Synthesis and biological evaluation of azido- and aziridino-hydroxyl- β-lactams through stereo- and regioselective epoxide ring opening

Article abstract of DOI:10.1021/jo0615652

(Chemical Equation Presented) Two new classes of azido- and aziridino-hydroxyl-β-lactam containing structures have been prepared by means of a stereo- and regioselective epoxide ring opening. The straightforwardness of the procedure makes this strategy us

Full text of DOI:10.1021/jo0615652

absorption.3,4 Since cardiovascular disease is the leading cause
of death in the industrialized world, the synthesis of new
polyfunctionalized azetidin-2-ones, possessing the minimum
requirements for cholesterol absorption control, has received
great attention. In a program directed to the synthesis of potential
CAI, we became interested in the functionalization of the C-3
side chain; the lipophilic phenyl group was chosen as the
substituent in the â-lactam ring C-4 position, as suggested by
the literature for bioactive Ezetimibe analogues.3a,b
We have recently reported the synthesis of 3-bromo-3-
alkenyl-azetidin-2-ones (1)5 via ketene-imine cycloaddition.6
This class of compounds is of great interest since the substitution
of the bromine in position 3 through SN2′ rearrangement7 and
the transformation of the double bond in the side chain give
access to a variety of derivatives.
Synthesis and Biological Evaluation of Azido- and
Aziridino-hydroxyl-â-lactams through Stereo-
and Regioselective Epoxide Ring Opening†
Fides Benfatti,‡ Giuliana Cardillo,*,‡ Luca Gentilucci,‡
Rossana Perciaccante,‡ Alessandra Tolomelli,‡ and
Alberico Catapano§
Department of Chemistry “G. Ciamician”, UniVersity of
Bologna, Via Selmi 2, 40126 Bologna, Italy, and Department of
Pharmacological Sciences, UniVersity of Milan, Via G.Balzeretti
9, 20133 Milan, Italy
giuliana.cardillo@unibo.it
In this work, the functionalization of the double bond is
described with a view to the formation of C-O and C-N bonds.
The reactions herein reported are characterized by total stereo-
control in all steps, high overall yield, and access to densely
functionalized â-lactams. Furthermore, only a few examples of
C-3 side chain amino and azido function-containing azetidinones
are reported in the literature.8
ReceiVed July 28, 2006
The azido group can be easily submitted to further transfor-
mations affording amines, aziridines, or cyclic nitrogen-contain-
ing compounds. Although the azido function is practically absent
in naturally occurring species, it is quite stable in a biological
environment, and lacking in toxicity, it has been introduced in
a variety of drugs,9 the most important one being the well-known
azidothymidine, AZT.
To this purpose, the treatment of substrates 1a-c with meta-
chloroperbenzoic acid (MCPBA) performed under concentrated
conditions (2 M in CH2Cl2) allowed the corresponding epoxides
to be obtained in a 1:1 mixture and an almost quantitative yield
(Scheme 1).10 The diastereomeric mixture of epoxides 2a-c
and 3a-c was separated by flash chromatography.
Two new classes of azido- and aziridino-hydroxyl-â-lactam
containing structures have been prepared by means of a
stereo- and regioselective epoxide ring opening. The straight-
forwardness of the procedure makes this strategy useful for
the synthesis of potentially bioactive compounds. Some
selected examples showed promising activity in acyl CoA-
cholesterol acyltransferase inhibition assays.
The first epoxide, 2a, to be eluted was a solid crystallized
from CHCl3, and its structure with the relative epoxide con-
(2) (a) Abell, A. D.; Oldham, D. Bioorg. Med. Chem. Lett. 1999, 9, 497-
500. (b) Haley, T. M.; Angier, S. J.; Borthwick, A. D.; Singh, R.; Micetich,
R. G. Drugs 2000, 3, 512-517. (c) Mascaretti, O. A.; Boschetti, C. E.;
Danelon, G. O.; Mata, E. G.; Roveri, A. A. Curr. Med. Chem. 1995, 1,
441-470. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. ReV. 1994, 14,
127-194. (e) Zhou, N. E.; Guo, D.; Thomas, A. G.; Reddy, A. V. N.; Kaleta,
J.; Purisima, E.; Menard, R.; Miceticha, R. G.; Singh, R. Bioorg. Med. Chem.
Lett. 2003, 13, 139-141.
(3) (a) Clader, J. W. Curr. Top. Med. Chem. 2005, 5, 231-233. (b)
Clader, J. W. Curr. Top. Med. Chem. 2005, 5, 243-256. (c) Clader, J. W.
Science 2004, 303, 1201-1204. (d) Kvaerno, L.; Werder, M.; Hauser, H.;
Carreira, E. M. J. Med. Chem. 2005, 48, 6035-6053.
(4) Catapano, A.; Brady, W. E.; King, T. R.; Palmisano, J. Curr. Med.
Res. Opin. 2005, 21, 1123-1130.
(5) Benfatti, F.; Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Perciaccante,
R.; Piccinelli, F.; Tolomelli, A. Synthesis 2005, 61-70.
(6) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org.
Chem. 1999, 12, 3223-3235.
(7) (a) Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Perciaccante, R.;
Piccinelli, F.; Tolomelli, A. Org. Lett. 2005, 7, 533-536. (b) Cardillo, G.;
Fabbroni, S.; Gentilucci, L.; Perciaccante, R.; Tolomelli, A. AdV. Synth.
Catal. 2005, 347, 833-838.
(8) (a) Lee, D. L.; Rapoport, H. J. Org. Chem. 1975, 40, 3491-3496.
(b) Baldwin, J. E.; Otsuka, M.; Wallace, P. M. Tetrahedron 1986, 42, 3097-
3110.
Azetidin-2-ones are important as key structural elements of
the most widely employed class of antibacterial agents; numer-
ous synthetic approaches to azetidin-2-ones have been reported.1
More recently, azetidin-2-ones have received great attention
since the discovery that some representative examples of these
compounds have shown potent and selective enzymatic inhibi-
tion.2 Over the past few years, a class of â-lactam based
structures containing hydroxy and keto functions in the C-3 side
chain were found to be very potent cholesterol absorption
inhibitors (CAI).3 Ezetimibe is a new example of a â-lactam
containing drug involving inhibition of intestinal cholesterol
† Dedicated to Professor Achille Umani-Ronchi on the occasion of his 70th
birthday.
‡ University of Bologna.
§ University of Milan.
(1) (a) Walsh, C. T. Nat. ReV. Microbiol. 2003, 1, 65-70. (b) Raja, A.;
Lebbos, J.; Kirkpatrick, P. Nat. ReV. Drug DiscoVery 2004, 3, 733-734.
(c) Singh, G. S. Mini ReV. Med. Chem. 2004, 4, 69-109. (d) Fisher, J. F.;
Meroueh, S. O.; Mobashery, S. Chem. ReV. 2005, 105, 395-424. (e)
Meegan, J. M.; Waldronm C. M.; Keaveny, R. D.; Neary, A. D. J. Chem.
Res. 1997, 158-159.
(9) Griffin, R. J. Prog. Med. Chem. 1994, 31, 121-232.
(10) Benfatti, F.; Cardillo, G.; Gentilucci, L.; Perciaccante, R.; Tolomelli,
A. Synlett 2005, 2204-2206.
10.1021/jo0615652 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/25/2006
J. Org. Chem. 2006, 71, 9229-9232
9229

SCHEME 1. Synthesis of Epoxides 2 and 3
The complete regio- and stereoselectivity can be rationalized
by the tendency of the aluminum to become tetrahedral through
an intramolecular coordination.15
The ab initio geometry-optimized structure of the aluminum
complex (DFT/B3LYP/6.31G* minimization) shows that the
computed atomic partial charges on C-1′ and C-2′ are very
similar. The attack of the azide occurs exclusively on the less
hindered C-2′ position since the attack to C-1′ is greatly
disfavored by the presence of the vicinal phenyl group more
than by the presence of the bulky bromine lying on the opposite
face of the lactam ring.
Furthermore, the formation of the aluminum complex,
promoting the ionization of the azide, favors the nucleophilic
anion attack via SN2 mechanism, with complete inversion of
the configuration (Figure 1). Subsequently, upon treatment of
compound 4 and 5 with 1 equiv of NaH in dry THF at 0 °C,
spiro-epoxides 6 and 7 could be obtained in quantitative yields
via the bromine displacement (Table 2).
It is noteworthy that a complete pathway from epoxides 2
and 3 to azides 4 and 5 and then to spiro-epoxides 6 and 7
does not require chromatographic purification, since the products
were obtained in high yield and in the absence of byproducts.
We next studied the reduction of the azido group. Extensive
experimentation was carried out in order to reduce the azido
group in the presence of sensitive functions such as epoxide
and bromide.16
However, any attempt to reduce the azide 4a with NaBH4 in
refluxing methanol failed. Under these conditions, spiro-epoxide
6a was obtained in moderate yield. The treatment of 6a with
BH2Cl-SMe2 as well as hydrogenation on Pd/C gave mixtures
of products.
Excellent results were observed by reducing azides 6a-c and
7a-c with Ph3P or Et3P.17 These reactions allowed aziridines
8a-c and 9a-c to be obtained in yields ranging from 50-
80%, via an aza-Payne-like ring opening18 of the epoxide
(Scheme 2).
TABLE 1. 1H NMR Data for Compounds 2a-c and 3a-c
entrya
epoxide
δ H1′
δ H2′
J1′-2′
1
2
3
4
5
6
2a
2b
2c
3a
3b
3c
3.27
3.19
3.26
3.38
3.37
3.41
3.57
3.48
3.49
2.82
2.81
2.95
2.2
2.0
2.1
2.1
2.3
2.4
a Spectra recorded in CDCl3 solution at 25 °C.
figuration was established by single-crystal X-ray analysis,11
thus allowing the (1′R*,2′S*) configuration to be attributed to
the newly introduced stereogenic centers. As a consequence the
(1′S*,2′R*) configuration was attributed to the isomer 3a.
1
The H NMR of 2a shows the hydrogen H1′ as a doublet
resonating at 3.29 ppm, while the hydrogen H2′ is a multiplet
deshielded at 3.59 ppm. The coupling constant, J1′-2′ ) 2.2 Hz,
accounts for a trans relationship. Semi-empirical calculations12
are in agreement with the X-ray structure, showing bromide
and epoxide in the more stable anti arrangement. NOE analysis
of 2a,b and 3a,b confirmed that this conformation is also the
preferred one in solution. The irradiation of the hydrogen at
C-4 on the lactam ring, indeed, enhances the signal relative to
H1. The same experiment performed on isomer 3a,b induced
enhancement at H2 of the epoxide.13 Finally, comparison of the
1H NMR chemical shifts for the pairs of compounds 2 and 3
revealed a complete regularity, allowing the relative configu-
ration to be confidently attributed to 2c and 3c and the absolute
configuration to be attributed to 2b and 3b. (Table 1).
The 1H NMR coupling constants of the aziridine protons (J2-3
) 2.0-3.0 Hz) account for a trans relationship, confirming the
stereochemistry attributed to the starting azides 6 and 7. In the
overall sequence from R-bromoepoxides to aziridines, the
stereochemical configuration of both C-1′ and C-2′ carbon atoms
has been inverted. The retention of the configuration at C-3, in
the last step, arises from mechanistic considerations.19 A possible
mechanism is reported in Scheme 3.
The regioselective ring opening of oxiranes provides a
convenient way to prepare polyfunctionalized compounds.
Successful ring openings of epoxyalcohols with diethylalumi-
num azide have been reported by Benedetti et al.14 aiming to
prepare 3-amino-1,2-diols that are present in several classes of
biologically active compounds. Therefore, the treatment of
epoxides 2a-c and 3a-c with Me2AlN3, prepared in situ from
sodium azide and Me2AlCl, gave the corresponding azides 4a-c
or 5a-c with a good yield and complete stereo- and regiose-
lectivity (Table 2). The ring opening of the epoxides occurred
only on the C-2′ position with inversion of the configuration.
The reaction proceeds by nucleophilic attack of a phospine
on the azide, to form an aza-ylide intermediate. The nucleophilic
nitrogen atom of the aza-ylide attacks the epoxide, inducing
(15) Davis, C. E. D.; Bailey, J. L.; Lockner, J. W.; Coates, R. M. J.
Org. Chem. 2003, 68, 75-82.
(16) (a) Nyffeler, P. T; Liang, C.-H.; Koeller, K. M; Wong, C.-H. J.
Am. Chem. Soc. 2002, 124, 10773-78. (b) Yamashita, M.; Ojima, I. J.
Am. Chem. Soc. 1983, 105, 6339-6342. (c) Boyer, J. H. J. Am. Chem.
Soc. 1951, 73, 5865-5866.
(17) (a) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635. (b)
Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37,
437-472. (c) Multzer, J.; Becker, R.; Brunner, E. J. Am. Chem. Soc. 1989,
111, 7500-7504. (d) Legters, J.; Thijs, L.; Zwanenburg, B. Tetrahedron
1991, 47, 5287-94. (e) Velasco, M. D.; Molina, P.; Fresneda, P. M.; Sanz,
M. A. Tetrahedron 2000, 56, 4079-4084.
(11) Crystal data for 2a: C20H20Br1N1O2; MW ) 386.28; monoclinic,
P2(1)/c; a ) 8.8729(11) Å, b ) 19.734(2) Å, c ) 21.236(3) Å, â ) 92.613-
(2)°; V) 3714.5(8) Å3; Z ) 8; Dcalc ) 1.381 Mg/m3; R1 ) 0.0474, wR2 )
0.1260 (final); goodness-of-fit on F2 ) 0.769. ORTEP plot is reported in
Supporting Information.
(12) Structures calculated with AM1 (HYPERCHEM 7.0 package).
(13) See Supporting Information.
(18) Ibuka, T. Chem. Soc. ReV. 1998, 27, 145-154.
(19) (a) Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2,
2141-2143. (b) Lin, F. L.; Hoyt, H. M.; van Halbeek, H.; Bergman, R.
G.; Bertozzi, C. R. J. Am. Chem. Soc. 2005, 127, 2686-2695.
(20) Ibuka, T. Chem. Soc. ReV. 1998, 27, 145-154.
(14) Benedetti, F.; Berti, F.; Norbedo, S. Tetrahedron Lett. 1998, 39,
7971-7974.
9230 J. Org. Chem., Vol. 71, No. 24, 2006

TABLE 2. Ring Opening of Epoxides 2 and 3 and Synthesis of Epoxides 6 and 7a
a Reaction conditions: (i) NaN3/Me2AlCl, toluene, -78 °C; (ii) NaH, THF, 0 °C.
SCHEME 2. Synthesis of Aziridines 8a-c and 9a-c
FIGURE 1. Azide anion nucleophilic attack on the aluminum complex
(ab initio geometry optimized structure with DFT/B3LYP/6.31G*).
the ring opening. Hydrolysis of the adduct produces the
aziridine-alcohol and liberates the phosphine oxide.
Finally, representative examples of aziridines and their azido
precursors were tested as acyl CoA-cholesterol acyltransferase
(ACAT) inhibitors21 using Lovastatin as a reference standard22
(IC50 ) 12 µM from literature data, IC50 ) 16.8 µM when
concurrently tested). ACAT is a key enzyme in controlling
cholesterol metabolism and represents a promising target for
the development of therapeutic agents.23 Although this test is
not strictly correlated with Ezetimibe activity,24 some indication
on the cholesterol absorption inhibition can be deduced, giving
rise to the preliminary results reported in Table 3. These
promising results do not allow for the elucidation of a structure-
activity relationship, but nevertheless the results confirm the
(21) Inhibition tests were performed by MDS Pharma Services on acyl
CoA-cholesterol acyltransferase from New Zealand derived albino rabbit
intestinal mucosa, using [14C]palmitoyl CoA (18 µM) as a substrate in 1%
DMSO-0.2 M potassium phosphate buffer (pH 7.4) and 1.5 mg/mL bovine
serum albumin at 25°C.
(23) Leon, C.; Hill, J. S.; Wasan, K. M. Pharm. Res. 2005, 10, 1578-
1588.
(22) (a) Largis, E. E.; Wang, C. H.; DeVries, V. G.; Schaffer, S. A. J.
Lipid Res. 1989, 30, 681-689. (b) Sliskovic, D. R.; White, A. D. Trends
Pharmacol. Sci. 1991, 12, 194-199.
(24) Clader, J. W.; Burnett, D. A.; Caplen, M. A.; Domalski, M. S.;
Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M. E.; Zhao, H.; Burrier, R. E.;
Salisbury, B.; Davis, H. R., Jr. J. Med. Chem. 1996, 39, 3684-3693.
J. Org. Chem, Vol. 71, No. 24, 2006 9231

SCHEME 3. Mechanistic Considerations on the
δ 1.08 (t, 3H, J ) 7.4 Hz), 1.59-1.74 (m, 1H), 2.04-2.18 (m,
1H), 3.29 (bs, 1H), 3.50 (dt, 1H, J ) 3.0, 8.7 Hz), 3.62 (d, 1H, J
) 8.7 Hz), 3.88 (d, 1H, J ) 14.8 Hz), 4.77 (s, 1H), 4.92 (d, 1H, J
) 14.8 Hz), 7.14-7.20 (m, 2H), 7.30-7.47 (m, 8H); 13C NMR
(50 MHz, CDCl3) δ 9.9, 24.5, 44.9, 64.3, 65.7, 73.8, 75.1, 128.2,
128.4, 128.6, 128.7, 129.0, 129.2, 133.0, 134.1, 166.3. Anal. Calcd
for C20H21BrN4O2: C, 55.95; H, 4.93; N, 13.05. Found: C, 55.92;
H, 4.90; N, 13.01.
Aza-Payne-like Ring Opening of Epoxide to Aziridine20
General Procedure for the Formation of Epoxides 6a-c and
7a-c. A solution of compound 4 or 5 (1 mmol) and NaH (1.2
equiv, 1.2 mmol, 29 mg) in dry CH2Cl2 (10 mL) was stirred at 0
°C for 2 h. The reaction was quenched by adding cold water
dropwise (1 mL) and was further diluted with water (10 mL), and
then layers were separated. The organic layer was dried over Na2-
SO4, and the solvent was removed under reduced pressure.
Compounds 6 and 7 were isolated pure and used in the following
step without further purification.
6a: HPLC-MS tR ) 16.0 min (M + 1) ) 349, (M + Na) ) 371
m/z; IR (neat) ν 3392, 3058, 3024, 2968, 2924, 2099, 1770, 1496,
1456, 1387, 1261, 1101, 1028 cm-1; 1H NMR (200 MHz, CDCl3)
δ 1.04 (t, 3H, J ) 7.4 Hz), 1.54-1.80 (m, 1H), 1.81-2.00 (m,
1H), 2.81 (d, 1H, J ) 8.4 Hz), 3.61 (dt, 1H, J ) 5.2, 8.4 Hz), 3.91
(d, 1H, J ) 15.0 Hz), 4.64 (s, 1H), 4.98 (d, 1H, J ) 15.0 Hz),
7.15-7.44 (m, 10H); 13C NMR (50 MHz, CDCl3) δ 9.6, 29.7, 44.9,
59.9, 61.6, 62.7, 74.3, 127.4, 128.0, 128.6, 128.7, 128.8, 129.2,
134.0, 134.6, 169.3. Anal. Calcd for C20H20N4O2: C, 68.95; H,
5.79; N, 16.08. Found: C, 68.93; H, 5.80; N, 16.11.
TABLE 3. ACAT Inhibition Activities of Some Selected Aziridino-
and Azido- Derivatives
entry
compd
4b
5b
8c
concn (µM)
% inhibitiona
1
2
3
4
10
10
10
16.8
65
60
22
50
Lovastatin
a Measured by quantitation of [14C]cholesterol ester by column chro-
matography.
General Procedure for the Tandem Reduction-Aza-Payne
Rearrangement to Compounds 8a-c and 9a-c. A solution of
azido-epoxide 6 or 7 (1 mmol) and Et3P (1.2 mmol, 1.2 equiv, 1.2
mL of 1 M solution in THF) in dry THF (5 mL) was stirred at
reflux under nitrogen atmosphere. After 2 h the reaction was stopped
by adding 6 M HCl (2 mL); THF was removed under reduced
pressure, and the residue was diluted with EtOAc. The two phases
were separated, and a 6 M solution of NaOH was added to the
aqueous layer to reach basic pH. The basic aqueous phase was then
extracted twice with EtOAc (10 mL); the organic layer was dried
over Na2SO4, and the solvent was removed under reduced pressure
to give the pure compounds 8 and 9.
potential application of these molecules as ACAT inhibitors.
In vivo assays in a murine model of yperlipidemia are currently
underway.
In summary, this investigation gave us the epoxide ring
opening with Me2AlN3 through a fast, regio- and stereoselective
process. Subsequent nucleophilic substitution on the bromine
atom afforded spiro derivatives in a quantitative yield. Finally
the tandem reduction/ring opening reaction of the epoxide gave
an easy access to a new class of aziridino-lactams. This chemo-,
regio-, and stereoselective method allows the synthesis of
hydroxy-aziridine and azido-epoxide-containing azetidin-2-ones.
The potential of these products as ACAT inhibitors and the
simplicity of the procedure make this strategy useful in bioactive
compound synthesis.
8a: Yield 59%; HPLC-MS tR ) 9.6 min (M + 1) ) 323, (M +
Na) ) 345 m/z; IR (neat) ν 3285, 3059, 3032, 1755, 1604, 1495,
1
1454, 1399, 1355, 1252, 1126, 1027 cm-1; H NMR (200 MHz,
CDCl3) δ 0.46 (t, 3H, J ) 7.4 Hz), 0.74-0.93 (m, 2H), 1.47 (bs,
1H), 1.87 (bs, 1H), 4.03 (d, 1H, J ) 15.0 Hz), 4.54 (s, 1H), 4.96
(d, 1H, J ) 15.0 Hz), 7.17-7.40 (m, 10H); 13C NMR (50 MHz,
CDCl3) δ 10.3, 20.2, 25.8, 29.7, 44.3, 67.0, 85.2, 127.2, 127.8,
128.3, 128.5, 128.8 (2C), 134.6, 134.9, 171.1. Anal. Calcd for
C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.52; H, 6.88;
N, 8.72.
Experimental Section
General Procedure for the Ring Opening of Epoxides 2a-c
and 3a-c. To a stirred solution of NaN3 (1 mmol) in toluene (3
mL) at 25 °C under nitrogen atmosphere was added dropwise
Me2AlCl (1 mmol, 1 equiv, 1 mL of 1 M solution in hexane). The
reaction was stirred for 4 h and then was cooled to -78 °C. Epoxide
2 or 3 (0.5 equiv, 0.5 mmol) was diluted in toluene (0.5 mL) and
then was added to the reaction mixture. The solution was stirred
overnight, slowly reaching room temperature, and then was diluted
with EtOAc, cooled to 5 °C, and added to a aqueous solution (5
mL) containing NaF (1 equiv, 1 mmol, 42 mg). The two phases
were stirred for 30 min and then were separated; the organic layer
was dried over Na2SO4, and the solvent was removed under reduced
pressure. Compounds 4 and 5 were used in the following step
without further purification.
Acknowledgment. We thank MIUR (PRIN 2004), CNR-
ISOF, and the University of Bologna (funds for selected topics)
for financial support. Mr. Andrea Garelli is gratefully acknowl-
edged for the LC-ESI-MS analysis. Dr. Fabio Piccinelli is
gratefully acknowledged for the X-ray analysis.
Supporting Information Available: General procedures, com-
plete characterization of compounds 2-9, X-ray data for 2a,
1
NOESY-1D experiments on 2a and on 3a, H NMR spectra for
compounds 2-9, and experimental details on biological assays. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
4a: HPLC-MS tR ) 13.8 min (M + 1) ) 429/431, (M + Na) )
451/453 m/z; IR (neat) ν 3420, 2966, 2925, 2108, 1752, 1647, 1457,
1399, 1356, 1264, 1107, 1170 cm-1; 1H NMR (300 MHz, CDCl3)
JO0615652
9232 J. Org. Chem., Vol. 71, No. 24, 2006