cis-tetrahydrofuran-3,4-diol structure as a key skeleton of new protecting groups removable by self-cyclization under oxidative conditions

Article abstract of DOI:10.1021/jo061006v

(Chemical Equation Presented) A variety of carbonate-type acyl groups having a cis-tetrahydrofuran-3,4-diol (1,4-anhydroerythritol) backbone structure and a TrS or MMTrS group have been examined as new "protected" protecting groups of the 5′-hydroxyl grou

Full text of DOI:10.1021/jo061006v

cis-Tetrahydrofuran-3,4-diol Structure as a Key Skeleton of New
Protecting Groups Removable by Self-Cyclization under Oxidative
Conditions
Eri Utagawa,†,§ Mitsuo Sekine,*,†,§ and Kohji Seio‡,§
Department of Life Science, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama 226-8501, Japan,
Frontier CollaboratiVe Research Center, Tokyo Institute of Technology, 4259 Nagatsuta,
Yokohama 226-8503, Japan, and CREST, Japan Science and Technology Agency, 4259 Nagatsuta,
Yokohama 226-8501, Japan
msekine@bio.titech.ac.jp
ReceiVed May 16, 2006
A variety of carbonate-type acyl groups having a cis-tetrahydrofuran-3,4-diol (1,4-anhydroerythritol)
backbone structure and a TrS or MMTrS group have been examined as new “protected” protecting groups
of the 5′-hydroxyl group of nucleosides. These acyl groups were designed in a manner where they could
be deprotected by I2-promoted removal of the TrS or MMTrS group followed by self-cyclization involving
an intramolecular attack of the once-generated neighboring hydroxyl group on the acyl carbon. It turned
out that these acyl groups could be introduced into the 5′-hydroxyl group of a 3′-O-protected thymidine
derivative by use of the corresponding acyl imidazolides or 4-nitrophenyl esters as well as by reaction
with carbonyldiimidazole or 4-nitrophenyl chloroformate. Among the acyl groups tested, it was found
that the CTFOC group could be easily introduced into the 5′-hydroxyl group of 3′-masked deoxyribo-
nucleoside derivatives and rapidly removed under mild conditions using iodine.
Introduction
groups in place of the acid-labile 4, 4′-dimethoxytrityl (DMTr)
group14 for the 5′-hydroxyl function. These new protocols
suppress the unfavorable depurination15-21 promoted by the acid
treatment during the detritylation step in the current DNA
synthesis.
In recent years, new oligodeoxynucleotide-synthesis protocols
that avoid acid treatment were developed by many groups.1-13
Some of them have developed oxidatively cleavable protecting
† Department of Life Science, Tokyo Institute of Technology.
‡ Frontier Collaborative Research Center, Tokyo Institute of Technology.
§ Japan Science and Technology Agency.
(1) Kocienski, P. J. Protecting Groups, 3rd ed.; Georg Thieme Verlag:
New York, 2005.
(2) Seio, K.; Sekine, M. Tetrahedron Lett. 2001, 42, 8657-8660.
(3) Seio, K.; Utagawa, E.; Sekine, M. HelV. Chim. Acta 2004, 87, 2318-
2333.
(4) Utagawa, E.; Seio, K.; Sekine, M. Nucleosides Nucleotides Nucleic
Acids 2005, 24, 927-929.
(5) (a) Sierzchala, A. B.; Dellinger, D. J.; Betley, J. R.; Wyrzykiewicz,
T. K.; Yamada, C. M.; Caruthers, M. H. J. Am. Chem. Soc. 2003, 125,
13427-13441. (b) Dellinger, D. J.; Caruthers, M. H.; Betley, J. R. U.S.
Patent 6,222, 030, April 24, 2001.
(6) Marchan, V.; Cieslak, J.; Livengood, V.; Beaucage, S. L. J. Am.
Chem. Soc. 2004, 126, 9601-9610.
(7) Chmielewski, M. K.; Marcha´n, V.; Cieslak, J.; Grajkowski, A.;
Livengood, V.; Mu¨nch, U.; Wilk, A.; Beaucage, S. L. J. Org. Chem. 2003,
26, 10003-10012.
(8) Bergmann, F.; Pfleiderer, W. HelV. Chim. Acta 1994, 77, 481-801.
(9) Lehmann, C.; Xu, Y. Z.; Christodoulou, C.; Tan, Z. K.; Gait, M. J.
Nucleic Acids Res. 1989, 17, 2379-2390.
(10) Iwai, S.; Ohtsuka, E. Tetrahedron Lett. 1988, 29, 5383-5386.
(11) Kamaike, K.; Takahashi, H.; Morohoshi, K.; Nataoka, N.; Kakinuma,
T. Ishido, Y. Acta Biochim. Pol. 1998, 45, 949-976.
(12) Fodor, S. P. A.; Read, J. L.; Pirrung, M. C.; Stryer, L. T.; Lu, A.;
Solas, D. Science 1991, 251, 767-773.
(13) Pease, A. C.; Solas, D.; Sullivan, E. J.; Cronin, M. T.; Holmes, C.
P.; Fodor, S. P. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 5022-5026.
(14) Schaller, H.; Weimann, B.; Lerch, B.; Khorana, H. G. J. Am. Chem.
Soc. 1963, 85, 3821-3827.
10.1021/jo061006v CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/26/2006
7668
J. Org. Chem. 2006, 71, 7668-7677

Protecting Groups RemoVable by Self-Cyclization
a
TABLE 1. Comparison of Self-Cyclization Kinetics after Treatment with 0.5 M I2
a Compounds 9, 24, 26, and 18 were used as their diastereomeric mixtures. Values in parenthesizes are the T1/2 of each diastereoisomers.
FIGURE 1. Structures of the MOB, TFOC, MTFOC, and CTFOC groups.
We have been interested in the protection of the hydroxyl
group as a sulfenic acid ester which can regenerate the original
hydroxyl function under nonacidic mild conditions. The first
example of sulfenate-type protecting groups in the field of
nucleic acid chemistry was shown by Letsinger et al. in 1964.22
They chose a 2,4-dinitrobenzenesulfenyl group to protect
hydroxyl groups and deprotected them by polarizable nucleo-
philes such as thiosulfate, cyanide and thiolate ions. We reported
4-methoxytritylthio (MMTrS) as a different sulfenate-type
protecting group removable under mild oxidative conditions.2
More recently, we have developed 2-[(4-methoxytritylsulfenyl)-
oxymethyl]benzoyl (MOB) as a new acyl-type protecting group
having an MMTrS group on the hydroxyl oxygen atom3 (see
Table 1). The MOB group could be readily introduced to the
5′-hydroxyl group of nucleosides and removed in two steps
including the oxidative cleavage of the S-O bond by iodine2-4,23
and the successive base-catalyzed self-cyclization. Oxidatively
cleavable protecting groups have been reported by several re-
search groups, and their usefulness in the synthesis of oligo-
deoxynucleotides has also been demonstrated. For example,
Caruthers has reported a new strategy for the synthesis of oligo-
deoxyribonucleotides by use of 4-chlorophenoxycarbonyl as a
new 5′-hydroxyl protecting group that can be removed by treat-
ment with H2O2 under slightly basic conditions.5 On the other
hand, Beaucage has reported 2,2,5,5-tetramethylpyrrolidin-3-
one-1-sulfinyl as a protecting group that can be removed by a
1 min treatment with 0.02 M I2 in THF-pyridine-H2O followed
by exposure to a solution of 0.1 M I2, 0.25 M 3-acetylpyridiine,
and 0.125 M trichloroacetic acid in THF-H2O for 8 min.6
In this paper, we report the development of new protected
protecting groups such as TFOC, MTFOC and CTFOC (Figure
1) having a TrS or an MMTrS moiety by use of a cis-tetra-
hydrofuran-3,4-diol (1,4-anhydroerythrito) skeleton capable of
rapid deprotection by the action of an aqueous I2 solution in
pyridine-H2O (9:1, v/v) in two steps. The detailed kinetic anal-
yses revealed that the MTFOC and CTFOC groups could be
deprotected more rapidly than the previously reported MOB
group, in the absence of base catalysts, and could be useful for
protection of hydroxyl functions removable under mild condi-
tions.
(15) Septak, M. Nucleic Acids Res. 1996, 24, 3053-3058.
(16) Schulhof, J. C.; Molko, D.; Teoule, R. Nucleic Acids Res. 1987,
15, 397-416.
(17) Kume, A.; Iwase, R.; Sekine, M.; Hata, T. Nucleic Acids Res. 1984,
12, 8525-8538.
(18) Froehler, B. C.; Matteuci, M. D. Nucleic Acids Res. 1983, 11, 8031-
8036.
(19) Schaller, H.; Weimann, G.; Lorch, B.; Khorana, H. G. J. Am. Chem.
Soc. 1963, 85, 3821-3827.
(20) Efcavitch, J. W.; Heiner, C. Nucleosides Nucleotides 1985, 4, 267.
(21) Caruthers, M. H. Acc. Chem. Res. 1991, 24, 278-284.
(22) Letsinger, R. L.; Fontaine J.; Mahadevan, V.; Schexnayder, D. A.;
Leone, R. E. J. Org. Chem. 1964, 29, 2615-2618.
As described in this paper, the TFOC, MTFOC, and CTFOC
groups and nucleoside derivatives incorporating these protecting
(23) Takaku, H.; Imai, K.; Nagai, M. Chem. Lett. 1988, 857-860.
J. Org. Chem, Vol. 71, No. 20, 2006 7669

Utagawa et al.
SCHEME 1. Synthesis of Acylating Agents 3a and 3ba
presence of 1.0 equiv of DBU gave a diastereomeric mixture
of the 5′-O-masked product 5 in 70% yield, as shown in Scheme
2. In contrast, when the imidazolide 3b was used as the acylating
agent, a catalytic amount of DBU27 (0.15 equiv) was sufficient,
and the reaction was completed within 3 h. Thus, compound 5
was obtained in 81% yield. These results clearly suggest that
the acylating agent 3b has higher reactivity than 3a.
An alternative approach to 5 was also developed, as shown
in Scheme 3. In this procedure, the thymidine 5′-O-carbonate
and carbamate derivatives 628 and 7 were prepared as nucleo-
side-type acylating agents by the reaction of 4 with 4-nitrophenyl
chloroformate and CDI, respectively. The reaction of nucleoside-
type acylating agents and the hydroxyl compound 2 successfully
gave the desired compound 5. In agreement with the above-
mentioned reactivity of 3a and 3b, it was also observed that
the reaction of 2 with the imidazolide 7 proceeded much faster
(3 h) than that with the 4-nitrophenyl carbonate derivative 6 (6
h). Thus, compound 5 was obtained in 76% yield by use of 6
and in a higher yield of 91% by use of 7. By comparing the
yields of 5 obtained by use of 3a, 3b, 6, and 7, it was concluded
that the use of nucleoside-type acylating agents such as 7 was
the best to introduce the TFOC group into the 5′-hydroxyl group
of thymidine.
In a similar way, 5′-O-MTFOC-3′-O-TBDMS-thymidine (9)
having a more labile MMTrS group in place of the TrS group
was also obtained in 93% yield by use of the alcohol 8 which
was synthesized in 82% yield from compound 1 and the
nucleoside-type acylating agent 7, as shown in Scheme 3. Both
5 and 9 were obtained as diastereomer mixtures. In both cases,
the diastereomer ratios were found to be 1:1 from the NMR
spectra.
Unfortunately, the isomers of 5 and 9 could not be separated
by silica gel column chromatography. Therefore, they were used
as isomeric mixtures in the kinetic studies described below.
Kinetics of Deprotection of the MTFOC Group. To see if
the erythritol structure will undergo self-cyclization at the second
stage required for removal of the protecting group, 9 was treated
with a 0.5 M solution of iodine in pyridine-d5/D2O (9:1, v/v)
and the reaction was monitored by 1H NMR (signals of the 1′-H
proton were compared, Scheme 4). As expected, the MMTrS
group was promptly removed from 9 within 1 min. It turned
out that the resulting alcohol intermediate 10 was gradually
converted to 4. The NMR analysis revealed that the half-life of
the intermediate 10 was 51 min. Because of the overlap of the
two 1′-H protons of the diastereomers of the intermediate 10,
the cyclization kinetic parameter should be considered as an
averaged value of the two diastereomers. Such averaged data,
however, are sufficient for the practical use of the MTFOC
group as a protecting group.
Design of New Protecting Groups by Considering Con-
formation Energies. We intended to design a new structure
which would lead to more rapid deprotection. For this purpose,
the conformation properties of cis-tetrahydrofuran-3,4-diol (11)
and cis-3,4-oxomethylenedioxy-tetrahydrofuran (12), the residue
of the MTFOC group generated after the self-cyclization, were
analyzed by the ab initio calculations (HF/6-31G*). The results
are shown in Figure 2. The lowest energy conformation of the
cyclized product 12 was an O1-exo envelope structure,29 whereas
a Reagents and conditions: (i) NaH, THF; (ii) TrSCl, THF, quant (iii)
4-NO2C6H4OC(O)Cl, pyridine, CH2Cl2, 77%; (iv) CDI, pyridine, quant.
groups can be used as mixtures of the stereoisomers because of
similar physicochemical properties of these isomers. Other pre-
vious diastereomeric protecting groups, such as 2,2,5,5-tetra-
methylpyrrolidin-3-one-1-sulfinyl,6 tetrahydropyran-2-yl,24 R-meth-
yl-2-nitropiperonyloxycarbonyl,25 and N-substituted 2-amino-
1-phenylethyl-1-yl-oxycarbonyl26 have been used as diastereo-
isomeric mixtures without incurring any crucial problems.
Results and Discussion
Introduction of the TFOC and MTFOC Groups into the
5′-Hydroxyl Group. To develop new protecting groups which
can be removed more readily than the MOB group in two steps
(Scheme 4) under mild conditions, we designed carbonate-type
protecting groups, that is, cis-[4-(tritylsulfenyloxy)tetrahydro-
furan-3-yl]oxycarbonyl (TFOC) and cis-[4-[(4-methoxytrityl)-
sulfenyloxy]tetrahydrofuran-3-yl]oxycarbonyl (MTFOC), having
a cis-tetrahydrofuran-3,4-diol backbone structure where one of
the hydroxyl functions is masked by a TrS and an MMTrS
group, respectively,3 as shown in Figure 1, Scheme 2 and
Scheme 3.
First of all, we studied the introduction of the TFOC group
into the 5′-hydroxyl group of nucleosides by use of 3′-O-(tert-
butyldimethylsilyl)thymidine (4, Scheme 2) as a model com-
pound. For this purpose, acylating agents 3a and 3b were syn-
thesized, as shown in Scheme 1. The reaction of 1,4-anhydro-
erythritol (1) with TrSCl gave the sulfenylated product 2, which
was obtained as a pair of two diastereoisomers, that is, the
(3S,4R)- and (3R,4S)-isomers. The reaction of 2 with 4-nitro-
phenyl chloroformate gave the active ester 3a, whereas the
reaction of 2 with carbonyldiimidazole (CDI) gave the urethane
3b, as shown in Scheme 1. The latter was used without further
purification for the next reaction. Both 3a and 3b were obtained
as diastereomeric mixtures.
Next, we compared the reactivity of 3a and 3b to the 5′-
hydroxyl group. The reaction of 4 with 3a for 13 h in the
(24) Green, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
(25) Pease, A. C.; Solas, D.; Sullivan, E. J.; Cronin, M. T.; Holmes, C.
P.; Fodor, S. P. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 5022-5026.
(26) Chimielewski, M. K.; Marchan, V.; Cieslak, J.; Grajkowski, A.;
Livengood, V.; Munch, U.; Wilk, A.; Beaucage, S. L. J. Org. Chem. 2003,
68, 10003-10012.
(27) Hu, Y.; Qiao, L.; Wang, S.; Rong, S.; Meuillet, E. J.; Berggren,
M.; Gallegos, A.; Powis, G.; Kozikowski, A. P. J. Med. Chem. 2000, 43,
3045-3051.
(28) Letsinger, R. L. Ogilvie, K. K. J. Org. Chem. 1967, 32, 296-300.
7670 J. Org. Chem., Vol. 71, No. 20, 2006

Protecting Groups RemoVable by Self-Cyclization
SCHEME 2. Introduction of the TFOC Group by Use of 3a and 3b into the 5′-Hydroxyl Groupa
a Reagents and conditions: (i) 3a, DBU, pyridine, 70%; (ii) 3b, DBU, pyridine, 81%.
SCHEME 3. Alternative Route to 5 and Synthesis of 9a
FIGURE 2. Structures (upper row) and the lowest energy conforma-
tions (lower row) of cis-tetrafuran-3,4-diol derivatives.
To confirm this idea, we designed 2,3-dihydroxy-7-oxabicyclo-
[2.2.1]heptane (13) and calculated the conformation energies
of it and its cyclic carbonate 14.
As the result, it was found that both of the cis-tetrahydrofuran-
diol part rings of 13 and 14 were fixed in the O7-exo form.
Therefore, it was expected that there is no necessary conforma-
tion change during the cyclization so that the reaction would
be accelerated. Such a bicyclic system having a conformationally
locked 1,2-diol function has recently been utilized as a base-
labile linker, which connects the DNA chain to a polymer
support, for the synthesis of oligodeoxynucleotides.30
Because 13 was not easily available,31,32 we designed a new
protecting group, CTFOC (Figure 1), which could be introduced
to the nucleosides as shown in Scheme 5. Compound 15 was
prepared by a Diels-Alder reaction33 of furan and N-benzyl-
maleimide. The dihydroxylation34,35 of 15 gave exo-N-(phen-
ylmethyl)-7-oxabicyclo[2.2.1]heptane-5,6-dihydroxy-2,3-dicar-
boximide (16) as shown in Scheme 5. Compound 16 was
converted to the MMTrS derivative 17, and the reaction of 17
with 7 gave the 5′-O-masked product 18 as a diastereomeric
mixture in 72% yield according to the almost identical protocols
shown in Schemes 1 and 3.
a Reagents and conditions: (i) 4-NO2C6H4OC(O)Cl, dioxane-pyridine,
82%; (ii) CDI, pyridine; (iii) 6, 2, DBU, 76%; (iv) 7, 2, DBU, pyridine,
91%; (v) NaH, THF; (vi) MMTrSCl, THF, 82%; (vii) 7, DBU, 93%.
SCHEME 4. Removal of the MTFOC Groupa
a Reagents and conditions: (i) 0.5 M I2, pyridine-d5/D2O (9:1, v/v).
the lowest energy conformation of 11 was the C3-endo or
C4-endo envelope form. Moreover, it was also proved that the
O1-exo envelope conformation of 11 (structure not shown in
Figure 2) was energetically less favorable by +5.0 kcal/mol
than the C3-endo or C4-endo form. These results indicated that
the cyclization of the intermediate 10 needs conformational
change of the five-membered ring from the lowest energy C3
(or C4) -endo form to the energetically unfavorable O1-exo
form. Therefore, we thought that faster cyclization could be
achieved by fixing the five-membered ring of the tetrahydrofuran
in O1-exo conformation by introduction of another ring structure.
Kinetics of Deprotection of the CTFOC Group. The
kinetics of the deprotection of the CTFOC group of 18 by the
1
aqueous iodine treatment was monitored by H NMR (signals
of the 1′-H proton were compared, Scheme 4.) As described
above, the half-life measured by this method should be regarded
(30) Guzaev, A. P.; Manoharan, M. J. Am. Chem. Soc. 2003, 125, 2380-
2381.
(31) Newman, M. S.; Addor, R. W. J. Am. Chem. Soc. 1955, 77, 3789-
3793.
(32) Lambert, J. B.; Larson, E. G. J. Am. Chem. Soc. 1985, 107, 7546-
7550.
(29) In this paper, the C3-endo-envelope structure means that C3 is
located at the opposite side of the diol function. The O1-exo-envelope
structure means that O1 is placed at the same side of the diol function. The
conformations of 13 and 14 are named similarly.
(33) Clevenger, R. C.; Turnbull, K. D. Synth. Commun. 2000, 30, 1379-
1388.
(34) Yang, W.; Koreeda, M. J. Org. Chem. 1992, 57, 3836-3839.
(35) Daniels, R.; Fischer, J. L. J. Org. Chem. 1963, 28, 320-322.
J. Org. Chem, Vol. 71, No. 20, 2006 7671

Utagawa et al.
SCHEME 5. Introduction of the CTFOC Group to Compound 7a
a Reagents and conditions: (i) 1,4-dioxane, 54%; (ii) OsO4, morpholine-N-oxide, acetone-H2O ) 6:1 (v/v), 83%; (iii) NaH, DMF; (iv) MMTrSCl, DMF,
53%; (v) 7, DBU, pyridine, 72%.
as the averaged values of the diastereomers. In addition to 18,
we studied the deprotection kinetics of the various protecting
groups 9, 19, 22, 24, and 26 (Table 1) to confirm the superiority
of the cis-tetrahydrofuran-3,4-diol structure of compound 9 and
the conformationally locked derivative 18 to other ring struc-
tures such as the benzene ring of 19 or 22, and the cyclohex-
ane ring of 24 or 26. Compound 19 was synthesized according
to the procedure reported previously.3 The 5-nitrobenzoyl-
type11 derivative 22 was prepared similarly. We also prepared
the cis-1,2-cyclohexanediol derivative 24 and the trans-1,2-
cyclohexanediol derivative 26 as regioisomeric mixtures ac-
cording to the procedure described above (see also Supporting
Information).
Apparently, these experiments showed the superiority of 9
(T1/2 ) 51 min) and 18 (T1/2 ) 6 min) which have a
cis-tetrahydrofuran-3,4-diol skeleton to the other substrates
(Table 1). Moreover, the CTFOC derivative 18 showed the
fastest deprotection rate of all. These results clearly showed the
advantage of the conformationally fixed structure as a new
protecting group skeleton capable of the rapid removal by its
self-cyclization. Neither the cis-diol derivative 24 with a six-
membered ring nor the trans-diol 26 cyclized even after
prolonged reaction time. These results indicated that both the
cis-diol and the five-membered ring were important structural
components which enabled the rapid deprotection of the
MTFOC and CTFOC groups.
In addition to the analysis of the averaged deprotection
kinetics, in the case of compounds 9 and 18, we could measure
deprotection kinetics of each diastereoisomer by monitoring the
methyl protons signals of the thymine. The values are shown
in Table 1. In the case of compound 9 having the MTFOC
group, one of the diastereoisomers cyclized 1.4 times more
rapidly with the T1/2 value of 44 min than the other with that of
61 min. Similarly, in the case of compound 18 having the
CTFOC group, the half-lives of two isomers were 7 and 5 min.
These results clearly showed that the cyclization kinetics of the
diastereomers were different, but the differences were not so
large, at most 1.4 times.
(27), 4-N-benzoyl-3′-O-(tert-butyldimethylsilyl)deoxycytidine
(28), and 3′-O-(tert-butyldimethylsilyl)-2-N-isobutyryldeoxygua-
nosine (29) with the CTFOC group and the deprotection to
clarify the applicability for all four deoxynucleosides. The
compounds were synthesized according to the procedure already
shown in Scheme 3. When adenosine derivative (27) and
cytidine derivative (28) were treated with 1.5 equiv of CDI,
the reactions proceeded smoothly to give the imidazolide
intermediates which could be converted to the target material
30 and 31 in 71% and 81% yields, respectively (Scheme 6). In
contrast, guanosine derivative 29 required 3 equiv of CDI to
complete the formation of the imidazolide. Moreover, the second
reaction of the imidazolide of dGiBu with 17 was very slow, 30
h to complete the reaction.
Next, we examined the removal of the CTFOC group of the
four deoxynucleosides 18, 30, 31, and 32 and the recovery of
the 5′-free nucleosides 4, 27, 28, and 29 by silica gel column
chromatography, considering the practical use of the CTFOC
group in synthetic chemistry (Scheme 6, step iii). Compound
18 was treated with 0.1 M I2 in pyridine-H2O (9:1, v/v), and
the reaction was monitored by silica gel TLC. To our surprise,
when the reaction mixture was checked after 5 min, the TLC
indicated the complete conversion of 18 to the 5′-free nucleoside
4, not to the intermediates before cyclization, despite the fact
that the half-life () 6 min) of the cyclization in solution was
longer (Table 1). These results indicated the acceleration of the
cyclization on TLC probably by the catalytic effects of silica
gel. On the basis of this observation, we established the
following procedure for removal of the CTFOC group.
The protected nucleosides 18, 30, 31, and 32 were treated
with 0.1 M I2 in the pyridine-H2O for 5 min. After the general
workup procedure (see Experimental Section), the solvents were
removed under reduced pressure, and the residues were chro-
matographed on a silica gel column to give the 5′-free
nucleosides which were generated by the silica gel catalyzed
cyclization on the column. The 5′-free nucleosides 4, 27, 28,
and 29 were obtained in quantitative yield, 83%, 95%, and 74%
yield, respectively as shown in Scheme 6. These results
confirmed the usefulness of the CTFOC group as the protecting
group; it could be removed under mild oxidative conditions in
combination with general workup procedure and silica gel
column chromatography.
Practical Method for Removal of the CTFOC Group from
All Four Canonical Deoxynucleosides. We also examined the
protection of the 5′-hydroxyl group of other nucleosides, that
is, 6-N-benzoyl-5′-O-(tert-butyldimethylsilyl)deoxyadenosine
7672 J. Org. Chem., Vol. 71, No. 20, 2006

Protecting Groups RemoVable by Self-Cyclization
SCHEME 6. Introduction of the CTFOC Group and Recovered Yields after the Deprotectiona
a Reagents and conditions: (i) CDI, pyridine; (ii) 17, DBU, pyridine, 72% for 18, 71% for 30, 81% for 31, 72% for 32; (iii) 0.1 M I2, pyridine-H2O (9:1,
v/v), then silica gel column chromatography; quant for 18, 83% for 30, 95% for 31, and 74% for 32.
Conclusion
methylpyrrolidin-3-one-1-sulfinyl group.6 In conclusion, we
reported the CTFOC group as a new protected protecting group
removable under mild oxidative conditions. It should be also
emphasized that the CTFOC group is the first example of the
carbonate-type protected protecting group utilizing such a cis-
diol structure.
In this paper we described new protecting groups, MTFOC
and CTFOC, which can be removed in two steps including the
cleavage of the MMTrS group under mild oxidative conditions
and the self-cyclization. These new protecting groups have the
cis-tetrahydrofuran-3,4-diol structure in which the two hydroxyl
groups are fixed in close proximity by the furan ring. In addition,
the five-membered ring of CTFOC group is fixed in O7-exo
conformation to avoid the energetically unfavorable conforma-
tion change during the cyclization. We revealed that the
conformation-lock of the five-membered ring accelerated the
second step self-cyclization 8.5-fold. We also demonstrated that
the CTFOC group could be introduced to the 5′-hydroxyl
function of all four canonical deoxynucleosides and removed
by the combination of the mild oxidation and silica gel assisted
cyclization of the resulting intermediates. The CTFOC group
is readily removable and can serve as protecting group for the
hydroxyl function of various compounds.
Introduction of the MTFOC and CTFOC groups to nucleo-
sides results in the formation of two diastereoisomers because
of the presence of a pair of chiral centers. In general, the mixture
of diastereomers can be used as described above. However,
when the MTFOC and CTFOC groups are applied to molecules
containing other diastereomeric protecting groups such as
2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinyl,6 tetrahydropyran-
2-yl,24 R-methyl-2-nitropiperonyloxycarbonyl,25 and N-substi-
tuted 2-amino-1-phenylethyl-1-yl-oxycarbonyl26 groups, the
resulting mixtures of isomers would be more complex. There-
fore, the MTFOC and CTFOC groups would be the most
valuable when applied to the solid-phase synthesis of oligode-
oxyribonucleotides. Especially, the most rapidly removable
CTFOC group should be useful in the oligonucleotide synthesis
without acid treatment as exemplified by precedents using the
MMTrS group3 as well as the aryloxycarbonyl group capable
of deprotection by the action of peroxide5 and 2,2,5,5-tetra-
Experimental Section
(3S,4R)- and (3R,4S)-4-(Tritylsulfenyloxy)tetrahydrofuran-
3-ol (2). To a solution of 1,4-anhydroerythritol (1) (0.14 g, 1.3
mmol) in THF (10 mL) was added NaH (64 mg, 1.6 mmol, 60%
in oil). The resulting mixture was stirred at room temperature for
40 min, and then tritylsulfenyl chloride (0.50 g, 1.6 mmol) was
added. After being stirred at room temperature for 2.5 h, the reaction
was quenched by addition of concentrated NH3 (1 mL). The solution
was diluted with ethyl acetate (25 mL) and washed once with water
(30 mL) and twice with saturated NaHCO3 (30 mL). The organic
layer was collected, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was chromatographed on a
silica gel column (20 g) with hexane-ethyl acetate (2:1, v/v) to
give 2 (0.51 g, quant): 1H NMR (500 MHz, CDCl3): δ 2.08 (s,
1H), 3.37-3.39 (m, 2H), 3.56 (dd, J ) 5.0, 9.5 Hz, 1H), 3.68-
3.72 (m, 2H), 3.87 (dd, J ) 5.5, 10.0 Hz, 3H) 7.27-7.40 (m, 15H).
13C NMR (67.8 MHz, CDCl3): δ 70.7, 71.0, 72.5, 87.3, 127.6,
128.2, 129.9, 142.3. ESI-MS: calcd for C23H22NaO3S (M + Na)+,
401.11819; found, 401.11115.
3′-O-tert-Butyldimethylsilyl-5′-O-[[[(3S,4R)- and (3R,4S)-4-
(tritylsulfenyloxy)tetrahydrofuran-3-yl]oxy]carbonyl]thymi-
dine (5). Method A. Compound 2 (0.38 g, 1.0 mmol) was rendered
anhydrous by repeated coevaporation with dry toluene and finally
dissolved in dry CH2Cl2 (1 mL). To the solution was added dry
pyridine (0.19 mL, 2.4 mmol). A solution of 4-nitrophenyl
chloroformate (0.24 g, 1.2 mmol) in CH2Cl2 (1 mL) was added
dropwise over 5 min to the CH2Cl2 solution of 2. After being stirred
at room temperature for 70 min, the reaction was quenched by
addition of water (1 mL). The solution was diluted with ethyl acetate
(30 mL) and washed three times with sat. NaHCO3 (30 mL). The
organic layer was collected, dried over MgSO4, filtered, and
J. Org. Chem, Vol. 71, No. 20, 2006 7673

Utagawa et al.
concentrated under reduced pressure. The residue was chromato-
graphed twice on a silica gel column (20 g) with hexane-ethyl
acetate (100:3, v/v) to give a crude mixture (0.42 g) which contained
the target material (3a) (90%), the starting material (2) (6%), and
4-nitrophenol (4%). Compound 3a: 1H NMR (500 MHz, CDCl3):
δ 3.29-3.36 (m, 2H), 3.81-3.90 (m, 3H), 4.92 (dd, J ) 5.13, 10.0
Hz, 1H), 7.22-7.38 (m, 17H), 8.19-8.22 (m, 2H). 13C NMR (67.8
MHz, CDCl3): δ 68.9, 70.4, 72.4, 76.5, 84.7, 121.8, 125.2, 127.4,
128.0, 129.8, 129.8, 142.1, 145.3, 151.8, 155.2.
A mixture of the carbonate intermediate 6 (0.18 g, 0.35 mmol)
and 2 (0.13 g, 0.35 mmol) was rendered anhydrous by repeated
coevaporation with dry pyridine and finally dissolved in dry pyridine
(1 mL). To this mixture was added DBU (52 µL, 0.35 mmol). After
being stirred at room temperature for 6 h, the solution was diluted
with ethyl acetate (20 mL) and washed once with water (20 mL)
and three times with saturated NaHCO3 (20 mL). The organic layer
was collected, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was chromatographed on an NH-
silica gel column with hexane-chloroform (1:1, v/v) to give 5 (0.20
g, 76%).
Method D. Compound 4 (1.8 g, 5.0 mmol) was rendered
anhydrous by repeated coevaporation with dry pyridine and finally
dissolved in dry pyridine (12 mL). To this solution was added
carbonyldiimidazole (1.2 g, 7.5 mmol). After being stirred for 1 h,
the solution was diluted with ethyl acetate (100 mL) and washed
three times with water (100 mL). The organic layer was collected,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue became an amorphous solid. On the basis of
the NMR analysis of this residue, it was confirmed that the starting
material was changed to 5′-O-[(1H-imidazol-1-yl)carbonyl]-3′-O-
(tert-butyldimethylsilyl)thymidine (7) completely. A portion of the
amorphous solid (0.23 g, 0.50 mmol) was rendered anhydrous by
repeated coevaporation with dry pyridine and finally dissolved in
dry pyridine (10 mL). Compound 2 (0.19 g, 0.50 mmol) was also
rendered anhydrous by repeated coevaporation with dry pyridine.
The pyridine solution of 7 was added to this residue. DBU (7.5
µL, 50 µmol) was added. After being stirred at room temperature
for 3 h, the solution was diluted with ethyl acetate (20 mL) and
washed four times with water (20 mL). The organic layer was
collected, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was chromatographed on a silica gel
column with hexane-ethyl acetate (3:1, v/v) to give 5 (0.35 g,
91%).
A mixture (0.42 g) of the crude product 3a, which was calculated
to contain 3a (0.40 g, 0.73 mmol), and 3′-O-(tert-butyldimethyl-
silyl)thymidine (4)36 (0.26 g, 0.73 mmol) was rendered anhydrous
by repeated coevaporation with dry pyridine and finally dissolved
in dry pyridine (3 mL). To this solution was added DBU (110 µL,
0.73 mmol). After being stirred at room temperature for 13 h, the
solution was diluted with ethyl acetate (30 mL) and washed three
times with saturated NaHCO3 (30 mL). The organic layer was
collected, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was chromatographed on an NH-
silica gel column with hexane-ethyl acetate (7:13, v/v) to give
compound 5 (0.39 g, 70%). 1H NMR (500 MHz, CDCl3): δ 0.042-
0.086 (m, 6H), 0.85-0.93 (m, 9H), 1.92 and 1.95 (2 × s, 3H),
2.12-2.32 (m, 2H), 3.24-3.26 (m, 2H), 3.72-3.84 (m, 3H), 4.06-
4.09 (m, 1H), 4.35-4.42 (m, 3H), 4.84-4.89 (m, 1H), 6.33-6.34
(m, 1H), 7.25-7.33 (m, 32H), 7.45 and 7.46 (2 × s, 1H), 9.08 and
9.10 (2 × br, 1H). 13C NMR (67.8 MHz, CDCl3): δ -4.9, -4.9,
-4.7, 12.6, 12.6, 17.9, 17.9, 25.7, 40.9, 41.0, 67.0, 67.1, 69.3,
69.3, 70.5, 70.7, 71.7, 71.8, 72.4, 75.7, 75.9, 84.5, 84.7, 84.8, 85.0,
85.1, 85.3, 111.3, 127.5, 127.6, 128.1, 130.0, 130.0, 135.3, 135.5,
142.3, 142.3, 150.0, 150.1, 154.1, 163.3. ESI-MS: calcd for
C40H48N2NaO9SSi (M + Na)+, 783.27420; found, 783.27197.
Method B. Compound 2 (0.19 g, 0.50 mmol) was rendered
anhydrous by repeated coevaporation with dry pyridine and finally
dissolved in dry pyridine (2 mL). To this solution was added
carbonyldiimidazole (0.12 g, 0.75 mmol). After being stirred for
50 min, the solution was diluted with ethyl acetate (20 mL) and
washed once with water (20 mL) and twice with brine (20 mL).
The organic layer was collected, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue became an
amorphous solid. On the basis of the NMR analysis of this residue,
it was confirmed that the starting material was completely changed
to 3-[[(1H-imidazol-1-yl)carbonyl]oxy]-4-(tritylsulfenyloxy)tetrahy-
(3S,4R)- and (3R,4S)-4-[[(4-Methoxytrityl)sulfenyl]oxy]tet-
rahydrofuran-3-ol (8). Compound 1 (0.13 g, 1.2 mmol) was
dissolved in THF (10 mL). To this solution was added NaH (59
mg, 1.5 mmol), and the resulting mixture was stirred for 40 min.
4-Methoxytritylsulfenyl chloride (0.50 mg, 1.5 mmol) was added.
After being stirred at room temperature for 4 h, the mixture was
quenched by the addition of concentrated NH3 (1 mL). The solution
was diluted with ethyl acetate (40 mL) and washed once with water
(50 mL) and twice with saturated NaHCO3 (50 mL). The organic
layer was collected, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was chromatographed on a
silica gel column (20 g) with hexane-ethyl acetate (8:2, v/v) to
1
drofuran (3b). H NMR (500 MHz, CDCl3): δ 3.31 (d, J ) 5.5
Hz, 1H), 3.70-3.75 (m, 2H), 3.84 (dd, J ) 6.0, 10.0 Hz, 1H),
4.92 (dd, J ) 5.0, 10.5 Hz, 1H), 7.00-7.37 (m, 17H), 8.10 (s,
1H). 13C NMR (67.8 MHz, CDCl3): δ 22.8, 69.4, 70.7, 72.5, 75.6,
84.8, 117.2, 127.5, 128.1, 129.9, 130.8, 137.3, 142.2, 148.0.
A mixture of 3b and 4 (0.12 g, 0.34 mmol) was rendered
anhydrous by repeated coevaporation with dry pyridine and finally
dissolved in dry pyridine (2 mL). To this mixture was added DBU
(7.5 µL, 0.05 mmol). After being stirred at room temperature for 3
h, the solution was diluted with ethyl acetate (20 mL) and washed
four times with brine (20 mL). The organic layer was collected,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was chromatographed on a silica gel column
with hexane-chloroform (1:1, v/v) to give 5 (0.21 g, 81%).
Method C. Compound 4 (1.8 g, 5.0 mmol) was rendered
anhydrous by repeated coevaporation with dry pyridine and finally
dissolved in dry pyridine (5 mL). A solution of 4-nitrophenyl
chloroformate (1.1 g, 5.0 mmol) in dioxane (5 mL) was added
dropwise over 100 min to the pyridine solution of 4. After being
stirred at room temperature for 1.5 h, the solution was diluted with
CHCl3 (100 mL) and washed three times with water (100 mL).
The organic layer was collected, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was chromato-
graphed on a silica gel column (100 g) with hexane-ethyl acetate
(1:4, v/v) to give 628 (2.1 g, 82%).
1
give 8 (0.41 g, 82%). H NMR (500 MHz, CDCl3): δ 2.53 (s,
1H), 3.33-3.39 (m, 2H), 3.50-3.53 (dd, J ) 5.1, 9.2 Hz, 1H),
3.65-3.73 (m, 2H), 3.74 (s, 3H), 3.86 (dd, J ) 5.3, 10.6 Hz, 1H),
6.80-7.20 (m, 2H), 7.22-7.28 (m, 8H), 7.37-7.38 (m, 4H). 13C
NMR (67.8 MHz, CDCl3): δ 55.0, 70.5, 70.8, 71.8, 72.1, 87.0,
113.2, 127.2, 127.9, 129.7, 129.7, 130.9, 133.6, 142.5, 142.6, 158.6.
Anal. Calcd for C24H24O4S: C, 70.56; H, 5.92; S, 7.85. Found: C,
70.37; H, 6.06; S, 7.69.
3′-O-tert-Butyldimethylsilyl- 5′-O-[[(3S, 4R)- and (3R, 4S)-4-
(4-metoxytrityl)sulfenyl]oxytetrahydrofuran-3-yl]oxycarbon-
ylthymidine (9). The above-mentioned amorphous solid of 7 (0.72
g, 1.6 mmol) was rendered anhydrous by repeated coevaporation
with dry pyridine. Compound 8 (0.65 g, 1.6 mmol) was also
rendered anhydrous by repeated coevaporation with dry pyridine
and finally dissolved in dry pyridine (10 mL). The solution was
added to 7. DBU (24 µL, 0.16 mmol) was added. After being stirred
for 2.5 h, the solution was diluted with ethyl acetate (80 mL) and
washed three times with burin (80 mL). The organic layer was
collected, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was chromatographed on a silica gel
column with hexane-ethyl acetate (5:1, v/v) to give 9 (1.2 g, 93%).
The ratio of the diastereomers was found to be 1:1 from the NMR
1
(36) Ogilvie, K. K. Can. J. Chem. 1973, 51, 3799-3807.
7674 J. Org. Chem., Vol. 71, No. 20, 2006
spectra. H NMR (500 MHz, CDCl3): δ 0.046-0.091 (m, 6H),

Protecting Groups RemoVable by Self-Cyclization
0.88-0.92 (m, 9H), 1.94 and 1.95 (2 × s, 3H), 2.12-2.32 (m, 2H),
3.26-3.33 (m, 2H), 3.73-3.86 (m, 6H), 4.05-4.10 (m, 1H), 4.35-
4.46 (m, 3H), 4.85-5.02 (m, 1H), 6.34-6.37 (m, 1H), 6.80-6.83
(m, 2H), 7.21-7.78 (m, 14H), 9.73 (br, 1H). 13C NMR (67.8 MHz,
CDCl3): δ -5.0, -5.0, -4.9, -4.8, 12.5, 12.5, 17.7, 17.8, 25.5,
40.7, 40.8, 55.1, 66.8, 66.9, 69.1, 69.2, 70.4, 70.6, 71.5, 71.6, 71.8,
71.8, 75.6, 75.7, 84.2, 84.5, 84.6, 84.8, 84.8, 85.1, 111.2, 111.2,
113.2, 127.3, 127.3, 127.9, 129.8, 129.8, 129.8, 131.0, 131.0, 133.6,
133.6, 135.2, 135.3, 142.5, 142.6, 150.4, 150.5, 154.0, 158.6, 158.7,
163.9, 163.9. ESI-MS calcd for C41H50N2NaO10SSi (M + Na)+,
813.28476; found, 813.28355.
matographed on a silica gel column with hexane-ethyl acetate (2:
1
1, v/v) to give 18 (0.35 g, 72%). H NMR (500 MHz, CDCl3): δ
0.03-0.09 (m, 6H), 0.87-0.90 (m, 9H), 1.93 (s, 3H) 2.16-2.29
(m, 1H), 2.67 (t, J ) 7.3 Hz, 1H), 3.42 and 3.50 (d, J ) 5.9, 6.1
Hz, 1H), 3.79 and 3.80 (2 × s, 3H), 3.97 and 4.03 (2 × s, 1H),
4.07-4.11 (m, 1H), 4.36-4.45 (m, 3H), 4.54 (s, 2H), 4.61 and
4.64 (2 × d, J ) 6.1, 5.9 Hz, 1H), 4.67 and 4.70 (2 × s, 1H), 6.37
(t, J ) 6.6 Hz, 1H), 6.84-6.87 (m, 2H), 7.21-7.47 (m, 17H), 9.61
(s, 1H). 13C NMR (67.8 MHz, CDCl3): δ -5.0, -4.9, -4.9, -4.8,
12.4, 12.5, 17.7, 25.5, 40.6, 40.7, 42.6, 44.8, 45.2, 55.0, 67.2, 67.3,
71.6, 71.6, 72.0, 81.0, 81.1, 82.4, 82.7, 84.2, 84.3, 84.6, 84.8, 88.1,
88.7, 111.2, 111.4, 113.3, 127.5, 127.7, 127.9, 128.0, 128.4, 129.6,
129.8, 131.1, 131.1, 133.3, 133.4, 134.8, 135.2, 135.2, 142.2, 142.5,
142.6, 150.4, 154.0, 158.7, 163.8, 163.9, 174.1, 174.6, 174.6.
ESI-MS: calcd for C52H57N3O12SSiNa (M + Na)+, 998.3324;
found, 998.3315.
Tetrabutylammonium 5-Nitro-2-hydroxymethylbenzoate (20).
6-Nitrophthalide (40 g, 0.22 mol) was dissolved in 10% tetrabu-
tylammonium hydroxide in water (560 mL). The solution was
heated under reflux for 1 h. The mixture was cooled to room
temperature and then concentrated under reduced pressure. The
residue was crystallized from ethyl acetate, and the crystals were
collected by filtration to give 20 (61 g, 63%). 1H NMR (500 MHz,
CDCl3): δ 0.97 (t, J ) 7.3 Hz, 12H), 1.38-1.44 (m, 8H), 1.61-
1.68 (m, 8H), 3.28 (t, J ) 8.5 Hz, 8H), 4.71 (s, 2H), 7.32-7.35
(m, 1H), 8.03-8.06 (m, 1H), 8.82-8.83 (m, 1H). 13C NMR (67.8
MHz, CDCl3): δ 129.9, 142.5, 146.8, 147.9, 170.5. Anal. Calcd
for C24H42N2O5: C, 65.72; H, 9.65; N, 6.39. Found: C, 65.42; H,
9.42; N, 6.33.
exo-N-(Phenylmethyl)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-di-
carboxiimide (15). To a solution of N-benzylmaleimide (1.87 g,
10 mmol) in dioxane (30 mL) was added furan (2.18 mL, 30 mmol).
°
The reaction apparatus was sealed, heated, and kept at 90 C for
12 h. After being cooled to the room temperature, the mixture was
evaporated under reduced pressure. Addition of ethyl acetate and
hexane to the residue gave compound 15 as crystals (1.39 g, 54%).
1
The structure of 15 was confirmed by comparison of its H NMR
chemical shifts with those reported in the previous paper.37
5,6-Dihydroxy-exo-N-(phenylmethyl)-7-oxabicyclo[2.2.1]-
heptane-2,3-dicarboximide (16). Compound 15 (5.7 g, 22 mmol)
was dissolved in acetone (180 mL). To this solution were added
water (30 mL), OsO4 (2.5 wt % in 2-methyl-2-propanol, 0.22 mmol,
2.8 mL) and N-methylmorpholine N-oxide (4.8 M in water, 5.6
mL, 27 mmol). The mixture was stirred in the dark at room
temperature for 18 h. From the suspended mixture, acetone was
removed by evaporation under reduced pressure. Filtration of the
precipitates followed by washing with MeOH gave 16 (5.4 g, 83%).
1H NMR (500 MHz, DMSO-d6): δ 3.08 (s, 2H), 3.90 (s, 2H), 4.31
(s, 2H), 4.54 (s, 2H), 4.97 (s, 2H), 7.17-7.32 (m, 5H). 13C NMR
(67.8 MHz, DMSO-d6): δ 41.6, 45.3, 71.8, 83.8, 126.9, 128.5,
135.8, 176.8. Anal. Calcd for C15H15NO5: C, 62.28; H, 5.23; N,
4.84. Found: C, 61.90; H, 5.07; N, 4.90. The stereochemistry of
this compound was assigned to be exo-cis-glycol on the basis of
the previous papers.34,35
Triethylammonium 5-Nitro-2-[(4-methoxytritylsulfenyl)oxy-
methyl]benzoate (21). Compound 20 (4.4 g, 10 mmol) was
suspended in THF (50 mL), and the mixture was heated to 47 °C
to give a clear solution. NaH (0.60 g, 15 mmol, 60% in oil) was
added, and the resulting suspension was stirred at 47 °C for 15
min. The reaction mixture was cooled to room temperature. To
this solution was added 4-methoxytritylsulfenyl chloride (5.1 g, 15
mmol). After being stirred for 20 min, the reaction was quenched
by the addition of concentrated ammonia (5 mL), and the solution
was partitioned between ethyl acetate (300 mL) and saturated
NaHCO3 (100 mL). The aqueous layer was removed, and the
organic layer was washed twice with saturated NaHCO3 (100 mL),
dried over MgSO4, filtered, and concentrated under reduced
pressure. The desired product was purified by using a two-layer
column of silica gel (100 g, upper layer) and NH silica gel (100 g,
lower layer) eluted with CHCl3-MeOH-NEt3 (100:2:10, v/v/v)
6-Hydroxyl-5-[[(4-methoxytrityl)sulfenyl]oxy]-exo-N-(phen-
ylmethyl)-7-oxabicyclo[2.2.1]heptane-2,3-dicarboximide (17). To
a solution of 16 (0.87 g, 3.0 mmol) in DMF (30 mL) was added
NaH (0.14 g, 3.6 mmol, 60% in oil). The mixture was stirred at
room temperature for 55 min, and then (4-methoxytrityl)sulfenyl
chloride (1.2 g, 3.6 mmol) was added. After being stirred for 3 h,
the mixture was quenched by the addition of concentrated NH3 (1
mL). The solution was diluted with ethyl acetate (50 mL) and
washed three times with water (50 mL). The organic layer was
collected, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was chromatographed on a silica
gel column (40 g) with hexane-ethyl acetate (2:1, v/v) to give
1
to give 21 (3.2 g, 54%). H NMR (500 MHz, CDCl3): δ 1.36 (t,
J ) 7.5 Hz, 9H), 3.13 (q, J ) 7.5 Hz, 6H), 3.76 (s, 3H), 4.92 (s,
2H), 6.78 (d, J ) 8.1 Hz, 2H), 7.24-7.44 (m, 13H), 8.11 (d, J )
8.5 Hz, 1H), 8.67 (s, 1H). 13C NMR (67.8 MHz, CDCl3): δ 8.6,
45.2, 45.4, 45.6, 55.1, 55.3, 72.0, 78.5, 113.2, 113.4, 124.9, 125.1,
127.2, 127.4, 127.9, 128.0, 130.0, 131.2, 131.3, 133.1, 134.1, 143.0,
146.6, 158.7, 169.4. Anal. Calcd for C34H38N2O6S-NEt3: C, 67.75;
H, 6.35; N, 4.65; S, 5.32. Found: C, 68.17; H, 6.02; N, 4.59; S,
5.20.
1
17 (0.94 g, 53%). H NMR (500 MHz, CDCl3): δ 2.18 (d, J )
6.8 Hz, 1H), 2.56 (d, J ) 7.1 Hz, 1H), 2.62 (d, J ) 8.5 Hz,
1H), 3.18 (d, J ) 6.1 Hz, 1H), 3.66 (t, J ) 7.2 Hz, 1H), 3.82 (s,
3H), 4.16 (d, J ) 0.49 Hz, 1H), 4.50 (d, J ) 0.73 Hz, 1H), 4.56 (s,
1H), 6.86-6.89 (m, 2H), 7.23-7.41 (m, 17H). 13C NMR (67.8
MHz, CDCl3): δ 42.7, 44.8, 45.5, 55.3, 72.3, 73.8, 82.3, 84.3, 88.1,
113.5, 127.6, 127.7, 127.9, 128.1, 128.2, 128.3, 128.7, 129.8, 129.9,
131.2, 133.5, 135.1, 142.3, 142.5, 158.9, 174.8, 175.3 ppm. ESI-
MS: calcd for C35H31NNaO6S (M + Na)+, 616.17643; found,
616.17214.
3′-O-tert-Butyldimethylsilyl-5′-O-[5-nitro-2-[(4-methoxytri-
tylsulfenyloxy)methyl]benzoyl]thymidine (22). Compound 4 (0.50
g, 1.4 mmol), 21 (0.60 g, 2.1 mmol), and 4-methoxypyridine-1-
oxide hydrate (0.13 g, 1.1 mmol) were separately rendered an-
hydrous by repeated coevaporation with dry pyridine and dissolved
in 2 mL, 5 mL, and 5 mL of dry pyridine, respectively. To the
solution of 4 were added successively the pyridine solution of
triethylammonium 5-nitro-2-[(4-methoxytritylsulfenyl)oxymethyl]-
benzoate and the pyridine solution of 4-methoxypyridine-1-oxide,
and finally N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.54
g, 2.1 mmol) was added. After being stirred at room temperature
for 13 h, the mixture was quenched by the addition of water (5
mL). The solution was diluted with ethyl acetate (200 mL) and
washed three times with saturated NaHCO3 (200 mL). The organic
layer was collected, dried over MgSO4, filtered, and concentrated
3′-O-tert-Butyldimethylsilyl-5′-O-CTFOC-thymidine (18). Com-
pound 17 (0.30 g, 0.50 mmol) was rendered anhydrous by repeated
coevaporation with dry pyridine and finally dissolved in dry pyridine
(5 mL). This solution was added to 7 (0.23 g, 0.50 mmol). To the
mixture was added 0.1 equiv of DBU (7.5 µL, 0.05 mmol). After
being stirred at room temperature for 4 h, the solution was diluted
with ethyl acetate (30 mL) and washed four times with burin (30
mL). The organic layer was collected, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was chro-
(37) Kwart, H.; Burchuk, I. J. Am. Chem. Soc. 1952, 74, 3094-3097.
J. Org. Chem, Vol. 71, No. 20, 2006 7675

Utagawa et al.
under reduced pressure. The residue was chromatographed on an
NH silica gel column with hexane-chloroform (1:1, v/v) to give
22 (1.2 g, 99%). 1H NMR (500 MHz, CDCl3): δ 0.11 (s,
6H), 0.91 (s, 9H), 1.76 (s, 3H), 2.19-2.24 (m, 1H), 2.33-2.38
(m, 1H), 3.78 (s, 3H), 4.15-4.18 (m, 1H), 4.41-4.43 (m, 1H),
4.44-4.48 (m, 1H), 4.82 (s, 2H), 6.20 (d, J ) 6.5 Hz, 1H),
6.80-6.82 (m, 2H), 7.13-7.39 (m, 14H), 8.25-8.27 (m, 2H), 8.66
(s, 1H). 13C NMR (67.8 MHz, CDCl3): δ -4.8, -4.7, 12.3, 17.9,
25.6, 40.4, 55.2, 64.5, 71.8, 72.1, 77.6, 84.1, 85.7, 111.2, 113.3,
124.9, 126.8, 127.4, 127.8, 128.1, 128.8, 129.9, 131.2, 133.8, 135.3,
142.8, 142.8, 146.5, 148.0, 149.8, 158.8, 163.2. Anal. Calcd for
C44H49N3O10SSi: C, 62.91; H, 5.88; N, 5.00; S, 3.82. Found: C,
63.34; H, 5.77; N, 4.68; S, 3.54.
2H), 1.60-1.63 (br, 1H), 1.72 (br, 1H), 1.78-1.82 (m, 1H), 2.93-
2.97 (m, 1H), 3.77 (s, 3H), 6.81-6.84 (m, 2H), 7.23-7.38 (m,
12H).
3′-O-tert-Butyldimethylsilyl-5′-O-[[(1S,2S) and (1R,2R)-[1-[(4-
methoxytrityl)sulfenyl]oxy]cyclohexane-2-yl]oxy]carbonyl]thy-
midine (26). The crude material 25 was rendered anhydrous by
repeated coevaporation with dry pyridine and finally dissolved in
dry pyridine (10 mL). The solution was added to compound 7 (0.26
g, 0.57 mmol). To the mixture was added 1.0 equiv of DBU (85
µL, 0.57 mmol). The resulting mixture was heated to 50 °C and
stirred for 3.5 h. Then the solution was diluted with ethyl acetate
(40 mL) and washed four times with burin (40 mL). The organic
layer was collected, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was chromatographed on a
silica gel column with hexane-ethyl acetate (4:1, v/v) to give 26
cis-1-[(4-Metoxytrityl)sulfenyl]oxy-cyclohexane-2-ol (23). cis-
1,2-Cyclohexanediol (0.23 g, 2.0 mmol) was dissolved in THF (10
mL). To this solution was added lithium bis(trimethylsilyl)amide
(1 M solution in THF, 2 mL), and the resulting solution was stirred
at room temperature for 30 min. 4-Methoxytritylsulfenyl chloride
(0.82 g, 2.4 mmol) was added. After being stirred at room
temperature for 4 h, the mixture was quenched by the addition of
concentrated NH3 (1 mL). The solution was diluted with ethyl
acetate (80 mL) and washed once with water (80 mL) and twice
with burin (80 mL). The organic layer was collected, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was chromatographed on a silica gel column (20 g) with
hexane-ethyl acetate (19:1, v/v) to give the crude product of 23
(0.43 g). 1H NMR (500 MHz, CDCl3): δ 0.93-0.97 (m, 1H), 1.12-
1.22 (m, 3H), 1.42-1.50 (m, 3H), 1.64-1.68 (m, 1H), 1.78 (br,
1H), 3.08-3.09 (m, 1H), 3.76 (s, 3H), 6.79-6.83 (m, 2H), 7.14-
7.40 (m, 12H).
1
(70 mg, 15%). H NMR (500 MHz, CDCl3): δ 0.049-0.086 (m,
6H), 0.83-0.88 (m, 10H), 0.96-1.02 (m, 1H), 1.13-1.26 (m, 3H),
1.40-1.45 (m, 1H), 1.52-1.58 (m, 1H), 1.85 and 1.86 (2 × s, 3H),
1.93-2.29 (m, 6H), 3.22-3.33 (m, 1H), 3.79 (s, 3H), 4.02-4.05
(m, 1H), 4.25-4.49 (m, 4H), 6.26 and 6.36 (t, J ) 6.6 Hz, 1H),
6.77-6.82 (m, 2H), 6.82-7.47 (m, 14H), 8.88 and 8.97 (2 × s,
1H). 13C NMR (67.8 MHz, CDCl3): δ -4.97, -4.88, -4.75, 12.6,
12.7, 17.9, 23.1, 23.3, 23.7, 25.6, 29.6, 30.2, 30.7, 31.1, 41.0, 41.1,
55.2, 66.0, 66.2, 71.4, 71.6, 71.9, 72.1, 80.4, 81.2, 84.5, 84.7, 84.9,
88.3, 89.4, 110.8, 111.0, 113.1, 127.2, 127.3, 127.7, 128.0, 128.2,
129.6, 130.0, 130.1, 130.2, 131.1, 131.2, 133.9, 134.4, 135.3, 135.5,
142.9, 143.1, 143.3, 143.4, 150.3, 154.2, 158.7, 163.6, 163.7. Anal.
Calcd for C43H54N2O9SSi-1/2H2O: C, 63.60; H, 6.83; N, 3.45.
Found: C, 63.57; H, 6.77; N, 3.54.
6-N-Benzoyl-3′-O-(tert-butyldimethylsilyl)-2′-deoxy-5′-O-CT-
FOC-adenosine (30). 6-N-Benzoyl-3′-O-(tert-butyldimethylsilyl)-
2′-deoxyadenosine (27)36 (0.47 g, 1.0 mmol) was rendered anhy-
drous by repeated coevaporation with dry pyridine and finally
dissolved in dry pyridine (7 mL). Carbonyldiimidazole (0.24 g, 1.5
mmol) was added, and the solution was stirred at room temperature
for 40 min. The solution was diluted with ethyl acetate (50 mL)
and washed three times with water (50 mL). The organic layer was
collected, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue became an amorphous solid. The
NMR analysis of this residue suggested that the starting material
was changed to the imidazolide intermediate completely. A portion
of the amorphous solid, the imidazolide (0.40 g, 0.70 mmol), was
rendered anhydrous by repeated coevaporation with dry pyridine.
Compound 17 (0.42 g, 0.70 mmol) was also rendered anhydrous
by repeated coevaporation with dry pyridine and dissolved in
pyridine (2.5 mL). To this solution were added the imidazolide
and DBU (11 µL, 0.07 mmol). After being stirred at ambient
temperature for 3 h, the solution was diluted with ethyl acetate (20
mL) and washed four times with water (20 mL) and burin (20 mL).
The organic layer was collected, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was chromato-
graphed on a silica gel column with hexane-ethyl acetate (1:1,
3′-O-tert-Butyldimethylsilyl-5′-O-[(1R,2S)- and (1S,2R)-[1-(4-
methoxytrityl)sulfenyl]oxycyclohexane-2-yl]oxycarbonylthymi-
dine (24). The crude material 23 was rendered anhydrous by
repeated coevaporation with dry pyridine and dissolved in pyridine
(5 mL). The solution was added to compound 7 (0.45 g, 1.0 mmol).
DBU (154 µL, 1.0 mmol) was added. After being stirred at ambient
temperature for 4 h, the solution was diluted with ethyl acetate (40
mL) and washed four times with burin (40 mL). The organic layer
was collected, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was chromatographed on a silica gel
column with hexane-ethyl acetate (4:1, v/v) to give 24 (0.38 g,
46%). 1H NMR (500 MHz, CDCl3): δ 0.044-0.077 (m, 6H), 0.76-
1.00 (m, 10H), 1.11-1.47 (m, 6H), 1.77-2.11 (m, 5H) 2.25-2.30
(m, 1H), 3.16 and 3.22 (2 × br, 1H), 3.79 (s, 3H), 4.03-4.07 (m,
1H), 4.26-4.47 (m, 3H), 4.45-4.47 (m, 1H), 6.29-6.36 (m, 1H),
6.78-6.83 (m, 2H), 7.22-7.50 (m, 14H), 8.89 (s, 1H). 13C NMR
(67.8 MHz, CDCl3): δ -5.0, -4.9, -4.9, -4.8, -4.7, 12.6, 12.7,
12.7, 17.9, 20.9, 21.5, 22.1, 22.1, 25.6, 25.7, 27.3, 27.7, 28.2, 28.6,
40.7, 40.9, 55.2, 55.2, 66.4, 66.5, 71.5, 71.6, 72.0, 72.1, 84.2,
84.5, 84.7, 84.8, 84.9, 85.2, 111.2, 113.1, 113.2, 127.2, 127.8,
130.0, 131.1, 131.2, 134.4, 134.4, 135.3, 135.7, 143.2, 143.3, 143.4,
150.2, 150.3, 154.2, 154.3, 158.7, 163.7. ESI-MS: calcd for
C43H54N2O9SSiNa (M + Na)+, 825.32115; found, 825.32612.
1
v/v) to give 30 (0.55 g, 71%). H NMR (500 MHz, CDCl3): δ
0.11-0.14 (m, 6H), 0.92-0.93 (m, 9H), 2.15-2.17 (m, 1H), 2.48-
2.51 (m, 1H), 2.67-2.71 (m, 1H), 2.82-2.84 (m, 1H), 3.47 and
3.74 (2 × d, J ) 4.9, 5.9 Hz, 1H), 3.74 and 3.77 (2 × s, 3H), 3.94
and 4.05 (2 × s, 1H), 4.20-4.56 (m, 5H), 4.66-4.68 (m, 1H),
4.70-4.73 (m, 1H), 6.48-6.51 (m, 1H), 6.81-6.84 (m, 2H), 7.16-
7.53 (m, 21H), 7.92 and 7.93 (2 × s, 1H), 7.99 and 8.01 (2 × s,
1H), 8.25 and 8.28 (2 × s, 1H), 8.73 and 8.77 (2 × s, 1H), 9.31
and 9.44 (2 × s, 1H). 13C NMR (67.8 MHz, CDCl3): δ -5.0, -4.9,
-4.86, 17.7, 25.5, 40.5, 40.6, 42.5, 44.9, 45.2, 55.0, 66.9, 67.5,
71.9, 72.2, 81.0, 82.5, 84.2, 84.7, 84.9, 88.0, 88.6, 113.3, 123.3,
123.4, 127.4, 127.5, 127.7, 127.8, 128.0, 128.4, 128.5, 129.8, 131.1,
132.4, 133.4, 133.6, 141.3, 141.5, 142.3, 142.6, 149.4, 151.2, 151.3,
152.3, 152.4, 154.0, 158.7, 164.5, 164.7, 174.2, 174.6. ESI-MS:
calcd for C59H61N6O11SSi (M + H)+, 1089.3883; found, 1089.3812.
4-N-Benzoyl-3′-O-(tert-butyldimethylsilyl)-2′-deoxy-5′-O-CT-
FOC-cytidine (31). 4-N-Benzoyl-3′-O-(tert-butyldimethylsilyl)-2′-
trans-1-[(4-Metoxytrityl)sulfenyl]oxy-cyclohexane-2-ol (25).
To a solution of trans-1,2-cyclohexanediol (0.23 g, 2.0 mmol) in
THF (5 mL) was added NaH (0.12 g, 3.0 mmol). The resulting
solution was stirred at 44 °C for 20 min, and then the mixture was
cooled to room temperature. To this mixture was added (4-meth-
oxytrityl)sulfenyl chloride (0.82 g, 2.4 mmol). After being stirred
at room temperature for 4 h, the mixture was quenched by addition
of concentrated NH3 (1 mL). The solution was diluted with ethyl
acetate (80 mL) and washed once with water (80 mL) and then
twice with burin (80 mL). The organic layer was collected, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was chromatographed on a silica gel column (20 g) with
1
hexane-ethyl acetate (100:7, v/v) to give crude 25 (0.24 g). H
NMR (500 MHz, CDCl3): δ 0.90-1.08 (m, 4H), 1.50-1.52 (br,
7676 J. Org. Chem., Vol. 71, No. 20, 2006

Protecting Groups RemoVable by Self-Cyclization
deoxycytidine (28)36 (0.89 g, 2.0 mmol) was rendered anhydrous
by repeated coevaporation with dry pyridine and finally dissolved
in dry pyridine (15 mL). Carbonyldiimidazole (0.49 g, 3.0 mmol)
was added, and the resulting mixture was stirred for 40 min. The
solution was diluted with ethyl acetate (40 mL) and washed three
times with water (40 mL). The organic layer was collected, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue became an amorphous solid. The NMR analysis of this
residue suggested that the starting material was completely changed
to the imidazolide intermediate. The the imidazolide was rendered
anhydrous by repeated coevaporation with dry pyridine and finally
dissolved in pyridine (4 mL). Compound 17 (1.2 g, 2.0 mmol) was
also rendered anhydrous by repeated coevaporation with dry
pyridine and dissolved in pyridine (4 mL). To the solution of the
imidazolide, 17 and DBU (30 µL, 0.2 mmol) were added. After
being stirred at room temperature for 2 h, the mixture was diluted
with ethyl acetate (40 mL) and washed four times with burin (40
mL). The organic layer was collected, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was chro-
matographed on a silica gel column with hexane-ethyl acetate (3:
solution was diluted with ethyl acetate (20 mL) and washed four
times with burin (20 mL). The organic layer was collected, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was chromatographed on a silica gel column with hexane-
1
ethyl acetate (1:1, v/v) to give 32 (0.40 g, 72%). H NMR (500
MHz, CDCl3): δ 0.10 and 0.14 (2 × s, 6H), 0.86-0.90 (m, 9H),
1.03-1.26 (m, 6H), 2.17-2.33 (m, 3H), 2.61-2.93 (m, 3H), 3.49
and 3.49 (2 × s, 1H), 3.80 (s, 3H), 3.91 and 3.94 (2 × s, 1H),
4.16-4.26 (m, 1H), 4.30-4.33 (m, 1H), 4.52-4.84 (m, 6H), 6.18-
6.22 (m, 1H), 6.84 and 6.85 (2 × s, 3H), 7.23-7.32 (m, 13H),
7.75 and 7.77 (2 × s, 1H), 8.92 and 9.16 (2 × s, 1H), 11.99 and
12.08 (2 × s, 1H). 13C NMR (67.8 MHz, CDCl3): δ -4.79, 17.8,
18.7, 18.9, 19.0, 25.6, 36.3, 39.2, 39.8, 42.7, 45.0, 45.4, 55.2, 67.3,
67.4, 72.2, 72.6, 72.9, 81.0, 81.2, 82.8, 84.6, 84.8, 85.6, 88.9, 89.0,
113.5, 121.9, 122.2, 127.2, 128.0, 128.0, 128.2, 128.6, 129.7, 129.9,
131.2, 133.3, 133.5, 135.0, 137.5, 138.0, 142.2, 142.3, 142.6, 147.2,
147.5,148.0, 154.2, 154.6, 155.4, 158.9, 174.3, 174.7, 178.6, 178.8.
ESI-MS: calcd for C56H62N6O12SSiNa (M + Na)+, 1093.38079;
found, 1093.3170.
Determination of the Self-Cyclization Rates by 1H NMR. The
self-cyclization rate was examined as follows. The starting material
(7.1 µmol) was dissolved in a 0.5 M solution of iodine in pyridine-
d5/D2O (9:1, v/v, 1.0 mL). An aliquot (700 µL) of the solution was
taken and placed into an NMR tube. The reaction was monitored
by 1H NMR by use of the 1′-H proton signals of the starting
material, the intermediate, and the product. The MMTrS groups
were removed within 1 min from all of the protecting groups to
give the intermediates. See also Supporting Information.
Removal of the CTFOC Group from 5′-O-CTFOC-deoxyri-
bonucleoside Derivatives. The typical procedure is as follows:
Compound 18 (0.23 g, 0.24 mmol) was suspended in the 0.1 M I2
solution (pyridine/H2O ) 9:1, v/v, 47 mL) for 5 min. Then the
mixture was quenched with saturated Na2S2O3 (100 mL). The
reaction was extracted with ethyl acetate (100 mL). The organic
layer was washed once with water (100 mL) and twice with brine
(100 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. The white powder appeared when hexane (2 mL)
was added portionwise to give 4 (90 mg, quant).
1
2, v/v) to give 31 (1.7 g, 81%). H NMR (500 MHz, CDCl3): δ
0.04 and 0.08 (2 × s, 6H), 0.84-0.90 (m, 9H), 2.15-2.25 (m, 2H),
2.77-2.82 (m, 1H), 3.41 and 3.49 (2 × d, J ) 5.8, 5.8, 1H), 3.76
and 3.77 (2 × s, 3H), 3.98 and 4.18 (2 × s, 1H), 4.14-4.18 (m,
1H), 4.33-4.42 (m, 2H), 4.47-4.59 (m, 3H), 4.66-4.69 (m, 1H),
4.72-4.73 (m, 1H), 6.23-6.29 (m, 1H), 6.81-6.85 (m, 2H), 7.19-
7.55 (m, 17H), 7.90-7.91 (m, 2H), 8.07 and 8.12 (2 × d, J ) 7.3,
7.6 Hz, 1H), 8.90 (br, 1H). 13C NMR (67.8 MHz, CDCl3): δ -5.09,
-4.82, 17.7, 17.7, 25.5, 41.7, 41.8, 42.5, 42.6, 44.9, 45.3, 45.4,
55.0, 66.8, 71.0, 71.1, 72.0, 77.8, 77.8, 81.1, 82.5, 82.7, 84.6, 84.8,
86.8, 87.0, 88.1, 88.6, 113.3, 127.4, 127.5, 127.6, 127.8, 128.0,
128.0, 128.4, 128.6, 129.7, 129.8, 131.1, 131.1, 132.8, 133.0, 133.4,
134.9, 142.3, 142.5, 154.0, 154.1, 158.7, 158.7, 162.2, 174.4, 174.7,
174.8. ESI-MS: calcd for C58H61N4O12SSi (M + H)+, 1065.3785;
found, 1065.3771.
3′-O-(tert-Butyldimethylsilyl)-2′-deoxy-2-N-isobutyryl-5′-O-
CTFOC-guanosine (32). 3′-O-(tert-Butyldimethylsilyl)-2′-deoxy-
2-N-isobutyrylguanosine (29)38 (0.41 g, 0.52 mmol) was rendered
anhydrous by repeated coevaporation with dry pyridine. The residue
was dissolved in dry pyridine (3 mL), and to this solution was added
carbonyldiimidazole (0.25 g, 1.6 mmol). After being stirred for 2
h, the solution was diluted with ethyl acetate (20 mL) and washed
three times with water (20 mL). The organic layer was collected,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue became an amorphous solid. The NMR
analysis suggested that the starting material was changed to the
imidazolide intermediate completely. The imidazolide was rendered
anhydrous by repeated coevaporation with dry pyridine and finally
dissolved in pyridine (1 mL). Compound 17 (0.31 g, 0.52 mmol)
was also rendered anhydrous by repeated coevaporation with dry
pyridine and dissolved in pyridine (1.5 mL). To the solution of the
imidazolide, 17 and DBU (7.8 µL, 50 µmol) were added. The
resulting solution was stirred at room temperature for 30 h. The
In a similar manner, 28 (0.53 g, 0.49 mmol), 29 (1.1 g, 1.0
mmol), and 30 (0.40 g, 0.37 mmol) were deprotected to give 22
(0.19 g, 83%), 23 (0.42 g, 95%), and 24 (0.12 g, 74%), respectively.
Acknowledgment. This work was supported by Grant-in-
Aid of CREST of JST (Japan Science and Technology) and
the Ministry of Education, Science, Sports and Culture, Grant-
in-aid for Scientific Research (A). This study was also supported
by Industrial Technology Research Grant Program in 2005 from
New Energy and Industrial Technology Development Organiza-
tion (NEDO) of Japan.
Supporting Information Available: List of experimental
procedures for the synthesis of the products other than those
described in Experimental Section. This material is available free
of charge via the Internet at http://pubs.acs.org.
(38) Patil, S. V.; Mane, R. B.; Salunkhe, M. M. Synth. Commun. 1994,
24, 2423-2428.
JO061006V
J. Org. Chem, Vol. 71, No. 20, 2006 7677