Rigid multivalent scaffolds based on adamantane

Article abstract of DOI:10.1021/jo702310g

(Chemical Equation Presented) We present two new synthetic strategies to rigid multivalent scaffolds of the general structure 1 based on adamantane. Both routes start from arylated adamantane derivatives and give the target compounds 12 and 18 in 5 and 7 steps, respectively. These scaffolds have been designed for the assembly of multivalent binders for cell surface epitopes. The adamantane nucleus exposes three carboxylic acid groups in a well-defined tripodal geometry for conjugation of targeting ligands. In addition, an amino group at the fourth bridgehead position provides a flexible linker for attachment of effector molecules such as contrast agents, radiotracers, or cytotoxins without interfering with the cell binding process.

Full text of DOI:10.1021/jo702310g

Rigid Multivalent Scaffolds Based on Adamantane
Khaled Nasr, Nadine Pannier, John V. Frangioni,* and Wolfgang Maison*,‡
†
‡
,†,§
DiVision of Hematology/Oncology, Department of Medicine, and Department of Radiology, Beth Israel
Deaconess Medical Center, SL-B05, 330 Brookline AVenue, Boston, Massachusetts 02215, and
Justus-Liebig-UniVersit a¨ t Giessen, Institut f u¨ r Organische Chemie, Heinrich-Buff-Ring 58,
3
5392 Giessen, Germany
wolfgang.maison@org.chemie.uni-giessen.de; jfrangio@bidmc.harVard.edu
ReceiVed October 25, 2007
We present two new synthetic strategies to rigid multivalent scaffolds of the general structure 1 based on
adamantane. Both routes start from arylated adamantane derivatives and give the target compounds 12
and 18 in 5 and 7 steps, respectively. These scaffolds have been designed for the assembly of multivalent
binders for cell surface epitopes. The adamantane nucleus exposes three carboxylic acid groups in a
well-defined tripodal geometry for conjugation of targeting ligands. In addition, an amino group at the
fourth bridgehead position provides a flexible linker for attachment of effector molecules such as contrast
agents, radiotracers, or cytotoxins without interfering with the cell binding process.
Introduction
as the shape, orientation, and flexibility of the scaffold to which
monomeric ligands are attached. Theoretically, the largest gain
of binding affinity for a given ligand-receptor interaction is
expected for a perfect fit of the ligands to the binding epitope.10
A scaffold for the assembly of multivalent ligands must therefore
orient the ligands in a defined and proper geometry for
Multivalency is a common phenomenon in nature to enhance
1
affinity and specificity of receptor ligand interactions. Chemists
have made use of this concept in various contexts.2
-9
The binding ability of multivalent agents is influenced by
the number, size, and orientation of the binding sites, as well
1
1-13
binding.
This geometry, along with other design criteria
(
such as the number of ligands, solubility, and biocompatibility),
†
Division of Hematology/Oncology, Department of Medicine, Beth Israel
may vary for different applications and in consequence, a variety
of different scaffolds have been used in the past.
Deaconess Medical Center.
‡
14-17
Institut f u¨ r Organische Chemie.
Department of Radiology, Beth Israel Deaconess Medical Center.
§
We have designed adamantyl scaffolds 2 (Figure 1) for
(
1) Mammen, M.; Chio, S.-K.; Whitesides, G. M. Angew. Chem., Int.
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multivalent interaction of small molecules with cell surface
(
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10.1021/jo702310g CCC: $40.75 © 2008 American Chemical Society
1
056
J. Org. Chem. 2008, 73, 1056-1060
Published on Web 01/08/2008

Rigid MultiValent Scaffolds
FIGURE 1. Schematic drawing of modular multivalent ligands 1 and
suitable scaffolds 2.
epitopes18 and have shown that this adamantane-based strategy
can improve binding affinity by over 1.5 logs, taking a prostate-
specific membrane antigen (PSMA) small molecule radiotracer
from an affinity of 9 nM19 to 400 pM. A special feature of
these conjugates is the geometry of the bridgehead-substituted
adamantanes, orienting three ligands in a tripodal recognition
motif and a fourth functional group for conjugation to contrast
agents without interfering with cell surface binding.
20
FIGURE 2. Retrosynthetic analysis of adamantyl scaffolds 3.
the most obvious choice, because a wide range of monosub-
stituted adamantanes 6 is commercially available at low price.
However, for the above-mentioned reasons, we have not found
practical reactions that permit introduction of three appropriate
functionalities into various different precursors 6.25
Despite our encouraging results, compounds like 2 (n ) 3)
are not ideal scaffolds, because the propionate linkers between
the adamantane nucleus and the ligands are flexible, rather than
rigid. However, the synthesis of more rigid derivatives 2 (n )
We were therefore focusing on the first two strategies in
Figure 2. An essential component of route I is an appropriately
0
) proved to be difficult due to the unique reactivity of
substituted adamantane derivatives. Other rigid scaffolds with
(
symmetrical) tetrasubstituted adamantane derivative 4 and
tripodal recognition motifs have been reported and successfully
26-38
used for applications in material science.21 However, these
various derivatives of this general structure are known.
For
our purpose tetracarboxymethyl adamantane 8 seemed to be the
most appropriate starting material, because we needed carboxylic
acids in the target scaffold 12 (for the conjugation of ligands)
and one of the carboxylic acids should be easy to convert to an
amine via Curtius reaction. However, none of the known
systems require rigidifying aromatic spacers and are therefore
not optimal for applications in polar media.
Results and Discussion
2
6,32,35
Functionalization of the bridgehead positions in adamantyl
scaffolds can be achieved most reliably by radical or cationic
syntheses of 8
is easily scalable, making 8 a precursor of
limited value.
22
chemistry. As a general trend, these substitutions become more
difficult with the number of (electron withdrawing) substituents
We have therefore first tried to develop a more practical
28
synthesis of 8. In this context tetraphenyladamantane 7 proved
3
9
attached to the other bridgehead positions. This is due to
to be a good precursor for oxidative degradation. As depicted
in Scheme 1, the conversion of 7 to the tetramethylester 8
worked, although the yield is not optimal. We decided to tolerate
statistical and/or electronic factors.2
3,24
In particular, electron-
withdrawing substituents (like carboxy groups) destabilize
cationic or radical intermediates leading frequently to drastic
reaction conditions for the introduction of additional functional-
ity.
The most obvious retrosynthetic strategies to differentially
substituted adamantyl scaffolds 3 are depicted in Figure 2. Route
I involves the desymmetrization of a tetrasubstituted adamantane
derivative 4 as a key step. In route II, a trisubstituted intermedi-
ate 5 is converted to the target structure 3. Route C is probably
(25) We have tried different reactions for bridgehead functionalization
such as arylations, halogenations, and Koch-Haaf-type reactions with
different substrates 6 (B ) NHR, OH, CN, CO2H, CH2NH3, CH2CN, CH2-
CO2H, (CH2)3NH2, (CH2)3CN, (CH2)3CO2H) and achieved only mono- or
disubstitution.
(26) Landa, S.; Kamycek, Z. Collect. Czech. Chem. Commun. 1959, 24,
004-4009.
4
(
(
(
27) Stetter, H.; Wulff, C. Chem. Ber. 1960, 93, 1366-1371.
28) Newman, H. Synthesis 1972, 692-693.
29) Sollott, G. P.; Gilbert, E. E. J. Org. Chem. 1980, 45, 5405-5408.
(
18) Maison, W.; Frangioni, J. V.; Pannier, N. Org. Lett. 2004, 6, 4567-
569.
19) Humblet, V.; Lapidus, R.; Williams, L. R.; Tsukamoto, T.; Rojas,
(30) Naemura, K.; Hokura, Y.; Nakazaki, M. Tetrahedron 1986, 42,
4
1763-1768.
(
(31) Reichert, V. R.; Mathias, L. J. Macromolecules 1994, 27, 7015-
7023.
C.; Majer, P.; Hin, B.; Ohnishi, S.; De Grand, A. M.; Zaheer, A.; Renze,
J. T.; Nakayama, A.; Slusher, B. S.; Frangioni, J. V. Mol. Imaging 2005, 4,
(32) Bashir-Hashemi, A.; Li, J.; Gelber, N. Tetrahedron Lett. 1995, 36,
1233-1236.
4
48-462.
20) Misra, P.; Humblet, V.; Pannier, N.; Maison, W.; Frangioni, J. V.
J. Nucl. Med. 2007, 48, 1379-1389.
21) (a) Li, Q.; Rukavishnikov, A. V.; Petukhov, P. A.; Zaikova, T. O.;
(
(33) Li, Q.; Rukavishnikov, A. V.; Petukhov, P. A.; Zaikova, T. O.; Jin,
C.; Keana, J. F. W. J. Org. Chem. 2003, 68, 4862-4869.
(34) Dave, P. R.; Duddu, R.; Yang, K.; Damavarapu, R.; Gelber, N.;
Surapaneni, R.; Gilardi, R. Tetrahedron Lett. 2004, 45, 2159-2162.
(35) Lee, G. S.; Bashara, J. N.; Sabih, G.; Oganesyan, A.; Godjoian, G.;
Duong, H. M.; Marinez, E. R.; Gutierrez, C. G. Org. Lett. 2004, 6, 1705-
1707.
(
Jin, C.; Keana, J. F. W. J. Org. Chem. 2003, 68, 4862-4869. (b) Li, Q.;
Jin, C.; Petukhov, P. A.; Rukavishnikov, A. V.; Zaikova, T. O.; Phadke,
A.; LaMunyon, D. H.; Lee, M. D.; Keana, J. F. J. Org. Chem. 2004, 69,
1
010-1019.
(
22) Moiseev, I. K.; Makarova, N. V.; Zemtsova, M. N. Russ. Chem.
(36) Kozhushkov, S. I.; Yufit, D. S.; Boese, R.; Blaeser, D.; Schreiner,
P. R.; de Meijere, A. Eur. J. Org. Chem. 2005, 1409-1415.
(37) Menger, F. M.; Migulin, V. A. J. Org. Chem. 1999, 64, 8916-
8921.
ReV. 1999, 68, 1001-1020. For a recent mechanistic analysis of these
reactions see: Fokin, A. A.; Shubina, T. E.; Gunchenko, P. A.; Isaev, S.
D.; Yurchenko, A. G.; Schreiner, P. R. J. Am. Chem. Soc. 2002, 124,
1
0718-10727.
(38) Martin, V. V.; Alferiev, I. S.; Weis, A. L. Tetrahedron Lett. 1999,
40, 223-226.
(39) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936-3938.
(
23) Fort, R. C.; Schleyer, P. v. R. Chem. ReV. 1964, 64, 277-300.
24) Saunders, M.; Jimenez-Vazquez, H. A. Chem. ReV. 1991, 91, 375-
(
3
97.
J. Org. Chem, Vol. 73, No. 3, 2008 1057

Nasr et al.
SCHEME 1. Synthesis of Rigid Adamantane Scaffold 12 Following General Route I (Figure 2)
SCHEME 2. Synthesis of Rigid Adamantane Scaffold 18 Following General Route II (Figure 2)
the low yield of these two early steps, because tetraphenylada-
mantane 7 can easily be generated in large quantities from
carefully, because any electron-withdrawing substituent (like
the desired carboxyl group) would deactivate the adamantane
nucleus for a fourth bridgehead substitution.
1-bromoadamantane as a cheap precursor. Immediate conversion
of the intermediate tetracarboxylic acid to its methyl ester 8 is
advantageous for workup and chromatographic purification of
the oxidation product. In addition, the following desymmetri-
zation by a partial ester hydrolysis requires the tetramethyl ester
Phenyl rings were again found to be excellent substitutes for
the carboxyl groups in the target compound 18 and we started
2
8
with known triphenyladamantane 13. Like tetraphenylada-
mantane 7, this compound can be easily prepared from cheap
1-bromoadamantane in one step via Friedel-Crafts chemistry.
We decided to introduce the fourth substituent to 13 via
bromination assuming that the resulting bromide 14 would be
a reasonable substrate for a radical addition to acrylonitrile.
Among many methods known for the bromination of adaman-
8
as a starting material to give 9 in very good yield.
The resulting monocarboxylic acid 9 is then converted by a
Curtius reaction40 to the corresponding amine, obtained as its
Boc-derivative 10 after reflux in t-BuOH. The Boc-group is
cleaved subsequently with TFA to give the free amine 11 in
good yield. This three-step procedure gave much better yields
than the direct acidic hydrolysis of the intermediate isocyanate
with water (in the latter case partial hydrolysis of the ester
groups was observed).
2
2
tane bridgeheads, only one proved to be compatible with our
strategy. The mild phase transfer catalyzed protocol developed
4
1
by Schreiner and co-worker gave bromide 14 in good yield.
This reaction is without precedence for highly substituted
adamantanes like 13 and provides, for the first time, an easy
access to tetrahedrally substituted derivatives like 14-18.
After installation of the bromine in 14, radical addition to
For later conjugation of this sterically hindered amine to bulky
effector molecules, we introduced an Ahx-spacer (6-aminohex-
anoic acid) at this stage with HATU coupling to give the
trimethylester 12 as an orthogonally protected scaffold, ready
for conjugation of ligands and effector molecules.
An alternative procedure for the synthesis of scaffolds 2 is
depicted in Scheme 2. This approach is following the general
route II (Figure 2) and does thus require the activation of a
relatively unreactive CH bond in a trisubstituted adamantane
for introduction of the last substituent. As mentioned above,
the three substituents A in intermediate 5 have to be selected
4
2
acrylonitrile was achieved in quantitative yield. The resulting
cyano compound 15 was then submitted to an oxidative
degradation of the phenyl rings with RuCl3 and H5IO6 to give
the tricarboxylic acid 16. The cyano group was then reduced
with hydrogen and PtO2 to give the amine 17, which was Boc-
protected in a final step to give the target compound 18 with a
(41) Fokin, A. A.; Schreiner, P. R. AdV. Synth. Catal. 2003, 345, 1035-
052.
1
(
42) Ohno, M.; Ishizaki, K.; Eguchi, S. J. Org. Chem. 1988, 53, 1285-
(40) Smith, P. A. S. Org. React. (N.Y.) 1946, 3, 337.
1288.
1058 J. Org. Chem., Vol. 73, No. 3, 2008

Rigid MultiValent Scaffolds
propionyl-spaced amine function for conjugation of effectors
and three carboxylic acids for attachment of ligands. It should
be noted that no chromatography is necessary for purification
of compounds 13-18 because all of them can easily be purified
by crystallization.
gel, EtOAc/hexane, 6:4, R
f
0.78) to give 65 mg of 11 as a colorless
solid (83%). H NMR (CDCl , 600 MHz) δ 3.65 (s, 9H), 2.03-
.89 (m, 12H); 13C NMR (CDCl
, 125 MHz) δ 175.9, 52.4, 52.1
1
3
1
4
3
3
+
3.2, 42.0, 38.8; HRMS (ESI) calcd for C16
26.1604, found 326.1598.
6
H24NO [M + H]
1
-Bromo-3,5,7-triphenyladamantane 14. To a solution of 1,3,5-
triphenyladamantane 13 (0.20 g, 0.55 mmol), tetrabrommethane
0.73 g, 2.2 mmol), and tetrabutylammoniumbromide (0.02 g, 0.06
Summary and Conclusion
(
mmol) in 5 mL of flourobenzene was added 3 mL NaOH (wt 50%)
and the resulting reaction mixture was heated to 75 °C for 24 h.
The solvent was evaporated in vacuo; the crude product was
suspended in water and extracted three times with 20 mL of
dichloromethane each time. The combined organic layers were dried
over Na SO and filtered and the solvent was evaporated in vacuo
2 4
to give the bromide 14. After crystallization from hexane/ethyl
acetate (1:1), 0.26 g (0.49 mmol; 89%) of 14 was isolated as a
In summary, we report efficient syntheses of new adamantane
scaffolds. Both routes are short and give the target compounds
12 and 18 in good yields. These scaffolds have been designed
to orient three carboxylic acids in a strictly defined tripodal
geometry for the conjugation of cell surface binders. In addition,
a primary amine allows the conjugation of the scaffold to an
effector molecule that is pointing away from the ligands and is
therefore unlikely to interfere with the binding process. We are
currently evaluating the potential of these scaffolds for various
multivalent ligand receptor interactions. It should be noted that
our scaffolds are providing a strictly defined tripodal recognition
motif (for surfaces) in combination with a fourth binding motif
with all four functionalities easily addressable by standard
1
yellow solid. H NMR (CDCl
3
, 400 MHz) δ 7.23-7.35 (m, 15H),
2
2
2
.62 (s, 6H), 2.17 (d, 3H, J ) 13.4 Hz), 2.14 (d, 3H, J ) 13.4
Hz); C NMR (CDCl , 100 MHz) δ 147.8, 128.7, 126.7, 125.0,
65.2, 52.8, 46.7, 42.3; HRMS (EI) calcd for C28
442.1296, found 442.1297.
13
3
+
H27Br; MS [M]
1,3,5-Triphenyl-7-(2-cyanoethyl)adamantane 15. A solution of
1-bromo-3,5,7-triphenyladamantane 14 (0.50 g, 1.13 mmol), acry-
lonitrile (0.18 g, 3.39 mmol), tributylstannane (0.65 g, 2.26 mmol),
and AIBN (19 mg, 0.113 mmol) in 10 mL of toluene was heated
2
1
conjugation techniques. Unlike other systems of that sort, no
rigidifying (hydrophobic) aromatic spacers are needed, making
them a particularly interesting choice for applications in polar
media. We suggest that our scaffolds might be of general use
to reflux for 6 h. Ethyl acetate and 1 M aqueous NH
added and the separated organic phase was washed with 1 M
aqueous NH solution and water, dried over Na SO , and filtered
3
solution were
as rigid tetravalent building blocks for applications in organic
chemistry43 and material science.44
3
2
4
and the solvent was evaporated in vacuo. The crude product was
purified by filtration over silica (byproducts were eluted with
hexane/ethyl acetate 2:1; product with ethyl acetate) to give 0.47 g
Experimental Section
1
of 15 (1.13 mmol; quant). H NMR (CDCl
7
3
, 400 MHz) δ 7.21-
3,5,7-Tricarboxymethyladamantane-1-carboxylic Acid 9. A
3
2
.44 (m, 15H), 2.42 (t, 2H, J ) 8.1 Hz), 2.12 (d, 3H, J ) 12.3
1
N solution of potassium hydroxide (0.01 mL, 0.01 mmol) was
2
3
Hz), 2.07 (d, 3H, J ) 12.3 Hz), 1.80 (t, 2H, J ) 8.1 Hz), 1.75 (s,
added to a solution of 1,3,5,7-tetracarboxymethyladamantane 8 (3.68
mg, 0.01 mmol) in 2 mL of acetonitrile/methanol/water (3:2:5).
The reaction mixture was stirred for 3 h and the completion of the
reaction was followed by thin layer chromatography. Solvents were
removed in vacuo and the aqueous solution was washed with
dichloromethane (3 × 5 mL). The aqueous layer was acidified with
6
1
C
H); 13C NMR (CDCl
2.5, 47.5, 46.0, 39.1, 39.0, 35.3, 11.5; HRMS (EI) calcd for
3
, 100 MHz) δ 149.0, 128.6, 126.4, 125.1,
+
31
H
31N [M] 417.2457, found 417.2452.
1,3,5-Tricarboxy-7-(2-cyanoethyl)adamantane 16. A solution
of 15 (550 mg, 1.3 mmol) and H IO (12.6 g, 55 mmol) in 50 mL
of CCl /MeCN/H O (3:2:3) was cooled to 0 °C and RuCl ‚3H
5
6
1
N HCl and extracted with dichloromethane (3 × 5 mL). The
4
2
3
2
O
combined extracts were dried over Na
in vacuo to give 3.1 mg of 9 as white crystals (90%). H NMR
CDCl
, 600 MHz) δ 3.70 (s, 9H), 2.02 (s, 6H), 2.03 (s, 6H); 13
NMR (CDCl , 125 MHz) δ 181.4, 175.6, 52.4, 42.0, 41.8, 38.7,
22 8
8.5; MS (ESI) [M - H] 353.4; HRMS (EI) calcd for C17H O -
2
SO
4
and solvent was removed
(69 mg, 0.3 mmol) was added. After stirring for 2 h at 0 °C and 40
1
h at rt, the resulting reaction mixture was poured on ice and excess
oxidant was destroyed by Na SO addition. The aqueous layer was
2 3
(
3
C
3
washed with ethyl acetate, acidified with 2 N HCl (pH 1), and
extracted three times with ethyl acetate. The combined organic
layers were dried over Na SO and filtered and the solvent was
-
3
+
[M] 354.1315, found 354.1312.
2
4
1
7-Amino-1,3,5-tricarboxymethyladamantane 11. DPPA (0.063
evaporated in vacuo to give 360 mg of 16 (1.1 mmol; 85%). H
3
mL, 0.29 mmol) and triethylamine (0.04 mL, 0.29 mmol) were
added to a solution of 3,5,7-tricarboxymethyladamantane-1-car-
boxylic acid 9 (86 mg, 0.24 mmol) dissolved in dichloromethane
NMR (DMSO-d , 400 MHz) δ 12.3 (br s, 3H), 2.46 (t, 2H, J )
6
2
2
7.9 Hz), 1.79 (d, 3H, J ) 13.7 Hz), 1.72 (d, 3H, J ) 13.7 Hz),
3
13
1.53 (t, 2H, J ) 7.9 Hz), 1.48 (s, 6H); C NMR (DMSO-d , 100
6
(2 mL). The reaction mixture was stirred for 1 h and the completion
MHz) δ 177.1, 121.4, 41.1, 40.7, 40.3, 36.8, 33.3, 10.3; HRMS
of the reaction was followed by TLC. An additional 10 mL of
dichloromethane was added and the reaction mixture was washed
(EI) calcd for C H NO [M]
+
321.1212, found 321.1208. Anal.
16
19
6
Calcd for C16
H 6.00; N 4.33.
,3,5-Tricarboxy-7-(3-aminopropyl)adamantane Hydrochlo-
ride 17. A solution of nitrile 16 (30 mg, 0.093 mmol) and PtO
H19NO : C 59.81; H 5.96; N 4.36. Found: C 59.86;
6
with water (3 × 10 mL), saturated NaHCO
3
solution (3 × 10 mL),
and saturated NaCl (3 × 10 mL) and dried over Na
2
SO
4
.
1
Dichloromethane was removed in vacuo and t-BuOH (50 mL) was
added. The reaction mixture was refluxed under nitrogen atmo-
sphere for 5 h. Excess t-BuOH was removed in vacuo and the
colorless residue (10) was treated with a solution of 50% of TFA
in dichloromethane (5 mL). The reaction mixture was stirred at
room temperature for 1 h. The solvent was removed in vacuo and
the white residue was purified by column chromatography (silica
2
(
(
4.2 mg, 0.019 mmol) in 10 mL of glacial acetic acid/conc. HCl
10:1) was hydrogenated (30 bar, rt) for 48 h. The resulting mixture
was filtered and the solvent was evaporated in vacuo. The crude
product was dissolved in water and washed two times with ethyl
acetate. After evaporation of water in vacuo, 33 mg (0.091 mmol;
1
9
8%) of 17 was isolated as colorless crystals. H NMR (D
2
O, 400
3
MHz) δ 2.96 (t, 2H, J ) 7.4 Hz), 1.94 (s, 6H), 1.64-1.69 (m,
(
43) Maison, W.; Frangioni, J. V. Angew. Chem., Int. Ed. 2003, 42,
726-4728.
44) Li, Q.; Jin, C.; Petukhov, P. A.; Rukavishnikov, A. V.; Zaikova, T.
O.; Phadke, A.; LaMunyon, D. H.; Lee, M. D.; Keana, J. F. J. Org. Chem.
004, 69, 1010-1019.
13
2
2
H), 1.61 (s, 6H), 1.30-1.34 (m, 2H); C NMR (D O, 100 MHz)
4
δ 180.8, 41.9, 40.9, 40.0, 38.5, 38.0, 33.0, 20.2; MS (ESI) [M -
(
+
+
Cl] 326.4; HRMS (EI) calcd for C16
found 326.1602.
H24NO
6
[M - Cl] 326.1604,
2
J. Org. Chem, Vol. 73, No. 3, 2008 1059

Nasr et al.
Acknowledgment. We gratefully acknowledge support from
the Deutsche Forschungsgemeinschaft (MA 2529/3). We thank
Barbara L. Clough for editing and Eugenia Trabucchi for
administrative assistance. This research was supported by NIH
grant R01-CA-115296 and grants from the Ellison Foundation
and Lewis Family Fund to J.V.F.
Supporting Information Available: Detailed experimental
procedures for compounds 8, 12, and 18, and copies of NMR spectra
for compounds 8, 9, 11, 12, and 14-18. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO702310G
1060 J. Org. Chem., Vol. 73, No. 3, 2008