Synthesis of the 5′-Fluoro-2′β-methyl analogues of neplanocin

Article abstract of DOI:10.1002/ejoc.201100062

Synthesis of the 5′-fluoro-2′-β-methyl analogues of neplanocin was carried out. Key intermediate cyclopentenone 19 was prepared from methyl α-D-mannopyranoside by a new approach consisting of ring-closing metathesis, stereoselective introduction of the 2′

Full text of DOI:10.1002/ejoc.201100062

FULL PAPER
DOI: 10.1002/ejoc.201100062
Synthesis of the 5Ј-Fluoro-2Јβ-methyl Analogues of Neplanocin
Hiroki Kumamoto,*[a] Marina Kobayashi,[a] Nobuyuki Kato,[b] Jan Balzarini,[c] and
Hiromichi Tanaka[a]
Keywords: Carbocycles / Nucleosides / Selenium / Electrophilic addition / Fluorine
Synthesis of the 5Ј-fluoro-2Ј-β-methyl analogues of neplano- selenenylation of the double bond as representative steps.
cin was carried out. Key intermediate cyclopentenone 19 was
prepared from methyl α- -mannopyranoside by a new ap-
proach consisting of ring-closing metathesis, stereoselective
Subsequent introduction of a fluorine atom at the 5Ј-position
of 19 was performed by electrophilic fluorination by using
Selectfluor.
D
introduction of the 2Ј-methyl group, and intramolecular oxy-
Carbocyclic nucleoside antibiotic neplanocin A (3) is
known to be a potent inhibitor against (S)-adenosyl-l-
homocysteine hydrolase (SAHase),[4a] which in turn leads
to inhibition of the multiplication of a wide variety of RNA
viruses.[4] Jeong et al. recently reported that compound 4,
which is the 5Ј-fluorinated analogue of 3, shows a higher
inhibitory activity against SAHase than mother compound
3.[5] In the present study, we designed and synthesized 5,
which is a hybrid of 1 (or 2) and 4.
Introduction
2Ј-Methyl ribonucleosides 1 and 2 (Figure 1) have been
reported to show significant inhibitory activity against pro-
liferation of the hepatitis C virus (HCV).[1] The 3Ј-valine
ester of 2Ј-methylcytidine (2, valopicitabine)[2] is currently
in phase II clinical trials. Further chemical modifications of
these compounds have also been executed to develop new
anti-HCV drugs.[3]
Results and Discussion
Our synthetic plan is depicted in Scheme 1. Title com-
pounds 5a and 5b can be synthesized through an SN2 reac-
tion between the respective nucleobase and fluorinated allyl
alcohol A, which can be prepared by electrophilic fluorin-
ation of ketone B. Compound B is the hydrogenation prod-
uct of cyclopentenone C. Although there have been pre-
cedents[3b,3e] for the preparation of C via 2-β-C-methyl-
ribonolactone, either from diacetone-d-glucose or from d-
Figure 1. Compounds 1–5.
[a] School of Pharmaceutical Sciences, Showa University,
1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax: +81-3-3784-8252
E-mail: kumamoto@pharm.showa-u.ac.jp
[b] Department of Molecular Biology, Okayama University
Graduate School of Medicine, Dentistry, and Pharmaceutical
Sciences,
2-5-1 Shikata-cho, Okayama 700-8558, Japan
[c] Rega Institute for Medical Research, Katholieke Universiteit
Leuven,
Minderbroedersstraat 10, 3000 Leuven, Belgium
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100062.
Scheme 1. Synthetic plan for 5a and 5b.
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fructose, we examined an original approach starting from Table 1. Intramolecular selenocyclization reaction of 14.
commercially available methyl α-d-mannopyranoside (6;
Scheme 2).
Entry
Conditions
T
[°C]
Time
[h]
Yield
[%]
1
2
3
4
PhSeCl, AgOTf
–78 to r.t.
–78 to r.t.
–78 to –30
–78 to –30
12
12
48
16
30
PhSeCl, AgOTf, (PhSe)2
PhSeCl, AgOTf, (PhSe)2
(PhSe)2, Br2, AgOTf
48
58[a]
89
[a] Compound 14 was recovered in 29% yield.
Compound 14 was treated with PhSeCl and AgOTf in
CH2Cl2 for 12 h (Table 1, Entry 1). Although disappearance
of starting material 14 was confirmed by TLC, requisite tri-
cyclic product 15 was obtained only in 30% yield. Addition
of 1.5 equiv. of (PhSe)2 gave a slight increase in the yield of
Scheme 2. Reagents and conditions: (a) see ref.[6]; (b) aq. HCHO, 15 (Table 1, Entry 2). Further improvement was observed
K2CO3, MeOH (80%); (c) TBDPSCl, DMAP, Et3N, CH2Cl2
when the reaction temperature was kept at –30 °C to give
(96%); (d) CH3Ph3PBr, BuLi, THF (92%); (e) 1. Umicore M2 (11,
15 in 58% yield along with the recovery of a considerable
0.73 mol-%), CH2Cl2; 2. PDC, 4 Å MS (93% from 10); (f) MeLi,
amount of unreacted 14 (29%; Table 1, Entry 3). As shown
in Entry 4, the best yield of 15 (89%) was obtained when
PhSeBr, prepared in situ from Br2 (1 equiv.) and an excess
THF, –78 °C (93%).
Compound 6 was converted into hemiacetal 7 in 86% amount of (PhSe)2 (2 equiv.), was employed instead of
yield by our reported method.[6] Aldol reaction between 7 PhSeCl.
and aqueous HCHO in the presence of K2CO3 gave 8, the
Although the actual role of (PhSe)2 is not known, one
preparation of which was recently reported by Jeong et al. possibility could be that it acts as a scavenger for the elec-
by using an epimer of 7.[7] Regioselective silylation of 8 gave trophilic benzyl halide or benzyl triflate that is generated
9 in 96% yield. Wittig reaction of 9 led to the formation of during the reaction. In fact, when isolated 15 was treated
diene 10 (92%).[7b–7d] Ring-closing metathesis of 10[7b–7d] by with benzyl triflate in CH2Cl2 at room temperature, disap-
using a catalytic amount of Umicore M2[8] (11, 0.73 mol- pearance of 15 was observed by TLC within 1 h and several
%) furnished the corresponding cyclopentenol, which was polar unknown products were obtained.
then oxidized with pyridinium dichromate (PDC) to give
Preparation of cyclopentenone 19 that corresponds to C
cyclopentenone 12 in almost quantitative yield. It is worth in Scheme 1 was carried out next (Scheme 3). Compound
noting from a practical viewpoint that every step in the re- 15 was treated with K2CO3 in MeOH to give diol 16. Con-
action sequence from 6 to 12 can be carried out on a multi- version of 16 into ketone 17 was conducted by m-CPBA
10 gram scale without decreasing the yield. Stereoselective oxidation of the phenylseleno group followed by syn elimi-
1,2-addition of MeLi to 12 gave allyl alcohol 13 in 93% nation of the resulting selenoxide. Treatment of 17 with Na-
yield, the stereochemistry of which was confirmed by an OMe gave vicinal diol 18 as a result of the elimination of
NOE experiment (1.9%, between Me and OSitBu).
acetone. Compound 18 was converted into acetonide 19
To transform 13 into requisite cyclopentenone
C
(75%) in a conventional manner. 1H and 13C NMR spectro-
(Scheme 1), introduction of an appropriate oxygen func- scopic data of 19 thus obtained are in full agreement with
tionality at the vinylic carbon is necessary. However, several those reported.[3e] Transformation of 19 into fluorocy-
approaches (hydroboration, oxymercuration, m-CPBA clopentenol 23 was carried out as follows: Compound 19
epoxidation, and dihydroxylation) all met with failure, pre- was hydrogenated in AcOEt in the presence of 10% Pd/C
sumably due to the fact that the double bond of 13 is highly to give 20 as a single isomer (stereochemistry of 20 was not
congested by the presence of the two tertiary carbinol car- determined.). Prior to carrying out electrophilic fluorin-
bon atoms. An intramolecular approach may be a promis- ation at the α-position, 20 was first treated with lithium
ing to overcome this problem. We turned our attention to hexamethyldisilazane (LHMDS) in the presence of TMSCl
an intramolecular oxyselenenylation reported by Kim et in THF. Reaction of the resulting silyl enol ether with Se-
al.[9] Benzyl carbonate 14 to be used for this reaction was lectfluor in MeCN was followed by simple extractive
prepared from 12 in 74% yield by treatment with MeLi fol- workup to give crude 21.[10] Regeneration of the double
lowed by CbzCl. Results of the selenocyclization by utiliz- bond was performed by LHMDS-mediated phenylselen-
ing 14 are summarized in Table 1.
ation of 21 and subsequent m-CPBA oxidation, which ef-
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Synthesis of the 5Ј-Fluoro-2Јβ-methyl Analogues of Neplanocin
Scheme 3. Reagents and conditions: (a) K2CO3, MeOH (quant.); (b) m-CPBA, 1,2-dichloroethane, reflux; (c) NaOMe, MeOH, –30 °C;
(d) TsOH, Me2C(OMe)2, acetone (75% from 16); (e) H2, 10% Pd/C, AcOEt (quant.); (f) 1) TMSCl, LHMDS, THF, –78 °C; 2) Selectfluor,
MeCN; (g) 1) TMSCl, LHMDS, PhSeCl, THF; 2) m-CPBA, NaHCO3, CH2Cl2 (48% from 20); (h) DIBALH, CH2Cl2, –78 °C (80%);
(i) Ac2O, pyridine (87%); (j) 1) bis(Boc)adenine, DIAD, Ph3P, THF; 2) 2 m HCl (54% from 23); (k) 1) N3-benzoyluracil, DIAD, Ph3P,
THF; 2) NaOMe, MeOH (50% from 23); (l) 1) TPSCl, DMAP, MeCN; 2) NH4OH (48% from 24); (m) 3 m HCl, MeOH (71%).
fected spontaneous selenoxide syn elimination to give fluo- cursor to key intermediate 19, was prepared in good overall
rocyclopentenone 22 in 48% overall yield from 20. Accord- yield (ca. 57%). Conversion into 19 was achieved by em-
ing to the report by Moon et al.,[3e] diisobutylaluminum ploying an intramolecular selenocyclization reaction. Elec-
hydride (DIBALH) was employed for the stereoselective trophilic fluorination by using Selectfluor moderately pro-
1,2-reduction of 22 to give allyl alcohol 23 in 80% yield. ceeded to introduce a fluorine atom at the 5Ј-position. Al-
The stereochemistry of 23 was confirmed by an NOE ex- though the anti-HIV, anti-HCV, and antitumor activities of
periment of its acetate 23a [1.9%, between Me (acetyl) and products 5a and 5b were evaluated, no significant activity
Me (acetonide)]. Finally, introduction of the nucleobase was observed.
was carried out. Allyl alcohol 23 was exposed to conven-
tional Mitsunobu conditions[11] [bis(Boc)adenine,[12] DIAD
and Ph3P in THF]. Title compound 5a was obtained after
removal of all the protecting groups. The regiochemistry of
5a was confirmed by HMBC spectra, namely, correlations
between 1Ј-H and C-8 and between 1Ј-H and C-4 of the
adenine ring were observed. An NOE experiment indicated
the stereochemistry of 5a as depicted in Scheme 3 (8-H/3Ј-
Experimental Section
General Methods: NMR spectra were recorded with a Jeol JNM
AL-400 or a Jeol JMN ECA-500 instrument spectrometer (1H: 400
or 500 MHz, 13C: 100 or 125 MHz, and 19F: 470 MHz). Chemical
sifts are reported relative to Me4Si, except for fluorine-containing
compounds where CFCl3 was used as an internal standard. Mass
spectra (MS) were taken in FAB mode with m-nitrobenzyl alcohol
as a matrix. Column chromatography was carried out on silica gel.
H, 1.0%). Cytosine analogue 5b was also synthesized by a
series of reactions: introduction of N3-benzoyluracil fol-
lowed by debenzoylation to give 24 (50%);[13] transforma-
Thin-layer chromatography (TLC) was performed on precoated sil-
tion of 24 into cytosine in a conventional manner [2,4,6-
triisopropylbenzenesulfonyl chloride (TPSCl), DMAP, and
Et3N then NH4OH] to give 25 (48%); deprotection under
the acidic conditions to form desired 5b (71%).
ica gel plate F254. When necessary, analytical samples were purified
by high-performance liquid chromatography (HPLC). THF was
distilled from benzophenone ketyl.
5,6-Dideoxy-2-hydroxymethyl-2,3-O-isopropylidene-α-D-lyxo-hex-
5-enofuranose (8): To a MeOH (150 mL) solution of 7 (20.7 g,
111 mmol) was added K2CO3 (7.68 g, 55.6 mmol) and 37 % aq.
HCHO (55 mL). The resulting mixture was heated at 70 °C for
12 h. After evaporation, the whole reaction mixture was purified by
flash column chromatography on silica gel (CHCl3/MeOH, 15:1).
Conclusions
The synthesis of 5Ј-fluoro-2Ј-β-methyl neplanocin ana-
logues was carried out. Cyclopentenone 12, a synthetic pre- Appropriate fractions were evaporated and dissolved in NH3/
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MeOH (ca. 150 mL) and kept at 4 °C for 12 h. After evaporation,
crude 8 (19.2 g, 80%, anomeric mixture ca. 2:1) was obtained as
an oil. This was used for the next step without further purification.
1H NMR (CDCl3 + D2O): δ = 1.41 (s, 3 H, Me), 1.46 (s, 1.5 H,
Me), 1.48 (s, 3 H, Me), 3.76 (d, J = 11.6 Hz, 0.5 H, CH2OH), 3.80
chromatography (hexane/AcOEt, 3:1) of the filtrate gave 12 (28.5 g,
93%) as an oil. [α]2D7 = +43.0 (c = 2.33, CHCl3). 1H NMR (CDCl3):
δ = 1.02 (s, 9 H, tBu), 1.34 (s, 3 H, Me), 1.38 (s, 3 H, Me), 3.85 (d,
J = 10.6 Hz, 1 H, CH2OSi), 3.90 (d, J = 10.6 Hz, 1 H, CH2OSi),
4.36 (s, 1 H, 3a-H), 6.24 (d, J = 6.0 Hz, 1 H, 6-H), 7.36–7.47 (m,
(d, J = 11.6 Hz, 0.5 H, CH2OH), 3.85 (d, J = 12.0 Hz, 1 H, 7 H, 6-H and Ph), 7.61–7.66 (m, 4 H, Ph) ppm. 13C NMR (CDCl3):
CH2OH), 3.97 (d, J = 12.0 Hz, 1 H, CH2OH), 4.06 (dd, J = 7.2,
3.2 Hz, 0.5 H, 4-H), 4.55 (d, J = 3.2 Hz, 0.5 H, 3-H), 4.58 (d, J =
δ = 19.2, 26.5, 26.7, 28.1, 65.6, 79.5, 89.2, 127.7, 127.8, 127.9, 132.5,
132.6, 134.1, 134.8,135.6, 135.7, 161.6, 203.7 ppm. MS (FAB): m/z
3.2 Hz, 1 H, 3-H), 4.63 (dd, J = 7.2, 3.2 Hz, 1 H, 4-H), 5.31–5.45 = 423 [M + H]+. C25H30O4Si (422.60): calcd. C 71.05, H 7.16;
( m , 4 . 5 H , C H = C H 2 a n d 1 - H ) , 5 . 9 2 – 6 . 0 4 ( m , 1 . 5 H ,
CH=CH2) ppm.
found C 71.32, H 7.21.
(3aR,4S,6aS)-6a-(tert-Butyldiphenylsiloxymethyl)-3a,6a-dihydro-
2,2,4-trimethylcyclopenta[1,3]dioxol-4-ol (13): To a stirred solution
of 12 (2.9 g, 6.86 mmol) in THF (50 mL) was added MeLi (1.09 m
in THF, 12.6 mL, 13.7 mmol) dropwise at –78 °C. The reaction
mixture was stirred for 1 h at room temperature and partitioned
between saturated aqueous NH4Cl and AcOEt. Column
chromatography (hexane/AcOEt, 4:1) of the organic layer gave 13
2-(tert-Butyldiphenylsiloxymethyl)-5,6-dideoxy-2,3-O-isopropyl-
idene-α-D-lyxo-hex-5-enofuranose (9): To a stirred mixture of 8
(19.1 g, 88.3 mmol), Et3N (36.9 mL, 264.9 mmol), and DMAP
(3.25 g, 26.5 mmol) in CH2Cl2 (200 mL) was added TBDPSCl
(24.1 mL, 92.7 mmol) over 3 h at 0 °C. The resulting mixture was
stirred for another 16 h at room temperature and partitioned be-
tween saturated aqueous NaHCO3 and CH2Cl2. Column
chromatography (hexane/AcOEt, 3:1) of the organic layer gave 9
(38.7 g, 96%, anomeric mixture ca. 4:1) as an oil. [α]2D6 = –34.6 (c
1
(2.8 g, 93%) as an oil. [α]2D7 = +29.3 (c = 0.60, CHCl3). H NMR
(CDCl3): δ = 1.06 (s, 9 H, tBu), 1.27 (s, 3 H, Me), 1.44 (s, 3 H,
Me), 1.45 (s, 3 H, Me), 3.20 (s, 1 H, OH), 3.55 (d, J = 11.2 Hz, 1
= 2.69, CHCl3). 1H NMR (CDCl3 + D2O): δ = 1.06 (s, 7.2 H, tBu), H, CH2OSi), 3.85 (d, J = 11.2 Hz, 1 H, CH2OSi), 4.26 (s, 1 H, 3a-
1.07 (s, 1.8 H, tBu), 1.17 (s, 1.8 H, Me), 1.29 (s, 2.4 H, Me), 1.44 H), 5.57 (d, J = 5.6 Hz, 1 H, CH=CH), 5.74 (d, J = 5.6 Hz, 1 H,
(s, 0.6 H, Me), 1.50 (s, 2.4 H, Me), 3.73–3.89 (m, 2.0 H, CH2OSi),
4.06–4.09 (m, 0.8 H, 4-H), 0.45 (d, J = 3.2 Hz, 0.2 H, 3-H), 4.52
(d, J = 3.2 Hz, 0.8 H, 3-H), 4.58–4.60 (m, 0.2 H,4-H), 5.13 (s, 0.8
CH=CH), 7.35–7.46 (m, 6 H, Ph), 7.66–7.73 (m, 4 H, Ph) ppm.
13C NMR (CDCl3): δ = 19.2, 25.3, 26.8, 27.9, 28.2, 65.8, 77.3, 79.4,
85.1, 95.2, 112.3, 127.7, 129.7, 129.9, 131.1, 132.8,132.9, 135.6,
H, 1-H), 5.30–5.43 (m, 2.2 H, CH=CH2 and 1-H), 5.91–6.02 (m, 1 135.7, 140.4 ppm. MS (FAB): m/z = 439 [M + H]+. C26H34O4Si
H, CH=CH2), 7.36–7.46 (m, 6 H, Ph), 7.63–7.71 (m, 4 H, Ph) ppm.
13C NMR (CDCl3): δ = 19.1, 19.2, 26.7, 26.8, 27.1, 27.2, 63.8, 65.0,
65.8, 81.8, 84.5, 89.0, 93.6, 97.0, 113.5, 113.8, 119.0, 119.2, 127.9,
130.0, 132.0, 132.2, 132.3, 132.6, 135.5, 135.6, 135.8 ppm. MS
(FAB): m/z = 493 [M + K]+. C26H34O5Si (454.64): calcd. C 68.69,
H 7.54; found C 68.49, H 7.64.
(438.64): calcd. C 71.19, H 7.81; found C 71.23, H 7.75.
Benzyl [(3aR,4S,6aS)-6a-(tert-Butyldiphenylsiloxymethyl)-3a,6a-di-
hydro-2,2,4-trimethylcyclopenta[1,3]dioxol-4-yl] Carbonate (14): To
a THF (200 nL) solution of 12 (10.0 g, 23.7 mmol) was added MeLi
(0.96 m in THF, 37.0 mL, 35.5 mmol) dropwise at –78 °C. After
stirring for 0.5 h at –78 °C, CbzCl (6.77 mL, 47.4 mmol) was
added. The reaction mixture was stirred for 2 h at room tempera-
ture and partitioned between saturated aqueous NaHCO3 and Ac-
OEt. Column chromatography (hexane/AcOEt, 9:1) of the organic
layer gave 14 (9.8 g, 74%) as an oil. [α]2D6 = +15.8 (c = 0.47, CHCl3).
(1R,4ЈS,5ЈS)-1-(5Ј-tert-Butyldiphenylsiloxymethyl)-(2Ј,2Ј-dimethyl-
5Ј-vinyl[1Ј,3Ј]dioxol-4Ј-yl)prop-2-en-1-ol (10): To a suspension of
Ph3PCH3Br (88.7 g, 248.2 mmol) in THF (300 mL) was added
BuLi (2.63 m in hexane, 88 mL, 231.6 mmol) dropwise at 0 °C. Af-
ter stirring for 1.5 h at 0 °C, a THF (100 mL) solution of 9 (37.6 g, 1H NMR (CDCl3): δ = 1.04 (s, 9 H, tBu), 1.31 (s, 3 H, Me), 1.36
82.7 mmol) was added. The reaction mixture was stirred for an-
other 48 h at room temperature and partitioned between H2O and
AcOEt. Column chromatography (hexane/AcOEt, 1:1) of the or-
ganic layer gave 10 (34.4 g, 92%) as an oil. [α]2D7 = –26.9 (c = 1.18,
CHCl3). 1H NMR (CDCl3): δ = 1.07 (s, 9 H, tBu), 1.47 (s, 3 H,
Me), 1.66 (s, 3 H, Me), 2.39 (d, J = 3.6 Hz, 1 H, OH), 3.52 (d, J
= 10.4 Hz, 1 H, CH2OSi), 3.63 (d, J = 10.4 Hz, 1 H, CH2OSi),
(s, 3 H, Me), 1.59 (s, 3 H, Me), 3.62 (d, J = 10.8 Hz, 1 H, CH2OSi),
3.82 (dd, J = 10.8, 1.6 Hz, 1 H, CH2OSi), 4.62 (s, 1 H, 3a-H), 5.10
(d, J = 11.6 Hz, 1 H, OCH2Ph), 5.25 (d, J = 11.6 Hz, 1 H,
OCH2Ph), 5.75 (d, J = 5.6 Hz, 1 H, CH=CH), 5.91 (d, J = 5.6 Hz,
1 H, CH=CH), 7.31–7.42 (m, 11 H, Ph), 7.64–7.67 (m, 4 H,
Ph) ppm. 13C NMR (CDCl3): δ = 19.2, 23.1, 26.8, 27.6, 28.3, 66.1,
69.0, 85.3, 88.6, 95.0, 112.5, 127.7, 128.1, 128.2, 128.4, 129.7, 129.8,
4.19–4.23 (m, 1 H, 1-H), 4.35 (d, J = 6.4 Hz, 1 H,1-H), 5.19–5.20 132.8, 132.9, 133.5, 135.6, 135.7, 136.7, 153.5 ppm. MS (FAB): m/z
(m, 1 H, CH=CH2), 5.22 (dd, J = 11.2, 2.0 Hz, 1 H, CH=CH2), = 573 [M + H]+. C34H40O6Si (572.77): calcd. C 71.30, H 7.04;
5.37–5.42 (m, 1 H, CH=CH2), 5.46 (dd, J = 16.6, 2.0 Hz, 1 H,
CH=CH2), 5.79 (ddd, J = 16.8, 10.4, 6.4 Hz, 1 H, 2-H), 5.88 (dd,
J = 16.8, 11.2 Hz, 1 H, CH=CH2), 7.36–7.45 (m, 6 H, Ph), 7.65–
7.70 (m, 4 H, Ph) ppm. 13C NMR (CDCl3): δ = 19.2, 26.8, 27.0,
28.0, 67.0, 71.4, 81.2, 84.4, 108.4, 116.5, 118.3, 127.7, 129.7, 129.8,
132.7, 132.8, 135.6, 135.7, 136.1, 136.2 ppm. MS (FAB): m/z = 453
[M + H]+. C27H36O4Si (452.66): calcd. C 71.64, H 8.02; found C
71.90, H 8.06.
found C 71.28, H 7.09.
Intramolecular Oxyselenenylation of 14 To Form 15: To a solution
of (PhSe)2 (8.24 g, 26.3 mmol) in CH2Cl2 (90 mL) was added Br2
(676 μL, 13.2 mmol) dropwise. After stirring for 2 h at room tem-
perature, AgOTf (6.76 g, 26.4 mmol) was added and stirring was
continued for another 20 min. After cooling the mixture to –78 °C,
a solution of 14 (7.4 g, 13.2 mmol) in CH2Cl2 (20 mL) was added.
The reaction mixture was gradually warmed to –30 °C with vigor-
(3aR,6aS)-6a-(tert-Butyldiphenylsiloxymethyl)-2,2-dimethyl-3a,6a- ous stirring for 16 h. Partition of the reaction mixture between sat-
dihydrocyclopenta[1,3]dioxol-4-one (12): A mixture of 10 (33.0 g,
72.9 mmol) and Umicore M2 (11; 500 mg, 0.53 mmol) in CH2Cl2
(500 mL) was stirred for 70 h at room temperature under positive
pressure of dry Ar in the dark. The resulting mixture was further
treated with PDC (54.9 g, 145.8 mmol) in the presence of 4 Å MS
(ca. 33 g) for 72 h. The reaction mixture was diluted with AcOEt
(ca. 100 mL) and filtered through a pad of silica gel. Column
urated aqueous NaHCO3 and CH2Cl2 was followed by column
chromatography (hexane/AcOEt, 2:1) of the organic layer. This
gave 15 (7.36 g, 89%) as a foam. [α]2D8 = –0.9 (c = 0.91, CHCl3). 1H
NMR (CDCl3): δ = 1.13 (s, 9 H, tBu), 1.22 (s, 3 H, Me), 1.45 (s, 3
H, Me), 1.55 (s, 3 H, Me), 3.84 (d, J = 10.8 Hz, 1 H, CH2OSi),
3.86 (d, J = 4.4 Hz, 1 H, CHSePh), 3.99 (d, J = 10.8 Hz, 1 H,
CH2OSi), 4.31 (s, 1 H, O-CH-), 4.71 (dd, J = 4.4, 0.8 Hz, 1 H, O-
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Synthesis of the 5Ј-Fluoro-2Јβ-methyl Analogues of Neplanocin
CH-), 7.26–7.30 (m, 3 H, Ph), 7.40–7.48 (m, 6 H, Ph), 7.53–7.55 (2
135.5, 135.6, 216.1 ppm. MS (FAB): m/z = 439 [M + H]+. HRMS
H, m Ph), 7.66–7.68 (m, 2 H, Ph), 7.72–7.75 (m, 2 H, Ph) ppm. 13
C
(FAB): calcd. for C26H35O4Si [M + H]+ 439.2305; found 439.2343.
NMR (CDCl3): δ = 19.2, 22.3, 26.1, 27.2, 27.5, 55.1, 66.2, 86.3,
86.4, 113.5, 127.9, 128.0, 129.4, 129.5, 130.2, 130.3, 131.7, 132.2,
133.6, 135.6, 136.0, 153.5 ppm. MS (FAB): m/z = 877 [M + H]+.
C33H38O6SeSi (637.71): calcd. C 62.15, H 6.01; found C 62.24, H
5.95.
(3aR,6aR)-6-(tert-Butyldiphenylsiloxymethyl)-5-fluoro-2,2,3a-tri-
methyl-3a,6a-dihydrocyclopenta[1,3]dioxol-4-one (22): To a stirred
mixture of 20 (782 mg, 1.78 mmol) and TMSCl (453 μL,
3.57 mmol) in THF (15 mL) was added LHMDS (1.55 m in THF,
1.38 mL, 2.14 mmol) dropwise at –78 °C. The reaction mixture was
stirred for 15 min at –78 °C and then partitioned between saturated
aqueous NaHCO3 and AcOEt. The organic layer was evaporated,
(3aS,4S,5R,6S,6aS)-6a-(tert-Butyldiphenylsiloxymethyl)-6-phenyl-
seleno-5,6,3a,6a-tetrahydro-2,2,4-trimethylcyclopenta[1,3]dioxole-
4,5-diol (16): To a mixture of 15 (1.67 g, 2.67 mmol), THF (5 mL), and the residue was dissolved in MeCN (10 mL). To this was added
and MeOH (25 mL) was added K2CO3 (1.84 g, 13.3 mmol). The
resulting mixture was stirred for 12 h at room temperature. The
reaction mixture was partitioned between 0.5 m HCl and CHCl3.
Compound 16 (1.60 g, quant.) was obtained as a foam after evapo-
ration of the organic layer. [α]2D9 = –10.6 (c = 0.34, CHCl3). 1H
NMR (CDCl3): δ = 1.11 (s, 9 H, tBu), 1.23 (s, 3 H, Me), 1.33 (s, 3
H, Me), 1.47 (s, 3 H, Me), 2.62 (d, J = 11.2 Hz, 1 H, OH), 3.20 (s,
1 H, OH), 3.50 (d, J = 11.2 Hz, 1 H, 6-H), 3.74 (d, J = 10.0 Hz, 1
Selectfluor (758 mg, 2.14 mmol) and NaHCO3 (300 mg,
3.57 mmol). The resulting suspension was stirred for 1 h at room
temperature. The mixture was partitioned between saturated aque-
ous NaHCO3 and AcOEt. The organic layer was filtered through
a pad of silica gel. Evaporation of the filtrate gave crude fluoride
21, which was used for the next reaction without further purifica-
tion. To a THF (18 mL) solution of above 21 was added LHMDS
(1.55 m in THF, 1.38 mL, 2.14 mmol) dropwise at –78 °C. The mix-
H, CH2OSi), 3.82 (t, J = 11.2 Hz, 1 H, 5-H), 4.06 (d, J = 10.0 Hz, ture was stirred for 5 min at –78 °C and then at 0 °C for 1 h. After
1 H, CH2OSi), 4.22 (s, 1 H, 3a-H), 7.19–7.27 (m, 3 H, Ph), 7.40– cooling the mixture to –78 °C, TMSCl (272 μL, 2.14 mmol) and a
7.47 (m, 6 H, Ph), 7.61–7.74 (m, 6 H, Ph) ppm. 13C NMR (CDCl3): THF (5 mL) solution of PhSeCl (511 mg, 2.67 mmol) were sequen-
δ = 19.1, 24.8, 27.0, 27.5, 28.1, 60.3, 67.2, 72.9, 81.9, 86.0, 88.0,
114.3, 126.8, 127.8, 127.9, 128.8, 130.0, 130.1, 131.3, 132.0, 132.6,
133.4, 135.7, 136.0 ppm. MS (FAB): m/z = 613 [M + H]+. C32H40O-
5SeSi (611.71): calcd. C 62.83, H 6.59; found C 62.97, H 6.58.
tially added. The whole reaction mixture was stirred for 15 min at
0 °C and then partitioned between saturated aqueous NaHCO3 and
AcOEt. The organic layer was evaporated and dissolved in CH2Cl2
(20 mL), and the resulting solution was treated with m-CPBA
(Ͼ65 %, 1.19 g, 4.45 mmol) and NaHCO3 (1.5 g, 17.8 mmol) at
0 °C for 0.5 h. Partition of the reaction mixture between saturated
aqueous NaHCO3 and CH2 Cl2 was followed by column
chromatography (hexane/AcOEt, 6:1) of the organic layer. This
gave 22 (387 mg, 48% from 20) as an oil. [α]2D8 = +9.8 (c = 0.49,
CHCl3). 1H NMR (CDCl3): δ = 1.09 (s, 9 H, tBu), 1.28 (s, 3 H,
Me), 1.45 (s, 6 H, Meϫ2), 4.53 (dd, J = 16.0, 3.2 Hz, 1 H, CH2OSi),
4.76 (dd, J = 16.0, 2.0 Hz, 1 H, CH2OSi), 4.91 (d, J = 6.4 Hz, 1
(3aR,6aR)-6-(tert-Butyldiphenylsiloxymethyl)-2,2,3a-trimethyl-
3a,6a-dihydrocyclopenta[1,3]dioxol-4-one (19): To a solution of 16
(12.0 g, 19.6 mmol) in 1,2-dichloroethane (150 mL) was added m-
CPBA (Ͼ65 %, 5.47 g, 20.6 mmol) at –30 °C. After stirring for
20 min at room temperature, iPr2NEt (11.9 mL, 68.6 mmol) was
added, and then the reaction mixture was heated at reflux for 2 h.
Partition of the reaction mixture between saturated aqueous
NaHCO3 and CH2Cl2 followed by flash column chromatography
(hexane/AcOEt, 1:3) of the organic layer gave crude ketone 17.
Crude 17 was dissolved in MeOH (100 mL) and treated with 1 m
NaOMe in MeOH (58.8 mL) at –30 °C. After stirring for 15 min
at 0 °C, the mixture was partitioned between saturated aqueous
NH4Cl and CH2Cl2. Crude enone 18 was obtained by evaporation
of the organic layer. Crude 18 thus obtained was treated with a
mixture of acetone (100 mL) and acetone dimethyl acetal (100 mL)
in the presence of TsOH·H2O (373 mg, 1.96 mmol) for 13 h at room
temperature. The reaction was quenched by adding Et3N (ca.
2 mL). Evaporation of the reaction mixture followed by column
chromatography (hexane/AcOEt, 5:1) of the residue gave 19 (6.39 g,
H, 6a-H), 7.35–7.48 (m, 6 H, Ph), 7.66–7.72 (m, 4 H, Ph) ppm. 13
C
NMR (CDCl3): δ = 19.2, 19.5, 26.8, 28.5, 28.6, 57.7, 79.7 (d, JC,F
= 6.0 Hz), 80.7 (d, JC,F = 6.0 Hz), 114.9, 127.8, 127.9, 130.0, 130.1,
132.3, 132.5, 135.5, 135.6, 146.2, 151.9 (d, JC,F = 292.7 Hz), 194.6
(d, JC,F = 15.6 Hz) ppm. 19F NMR (CDCl3): δ = –138.3 ppm. MS
(FAB): m/z = 455 [M + H]+. C26H31FO4Si (454.61): calcd. C 68.69,
H 6.87; found C 68.62, H 6.99.
DIBALH Reduction of 22 To Form 23: To a CH2Cl2 (28 mL) solu-
tion of 22 (1.27 g, 2.79 mmol) was added DIBALH (1.0 m in tolu-
ene, 5.59 mL, 5.59 mmol) dropwise at –78 °C. After stirring for 1 h
at –78 °C, the reaction mixture was partitioned between 0.5 m HCl
and CH2Cl2. HPLC separation (hexane/AcOEt, 4:1) of the organic
layer gave 23 (tR = 9.3 min, 1.02 g, 80%) as an oil. [α]2D6 = +43.5 (c
1
75% from 16) as an oil. HNMR and 13C NMR of 19 were in full
agreement with the reported data.[3e] [α]2D4 = +8.3 (c = 1.20, CHCl3)
{ref.[3e] [α]2D5 = +4.8 (c = 1.06, CHCl3)}. MS (FAB): m/z = 437 [M
+ H]+. C26H32O4Si (436.62): calcd. C 71.52, H 7.39; found C 71.61,
H 7.42.
1
= 1.29, CHCl3). H NMR (CDCl3): δ = 1.06 (s, 9 H, tBu), 1.31 (s,
3 H, Me), 1.48 (s, 3 H, Me), 1.49 (s, 3 H, Me), 2.80 (d, J = 9.0 Hz,
1 H, OH), 4.01 (dd, J = 9.0, 1.6 Hz, 1 H, CH-OH), 4.22 (dd, J =
12.8, 2.8 Hz, 1 H, CH2OSi), 4.48 (d, J = 12.8 Hz, 1 H, CH2OSi),
4.76 (d, J = 7.6 Hz, 1 H, O-CH), 7.36–7.46 (m, 6 H, Ph), 7.66–7.71
(m, 4 H, Ph) ppm. 13C NMR (CDCl3): δ = 19.2, 24.1, 28.9, 29.1,
Hydrogenation of 19 To Form 20: A mixture of 19 (6.04 g,
13.8 mmol) and 10% Pd/C (3.0 g) in AcOEt (70 mL) was stirred
under positive pressure (1 atm) of H2 for 20 h. Filtration of the
reaction mixture through a pad of Celite followed by evaporation
of the filtrate gave 20 (6.05 g, quant.) as an oil. [α]2D8 = –71.2 (c =
55.5, 74.8 (JC,F = 20.4 Hz), 83.0 (JC,F = 6.0 Hz), 84.0 (JC,F
=
7.2 Hz), 112.7, 117.2, 127.6, 127.7, 129.7, 129.8, 133.0, 133.2, 135.6,
135.7, 156.7 (JC,F = 290.3 Hz) ppm. 19F NMR (CDCl3): δ =
–128.3 ppm. MS (FAB): m/z = 457 [M + H]+. C26H33FO4Si
(456.63): calcd. C 68.39, H 7.28; found C 768.04, H 7.28.
1
1.17, CHCl3). H NMR (CDCl3): δ = 1.08 (s, 9 H, tBu), 1.32 (s, 3
H, Me), 1.33 (s, 3 H, Me), 1.37 (s, 3 H, Me), 2.24 (dd, J = 17.2,
12.4 Hz, 1 H, -CH2CO), 2.33 (dd, J = 17.2, 8.0 Hz, 1 H, -CH2CO),
2.38–2.45 (m, 1 H, -CH2CH-), 3.82 (dd, J = 10.0, 6.4 Hz, 1 H,
CH2OSi), 3.94 (dd, J = 10.0, 8.0 Hz, 1 H, CH2OSi), 4.44 (d, J =
Acetylation of 23 To Form 23a: To a pyridine (3 mL) solution of
23 (34 mg, 0.075 mmol) was added Ac2O (35 μL, 0.37 mmol). The
3.2 Hz, 1 H, O-CH), 7.36–7.45 (m, 6 H, Ph), 7.66–7.72 (4 H, m. resulting mixture was stirred for 4 h at room temperature. After
Ph) ppm. 13C NMR (CDCl3): δ = 17.0, 19.2, 26.5, 26.8, 27.1, 36.6,
evaporation of all of volatiles, the residue was purified by prepara-
37.1, 63.5, 82.2, 85.5, 111.4, 127.6, 127.7, 129.7, 133.4, 133.6, 134.8,
tive TLC (hexane/AcOEt, 4:1). This gave 23a (32 mg, 87%) as an
Eur. J. Org. Chem. 2011, 2685–2691
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2689

H. Kumamoto, M. Kobayashi, N. Kato, J. Balzarini, H. Tanaka
FULL PAPER
oil. 1H NMR (CDCl3): δ = 1.07 (s, 9 H, tBu), 1.38 (s, 3 H, Me2C), DMAP (103 mg, 0.84 mmol), and Et3N (117 μL, 0.84 mmol) was
1.42 (s, 3 H, Me2C), 1.53 (s, 3 H, Me), 2.11 (s, 3 H, Ac), 4.30 (dd, treated with TPSCl (254 mg, 0.84 mmol) for 0.5 h at room tempera-
J = 13.2, 2.8 Hz, 1 H, CH2OSi), 4.53 (d, J = 13.2 Hz, 1 H, ture. The reaction mixture was then treated with NH4OH (26%,
CH2OSi), 4.69 (d, J = 7.4 Hz, 1 H, CH-O), 4.99 (s, 1 H, CHOAc), ca. 10 mL) for 20 h at room temperature with stirring. After evapo-
7.37–7.45 (m, 6 H, Ph), 7.67–7.70 (m, 4 H, Ph) ppm. 13C NMR
(CDCl3): δ = 19.2, 20.8, 25.3, 26.7, 27.7, 27.9, 56.0, 76.6 (d, JC,F
18.0 Hz), 81.7 (d, JC,F = 7.2 Hz), 84.9 (d, JC,F = 7.2 Hz), 113.3,
ration, the residue was purified by column chromatography (Ac-
OEt/MeOH, 7:1) to give 25 (111 mg, 48%) as a foam. [α]2D6 = +60.5
(c = 0.46, CHCl3). 1H NMR (CDCl3 + D2O): δ = 1.08 (s, 9 H,
=
121.0 (d, JC,F = 3.6 Hz), 127.6, 127.7, 129.7, 129.8, 133.0, 133.1, tBu), 1.16 (s, 3 H, Me), 1.32 (s, 3 H, Me), 1.43 (s, 3 H, Me), 4.31
135.5, 135.6, 153.0 (d, JC,F = 287.9 Hz), 170.3 ppm. MS (FAB):
(d, J = 13.2 Hz, 1 H, CH2OSi), 4.58 (d, J = 13.2 Hz, 1 H, CH2OSi),
4.86 (d, J = 6.4 Hz, 1 H, 3Ј-H), 5.76 (s, 1 H, 1Ј-H), 5.86 (d, J =
6.4 Hz, 1 H, 5-H), 6.68 (d, J = 6.4 Hz, 1 H, 6-H), 7.38–7.44 (m, 4
H, Ph), 7.45–7.47 (m, 2 H, Ph), 7.68–7.71 (m, 4 H, Ph) ppm. 13C
NMR (CDCl3): δ = 19.2, 21.2, 26.8, 28.7, 29.0, 55.9, 66.4 (d, JC,F
= 18.0 Hz), 85.3 (d, JC,F = 8.4 Hz), 86.4 (d, JC,F = 6.0 Hz), 95.7,
112.4, 123.7, 127.7, 127.8, 129.8, 129.9, 132.8, 133.1, 135.5, 135.7,
140.6, 150.2 (d, JC,F = 287.9 Hz), 156.7, 165.6 ppm. 19F NMR
(CDCl3): δ = –124.6 ppm. MS (FAB): m/z = 550 [M + H]+.
C30H36FN3O4Si·1/5H2O (553.31): calcd. C 65.07, H 6.63, N 7.59;
found C 64.88, H 6.56, N 7.54.
m/z = 499 [M + H]+.
9-[(1S,2S,3R)-2,3-Dihydroxy-5-fluoro-4-hydroxymethyl-2-methyl-
4-cyclopenten-1-yl]adenine (5a): To a mixture of 23 (228 mg,
0.5 mmol), Ph3P (197 mg, 0.75 mmol), and N6-bis(Boc)adenine
(252 mg, 0.75 mmol) in THF (10 mL) was added DIAD (148 μL,
0.75 mmol) dropwise at 0 °C. After stirring for 70 h at room tem-
perature, the reaction mixture was evaporated, and the resulting
residue was purified by column chromatography on silica gel (hex-
ane/AcOEt, 3:1). Appropriate fractions were combined, and the
solvents were evaporated. The residue was dissolved in a mixture
of THF (5 mL) and 2 m HCl (5 mL). The resulting mixture was
heated at 50 °C for 24 h and neutralized with NH4OH (26%, ca.
10 mL), and the solvents were evaporated. Column chromatog-
raphy (AcOEt/MeOH, 7:1) of the residue gave 5a (80 mg, 54%
from 23) as a foam. [α]2D9 = –142.0 (c = 0.29, MeOH). 1H NMR
([D6]DMSO + D2O): δ = 0.80 (s, 3 H, Me), 3.97 (d, J = 13.2 Hz,
1 H, CH2OH), 4.27 (d, J = 13.2 Hz, 1 H, CH2OH), 4.46 (d, J =
6.4 Hz, 1 H, 3Ј-H), 5.37 (s, 1 H, 1Ј-H), 8.08 (s, 1 H, 8-H), 8.17 (s,
1 H, 2-H) ppm. 13C NMR ([D6]DMSO): δ = 21.5, 52.5, 64.1 (d,
JC,F = 16.8 Hz), 75.1 (d, JC,F = 7.2 Hz), 76.1 (d, JC,F = 4.8 Hz),
118.8, 123.5, 139.0, 149.9, 150.6 (d, JC,F = 281.9 Hz), 152.8,
156.0 ppm. 19F NMR ([D6]DMSO): δ = –131.7 ppm. MS (FAB):
m/z = 296 [M + H]+. C12H14FN5O3·1/2H2O (304.28): calcd. C
47.37, H 4.97, N 23.01; found C 47.72, H 5.14, N 22.66.
1-[(1S,2S,3R)-2,3-Dihydroxy-5-fluoro-4-hydroxymethyl-2-methyl-
4-cyclopenten-1-yl]cytosine (5b):
A mixture of 25 (103 mg,
187 μmol) and 3 m HCl (6 mL) in MeOH (6 mL) was stirred at
room temperature for 48 h. After neutralization with NH4OH
(26%, ca. 10 mL), the mixture was evaporated. Preparative TLC
(CHCl3/MeOH, 3:1, developed 6ϫ) of the residue gave 5b (36 mg,
71%) as a solid. M.p. 140–142 °C. [α]1D4 = –43.5 (c = 0.42, MeOH).
1H NMR (CD3OD): δ = 1.09 (s, 3 H, Me), 4.12 (d, J = 12.6 Hz, 1
H, CH2OH), 4.39–4.41 (m, 2 H, CH2OH and 3Ј-H), 5.55 (br., 1 H,
1Ј-H), 5.93 (d, J = 7.4 Hz, 1 H, 5-H), 7.40 (d, J = 7.4 Hz, 1 H, 6-
H) ppm. 13C NMR (CD3OD): δ = 22.4, 54.4, 68.5, (d, JC,F
=
19.2 Hz), 77.7, 96.9, 126.4, 129.8, 143.5, 153.9 (d, JC,F = 283.1 Hz),
159.5, 167.6 ppm. 19F NMR (CD3OD): δ = –130.1 ppm. MS
(FAB): m/z = 272 [M + H]+. HRMS (FAB): calcd. for C11H15FO4
272.1047 [M + H]+; found 272.1047.
1-{(3aS,4S,6aR)-6-(tert-Butyldiphenylsiloxymethyl)-5-fluoro-2,2,3a-
trimethyl-3a,6a-dihydrocyclopenta[1,3]dioxol-4-yl}uracil (24): To a
stirred solution of Ph3P (572 mg, 2.18 mmol) in THF (5 mL) was
added DIAD (430 μL, 2.18 mmol) at 0 °C. After stirring for
10 min, N3-benzoyluracil (471 mg, 2.18 mmol) in THF (10 mL) and
23 (397 mg, 9.87 mmol) in THF (5 mL) were sequentially added at
–40 °C. The reaction mixture was stirred for 66 h at room tempera-
ture and then partitioned between brine and Et2O. After evapora-
tion of the organic layer, the residue was treated with NaOMe
(470 mg, 7.7 mmol) in MeOH (30 mL) at room temperature for
24 h. Partition of the reaction mixture between 0.5 m HCl and
CH2Cl2 followed by column chromatography (hexane/Et2O, 1:3) of
the organic layer gave 24 (239 mg, 50% from 23) as a foam. [α]2D6
= +36.0 (c = 0.67, CHCl3). 1H NMR (CDCl3): δ = 1.09 (s, 9 H,
tBu), 1.20 (s, 3 H, Me), 1.34 (s, 3 H, Me), 1.45 (s, 3 H, Me), 4.32
(d, J = 13.2 Hz, 1 H, CH2OSi), 4.61 (d, J = 13.2 Hz, 1 H, CH2OSi),
4.88 (d, J = 6.4 Hz, 1 H, 3Ј-H), 5.60 (s, 1 H, 1Ј-H), 5.68 (d, J =
8.0 Hz, 1 H, 5-H), 6.58 (d, J = 8.0 Hz, 1 H, 6-H), 7.40–7.49 (m, 6
H, Ph), 7.68–7.70 (m, 4 H, Ph), 8.74 (br., 1 H, NH) ppm. 13C NMR
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H, 13C, and 19F NMR spectra for all described
compounds.
Acknowledgments
The authors are grateful to Ms. Y. Odanaka and S. S. Matsubayashi
(Center for Instrumental Analysis, Showa University) for technical
assistance with NMR spectroscopy, MS, and elemental analyses.
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(CDCl3): δ = 21.1, 21.9, 26.8, 28.6, 29.0, 55.9, 66.9 (d, JC,F
=
18.0 Hz), 85.1 (d, JC,F = 7.2 Hz), 85.9 (d, JC,F = 4.8 Hz), 103.0,
112.8, 124.7, 127.8, 130.0, 132.7, 133.1, 135.5, 135.7, 139.7, 148.8
(d, JC,F = 287.9 Hz), 161.0, 162.5 ppm. 19F NMR (CDCl3): δ =
–124.8 ppm. MS (FAB): m/z = 551 [M + H]+. C30H35FN2O5Si·3/
4H2O (564.20): calcd. C 63.87, H 6.52, N 4.97; found C 63.67, H
6.35, N 5.35.
1-{(3aS,4S,6aR)-6-(tert-Butyldiphenylsiloxymethyl)-5-fluoro-2,2,3a-
trimethyl-3a,6a-dihydrocyclopenta[1,3]dioxol-4-yl}cytosine (25): A
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2685–2691

Synthesis of the 5Ј-Fluoro-2Јβ-methyl Analogues of Neplanocin
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Received: January 17, 2011
Published Online: March 25, 2011
Eur. J. Org. Chem. 2011, 2685–2691
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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