1, 48.0, 25.7, 18.3, −4.3; ESIMS-LR m/z = 500
[(M + Na)+]; ESIMS-HR calcd for C28H35O4NNaSi 500.2233, found
500.2235.
EXPERIMENTAL SECTION
■
General Experimental Methods. NMR spectra were reported in
parts per million (δ) relative to tetramethylsilane (0.00 ppm) for
proton and carbon and H3PO4 (0.00 ppm) for phosphorus as internal
or external standard. Coupling constants (J) are reported in hertz
(Hz). Abbreviations of multiplicity are as follows: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; br, broad. Assignment was based on
1H−1H COSY, HMQC, and HMBC NMR spectra. Experiments
conducted using microwave irradiation were carried out in sealed vials
with temperature determination by means of infrared sensor. All
reactions except for the aqueous-phase reactions and the deprotection
reactions were carried out under the argon gas atmosphere unless
otherwise noted. Isolated yields were calculated by weighing products,
and the weights of starting materials and products were not
calibrated.19
Table 1, Entry 1. A mixture of 13 (48 mg, 0.10 mmol) in THF (2
mL) was treated with TBAF (1.0 M solution in THF, 0.15 mL, 0.15
mmol) at room temperature for 24 h. The mixture was concentrated,
and the residue was purified by silica gel column chromatography (1 ×
5 cm, hexane/AcOEt = 1/1) to give N-(4-hydroxy-2-methoxybenzyl)-
1
p-benzanisidide (16) (36.0 mg, 98%) as a colorless oil: H NMR (500
MHz, CDCl3) δ 7.40 (br s, 1H, HMB-4-OH), 7.30 (m, 2H, Bz), 7.20−
7.15 (m, 4H, Bz and HMB-6), 6.81 (d, 1H, H-2′, J = 8.0 Hz), 6.60 (d,
2H, H-3′, J = 8.0 Hz), 6.33 (d, 1H, HMB-5, J = 7.4 Hz), 6.32 (d, 1H,
HMB-3), 5.03 (s, 2H, HMB-CH2), 3.68 (s, 3H, OMe), 3.51 (s, 3H,
OMe); 13C NMR (125 MHz, CDCl3) δ 158.5, 158.0, 157.3, 136.3,
130.5, 129.6, 129.0, 128.7, 127.9, 116.6, 113.9, 107.3, 99.0, 55.4, 55.2,
48.7; ESIMS-LR m/z = 386 [(M + Na)+]; ESIMS-HR calcd for
C22H21O4NNa 386.1368, found 386.1360.
4-tert-Butyldimethylsiloxy-2-methoxybenzaldehyde (11). A
solution of 4-hydroxy-2-methoxybenzaldehyde (10) (1.0 g, 6.6 mmol)
in DMF (10 mL) was treated with imidazole (1.1 g, 16 mmol) and
TBSCl (1.2 g, 7.9 mmol) at 0 °C, and the mixture was stirred at room
temperature for 30 min. The reaction was quenched with H2O (10
mL), and the mixture was extracted with AcOEt (50 mL). The organic
layer was washed with H2O (30 mL × 2), 0.1 N aqueous HCl (30
mL), saturated aqueous NaHCO3 (30 mL), and brine (30 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified by silica
gel column chromatography (3 × 5 cm, hexane/AcOEt = 15/1) to
Table 1, Entry 2. A mixture of 13 (48 mg, 0.10 mmol) and TBAF
(1.0 M solution in THF, 0.20 mL, 0.20 mmol) in THF (2 mL) was
stirred at 150 °C under microwave irradiation for 10 min. The mixture
was concentrated, and the residue was purified by silica gel column
chromatography (1 × 6 cm, hexane/AcOEt = 4/1) to give 15 (22.0
1
mg, 0.097 mmol, 97%) as a white solid: H NMR (500 MHz, CDCl3)
δ 7.91 (br s, 1H, CONH), 7.85 (d, 2H, Bz, J = 7.4 Hz), 7.53 (d, 2H,
H-2′, J = 8.6 Hz), 7.51 (t, 1H, Bz, J = 7.4 Hz), 7.45 (t, 2H, Bz, J = 7.4
Hz), 6.88 (d, 2H, H-3′, J = 8.6 Hz), 3.80 (s, 3H, OMe); 13C NMR
(125 MHz, CDCl3) δ 165.8, 156.7, 135.1, 131.8, 131.1, 128.8, 127.1,
122.3, 114.3, 55.6. This is a known compound reported in the
literature.19
1
give 11 (1.7 g, 97%) as a white solid: H NMR (500 MHz, CDCl3) δ
10.29 (s, 1H, CHO), 7.73 (d, 1H, H-6, J = 8.6 Hz), 6.46 (dd, 1H, H-5,
J = 2.3, 8.6 Hz), 6.39 (d, 1H, H-3, J = 2.3 Hz), 3.88 (s, 3H, OMe),
0.99 (s, 9H, tBu), 0.25 (s, 6H, Me × 2); 13C NMR (125 MHz, CDCl3)
δ 188.6, 163.8, 163.1, 130.6, 119.5, 112.6, 103.5, 55.7, 25.7, 18.4, −4.2;
Table 1, Entry 3. A mixture of 13 (48 mg, 0.10 mmol) and CsF (75
mg, 0.50 mmol) in 1,4-dioxane−H2O (3:1 (v/v), 1 mL) was refluxed
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Article
at 120 °C for 12 h. The mixture was partitioned between AcOEt (20
mL) and H2O (10 mL). The organic layers were washed with brine
(10 mL), dried (Na2SO4), filtered, and concentrated. The residue was
purified by silica gel column chromatography (1 × 6 cm, hexane/
AcOEt = 4/1) to give 15 (21.0 mg, 93%) as a white solid.
Table 1, Entry 4. A mixture of 13 (48 mg, 0.10 mmol) and CsF (75
mg, 0.50 mmol) in 1,4-dioxane−H2O (3:1 (v/v), 1 mL) was stirred at
150 °C under microwave irradiation for 20 min. The mixture was
partitioned between AcOEt (20 mL) and H2O (10 mL). The organic
layers were washed with brine (10 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by silica gel column
chromatography (1 × 6 cm, hexane/AcOEt = 4/1) to give 15 (21.5
mg, 95%) as a white solid.
Table 1, Entry 5. A mixture of 13 (48 mg, 0.10 mmol) and K2CO3
(69 mg, 0.50 mmol) in MeOH (2 mL) was refluxed for 9 h. The
residue was partitioned between AcOEt (20 mL) and H2O (10 mL),
and the organic layer was washed with brine (10 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified by silica gel
column chromatography (1 × 7 cm, hexane/AcOEt = 4/1) to give 15
(20.5 mg, 90%) as a white solid.
Table 1, Entry 6. A mixture of 13 (48 mg, 0.10 mmol) and K2CO3
(69 mg, 0.50 mmol) in MeOH (2 mL) was stirred at 100 °C under
microwave irradiation for 10 min. The residue was partitioned between
AcOEt (20 mL) and H2O (10 mL), and the organic layer was washed
with brine (10 mL), dried (Na2SO4), filtered and concentrated. The
residue was purified by silica gel column chromatography (1 × 7 cm,
hexane/AcOEt = 4/1) to give 15 (21.0 mg, 93%) as a white solid.
Table 1, Entry 7. Compound 13 (48 mg, 0.10 mmol) was treated
with 80% aqueous TFA (1 mL) at room temperature for 30 min. The
mixture was concentrated, and the residue was purified by silica gel
column chromatography (1 × 6 cm, hexane/AcOEt = 4/1) to give 15
(19.0 mg, 84%) as a white solid.
Table 1, Entry 8. A solution of 13 (48 mg, 0.10 mmol) in CH2Cl2−
H2O (10:1 (v/v), 1 mL) was treated with DDQ (34 mg, 0.15 mmol)
at room temperature for 30 h. The reaction was quenched with
saturated aqueous NaHCO3 (2 mL), and the mixture was extracted
with AcOEt (20 mL). The organic layers were washed with saturated
aqueous NaHCO3 (10 mL × 3) and brine (10 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified by silica gel
column chromatography (1 × 7 cm, hexane/AcOEt = 4/1) to give 15
(18.8 mg, 83%) as a white solid.
Table 1, Entry 9. A solution of 13 (36 mg, 0.10 mmol) in CH2Cl2−
H2O (10:1 (v/v), 1 mL) was treated with DDQ (34 mg, 0.15 mmol)
at room temperature for 20 min. The reaction was quenched with
saturated aqueous NaHCO3 (2 mL), and the mixture was extracted
with AcOEt (20 mL). The organic layers were washed with saturated
aqueous NaHCO3 (10 mL × 3) and brine (10 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified by silica gel
column chromatography (1 × 7 cm, hexane/AcOEt = 4/1) to give 15
(21.5 mg, 95%) as a white solid.
Table 1, Entry 10. A solution of 13 (48 mg, 0.10 mmol) in
MeCN−H2O (3/1 (v/v), 2 mL) was treated with ceric ammonium
nitrate (220 mg, 0.40 mmol) at room temeperature for 1 h. The
mixture was partitioned between AcOEt (30 mL) and H2O (20 mL).
The organic layer was washed with saturated aqueous NaHCO3
(20 mL × 2) and brine (20 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by preparative TLC
(hexane/AcOEt = 2/1 × 2) to give 15 (6.5 mg, 29%) as a white solid.
4-tert-Butyldimethylsiloxybenzaldehyde (19). A solution of
4-hydroxybenzaldehyde (17) (5.0 g, 41 mmol) in DMF (50 mL) was
treated with imidazole (7.2 g, 106 mmol) and TBSCl (8.0 g, 53 mmol)
at 0 °C, and the mixture was stirred at room temperature for 2 h. The
reaction was quenched with H2O (20 mL) at 0 °C, and the mixture
was extracted with AcOEt (200 mL). The organic layer was washed
with H2O (100 mL × 3), 0.1 N aqueous HCl (100 mL), saturated
NaHCO3 (100 mL), and brine (100 mL), dried (Na2SO4), filtered,
and concentrated. The residue was purified by silica gel column
chromatography (3 × 10 cm, hexane/AcOEt = 4/1) to give 19 (9.4 g,
98%) as a colorless syrup: 1H NMR (500 MHz, CDCl3) δ 9.89 (s, 1H,
CHO), 7.78 (d, 2H, H-2, J = 8.6 Hz), 6.94 (d, 2H, H-3, J = 8.6 Hz),
0.99 (s, 9H, tBu), 0.25 (s, 6H, Me × 2); 13C NMR (125 MHz, CDCl3)
δ 191.1, 161.6, 132.1, 130.5, 120.6, 25.7, 18.4, −4.2. This is a known
compound reported in the literature.20
N-(4-tert-Butyldimethylsiloxybenzyl)-4-methoxyaniline
(21). A solution of p-anisidine (180 mg, 1.4 mmol), 19 (400 mg, 1.6
mmol), and AcOH (0.28 mL, 7.0 mmol) in CH2Cl2 (10 mL) was
stirred at room temperature for 20 min. NaBH(OAc)3 (590 mg, 2.8
mmol) was added to the solution at 0 °C, and the mixture was stirred
at room temperature for 30 min. The reaction was quenched with
saturated aqueous NaHCO3 (10 mL) at 0 °C, and the mixture was
extracted with AcOEt (50 mL). The organic layers were washed with
saturated aqueous NaHCO3 (30 mL × 2) and brine (30 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified by silica
gel column chromatography (2 × 10 cm, hexane/AcOEt = 8/1) to
give 21 (460 mg, 96%) as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 7.22 (d, 2H, SiB-2, J = 8.6 Hz), 6.80 (d, 2H, SiB-3, J = 8.6 Hz), 6.78
(d, 2H, H-2, J = 9.2 Hz), 6.61 (d, 2H, H-3, J = 9.2 Hz), 4.19 (s, 2H,
t
SiB-CH2), 3.74 (s, 4H, OMe and NH), 0.99 (s, 9H, Bu), 0.20 (s, 6H,
Me × 2); 13C NMR (125 MHz, CDCl3) δ 154.9, 152.3, 142.7, 132.4,
128.9, 120.3, 115.0, 114.2, 56.0, 49.0, 25.8, 18.3, −4.3; ESIMS-LR
m/z = 366 [(M + Na)+]; ESIMS-HR calcd for C20H29O2NNaSi
366.1865, found 366.1857.
N-(4-tert-Butyldimethylsiloxybenzyl)-N-(4-methoxyphenyl)-
benzamide (23). A solution of 21 (480 mg, 1.4 mmol) in CH2Cl2 (5
mL) was treated with benzoyl chloride (0.20 mL, 1.7 mmol) and Et3N
(0.47 mL, 3.4 mmol) at 0 °C, and the mixture was stirred at room
temperature for 10 min. The reaction was quenched with H2O (5 mL)
at 0 °C, and the mixture was extracted with AcOEt (50 mL). The
organic layers were washed with 0.1 N aqueous HCl (30 mL),
saturated aqueous NaHCO3 (30 mL × 2), and brine (30 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified by silica
gel column chromatography (2 × 10 cm, hexane/AcOEt = 5/1) to
give 23 (620 mg, 99%) as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 7.31 (d, 2H, SiB-2, J = 7.5 Hz), 7.21−7.13 (m, 5H, Bz), 6.75 (m, 4H,
SiB-3 and H-2′), 6.62 (d, 2H, H-3′, J = 9.2 Hz), 5.00 (s, 2H, SiB-CH2),
3.69 (s, 3H, OMe), 0.97 (s, 9H, tBu), 0.18 (s, 6H, Me × 2); 13C NMR
(125 MHz, CDCl3) δ 170.6, 158.0, 155.0, 136.4, 136.1, 130.5, 130.1,
129.4, 129.3, 128.7, 127.8, 120.1, 114.1, 55.3, 53.4, 25.8, 18.3, −4.3;
ESIMS-LR m/z = 470 [(M + Na)+]; ESIMS-HR calcd for
C27H33O3NNaSi 470.2122, found 470.2116.
4-tert-Butyldimethylsiloxy-2,6-dimethoxybenzaldehyde
(20). A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (18) (730
mg, 4.0 mmol) in DMF (5 mL) was treated with imidazole (650 mg,
9.6 mmol) and TBSCl (730 mg, 4.8 mmol) at 0 °C, and the mixture
was stirred at room temperature for 2 h. The reaction was quenched
with H2O (5 mL), and the mixture was extracted with AcOEt (50
mL). The organic layer was washed with H2O (50 mL × 2) and brine
(30 mL), dried (Na2SO4), filtered, and concentrated. The residue was
purified by silica gel column chromatography (2 × 8 cm, hexane/
AcOEt = 4/1) to give 20 (1.1 g, 94%) as a pale yellow syrup: 1H NMR
(500 MHz, CDCl3) δ 10.30 (s, 1H, CHO), 5.98 (s, 2H, H-3 and H-5),
t
3.81 (s, 6H, OMe × 2), 0.96 (s, 9H, Bu), 0.22 (s, 6H, Me × 2); 13C
NMR (125 MHz, CDCl3) δ 188.0, 164.0, 163.3, 109.1, 96.2, 56.0, 25.6,
18.3, −4.2; ESIMS-LR m/z = 319 [(M + Na)+]; ESIMS-HR calcd for
C15H24O4NaSi 319.1342, found 319.1334.
N-(4-tert-Butyldimethylsiloxy-2,6-dimethoxybenzyl)-4-me-
thoxyaniline (22). A mixture of 20 (360 mg, 1.2 mmol), p-anisidine
(160 mg, 1.3 mmol), and AcOH (0.34 mL, 6.0 mmol) in CH2Cl2 (10
mL) was stirred at room temperature for 10 min. NaBH(OAc)3 (380
mg, 1.8 mmol) was added to the mixture at 0 °C, and the resulting
mixture was stirred at room temperature for 30 min. The reaction was
quenched with saturated aqueous NaHCO3 (10 mL), and the mixture
was extracted with AcOEt (50 mL). The organic layers were washed
with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified by silica
gel column chromatography (2 × 10 cm, hexane/AcOEt = 5/1) to
1
give 22 (440 mg, 91%) as an yellow syrup: H NMR (500 MHz,
CDCl3) δ 6.76 (d, 2H, H-2, J = 8.6 Hz), 6.71 (d, 1H, H-3, J = 8.6 Hz),
6.05 (s, 2H, SiDMB-3 and SiDMB-5), 4.22 (s, 2H, SiDMB-CH2), 3.78
t
(s, 6H, SiDMB-OMe × 2), 3.74 (s, 3H, OMe), 0.99 (s, 9H, Bu), 0.21
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(s, 6H, Me × 2); 13C NMR (125 MHz, CDCl3) δ 159.2, 156.6, 152.2,
143.4, 115.2, 114.7, 108.8, 96.6, 55.9, 55.8, 37.8, 25.8, 18.3, −4.2;
ESIMS-LR m/z = 426 [(M + Na)+]; ESIMS-HR calcd for
C22H33O4NNaSi 426.2077, found 426.2070.
mg, 0.80 mmol) at room temperature for 10 min. The reaction was
quenched with H2O (10 mL), and the mixture was partitioned
between AcOEt (50 mL) and H2O (30 mL). The organic layers were
washed with 1 N aqueous HCl (30 mL), saturated aqueous NaHCO3
(30 mL), and brine (30 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by silica gel column
chromatography (2 × 6 cm, hexane/AcOEt = 4/1) to give 14c (210
N-(4-tert-Butyldimethylsiloxy-2,6-dimethoxybenzyl)-N-(4-
methoxyphenyl)benzamide (24). A solution of 22 (380 mg, 0.94
mmol) in CH2Cl2 (5 mL) was treated with benzoyl chloride (0.13 mL,
1.1 mmol) and Et3N (0.31 mL, 2.2 mmol) at 0 °C for 10 min. The
reaction was quenched with H2O (5 mL), and the mixture was
extracted with AcOEt (50 mL). The organic layers were washed with
0.1 N aqueous HCl (30 mL), saturated aqueous NaHCO3 (30 mL),
and brine (30 mL), dried (Na2SO4), filtered, and concentrated. The
residue was purified by silica gel column chromatography (1 × 10 cm,
hexane/AcOEt = 4/1) to give 24 (470 mg, 98%) as a pale yellow
syrup: 1H NMR (400 MHz, CDCl3) δ 7.25 (br s, 2H, Bz), 7.13 (br s,
3H, Bz), 6.65 (br s, 2H, H-2′), 6.47 (br s, 2H, H-3′), 5.89 (s, 2H,
SiDMB-3 and SiDMB-5), 5.09 (s, 2H, SiDMB-CH2), 3.63 (s, 3H,
1
mg, 99%) as a colorless oil: H NMR (500 MHz, CDCl3) δ 8.08 (d,
2H, Bz, J = 6.9 Hz), 7.53 (t, 1H, Bz, J = 7.5 Hz), 7.41 (t, 2H, Bz, J =
7.5 Hz), 7.09 (d, 1H, SiMB-6, J = 8.0 Hz), 6.97 (d, 2H, H-2′, J = 8.5
Hz), 6.79 (d, 2H, H-3′, J = 8.5 Hz), 6.35 (dd, 1H, SiMB-5, J = 2.3, 8.0
Hz), 6.25 (d, 1H, SiMB-3, J = 2.3 Hz), 4.87 (s, 2H, SiMB-CH2), 4.58
(s, 2H, C(O)CH2), 0.97 (s, 9H, tBu), 0.18 (s, 6H, Me × 2); 13C NMR
(125 MHz, CDCl3) δ 166.5, 166.3, 159.3, 158.6, 156.4, 133.1, 132.8,
131.4, 130.0, 129.7, 129.6, 128.3, 117.9, 114.5, 111.7, 103.3, 62.4, 55.4,
55.1, 47.2, 25.7, 18.3, −4.3; ESIMS-LR m/z = 558 [(M + Na)+];
ESIMS-HR calcd for C30H37O6NNaSi 558.2288, found 558.2279.
Oα-(4-Methoxybenzyl)-N-(4-tert-butyldimethylsiloxy-2-me-
thoxybenzyl)-N-(4-methoxyphenyl)glycolamide (14d). A mix-
ture of 12 (190 mg, 0.50 mmol), Oα-p-methoxybenzylglycolic acid22
(120 mg, 0.60 mmol), and DMAP (1 mg) in CH2Cl2 (5 mL) was
treated with EDCI (192 mg, 1.0 mmol) at room temperature for 20
min. The reaction was quenched with H2O (10 mL), and the mixture
was partitioned between AcOEt (50 mL) and H2O (30 mL). The
organic layers were washed with 1 N aqueous HCl (30 mL), saturated
aqueous NaHCO3 (30 mL), and brine (30 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified by silica gel
column chromatography (1 × 7 cm, hexane/AcOEt = 5/2) to give 14d
(260 mg, 94%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.22
(d, 2H, PMB-2, J = 8.6 Hz), 7.06 (d, 1H, SiMB-6, J = 8.6 Hz), 6.81 (d,
2H, PMB-3, J = 8.6 Hz), 6.79 (d, 2H, H-2′, J = 9.1 Hz), 6.71 (d, 2H,
H-3′, J = 9.1 Hz), 6.33 (dd, 1H, SiMB-5, J = 2.3, 8.6 Hz), 6.23 (d, 1H,
SiMB-3, J = 2.3 Hz), 4.84 (s, 2H, benzyl-CH2), 4.50 (s, 2H, benzyl-
CH2), 3.80 (s, 2H, C(O)CH2), 3.77 (s, 3H, OMe), 3.74 (s, 3H, OMe),
3.51 (s, 3H, OMe), 0.96 (s, 9H, tBu), 0.17 (s, 6H, Me × 2); 13C NMR
(125 MHz, CDCl3) δ 169.3, 159.3, 159.0, 158.5, 156.3, 133.3, 131.3,
129.8, 129.7, 129.5, 118.2, 114.2, 113.7, 111.7, 103.3, 72.7, 67.9, 55.4,
55.3, 55.2, 46.8, 25.8, 18.3, −4.3; ESIMS-LR m/z = 574 [(M + Na)+];
ESIMS-HR calcd for C31H41O6NNaSi 574.2601, found 574.2596.
Table 3. General Procedure for the Removal of the SiMB
Group under Basic Conditions Using a Microwave Reactor
(Method A). A mixture of the substrate (0.10 mmol) and CsF (75
mg, 0.50 mmol, 5 equiv) in 1,4-dioxane−H2O (3:1 (v/v), 1 mL) was
stirred at 150 °C under microwave irradiation until the reaction was
complete (checked by TLC). The mixture was partitioned between
AcOEt and H2O. The organic layers were washed with brine, dried
(Na2SO4), filtered, and concentrated. The residue was purified by silica
gel column chromatography, eluting with hexane/AcOEt mixtures, to
afford the corresponding carboxamides.
General Procedure for the Removal of the SiMB Group
under Acidic Conditions (Method B). The substrate (0.10 mmol)
was treated with 80% aqueous TFA (1 mL) at room temperature until
the reaction was complete (checked by TLC). The mixture was
concentrated, and the residue was purified by silica gel column
chromatography, eluting with hexane/AcOEt mixtures, to afford the
corresponding carboxamides.
General Procedure for the Removal of the SiMB Group
under Oxidative Conditions (Method C). A solution of the
substrate (0.10 mmol) in CH2Cl2−H2O (10:1 (v/v), 1 mL) was
treated with DDQ (34 mg, 0.15 mmol, 1.5 equiv) at room temperature
until the reaction was complete (checked by TLC). The reaction was
quenched with saturated aqueous NaHCO3, and the mixture was
extracted with AcOEt. The organic layers were washed with saturated
aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and
concentrated. The residue was purified by silica gel column
chromatography, eluting with hexane/AcOEt mixtures, to afford the
corresponding carboxamides.
t
OMe), 3.61 (s, 6H, OMe × 2), 0.95 (s, 9H, Bu), 0.15 (s, 6H, Me ×
2); 13C NMR (100 MHz, CDCl3) δ 159.6, 157.8, 157.0, 137.6, 130.1,
128.8, 128.4, 127.6, 113.0, 106.3, 96.4, 55.6, 55.2, 25.8, 18.4, −4.3;
ESIMS-LR m/z = 530 [(M + Na)+]; ESIMS-HR calcd for
C29H37O5NNa 530.2339, found 530.2324.
N-(4-tert-Butyldimethylsiloxy-2-methoxybenzyl)-N-(4-me-
thoxyphenyl)-tert-butoxycarbonylaminoacetamide (14a). A
mixture of 12 (80 mg, 0.20 mmol), N-Boc-glycine (46 mg, 0.26
mmol), and DMAP (1 mg) in CH2Cl2 (2 mL) was treated with EDCI
(77 mg, 0.40 mmol) at room temperature for 10 min. The reaction
was quenched with H2O, and the mixture was extracted with AcOEt
(30 mL). The organic layers were washed with 0.1 N aqueous HCl (20
mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified by silica
gel column chromatography (1 × 8 cm, hexane/AcOEt = 3/1) to give
1
14a (100 mg, 95%) as a colorless oil: H NMR (500 MHz, CDCl3) δ
6.99 (d, 1H, SiMB-6, J = 8.0 Hz), 6.83 (d, 2H, H-2′, J = 8.6 Hz), 6.73
(d, 2H, H-3′, J = 8.6 Hz), 6.31 (dd, 1H, SiMB-5, J = 2.3, 8.0 Hz), 6.23
(d, 1H, SiMB-3, J = 2.3 Hz), 5.48 (br s, 1H, BocNH), 4.81 (s, 2H,
SiMB-CH2), 4.73 (s, 3H, OMe), 3.56 (d, 2H, C(O)CH2, J = 4.6 Hz),
t
t
3.51 (s, 3H, OMe), 1.38 (s, 9H, Bu), 0.94 (s, 9H, Bu), 0.15 (s, 6H,
Me × 2); 13C NMR (125 MHz, CDCl3) δ 168.7, 159.2, 158.5, 156.4,
155.8, 132.9, 131.2, 129.5, 117.8, 114.6, 111.6, 103.3, 79.4, 55.4, 55.1,
47.3, 43.3, 28.4, 25.7, 18.3, −4.3; ESIMS-LR m/z = 553 [(M + Na)+];
ESIMS-HR calcd for C28H42O6N2NaSi 553.2710, found 553.2705.
N-(4-tert-Butyldimethylsiloxy-2-methoxybenzyl)-N-(4-me-
thoxyphenyl)-9-fluorenylmethyloxycarbonylaminoacetamide
(14b). A mixture of 12 (80 mg, 0.20 mmol), N-Fmoc-glycine (77 mg,
0.26 mmol), and DMAP (1 mg) in CH2Cl2 (2 mL) was treated with
EDCI (77 mg, 0.40 mmol) at room temperature for 30 min. The
reaction was quenched with H2O, and the mixture was extracted with
AcOEt (30 mL). The organic layers were washed with 0.1 N aqueous
HCl (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20
mL), dried (Na2SO4), filtered, and concentrated. The residue was
purified by silica gel column chromatography (1 × 7 cm, hexane/
AcOEt = 3/1) to give 14b (130 mg, quant) as a white foam: 1H NMR
(500 MHz, CDCl3) δ 7.76 (d, 2H, Fmoc-aromatic, J = 7.4 Hz), 7.62
(d, 2H, Fmoc-aromatic, J = 7.4 Hz), 7.39 (t, 2H, Fmoc-aromatic, J =
7.4 Hz), 7.31 (t, 2H, Fmoc-aromatic, J = 7.4 Hz), 7.05 (d, 1H, SiMB-6,
J = 8.0 Hz), 6.88 (d, 2H, H-2′, J = 8.6 Hz), 6.78 (d, 2H, H-3′, J = 8.6
Hz), 6.37 (d, 1H, SiMB-5, J = 8.0 Hz), 6.29 (s, 1H, SiMB-3), 5.91 (br
s, 1H, FmocNH), 4.88 (s, 2H, SiMB-CH2), 4.34 (d, 2H, Fmoc-CH2,
J = 7.5 Hz), 4.22 (t, 1H, Fmoc-9, J = 7.5 Hz), 3.76 (s, 3H, OMe), 3.70
t
(d, 2H, C(O)CH2, J = 4.0 Hz), 3.56 (s, 3H, OMe), 0.99 (s, 9H, Bu),
0.21 (s, 6H, Me × 2); 13C NMR (125 MHz, CDCl3) δ 168.3, 159.3,
158.5, 156.5, 156.2, 144.0, 141.3, 132.7, 131.3, 129.5, 127.7, 127.1,
125.2, 120.0, 117.7, 114.6, 111.7, 103.4, 67.0, 55.4, 55.2, 47.4, 47.1,
43.6, 25.7, 18.3, −4.3; ESIMS-LR m/z = 675 [(M + Na)+]; ESIMS-
HR calcd for C38H44O6N2NaSi 675.2866, found 675.2850.
Oα-Benzoyl-N-(4-tert-butyldimethylsiloxy-2-methoxyben-
zyl)-N-(4-methoxyphenyl)glycolamide (14c). A mixture of 12
(150 mg, 0.40 mmol), Oα-benzoylglycolic acid21 (95 mg, 0.52 mmol),
and DMAP (1 mg) in CH2Cl2 (4 mL) was treated with EDCI (150
2-[N-Benzoyl-N-(2,4-dimethoxybenzyl)]aminoacetic Acid
(31). A mixture of 30 (960 mg, 2.3 mmol) and 10% Pd/C (290
mg) in MeOH (30 mL) was vigorously stirred under H2 atmosphere at
9285
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Article
room temperature for 1 h. The insoluble was filtered off through a
Celite pad, and the filtrate was concentrated in vacuo. The residue was
purified by silica gel column chromatography (2 × 6 cm, 10% MeOH
43.8; ESIMS-LR m/z = 514 [(M + Na)+]; ESIMS-HR calcd for
C27H29O6N3Na 514.1954, found 514.1952.
2 - [ N - [ 2 - ( N - B e n z o y l ) a m i n o a c e t y l ] ] a m i n o - N - ( 4 -
methoxyphenyl)acetamide (34). From 32. Compound 32 (74
mg, 0.10 mmol) was treated with 80% aqueous TFA (2 mL) at room
temperature for 4 h. The mixture was concentrated in vacuo, and the
residue was triturated with CHCl3−MeOH to give 34 (30 mg, 88%) as
a white solid. From 36. A mixture of 36 (26 mg, 0.050 mmol) and CsF
(38 mg, 0.25 mmol) in 1,4-dioxane−H2O (3/1 (v/v), 1 mL) was
stirred at 150 °C under microwave irradiation for 1 h. The mixture was
concentrated and the residue was purified by silica gel column
chromatography (1 × 9) cm, 6% MeOH in CHCl3) to give 34 (16 mg,
88%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H,
CONH), 8.92 (t, 1H, CONH, J = 5.7 Hz), 8.33 (t, 1H, CONH, J = 5.7
Hz), 7.90 (d, 2H, Bz, J = 7.5 Hz), 7.53 (d, 2H, H-2′, J = 8.6 Hz), 7.48
(m, 3H, Bz), 6.88 (d, 2H, H-3′, J = 8.6 Hz), 3.92 (d, 2H, CH2, J = 5.7
Hz), 3.86 (d, 2H, CH2, J = 5.7 Hz), 3.71 (s, 3H, OMe); 13C NMR
(125 MHz, DMSO-d6) δ 169.5, 167.1, 166.9, 155.2, 133.8, 131.9,
131.5, 128.3, 127.4, 120.7, 113.9, 55.2, 43.0, 42.6; ESIMS-LR m/z =
364 [(M + Na)+]; ESIMS-HR calcd for C18H19O4N3Na 364.1273,
found 364.1272.
1
in CHCl3) to give 31 (690 mg, 91%) as a colorless syrup: H NMR
(500 MHz, CDCl3, 20 °C, 4:1 mixture of rotamers, data for major
rotamer) δ 7.53 (d, 2H, Bz, J = 6.9 Hz), 7.40 (m, 3H, Bz), 6.99 (d, 1H,
DMB-6, J = 8.0 Hz), 6.44 (d, 1H, DMB-5, J = 8.0 Hz), 6.41 (s, 1H,
DMB-3), 4.52 (s, 2H, DMB-CH2), 4.17 (s, 2H, CH2), 3.79 (s, 3H,
OMe), 3.71 (s, 3H, OMe); 13C NMR (125 MHz, CDCl3, 20 °C, 4:1
mixture of rotamers, observed peaks were described) δ 173.7, 173.5,
161.1, 158.7, 135.4, 130.2, 129.9, 128.7, 128.5, 127.4, 126.7, 116.0,
104.2, 98.7, 55.5, 55.2, 49.7, 46.8; ESIMS-LR (negative) m/z = 328
[(M − H)−]; ESIMS-HR calcd for C18H18O5N 328.1185, found
328.1198.
2-[N-[2-[N-Benzoyl-N-(2,4-dimethoxybenzyl)]aminoacetyl]-
N-[4-tert-butyldimethylsiloxy-2-methoxybenzyl]]amino-N-(4-
methoxyphenyl)acetamide (32). A mixture of 28 (430 mg, 2.0
mmol) and 11 (550 mg, 2.1 mmol) in CH2Cl2 (10 mL) was stirred at
room temperature for 20 min. NaBH(OAc)3 (640 mg, 3.0 mmol) was
added to the mixture at 0 °C, and the resulting mixture was stirred at
room temperature for 30 min. The reaction was quenched with
saturated aqueous NaHCO3 (30 mL), and the mixture was extracted
with AcOEt (100 mL). The organic layers were washed with saturated
aqueous NaHCO3 (50 mL) and brine (60 mL), dried (Na2SO4),
filtered, and concentrated to give a crude N-SiMB amine 29.
Compound 29 was dissolved in CH2Cl2 (20 mL), and the solution
was treated with 31 (660 mg, 2.0 mmol), DMAP (24 mg, 0.20 mmol),
and EDCI (580 mg, 3.0 mmol) at room temperature for 1 h. The
reaction was quenched with H2O (20 mL), and the mixture was
extracted with AcOEt (150 mL). The organic layers were washed with
0.1 N aqueous HCl (100 mL × 2), saturated aqueous NaHCO3 (100
mL × 2), and brine (100 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by silica gel column
chromatography (2 × 14 cm, hexane/AcOEt = 2/1) to give 32 (1.1 g,
2-[N-[2-[N-Benzoyl-N-(2,4-dimethoxybenzyl)]aminoacetyl]-
N-[4-hydroxy-2-methoxybenzyl]]amino-N-(4-methoxyphenyl)-
acetamide. A solution of 32 (150 mg, 0.20 mmol) in THF (3 mL)
was treated with TBAF (1.0 M solution in THF, 0.24 mL, 0.24 mmol)
at room temperature for 10 min. The mixture was concentrated, and
the residue was purified by silica gel column chromatography (1 × 7
cm, 2% MeOH in CHCl3) to give the titled compound (125 mg, 99%)
as a white foam: 1H NMR (500 MHz, CDCl3, 20 °C, 8.3:1.9:1 mixture
of rotamers, data for major rotamer) δ 8.62 (br s, 1H, CONH), 8.18
(br s, 1H, HMB-4-OH), 7.55 (d, 2H, Bz, J = 6.9 Hz), 7.45 (d, 2H, H-
2′, J = 9.2 Hz), 7.40 (m, 3H, Bz), 7.14 (d, 1H, HMB-6, J = 8.0 Hz),
6.87 (d, 1H, DMB-6, J = 8.0 Hz), 6.75 (d, 2H, H-3′, J = 9.2 Hz), 6.47
(dd, 1H, HMB-5, J = 2.3, 8.0 Hz), 6.42 (d, 1H, HMB-3, J = 2.3 Hz),
6.30 (m, 2H, DMB-3 and DMB-5), 4.63 (s, 2H, benzyl-CH2), 4.48 (s,
2H, benzyl-CH2), 4.38 (s, 2H, CH2), 4.13 (s, 2H, CH2), 3.83 (s, 3H,
1
74% over two steps) as a white foam: H NMR (500 MHz, CDCl3,
20 °C, 7.1:1.6:1 mixture of rotamers, data for major rotamer) δ 8.51
(br s, 1H, CONH), 7.53 (m, 4H, H-2′and Bz), 7.40 (m, 3H, Bz), 7.19
(d, 1H, SiMB-6, J = 8.6 Hz), 6.99 (d, 1H, DMB-6, J = 8.9 Hz), 6.77 (d,
2H, H-3′, J = 9.1 Hz), 6.48 (dd, 1H, SiMB-5, J = 2.3, 8.6 Hz), 6.42 (d,
1H, SiMB-3, J = 2.3 Hz), 6.38 (dd, 1H, DMB-5, J = 2.3, 8.9 Hz), 6.30
(d, 1H, DMB-3, J = 2.3 Hz), 4.65 (s, 2H, SiMB-CH2), 4.58 (s, 2H,
DMB-CH2), 4.31 (s, 2H, CH2), 4.16 (s, 2H, CH2), 3.80 (s, 3H, OMe),
3.75 (s, 3H, OMe), 3.70 (s, 3H, OMe), 3.67 (s, 3H, OMe), 0.96 (s,
9H, tBu), 0.17 (s, 6H, Me × 2); 13C NMR (125 MHz, CDCl3, 20 °C,
7.1:1.6:1 mixture of rotamers, observed peaks were described) δ 173.4,
172.8, 170.1, 168.5, 166.8, 160.7, 158.8, 158.6, 158.5, 157.3, 157.0,
156.4, 156.1, 135.6, 131.9, 131.6, 131.1, 130.2, 130.1, 130.0, 129.7,
129.5, 129.4, 129.2, 128.6, 128.4, 127.3, 126.7, 122.0, 121.6, 121.5,
117.1, 116.8, 116.7, 116.0, 114.2, 113.9, 113.8, 111.9, 111.7, 104.1,
103.6, 103.4, 98.7, 55.5, 55.2, 52.0, 50.7, 50.4, 50.3, 49.7, 48.4, 47.0,
46.5, 45.4, 25.7, 18.3, −4.3; ESIMS-LR m/z = 764 [(M + Na)+];
ESIMS-HR calcd for C41H51O8N3NaSi 764.3343, found 764.3344.
2-[N-[2-[N-Benzoyl-N-(2,4-dimethoxybenzyl)]aminoacetyl]]-
amino-N-(4-methoxyphenyl)acetamide (33). A mixture of 32
(74 mg, 0.10 mmol) and CsF (75 mg, 0.50 mmol) in 1,4-dioxane−
H2O (3/1 (v/v), 2 mL) was stirred at 150 °C under microwave
irradiation for 30 min. The mixture was extracted with AcOEt (30
mL), and the organic layers were washed with H2O (20 mL) and brine
(20 mL), dried (Na2SO4), filtered, and concentrated. The residue was
purified by silica gel column chromatography (1 × 10 cm, 2% MeOH
OMe), 3.76 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.56 (s, 3H, OMe); 13
C
NMR (125 MHz, CDCl3, 20 °C, 8.3:1.9:1 mixture of rotamers,
observed peaks were described) δ 173.7, 169.9, 167.5, 160.9, 158.8,
158.7, 158.6, 156.4, 135.5, 131.1, 130.7, 130.2, 129.5, 128.5, 127.4,
127.3, 122.2, 122.0, 116.7, 114.0, 113.7, 107.4, 104.2, 99.4, 98.8, 55.5,
55.3, 55.2, 50.3, 50.0, 48.2, 46.6; ESIMS-LR m/z = 650 [(M + Na)+];
ESIMS-HR calcd for C35H37O8N3Na 650.2478, found 650.2479.
2-[N-]2-[N-Benzoyl-N-(2,4-dimethoxybenzyl)]aminoacetyl]-
N-[4-acetoxy-2-methoxybenzyl (AcMB)]]amino-N-(4-
methoxyphenyl)acetamide (35). A solution of 2-[N-]2-[N-benzo-
yl-N-(2,4-dimethoxybenzyl)]aminoacetyl]-N-[4-hydroxy-2-
methoxybenzyl]]amino-N-(4-methoxyphenyl)acetamide (120 mg,
0.19 mmol), DMAP (2.3 mg, 0.019 mmol), and Et3N (64 mL, 0.46
mmol) in MeCN (3 mL) was treated with Ac2O (22 mL, 0.23 mmol)
at 0 °C, and the mixture was stirred at the same temperature for 10
min. The reaction was quenched with H2O (5 mL), and the mixture
was extracted with AcOEt (30 mL). The organic layers were washed
with 0.1 N aqueous HCl (15 mL), saturated aqueous NaHCO3 (15
mL), and brine (15 mL), dried (Na2SO4), filtered, and concentrated to
1
give 35 (120 mg, 94%) as a white foam: H NMR (500 MHz, CDCl3,
20 °C, 6.7:2:1 mixture of rotamers, data for major rotamer) δ 8.65 (br
s, 1H, CONH), 7.53 (m, 5H, H-2′and Bz), 7.38 (m, 3H, AcMB-6 and
Bz), 7.16 (d, 1H, DMB-6, J = 8.6 Hz), 6.76 (d, 2H, H-3′, J = 9.2 Hz),
6.65 (dd, 1H, AcMB-5, J = 2.3, 8.0 Hz), 6.58 (d, 1H, AcMB-3, J = 2.3
Hz), 6.47 (dd, 1H, DMB-5, J = 2.3, 8.6 Hz), 6.42 (d, 1H, DMB-3, J =
2.3 Hz), 4.66 (s, 2H, DMB-CH2), 4.64 (s, 2H, AcMB-CH2), 4.23 (s,
2H, CH2), 4.16 (s, 2H, CH2), 3.78 (s, 3H, OMe), 3.74 (s, 3H, OMe),
3.72 (s, 3H, OMe), 3.68 (s, 3H, OMe), 2.27 (s, 3H, Ac); 13C NMR
(125 MHz, CDCl3, 20 °C, 6.7:2:1 mixture of rotamers, observed peaks
were described) δ 173.3, 172.8, 170.2, 169.3, 168.6, 166.7, 166.1,
160.7, 158.5, 158.4, 158.0, 156.3, 156.1, 151.7, 151.4, 135.5, 131.5,
131.0, 130.1, 130.0, 129.5, 129.3, 129.2, 128.7, 128.6, 128.4, 128.3,
127.3, 127.2, 126.6, 122.0, 121.9, 121.6, 121.5, 121.0, 116.6, 114.1,
13.9, 113.6, 113.5, 104.9, 104.6, 104.1, 98.7, 98.5, 55.6, 55.4, 55.2, 52.1,
1
in CHCl3) to give 33 (47 mg, 96%) as a white foam: H NMR (500
MHz, CDCl3) δ 8.88 (br s, 1H, CONH), 7.50 (m, 4H, H-2′and Bz),
7.39 (m, 3H, Bz), 7.29 (br s, 1H, CONH), 7.03 (d, 1H, DMB-6, J =
8.6 Hz), 6.73 (d, 2H, H-3′, J = 9.2 Hz), 6.40 (dd, 1H, DMB-5, J = 2.3,
8.6 Hz), 6.38 (d, 1H, DMB-3, J = 2.3 Hz), 4.58 (s, 2H, DMB-CH2),
4.03 (s, 2H, CH2), 3.98 (d, 2H, CH2, J = 5.7 Hz), 3.74 (s, 3H, OMe),
3.72 (s, 3H, OMe), 3.67 (s, 3H, OMe); 13C NMR (125 MHz, CDCl3)
δ 173.5, 169.6, 167.0, 161.1, 158.6, 156.2, 135.2, 131.2, 130.3, 128.5,
127.3, 121.6, 115.9, 114.0, 104.3, 98.7, 55.4, 55.3, 55.1, 50.7, 49.7,
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50.7, 50.3, 50.2, 48.2, 46.7, 46.3, 45.3, 25.7, 21.2; ESIMS-LR m/z =
692 [(M + Na)+]; ESIMS-HR calcd for C37H39O9N3Na 692.2584,
found 692.2583.
Hz), 5.94 (ddt, 1H, H-2′, J = 5.7, 10.3, 17.1 Hz), 5.45 (d, 1H, SiMB-
CH2, J = 13.7 Hz), 4.99 (dd, 1H, H-3′-cis, J = 1.7, 10.3 Hz), 4.97 (d,
1H, MOM-CH2, J = 6.9 Hz), 4.89 (dd, 1H, H-3′-trans, J = 1.7, 17.1
Hz), 4.86 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.85 (d, 1H, MOM-CH2,
J = 6.3 Hz), 4.80 (d, 1H, MOM-CH2, J = 6.9 Hz), 4.24 (d, 1H, SiMB-
CH2, J = 13.7 Hz), 3.77 (s, 3H, OMe), 3.76 (d, 1H, BrCH2, J = 11.4
Hz), 3.70 (d, 1H, BrCH2, J = 11.4 Hz), 3.53 (s, 3H, OMe), 3.46 (s,
3H, OMe), 3.41 (dd, 1H, H-1′, J = 5.7, 14.9 Hz), 3.35 (dd, 1H, H-1′,
2-[N-(2-N-Benzoylaminoacetyl)-N-(4-acetoxy-2-
methoxybenzyl)]amino-N-(4-methoxyphenyl)acetamide (36).
(a) Acidic Conditions. Compound 35 (67 mg, 0.10 mmol) was
treated with 80% aqueous TFA at room temperature for 30 min. The
mixture was concentrated in vacuo, and the residue was purified by
silica gel column chromatography (1 × 8 cm, 1% MeOH in CHCl3) to
give 36 (44 mg, 85%) as a white foam. (b) Oxidative Conditions. A
mixture of 35 (67 mg, 0.10 mmol) and DDQ (34 mg, 0.15 mmol) in
CH2Cl2−H2O (10:1 (v/v), 1 mL) was stirred at room temperature for
48 h. The mixture was diluted with AcOEt (20 mL), and the organic
layers were washed wih saturated aqueous NaHCO3 (20 mL × 3) and
brine (20 mL), dried (Na2SO4), filtered, and concentrated. The
residue was purified by silica gel column chromatography (1 × 7 cm,
t
J = 5.7, 14.9 Hz), 3.34 (s, 3H, OMe), 0.92 (s, 9H, Bu), 0.13 (s, 3H,
Me), 0.12 (s, 3H, Me); 13C NMR (125 MHz, CDCl3) δ 166.6, 158.6,
156.5, 148.7, 147.5, 146.5, 136.6, 131.5, 130.0, 128.2, 117.7, 116.1,
115.3, 111.4, 103.0, 100.2, 95.4, 61.0, 57.4, 56.0, 55.0, 46.3, 29.3, 28.8,
25.7, 18.2, −4.4; ESIMS-LR m/z = 676 [(M + Na)+]; ESIMS-HR
calcd for C30H44O8BrNNaSi 676.1917, found 676.1912.
N-(3-Allyl-4-methoxy-2,5-bis-methoxymethoxyphenyl)-N-
( 4 - t e r t - b u t y l d i m e t h y l s i l o x y - 2 - m e t h o x y b e n z y l ) -
diethylphosphonoacetamide (38). A mixture of N-(3-allyl-4-
methoxy-2,5-dimethoxymethoxyphenyl)-N-(4-tert-butyldimethylsi-
loxy-2-methoxybenzyl)bromoacetamide (1.8 g, 2.8 mmol) and triethyl
phosphite (15 mL) was stirred at 100 °C for 4 h. The mixture was
concentrated, and the residue was purified by silica gel column
chromatography (2 × 5 cm, hexane/AcOEt = 1/1) to give 38 (1.9 g,
1
2% MeOH in CHCl3) to give 36 (36 mg, 70%) as a white foam: H
NMR (500 MHz, CDCl3, 20 °C, 3.4:1 mixture of rotamers, data for
major rotamer) δ 8.25 (br s, 1H, CONH), 7.80 (d, 2H, Bz, J = 7.5
Hz), 7.46 (t, 1H, CONH, J = 4.0 Hz), 7.38 (d, 2H, H-2′, J = 8.6 Hz),
7.35 (m, 3H, Bz), 7.15 (d, 1H, AcMB-6, J = 8.0 Hz), 6.78 (d, 2H, H-3′,
J = 8.6 Hz), 6.69 (dd, 1H, AcMB-5, J = 2.3, 8.0 Hz), 6.62 (d, 1H,
AcMB-3, J = 2.3 Hz), 4.63 (s, 2H, AcMB-CH2), 4.45 (d, 2H,
C(O)CH2, J = 4.0 Hz), 4.11 (s, 2H, C(O)CH2), 3.79 (s, 3H, OMe),
3.74 (s, 3H, OMe), 2.30 (s, 3H, Ac); 13C NMR (125 MHz, CDCl3, 20
°C, 3.2:1 mixture of rotamers, observed peaks were described) δ 170.6,
169.6, 169.5, 169.4, 167.8, 166.4, 165.9, 158.4, 158.3, 156.4, 151.9,
151.4, 133.5, 131.8, 131.1, 130.9, 130.7, 129.6, 128.6, 127.2, 122.1,
121.8, 121.7, 114.0, 113.7, 105.1, 104.7, 55.7, 55.5, 50.8, 50.3, 47.9,
45.8, 42.0, 41.7, 29.8, 21.2; ESIMS-LR m/z = 542 [(M + Na)+];
ESIMS-HR calcd for C28H29O7N3Na 542.1903, found 542.1902.
N-(4-tert-Butyldimethylsiloxy-2-methoxybenzyl)-3-allyl-4-
methoxy-2,5-dimethoxymethoxyaniline. A mixture of 37 (2.1 g,
7.4 mmol), 11 (2.1 g, 8.1 mmol), and AcOH (2.1 mL, 37 mmol) in
CH2Cl2 (50 mL) was stirred at room temperature for 10 min. The
mixture was treated with NaBH(OAc)3 (6.4 g, 30 mmol) at 0 °C, and
the resulting mixture was stirred at room temperature for 20 min. The
reaction was quenched with saturated aqueous NaHCO3 (100 mL),
and the mixture was extracted with AcOEt (250 mL). The organic
layers were washed with saturated aqueous NaHCO3 (200 mL) and
brine (200 mL), dried (Na2SO4), filtered, and concentrated. The
residue was purified by silica gel column chromatography (2 × 20 cm,
hexane/AcOEt = 10/1) to give the titled compound (3.6 g, 92%) as a
1
95%) as a colorless oil: H NMR (500 MHz, CDCl3, 20 °C, 99:1
mixture of rotamers) δ 7.10 (d, 1H, SiMB-6, J = 8.6 Hz), 6.67 (s, 1H,
H-6), 6.25 (dd, 1H, SiMB-5, J = 2.3, 8.6 Hz), 6.14 (d, 1H, SiMB-3, J =
2.3 Hz), 5.89 (ddt, 1H, H-2′, J = 5.8, 10.3, 17.5 Hz), 5.39 (d, 1H,
SiMB-CH2, J = 14.5 Hz), 4.97 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.94
(dd, 1H, H-3′-cis, J = 1.7, 10.3 Hz), 4.86 (dd, 1H, H-3′-trans, J = 1.7,
17.5 Hz), 4.85 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.80 (d, 1H, MOM-
CH2, J = 6.3 Hz), 4.76 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.22 (d, 1H,
SiMB-CH2, J = 14.5 Hz), 4.04 (m, 4H, OCH2 × 2), 3.73 (s, H, OMe),
3.48 (s, 3H, OMe), 3.44 (s, 3H, OMe), 3.37 (dd, 1H, H-1′, J = 5.8,
14.9 Hz), 3.30 (dd, 1H, H-1′, J = 5.8, 14.9 Hz), 3.29 (s, 3H, OMe),
2.91 (dd, 1H, C(O)CH2, J = 15.4, 19.4 Hz), 2.77 (dd, 1H, C(O)CH2,
t
J = 14.9, 22.9 Hz), 1.24 (m, 6H, Me × 2), 0.88 (s, 9H, Bu), 0.09 (s,
3H, Me), 0.08 (s, 3H, Me); 13C NMR (125 MHz, CDCl3) δ 165.5,
158.5, 156.3, 148.6, 147.2, 146.7, 136.8, 131.1, 1310, 128.3, 118.0,
116.6, 115.3, 111.4, 103.0, 100.2, 95.5, 62.7, 62.6, 62.2, 61.0, 57.5, 56.2,
55.1, 46.0, 34.2, 33.1, 29.4, 25.8, 18.3, 16.6, 16.5, 16.4, −4.4; 31P NMR
(202 MHz, CDCl3) δ 23.1; ESIMS-LR m/z = 734 [(M + Na)+];
ESIMS-HR calcd for C34H54O11NNaPSi 734.3101, found 734.3095.
N-(3-Allyl-4-methoxy-2,5-bis-methoxymethoxyphenyl)-N-
(4-tert-butyldimethylsiloxy-2-methoxybenzyl) (E)-3-O-Allyl-1-
(6-amino-N6-trityl-9H-purin-9-yl)-2-O-tert-butyldimethylsilyl-
5,6-dideoxy-β-D-ribo-5-eneheptofuranuronamide (41a). A sol-
ution of 39a (500 mg, 0.75 mmol) in CH2Cl2 (5 mL) was treated with
Dess−Martin periodinane (470 mg, 1.1 mmol) at 0 °C for 1 h. The
reaction was quenched with saturated aqueous Na2S2O3 (10 mL) and
saturated aqueous NaHCO3 (10 mL), and the mixture was stirred at
0 °C for 15 min. The mixture was extracted with AcOEt (40 mL), and
the organic layers were washed with saturated aqueous NaHCO3 (20
mL × 2) and brine (20 mL), dried (Na2SO4), filtered, and
concentrated to give crude aldehyde 40a as a white foam. Compound
40a (500 mg, 0.75 mmol) was added to a mixture of 38 (530 mg, 0.75
mmol), Zn(OTf)2 (330 mg, 0.90 mmol), Et3N (0.42 mL, 3.0 mmol),
and TMEDA (0.14 mL, 0.90 mmol) in THF (7 mL) at room
temperature, and the resulting mixture was stirred at the same
temperature for 16 h. The mixture was partitioned between AcOEt
(100 mL) and H2O (60 mL). The organic layers were washed with 0.1
N aqueous HCl (80 mL), saturated aqueous NaHCO3 (80 mL), and
brine (60 mL), dried (Na2SO4), filtered, and concentrated. The
residue was purified by flash silica gel column chromatography (2 × 20
cm, hexane/AcOEt = 3/1) to give 41a (850 mg, 93%) as a white foam:
1H NMR (500 MHz, CDCl3, 20 °C, 4:3 mixture of rotamers) data for
1
red oil: H NMR (500 MHz, CDCl3) δ 7.15 (d, 1H, SiMB-6, J = 8.6
Hz), 6.48 (s, 1H, H-6), 6.40 (m, 2H, SiMB-3 and SiMB-5), 6.00 (ddt,
1H, H-2′, J = 6.3, 9.2, 16.7 Hz), 5.15 (s, 2H, MOM-CH2), 5.02 (dd,
1H, H-3′-trans, J = 1.7, 16.7 Hz), 5.00 (dd, 1H, H-3′-cis, J = 1.7, 9.2
Hz), 4.89 (s, 2H, MOM-CH2), 4.73 (br s, 1H, NH), 4.22 (s, 2H,
SiMB-CH2), 3.81 (s, 3H, OMe), 3.76 (s, 3H, OMe), 3.52 (s, 3H,
OMe), 3.50 (s, 3H, OMe), 3.42 (d, 2H, H-1′, J = 6.3 Hz), 1.00 (s, 9H,
tBu), 0.22 (s, 6H, Me × 2); 13C NMR (125 MHz, CDCl3) δ 158.3,
156.0, 147.6, 138.9, 138.8, 137.9, 137.6, 129.7, 127.2, 120.3, 114.8,
111.4, 103.4, 99.8, 99.7, 95.8, 61.2, 57.3, 56.1, 55.3, 43.0, 29.3, 25.7,
18.3, −4.3; ESIMS-LR m/z = 556 [(M + Na)+]; ESIMS-HR calcd for
C28H43O7NNaSi 556.2706, found 556.2707.
N-(3-Allyl-4-methoxy-2,5-dimethoxymethoxyphenyl)-N-(4-
tert-butyldimethylsiloxy-2-methoxybenzyl)bromoacetamide.
A solution of N-(4-tert-butyldimethylsiloxy-2-methoxybenzyl)-3-allyl-
4-methoxy-2,5-dimethoxymethoxyaniline (2.0 g, 3.7 mmol) in CH2Cl2
(20 mL) was treated with bromoacetyl chloride (0.37 mL, 4.5 mmol)
and Et3N (1.3 mL, 8.9 mmol) at 0 °C, and the mixture was stirred at
room temperature for 20 min. The reaction was quenched with H2O
(10 mL), and the mixture was extracted with AcOEt (80 mL). The
organic layers were washed with 0.1 N aqueous HCl (40 mL),
saturated aqueous NaHCO3 (40 mL), and brine (40 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified by silica
gel column chromatography (2 × 15 cm, hexane/AcOEt = 5/1) to
give the titled compound (2.3 g, 95%) as a white solid: 1H NMR (500
MHz, CDCl3) δ 7.03 (d, 1H, SiMB-6, J = 8.0 Hz), 6.58 (s, 1H, H-6),
6.27 (dd, 1H, SiMB-5, J = 2.3, 8.0 Hz), 6.19 (d, 1H, SiMB-3, J = 2.3
major rotamer; δ 7.99 (s, 1H, H-2), 7.69 (s, 1H, H-8), 7.36−7.22 (m,
15H, Tr), 7.15 (d, 1H, SiMB-6, J = 8.6 Hz), 7.06 (dd, 1H, H-5′, J = 5.1,
15.4 Hz), 6.93 (br s, 1H, NHTr), 6.38 (s, 1H, H-6″), 6.32 (dd, 1H,
SiMB-5, J = 2.3, 8.6 Hz), 6.28 (dd, 1H, H-6′, J = 1.7, 15.4 Hz), 6.19 (d,
1H, SiMB-3, J = 2.3 Hz), 6.01 (d, 1H, H-1′, J = 5.1 Hz), 5.97 (m, 1H,
H-8′), 5.85 (m, 1H, H-11′), 5.50 (d, 1H, SiMB-CH2, J = 14.3 Hz), 5.25
9287
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Article
(dd, 1H, H-12′-trans, J = 1.2, 17.2 Hz), 5.17 (dd, 1H, H-12′-cis, J = 1.2,
10.3 Hz), 5.00 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.95 (m, 2H, H-9′),
4.90 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.84 (d, 1H, MOM-CH2, J = 5.9
Hz), 4.81 (d, 1H, MOM-CH2, J = 5.9 Hz), 4.70 (dt, 1H, H-4′, J = 1.7,
4.6 Hz), 4.60 (t, 1H, H-2′, J = 4.6 Hz), 4.42 (d, 1H, SiMB-CH2, J =
14.3 Hz), 4.14 (dd, 1H, H-10′a, J = 5.7, 12.6 Hz), 4.01 (dd, 1H, H-
10′b, J = 5.7, 12.6 Hz), 3.86 (t, 1, H-3′, J = 4.6 Hz), 3.66 (s, 3H, OMe),
3.50 (s, 3H, OMe), 3.49 (s, 3H, OMe), 3.45 (m, 2H, H-7′), 3.20 (s,
3H, OMe), 0.95 (s, 9H, tBu), 0.77 (s, 9H, tBu), 0.16 (s, 3H, Me), 0.15
(s, 3H, Me), −0.01 (s, 3H, Me), −0.16 (s, 3H, Me); 13C NMR (125
MHz, CDCl3, 20 °C, 4:3 mixture of rotamers, observed peaks were
described) δ 165.2, 158.6, 156.4, 154.2, 152.5, 149.0, 148.7, 148.5,
147.3, 147.2, 146.6, 146.5, 145.2, 145.1, 140.8, 138.4, 138.0, 136.9,
134.1, 134.0, 131.8, 131.7, 130.3, 130.2, 129.1, 128.7, 128.5, 128.0,
127.0, 124.3, 123.2, 121.7, 121.3, 118.2, 117.7, 116.8, 115.2, 111.5,
103.0, 99.9, 99.8, 95.6, 95.3, 89.9, 88.1, 81.8, 81.5, 80.9, 74.4, 74.3,
71.8, 71.5, 71.4, 61.1, 60.9, 57.4, 56.2, 56.0, 55.1, 45.8, 29.6, 29.3, 25.8,
25.7, 25.6, 18.3, 18.1, 18.0, −4.3, −4.8, −4.9, −5.0, −5.1; ESIMS-LR
m/z = 1242 [(M + Na)+]; ESIMS-HR calcd for C68H86O11N6NaSi2
1241.5791, found 1241.5792.
Cyclophanes 43a. A mixture of 41a (530 mg, 0.43 mmol) and
Grubbs' first catalyst (1.7 mg, 2.1 μmol) in CH2Cl2 (4.3 mL) was
refluxed for 5 h. The solvent was removed in vacuo, and the residue
was purified by flash silica gel column chromatography (2 × 20 cm,
hexane/AcOEt = 3/1) to give (+)-trans-43a (131 mg, 25%) as a white
foam and a mixture of (−)-trans-43a and cis-43. The mixture was
further purified by flash silica gel column chromatography (2 × 20 cm,
hexane/CHCl3/MeOH = 2/3/0.01) to give (−)-trans-43a (214 mg,
42%) as a white foam and cis-43a (155 mg, 31%) as a white foam
−0.10 (s, 3H, Me), −0.38 (s, 3H, Me); 13C NMR (125 MHz, CDCl3)
δ 166.3, 158.6, 156.6, 154.3, 152.5, 149.0, 148.1, 147.0, 145.2, 141.4,
138.9, 135.1, 131.8, 131.7, 129.1, 128.8, 128.0, 127.1, 127.0, 123.8,
121.8, 118.5, 114.0, 112.0, 103.5, 99.8, 95.7, 88.5, 84.1, 79.2, 74.5, 71.6,
71.0, 61.6, 57.4, 56.4, 55.3, 46.7, 26.3, 25.8, 25.6, 18.3, 18.0, −4.3, −4.9,
−5.4; ESIMS-LR m/z = 1213 [(M + Na)+]; ESIMS-HR calcd for
C66H82O11N6NaSi2 1213.5478, found 1213.5486. Data for cis-43a: Rf =
0.55 (hexane/AcOEt = 2/1 × 2) or 0.85 (5% MeOH in CHCl3 × 2);
[α]22D −95.5 (c 1.35, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.98 (s,
1H, H-2), 7.91 (s, 1H, H-8), 7.38−7.24 (m, 16H, Tr and SiMB-6),
6.97 (dd, 1H, H-5′, J = 6.8, 15.8 Hz), 6.96 (br s, 1H, NHTr), 6.68 (s,
1H, H-6″), 6.40 (dd, 1H, SiMB-5, J = 2.3, 8.2 Hz), 6.29 (d, 1H, SiMB-
3, J = 2.3 Hz), 6.11 (dd, 1H, H-6′, J = 1.4, 15.8 Hz), 6.10 (m, 1H, H-
8′), 5.79 (s, 1H, H-1′), 5.55 (dt, 1H, H-9′, J = 4.6, 10.4 Hz), 5.23 (d,
1H, SiMB-CH2, J = 14.5 Hz), 4.98 (d, 1H, MOM-CH2, J = 6.4 Hz),
4.94 (d, 1H, MOM-CH2, J = 6.4 Hz), 4.88 (d, 1H, H-2′, J = 5.0 Hz),
4.58 (t, 1H, H-4′, J = 6.8 Hz), 4.53 (d, 1H, SiMB-CH2, J = 14.5 Hz),
4.51 (d, 1H, MOM-CH2, J = 5.9 Hz), 4.45 (d, 1H, MOM-CH2, J = 5.9
Hz), 4.42 (t, 1H, H-10′a, J = 10.0 Hz), 4.00 (dd, 1H, H-3′, J = 5.0, 8.6
Hz), 3.92 (s, 3H, OMe), 3.79 (dd, 1H, H-10′b, J = 4.6, 9.9 Hz), 3.59
(m, 1H, H-7′a), 3.58 (s, 3H, OMe), 3.44 (s, 3H, OMe), 3.43 (s, 3H,
t
OMe), 3.06 (dd, 1H, H-7′b, J = 7.7, 12.7 Hz), 0.98 (s, 9H, Bu), 0.89
t
(s, 9H, Bu), 0.19 (s, 3H, Me), 0.18 (s, 3H, Me), 0.10 (s, 3H, Me),
0.09 (s, 3H, Me); 13C NMR (125 MHz, CDCl3) δ 167.0, 158.6, 156.6,
154.2, 152.3, 148.2, 147.9, 146.8, 145.2, 145.1, 141.2, 138.6, 131.8,
131.6, 131.4, 129.6, 129.1, 128.0, 127.2, 127.0, 125.0, 121.9, 118.7,
113.7, 111.9, 103.4, 100.3, 95.5, 92.3, 82.1, 81.2, 73.8, 71.5, 67.1, 61.0,
58.0, 56.4, 55.2, 47.0, 25.9, 25.8, 23.2, 18.3, 18.2, −4.3, −4.6, −4.7;
ESIMS-LR m/z = 1213 [(M + Na)+]; ESIMS-HR calcd for
C66H82O11N6NaSi2 1213.5478, found 1213.5488.
(total 98% yield, trans/cis = 2.2:1). Data for (+)-trans-43a: Rf = 0.65
1
(hexane/AcOEt = 2/1 × 2); [α]21 +54.4 (c 1.08, CHCl3); H NMR
Cyclophane (+)-trans-44a. A solution of (+)-trans-43a (19 mg,
0.016 mmol) in THF (0.5 mL) was treated with TBAF (1.0 M
solution in THF, 48 μL, 0.048 mmol) at room temperature for 10 min.
The solvent was removed in vacuo, and the residue was purified by
silica gel column chromatography (0.5 × 10 cm, 2% MeOH in CHCl3)
D
(500 MHz, CDCl3) δ 7.85 (s, 1H, H-2), 7.51 (s, 1H, H-8), 7.32−7.22
(m, 16H, Tr and SiMB-6), 6.86 (br s, 1H, NHTr), 6.76 (dd, 1H, H-5′,
J = 4.6, 15.4 Hz), 6.67 (s, 1H, H-6″), 6.39 (dd, 1H, SiMB-5, J = 2.3, 8.0
Hz), 6.30 (d, 1H, SiMB-3, J = 2.3 Hz), 6.08 (dd, 1H, H-6′, J = 1.1, 15.4
Hz), 5.77 (d, 1H, H-1′, J = 2.3 Hz), 5.71 (ddd, 1H, H-8′, J = 4.6, 8.0,
14.9 Hz), 5.47 (ddd, 1H, H-9′, J = 6.9, 8.0, 14.9 Hz), 5.24 (d, 1H,
SiMB-CH2, J = 14.3 Hz), 4.95 (d, 1H, MOM-CH2, J = 6.8 Hz), 4.79
(d, 1H, MOM-CH2, J = 6.8 Hz), 4.67 (d, 1H, MOM-CH2, J = 5.8 Hz),
4.65 (d, 1H, MOM-CH2, J = 5.8 Hz), 4.58 (ddd, 1H, H-4′, J = 1.1, 4.6,
8.0 Hz), 4.53 (d, 1H, SiMB-CH2, J = 14.3 Hz), 4.50 (dd, 1H, H-2′, J =
2.3, 4.6 Hz), 4.13 (dd, 1H, H-10′a, J = 6.9, 13.2 Hz), 3.89 (dd, 1H, H-
3′, J = 4.6, 8.0 Hz), 3.78 (s, 3H, OMe), 3.61 (s, 3H, OMe), 3.55 (dd,
1H, H-10′b, J = 8.0, 13.2 Hz), 3.48 (s, 3H, OMe), 3.47 (dd, 1H, H-7′a,
J = 4.6, 13.8 Hz), 3.33 (dd, 1H, H-7′b, J = 8.0, 13.8 Hz), 3.30 (s, 3H,
to give (+)-trans-44a (15 mg, 97%) as a white solid: [α]21 +55.5 (c
D
1.11, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.74 (s, 1H, H-2), 7.73
(s, 1H, H-8), 7.65 (br s, 1H, HMB-4-OH), 7.33−7.21 (m, 15H, Tr),
7.16 (d, 1H, HMB-6, J = 8.0 Hz), 7.13 (br s, 1H, NHTr), 6.67 (s, 1H,
H-6″), 6.65 (dd, 1H, H-5′, J = 5.2, 16.0 Hz), 6.32 (dd, 1H, HMB-5, J =
2.3, 8.0 Hz), 6.26 (d, 1H, HMB-3, J = 2.3 Hz), 6.12 (dd, 1H, H-6′, J =
1.1, 16.0 Hz), 5.80 (d, 1H, H-1′, J = 3.4 Hz), 5.79 (ddd, 1H, H-8′, J =
5.2, 8.0, 15.5 Hz), 5.53 (ddd, 1H, H-9′, J = 6.3, 8.0, 15.5 Hz), 5.23 (d,
1H, HMB-CH2, J = 14.3 Hz), 4.84 (d, 1H, MOM-CH2, J = 6.9 Hz),
4.72 (d, 1H, MOM-CH2, J = 6.9 Hz), 4.68 (d, 1H, MOM-CH2, J = 5.7
Hz), 4.65 (d, 1H, MOM-CH2, J = 5.7 Hz), 4.52 (d, 1H, HMB-CH2,
J = 14.3 Hz), 4.47 (t, 1H, H-4′, J = 5.8 Hz), 4.40 (br s, 1H, H-2′), 4.24
(t, 1H, H-3′, J = 6.3 Hz), 4.22 (dd, 1H, H-10′a, J = 6.3, 12.6 Hz), 3.98
(br s, 1H, 2′−OH), 3.80 (s, 3H, OMe), 3.70 (dd, 1H, H-10′b, J = 8.0,
12.6 Hz), 3.57 (s, 3H, OMe), 3.48 (s, 3H, OMe), 3.46 (m, 1H, H-7′a),
3.34 (dd, 1H, H-7′b, J = 8.0, 13.1 Hz), 3.26 (s, 3H, OMe); 13C NMR
(125 MHz, CDCl3) δ 167.2, 158.7, 157.4, 154.1, 152.2, 148.1, 147.3,
146.9, 146.4, 144.9, 138.6, 136.3, 135.9, 132.1, 131.7, 129.2, 129.1,
127.9, 127.0, 125.9, 125.5, 121.2, 116.9, 113.3, 107.4, 100.1, 99.0, 95.5,
90.6, 80.3, 75.3, 73.4, 71.4, 70.2, 61.5, 57.8, 56.3, 55.3, 47.1, 27.4, 25.8;
ESIMS-LR m/z = 985 [(M + Na)+]; ESIMS-HR calcd for
C54H54O11N6Na 985.3748, found 985.3738.
t
t
OMe), 0.98 (s, 9H, Bu), 0.86 (s, 9H, Bu), 0.19 (s, 3H, Me), 0.18 (s,
3H, Me), 0.01 (s, 3H, Me), −0.09 (s, 3H, Me); 13C NMR (125 MHz,
CDCl3) δ 167.1, 158.5, 156.5, 154.1, 152.4, 148.3, 147.2, 147.0, 146.8,
145.1, 138.4, 136.8, 134.9, 132.1, 131.8, 129.1, 128.0, 127.0, 126.0,
125.2, 121.7, 118.5, 113.7, 111.9, 103.4, 100.0, 95.7, 90.5, 79.4, 76.1,
73.7, 71.4, 69.8, 61.5, 57.8, 56.3, 55.3, 46.8, 29.8, 27.3, 25.8, 25.7, 18.3,
18.1, −4.3, −4.7, −4.8; ESIMS-LR m/z = 1213 [(M + Na)+]; ESIMS-
HR calcd for C66H82O11N6NaSi2 1213.5478, found 1213.5452. Data
for (−)-trans-43a: Rf = 0.55 (hexane/AcOEt = 2/1 × 2) or 0.80 (5%
1
MeOH in CHCl3 × 2); [α]22 −118.8 (c 0.80, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 8.03 (s, 1H, H-2), 7.83 (s, 1H, H-8), 7.35−7.22
(m, 16H, Tr and SiMB-6), 7.07 (dd, 1H, H-5′, J = 6.4, 15.9 Hz), 6.90
(br s, 1H, NHTr), 6.71 (s, 1H, H-6″), 6.40 (dd, 1H, SiMB-5, J = 2.2,
8.1 Hz), 6.30 (d, 1H, SiMB-3, J = 2.2 Hz), 5.96 (dd, 1H, H-8′, J = 5.0,
15.8 Hz), 5.85 (d, 1H, H-1′, J = 6.8 Hz), 5.84 (dd, 1H, H-6′, J = 1.8,
15.9 Hz), 5.26 (d, 1H, SiMB-CH2, J = 14.5 Hz), 5.01 (d, 1H, MOM-
CH2, J = 6.3 Hz), 4.96 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.86 (br t, 1H,
H-9′, J = 12.6 Hz), 4.80 (t, 1H, H-2′, J = 6.4 Hz), 4.60 (d, 1H, MOM-
CH2, J = 5.9 Hz), 4.55 (ddd, 1H, H-4′, J = 1.8, 2.9, 6.4 Hz), 4.54 (d,
1H, SiMB-CH2, J = 14.5 Hz), 4.52 (d, 1H, MOM-CH2, J = 5.9 Hz),
4.29 (br d, 1H, H-10′a, J = 13.2 Hz), 3.95 (dd, 1H, H-10′b, J = 10.0,
13.2 Hz), 3.92 (dd, 1H, H-3′, J = 2.9, 5.1 Hz), 3.82 (s, 3H, OMe), 3.60
(s, 3H, OMe), 3.55 (dd, 1H, H-7′a, J = 2.2, 16.3 Hz), 3.45 (s, 3H,
OMe), 3.40 (s, 3H, OMe), 3.26 (dd, 1H, H-7′b, J = 6.4, 16.3 Hz), 0.97
Cyclophane (+)-trans-45a. A mixture of (+)-trans-44a (5.0 mg,
5.2 μmol) and CsF (3.2 mg, 0.021 mmol) in 1,4-dioxane−H2O (3/1
(v/v), 1 mL) was refluxed for 16 h. The mixture was extracted with
CHCl3 (20 mL), and the organic layer was washed with brine (10
mL), dried (Na2SO4), filtered, and concentrated. The residue was
purified by preparative TLC (5% MeOH in CHCl3) to give (+)-trans-
45a (3.9 mg, 91%) as a white solid: [α]21D +51.3 (c 1.60, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.71 (s, 1H, H-2), 7.70 (s, 1H, H-8),
7.33−7.22 (m, 15H, Tr), 6.92 (br s, 1H, CONH), 6.85 (br s, 1H,
NHTr), 6.79 (s, 1H, H-6″), 6.58 (dd, 1H, H-5′, J = 5.1, 16.0 Hz), 6.11
(dd, 1H, H-6′, J = 1.1, 16.0 Hz), 5.84 (ddd, 1H, H-8′, J = 3.4, 8.6, 14.9
Hz), 5.81 (d, 1H, H-1′, J = 2.3 Hz), 5.56 (ddd, 1H, H-9′, J = 6.3, 8.1,
14.9 Hz), 5.03 (d, 1H, 5″-MOM-CH2, J = 6.9 Hz), 4.93 (d, 1H,
t
t
(s, 9H, Bu), 0.75 (s, 9H, Bu), 0.19 (s, 3H, Me), 0.18 (s, 3H, Me),
9288
dx.doi.org/10.1021/jo201495w|J. Org. Chem. 2011, 76, 9278−9293

The Journal of Organic Chemistry
Article
2″-MOM-CH2, J = 6.3 Hz), 4.89 (d, 1H, 2″-MOM-CH2, J = 6.3 Hz), 4.87
(d, 1H, 5″-MOM-CH2, J = 6.9 Hz), 4.48 (m, 1H, H-4′), 4.45 (m, 2H,
H-2′ and 2′-OH), 4.25 (dd, 1H, H-10′a, J = 6.3, 12.6 Hz), 3.82 (s, 3H,
4″-OMe), 3.77 (d, 1H, H-3′, J = 2.9 Hz), 3.71 (dd, 1H, H-10′b, J = 8.1,
12.6 Hz), 3.54 (s, 3H, 2″-MOM-OMe), 3.52 (dd, 1H, H-7′a, J = 3.4,
14.3 Hz), 3.37 (s, 3H, 5″-MOM-OMe), 3.35 (dd, 1H, H-7″b, J = 8.6,
14.3 Hz); 13C NMR (125 MHz, CDCl3) δ 167.8, 154.2, 152.1, 148.0,
147.6, 146.9, 146.0, 145.0, 139.0, 137.7, 135.5, 129.7, 129.1, 128.0,
127.0, 126.5, 125.7, 124.0, 121.6, 112.6, 99.8, 95.3, 90.7, 81.0, 75.9,
73.4, 71.4, 70.4, 61.5, 58.2, 56.5, 27.2; ESIMS-LR m/z = 849 [(M +
Na)+]; ESIMS-HR calcd for C46H46O9N6Na 849.3224, found
849.3209.
H-8′, J = 9.2 Hz), 6.08 (dd, 1H, H-6′, J = 1.1, 16.0 Hz), 5.90 (d, 1H, H-
1′, J = 1.2 Hz), 5.57 (dt, 1H, H-9′, J = 4.0, 10.3 Hz), 5.17 (d, 1H,
MOM-CH2, J = 6.8 Hz), 5.15 (d, 1H, MOM-CH2, J = 6.8 Hz), 4.85
(d, 1H, MOM-CH2, J = 5.8 Hz), 4.82 (d, 1H, MOM-CH2, J = 5.8 Hz),
4.70 (d, 1H, H-2′, J = 5.1 Hz), 4.66 (br t, 1H, H-10′a, J = 10.3 Hz),
4.56 (dd, 1H, H-3′, J = 5.1, 8.1 Hz), 4.46 (t, 1H, H-4′, J = 6.3 Hz), 3.94
(s, 3H, OMe), 3.93 (overlapping, 1H, H-10′b), 3.67 (dd, 1H, H-7′a, J =
9.2, 13.8 Hz), 3.54 (s, 3H, OMe), 3.52 (s, 3H, OMe), 3.27 (br s, 1H,
2′−OH), 3.14 (dd, 1H, H-7′b, J = 7.5, 13.8 Hz); 13C NMR (125 MHz,
CDCl3) δ 167.7, 154.3, 152.3, 148.1, 148.0, 147.2, 145.0, 144.7, 142.3,
139.2, 132.5, 130.0, 129.1, 128.1, 127.1, 126.2, 125.9, 122.9, 121.8,
113.3, 100.2, 95.5, 91.6, 82.2, 81.4, 72.7, 71.6, 67.4, 61.1, 58.5, 56.6,
23.0; ESIMS-LR m/z = 849 [(M + Na)+]; ESIMS-HR calcd for
C46H46O9N6Na 849.3224, found 849.3221.
cis-4. A solution of cis-45a (9.0 mg, 0.010 mmol) in CH2Cl2 (0.5
mL) was treated with Et3SiH (16 mL, 0.10 mmol) and TFA (0.6 mL)
at 0 °C, and the mixture was stirred at room temperature for 3 h. The
mixture was concentrated in vacuo to give a crude hydroquinone. A
mixture of the crude hydroquinone and Pd/C (20 mg) in MeOH (1
mL) was vigorously stirred under air at room temperature for 30 min.
The insolubles were filtered off through a Celite pad and washed with
hot MeOH. The filtrate was concentrated, and the residue was purified
by flash silica gel column chromatography (0.5 × 6 cm, 6% MeOH in
CHCl3) to give cis-4 (4.1 mg, 83% over two steps) as a yellow solid:
1H NMR (500 MHz, DMSO-d6) δ 10.10 (br s, 1H, CONH), 8.34 (s,
1H, H-2), 8.16 (s, 1H, H-8), 7.33 (br s, 2H, 6-NH2), 6.62 (dd, 1H, H-
5′, J = 6.3, 15.5 Hz), 6.21 (s, 1H, H-6″), 5.89 (d, 1H, H-1′, J = 2.3 Hz),
5.82 (d, 1H, H-6′, J = 15.5 Hz), 5.77 (dt, 1H, H-8′, J = 6.9, 10.3 Hz),
5.65 (dt, 1H, H-9′, J = 5.1, 10.3 Hz), 5.54 (d, 1H, 2′−OH, J = 5.2 Hz),
4.66 (dt, 1H, H-2′, J = 2.3, 5.2 Hz), 4.39 (t, 1H, H-4′, J = 6.9 Hz), 4.22
(t, 1H, H-10′a, J = 9.7 Hz), 4.06 (t, 1H, H-3′, J = 5.2 Hz), 4.04 (s, 3H,
OMe), 3.95 (dd, 1H, H-10′b, J = 5.1, 10.3 Hz), 3.51 (br t, 1H, H-7′a,
J = 10.9 Hz), 2.83 (dd, 1H, H-7′b, J = 6.3, 12.6 Hz); 13C NMR (125
MHz, DMSO-d6) δ 182.9, 182.7, 166.6, 155.3, 152.8, 148.4, 142.2,
141.2, 128.8, 127.5, 127.4, 119.2, 119.1, 117.6, 115.2, 90.0, 81.6, 80.3,
71.8, 65.3, 61.2, 20.3; ESIMS-LR m/z = 517 [(M + Na)+]; ESIMS-HR
calcd for C23H22O7N6Na 517.1448, found 517.1443.
trans-4. A solution of (+)-trans-45a (100 mg, 0.12 mmol) in
CH2Cl2 (0.6 mL) was treated with Et3SiH (0.19 mL, 1.2 mmol) and
TFA (1.4 mL) at 0 °C, and the mixture was stirred at room
temperature for 2 h. The mixture was concentrated to give a crude
hydroquinone. A mixture of the crude hydroquinone and Pd/C (60
mg) in MeOH (3 mL) was stirred at room temperature for 1 h. The
insolubles were filtered off through a Celite pad and washed with hot
MeOH. The filtrate was concentrated, and the residue was purified by
silica gel column chromatography (1 × 7 cm, 6% MeOH in CHCl3) to
1
give trans-4 (49 mg, 84% over two steps) as a yellow solid: H NMR
(500 MHz, DMSO-d6, 80 °C) δ 9.85 (s, 1H, CONH), 8.22 (s, 1H, H-
2), 8.13 (s, 1H, H-8), 6.98 (br s, 2H, 6-NH2), 6.50 (m, 1H, H-5′), 6.26
(s, 1H, H-6″), 5.88 (m, 1H, H-6′), 5.84 (d, 1H, H-1′, J = 5.1 Hz), 5.82
(m, 1H, H-8′), 5.54 (m, 1H, H-9′, J = 14.3 Hz), 5.27 (d, 1H, 2′−OH,
J = 5.8 Hz), 4.80 (m, 1H, H-2′), 4.45 (br s, 1H, H-4′), 4.20 (dd, 1H, H-
10′a, J = 4.0, 12.6 Hz), 4.07 (m, 1H, H-3′), 4.00 (s, 3H, OMe), 3.91
(dd, 1H, H-10′b, J = 9.1, 12.6 Hz), 3.25 (br d, 1H, H-7′a, J = 14.9 Hz),
3.16 (dd, 1H, H-7′b, J = 6.3, 12.6 Hz); 13C NMR (125 MHz, DMSO-
d6, 80 °C) δ 183.2, 182.3, 166.2, 154.9, 154.6, 150.6, 148.9, 143.0,
140.0, 132.0, 128.1, 127.3, 119.0, 87.8, 80.9, 76.8, 71.7, 68.8, 60.8, 24.7;
ESIMS-LR m/z = 517 [(M + Na)+]; ESIMS-HR calcd for
C23H22O7N6Na 517.1448, found 517.1442.
cis-44a. A solution of cis-43a (27 mg, 0.022 mmol) in THF (1
mL) was treated with TBAF (1.0 M solution in THF, 66 μL, 0.066
mmol) at room temperature for 30 min. The solvent was removed in
vacuo, and the residue was purified by silica gel column
6-Amino-9-[3-deoxy-3-C-allyl-2,5-O-bis(tert-butyldimethyl-
silyl)-β-D-pentofuranosyl]-9H-purine (49). A mixture of 4723 (3.7
g, 7.4 mmol) and DMAP (3.6 g, 30 mmol) in CH2Cl2 (50 mL) was
treated with phenyl chlorothionoformate (1.2 mL, 8.2 mmol) at 0 °C
for 2 h. The mixture was stirred at room temperature for 14 h. The
reaction was quenched with saturated aqueous NaHCO3 (30 mL) at
0 °C, and the mixture was vigorously stirred for 15 min. The mixture
was extracted with AcOEt (300 mL), and the organic layers were
washed with H2O (100 mL), 0.1 N aqueous HCl (150 mL × 3),
saturated aqueous NaHCO3 (200 mL), and brine (200 mL), dried
(Na2SO4), filtered, and concentrated to give crude phenoxy
thionocarbonate 48.17 A mixture of 48, allyl tributyltin (9.2 mL, 30
mmol), and AIBN (0.60 g, 3.7 mmol) in chlorobenzene (14 mL) was
refluxed for 1 h. The mixture was cooled to room temperature and
directly purified by flash silica gel column chromatography (3 × 25 cm,
chromatography (1 × 10 cm, 2% MeOH in CHCl3) to give cis-44a
1
(20 mg, 95%) as a white solid: [α]22 −107.3 (c 0.87, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.98 (s, 1H, H-2), 7.89 (s, 1H, H-8), 7.50
(br s, 1H, HMB-4-OH), 7.35−7.22 (m, 15H, Tr), 7.18 (d, 1H, HMB-
6, J = 8.0 Hz), 7.13 (br s, 1H, NHTr), 6.91 (dd, 1H, H-5′, J = 6.8, 16.0
Hz), 6.68 (s, 1H, H-6″), 6.32 (dd, 1H, HMB-5, J = 2.3, 8.0 Hz), 6.26
(d, 1H, HMB-3, J = 2.3 Hz), 6.17 (dt, 1H, H-8′, J = 8.0, 10.3 Hz), 6.02
(d, 1H, H-6′, J = 16.0 Hz), 5.89 (d, 1H, H-1′, J = 1.2 Hz), 5.55 (dt, 1H,
H-9′, J = 4.6, 10.3 Hz), 5.23 (d, 1H, HMB-CH2, J = 14.3 Hz), 4.97 (d,
1H, MOM-CH2, J = 6.3 Hz), 4.92 (d, 1H, MOM-CH2, J = 6.3 Hz),
4.67 (d, 1H, H-2′, J = 4.0 Hz), 4.59 (d, 1H, MOM-CH2, J = 5.8 Hz),
4.53 (t, 1H, H-10′a, J = 10.3 Hz), 4.51 (d, 1H, MOM-CH2, J = 5.8
Hz), 4.46 (d, 1H, HMB-CH2, J = 14.3 Hz), 4.39 (m, 2H, H-3′ and H-
4′), 3.91 (s, 3H, OMe), 3.90 (m, 1H, H-10′b), 3.60 (dd, 1H, H-7′a, J =
8.0, 13.2 Hz), 3.54 (s, 3H, OMe), 3.45 (s, 3H, OMe), 3.41 (s, 3H,
OMe), 3.07 (dd, 1H, H-7′b, J = 7.5, 13.2 Hz); 13C NMR (125 MHz,
CDCl3) δ 167.1, 158.8, 157.5, 154.2, 152.3, 148.1, 146.9, 145.2, 144.9,
140.5, 138.8, 132.4, 132.0, 131.2, 129.4, 129.1, 128.0, 127.0, 126.5,
125.3, 121.5, 117.0, 114.0, 107.4, 100.5, 99.1, 95.6, 91.4, 81.9, 81.8,
72.9, 71.5, 67.5, 61.0, 58.0, 56.4, 55.2, 47.3, 23.2; ESIMS-LR m/z =
985 [(M + Na)+]; ESIMS-HR calcd for C54H54O11N6Na 985.3748,
found 985.3741.
hexane/AcOEt = 1:1) to give 49 (2.7 g, 71% over two steps) as a white
1
solid: [α]20 −5.8 (c 1.15, CHCl3); H NMR (500 MHz, CDCl3) δ
D
8.42 (s, 1H, H-2), 8.33 (s, 1H, H-8), 6.00 (s, 1H, H-1′), 5.73 (m, 1H,
H-2″), 5.70 (br s, 2H, 6-NH2), 5.06 (dd, 1H, H-3″-trans, J = 1.1, 15.5
Hz), 4.99 (dd, 1H, H-3″-cis, J = 1.1, 10.3 Hz), 4.50 (d, 1H, H-2′, J = 3.4
Hz), 4.13 (m, 2H, H-4′and H-5′a), 3.77 (dd, 1H, H-5′b, J = 2.3, 11.4
Hz), 2.39 (m, 2H, H-3′and H-1″a), 2.07 (m, 1H, H-1″b), 0.95 (s, 9H,
t
tBu), 0.94 (s, 9H, Bu), 0.29 (s, 3H, Me), 0.15 (s, 3H, Me), 0.13 (s,
3H, Me), 0.12 (s, 3H, Me); 13C NMR (125 MHz, CDCl3) δ 155.3,
152.8, 149.5, 139.4, 136.0, 120.2, 116.6, 90.8, 85.1, 78.1, 62.5, 40.6,
29.1, 26.2, 26.0, 18.7, 18.2, −4.0, −5.1, −5.3; FABMS-LR m/z = 520
[(M + Na)+]. Anal. Calcd for C25H45N5O3Si2: C, 57.76; H, 8.73; N,
13.47. Found: C, 57.51; H, 8.62; N, 13.23.
cis-45a. A mixture of cis-44a (8.0 mg, 8.6 μmol) and CsF (15 mg,
0.086 mmol) in 1,4-dioxane−H2O (3/1 (v/v), 1 mL) was refluxed for
21 h. The mixture was extracted with CHCl3 (20 mL), and the organic
layer was washed with brine (10 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by silica gel column
chromatography (0.5 × 5 cm, 3% MeOH in CHCl3) to give cis-45a
6-Amino-9-[3-deoxy-3-C-allyl-2,5-O-bis(tert-butyldimethyl-
silyl)-β-D-pentofuranosyl]-N6-trityl-9H-purine. A solution of 49
(1.0 g, 1.9 mmol) and Et3N (0.80 mL, 5.8 mmol) in CH2Cl2 (10 mL)
was treated with TrCl (800 mg, 2.9 mmol) at room temperature for 40 h.
The reaction was quenched with H2O (20 mL), and the mixture was
1
(6.5 mg, 91%) as a white solid: [α]22 −104.6 (c 0.92, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.99 (s, 1H, H-2), 7.84 (s, 1H, H-8),
7.36−7.22 (m, 15H, Tr), 6.99 (dd, 1H, H-5′, J = 6.3, 16.0 Hz), 6.98 (s,
1H, NHTr), 6.94 (br s, 1H, CONH), 6.88 (s, 1H, H-6″), 6.17 (q, 1H,
9289
dx.doi.org/10.1021/jo201495w|J. Org. Chem. 2011, 76, 9278−9293

The Journal of Organic Chemistry
Article
extracted with AcOEt (100 mL). The organic layers were washed with
brine (50 mL), dried (Na2SO4), filtered, and concentrated. The
residue was purified by silica gel column chromatography (2 × 12 cm,
hexane/AcOEt = 9/1) to give the titled compound (1.2 g, 83%) as a
2.3 Hz), 6.21 (d, 0.5H, SiMB-3, J = 2.3 Hz), 6.17 (d, 0.5H, H-6′, J =
17.2 Hz), 5.97 (m, 1H, H-8′), 5.91 (s, 0.5H, H-1′), 5.89 (s, 0.5H, H-
1′), 5.67 (m, 1H, H-11′), 5.51 (d, 0.5H, SiMB-CH2, J = 14.3 Hz), 5.47
(d, 0.5H, SiMB-CH2, J = 14.3 Hz), 5.06−4.87 (m, 7H, H-9′, H-12′ and
MOM-CH2), 4.83 (d, 0.5H, MOM-CH2, J = 5.7 Hz), 4.81 (d, 0.5H,
MOM-CH2, J = 5.7 Hz), 4.67 (d, 0.5H, H-2′, J = 4.0 Hz), 4.59 (d,
0.5H, H-2′, J = 3.4 Hz), 4.52 (dd, 0.5H, H-4′, J = 5.7, 8.5 Hz), 4.47
(overlapping, 0.5H, H-4′), 4.45 (d, 0.5H, SiMB-CH2, J = 14.3 Hz),
4.44 (d, 0.5H, SiMB-CH2, J = 14.3 Hz), 3.79 (s, 1.5H, OMe), 3.75 (s,
1.5H, OMe), 3.53 (s, 1.5H, OMe), 3.52 (s, 1.5H, OMe), 3.51 (s, 1.5H,
OMe), 3.49 (s, 1.5H, OMe), 3.45 (m, 2H, H-7′), 3.33 (s, 1.5H, OMe),
3.30 (s, 1.5H, OMe), 2.30 (m, 1H, H-10′a), 2.09 (m, 2H, H-3′ and H-
10′b), 0.97 (s, 4.5H, tBu), 0.96 (s, 4.5H, tBu), 0.91 (s, 4.5H, tBu), 0.90
white foam: [α]20 −16.8 (c 0.94, CHCl3); 1H NMR (500 MHz,
D
CDCl3) δ 8.35 (s, 1H, H-2), 8.01 (s, 1H, H-8), 7.40−7.20 (m,
15H,Tr), 6.96 (br s, 1H, NHTr), 5.96 (s, 1H, H-1′), 5.75 (m, 1H, H-
2″), 5.09 (dd, 1H, H-3″-trans, J = 1.2, 16.7 Hz), 5.02 (dd, 1H, H-3″-cis,
J = 1.2, 10.3 Hz), 4.55 (d, 1H, H-2′, J = 2.9 Hz), 4.14 (m, 2H, H-4′ and
H-5′a), 3.79 (dd, 1H, H-5′b, J = 2.3, 11.5 Hz), 2.43 (m, 2H, H-3′ and
H-1″a), 2.11 (dt, 1H, H-1″b, J = 8.0, 9.2 Hz), 0.97 (s, 9H, tBu), 0.93 (s,
t
9H, Bu), 0.25 (s, 3H, Me), 0.17 (s, 3H, Me), 0.15 (s, 3H, Me), 0.11
(s, 3H, Me); 13C NMR (125 MHz, CDCl3) δ 154.0, 152.0, 148.4,
145.2, 144.0, 138.6, 136.1, 129.6, 129.2, 128.4, 128.1, 128.0, 127.9,
127.3, 126.9, 126.4, 121.4, 116.6, 90.7, 85.0, 77.9, 71.4, 62.7, 40.8, 29.2,
26.2, 26.0, 18.7, 18.2, −4.1, −5.1, −5.3; ESIMS-LR m/z = 784 [(M +
Na)+]; ESIMS-HR calcd for C44H59O3N5NaSi2 784.4054, found
784.4049.
t
(s, 4.5H, Bu), 0.24 (s, 1.5H, Me), 0.22 (s, 1.5H, Me), 0.18 (s, 1.5H,
Me), 0.17 (s, 1.5H, Me), 0.16 (s, 1.5H, Me), 0.15 (s, 1.5H, Me), 0.11
(s, 1.5H, Me), 0.11 (s, 1.5H, Me); 13C NMR (125 MHz, CDCl3, 20
°C, 1:1 mixture of rotamers, observed peaks were described) δ 165.3,
165.2, 158.6, 156.4, 156.3, 154.0, 152.2, 152.1, 148.5, 148.4, 148.2,
148.1, 147.4, 147.3, 146.6, 146.5, 145.2, 145.1, 141.2, 141.1, 137.8,
137.7, 136.8, 135.5, 135.4, 131.7, 130.3, 130.2, 129.1, 128.7, 128.5,
127.9, 126.9, 124.6, 123.6, 121.6, 121.4, 118.2, 118.1, 116.9, 116.7,
116.6, 116.4, 115.2, 111.5, 111.4, 103.1, 103.0, 100.0, 99.8, 95.5, 95.4,
92.0, 91.4, 83.9, 83.4, 71.3, 61.0, 60.9, 57.4, 57.3, 56.1, 56.0, 55.1, 55.0,
47.1, 47.0, 45.8, 45.7, 29.8, 29.5, 29.3, 28.4, 28.0, 25.9, 25.7, 18.3, 18.1,
−4.0, −4.1, −4.3, −5.2; ESIMS-LR m/z = 1226 [(M + Na)+]; ESIMS-
HR calcd for C68H86O10N6NaSi2 1225.5842, found 1225.5841.
6-Amino-9-(3-deoxy-3-C-allyl-2-O-tert-butyldimethylsilyl-β-
D-pentofuranosyl)-N6-trityl-9H-purine (39b). A mixture of 6-
amino-9-[3-deoxy-3-C-allyl-2,5-O-bis(tert-butyldimethylsilyl)-β-D-pen-
tofuranosyl]-N6-trityl-9H-purine (1.3 g, 1.7 mmol) and AcOH (0.20
mL, 3.4 mmol) in THF (10 mL) was treated with TBAF (1.0 M
solution in THF, 1.7 mL, 1.7 mmol) at −20 °C for 1 h, and then the
mixture was stirred at −5 °C for 10 h. The solvent was removed in
vacuo, and the residue was purified by silica gel column
Cyclophanes 43b. A mixture of 41b (1.1 g, 0.91 mmol) and
Grubbs' first-generation catalyst (3.7 mg, 4.6 μmol) in CH2Cl2 (10
mL) was refluxed for 7 h. The solvent was removed in vacuo, and the
residue was purified by flash silica gel column chromatography (2 × 25
cm, hexane/AcOEt = 2/1) to give (−)-trans-43b (890 mg, 84%) as a
white foam, (+)-trans-43b (75 mg, 7.0%) as a white foam, and cis-43b
(70 mg, 6.6%) as a white foam (total 98% yield, trans/cis = 13.8:1).
chromatography (1 × 10 cm, hexane/AcOEt = 3/1) to give 39b
1
(860 mg, 78%) as a white foam: [α]20 −68.3 (c 1.00, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 8.00 (s, 1H, H-2), 7.80 (s, 1H, H-8),
7.35−7.20 (m, 15H, Tr), 7.06 (br s, 1H, NHTr), 6.38 (br s, 1H, 5′−
OH), 5.80 (m, 1H, H-2″), 5.63 (d, 1H, H-1′, J = 6.3 Hz), 5.14 (d, 1H,
H-3′-trans, J = 14.0 Hz), 5.11 (d, 1H, H-3′-cis, J = 9.1 Hz), 5.02 (t, 1H,
H-2′, J = 6.8 Hz), 4.19 (d, 1H, H-4′, J = 1.3 Hz), 3.96 (dd, 1H, H-5′a,
J = 1.3, 12.2 Hz), 3.49 (d, 1H, H-5′b, J = 12.2 Hz), 2.62 (m, 1H, H-3′),
Data for (−)-trans-43b: Rf = 0.50 (hexane/AcOEt = 2/1 × 3); [α]18
D
−121.8 (c 1.07, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 1H,
H-2), 7.98 (s, 1H, H-8), 7.37−7.23 (m, 16H, Tr and SiMB-6), 6.95 (br
s, 1H, NHTr), 6.60 (s, 1H, H-6″), 6.40 (dd, 1H, SiMB-5, J = 2.3, 8.6
Hz), 6.37 (dd, 1H, H-5′, J = 9.2, 15.5 Hz), 6.34 (d, 1H, SiMB-3, J = 2.3
Hz), 5.73 (s, 1H, H-1′), 5.68 (d, 1H, H-6′, J = 15.5 Hz), 5.50 (dt, 1H,
H-8′, J = 5.3, 14.9 Hz), 5.31 (d, 1H, SiMB-CH2, J = 13.7 Hz), 5.01 (d,
1H, MOM-CH2, J = 6.3 Hz), 4.98 (d, 1H, H-2′, J = 3.5 Hz), 4.95 (d,
1H, MOM-CH2, J = 6.3 Hz), 4.77 (ddd, 1H, H-9′, J = 6.3, 8.0, 14.9
Hz), 4.63 (d, 1H, MOM-CH2, J = 5.7 Hz), 4.61 (d, 1H, MOM-CH2,
J = 5.7 Hz), 4.39 (t, 1H, H-4′, J = 9.1 Hz), 4.30 (d, 1H, SiMB-CH2, J =
13.7 Hz), 3.78 (s, 3H, OMe), 3.66 (s, 3H, OMe), 3.45 (s, 6H, OMe ×
2), 3.44 (d, 1H, H-7′a, J = 16.0 Hz), 3.16 (dd, 1H, H-7′b, J = 5.3, 16.0
t
2.55 (m, 1H, H-1′a), 2.13 (m, 1H, H-1′b), 0.79 (s, 9H, Bu), −0.12 (s,
3H, Me), −0.37 (s, 3H, Me); 13C NMR (100 MHz, CDCl3) δ 154.8,
151.9, 147.5, 144.9, 140.0, 136.1, 129.1, 128.0, 127.1, 122.5, 117.5,
92.5, 85.6, 77.4, 75.0, 71.8, 64.7, 41.9, 31.8, 25.7, 18.0, −5.1, −5.6;
ESIMS-LR m/z = 670 [(M + Na)+]; ESIMS-HR calcd for
C38H45O3N5NaSi 670.3189, found 670.3184.
N-(3-Allyl-4-methoxy-2,5-bis-methoxymethoxyphenyl)-N-
(4-tert-butyldimethylsiloxy-2-methoxybenzyl) (E)-3-C-Allyl-1-
(6-amino-N6-trityl-9H-purin-9-yl)-2-O-tert-butyldimethylsilyl-
3,5,6-trideoxy-β-D-ribo-5-eneheptofuranuronamide (41b). A
solution of 39b (150 mg, 0.23 mmol) in CH2Cl2 (5 mL) was treated
with Dess−Martin periodinane (200 mg, 0.46 mmol) at 0 °C, and the
mixture was stirred at room temperature for 30 min. The reaction was
quenched with saturated aqueous Na2S2O3 (10 mL) and saturated
aqueous NaHCO3 (10 mL) at 0 °C and stirred for 20 min. The
mixture was extracted with AcOEt (40 mL), and the organic layers
were washed with saturated aqueous NaHCO3 (20 mL) and brine (20
mL), dried (Na2SO4), filtered, and concentrated to give a crude
aldehyde 40b. Compound 40b (150 mg, 0.23 mmol) was added to a
mixture of 38 (160 mg, 0.23 mmol), Zn(OTf)2 (100 mg, 0.28 mmol),
Et3N (0.14 mL, 0.92 mmol), and TMEDA (42 mL, 0.28 mmol) in
THF (3 mL), and the mixture was stirred at room temperature for 4 h.
The mixture was partitioned between AcOEt (50 mL) and H2O (40
mL), and the organic layers were washed with 0.1 N aqueous HCl (50
mL), saturated aqueous NaHCO3 (50 mL), and brine (30 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified by flash
silica gel column chromatography (1 × 25 cm, hexane/AcOEt = 3/1)
t
Hz), 2.22 (m, 3H, H-3′ and H-10′), 0.99 (s, 9H, Bu), 0.87 (s, 9H,
tBu), 0.20 (s, 3H, Me), 0.19 (s, 3H, Me), 0.12 (s, 3H, Me), 0.09 (s,
3H, Me); 13C NMR (125 MHz, CDCl3) δ 168.6, 158.8, 156.7, 154.1,
152.1, 148.5, 148.2, 147.6, 147.3, 145.2, 138.9, 138.6, 132.2, 131.7,
129.6, 129.1, 128.6, 128.0, 127.8, 127.0, 121.9, 118.6, 113.6, 111.8,
103.5, 100.1, 95.7, 92.4, 86.4, 78.8, 71.4, 61.6, 57.6, 56.4, 55.3, 48.3,
46.6, 31.2, 27.2, 25.9, 25.8, 18.3, 18.2, −4.3, −4.4, −4.9; ESIMS-LR m/
z = 1198 [(M + Na)+]; ESIMS-HR calcd for C66H82O10N6NaSi2
1197.5523, found 1197.5512. Data for (+)-trans-43b: Rf = 0.55
1
(hexane/AcOEt = 2/1 × 3); [α]20 54.6 (c 0.85, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 7.94 (s, 1H, H-2), 7.78 (s, 1H, H-8), 7.34−7.21
(m, 16H, Tr and SiMB-6), 6.87 (br s, 1H, NHTr), 6.74 (s, 1H, H-6″),
6.70 (dd, 1H, H-5′, J = 4.6, 16.0 Hz), 6.41 (dd, 1H, SiMB-5, J = 2.3, 8.6
Hz), 6.31 (d, 1H, SiMB-3, J = 2.3 Hz), 5.77 (s, 1H, H-1′), 5.75 (dt, 1H,
H-8′, J = 6.3, 14.9 Hz), 5.66 (dd, 1H, H-6′, J = 1.7, 16.0 Hz), 5.18 (d,
1H, SiMB-CH2, J = 14.3 Hz), 5.04 (d, 1H, MOM-CH2, J = 6.3 Hz),
4.97 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.67−4.60 (m, 4H, H-2′, H-4′,
H-9′ and SiMB-CH2), 4.46 (d, 1H, MOM-CH2, J = 5.7 Hz), 4.44 (d,
1H, MOM-CH2, J = 5.7 Hz), 3.78 (s, 3H, OMe), 3.62 (s, 3H, OMe),
3.44 (s, 3H, OMe), 3.40 (s, 3H, OMe), 3.35 (br d, 1H, H-7′a, J = 14.9
Hz), 3.19 (dd, 1H, H-7′b, J = 6.3, 14.9 Hz), 2.20 (m, 2H, H-3′ and H-
1
to give 41b (250 mg, 90% over two steps) as a white foam: H NMR
(500 MHz, CDCl3, 20 °C, 1:1 mixture of rotamers) δ 7.99 (s, 0.5H, H-
2), 7.98 (s, 0.5H, H-2), 7.81 (s, 0.5H, H-8), 7.80 (s, 0.5H, H-8), 7.37−
7.21 (m, 15H, Tr), 7.19 (d, 0.5H, SiMB-6, J = 8.0 Hz), 7.18 (d, 0.5H,
SiMB-6, J = 8.0 Hz), 7.02 (dd, 0.5H, H-5′, J = 5.7, 17.2 Hz), 7.00 (dd,
0.5H, H-5′, J = 6.9, 17.2 Hz), 6.96 (br s, 0.5H, NHTr), 6.95 (br s,
0.5H, NHTr), 6.49 (s, 0.5H, H-6″), 6.43 (s, 0.5H, H-6″), 6.35 (dd,
0.5H, SiMB-5, J = 2.3, 8.0 Hz), 6.33 (dd, 0.5H, SiMB-5, J = 2.3, 8.0
Hz), 6.25 (dd, 0.5H, H-6′, J = 1.1, 17.2 Hz), 6.23 (d, 0.5H, SiMB-3, J =
t
t
10′a), 1.96 (m, 1H, H-10′b), 0.98 (s, 9H, Bu), 0.89 (s, 9H, Bu), 0.20
(s, 3H, Me), 0.19 (s, 3H, Me), 0.18 (s, 3H, Me), 0.08 (s, 3H, Me); 13
C
NMR (125 MHz, CDCl3) δ 167.4, 158.6, 156.6, 154.0, 152.1, 148.1,
9290
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Article
147.3, 147.0, 146.3, 145.1, 138.4, 137.0, 132.3, 131.9, 130.7, 130.5,
129.6, 129.1, 128.0, 127.0, 125.7, 121.7, 118.6, 112.6, 112.0, 103.5,
99.9, 95.7, 91.0, 84.5, 79.9, 71.4, 61.6, 57.6, 56.4, 55.3, 46.3, 43.9, 30.7,
25.9, 25.8, 18.3, 18.1, −4.2, −4.3, −5.0; ESIMS-LR m/z = 1198 [(M +
Na)+]; ESIMS-HR calcd for C66H82O10N6NaSi2 1197.5523, found
1197.5511. Data for cis-43b: Rf = 0.60 (hexane/AcOEt = 2/1 × 3);
[α]18D 102.3 (c 1.11, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.90 (s,
1H, H-2), 7.61 (s, 1H, H-8), 7.36−7.23 (m, 16H, Tr and SiMB-6),
6.87 (br s, 1H, NHTr), 6.72 (s, 1H, H-6″), 6.42 (dd, 1H, SiMB-5, J =
2.3, 8.1 Hz), 6.33 (d, 1H, SiMB-3, J = 2.3 Hz), 5.99 (d, 1H, H-6′, J =
16.0 Hz), 5.95 (dt, 1H, H-8′, J = 5.1, 10.3 Hz), 5.75 (s, 1H, H-1′), 5.54
(dd, 1H, H-5′, J = 8.6, 16.0 Hz), 5.32 (overlapping, 1H, H-9′), 5.30 (d,
1H, SiMB-CH2, J = 14.9 Hz), 4.87 (d, 1H, MOM-CH2, J = 6.3 Hz),
4.85 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.65 (d, 1H, H-2′, J = 4.6 Hz),
4.57 (d, 1H, MOM-CH2, J = 5.8 Hz), 4.55 (d, 1H, MOM-CH2, J = 5.8
Hz), 4.53 (d, 1H, SiMB-CH2, J = 14.9 Hz), 4.22 (dd, 1H, H-4′, J = 8.6,
10.9 Hz), 3.63 (s, 3H, OMe), 3.60 (s, 3H, OMe), 3.52 (dd, 1H, H-7′a,
J = 5.7, 15.3 Hz), 3.47 (s, 3H, OMe), 3.26 (s, 3H, OMe), 2.97 (dd, 1H,
H-7′b, J = 9.2, 15.3 Hz), 2.01 (m, 2H, H-10′), 1.08 (m, 1H, H-3′), 0.99
(s, 9H, Bu), 0.92 (s, 9H, Bu), 0.20 (s, 3H, Me), 0.19 (s, 3H, Me),
0.18 (s, 3H, Me), 0.12 (s, 3H, Me); 13C NMR (125 MHz, CDCl3) δ
168.3, 158.4, 156.5, 154.0, 152.2, 147.9, 147.6, 147.0, 145.1, 144.0,
137.9, 136.7, 133.5, 131.4, 131.3, 130.0, 129.1, 128.6, 128.0, 127.0,
126.5, 121.6, 118.7, 112.9, 112.0, 103.5, 100.4, 95.9, 93.0, 84.3, 75.8,
71.3, 60.7, 58.0, 56.5, 55.3, 48.3, 46.6, 25.9, 25.8, 23.1, 18.3, 18.1, −3.9,
−4.2, −5.2; ESIMS-LR m/z = 1198 [(M + Na)+]; ESIMS-HR calcd
for C66H82O10N6NaSi2 1197.5523, found 1197.5504.
(−)-trans-44b. A solution of (−)-trans-43b (580 mg, 0.49 mmol)
in THF (10 mL) was treated with TBAF (1.0 M solution in THF, 1.2
mL, 1.2 mmol) at room temperature for 20 min. The mixture was
concentrated, and the residue was purified by silica gel column
chromatography (2 × 10 cm, 3% MeOH in CHCl3) to give (−)-trans-
44b (460 mg, 99%) as a white foam: [α]18D −93.1 (c 0.95, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 8.10 (s, 1H, H-2), 8.00 (br s, 1H, SiMB-4-
OH), 7.95 (s, 1H, H-8), 7.35−7.17 (m, 17H, Tr, NHTr and SiMB-6),
6.60 (s, 1H, H-6″), 6.40 (dd, 1H, H-5′, J = 9.7, 15.5 Hz), 6.37 (dd, 1H,
SiMB-5, J = 2.3, 8.1 Hz), 6.33 (d, 1H, SiMB-3, J = 2.3 Hz), 5.73 (s, 1H,
H-1′), 5.66 (d, 1H, H-6′, J = 15.5 Hz), 5.50 (ddd, 1H, H-8′, J = 4.6, 5.7,
14.9 Hz), 5.30 (d, 1H, SiMB-CH2, J = 14.3 Hz), 4.97 (d, 1H, MOM-
CH2, J = 6.9 Hz), 4.92 (d, 1H, MOM-CH2, J = 6.9 Hz), 4.92
(overlapping, 1H, 2′−OH), 4.83 (dt, 1H, H-9′, J = 6.9, 14.9 Hz), 4.66
(s, 2H, MOM-CH2), 4.65 (overlapping, 1H, H-2′), 4.34 (t, 1H, H-4′,
J = 8.6 Hz), 4.30 (d, 1H, SiMB-CH2, J = 14.3 Hz), 3.77 (s, 3H, OMe),
3.61 (s, 3H, OMe), 3.43 (s, 3H, OMe), 3.43 (overlapping, 1H, H-7′a),
3.37 (s, 3H, OMe), 3.16 (dd, 1H, H-7′b, J = 6.3, 15.4 Hz), 2.36 (t, 1H,
H-10′a, J = 10.9 Hz), 2.22 (m, 2H, H-3′and H-10′b); 13C NMR (125
MHz, CDCl3) δ 168.7, 159.2, 157.7, 154.4, 151.8, 148.6, 148.0, 147.8,
147.3, 145.1, 138.4, 138.3, 132.6, 131.6, 129.7, 129.2, 128.8, 128.2,
128.0, 127.0, 121.7, 117.3, 114.1, 107.6, 100.2, 99.5, 96.0, 92.7, 86.7,
77.9, 71.7, 61.5, 57.6, 56.4, 55.4, 47.7, 46.8, 31.7, 30.8, 27.3, 22.8, 14.2;
ESIMS-LR m/z = 969 [(M + Na)+]; ESIMS-HR calcd for
C54H54O10N6Na 969.3799, found 969.3794.
(−)-trans-45b. A mixture of (−)-trans-44b (15 mg, 0.016 mmol)
and CsF (12 mg, 0.080 mmol) in 1,4-dioxane−H2O (3:1 (v/v), 2 mL)
was stirred at 150 °C under microwave irradiation for 90 min. The
mixture was concentrated, and the residue was partitioned between
CHCl3 (10 mL) and H2O (5 mL). The organic layer was washed with
brine (5 mL), dried (Na2SO4), filtered, and concentrated. The residue
was purified by silica gel column chromatpgraphy (0.5 × 5 cm, 3%
MeOH in CHCl3) to give (−)-trans-45b (12 mg, 93%) as a white
foam: [α]18D −144.7 (c 0.80, CHCl3); 1H NMR (500 MHz, CDCl3) δ
8.00 (s, 1H, H-2), 7.94 (s, 1H, H-8), 7.34−7.21 (m, 15H, Tr), 7.06 (br
s, 1H, NHTr), 7.04 (br s, 1H, CONH), 6.44 (dd, 1H, H-5′, J = 8.6,
16.0 Hz), 5.75 (d, 1H, H-6′, J = 16.0 Hz), 5.74 (d, 1H, H-1′, J = 2.8
Hz), 5.57 (dt, 1H, H-8′, J = 5.7, 15.5 Hz), 5.24 (br s, 1H, 2′−OH),
5.21 (d, 1H, MOM-CH2, J = 6.8 Hz), 5.17 (d, 1H, MOM-CH2, J = 6.8
Hz), 4.81 (overlapping, 1H, H-9′), 4.81 (d, 1H, MOM-CH2, J = 6.3
Hz), 4.77 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.65 (br d, 1H, H-2′, J = 2.8
Hz), 4.42 (t, 1H, H-4′, J = 8.6 Hz), 3.80 (s, 3H, OMe), 3.53 (s, 3H,
OMe), 3.49 (s, 6H, OMe × 2), 3.48 (overlapping, 1H, H-7′a), 3.12
(dd, 1H, H-7′b, J = 5.7, 15.5 Hz), 2.40 (t, 1H, H-10′a, J = 10.3 Hz),
2.25 (m, 2H, H-3′ and H-10′b); 13C NMR (100 MHz, CDCl3) δ 170.1,
154.3, 151.8, 148.7, 148.2, 147.7, 144.9, 139.7, 138.0, 129.1, 128.0,
127.7, 127.6, 127.1, 126.1, 121.6, 113.7, 99.9, 95.6, 92.4, 86.4, 77.6,
71.5, 61.7, 58.0, 56.6, 47.5, 30.8, 29.8, 27.1; ESIMS-LR m/z = 811 [(M +
H)+]; ESIMS-HR calcd for C46H47O8N6 811.3455, found 811.3450.
trans-46. A solution of trans-45b (140 mg, 0.17 mmol) in CH2Cl2
(2 mL) was treated with Et3SiH (0.13 mL, 0.85 mmol) and TFA (2
mL) at 0 °C, and the mixture was stirred at room temperature for 2 h.
The mixture was concentrated in vacuo to give a crude hydroquinone.
A mixture of the crude hydroquinone and Pd/C (100 mg) in MeOH
(4 mL) was vigorously stirred under air atmosphere at room
temperature for 1 h. The insolubles were filtered off through a Celite
pad and washed with hot MeOH. The filtrate was concentrated, and
the residue was triturated with MeOH to give trans-46 (42 mg, 52%
over two steps) as a yellow solid. The resulting residue was purified by
silica gel column chromatography (1 × 6 cm, 8% MeOH in CHCl3) to
give trans-46 (31 mg, 38% over two steps) as a yellow solid (total 90%
1
over two steps): H NMR (500 MHz, DMSO-d6) δ 10.03 (br s, 1H,
t
t
CONH), 8.49 (s, 1H, H-2), 8.33 (s, 1H, H-8), 8.20 (br s, 2H, 6-NH2),
6.20 (dd, 1H, H-5′, J = 9.2, 15.5 Hz), 6.17 (s, 1H, H-6″), 5.90 (d, 1H,
H-1′, J = 1.7 Hz), 5.83 (d, 1H, H-6′, J = 15.5 Hz), 5.80 (br s, 1H, 2′−
OH), 5.42−5.33 (m, 2H, H-8′and H-9′), 4.65 (dd, 1H, H-2′, J = 1.7,
6.3 Hz), 4.36 (t, 1H, H-4′, J = 8.6 Hz), 3.94 (s, 3H, OMe), 3.13 (d,
1H, H-7′a, J = 13.8 Hz), 3.01 (dd, 1H, H-7′b, J = 8.1, 13.8 Hz), 2.63
(m, 1H, H-3′), 2.39 (br d, 1H, H-10′a, J = 13.2 Hz), 2.20 (m, 1H, H-
10′b); 13C NMR (125 MHz, DMSO-d6) δ 184.4, 182.9, 167.5, 154.1,
152.7, 148.5, 148.4, 144.5, 142.2, 140.8, 132.7, 128.6, 128.3, 125.4,
118.9, 118.8, 90.3, 85.1, 76.9, 61.3, 46.1, 31.1, 25.8; ESIMS-LR m/z =
477 [(M − H)−]; ESIMS-HR calcd for C23H21O6N6 477.1528, found
477.1541.
cis-44b. A solution of cis-43b (40 mg, 0.034 mmol) in THF (1
mL) was treated with TBAF (1.0 M solution in THF, 85 μL, 0.085
mmol) at room temperature for 10 min. The mixture was
concentrated, and the residue was purified by silica gel column
chromatography (1 × 6 cm, 3% MeOH in CHCl3) to give cis-44b (31
1
mg, 98%) as a white foam: [α]19 138.4 (c 0.95, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 9.48 (br s, 1H, HMB-4-OH), 7.93 (s, 1H, H-2),
7.69 (s, 1H, H-8), 7.38 (br s, 1H, NHTr), 7.34−7.18 (m, 16H, Tr and
HMB-6), 6.71 (s, 1H, H-6″), 6.37 (dd, 1H, HMB-5, J = 1.7, 8.0 Hz),
6.16 (d, 1H, HMB-3, J = 1.7 Hz), 6.00 (d, 1H, H-6′, J = 16.1 Hz), 5.93
(dt, 1H, H-8′, J = 5.7, 9.2 Hz), 5.89 (s, 1H, H-1′), 5.51 (dd, 1H, H-5′,
J = 8.0, 16.1 Hz), 5.38 (d, 1H, HMB-CH2, J = 14.3 Hz), 5.37 (m, 1H,
H-9′), 5.24 (br s, 1H, 2′−OH), 4.87 (s, 2H, MOM-CH2), 4.70 (d, 1H,
MOM-CH2, J = 5.7 Hz), 4.68 (d, 1H, MOM-CH2, J = 5.7 Hz), 4.43
(d, 1H, HMB-CH2, J = 14.3 Hz), 4.42 (overlapping, 1H, H-2′), 4.24 (t,
1H, H-4′, J = 8.6 Hz), 3.62 (s, 3H, OMe), 3.58 (s, 3H, OMe), 3.53
(dd, 1H, H-7′a, J = 5.7, 13.7 Hz), 3.50 (s, 3H, OMe), 3.30 (s, 3H,
OMe), 2.97 (dd, 1H, H-7′b, J = 8.6, 13.7 Hz), 2.05 (m, 2H, H-10′),
0.83 (m, 1H, H-3′); 13C NMR (125 MHz, CDCl3) δ 168.5, 158.6,
157.5, 154.0, 152.0, 148.0, 147.2, 146.9, 144.8, 144.5, 136.9, 136.8,
133.7, 131.5, 131.3, 129.8, 129.1, 128.6, 127.9, 127.0, 126.5, 121.1,
117.3, 113.9, 107.6, 100.5, 99.3, 96.1, 93.4, 84.3, 75.1, 71.5, 60.7, 58.1,
56.4, 55.4, 47.7, 46.6, 25.8, 23.1, 21.0; ESIMS-LR m/z = 947 [(M +
H)+]; ESIMS-HR calcd for C54H55O10N6 947.3980, found 947.3974.
cis-45b. A mixture of cis-44b (30 mg, 0.031 mmol) and CsF (24
mg, 0.15 mmol) in 1,4-dioxane−H2O (3:1 (v/v), 2 mL) was stirred at
150 °C under microwave irradiation for 60 min. The mixture was
concentrated, and the residue was partitioned between CHCl3 (10
mL) and H2O (5 mL). The organic layer was washed with brine (5
mL), dried (Na2SO4), filtered, and concentrated. The residue was
purified by silica gel column chromatpgraphy (0.5 × 5 cm, 3% MeOH
in CHCl3) to give cis-45b (22 mg, 87%) as a white foam. [α]D18 104.9
1
(c 0.61, CHCl3); H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H, H-2),
7.63 (s, 1H, H-8), 7.37 (br s, 1H, CONH), 7.32−7.21 (m, 15H, Tr),
6.99 (br s, 1H, NHTr), 6.87 (s, 1H, H-6″), 5.98 (d, 1H, H-6′, J = 16.3
Hz), 5.95 (m, 1H, H-8′), 5.89 (s, 1H, H-1′), 5.58 (dd, 1H, H-5′, J = 8.2,
16.3 Hz), 5.40 (ddd, 1H, H-9′, J = 2.3, 5.0, 10.4 Hz), 5.10 (d, 1H,
MOM-CH2, J = 6.3 Hz), 5.02 (d, 1H, MOM-CH2, J = 6.3 Hz), 4.92
(d, 1H, 2′-OH, J = 2.7 Hz), 4.87 (d, 1H, MOM-CH2, J = 5.9 Hz), 4.82
9291
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Article
(d, 1H, MOM-CH2, J = 5.9 Hz), 4.52 (t, 1H, H-2′, J = 3.7 Hz), 4.30
(dd, 1H, H-4′, J = 8.2, 10.4 Hz), 3.63 (s, 3H, OMe), 3.55 (overlapping,
1H, H-7′a), 3.54 (s, 3H, OMe), 3.39 (s, 3H, OMe), 3.00 (dd, 1H, H-
7′b, J = 9.0, 14.0 Hz), 2.17−2.02 (m, 2H, H-10′), 0.95 (m, 1H, H-3′);
13C NMR (125 MHz, CDCl3) δ 169.5, 154.2, 152.0, 147.7, 147.5,
147.4, 144.9, 143.7, 137.9, 137.4, 132.1, 129.7, 129.0, 128.9, 128.1,
128.0, 127.1, 124.7, 121.7, 112.1, 100.3, 95.7, 93.5, 84.2, 75.2, 71.5,
60.7, 58.4, 56.6, 47.9, 29.9, 22.9, 21.1; ESIMS-LR m/z = 833 [(M +
Na)+]; ESIMS-HR calcd for C46H46O8N6Na 833.3275, found
833.3271.
cis-46. A solution of cis-45b (40 mg, 0.025 mmol) in CH2Cl2 (0.5
mL) was treated with Et3SiH (20 μL, 0.12 mmol) and TFA (0.6 mL)
at 0 °C, and the mixture was stirred at room temperature for 3 h. The
mixture was concentrated in vacuo to give a crude hydroquinone. A
mixture of the crude hydroquinone and Pd/C (20 mg) in MeOH (3
mL) was vigorously stirred under air atmosphere at room temperature
for 30 min. The insolubles were filtered off through a Celite pad and
washed with hot MeOH. The filtrate was concentrated, and the
residue was purified by silica gel column chromatography (1 × 5 cm,
8% MeOH in CHCl3) to give cis-46 (9.6 mg, 79% over two steps) as a
yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 10.0 (br s, 1H,
CONH), 8.16 (s, 1H, H-2), 7.87 (s, 1H, H-8), 7.25 (br s, 2H, 6-NH2),
6.24 (s, 1H, H-6″), 6.09 (dd, 1H, H-5′, J = 8.0, 16.1 Hz), 6.03 (d, 1H,
H-6′, J = 16.1 Hz), 5.95 (d, 1H, 2′−OH, J = 5.2 Hz), 5.93 (s, 1H, H-
1′), 5.80 (m, 1H, H-8′), 5.48 (br t, 1H, H-9′, J = 10.3 Hz), 4.36 (t, 1H,
H-2′, J = 5.2 Hz), 4.20 (dd, 1H, H-4′, J = 8.0, 10.9 Hz), 3.92 (s, 3H, 4″-
OMe), 3.38 (dd, 1H, H-7′b, J = 8.0, 13.8 Hz), 2.65 (dd, 1H, H-7′a, J =
8.0, 13.8 Hz), 2.22 (dt, 1H, H-3′, J = 5.2, 10.9 Hz), 2.03 (dt, 1H, H-
10′a, J = 4.0, 13.2 Hz), 1.71 (br t, 1H, H-10′b, J = 12.0 Hz); 13C NMR
(125 MHz, DMSO-d6) δ 183.9, 182.9, 168.6, 156.1, 156.0, 152.1,
148.5, 144.5, 139.9, 137.6, 130.6, 130.2, 129.9, 126.4, 119.6, 117.2,
93.2, 83.6, 74.8, 60.8, 47.7, 21.5, 20.0; ESIMS-LR m/z = 477 [(M−
H)−]; ESIMS-HR calcd for C23H21O6N6 477.1528, found 477.1539.
Mosser, S. D.; Johnston, V. K.; Wong, B. K.; Miller-Stein, C. M.;
Hershey, J. C.; Graham, S. L.; Vacca, J. P.; Williams, T. M. J. Med.
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(4) Muranaka, K.; Ichikawa, S.; Matsuda, A. Tetrahedron Lett. 2009,
50, 5102−5106.
(5) A significant range of substituted benzyl protecting groups for
alcohol is reported. For examples, see: (a) Kang, J.; Lim, G. J.; Yoon, S.
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(8) A p-siloxybenzylidene acetal protecting group for diols has also
been described: Kaburagi, Y.; Osajima, H.; Shimada, K.; Tokuyama,
H.; Fukuyama, T. Tetrahedron Lett. 2004, 45, 3817−3821.
(9) Introducing the SiMB group directly to the p-benzanisidide 15
was also investigated. N-Alkylation of 15 with 4-(tert-butyldimethylsi-
loxy)-2-methoxybenzyl chloride or bromide gave no desired product
13 because the halides quickly decomposed. Mitsunobu reaction using
4-(tert-butyldimethylsiloxy)-2-methoxybenzyl alcohol in the presence
of PPh3 and DIAD in CH2Cl2 did not proceed at all. The modified
Mitsunobu-type conditions using cyanomethylenetributylphosphorane
in refluxing toluene gave 15; however, the isolated chemical yield was
low (34%).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 31P NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*(S.I.) Phone: (+81) 11-706-3763. Fax: (+81) 11-706-4980.
E-mail: ichikawa@pharm.hokudai.ac.jp. (A.M.) Phone: (+81)
11-706-3228. Fax: (+81) 11-706-4980. E-mail: matuda@pharm.
hokudai.ac.jp.
(10) Sykes, B. M.; Atwell, G. J.; Hogg, A.; Wilson, W. R.; O’Connor,
C. J.; Denny, W. A. J. Med. Chem. 1999, 42, 346−355.
(11) Adediran, S. A.; Cabaret, D.; Flavell, R. R.; Sammons, J. A.;
Wakselman, M.; Pratt, R. F. Bioorg. Med. Chem. 2006, 14, 7023−7033.
(12) Shauer, D. J.; Helquist, P. Synthesis 2006, 21, 3654−3660.
(13) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−4156.
(14) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. 1995, 34, 2039−2041.
(15) The trans-43a and trans-43b included both (+)- and
(−)-atropisomers, which were separated by chromatography. One of
the atropisomers was used for the next reaction. It was confirmed that
the use of the other atropisomer also gave similar results to afford
trans-4 or trans-46.
ACKNOWLEDGMENTS
■
This work supported by Grants-in-Aid for Scientific Research
from the Japan Society for the Promotion of Science (JSPS).
We thank Ms. S. Oka (Instrumental Analysis Division, Equipment
Management Center, Creative Research Institution, Hokkaido
University) for measurement of the mass spectra.
REFERENCES
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