Proline derived spirobarbiturates as highly effective β-turn mimetics incorporating polar and functionalizable constraint elements

Article abstract of DOI:10.1021/jo702573z

(Chemical Equation Presented) A practical and efficient synthesis of spirobarbiturates of type III is reported when NH acidity of the imide function of the hydrophilic linker element allowed the introduction of different substituents. Structural characterization, which was based on both X-ray crystallography and spectroscopic investigations, indicated type II β-turn formation. Introduction of the molecular scaffold into solid phase peptide synthesis gave rise to spirocyclic neuropeptide analogs.

Full text of DOI:10.1021/jo702573z

Proline Derived Spirobarbiturates as Highly
Effective ꢀ-Turn Mimetics Incorporating Polar
and Functionalizable Constraint Elements
Luelak Lomlim,† Juergen Einsiedel,† Frank W. Heinemann,‡
Karsten Meyer,‡ and Peter Gmeiner*,†
Department of Chemistry and Pharmacy, Emil Fischer
Center, Chair of Medicinal Chemistry, Friedrich Alexander
UniVersity, Schuhstrasse 19, D-91052 Erlangen, Germany,
and Department of Chemistry and Pharmacy, Chair of
Inorganic Chemistry, Friedrich Alexander UniVersity,
Egerlandstrasse 1, D-91058 Erlangen, Germany
FIGURE 1. Modification of constraint elements.
conformational freedom and, thus, binding-associated loss
of entropy can be decreased.3 The most powerful ꢀ-turn
mimetics have been derived from the functionally important
amino acid proline4 when the introduction of suitable
constraint elements led to lactam-bridged molecular scaf-
folds.5 Employing both saturated and unsaturated constraint
elements leading to Freidinger-type (I)6 and dehydro-
Freidinger-type (II) spirocycles,7 respectively, we were able
to establish a molecular building-kit that allows adjustment
of a wide range of dihedral angles (Figure 1).
gmeiner@pharmazie.uni-erlangen.de
ReceiVed NoVember 30, 2007
To complement these investigations, we aimed to construct
spirocyclic analogues incorporating polar, “backbone-like”
constraint elements. Interestingly, such a concept was described
for conformationally constrained nucleosides when a barbituric
acid moiety was incorporated into a spirocyclic system.8
Following the concept of privileged structures, we planned
to synthesize and to conformationally evaluate spirobarbiturates
of type III. Such molecular scaffolds should be available via
cyclocondensation reactions as described for the preparation of
barbiturate-type drugs.9 NH acidity of the hydrophilic linker
element should allow the introduction of different substituents.
These could serve as molecular probes exploring binding pockets
of complementary target proteins. We herein present a practical
synthesis of model peptide surrogates of type III, solid-phase
supported application toward two artificial neuropeptide mi-
A practical and efficient synthesis of spirobarbiturates of type
III is reported when NH acidity of the imide function of the
hydrophilic linker element allowed the introduction of
different substituents. Structural characterization, which was
based on both X-ray crystallography and spectroscopic
investigations, indicated type II ꢀ-turn formation. Introduc-
tion of the molecular scaffold into solid phase peptide
synthesis gave rise to spirocyclic neuropeptide analogs.
Since reverse-turn motifs play a crucial role in molecular
recognition and signal transduction,1 the development of
privileged scaffolds nucleating turn structures has attracted
remarkable interest.2 Upon introduction of constraint elements
into biologically active peptides, the number of degrees of
(4) Paul, A.; Bittermann, H.; Gmeiner, P. Tetrahedron 2006, 62, 8919–8927,
and references cited therein.
(5) (a) Belvisi, L.; Colombo, L.; Manzoni, L.; Potenza, D.; Scolastico, C.
Synlett 2004, 9, 1449–1471. (b) Fernández, M. M.; Diez, A.; Rubiralta, M.;
Montenegro, E.; Casamitjana, N. J. Org. Chem. 2002, 67, 7587–7599. (c)
Jeannotte, G.; Lubell, W. D. J. Am. Chem. Soc. 2004, 126, 14334–14335. (d)
Wang, W.; Xiong, C.; Hruby, V. J. Tetrahedron Lett. 2001, 42, 3159–3561. (e)
Mueller, R.; Revesz, L Tetrahedron Lett. 2001, 35, 4091–4092. (f) Ward, P.;
Ewan, G. B.; Jordan, C. C.; Ireland, S. J.; Hagan, R. M.; Brown, J. R J. Med.
Chem. 1990, 33, 1848–1851. (g) Hoffmann, T.; Lanig, H.; Waibel, R.; Gmeiner,
P. Angew. Chem. 2001, 113, 3465–3468. (h) Hoffmann, T.; Lanig, H.; Waibel,
R.; Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40, 3361–3364. (i) Einsiedel, J.;
Lanig, H.; Waibel, R.; Gmeiner, P. J. Org. Chem. 2007, 72, 9102–9113.
(6) (a) Müller, G.; Hessler, G.; Decornez, H. Y. Angew. Chem., Int. Ed. 2000,
39, 894–896. Angew. Chem. 2000, 112, 926–928. (b) Hinds, M. G.; Welsh, J. H.;
Brennand, D. M.; Fisher, J.; Glennie, M. J.; Richards, N. G. J.; Turner, D. L.;
Robinson, J. A. J. Med. Chem. 1991, 34, 1777–1789. (c) Ward, P.; Ewan, G. B.;
Jordan, C. C.; Ireland, S. J.; Hagan, R. M.; Brown, J. R J. Med. Chem. 1990,
33, 1848–1851. (d) Bittermann, H.; Einsiedel, J.; Hübner, H.; Gmeiner, P. J. Med.
Chem. 2004, 47, 5587–5590. (e) Bittermann, H.; Gmeiner, P. J. Org. Chem.
2006, 71, 97–102.
† Chair of Medicinal Chemistry.
‡ Chair of Inorganic Chemistry.
(1) (a) Ohage, E. C.; GramL, W.; Walter, M. M.; Steinbacher, S.; Steipe, B
Protein Sci. 1997, 6, 233–241. (b) Zhou, H. X.; Hoess, R. H.; deGrado, W. F.
Nat. Struct. Biol. 1996, 3, 446–451. (c) Venkatachalam, C. M. Biopolymers 1968,
6, 1425–1436. (d) Tyndall, J. D. A.; Pfeiffer, B.; Abbenante, G.; Fairlie, D. P.
Chem. ReV. 2005, 105, 793–826.
(2) For examples, see: (a) Weber, K.; Ohnmacht, U.; Gmeiner, P. J. Org.
Chem. 2000, 65, 7406–7416. (b) Thomas, C.; Ohnmacht, U.; Niger, M.; Gmeiner,
P. Bioorg. Med. Chem. Lett. 1998, 8, 2885–2890. (c) Haubner, R.; Schmitt, W.;
Holzemann, G.; Goodman, S. L.; Jonczyk, A.; Kessler, H. J. Am. Chem. Soc.
1996, 118, 7881–7891. (d) Liu, R.; Dong, D. L.-Y.; Sherlock, R.; Nestler, H. P.;
Gennari, C.; Mielgo, A.; Scolastico, C. Bioorg. Med. Chem. Lett. 1999, 9, 847–
852.
(3) For recent reviews and articles, see: (a) Cluzeau, J.; Lubell, W. D.
Biopolymers (Pept. Sci.) 2005, 80, 98–150. (b) Maison, W.; Prenzel, A. H. G. P.
Biopolymers 2005, 7, 1031–1048. (c) Hanessian, S.; McNaughton-Smith, G.;
Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789–12854. (d)
Freidinger, R. M. J. Med. Chem. 2003, 46, 5553–5566. (e) Halab, L.; Gosselin,
F.; Lubell, W. D. Biopolymers (Pept. Sci.) 2000, 55, 101–122. (f) Hoffmann,
T.; Waibel, R.; Gmeiner, P J. Org. Chem. 2003, 68, 62–69.
(7) Bittermann, H.; Boeckler, F.; Einsiedel, J.; Gmeiner, P. Chem. Eur. J.
2006, 24, 6315–6322.
(8) Renard, A.; Lhomme, J.; Kotera, M. J. Org. Chem. 2002, 67, 1302–
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3608 J. Org. Chem. 2008, 73, 3608–3611
10.1021/jo702573z CCC: $40.75 2008 American Chemical Society
Published on Web 03/26/2008

SCHEME 1a
dicarboxylic ester 1 resulted in a 55–71% formation of the
spirobarbiturate 3a-c (Scheme 1). Employing HATU as an
activating agent, carboxamide formation could be performed
giving access to the N-protected Pro-GlyNHMe surrogate 4a
in racemic form. Furthermore, the conformatively constrained
Pro-Phe-NHMe and Pro-Tyr(ODcb)-NHMe analogues 4b and
4c, both as 1:1 mixtures of diastereomers, were obtained. Finally,
preparative HPLC gave rise to the isomerically pure model
peptide surrogates 4b1, 4b2, 4c1, and 4c2.
X-ray diffraction analysis of the model peptide surrogate 4b1
was performed to provide helpful information on both the
conformational properties in solid state and the absolute
stereochemistry of the spirocyclic center which clearly revealed
(R)-configuration (Figure 2). Due to reverse CIP priority-based
assignments, the disposition of the backbone-forming carboxa-
mide function of 4b1 is identical to that of natural (S)-proline
amide. Based on the X-ray structure of the reference scaffold
4b1, overall similarities of 1H NMR data and analogous elution
profiles allowed determination of the spirocyclic stereogenic
centers of 4c1 and 4c2 to be (R) and (S), respectively.
a Key: (a) t-BuOK, DMSO, rt, 16 h; (b) CH3NH2 ·HCl, HATU, DBU,
NMP, rt, 15 min–3 h; (d) prep HPLC, silica gel, diisopropyl ether/
acetonitrile; Dcb: 2,6-dichlorobenzyl.
metics and structural characterization which was based on both
X-ray crystallography and spectroscopic investigations.
The construction of the novel spirocyclic scaffolds was
envisioned by a base-promoted cylocondensation reaction of
N-carbamoyl-substituted amino acids with a suitably N-protected
R-carboxyproline diester (Scheme 1). Starting from N-Boc-
protected diethylaminomalonate and 1,3-dibromopropane in the
presence of base, the prochiral building block 110 was prepared
in 90% yield when the addition of KI significantly increased
the efficiency of the cyclization. Our initial attempts to the
synthesis of the spirocyclic scaffold including the treatment of
the dicarboxylate 1 with N-carbamoyl glycine benzylester and
EtONa or t-BuOK failed. This is putatively due to the high
energetic demand for the generation of a 1,2-dianion from the
initially formed ester enolate. To circumvent this problem, we
planned to react diester 1 with free N-carbamoylamino acids in
presence of an excess of base, because formation of a carboxyl-
ate anion should prevent from deprotonation at CR and facilitate
optical integrity in case of chiral amino acid derivatives. To
approach to representative building blocks, the urea derivatives
2a-c were synthesized by N-carbamoylation of glycine, (S)-
phenylalanine and O-(2,6-dichlorobenzyl)-(S)-tyrosine with
KOCN, according to previously reported protocols.11 In fact,
deprotonation of the carbamoyl amino acids 2a-c by 3 equiv
of t-BuOK in DMSO and subsequent addition of the pyrrolidine
FIGURE 2. Thermal ellipsoid plot of the molecular structure of 4b1
(50% probability ellipsoids).
Taking advantage of the NH acidity of our linker elements,
we intended to introduce different substituents which can be
exploited as biomolecular probes. To facilitate a chemoselective
N-alkylation, orthogonal protection of the carboxylic acid
function should be first conducted. TCE-esters are known to
be resistant toward acidic and basic conditions and can be readily
removed by reductive cleavage with zinc dust.12 In detail, EDC/
DMAP promoted esterification of 3a-c with 2,2,2-trichloro-
ethanol afforded the 2,2,2-trichloroethyl (TCE) esters 5a-c.
Upon deprotonation of the imides 5a-c by NaH and treatment
with methyl iodide, benzyl bromide or (DcbO)-benzyl bro-
mide,13 N-alkylation was observed giving access to the func-
tionalized scaffolds 6a-e in 62–85% yield. Zn-mediated TCE
deprotection of the representatives 6b-e could be accomplished
when we obtained the free carboxylic acid derivatives 7a-d.
To approach to the model peptide surrogates of type 8, HATU-
promoted peptide coupling and subsequent aminolysis were
performed.
(10) (a) Galons, H.; Damianos, N.; Miocque, M.; Bram, G. In Second Forum
on Peptides; Aubry, A., Marraud, M., Vitoux, B., Eds.; Collogue INSERM/
John Libbey Eurotext Ltd.: Paris, 1989; Vol. 174, pp 281–288. (b) Aboujaoude,
E. E.; Collignon, N.; Savignac, P.; Bensoam, J Phosphorus Sulfur 1987, 34,
93–104.
Finally, separation of the diastereomers 8a1/8a2 and 8b1/
8b2 was done by HPLC using normal-phase conditions,
followed by an NMR-based configurational assignment using
4b1 as a reference structure.
(11) Preparation of the urea derivatives according to: (a) Moschel, R. C.;
Hudgins, R. W.; Dipple, A. J. Org. Chem. 1986, 51, 4180–4185. (b) Taillades,
J.; Boiteau, L.; Beuzelin, I.; Lagrille, O.; Biron, J.-P.; Vayaboury, W.;
Vandenabeele-Trambouze, O.; Giani, O.; Commeyras, A. J. Chem. Soc., Perkin
Trans. 2 2001, 1247, 1254. (c) 2b: [R]20 +37.8 (c 1.0, MeOH); [R]20 +39.2
D
D
(c 1.0, MeOH) is reported in: Sarges, R.; Howard, H. R; Donahue, K. M.; Welch,
W. M.; Dominy, B. W.; Weissman, A.; Koe, B. K.; Bordners, J. J. Med. Chem
1986, 29, 8–19. (d) Casimir, J. R.; Tourwé, D.; Iterbeke, K.; Guichard, G J.
Org. Chem. 2000, 65, 6487–6492.
(12) Jou, G.; Gonzales, F.; Albericio, F.; Lloyd-Williams, P.; Giralt, E. J.
Org. Chem. 1997, 62, 354–366.
(13) Warrellow, G. J.; Porter, J. R.; Archibald, S. C.; Head, J. C. Chem.
Abstr. 2000, 132, 265095 WO 2000020396, 2000.
J. Org. Chem. Vol. 73, No. 9, 2008 3609

SCHEME 2a
SCHEME 3a
a Key: (a) Fmoc-Leu-Wang resin, piperidine/DMF (1:4), µ: 5 × 5 s,
100W, 5× cooling to -10 °C; (b) Fmoc-Ile-OH, PyBOP, DIPEA, HOBt,
DMF, µ: 15 × 10 s, 50 W, 15× cooling to -10 °C; (c) (1) Fmoc
deprotection (see a), (2) 3c or 7a, conditions see (b) for 3c: reagents for a
2nd µ-assisted coupling: HATU, DIPEA, DMF; (d) H2SO4/dioxane (1:9),
8 °C, 2 h; (e) Fmoc-Arg(Pbf)-OH, BTC, 2,6-lutidine, rt, 1 h; (f) (1) Fmoc
deprotection (see a), (2) coupling of Fmoc-Arg(Pbf)-OH (see b), (3) Fmoc
deprotection (see a); (g) TFA, phenol, H2O, triisopropylsilane 88:5:5:2, 2 h;
(h) RP-HPLC; (i) H2, 20% Pd(OH)2/C, MeOH; (j) RP-HPLC.
and coupling with Fmoc(Pbf)-arginine, TFA-promoted cleavage,
preparative HPLC and palladium-catalyzed hydrogenolysis of
the 2,6-dichlorobenzyl group, the target peptides 9 and 10 were
isolated in isomerically pure form.
Employing X-ray crystallographic data, we clearly identified
a type II ꢀ-turn structure for the model peptide scaffold 4b1
(Figure 3) when an intramolecular hydrogen bond with a
distance of 2.21 Å17 could be unambiguously deduced between
the methyl amide N-Hi+3 and the CdO function in position i.
The backbone dihedral angles of proline (φi+1: -61.1°/Ψi+1
:
137.7°) and phenylalanine (φi+2: 65.9°/Ψi+2: 17.4°) were
deviating by less than 30° 18 from the canonical angles of –60°,
120°, 80°, and 0°, respectively, thus correlating well with the
ideal form of a type II ꢀ-turn.19 The distance from the tert-
butoxy oxygen and the methylamide carbon (d Oi-Ci+3
representing the distance between CRi and CRi+3, respectively)
was found substantially shorter than 7 Å (5.07 Å), indicating
that a U-turn is adopted. Additionally, the low pseudodihedral
angle ꢀ (Ci-CRi+1-CRi+2-Ni+3) of 9.3° revealed an almost
coplanar spatial arrangement and, thus, antiparallel pleated
ꢀ-sheet nucleating properties.
a Key: (a) 2,2,2-trichloroethanol, EDC, DMAP, CH2Cl2, rt, 16 h; (b)
CH3I or 2,6-Cl2Bn-OBnBr, NaH, DMF, rt; (c) Zn dust, 1 M NH4OAc, THF,
rt, 24 h; (d) CH3NH2 ·HCl, HATU, DBU, NMP, rt, 15 min–3 h; (e) HPLC;
Dcb: 2,6-dichlorobenzyl.
To apply our methodology to the synthesis of biologically
relevant peptide mimetics, we intended to incorporate our
molecular scaffolds of type III into NT(8–13) (H-Arg-Arg-Pro-
Tyr-Ile-Leu-OH), the active portion of the neuropeptide neu-
rotensin.14 Since the Pro-Tyr fragment is known to be of special
importance for receptor recognition, introduction of the structural
congeners 3c and 7a should give access to valuable molecular
probes of type 9 and 10, respectively (Scheme 3). Thus, Fmoc-
isoleucine was coupled using PYBOP as an activating reagent
to N-deprotected Leu immobilized on Wang resin. Microwave
acceleration proved to be advantageous for both Fmoc-depro-
tection of the resin and acylation. Subsequently, µ-wave assisted
coupling of the building blocks 3c and 7a was performed when
a second acylation with HATU was necessary to complete the
ligation of 3c. Cleavage of the Boc function was done according
to a previously published protocol employing 10% sulfuric acid
in dioxan at 8 °C, thus preventing liberation of the peptide from
the solid support.15 Since the pyrrolidine nitrogen of the
spirobarbiturate system was not susceptible to acylation reactions
with common peptide coupling reagents, we employed the
recently introduced BTC (bis-trichloromethylcarbonate),16 which
proved successful for the coupling of Fmoc(Pbf)-arginine to the
sterically hindered amine function. After a further deprotection
FIGURE 3. Geometric parameters of 4b1.
To evaluate the structural behavior of the model peptide
mimetic 4b1 in solution, we performed conformational studies
based on FT-IR and 1H NMR spectroscopy. To exclude
intermolecular interactions, spectra were recorded at 2 mM
concentrations.201H NMR spectra of 4b1 showed two peaks for
(17) Belvisi, L.; Gennari, G.; Mielgo, A.; Potenza, D.; Scolastico, C. Eur. J.
Org. Chem. 1999, 38, 9–400.
(14) Hong, F.; Cusack, B.; Fauq, A.; Richelson, E. Curr. Med. Chem. 1997,
4, 412–434.
(18) Lewis, P. N.; Momany, F. A.; Scheraga, H. A. Biochim. Biophys. Acta
1973, 303, 249–255.
(15) Trivedi, H. S.; Anson, M.; Steel, P. G.; Worley, J. Synlett 2001, 12,
1932–1934.
(19) Ball, J. B.; Hughes, R. A.; Alewood, P. F.; Andrews, P. R. Tetrahedron
1993, 49, 3467–3478.
(16) Falb, E.; Yechezkel, T.; Salitra, Y.; Gilon, C. J. Peptide Res. 1999, 53,
507–517.
(20) Boussard, G.; Marraud, M J. Am. Chem. Soc. 1985, 107, 1825–1828.
3610 J. Org. Chem. Vol. 73, No. 9, 2008

was added, and a pH ≈ 7 was adjusted by the addition of 5% citric
acid. After extraction with EtOAc, the combined organic layer was
washed with H2O and brine and dried over MgSO4. The solvent
was removed in vacuo, and the product was purified by flash column
chromatography.
General Method for the N-Alkylation of the Barbiturate
Scaffolds to Give 6a-e. An oily suspension of NaH (60%) was
washed 2× with dry hexane, and then DMF (4 mL) was added
and the mixture cooled to 0 °C. A solution of the corresponding
barbiturate derivative in DMF (3–10 mL) was added dropwise. After
the development of H2, a solution of the respective alkyl halide in
DMF (3 mL) was added, and the reaction mixture was allowed to
stir at rt for 16 h. Thereafter, 5% citric acid was added, and
extraction with ethylacetate (3 × ) was performed. The organic
layer was washed with H2O and brine, dried over MgSO4, and
evaporated, and the residue was purified by flash column
chromatography.
General Method for the Reductive Ester Cleavage To
Give 7a-d. To a solution of the respective 2,2,2-trichloroethyl ester
in THF was added zinc dust and then an aqueous 1 M NH4OAc
solution. After vigorous stirring for 24 h at rt, the mixture was
filtered through Celite and washed with THF. Subsequently, the
solvent was removed in vacuo, and the residue was partitioned
between 5% citric acid and EtOAc. The organic layer was washed
with H2O and brine and dried over MgSO4, and the solvent was
removed in vacuo. The residue was purified by flash column
chromatography.
amide NH, a major peak at 6.52 ppm (95%) and a minor peak
at 5.87 ppm (5%) indicating the presence of two conformers.
Temperature dependent chemical shifts as a measure for the
stability of secondary structures were studied between 273 and
313 K in CDCl3 recorded in 10 K steps, revealing a low ∆δ∆T
value of –3.1 ppb/K for the NH of the major conformer. IR
spectra of 4b1 (CHCl3) displayed NH stretching vibrations at
3381 cm-1 and a very weak shoulder above 3450 cm-1. Thus,
we concluded, that an intramolecular hydrogen bond is strongly
favored. The above-mentioned diagnostic values for the spirobar-
biturates 4a,b2,c1/2 and 8a1/2,b1/2 (δ(NH): 6.41–6.56 ppm;
ν(NH): 3380–3402 cm-1; ∆δ∆T: (-4.8)-(-2.4) ppb/K) were
very similar to the data measured for reference peptide surrogate
4b1 clearly indicating the preferred formation of type II ꢀ-turn
secondary structures for all compounds investigated.
In conclusion, an efficient methodology was established that
gives access to a novel type of ꢀ-turn nucleating scaffolds
incorporating polar, “backbone-like” constraint elements.
Experimental Section
General Method for the Synthesis of the Barbiturate
Scaffolds 3a-c. To a solution of t-BuOK in DMSO ( 0.5 mmol/
mL) was added the respective urea (2a-c) dissolved in DMSO
(0.15 mmol/mL) at 10 °C. After 10 min of stirring, a solution of
pyrrolidine-1,2,2-tricarboxylic acid 1-tert-butyl ester 2,2-diethyl
ester (1) in DMSO (0.3 mmol/mL) was added. The reaction mixture
stirred at rt for 20 h, and then 5% aq citric acid was added and
extraction with EtOAc was performed. After the organic layer was
washed with H2O and brine and dried with MgSO4, the solvent
was evaporated and the residue was purified by flash column
chromatography.
Acknowledgment. We thank I. Torres-Berger, M. Kettler,
and Dr. R. Waibel for technical assistance and helpful discus-
sions, respectively. This work was supported by the DFG (Gm
13/7).
General Method for the Synthesis of the Methyl Amides
4a-c and 8a,b. A solution of the carboxylic acid, methylamine
hydrochloride, and HATU in NMP (2 mL) was stirred for 10 min
at rt, and then a solution of DBU in NMP (2 mL) was added
dropwise. After 15 min–3 h, 5% citric acid was added, and
extraction with EtOAc was performed. The organic layer was
washed with H2O and brine, dried over MgSO4, and evaporated.
The product was purified by flash column chromatography.
General Method for the Synthesis of 2,2,2-Trichloroethyl
Ester Derivatives 5a-c. To a stirred solution of the respective
carboxylic acid, 2,2,2-trichloroethanol, and DMAP in CH2Cl2 was
added EDC at 0 °C. After 1 h, the solution was allowed to stir at
rt for 18 h. Thereafter, the solvent was removed in vacuo, H2O
Supporting Information Available: Experimental and ana-
lytical data (for compounds 1, 2c, and 3–10 including epimer-
ization study of 3b,c, HPLC data and conformational analysis
data for 4a,b1/b2,c and 8a1/2,b1/2 as well as details of the X-ray
crystal structure determination of 4b1 in CIF format. This
material is available free of charge via the Internet at http://
pubs.acs.org. CCDC-668906 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
JO702573Z
J. Org. Chem. Vol. 73, No. 9, 2008 3611