Synthesis of kaempferitrin

Article abstract of DOI:10.1021/jo070502w

(Chemical Equation Presented) A short synthesis of Kaempferitrin (1), a 3,7-diglycosylflavone, is reported. Key features include the synthesis of a protected form of kaempferol in which all four hydroxy groups are differentiated and the first bis-glycosyl

Full text of DOI:10.1021/jo070502w

Synthesis of Kaempferitrin
Sameer Urgaonkar and Jared T. Shaw*,†
Chemical Biology Program, Broad Institute of HarVard and
MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142
shaw@broad.harVard.edu
ReceiVed March 13, 2007
FIGURE 1. Structure of Kaempferitrin (kaempferol 3,7-di-O-rham-
noside, 1).
positive and Gram negative bacteria. This report also notes that
Kaempferitrin caused filamentation in E. coli, which can be
indicative of DNA damage,9 inhibition of DNA topoisomerase
II (DNA gyrase),10 or inhibition of bacterial cell division.11 Our
interest in natural products which inhibit bacterial cell division,
including the tubulin-like protein FtsZ,12 prompted us to develop
a synthesis of 1 as a basis for studies to elucidate the origin of
this compound’s biological activity.
The synthesis of mono-glycosyl flavones has witnessed
considerable attention from the synthetic community.13 On the
other hand, preparation of bis-glycosylated flavones has largely
remained unexplored. In fact, to the best of our knowledge,
calabricoside A represents the only example of a bis-glycosy-
lated flavone synthesized to date.14 Here, we report the first
synthesis of Kaempferitrin, a bis-glycosylated flavone, and its
biological study. A feature of our synthetic approach is that
O-glycosylation at any position of Kaempferol is potentially
possible due to the orthogonality of the protecting groups that
are employed.
A short synthesis of Kaempferitrin (1), a 3,7-diglycosylfla-
vone, is reported. Key features include the synthesis of a
protected form of kaempferol in which all four hydroxy
groups are differentiated and the first bis-glycosylation of a
dihydroxyflavone. This synthesis will allow the preparation
of derivatives for further explorations into the origins of this
compound’s biological activity.
Glycosylated flavanoids are ubiquitous in plants and exhibit
a broad spectrum of biological activities1 including antimicro-
bial2 and antidiabetic3 properties as well as inhibition of HIV
reverse transcriptase4 and DNA topoisomerase I.5 Kaempferitrin
(1), a 3,7-diglycosylflavone (Figure 1), is produced by several
plant species and is reported to have a significant hypoglycemic
effect in diabetic rats and has antioxidant properties comparable
to those of quercetin.6 A report in 20017 indicated that this
compound, isolated from L. corniculatus,8 exhibited antimicro-
bial activity comparable to several antibiotics against Gram
Our retrosynthetic plan (Scheme 1) relies on the formation
of protected Kaempferitrin 5 upon bis-O-glycosylation of a
suitably protected 3,7-dihydroxyflavone 4. We hoped to obtain
this compound from the cyclization of benzoate ester 3.
Commercially available phloroglucinol 2 could then serve as
the starting point. At the outset, we realized that the judicious
choice of protecting groups for the phenolic hydroxyl groups
at the 3-, 5-, 7-, and 12-positions would be vital for making
this synthesis general.
Our synthetic approach to 1 commenced with the preparation
of protected 3,7-dihydroxyflavone 11, as illustrated in Scheme
2. The R-methoxy ketone functionality in 6 was introduced by
using the Houben-Hoesch reaction of phloroglucinol.15 Taking
† Current address: Department of Chemistry, University of California, One
Shields Ave., Davis, California 95616 (e-mail: shaw@chem.ucdavis.edu).
(1) (a) Costa, S. S.; Jossang, A.; Bodo, B.; Souza, M. I. M.; Moraes, V.
L. G. J. Nat. Prod. 1994, 57, 1503-1510. (b) Toker, G.; Kuepeli, E.;
Memisoglu, M.; Yesilada, E. J. Ethnopharmacol. 2004, 95, 393-397. (c)
Zheng, X.; Hu, Y.; Liu, J.; Ouyang, K. Bioorg. Med. Chem. Lett. 2005, 15,
4531-4535.
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Tosun, F.; Ruedi, P. Antimicrob. Agents Chemother. 2006, 50, 1352-1364.
(3) (a) Matsuda, H.; Morikawa, T.; Yoshikawa, M. Pure Appl. Chem.
2002, 74, 1301-1308. (b) Jorge, A. P.; Horst, H.; de Sousa, E.; Pizzolatti,
M. G.; Silva, F. R. M. B. Chem.-Biol. Interact. 2004, 149, 89-96.
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Chem. Pharm. Bull. 2001, 49, 546-550.
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Marshall, R.; Wu, X.; Hecht, S. M. Bioorg. Med. Chem. Lett. 2005, 15,
813-816.
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832.
(9) Norman, A.; Hansen, L. H.; Sorensen, S. J. Mutat. Res. 2006, 603,
164-172.
(10) Piddock, L. J. V.; Walters, R. N.; Diver, J. M. Antimicrob. Agents
Chemother. 1990, 34, 2331-2336.
(11) Vollmer, W. Appl. Microbiol. Biotechnol. 2006, 73, 37-47.
(12) Urgaonkar, S.; La Pierre, H. S.; Meir, I.; Lund, H.; RayChaudhuri,
D.; Shaw, J. T. Org. Lett. 2005, 7, 5609-5612.
(13) (a) Caldwell, S. T.; Crozier, A.; Hartley, R. C. Tetrahedron 2000,
56, 4101-4106. (b) Dangles, O.; Alluis, B. HelV. Chim. Acta 2001, 84,
1133-1156. (c) Bouktaib, M.; Atmani, A.; Rolando, C. Tetrahedron Lett.
2002, 43, 6263-6266. (d) Li, M.; Han, X.; Yu, B. Tetrahedron Lett. 2002,
43, 9467-9470. (e) Li, M.; Han, X.; Yu, B. J. Org. Chem. 2003, 68, 6842-
6845. (f) Du, Y.; Wei, G.; Linhardt, R. J. J. Org. Chem. 2004, 69, 2206-
2209. (g) Chen, Z.; Hu, Y.; Wu, H.; Jiang, H. Tetrahedron Lett. 2004, 14,
3949-3952. (h) Maloney, D. J.; Hecht, S. M. Org. Lett. 2005, 7, 1097-
1099. (i) Peng, W.; Li, Y.; Zhu, C.; Han, X.; Yu, B. Carbohydr. Res. 2005,
340, 1682-1688. (j) Caldwell, S. T.; Petersson, H. M.; Farrugia, L. J.;
Mullen, W.; Crozier, A.; Hartley, R. C. Tetrahedron 2006, 62, 7257-7265.
(14) Du, Y.; Wei, G.; Linhardt, R. J. Tetrahedron Lett. 2003, 44, 6887-
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(7) Abdel-Ghani, A. E.; Hafez, S. S.; Aziz, E. M. A.; El-Shazly, A. M.
Alexandria J. Pharm. Sci. 2001, 15, 103-108.
(8) Also known as “birdsfoot trefoil”.
10.1021/jo070502w CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/11/2007
4582
J. Org. Chem. 2007, 72, 4582-4585

SCHEME 1. Synthetic Plan
SCHEME 3. Completion of the Synthesis of Kaempferitrin
(1)
SCHEME 2. Synthesis of Protected 3,7-Dihydroxyflavone
(11)
when the above cyclization was performed with the TBDPS-
protected (instead of MOM-protected) benzoate ester, the only
product isolated was 5,7-dihydroxyflavone (not shown) under-
lining the importance of the MOM group protection. Tosylation
of the resulting phenol 9 gave fully protected Kaempferol 10
in 92% yield. In principle, protecting groups on 10 could be
selectively removed thereby providing each site for glycosyla-
tion. Transformation of protected Kaempferol 10 into the key
intermediate 11 was achieved in high yield in one pot with use
of AlBr3 followed by treatment with HCl (1.25 M in MeOH).17
With 3,7-dihydroxyflavone 11 in hand, the bis-glycosylation
reaction was investigated (Scheme 3). An initial attempt to effect
the bis-glycosylation with tri-O-acetylrhamnose trichloroace-
timidate18 as the donor and TMSOTf as an activator proved to
be unsuccessful. Monitoring the reaction by LC/MS suggested
that the reaction proceeded initially but decomposition occurred
with time probably due to the sensitive nature of the flavone to
acidic conditions. Gratifyingly, switching the donor to tri-O-
acetylrhamnose bromide 1219 and the activator to Ag2O gave
the desired bis-glycosylated flavone 13 in high conversion
(>95% by LC/MS and exclusively R-isomer was formed) with
trace amounts of mono-glycosylated product. Increasing the
amount of 12 relative to Ag2O did not result in complete
conversion. At this point it is important to mention that it was
necessary to protect the C5 -OH group of 9 (conversion of 9
to 10, Scheme 2) as our model study on glycosylation of chrysin,
a 5,7-dihydroxyflavone, showed no selectivity and both -OH
groups were glycosylated with 12/Ag2O.
advantage of hydrogen bonding between the carbonyl and an
ortho phenolic -OH group, 6 was selectively protected as the
bis-MOM ether 7 in 68% yield. Benzoylation of the free
phenolic -OH group of 7 afforded 8 in 82% yield. Next, the
key cyclization of benzoate ester 8 to 5-hydroxyflavone 9 was
attempted. Satisfyingly, heating of 8 in the presence of K2CO3
in pyridine resulted in the desired transformation in moderate
yield (35-42%).5a,13j,16 Notably, the MOM group ortho to the
carbonyl was cleaved under the basic conditions. Interestingly,
The final task in completing the synthesis of Kaempferitrin
involved the removal of all protecting groups (Scheme 3). We
(17) De la Torre, M. D. L.; Rodrigues, A. G. P.; Tome´, A. C.; Silva, A.
M. S.; Cavaleiro, J. A. S. Tetrahedron 2004, 60, 3581-3592.
(18) Ota, M.; Takahashi, K.; Kofujita, H. J. Wood Sci. 1998, 44, 320-
326.
(19) Bebault, G. M.; Dution, G. G. S.; Warfield, C. K. Carbohydr. Res.
1974, 34, 174-179.
(15) Mustafa, K. A.; Kjaergaard, H. G.; Perry, N. B.; Weavers, R. T.
Tetrahedron 2003, 59, 6113-6120.
(16) Tanaka, H.; Stohlmeyer, M. M.; Wandless, T. J.; Taylor, L. P.
Tetrahedron Lett. 2000, 41, 9735-9739.
J. Org. Chem, Vol. 72, No. 12, 2007 4583

CDCl3) δ 8.05-8.00 (m, 4H), 7.47-7.32 (m, 7H), 7.09-7.06 (m,
3H), 6.92 (d, J ) 2.1 Hz, 1H), 5.23 (s, 2H), 5.14 (s, 2H), 3.77 (s,
3H), 3.49 (s, 3H), 2.43 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ
172.1, 160.6, 160.1, 157.3, 153.6, 147.6, 145.2, 141.0, 136.4, 132.9,
129.9, 129.5, 129.0, 128.6, 128.1, 127.4, 123.0, 114.8, 110.0, 102.4,
94.6, 70.1, 59.8, 56.5, 21.7. HRMS (ESI) m/z calcd for C32H28O9S
(M + H)+ 589.1525, found 589.1533.
4′-Benzyloxy-3,7-dihydroxy-5-[((4-methylphenyl)sulfonyl)oxy]-
flavone (11). To an ice-cold solution of 10 (85 mg, 0.144 mmol,
1.0 equiv) in 3 mL of dry CH3CN was added AlBr3 (43 mg,
0.16 mmol, 1.1 equiv) and the mixture was stirred at that
temperature for 1 h. Then, 3 mL of 1.25 M HCl in MeOH was
added to the mixture which was then refluxed for 1 h. The mixture
was concentrated and the crude product was purified by flash
column chromatography (0 to 10% MeOH/hexanes) to yield 11 as
a yellow solid. Yield: 74.6 mg, 97%. Rf 0.52 in 10% MeOH/CH2-
Cl2. 1H NMR (300 MHz, CD3COCD3) δ 8.07-8.04 (m, 2H), 7.79-
7.77 (m, 2H), 7.40-7.21 (m, 7H), 7.07-7.04 (m, 2H), 6.90 (d, J
) 2.4 Hz, 1H), 6.64 (d, J ) 2.4 Hz, 1H), 5.10 (s, 2H), 2.30 (s,
3H); 13C NMR (75.5 MHz, CD3COCD3) δ 172.0, 163.3, 162.0,
159.6, 149.8, 147.6, 144.7, 139.4, 134.9, 131.5, 131.0, 130.8, 130.4,
129.8, 129.5, 125.6, 116.8, 110.7, 110.4, 103.9, 71.7, 22.6. HRMS
(ESI) m/z calcd for C29H22O8S (M + Na)+ 553.0927, found
553.0933.
decided to first debenzylate 13. Surprisingly, subjection of 13
to standard hydrogenation conditions, i.e., H2 (1 atm, balloon),
10% Pd/C in EtOH-EtOAc (1:1) or pure EtOAc, afforded a
mixture of compounds that were identified as the expected
debenzylated flavone 14 and the unexpected flavone 15 resulting
from debenzylation as well as detosylation of 13, in almost 1:1
ratio (LC/MS). Although this result was unforeseen it did not
have any implications on our final step.
Without purification, the mixture of 14 and 15 was treated
with K2CO3 in MeOH at 70 °C for 1 h providing Kaempferitrin
in 35% yield from 11. Purification of Kaempferitrin was
1
performed by using reverse-phase HPLC. The H NMR and
13C NMR spectra of synthetic 1 were consistent with published
values20 and with the spectrum of an authentic sample,21 as were
the retention time and mass spectrum as observed by LC/MS.
We have examined the antibacterial activity of 1 and found
that growth of E. coli is not significantly affected by concentra-
tions of up to 80 µM. Although this conflicts directly with one
previous report,7 it is consistent with a more recent study.22
Further studies to elucidate the origin of antimicrobial activities
of extracts from L. corniculatus are underway.
In conclusion, we report the first synthesis of Kaempferitrin,
which was completed in 9 steps from commercially available
phloroglucinol. The judicious choice of protecting groups
employed offers the potential to effect O-glycosylation at any
position of Kaempferol after selectively removing the protecting
group of that position. We have also accomplished the first bis-
glycosylation of a dihydroxyflavone.
4′-Benzyloxy-3,7-O-(2′′,3′′,4′′-triacetyloxy-R-L-rhamnopyran-
osyl)-5-[((4-methylphenyl)sulfonyl)oxy]flavone (13). A mixture
of 3,7-dihydroxyflavone 11 (47.5 mg, 0.089 mmol, 1.0 equiv),
rhamnose bromide 12 (67 mg, 0.188 mmol, 2.1 equiv), and Ag2O
(46 mg, 0.196 mmol, 2.2 equiv) was heated at 40 °C in the presence
of 4 Å molecular sieves in dry CH2Cl2 (2 mL) under argon
atmosphere for 36 h. The LC-MS analysis of the crude reaction
mixture showed the complete consumption of 11 and the formation
of 13 in >95% and a trace amount of mono-glycosylated product.
The reaction mixture was filtered off through celite and was used
in the next step without further purification. However, for analytical
purposes, compound 13 was purified by reverse phase HPLC. Rf
0.7 in 5% MeOH/CH2Cl2. 1H NMR (500 MHz, CDCl3) δ 8.00 (d,
J ) 8 Hz, 2H), 7.85 (d, J ) 8.5 Hz, 2H), 7.45-7.35 (m, 7H),
7.14-7.11 (m, 3H), 7.07 (d, J ) 2.5 Hz, 1H), 5.70 (dd, J )
1.5 Hz, 1H), 5.55 (d, J ) 1.0 Hz, 1H), 5.49 (d, J ) 1.5 Hz, 1H),
5.46-5.44 (m, 2H), 5.31 (dd, J ) 3.5, 6.5 Hz, 1H), 5.19-5.15 (m,
3H), 4.95 (t, J ) 10 Hz, 1H), 3.94-3.88 (m, 1H), 3.41-3.35 (m,
1H), 2.46 (s, 3H), 2.21 (s, 3H), 2.15 (s, 3H), 2.07 (s, 3H), 2.04 (s,
3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.25 (d, J ) 6 Hz, 3H), 0.87 (d, J
Experimental Section
4′-Benzyloxy-5-hydroxy-3-methoxy-7-(methoxymethyloxy)fla-
vone (9). A mixture of 8 (261 mg, 5.26 mmol, 1.0 equiv) and
anhydrous K2CO3 (581 mg, 4.20 mmol, 8.0 equiv) in dry pyridine
(2 mL) was refluxed for 1 h. After cooling, the solvent was removed
in vacuo and the resulting residue was directly subjected to flash
column chromatography (0 to 20% EtOAc/hexanes) to yield 9 as
yellow viscous oil that solidified upon standing. Yield: 96 mg,
42%. This reaction provided lower yields when performed on a
larger scale. Rf 0.86 in 50% EtOAc/hexanes. 1H NMR (300 MHz,
CDCl3) δ 12.62 (s, 1H), 8.11-8.07 (m, 2H), 7.48-7.36 (m, 5H),
7.11-7.08 (m, 2H), 6.63 (d, J ) 2.1 Hz, 1H), 6.46 (d, J ) 2.1 Hz,
1H), 5.24 (s, 2H), 5.16 (s, 2H), 3.86 (s, 3H), 3.50 (s, 3H); 13C
NMR (75.5 MHz, CDCl3) δ 178.8, 162.8, 161.8, 160.8, 156.5,
156.0, 138.9, 136.2, 130.2, 128.7, 128.2, 127.5, 122.9, 114.9, 106.6,
99.6, 94.2, 94.0, 70.1, 60.1, 56.4. HRMS (ESI) m/z calcd for
C25H22O7 (M + H)+ 435.1444, found 435.1436.
4′-Benzyloxy-3-methoxy-7-(methoxymethyloxy)-5-[((4-meth-
ylphenyl)sulfonyl)oxy]flavone (10). A mixture of flavone 9
(60 mg, 0.14 mmol, 1.0 equiv), p-TosCl (106 mg, 0.55 mmol,
4.0 equiv), and anhydrous K2CO3 (150 mg, 1.08 mmol, 7.83 equiv)
in dry MeCN (5 mL) was heated at 60 °C for 3 h. The remaining
K2CO3 was filtered off and the filtrate was evaporated until dryness.
The crude product was purified by flash column chromatography
(0 to 30% EtOAc/hexanes) to yield 8 as a white solid. Yield:
75 mg, 92%. Rf 0.29 in 30% EtOAc/hexanes. 1H NMR (300 MHz,
1
) 6.5 Hz, 3H); H NMR (500 MHz, CD3OD) δ 7.84 (d, J )
8.5 Hz, 2H), 7.76 (d, J ) 8.0 Hz, 2H), 7.45 (d, J ) 7.5 Hz, 2H),
7.38-7.29 (m, 6H), 7.18 (d, J ) 9.0 Hz, 2H), 6.97 (d, J ) 2.0 Hz,
1H), 5.73 (br s, 1H), 5.59 (dd, J ) 1.5 Hz, 1H), 5.49-5.48 (m,
1H), 5.40 (dd, J ) 3.5, 6.5 Hz, 1H), 5.29 (d, J ) 1.0 Hz, 1H), 5.22
(dd, J ) 3.5, 7.0 Hz, 1H), 5.17 (s, 2H), 5.14 (t, J ) 10 Hz, 2H),
3.96-3.91 (m, 1H), 3.17-3.14 (m, 1H), 2.42 (s, 3H), 2.18 (s, 3H),
2.16 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3H), 1.94 (s, 3H),
1.21 (d, J ) 6.5 Hz, 3H), 0.78 (d, J ) 6.5 Hz, 3H), one proton is
obscured due to the solvent peak; 13C NMR (125 MHz, CDCl3) δ
171.2, 169.94, 169.92, 169.9, 169.8, 169.5, 160.9, 158.4, 157.3,
155.2, 147.9, 145.6, 136.6, 132.4, 130.5, 129.7, 129.1, 128.7, 128.2,
127.4, 122.4, 115.0, 113.7, 110.1, 103.1, 98.0, 95.7, 70.6, 70.4,
70.2, 69.2, 69.0, 68.9, 68.5, 68.2, 68.0, 29.7, 21.8, 20.9, 20.8, 20.75,
20.74, 20.7, 17.4, 17.1. HRMS (ESI) m/z calcd for C53H54O22S (M
+ Na)+ 1097.2725, found 1097.2734.
(20) Pauli, G. F. J. Nat. Prod. 2000, 63, 834-838.
Kaempferitrin (1). A mixture of crude compound 13 (obtained
above) and 10% palladium on carbon (75 mg) were stirred in EtOAc
(5 mL) under an atmosphere of hydrogen at room temperature for
14 h. The solution was filtered through a plug of celite eluting with
EtOAc. The LC-MS analysis of filtrate showed the formation of
two compounds which were identified as 14 and 15. The filtrate
was concentrated and without further purification was treated with
anhydrous K2CO3 (50 mg) in 2 mL of dry MeOH at 70 °C for
(21) Provided by M. G. Pizzolatti, Departamento de Qu´ımica, Univer-
sidade Federal de Santa Catarina, Campus Trindade 88010-970 Florian-
o´polis, SC, Brazil. Fax: (55) 048 3319711. E-mail: mgpizzo@qmc.ufsc.br.
(22) Deachathai, S.; Mahabusarakam, W.; Phongpaichit, S.; Taylor, W.
C.; Zhang, Y. J.; Yang, C. R. Phytochemistry 2006, 67, 464-469. In this
study, Kaempferitrin shows no activity against two strains of S. aureus up
to 128 µg/mL (>220 µM), whereas Abdel-Ghani (ref 7) observed
comparable activities between Kaempferitrin (50 µg/disc), oxytetracycline
(30 µg/disc), and gentamycin (10 µg/disc) against S. aureus.
4584 J. Org. Chem., Vol. 72, No. 12, 2007

90 min. The reaction mixture was cooled to room temperature and
then acidified to pH ca. 1-2 with Dowex-50 ion-exchange resin.
The mixture was concentrated and purified by reverse phase HPLC
to give 1 as a yellow solid. Yield: 18 mg, 35% from 11. Reverse
phase purification was carried out on an Xterra C18 column (19 ×
50 mm2, 5 µm). The flow rate was 30 mL/min with mobile phase
A as water and B as acetonitrile. Both mobile phases had 0.01%
formic acid added. The gradient ranged from 5% to 95% B over
10 min and was followed by a 3 min wash at the end with 95% B.
1H NMR (500 MHz, CD3OD) δ 8.53 (br s, 1H), 7.80 (d, J ) 8 Hz,
2H), 6.94 (d, J ) 7.5 Hz, 2H), 6.72 (s, 1H), 6.46 (s, 1H), 5.55
(s, 1H), 5.39 (s, 1H), 4.21 (d, J ) Hz, 1H), 4.00 (br s, 1H), 3.83-
3.81 (m, 1H), 3.71-3.70 (m, 1H), 3.60-3.57 (m, 1H), 3.48 (t, J )
9 Hz, 1H), 3.34-3.32 (m, 2H), 1.26 (d, J ) 5.5 Hz, 3H), 0.93 (d,
J ) 4.5 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 179.9, 163.6,
163.1, 161.8, 159.9, 158.2, 136.5, 132.0, 122.5, 116.6, 107.6, 103.6,
100.6, 99.9, 95.7, 73.6, 73.2, 72.2, 72.14, 72.12, 72.0, 71.7, 71.3,
18.1, 17.7. HRMS (ESI) m/z calcd for C27H30O14 (M + Na)+
601.1533, found 601.1523.
Acknowledgment. This work was funded by the National
Institute for Allergy and Infectious Disease (NIH R03 AI062905-
01) and conducted under the aegis of the Broad Institute Center
for Chemical Methodology and Library Development (CMLD,
NIGMS P50 GM069721). The authors thank M. Pizzolatti
(UFSC, Brazil) for providing an authentic sample of Kaempfer-
itrin and Prof. Jon Clardy (Harvard Medical School) for helpful
discussions. Alan Provost and Chris Johnson (Broad Institute
of Harvard and MIT, Chemical Technology Platform) are
acknowledged for analytical support.
Supporting Information Available: General methods, experi-
mental procedures for compounds 6-8, characterization data, and
1
copies of the H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070502W
J. Org. Chem, Vol. 72, No. 12, 2007 4585