Efficient synthesis of 2′-C-β-methylguanosine

Article abstract of DOI:10.1021/jo0602165

2′-β-Methyl nucleosides have potential value as therapeutic agents and as nucleoside analogues for exploring RNA biology. Here we develop a strategy for efficient synthesis for 2′-C-β-methylguanosine (3). Starting from 1,2,3,5-tetra-O-benzoyl-2-C-β-methyl

Full text of DOI:10.1021/jo0602165

specific residues within a functional RNA.5 Additionally,
â-branched nucleosides present a structural context in which
to install substituents of varying electron-withdrawing power,
thereby enabling systematic variation of the 2′-hydroxyl group
pKa.6-9 Here we focus on the synthesis of 2′-C-â-methylgua-
nosine, which we hope to use for mechanistic investigations of
group I intron self-splicing.10
Efficient Synthesis of 2′-C-â-Methylguanosine
Nan-Sheng Li* and Joseph A. Piccirilli*
Howard Hughes Medical Institute, Department of Biochemistry
& Molecular Biology and Department of Chemistry,
The UniVersity of Chicago, 5841 South Maryland AVenue,
MC 1028, Chicago, Illinois 60637
Two syntheses of 2′-C-â-methylguanosine have been reported
in the literature, both involving glycosylation of purines with
an appropriately protected 2′-C-â-methylribose derivative.2,11
In a 1968 patent, Walton described the synthesis of 2′-C-â-
methylguanosine via the reaction of 2,3,5-tri-O-benzoyl-2-C-
methyl-â-D-ribofuranosyl chloride with chloromercuripurine.
Preparation of the glycosylating agent required eight steps from
2,3-O-isopropylidene-D-glyceraldehyde and gave low overall
yield.11,12 Additionally, the yield and selectivity of the glyco-
sylation reactions with this reagent were not disclosed.
Recently, Harry-O’kuru et al. reported an efficient synthesis
of the 2′-C-â-methyl ribofuranosylating agent, 1,2,3,5-tetra-O-
benzoyl-2-C-methyl-D-ribofuranose (1), in three steps (43%
overall yield) starting from commercially available 1,3,5-tri-O-
benzoyl-R-D-ribofuranose (Pfanstiehl Laboratories, Inc.).1,13 This
reagent glycosylates persilylated nucleobases (uracil, 6-azauracil,
N6-benzoyladenine, and 6-methylthiopurine), but the reaction
with guanine was not reported. Franchetti et al. used 1 in
reactions with 6-chloropurine and 2,6-dichloropurine and ob-
tained the corresponding nucleoside derivatives in high yields.14
Isis Pharmaceuticals and Merck Research Laboratories extended
this approach to 2-amino-6-chloropurine, leading to the synthesis
of 2′-C-â-methylguanosine in three steps from 1 with 34%
overall yield.2 Here we show by systematic investigation of
reaction conditions that 1 reacts directly with persilylated N2-
acetylguanine, resulting in an efficient two-step synthetic
approach to 2′-C-â-methylguanosine.
nli@uchicago.edu; jpicciri@uchicago.edu
ReceiVed February 1, 2006
2′-â-Methyl nucleosides have potential value as therapeutic
agents and as nucleoside analogues for exploring RNA
biology. Here we develop a strategy for efficient synthesis
for 2′-C-â-methylguanosine (3). Starting from 1,2,3,5-tetra-
O-benzoyl-2-C-â-methyl-D-ribofuranose (1) and N2-acetylgua-
nine, we obtained the title compound in two steps (78%
overall yield) with high stereoselectivity (â/R > 99:1) and
high regioselectivity (N9/N7 > 99:1). Extension of this
strategy to the classic synthesis of guanosine also resulted
in high stereoselectivity (â/R ) 99:1) and improved regio-
selectivity (N9/N7 ) 97:3).
In 1981, Vorbru¨ggen et al. described the synthesis of
guanosine by glycosylation of persilylated N2-acetylguanine with
1-O-acetyl-2,3,5-tri-O-benzoyl-â-D-ribofuranose (4).15 Under
thermodynamic conditions (trimethylsilyl triflate as catalyst/1,2-
dichloroethane as solvent/at reflux), the glycosylation gave N9
and N7 products in a ∼6:1 ratio (79% yield).16 To improve the
regioselectivity for the N9 isomer, Robins and co-workers17,18
used persilylated N2-acetyl-6-O-diphenylcarbamoylguanine, which
bears a bulky protecting group at the 6-oxygen atom. Reaction
2′-C-Branched nucleosides have attracted much attention as
potential anticancer and antiviral agents and as probes to study
nucleic acid biology.1-3 Recently, Eldrup et al. identified 2′-
C-â-methylribonucleosides as potent nucleoside inhibitors of
Hepatitis C virus RNA replication.2,3 Considering their ability
to impart nuclease resistance to oligonucleotides, â-branched
nucleosides also hold promise as components of oligonucleotide
regulators of gene expression via antisense, ribozyme, or small
interfering RNAs. Our interest in â-branched nucleosides
emanates from their potential to reveal structural and mechanistic
features of RNA-mediated biological processes.4 For example,
the strong preference of 2′-â-methyl nucleosides for the 3′-endo
sugar pucker provides a strategy to probe the conformation of
(5) Li, N.-S.; Piccirilli, J. A. J. Org. Chem. 2003, 68, 6799.
(6) Li, N.-S.; Tang, X.-Q.; Piccirilli, J. A. Org. Lett. 2001, 3, 1025.
(7) Tang, X.-Q.; Liao, X.; Piccirilli, J. A. J. Org. Chem. 1999, 64, 747.
(8) Ye, J.-D.; Liao, X.; Piccirilli, J. A. J. Org. Chem. 2005, 70, 7902.
(9) Dai, Q.; Piccirilli, J. A. Org. Lett. 2003, 5, 807.
(10) Cech, T. R.; Herschlag, D. In Catalytic RNA, 2nd ed.; Lilley, D.
M. J., Eckstein, F., Eds.; Springer: New York, 1997.
(11) Walton, E. France Patent 1521076, 1968.
(12) Lopez-Herrera, F. J.; Sarabia-Garcia, F.; Pino-Gonzalez, M. S.;
Garcia-Aranda, J. F. J. Carbohydr. Chem. 1994, 13, 767.
(13) Cook, G. P.; Greenberg, M. M. J. Org. Chem. 1994, 59, 4704.
(14) Franchetti, P.; Cappellacci, L.; Marchetti, S.; Trincavelli, L.; Martin,
C.; Mazzoni, M. R.; Lucacchini, A.; Grifantini, M. J. Med. Chem. 1998,
41, 1708.
(15) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234.
(16) Garner, P.; Ramakanth, S. J. Org. Chem. 1988, 53, 1294.
(17) Zou, R.; Robins, M. J. Can. J. Chem. 1987, 65, 1436.
(18) Robins, M. J.; Zou, R.; Guo, Z.; Wnuk, S. F. J. Org. Chem. 1996,
61, 9207.
(1) Harry-O’kuru, R. E.; Smith, J. M.; Wolfe, M. S. J. Org. Chem. 1997,
62, 1754 and references therein.
(2) Eldrup, A. B.; Allerson, C. R.; Bennett, C. F.; Bera, S.; Bhat, B.;
Bhat, N.; Bosserman, M. R.; Brooks, J.; Burlein, C.; Carroll, S. S.; Cook,
P. D.; Getty, K. L.; MacCoss, M.; McMasters, D. R.; Olson, D. B.; Prakash,
T. P.; Prhavc, M.; Song, Q.; Tomassini, J. E.; Xia, J. J. Med. Chem. 2004,
47, 2283.
(3) Eldrup, A. B.; Prhavc, M.; Brooks, J.; Bhat, B.; Prakash, T. P.; Song,
Q.; Bera, S.; Bhat, N.; Dande, P.; Cook, P. D.; Bennett, C. F.; Carroll, S.
S.; Ball, R. G.; Bosserman, M.; Burlein, C.; Colwell, L. F.; Fay, J. F.; Flores,
O. A.; Getty, K.; LaFemina, R. L.; Leone, J.; MacCoss, M.; McMasters,
D. R.; Tomassini, J. E.; Langen, D. V.; Wolanski, B.; Olson, D. B. J. Med.
Chem. 2004, 47, 5284.
(4) Gordon, P. M.; Fong, R.; Deb, S.; Li, N.-S.; Schwans, J. P.; Ye,
J.-D.; Piccirilli, J. A. Chem. Biol. 2004, 11, 237.
10.1021/jo0602165 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/20/2006
4018
J. Org. Chem. 2006, 71, 4018-4020

SCHEME 1a
a Reagents and conditions: (i) persilylated N2-acetylguanine (2.5 equiv), TMSOTf (2.5 equiv), p-xylene, reflux, 6 h, 80%; (ii) NH3/MeOH, 0-4 °C,
48 h, 98%.
TABLE 1. Reaction of Persilylated N2-Acetylguanine with
with 1,2,3,5-tetra-O-acetyl-â-D-ribofuranose in toluene (80 °C)
1,2,3,5-Tetra-O-benzoyl-2-C-â-methyl-D-ribofuranose (1)
gave the 9-glycosyl guanine derivative exclusively (91% yield).
molar
ratiob
temp
(°C)
time
(h)
yield
(%)d
To construct 2′-C-â-methylguanosine, we began with persi-
lylated N2-acetyl-6-O-diphenylcarbamoylguanine, hoping to
direct regiochemistry (N-9) in the same manner as Robins et
al.17,18 We investigated the reaction of this nucleobase with 1
using trimethylsilyl triflate as catalyst. After being stirred
overnight either in toluene at 80 °C or in refluxing benzene,
the reaction mixture produced no glycosylation product, as
judged by TLC. Although some 1 remained, the protected
nucleobase decomposed completely. Refluxing the reaction
mixture overnight in toluene resulted in decomposition of both
1 and the nucleobase. Refluxing the reaction mixture in 1,2-
dichloroethane for 8 h completely consumed 1 and generated
the N9 and N7 regioisomers in ∼40% yield, isolated as a ∼7:3
mixture of N2-acetyl-2′,3′,5′-tri-O-benzyl-2′-C-â-methylgua-
nosine and the N2-acetyl-2′,3′,5′-tri-O-benzyl-2′-C-â-methyl-7-
guanosine.19 However, these products lacked the diphenylcar-
bamyl group, apparently precluding its regioselective advantage
during the reaction.
We therefore considered the use of N2-acetylguanine directly
in reactions with 1 (Scheme 1). We carried out reactions under
a range of conditions (varying molar ratio of reactants and
catalyst, solvent, reaction temperature, and time). The results
are summarized in Table 1. For optimization of conditions, all
reactions contained 0.1 mmol sugar substrate. Under the
conditions used by Harry-O’Kuru et al. (refluxing acetonitrile
with trimethylsilyl triflate as catalyst1) the reaction gave the
regioisomers in lower yield and with weaker stereoselectivity
relative to other conditions (Table 1, entries 1 and 2). In
refluxing benzene, the reaction remained incomplete after 24 h
(Table 1, entry 3). We varied solvent and found the N9-
regioselectivity to increase in the following order: MeCN <
1,2-dichloroethane < benzene < toluene < o-xylene < m-xylene
< p-xylene, mirroring the polarity and boiling point (reaction
temperature) orders. Apparently, nonpolar solvents and higher
reaction temperatures favor the thermodynamic product (N9),
as described previously for the synthesis of guanosine.16 Without
silylation, N2-acetylguanine exhibited no regioselectivity in the
reaction with 1 (Table 1, entry 10). Use of tert-butyldimethylsilyl
triflate instead of trimethylsilyl triflate as catalyst had no
significant effect on the reaction (Table 1, entries 8 and 9). We
achieved the highest N9-regioselectivity (N9/N7 ) 98:2) using
p-xylene at 140 °C for 5 h (Table 1, entry 12). Shorter reaction
times (Table 1, entries 12 and 15) or less nucleobase and catalyst
(Table 1, entries 12 and 16) decreased the formation of the 9-â-
isomer. After we adjusted the reaction time and the reagent
amount appropriately, we carried out the glycosylation on a 1.0
mmol scale in refluxing p-xylene for 6 h using a molar ratio of
entrya
solvent
MeCN
MeCN
benzene
ratioc
1
2
3
4
5
6
7
8
1:4:4
reflux (82)
reflux (82)
reflux (80)
5
22
24
5
16
22
24
19
22
24
22
5
74:26
90:10
91:9
90:10
89:11
90:10
93:7
96:4
95:5
50:50
94:6
98:2
43
44
27
68
64
74
63
65
65
50
58
89
57
72
88
91
80
1:4:4
1:4:4
1:4:4
1:4:4
1:4:4
1:4:4
1:4:5.5
1:4:5.5
1:4:5.5
1:4:4
1:4:4
1:4:4
1:4:4
1:4:4
1:2:2
ClCH2CH2Cl reflux (84)
ClCH2CH2Cl reflux (84)
ClCH2CH2Cl reflux (84)
toluene
toluene
toluene
toluene
m-xylene
p-xylene
o-xylene
m-xylene
p-xylene
p-xylene
100
reflux (111)
reflux (111)
reflux (111)
100
140
140
140
140
140
reflux (140)
9e
10f
11
12
13
14
15
16
17g
5
5
3
8
96:4
97:3
95:5
94:6
1:2.5:2.5 p-xylene
6
>99:1
a All reactions were carried out on a 0.1 mmol scale of sugar substrate
except entry 17, which was carried out on a 1.0 mmol scale. b Sugar:
nucleobase:catalyst. c Ratio calculated by the integration of 1′-H (δ 6.72
and 6.98) from 1H NMR spectra. d Isolated yield of 7- and 9-â-isomers.
e tert-Butyldimethylsilyl triflate as a catalyst. f In this experiment, the base
was not persilylated. g 1.0 mmol scale.
sugar:nucleobase:catalyst ) 1:2.5:2.5. The reaction proceeded
with N9-isomer regioselectivity and gave the 2′-C-â-methylgua-
nosine derivative 2 in 80% yield.
Deprotection of 2 with ammonia in methanol gave 2′-C-â-
methylguanosine (3) in 98% yield. The structure of 3 was
confirmed by a 1D NOE difference experiment. When the 2′-
methyl (δ 0.80) was irradiated, we observed NOEs for 3′-H
(3.9%), 8-H (1.9%), 1′-H (4.5%), and 2′-OH (5.9%). These
results indicate that the 2′-C-methyl group, 3′-H, and guanine
base are on the same side of the ribose ring. The NOE between
the 2′-methyl group and 1′-H and the large J3′-4′ coupling
constant (9.1 Hz) suggest that 3 populates the 3′-endo config-
uration predominantly. For nucleosides that populate the 2′-
endo configuration, the 3′-H and 4′-H usually exhibit signifi-
cantly smaller J3′-4′ values (∼2.0-2.5 Hz).20
The high regioselectivity, stereoselectivity, and yield achieved
for the reaction of N2-acetylguanine with 1 prompted us to
examine the effect of different solvents on the classic Vor-
bru¨ggen reaction, which involves the glycosylation of persi-
lylated N2-acetylguanine with ribofuranose 4 to give 5 (Scheme
2). We carried out the reaction in refluxing 1,2-dichloroethane,
toluene, and p-xylene (Table 2). Refluxing the reactants in
toluene for 6 h (Table 2, entry 4) gave the highest 9-â
regioselectivity (9-â/7-â 96:3), significantly higher than the
literature conditions (9-â/7-â 6:1, Table 2, entry 3).16 At the
1
(19) The ratio was determined by the H NMR of the product (1′-H of
(20) Schmit, C.; Bevierre, M.-O.; Mesmaeker, A. D.; Altmann, K.-H.
N7 isomer δ 6.98; 1′-H of N9 isomer δ 6.72).
Bioorg., Med. Chem. Lett. 1994, 4, 1969.
J. Org. Chem, Vol. 71, No. 10, 2006 4019

SCHEME 2 a
the aqueous layer was extracted with dichloromethane. The organic
layers were combined, washed with brine, and dried over anhydrous
magnesium sulfate. The magnesium sulfate was filtered off, and
the solvent was removed by evaporation under vacuum. The residue
was purified by silica gel chromatography, eluting with 2%
methanol in chloroform, to give product as a white foam: 58 mg
(89% yield). 1H NMR of the product showed that the ratio of 9-â-
isomer to 7-â-isomer was 98:2.
Table 1, entry 17 (1.0 mmol scale synthesis): persilylated N2-
acetylguanosine (2.47 mmol) was prepared from N2-acetylguanosine
(477 mg, 2.47 mmol), dry pyridine (3.0 mL), and 1,1,1,3,3,3-
hexamethyldisilazane (10 mL) according to the procedure described
above. To the flask containing persilylated N2-acetylguanine (2.47
mmol) was added 1,2,3,5-tetra-O-benzoyl-2-C-â-methylribofuranose
(580 mg, 1.0 mmol), p-xylene (30 mL), and trimethylsilyl triflate
(0.45 mL, 2.5 mmol) under argon. The reaction mixture was stirred
at reflux for 6 h. After workup, the residue was purified by silica
gel chromatography to give product as a white foam: 520 mg (80%
yield).1H NMR of the product showed that the ratio of the 9-â-
isomer to 7-â-isomer was greater than 99:1. 1H NMR (CDCl3/TMS)
δ 10.34 (s, 1H), 8.15-7.22 (m, 16H), 6.72 (s, 1H), 6.55 (d, 1H,
J ) 8.0 Hz), 5.77 (m, 1H), 4.88 (m, 1H), 4.49 (dd, 1H, J ) 5.6,
10.8 Hz), 2.47 (s, 3H), 1.50 (s, 3H); 13C NMR (CDCl3) δ 172.4,
167.0, 165.4, 165.1, 155.6, 147.7, 147.2, 138.7, 133.8, 133.48,
133.45, 129.8, 129.7, 129.5, 128.8, 128.6, 128.5, 128.3, 128.2,
122.6, 89.5, 87.3, 77.3, 76.5, 63.0, 24.3, 17.7; HRMS cacld for
C34H30N5O9 [MH+] 652.2044, found 652.2047.
a Reagents and conditions: (i) persilylated N2-acetylguanine (4.0 equiv),
TMSOTf (4.0 equiv), toluene, 6 h.
TABLE 2. Reaction of N2-Acetylguanine with
1-O-Acetyl-2,3,5-tri-O-benzoyl-â-D-ribofuranose (4)
temp
(°C)
time
(h)
yield
(%)c
entrya
solvent
ratiob
1
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
toluene
reflux (84)
reflux (84)
reflux (84)
reflux (111)
reflux (140)
2
6
1.5
6
5
87:13:0
92:8:0
6:1:0
96:3:1
94:3:3
66
88
79
>99
99
2
3d
4
5
p-xylene
a All Reactions were carried out with 0.1 mmol sugar and a molar ratio
of sugar:nucleobase:catalyst (1:4:4). Trimethylsilyl triflate (89 mg, 0.40
mmol) was added slowly with vigorous stirring at room temperature. b Ratio
of 9-â/7-â/9-R isomers calculated from 1H NMR. c Combined isolated yield
of isomers. d Literature result (molar ratio of sugar:nucleobase:catalyst )
1:1.4-1.7:2.1-2.4).16
N2-Acetyl-2′,3′,5′-tri-O-benzoyl-â-guanosine (5).16 The reaction
(0.1 mmol scale) was carried out in refluxing toluene for 6 h (Table
2, entry 3) following the procedure described above. The product
(64 mg, 100%) was isolated by silica gel chromatography, eluting
with 2% methanol in chloroform as a white foam. 1H NMR of the
product showed that the ratio of the 9-â-isomer to 7-â-isomer to
9-R-isomer was 96:3:1.1H NMR (CDCl3/TMS) δ 12.07 (s, 1H),
10.15 (s, 1H), 7.91-7.86 (m, 7H), 7.54-7.52 (m, 3H), 7.35-7.32
(m, 6H), 6.35 (m, 1H), 6.29 (m, 1H), 6.25 (m, 1H), 4.92 (dd, 1H,
J ) 5.1, 11.7 Hz), 4.79 (m, 1H), 4.65 (dd, 1H, J ) 5.7, 11.7 Hz),
2.31 (s, 3H); 13C NMR (CDCl3) δ 172.3, 166.6, 165.3, 165.2, 155.5,
147.7, 147.6, 138.8, 133.8, 133.6, 133.5, 129.7, 129.6, 129.5, 129.0,
128.5, 128.42, 128.41, 128.3, 122.4, 88.3, 80.0, 73.8, 71.5, 63.2,
24.2.
higher temperatures allowed by toluene or p-xylene (Table 2,
entries 4 and 5), the reaction produces a small amount of the
R-isomer (possibly 9-R), consistent with previous observations
for trimethylsilyl triflate catalyzed glycosylation reactions.6 Kiss
et al. also reported that at room temperature, trimethylsilyl
triflate catalyzed â to R epimerization of uridine derivatives
over the course of a week.21 The guanosine derivative 5 may
epimerize more rapidly at the higher reaction temperatures used
in our study.
In summary, systematic variation of reaction conditions has
led to an efficient, straightforward synthesis of 2′-C-â-meth-
ylguanosine with high regio- and stereoselectivity. This strategy
also improved regioselectivity in the synthesis of guanosine and
may provide a generally useful approach for the synthesis of
other guanosine nucleosides by glycosylation.
2′-C-â-Methylguanosine (3).2 N2-Acetyl-2′,3′,5′-tri-O-benzoyl-
2′-C-â-methylguanosine (146 mg, 0.224 mmol) in methanol (20
mL) was saturated with ammonia for 30 min at 0 °C, then sealed
and kept in a refrigerator (4 °C) for 48 h. The solvent was removed
by evaporation under vacuum, and the residue was isolated by silica
gel chromatography, eluting with 20% methanol in chloroform, to
1
give product as a white powder: 65 mg (98% yield). H NMR
(D2O/CD3OD) δ 8.01 (s, 1H), 5.91 (s, 1H), 4.83 (br s, 5H), 4.16
(s, 1H, J ) 9.1 Hz), 4.07 (m, 1H), 4.02 (dd, 1H, J ) 12.9, 2.1 Hz),
3.88 (dd, 1H, J ) 12.9, 3.80 Hz), 0.97 (s, 3H); 1H NMR (DMSO-
d6) δ 10.62 (br s, 1H), 8.05 (s, 1H), 6.52 (br s, 2H), 5.73 (s, 1H),
5.27 (d, 1H, J ) 6.6 Hz), 5.16 (t, 1H, J ) 4.9 Hz), 5.07 (s, 1H),
3.97 (m, 1H), 3.85 (m, 1H), 3.81 (dd, 1H, J ) 12.4, 5.0 Hz), 3.64
(dd, 1H, J ) 12.4, 3.0 Hz), 0.80 (s, 3H); 13C NMR (D2O/CD3OD)
δ 159.8, 154.9, 152.0, 138.1, 117.1, 92.0, 83.1, 80.2, 73.4, 61.0,
19.9; HRMS cacld for C11H16N5O5 [MH+] 298.1151, found
298.1140.
Experimental Section
N2-Acetyl-2′,3′,5′-tri-O-benzoyl-2′-C-â-methylguanosine (2).
The procedure for Table 1, entry 12 (0.10 mmol scale synthesis),
is representative. Under an argon atmosphere, a mixture of N2-
acetylguanine (77 mg, 0.40 mmol), dry pyridine (0.50 mL), and
1,1,1,3,3,3-hexamethyldisilazane (1.5 mL) was heated to reflux for
30 min to obtain a clear solution. The solvent was removed carefully
under vacuum, and the residue was dried under high vacuum for 1
h. To the flask containing persilylated N2-acetylguanosine (0.40
mmol) was added p-xylene (5.0 mL) and 1,2,3,5-tetra-O-benzoyl-
2-C-â-methylribofuranose (58 mg, 0.10 mmol). To the resulting
mixture was added trimethylsilyl triflate (89 mg, 0.40 mmol) slowly
with vigorous stirring at room temperature. After the reaction
mixture was stirred under an argon atmosphere at 140 °C for 5 h,
TLC showed that the reaction was complete. The reaction mixture
was cooled to room temperature and quenched with saturated
aqueous sodium bicarbonate. The organic layer was separated, and
Acknowledgment. N.-S.L. is a Research Specialist and
J.A.P. is an Associate Investigator of the Howard Hughes
Medical Institute. We thank S. R. Das, J. Ye, Q. Dai, C. Lea,
S. Koo, and R. Fong for helpful discussions and critical
comments on the manuscript.
Supporting Information Available: 1H NMR and 13C NMR
spectra of 2, 3, and 5 and the NOE difference spectra of 3. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(21) Kiss, J.; D’Souza, R.; van Koeveringe, J. A.; Arnold, W. HelV. Chim.
Acta 1982, 65, 1522.
JO0602165
4020 J. Org. Chem., Vol. 71, No. 10, 2006