Selenosugars are interesting targets of organic synthesis as they would possess potential biological activities. However, 4-selenotherofuranose derivatives, which have trans configuration for the two dihydroxy substituents at the 2,3-positions and a glycoside bond at the anomeric position, are not available in the current selenosugar library. In this study, racemic 4-selenothreofuranose derivatives were synthesized from trans-3,4-dioxygenated tetrahydroselenophenes in 77-99% yields with the α/β selectivity about 7:3 via oxidation and subsequent seleno-Pummerer rearrangement. The acetoxy group introduced at the anomeric position was then substituted with various nucleophiles, including activated 6-chloropurine, which afforded 4'-selenothreonucleoside derivatives, in the presence of BF3·OEt2 or TMSOTf. The stereochemistry of the selenosugar products was established by 1H NMR spectroscopy as well as X-ray analysis. The similar α/β selectivity observed in the latter glycosylation reaction to that in the former seleno-Pummerer rearrangement suggested the mediation of a common selenonium intermediate (-Se+=C<). It was also suggested that an unexpected interaction between the ester protecting group at the 3-position of the selenofuranose ring and the anomeric carbon atom decreases the α/β selectivity.
Selenosugars are interesting targets of organic synthesis as they would possess potential biological activities. However, 4-selenotherofuranose derivatives, which have trans configuration for the two dihydroxy substituents at the 2,3-positions and a glycoside bond at the anomeric position, are not available in the current selenosugar library. In this study, racemic 4-selenothreofuranose derivatives were synthesized from trans-3,4-dioxygenated tetrahydroselenophenes in 77-99% yields with the α/β selectivity about 7:3 via oxidation and subsequent seleno-Pummerer rearrangement. The acetoxy group introduced at the anomeric position was then substituted with various nucleophiles, including activated 6-chloropurine, which afforded 4'-selenothreonucleoside derivatives, in the presence of BF3·OEt2 or TMSOTf. The stereochemistry of the selenosugar products was established by 1HNMR spectroscopy as well as X-ray analysis. The similar α/β selectivity observed in the latter glycosylation reaction to that in the former seleno-Pummerer rearrangement suggested the mediation of a common selenonium intermediate (-Se+=C<). It was also suggested that an unexpected interaction between the ester protecting group at the 3-position of the selenofuranose ring and the anomeric carbon atom decreases the α/β selectivity.
Selenosugars
are intriguing carbohydrates which bring a biologically
unique selenium atom substituting the oxygen atom or at any other
positions of a sugar molecule. Various selenosugars have already been
synthesized[1−6] during the course of an extensive research on thiosugars and their
conjugates with a nucleobase, that is, thionucleosides.[7−11] Some representative examples are shown in Figure . Ogra and co-workers[12,13] characterized 1β-methylseleno-N-acetyl-d-galactosamine (1) as a major urinary selenium
metabolite of rats fed with sodium selenite. Benzyl (Bn)-protected
1,4-anhydro-4-seleno-d-arabinitol (2) was synthesized
by Pinto’s group[14] and Se-alkylated
to afford selenium congeners of ponkoranol, which exhibited high inhibitory
activities against glucosidase enzymes.[15] The same group also reported the synthesis of 4-seleno-d-galactitol derivative (3a) and investigated its functionalization
applying Pummerer-like reactions.[16] On
the other hand, significant in vitro antioxidant activities of 1,4-anhydro-4-seleno-d-talitol (3b) and the related selenosugars were
recently reported by Davies and Schiesser.[17] In the meantime, Pinto and co-workers[18,19] succeeded
in the stereoselective synthesis of a series of 4′-seleno-d-ribonucleosides (4) and applied the thymidine
variant to the synthesis of oligonucleotides, which revealed a unique
conformational shift arising from the introduced selenonucleoside.
Thus, selenosugars and selenonucleosides are interesting targets of
organic synthesis as they would possess potential biological activities,
such as enzyme inhibitors,[14,15] antioxidants,[17,20] antibiotics,[21−23] and so forth.[24] However,
4-selenotherofuranose derivatives, which have trans configuration
for the two dihydroxy substituents at the 2,3-positions such as 2 and 3a and a glycoside bond at the anomeric
position, are not available in the current selenosugar library.
Figure 1
Examples of
selenosugars.
Examples of
n class="Chemical">selenosugars.
To access 4′-n class="Chemical">selenonucleoside
derivatives, such as 4, Pummerer rearrangement[25−27] is a useful synthetic
tool. Indeed, the reaction has successfully been applied to the synthesis
of various 4′-selenonucleosides via stereoselective introduction
of a nucleobase into a tetrahydroselenophene skeleton.[18,28−30] The typical synthetic schemes are shown in Scheme along with that
employed in this study. Minakawa[29] synthesized
4′-selenouridine and 4′-selenocytidine applying the
Pummerer-like reaction to a selenosugar substrate protected with tetraisopropyldisiloxan-1,3-diyl
(TIPDS) and 2,4-dimethoxybenzoyl groups. The selenosugar was oxidized
by iodosylbenzene, which generated a selenonium intermediate in the
presence of 2,6-lutidine and trimethylsilyl trifluoromethanesufonate
(TMSOTf), and reacted with a nucleobase (Scheme a). On the other hand, Jeong[31] synthesized 4′-selenoribonucleoside derivatives
applying a two-step strategy (Scheme b). The selenosugar substrate was first converted to
a selenoribose derivative by seleno-Pummerer rearrangement, and then
the acetoxy group introduced at the anomeric position was substituted
with a nucleobase activated with N,O-bis(trimethylsilyl)acetamide (BSA) in the presence of TMSOTf. In
these syntheses, the β anomers were dominantly obtained due
to the intramolecular interaction between the anomeric carbon atom
and the neighboring substituent during the selenonium intermediate.
Scheme 1
Synthesis of Selenonucleosides
In our group, aan class="Chemical">water-soluble n class="Chemical">cyclic selenide, trans-3,4-dihydroxy-1-selenolane (DHS, 5), was developed
and utilized as a redox reagent for oxidative folding of various proteins,[32−34] a selenoenzyme model,[35−37] a radical scavenger,[38−40] and so forth[41] with pertinent modifications.
As another possible application of 5, we have planned
its transformation to selenothreofuranose derivatives having a trans-2,3-dioxygenated configuration (Scheme c). Herein, we report that the seleno-Pummerer
rearrangement of 5 with acid anhydrides affords 4-selenothreofuranose
derivatives in good yields (77–99%). The acyloxy substituent
introduced at the anomeric position can be further converted to other
functional groups by the treatment with various nucleophiles, including
an activated purine base, in the presence of a Lewis acid.
Results
and Discussion
Se-Pummerer Rearrangement of 5
After protecting
the hydroxy groups of ran class="Chemical">acemic 5, the obtained n class="Chemical">6a–f were oxidized to selenoxides 7a–f and were reacted
with acid anhydrides to induce seleno-Pummerer rearrangement. The
results are summarized in Table .
Table 1
Conversion of Protected DHS (6a–f) to 4-Selenothreofuranose Derivatives (8a–f) via Oxidation and Subsequent Seleno-Pummerer Rearrangement
condition
entry
substrate
X
R
(RCO)2O
solvent
temp/time
product
yield (%)
α/β ratioa
1
6a
Ac
Me
neat
100 °C/1 h
8a
79
56:44
2
6a
Ac
Me
1.2 eq
toluene
70 °C/2.5 h
8a
52
49:51
3
6b
Bz
Me
>10 eq
toluene
100 °C/2 h
8b
83
45:55
4
6c
Bn
Me
2 eq
toluene
90 °C/1.5 h
8c
94
68:32
5
6d
PMBb
Me
>10 eq
toluene
100 °C/2 h
8d
87
69:31
6
6e
TBS
Me
neat
100 °C/1 h
8e
88
70:30
7
6f
TIPDSc
Me
3 eq
toluene
90 °C /2 h
8f
98
81:19
8
6b
Bz
Ph
2 eq
toluene
90 °C/1.5 h
8b′
77
50:50
9
6c
Bn
Ph
2 eq
toluene
90 °C/1.5 h
8c′
99
75:25
Ratios were determined by integration
of the 1H NMR peaks for 8. See the text for
details.
Ratios were determined by integration
of the 1HNMR peaks for 8. See the text for
details.n class="Chemical">4-Methoxybenzyl.
n class="Chemical">Tetraisopropyldisiloxan-1,3-diyl
(-Si(iPr)2OSi(iPr)2-).
In our initial attempt, selenide6a (X
= Ac) was oxidized
by m-chloroperoxybenzoic acid (mCPBA). However, selenoxide 7a could not be isolated due to the reduction back to 6a. Therefore, acetic anhydride (Ac2O) was added
to the crude mixture without isolation of 7a. In this
case, however, rearrangement product 8a was obtained
in low yields (∼30%) probably due to an adverse effect of the
coexisting byproducts from mCPBA. Indeed, when the oxidant was changed
to hydrogen peroxide (H2O2), the reaction of
the crude product 7a with Ac2O afforded 8a in 79% yield (entry 1). The yield was decreased with the
formation of the deacetylated products when the reaction was carried
out in toluene (entry 2). Similar reaction conditions were applied
for 6b–f to obtain the corresponding rearrangement
products 8b–f in 83–98% yields (entries
3–7). Similarly, when benzoic anhydride (Bz2O) was
employed instead of Ac2O, the expected products (8b′and 8c′) were obtained in good
yields (entries 8 and 9). The results demonstrated that the DHS (5) can be efficiently converted to 4-selenothreofuranose derivatives
applying the seleno-Pummerer rearrangement reaction. We also attempted
to introduce a chloride or a nucleobase at the 2-position of 6 using thionyl chloride or activated uracil[28] instead of Ac2O, but the desired products were
not obtained.
Assignment of the α and β Anomers
Seleno-Pummerer
rearrangement products 8a–f were obtained as a
mixture of α and β anomers. These stereoisomers could
not be separated by chromatography, but they exhibited different peaks
in the NMR spectra. Indeed, their α/β ratios could be
determined by integrating the clearly separated peaks in the 1HNMR spectrum. For example, in the case of 8a (Table , entry 1),
the major anomer showed the peaks at δ 6.03 (d, C1H), 5.61 (dd, C2H), 5.37 (q, C3H), 3.25 (dd,
C4HA), and 3.14 (dd, C4HB), while the corresponding peaks for the minor anomer appeared separately
at δ 6.22 (d, C1H), 5.50 (m, C2H), 5.24
(dd, C3H), 3.31 (dd, C4HA), and 2.68
(dd, C4HB). A downfield shift of C1H and an upfield shift of C4HB observed for
the minor anomer were particularly remarkable. Similar spectral features
were commonly detected for the other seleno-Pummerer rearrangement
products (see Table S1). The ratios of
the major and minor anomers thus determined were about 7:3 except
for 8a (X = Ac), 8b (X = Bz), and 8b′ (X = Bz) having ester protections (Table , entries 1–3 and 8).
It is also notable that in the case of a cyclic protecting group,
that is, for 8f (X = TIPDS), the ratio was improved presumably
due to the restriction of the conformational flexibility.Assignments
of the stereochemistry for the major and minor anomers were unambiguously
established by isolation of the one isomer of 8b′ (X = Bz and R = Ph) by recrystallization. The single-crystal X-ray
analysis revealed that the isolated isomer has all trans configuration
for the three OBz substituents (Figure A). According to the formal nomenclature rule as well
as a recent literature,[42] this isomer,
which has an upward substituent at the anomeric position, is hereafter
called an α anomer. It should be noted that the assignment is
opposite to those for d-glucopyranose and d-ribofuranose.
The OBz substituents at the C2 and C3 positions
of the 4-selenothreofuranose ring resided in the axial directions.
A similar diaxial structure is frequently observed for the derivatives
of 5(43,44) as well as for 6b (Figure S1), suggesting a significant
preference of the 4-selenothreofuranose skeleton to adopt a diaxial
conformation. Another OBz substituent of 8b′ at
the C1 or anomeric position was tilted from the axial direction
due to a twisted structure of the 4-selenothreofuranose ring. Since
the α anomer of 8b′ showed in the 1HNMR spectrum characteristic features (Figure B) similar to those observed for the major
anomers of 8a–f and 8c′, it
was confirmed that an α anomer was usually obtained as a major
product of seleno-Pummerer rearrangement for 6 (see Table ). Interestingly,
the coupling constants observed for the C1H proton (3JH) were
small (2.5–4.0 and 4.0–5.0 Hz for the α and β
anomers of 8, respectively) (Table S1), suggesting a gauche form of the C1H and C2H protons for both anomers. This is indeed consistent with
a 2,3-diaxial conformation as observed for 8b′ in the solid state (Figure A). Thus, the 4-selenothreofuranose derivatives may maintain
a similar 2,3-diaxial conformation in solution too for both anomers.
Figure 2
Structural
characterization of 8b′ (X = Bz
and R = Ph). (A) Molecular structure for the α anomer of 8b′ determined by X-ray analysis. The ellipsoids are
drawn with 50% probability. (B) 1H NMR spectra for the
isolated α anomer of 8b′ and the mixture
of the α and β anomers in the regions of the CH protons
(top) and the CH2 protons (bottom).
Structural
characterization of 8b′ (X = Bz
and R = Ph). (A) Molecular structure for the α anomer of 8b′ determined by X-ray analysis. The ellipsoids are
drawn with 50% probability. (B) 1HNMR spectra for the
isolated α anomer of 8b′ and the mixture
of the α and β anomers in the regions of the CH protons
(top) and the CH2 protons (bottom).
Glycosylation of 4-Selenothreofuranose Derivatives
Subsequently,
we substituted the acetoxy (OAc) group at the anomeric
position of 8a–f to other functional groups, including
a nucleobase analogue. As a pilot experiment, the reactions of 8c (X = Bn and R = Me) with methanol (MeOH) in the presence
of an acid or a base were investigated (Table ).
Table 2
Methanolysis and
Glycosylation of 8c
entry
acid or base
eq
condition
yield of 9c (%)a
yield of 10c (%)a
1
K2CO3
0.5
0 °C/1.5 h
48 (76:24)
0
2
BF3·OEt2
6
rt/18 h
88 (66:34)
7
3
BF3·OEt2
1.5
reflux/18 h
0
95 (72:28)
4
AlCl3
3
rt/18 h
66 (67:33)
0
5
TMSOTf
4
rt/18 h
56 (73:27)
17 (49:51)
6
TMSOTf
1
reflux/18 h
0
86 (54:46)
The values in parentheses
are the
α/β ratios determined by integration of the 1H NMR peaks.
The values in parentheses
are the
α/β ratios determined by integn class="Species">ration of the 1HNMR peaks.
When potassium
an class="Chemical">carbonate was employed as a base in n class="Chemical">MeOH, methanolysis
took place, producing hemiselenoacetal9c in 48% yield
(entry 1). In this reaction, a plausible diselenide byproduct, which
would be formed by air oxidation of the ring-opened selenol isomer
of 9c, was also obtained. The α/β anomeric
ratio of 9c was 76:24, which was slightly augmented from
that of the substrate’s starting anomeric composition. On the
other hand, when boron trifluoride etherate (BF3·OEt2) was applied as a Lewis acid, the yield of 9c was significantly improved (entry 2), accompanied by formation of
a small amount of glycoside10c. Thus, the occurrence
of glycosylation of 8c in addition to the methanolysis
was suggested. Indeed, when the reaction was carried out at the reflux
temperature, 10c was obtained almost quantitatively with
the α/β ratio of 72:28 (entry 3). These anomers could
be separated by column chromatography and clearly characterized by
NMR. NOESY experiments for the major and minor anomers showed the
cross peaks between C1H and C3H protons and
between C1H and C2H protons, respectively, confirming
the assignments of the major/minor products to the α/β
anomers (Figures S57 and S62). Similarly,
in applications of aluminum chloride (AlCl3) and TMSOTf
as a Lewis acid, methanolysis product 9c was obtained
predominantly at room temperature, whereas at the reflux temperature,
glycoside10c was obtained in a good yield when TMSOTf
was employed (entries 4–6). Thus, it was found that the OAc
group at the anomeric position of 8c can be effectively
substituted by a methoxy group using BF3·OEt2 or TMSOTf as a Lewis acid. It is likely, however, that the α/β
selectivity of the glycosylation products would be decreased by the
use of TMSOTf.
We subsequently investigated the scope of the
glycosylation reaction
of 8 with various nucleophiles using BF3·OEt2 (Scheme ).
In ethanol instead of MeOH, the corresponding ethoxide11c was obtained in 84% yield. Allyltrimethylsilane (allylTMS) and anisole
also worked as glycosyl acceptors to produce C-glycosides12c, 12e, and 13c, although the
yields were low to moderate. Similar C-glycosylation
was previously reported for the corresponding threose derivative with
a better yield (88% using SnBr4),[45] suggesting the difficulty in the glycosylation of the 4-selenothreofuranose
skeleton. Acetonitrile (MeCN) reacted with 8a (X = Ac)
and 8b (X = Bz) at room temperature to afford glycosides14a and 14b, respectively. The N-glycosylation also proceeded using TMSOTf but with an inverted α/β
ratio. On the other hand, phenol and thioanisole did not work as a
glycosyl acceptor in this transformation reaction.
Scheme 2
Scope of the Glycosylation
of 8 with Various Acceptors
TMSOTf (3 eq) was used instead
of BF3·OEt2.
Scope of the Glycosylation
of 8 with Various Acceptors
n class="Chemical">TMSOTf (3 n class="Chemical">eq) was used instead
of n class="Chemical">BF3·OEt2.
The
anomeric mixture of an class="Chemical">14a was recrystallized, and
the molecular structure was determined by X-ray analysis. The results
revealed that the crystals can be characterized as a 2:1 mixture of
the α and β anomers, which were disordered in the crystal
(Figure S2). Thus, it was reconfirmed that
the α anomer was predominantly produced.
Synthesis of 4′-Selenothreonucleside
Derivatives
Having been encouraged with the formation of N-glycosylated
products in the presence of Lewis acids, we next investigated introduction
of a nucleobase at the anomeric position of 8, which
was obtained by seleno-Pummerer rearrangement (Table ), according to Jeong’s procedure.[31] However, all attempts were unsuccessful with 8b (X = Bz) having ester protecting groups, resulting in the
formation of a complex mixture of unknown products with a recovery
of a small amount of 8b (Table , entry 1). On the other hand, 4′-selenothreonucleoside
derivatives 15 and 16 were obtained from 8c (X = Bn) and 8f (X = TIPDS), having ethereal
protections, by the reaction with 6-chloropurineactivated with BSA
(entries 2–7).
Table 3
Synthesis of 4′-Selenothreonucleoside
Derivatives
entry
substrate
X
Lewis acid, eq
condition
yield of 15 (%)a
yield of 16 (%)a
1
8b
Bz
BF3·OEt2, 2
toluene/100 °C/18 h
0
0
2
8c
Bn
BF3·OEt2, 2
toluene/100 °C/1 h
3 (68:32)
10 (70:30)
3
8c
Bn
TMSOTf, 1
toluene/90 °C/18 h
27 (66:34)
36 (65:35)
4b
8c
Bn
TMSOTf, 1
toluene/90 °C/18 h
31 (62:38)
23 (61:39)
5
8c
Bn
TMSOTf, 1
MeCN/80 °C/3 h
3 (70:30)
19 (68:32)
6
8f
TIPDS
TMSOTf, 1
toluene/90 °C/18 h
11 (53:47)c
32 (34:66)c
7b
8f
TIPDS
TMSOTf, 1
toluene/90 °C/18 h
22 (52:48)c
25 (37:63)c
The values in parentheses are the
α/β ratios determined by integration of the 1H NMR peaks.
6-Chloropurine
1.2 eq and BSA 2.0
eq were used.
The yields
and α/β ratios
were determined based on the weights of the α and β anomers
isolated by column chromatography.
The values in parentheses are the
α/β ratios determined by integn class="Species">ration of the 1HNMR peaks.
al">6-Chloropurine
1.2 eq and BSA 2.0
eq were used.
The yields
and α/β an class="Species">ratios
were determined based on the weights of the α and β anomers
isolated by column chromatography.
When an class="Chemical">BF3·OEt2 was employed
as a Lewis
n class="Chemical">acid in toluene, the desired N-9 isomer (15c) and the
N-7 isomer (16c) were obtained from 8c (X
= Bn) in 3 and 10% yields, respectively (entry 2). Their α/β
ratios were about 7:3 (vide infra for the assignments), which was
the same as that of reactant 8c (see Table ). In this reaction, a polymerized
yellow viscous material was generated in a prolonged reaction. The
yields of 15c and 16c were significantly
improved by using TMSOTf instead of BF3·OEt2 (entry 3). The total yield (63%) was comparable with those reported
for the syntheses of 4′-selenoribonucleoside derivatives (Scheme ). Interestingly,
the ratio of 15c to 16c was inverted when
the amounts of 6-chloropurine and BSA were reduced to 1.2 and 2.0
eqs, respectively, while the total yield was slightly decreased (entry
4). The result suggested that the amount of the activated nucleobase
can influence the ratio of the N-9 and N-7 adducts. We further investigated
the reaction in MeCNaccording to the literature.[7] However, the yields of 15c and 16c were decreased (entry 5), probably due to the occurrence of the
reaction between 8c and MeCN (see Scheme ).
When similar rean class="Chemical">action conditions
were applied for 8f with cyclic TIPDS protection, expected
products 15f and 16f were obtained in slightly
decreased yields
(entries 6 and 7). In this case, however, the α and β
anomers could be separated by silica gel column chromatography for
both the products, and the molecular structures of the four stereoisomers
(i.e., α-15f, β-15f, α-16f, and β-16f) were determined by X-ray analysis
(Figure A).
Figure 3
Structural
characterization of 15f and 16f (X = TIPDS).
(A) Molecular structure for the α and β
anomers determined by X-ray analysis. The ellipsoids are drawn with
50% probability. Hydrogen atoms of β-16f were omitted
for clarity. (B) 1H NMR spectra for the isolated α
and β anomers in the regions of the aromatic protons (left)
and the furanose CH2 protons (right).
Structural
characterization of 15f and 16f (X = TIPDS).
(A) Molecular structure for the α and β
anomers determined by X-ray analysis. The ellipsoids are drawn with
50% probability. Hydrogen atoms of β-16f were omitted
for clarity. (B) 1HNMR spectra for the isolated α
and β anomers in the regions of the aromatic protons (left)
and the furanoseCH2 protons (right).In contrast to 8b′ (Figure A) and n class="Chemical">14a (Figure S2), the two substituents on the C2′
and C3′ carbon atoms occupy equatorial positions
of the furanose ring. This would be attributed to the conformational
constraint by the cyclic TIPDS protection. Importantly, the comparison
of their 1HNMR spectra with each other revealed convenient
clues for the assignments of stereochemistry for the 4′-selenothreofuranose
derivatives. The first clue was regarding the assignment of the N-9
(15) and N-7 (16) isomers. In the 1HNMR spectra for α- and β-15f (Figure B), the
two aromatic protons of the 6-chloropurine were shifted toward upfield
compared to α- and β-16f. The
second clue was for the assignment of α and β anomers.
The NMR peaks of the furanoseCH2 protons were more widely
separated from each other for β-15f and β-16f than those for α-15f and α-16f. The latter feature was consonant with that observed for the α
and β anomers of 8a–f (vide supra). Applying
these clues (i.e., an upfield shift of the aromatic protons for the
N-9 isomer and a wide separation of the ring CH2 protons
for the β isomer), we could easily assign the stereochemistry
for the four stereoisomers of 15c and 16c.
Mechanistic Insights into the Stereoselectivity of the Seleno-Pummerer-Type
Reactions
Formation of C- and N-glycosylation products (Scheme ) suggested that the C–O covalent bond at the
anomeric position of 8 was cleaved by the Lewis acid
to generate a selenonium ion (−Se+=C<)
as a possible intermediate. In addition, similar α/β ratios
(∼7:3) were observed for the glycosylation for the substrates
with ethereal protections (Scheme and Tables and 3) and the seleno-Pummerer rearrangement
(Table ), suggesting
the same selenonium intermediate being involved in both reactions.
Based on these considerations, a mechanism for the glycosylation was
proposed as shown in Scheme .
Scheme 3
Proposed Mechanism for Glycosylation of 8
Complex 17 between
the an class="Chemical">Lewis acid and substn class="Species">rate 8 would produce selenonium
ion 18 via elimination
of an acetate anion from the anomeric position. The elimination process
would compete with a nucleophilic attack of an alcohol molecule at
the carbonyl C atom of the OAc group because a methanolysis product
was obtained in the reaction of Table . However, the elimination would preferentially proceed
at high temperatures or in the absence of alcohol. Selenonium 18 should be stabilized by the resonance with a canonical
carbocation structure, which would accept an attack of a nucleophile
predominantly from the α direction (i.e., the anti direction with respect to the OX substituent at the C2 atom) due to the steric repulsion in the β attack (i.e., the syn attack with respect to the OX substituent at the C2 atom). When TSMOTf was employed as a Lewis acid, a significant
decrease in the α-attack selectivity was frequently observed
(entries 5 and 6 in Table , 14b in Scheme , and entries 6 and 7 in Table ). One possible explanation for this behavior
may be the participation of a triflate anion, which would weakly interact
to the cationic anomeric C atom preferentially from the α direction.
It is well established that when anucleobase is introduced at
the anomeric position of ribose in the presence of a Lewis acid, an
acyloxy substituent at the 2-position strongly stabilizes the cationic
anomeric C atom in the oxonium intermediate from the syn direction forming a cyclic structure, which sterically controls
the attack of a nucleobase from the anti direction.[46,47] Such a neighboring group participation is well known in the corresponding
thionium intermediates[48] and was applied
for the stereoselective synthesis of thioribonucleosides[7,49] and selenoribonucleosides (Scheme a).[29] In our reactions of Table and Scheme , the α/β selectivity
obviously decreased for the substrates having ester protections against
our expectation. This suggested that the contribution from the 2-acyloxy
group is not effective in the 4-selenothreofuranose skeleton. To elucidate
the reason for the decreased α/β selectivity, quantum
chemical calculation was performed for selenonium ion 18.The calculation was carried out at the B3LYP/6-31+G(d,p)
level
for 18′ (X = H) and 18″ (X
= Ac). The obtained stable structures, as well as those for the n class="Chemical">sulfur
analogues 19′ and 19″, are
shown in Figure .
Figure 4
Fully
optimized structures obtained for selenonium ions 18′ and 18″ and thionium ions 19′ and 19″ at B3LYP/6-31+G(d,p).
Fully
optimized structures obtained for an class="Chemical">selenonium ions 18′ and 18″ and thionium ions 19′ and 19″ at B3LYP/6-31+G(d,p).
In the optimized structures of 18′ and 19′ having two OH groups, the anomeric C atom adopts
ansp2-hybridized planar structure. Comparison of the natural
population analysis (n class="Chemical">NPA) charges of the C atoms indicated a less
electrophilicity of 18′ than that of 19′. On the other hand, two stable structures A and B, which have a
strong interaction between the anomeric C atom and the OAc group at
the 2- or 3-position, respectively, were found for 18″ and 19″. The relative energy (ΔE) of structure B with respect to structure A for selenonium 18″ was significantly smaller than that for thionium 19″ (ΔΔE = −3.8
kcal/mol), suggesting a stronger interaction of the OAc group at the
3-position for 18″. This would be reflected by
a shorter O–C1 atomic distance observed for 18″B (1.51 Å) than that for 19″B (1.53 Å). The stronger interaction would hinder the α
attack of a nucleophile at the anomeric C atom for 4-selenothreofuranose
derivatives having ester protections, resulting in the diminishing
α/β selectivity. For the case of 4-selenothreofuranose
derivatives having ethereal protection, such interactions as predicted
for 18″A and 18″B are not
feasible; hence, the stereoselectivity of the nucleophilic attack
would be simply controlled by the steric and/or conformational consequences
derived from the protecting groups.
Conclusions
In
this study, we have synthesized a series of 4-selenothreofuranose
derivatives (8–14) starting from n class="Chemical">DHS (5) via seleno-Pummerer rearrangement and subsequent nucleophilic substitution
reaction in the presence of BF3·OEt2 or
TMSOTf. The both reactions would be mediated by selenonium 18 as a common intermediate. The most selenosugars were obtained as
a ca. 7:3 mixture of α and β anomers. However, the α/β
selectivity was decreased when the 2- and 3-positions were protected
with ester functional groups because of the unexpected interaction
between the carbonyl O atom of the protecting group at the 3-position
and the anomeric C1 atom. On the other hand, the α/β
selectivity was slightly augmented when a cyclic protecting group,
that is, TIPDS, was applied (Table , entry 7). We further succeeded in the synthesis of
4′-selenothreonucleoside derivatives (15cf and 16cf) by N-glycosylation of 8c (X = Bn) and 8f (X = TIPDS) with activated 6-chloropurine.
The stereochemistry of all 4-selenothreose derivatives was unambiguously
characterized by 1HNMR spectroscopy as well as X-ray analysis.
Since an class="Chemical">selenosugars frn class="Chemical">equently exhibit greater biological activities
than the corresponding sulfur analogues,[19,22−24] the 4-selenothreose derivatives synthesized in this
study will be attractive as new-type building blocks for selenosugar-based
drugs with versatile bioactivities. Their incorporation into threose
nucleic acid, which is an artificial nucleic acid capable of carrying
the genetic information,[42,50] will also be an intriguing
challenge for developing novel variants of TNA.
Experimental Section
General
Procedure
1H (500 MHz), n class="Chemical">13C (125.8
MHz), and 77Se (95.4 MHz) NMR spectra were recorded
on a Bruker AV-500 spectrometer at 298 K. High-resolution mass spectra
(HRMS) were recorded on a JEOL JMS-T100LP mass spectrometer under
atmospheric pressure chemical ionization (APCI+) conditions. MALDI-TOF
mass spectra were recorded on a JEOL JMS-S3000 mass spectrometer with
a high-resolution mode. The sample was dispersed in the matrix of
α-cyano-4-hydroxycinnamic acid or 2,5-dihydroxybenzoic acid
with potassium iodide or sliver nitrate as a cationization agent and
polyethylene glycol as an internal standard. All reactions for the
synthesis were monitored by thin-layer chromatography, which was performed
on precoated sheets of silica gel 60 purchased from Merck Millipore.
Gel permeation chromatography (GPC) was performed with a JAI LC-918
high-performance liquid chromatograph (HPLC) system using CHCl3 as an eluent. Racemic trans-3,4-dihydroxytetrahydroselenophene
(or trans-3,4-dihydroxyselenolane, DHS, 5) was synthesized according to the literature procedure.[51] All other chemicals were used as purchased without
further purification.
To the solution of 5 (500 mg, 3.0
mmol) in tetrahydrofuran (THF, 7.5 mL) were added triethylamine (2.1
mL, 15 mmol) and acetic anhydride (1.1 mL, 12 mmol). The mixture was
stirred at 35 °C overnight. After removal of the solvent by evaporation,
the residual material was dissolved in diethyl ether. The organic
layer was washed with a saturated aqueous solution of ammonium chloride,
a saturated aqueous solution of sodium bicarbonate, and then brine
and was dried over magnesium sulfate. The crude product was purified
by silica gel column chromatography (hexane–diethyl ether 1:1)
to afford 6a as a colorless solid. Yield 627 mg, 84%.
mp 44–45 °C. 1HNMR (CDCl3): δ
5.36 (m, 2H), 3.23 (m, 2H), 2.96 (m, 2H), 2.07 (s, 6H). 13CNMR (CDCl3): δ 169.8, 78.2, 24.4, 21.0. Anal.
Calcd for C8H12O4Se: C, 38.26; H,
4.82. Found: C, 38.50; H, 5.01.
To the solution of 5 (100 mg, 0.6
mmol) in dichloromethane (DCM, 3 mL) were added triethylamine (0.17
mL, 1.2 mmol) and benzoyl chloride (0.14 mL, 1.2 mmol). The mixture
was stirred at room temperature. After completion of the reaction,
the reaction mixture was added with water and extracted with DCM (×2).
The combined organic layer was washed with a saturated aqueous solution
of ammonium chloride, a saturated aqueous solution of sodium bicarbonate,
and then brine and was dried over magnesium sulfate. The crude product
obtained was purified by silica gel column chromatography (hexane–diethyl
ether 5:1) to afford 6b as colorless crystals. Yield
221 mg, 98%. mp 121–126 °C. 1HNMR (CDCl3): δ 8.03 (m, 4H), 7.58 (m, 2H), 7.45 (m, 4H), 5.79
(m, 2H), 3.45 (m, 2H), 3.18 (m, 2H). 13CNMR (CDCl3): δ 171.7, 165.4, 133.8, 133.5, 130.2, 129.8, 129.5,
129.2, 128.5, 78.6, 24.4. 77Se NMR (CDCl3):
δ 118.9. HRMS (APCI-TOF) m/z: calcd for C18H16NaO4Se+ [M + Na]+, 399.0106; found, 399.0040. The molecular structure
of 6b was determined by X-ray analysis.
To the solution of 5 (300 mg, 1.8
mmol) in DMF (4 mL) cooled on ann class="Chemical">ice bath were added sodium hydride
(132 mg, 5.5 mmol) and benzyl bromide (0.42 mL, 3.0 mmol). The mixture
was stirred at room temperature overnight. The reaction mixture was
further added with sodium hydride (60 mg, 2.5 mmol) and stirred. After
completion of the reaction, the mixture was added with brine and extracted
with ethyl acetate (×3). The combined organic layer was washed
with water and then brine and dried over magnesium sulfate. The crude
product was purified by silica gel column chromatography (hexane–ethyl
acetate 17:1) to afford 6c as a colorless oil. Yield
503 mg, 82%. 1HNMR (CDCl3): δ 7.36–7.26
(m, 10H), 4.63 (d, J = 12.0 Hz, 2H), 4.56 (d, J = 12.0 Hz, 2H), 4.19 (m, 2H), 3.08 (dd, J = 4.0 and 10.0 Hz, 2H), 2.98 (dd, J = 3.0 and 10.0
Hz, 2H). 13CNMR (CDCl3): δ 138.4, 128.6,
127.9, 127.8, 84.5, 71.4, 24.8. 77Se NMR (CDCl3): δ 98.3. Anal. Calcd for C18H20O2Se: C, 62.25; H, 5.80. Found: C, 62.47; H, 5.79.
To the solution of 5 (32 mg,
0.19 mmol) in DMF (1.5 mL) were added sodium hydride (35 mg, 1.5 mmol)
and p-methoxybenzyl chloride (0.090 mL, 0.66 mmol).
The mixture was stirred at room temperature overnight. The reaction
mixture was added with water and extracted with ethyl acetate (×3).
The combined organic layer was washed with water and then brine and
dried over magnesium sulfate. The crude product was purified by silica
gel column chromatography (hexane–ethyl acetate 3:1) to afford 6d as a colorless oil. Yield 36 mg, 47%. 1HNMR
(CDCl3): δ 7.23 (d, J = 9.0 Hz,
4H), 6.87 (d, J = 9.0 Hz, 4H), 4.53 (d, J = 12.0 Hz, 2H), 4.47 (d, J = 12.0 Hz, 2H), 4.13
(m, 2H), 3.81 (s, 6H), 3.04 (dd, J = 4.0 and 10.5
Hz, 2H), 2.93 (m, 2H). 13CNMR (CDCl3): δ
159.3, 130.2, 129.3, 113.8, 83.9, 71.0, 55.3, 24.6. HRMS (MALDI-TOF-MS) m/z: calcd for C20H24AgO4Se+ [M + Ag]+, 514.9885; found,
514.9996.
To the solution of 5 (50 mg,
0.3 mmol) in DCM (3 mL) were added imidazole (16 mg, 0.24 mmol) and tert-butyldimethylsilyl chloride (47 mg, 0.3 mmol). The
mixture was stirred at room temperature for 5 h. The reaction mixture
was further added with imidazole (18 mg, 0.27 mmol) and tert-butyldimethylsilyl chloride (49 mg, 0.3 mmol) several times. After
completion of the reaction, the mixture was added with water and extracted
with DCM (×3). The combined organic layer was washed with brine
and dried over magnesium sulfate. The crude product was purified by
silica gel column chromatography (hexane–diethyl ether 3:1)
to afford 6e as colorless crystals. Yield 105 mg, 88%.
mp 38–39 °C. 1HNMR (CDCl3): δ
4.15 (m, 2H), 3.07 (dd, J = 3.5 and 10.0 Hz, 2H),
2.72 (dd, J = 2.5 and 9.0 Hz, 2H), 0.88 (s, 18H),
0.08 (s, 6H), 0.07 (s, 6H). 13CNMR (CDCl3):
δ 78.6, 24.4, 16.8, 0.0, −0.1,-4.3, −4.3. Anal.
Calcd for C16H36O2SeSi2: C, 48.58; H, 9.17. Found: C, 48.86; H, 9.50.
Under the an class="Chemical">nitrogen atmosphere, 5 (113 mg, 0.68 mmol)
and n class="Chemical">imidazole (148 mg, 2.0 mmol) were dissolved in pyridine (5 mL)
on an ice bath. To the solution was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane
(0.34 mL, 1.0 mmol). The mixture was stirred at room temperature overnight.
The mixture was then added with water and extracted with ethyl acetate
(×3). The combined organic layer was washed with brine and dried
over magnesium sulfate. The crude product was purified by silica gel
column chromatography (hexane–diethyl ether 20:1) to afford 6f as a colorless oil. Yield 256 mg, 93%. 1HNMR
(CDCl3): δ 4.17 (m, 2H), 2.85 (m, 2H), 2.74 (m, 2H),
1.06–0.87 (m, 28H). 13CNMR (CDCl3):
δ 81.1, 21.1, 17.5, 17.5, 17.3, 17.2, 13.0, 12.4. 77Se NMR (CDCl3): δ 39.4. HRMS (MALDI-TOF-MS) m/z: calcd for C16H34AgO3SeSi2+ [M + Ag]+,
517.0257; found, 517.0283.
General Procedure of Seleno-Pummerer
Rearrangement
To the solution of 6 (0.40 mmol)
in THF (3 mL) was added
aqueous H2O2 (30%, 1–3 eq). The mixture
was stirred at room temperature for 1–5 h. After the removal
of the solvent by evaporation, the resulting selenoxide 7 was dissolved in Ac2O (1.6 mL) or toluene (3 mL) containing
excess Ac2O. The mixture was stirred at 90–100 °C
for 1–2 h. Water (5 mL) was added, and the mixture was extracted
with ethyl acetate (AcOEt) (×3). The combined organic layer was
washed with a saturated aqueous solution of sodium bicarbonate and
then brine and dried over magnesium sulfate. The crude product obtained
was purified by silica gel column chromatography (hexane–ethyl
acetate) and/or GPC to yield 8 as a mixture of α
and β anomers.
To the solution of an class="Chemical">8c (108
mg, 0.27 mmol) in n class="Chemical">methanol (5 mL) was added BF3·OEt2 (52 μL, 0.40 mmol). The mixture was refluxed overnight.
The reaction mixture was added with an aqueous solution of sodium
carbonate (10%) and extracted with AcOEt (×3). The combined organic
layer was washed with brine and dried over magnesium sulfate. The
crude product was purified by silica gel column chromatography (hexane–ethyl
acetate 7:1) to yield 10c (97 mg, 95% yield) as a mixture
of α and β anomers (72:28). The anomers could be separated
by silica gel column chromatography.
Similarly, 11c was obtained
from 8c in refluxing ethanol. The α and β
anomers could be separated by silica gel column chromatography (hexane–ethyl
acetate 10:1). Colorless oil. Yield 84% (α/β = 53:47).
To the solution of an class="Chemical">8e (132
mg, 0.29 mmol) in n class="Chemical">toluene (4 mL) were added allylTMS (97 μL,
0.58 mmol) and BF3·OEt2 (160 μL,
1.2 mmol). The mixture was stirred at room temperature overnight.
The reaction mixture was added with a saturated aqueous solution of
sodium bicarbonate and extracted with AcOEt (×3). The combined
organic layer was washed with brine and dried over magnesium sulfate.
The crude product was purified by GPC. 8e was obtained
as a mixture with a small amount of an unknown compound (<10%),
which could not be separated by chromatography. Colorless oil. Yield
19 mg, 15% (α/β = 59:41). 1HNMR (CDCl3): δ 5.82–5.68 (m, 1H, α and β),
5.10–4.96 (m, 2H, α and β), 4.23–4.19 (m,
1H, α and β), 3.93–3.89 (m, 1H, α and β),
3.76 (m, 1H, β), 3.33 (m, 1H, α), 3.19–3.14 (m,
1H, α and β), 2.83–2.65 (m, 2H, α and β),
2.55 (m, 1H, β), 2.44–2.37 (m, 1H, α and β),
0.88–0.85 (s, 18H, α and β), 0.07–0.04 (s,
12H, α and β). 13CNMR (CDCl3):
δ 137.8, 137.4, 116.2, 115.7, 83.7, 81.3, 81.0, 79.8, 48.7,
45.9, 40.3, 35.3, 29.3, 28.9, 25.9, 25.8, 25.8, 18.1, 18.0, 18.0,
17.9, −4.2, −4.5, −4.6, −4.6, −4.7,
−4.7. 77Se NMR (CDCl3): δ 196.0
(β), 179.5 (α). HRMS (MALDI-TOF-MS) m/z: calcd for C19H40AgO2SeSi2+ [M + Ag]+, 543.0777;
found, 543.0836.
To the solution of an class="Chemical">8a (15
mg, 0.05 mmol) in n class="Chemical">acetonitrile (1 mL) cooled on an ice bath was added
BF3·OEt2 (27 μL, 0.21 mmol). The
mixture was stirred at 0 °C for 1.5 h. The reaction mixture was
added with a saturated aqueous solution of sodium bicarbonate and
extracted with AcOEt (×3). The combined organic layer was washed
with water and then brine and dried over magnesium sulfate. The crude
product was purified by GPC to yield 14a as colorless
crystals. Yield 9.2 mg, 63% (α/β = 57:43). mp 96–139
°C. 1HNMR (CDCl3): δ 6.30 (d, J = 8.5 Hz, 1H, β), 5.98 (dd, J =
5.0 and 9.0 Hz, 1H, α), 5.92 (d, J = 9.0 Hz,
1H, α), 5.61 (dd, J = 5.5 and 8.5 Hz, 1H, β),
5.39–5.23 (m, 2H, α and β), 3.38 (dd, J = 5.5 and 11.0 Hz, 1H, α), 3.24 (dd, J =
5.5 and 10.5 Hz, 1H, β), 3.12 (dd, J = 6.0
and 10.5 Hz, 1H, β), 2.89 (dd, J = 5.0 and
11.0 Hz, 1H, α), 2.14–1.98 (s, 9H, α and β). 13CNMR (CDCl3): δ 170.5, 170.0, 169.6, 169.6,
169.4, 169.4, 80.3, 77.1, 76.2, 75.7, 49.5, 47.2, 23.5, 23.4, 23.3,
23.1, 21.0, 20.9, 20.9. 77Se NMR (CDCl3): δ
286.3 (α), 267.6 (β). HRMS (MALDI-TOF-MS) m/z: calcd for C10H15NNaO5Se+ [M + Na]+, 332.0008; found, 332.0027.
The molecular structure of the anomeric mixture was determined by
X-ray analysis.
To the solution of an class="Chemical">8b (63
mg, 0.15 mmol) in n class="Chemical">acetonitrile (4 mL) cooled on an ice bath was added
BF3·OEt2 (47 μL, 0.36 mmol). After
stirring at 0 °C for 1.5 h, the mixture was further added with
BF3·OEt2 (24 μL, 0.18 mmol) and stirred
at 0 °C for 1 h. The reaction mixture was added with a saturated
aqueous solution of sodium bicarbonate and extracted with AcOEt (×3).
The combined organic layer was washed with water and then brine and
dried over magnesium sulfate. The crude product was purified by GPC
to yield 14b as a white solid. Yield 59 mg, 94% yield
as a mixture of α and β anomers (58:42). mp 180–185
°C. 1HNMR (CDCl3): δ 8.01 (m, 4H,
α and β), 7.60–7.40 (m, 6H, α and β),
6.63 (d, J = 8.0 Hz, 1H, β), 6.30 (d, J = 9.0 Hz, 1H, α), 6.23 (dd, J =
5.5 and 9.5 Hz, 1H, α), 5.81–5.68 (m, 2H, α and
β), 3.60 (dd, J = 5.5 and 11.0 Hz, 1H, α),
3.42 (dd, J = 5.5 and 10.5 Hz, 1H, β), 3.32
(dd, J = 6.5 and 10.5 Hz, 1H, β), 3.10 (dd, J = 5.0 and 11.0 Hz, 1H, α), 1.96 (s, 3H, α
and β). 13CNMR (CDCl3): δ 169.8,
166.1, 165.5, 165.2, 165.0, 133.9, 133.8, 133.7, 130.0, 129.9, 129.9,
129.6, 129.2, 129.1, 128.9, 128.7, 128.7, 128.7, 128.6, 128.6, 80.6,
77.6, 76.5, 49.1, 47.8, 23.9, 23.3, 23.2, 22.6. 77Se NMR
(CDCl3): δ 288.0 (α), 272.9 (β). HRMS
(MALDI-TOF-MS) m/z: calcd for C20H19NaO5Se+ [M + Na]+, 456.0321; found, 456.0317.
9-((3R,4R/3S,4S)-3,4-Bis(benzyloxy)tetrahydroselenophen-2-yl)-6-chloro-9H-purine (15c) and 7-((3R,4R/3S,4S)-3,4-Bis(benzyloxy)tetrahydroselenophen-2-yl)-6-chloro-7H-purine (16c)
Ina 50 mL two-neck
round-bottom flask, 6-chloropurine (326 mg, 2.0 mmol) and BSA (80%,
1.08 mL, 3.4 mmol) were dissolved in toluene (14 mL) under a nitrogen
atmosphere. The mixture was stirred at 90 °C for 1 h. To the
resulting yellow solution was added a solution of 8c (418
mg, 1.0 mmol) and TMSOTf (190 μL, 1.0 mmol) in toluene (4.5
mL). The mixture was stirred at 90 °C overnight to afford an
orange solution with a brown oily material. The reaction mixture was
added with a saturated aqueous sodium bicarbonate solution and extracted
with AcOEt (×3). The combined organic layer was washed with brine
and dried over magnesium sulfate. The crude products were purified
by silica gel column chromatography (hexane–ethyl acetate 1:2
to 1:1).
6-Chloro-9-((5aR,8aR/5aS,8aS)-2,2,4,4-tetraisopropyltetrahydroselenopheno[3,4-f][1,3,5,2,4]trioxadisilepin-6-yl)-9H-purine (15f) and 6-Chloro-7-((5aR,8aR/5aS,8aS)-2,2,4,4-tetraisopropyltetrahydroselenopheno[3,4-f][1,3,5,2,4]trioxadisilepin-6-yl)-7H-purine (16f)
Ina 50 mL two-neck round-bottom
flask, 6-chloropurine (194 mg, 1.2 mmol) and BSA (80%, 0.62 mL, 2.0
mmol) were dissolved in toluene (13 mL) under a nitrogen atmosphere.
The mixture was stirred at 90 °C for 1 h. To the resulting yellow
solution was added a solution of 8f (472 mg, 1.0 mmol)
and TMSOTf (190 μL, 1.0 mmol) dissolved in toluene (4 mL). The
mixture was stirred at 90 °C overnight to afford an orange solution
with a brown oily material. The reaction mixture was added with a
saturated aqueous sodium bicarbonate solution and extracted with AcOEt
(×3). The combined organic layer was washed with brine and dried
over magnesium sulfate. The crude products were purified by silica
gel column chromatography (hexane–ethyl acetate 3:1 to 2:1).
Single-crystal X-ray
diffran class="Chemical">action measurements
were performed on a Rigaku XtaLAB P200 diffractometer using graphite
monochromated Mo Kα radiation (λ = 0.71075 Å) or
Cu Kα radiation (λ = 1.54187 Å). Diffraction data
were collected and processed with CrysAlisPro version 1.171.39.46
(Rigaku Corporation) for 6b, 14a, α-15f, β-15f, α-16f, and β-16f and with CrystalClear (Rigaku Corporation) for 8b′. The structures were solved by the dual-space algorithm using SHELXT
(Version 2014/5)[52] and refined by the full-matrix
least-squares method on F2 using SHELXL
(Version 2018/3).[53] All calculations were
performed using the CrystalStructure software package (Rigaku Corporation).
The CIF files for these compounds were deposited on CCDC (CCDC 2046025–2046027,
2061703–2061704, and 2064007–2064008).
Theoretical
Calculation
Quantum chemical calculation
was performed using a Gaussian09 rev.B.01 program[54] at the B3LYP/6-31+G(d,p) level in vacuo. The geometries
of cations 18′, 18″A, 18″B, 19′, 19″A, and 19″B were fully optimized. The resulting
structure was characterized as a stationary point with no imaginary
vibrational frequency. The atomic charges were obtained by NPA.[55]
Authors: Varughese Alexander; Won Jun Choi; Jeongha Chun; Hea Ok Kim; Ji Hye Jeon; Dilip K Tosh; Hyuk Woo Lee; Girish Chandra; Jungwon Choi; Lak Shin Jeong Journal: Org Lett Date: 2010-05-21 Impact factor: 6.005
Authors: Jonathan K Watts; Blair D Johnston; Kumarasamy Jayakanthan; Alexander S Wahba; B Mario Pinto; Masad J Damha Journal: J Am Chem Soc Date: 2008-06-11 Impact factor: 15.419
Figure 1
Scheme 1
Figure 2
Scheme 2
Figure 3
Scheme 3
Figure 4