An efficient synthesis of the constrained peptidomimetic 2-oxo-3-(N-9-fluorenyloxy-carbonylamino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid from pyroglutamic acid

Article abstract of DOI:10.1021/jo0515935

Azabicyclo[X.Y.0]alkane amino acids are rigid dipeptide mimetics that are useful tools for structure-activity studies in peptide-based drug discovery. Herein, we report an efficient synthesis of three diastereomers of 9-tert-butoxycarbonyl-2-oxo-3-(N-tert

Full text of DOI:10.1021/jo0515935

An Efficient Synthesis of the Constrained
Peptidomimetic 2-Oxo-3-(N-9-fluorenyloxy-
carbonylamino)-1-azabicyclo[4.3.0]nonane-
9-carboxylic Acid from Pyroglutamic Acid
Pijus Kumar Mandal,† Kumar K. Kaluarachchi,†
Douglas Ogrin,‡ Simon G. Bott,§ and
John S. McMurray*,†
FIGURE 1. Structure of azabicyclo[X.Y.0]-alkane amino acids.
Department of Neuro-Oncology, The University of Texas
M. D. Anderson Cancer Center, Box 316, 1515 Holcombe
Boulevard, Houston, Texas 77030, Department of Chemistry,
Rice University, 6100 Main, Houston, Texas 77005, and
Department of Chemistry, The University of Houston,
4800 Calhoun, Houston, Texas 77204
because of their rigid conformations that are able to
constrain the æi, ω, and ψi+1 backbone dihedral angles
within the bicyclic framework.2 Heterosubstituted AZAB-
IC analogues (type II) have also been reported.3 The
growing use of these mimetics in the investigation of
stucture-activity relationships of biologically active pep-
tides has created a demand for new, efficient methodology
for their synthesis. In connection with an ongoing pro-
gram on the development of peptide-based inhibitors of
signal transduction enzymes, we were interested in
dipeptide mimetics of AZABIC type I, where m ) 1, n )
1, and azabicyclo[4.3.0]nonane 1 and its homologues
where m ) 2, 3 and n ) 1.4
jsmcmur@mdanderson.org
Received July 29, 2005
Though many methods have been reported for the
synthesis of azabicyclo[4.3.0]nonane 1 and its ana-
logues,2,5 the majority of approaches suffer from relatively
long reaction sequences, thus limiting practical acces-
sibility. Here we report an efficient strategy for synthesis
of three stereoisomers of lactam 1 starting with inex-
pensive and commercially available pyroglutamic acid.
A number of the published methods for the synthesis
of 1 center on intramolecular reductive amination and
lactam cyclization of appropriately N-deprotected δ-oxo-
R,ω-diaminoazelates (2, Scheme 1). Thus, the preparation
of 2 is the key to the synthetic scheme.
Two general methods have been reported for the
synthesis of 2. In the first, symmetrical ketones, protected
as 1,3-dioxolanes, were alkylated with glycine equiva-
lents, which were then unmasked to provide 5-oxodiami-
noazelates. Mueller and Revesz5a alkylated 2 mol of the
Azabicyclo[X.Y.0]alkane amino acids are rigid dipeptide
mimetics that are useful tools for structure-activity studies
in peptide-based drug discovery. Herein, we report an
efficient synthesis of three diastereomers of 9-tert-butoxy-
carbonyl-2-oxo-3-(N-tert-butoxycarbonylamino)-1-azabicyclo-
[4.3.0]nonane (3S,6S,9S, 3S,6R,9R, and 3S,6R,9S). Methyl
N-Boc-pyroglutamate is cleaved with vinylmagnesium bro-
mide to produce an acyclic γ-vinyl ketone. Michael addition
of N-diphenylmethyleneglycine tert-butyl ester produces the
N-Boc-δ-oxo-R,ω-diaminoazelate intermediate, which, on
hydrogenloysis, gives the fused ring system. Acidolytic
deprotection followed by Fmoc-protection provided building
blocks suitable for solid-phase synthesis.
(2) Extensive review: Hanessian, S.; McNaughton-Smith, G.; Lom-
bart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789-12854. (b)
Gillespie, P.; Cicariello, J.; Olson, G. L. Biopolymers 1997, 43, 191-
217. (c) Eguchi, M.; Kahn, M. Mini Rev. Med. Chem. 2002, 2, 447-
462.
(3) (a) Slomczynska, U.; Chalmers, D. K.; Cornille, F.; Smythe, M.
L.; Beusen, D. D.; Moeller, K. D.; Marshall, G. R. J. Org. Chem. 1996,
61, 1198-204. (b) Zhang, X.; Jiang, W.; Schmitt, A. C. Tetrahedron
Lett. 2001, 42, 4943-4945.
Considerable effort has been applied to the synthesis
of conformationally restricted peptides and peptidomi-
metics and the study of their effects on biological activ-
ity.1 In this area, azabicyclo[X.Y.0]alkane amino acids
(Figure 1, AZABIC Type I) are particularly attractive
(4) A preliminary communication of this work was presented at the
3rd International and 28th European Peptide Symposium, Sept 2004,
Prague, Czech Republic. Mandal, P. K.; Kaluarachchi, K. K.; McMur-
ray, J. S. Proc. 3rd Int. 23rd Eur. Peptide Symp., in press.
(5) (a) Mueller, R.; Revesz, L. Tetrahedron Lett. 1994, 35, 4091-
4092. (b) Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1994, 59, 6147-
6149. (c) Lombart, H.-G.; Lubell, W. D. J. Org. Chem. 1996, 61, 9437-
9446. (d) Halab, L.; Gosselin, F.; Lubell, W. D. Bioploymers (Peptide
Sci.) 2000, 55, 101 and references therein. (e) Polyak, F.; Lubell, W.
D. J. Org. Chem. 1998, 63, 5937-5949. (f) Kim, H.-O.; Kahn, M.
Tetrahedron Lett. 1997, 38, 6483-6484. (g) Wang, W.; Xiong, C.; Hruby,
V. J. Tetrahedron Lett. 2001, 42, 3159-3161. (h) Mulzer, J.; Schlzchen,
F.; Bats, J.-W. Tetrahedron 2000, 56, 4289-4298. (i) Beal, L. M.; Liu,
B.; Chu, W.; Moeller, K. D. Tetrahedron 2000, 56, 10113-10125. (j)
Angiolini, M.; Araneo, S.; Belvisi, L.; Cesarotti, E.; Checchia, A.; Crippa,
L.; Manzoni, L.; Scolastico, C. Eur. J. Org. Chem. 2000, 2571-2581.
(k) Hanessian, S.; Sailes, H.; Munro, A.; Therrien, E. J. Org. Chem.
2003, 68, 7219-7233.
* To whom correspondence should be addressed. Tel: 713-745-3763.
Fax: 713-745-1183.
† The University of Texas M. D. Anderson Cancer Center.
‡ Rice University.
§ The University of Houston.
(1) Reviews regarding conformational and topographical consider-
ations in designing peptidomimetics including turn mimetics: (a)
Hruby, V. J. Life Sci. 1982, 31, 189-199. (b) Hruby, V. J.; Al-Obeidi,
F.; Kazamierski, W. M. Biochem. J. 1990, 268, 249-262. (c) Hruby,
V. J.; Balse, P. M. Curr. Top. Med. Chem. 2000, 7, 945-970. Reviews
for the application of peptidomimetics including turn mimetics: (d)
Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699-
1720.
10.1021/jo0515935 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/28/2005
10128
J. Org. Chem. 2005, 70, 10128-10131

SCHEME 1
SCHEME 2a
a Key: (a) (i) MeOH, SOCl2, DMF(cat), rt, 4 h, (ii) (Boc)2O, DIEA,
DMAP, dry DMF, rt 3 h, 90%; (b) vinylmagnesium bromide, THF,
Scho¨llkopf bislactim ether with bis-iodethyl 1,3-dioxolane
to prepare a masked azelate. Acid hydrolysis gave di-
methyl 5-oxo-2,6-diamino azelate ready for reductive
amination/ring closure. This methodology required mul-
tistep preparation of the diiodoethyl dioxolane, and
although the alkylation was highly stereoselective, it was
not stereospecific. In a similar method, Wang et al.5g
reduced 1,3-dioxolane-protected diethyl 1,3-acetonedi-
carboxylate to the corresponding dialdehyde, which was
extended with Horner-Emmons olefination with (MeO)2P-
(O)CH(NHCbz)CO2Me to give 2,7-didehydro 2. The diene
was reduced to (2S,7S) or (2R,7R) diastereomers by
stereoselectve hydrogenation using Burk’s chiral rhodium
catalysts. Conversion to 1 was accomplished by hydro-
genation over palladium on charcoal. The second ap-
proach involved Claisen condensation of glutamic acid
derivatives. Lubell and colleagues5b condensed two iden-
tical N-[9-(9-phenylfluorenyl)}glutamate molecules which
was followed by decarboxylation of the â-ketoester to
achieve the 5-oxoazelate. Hydrogenolysis of the 9-(9-
phenylfluorenyl) protecting groups was accompanied by
reductive amination and cyclization to give 1. Kahn et
al.5f adopted a similar approach, but condensed glutamates
with different amino group protection to give an asym-
metric azelate, which was then taken on to azabic
synthesis. While these methods were elegant, the mul-
tistep sequences, expensive catalysts, and “nonstandard”
protecting groups (in some cases) can limit practical
application.
t
-40°C to rt, 3 h, 80%; (c) (Ph)2dNCH2CO2 Bu, Cs2CO3, THF, 74%;
(d) 10% Pd-C, 9:1 EtOH/AcOH, 24 h, 68% (e) (i) TFA, Et3SiH,
CH2Cl2, (ii) Fmoc-OSu, 10% Na2CO3, 1,4-dioxane, 12 h, 74%; (f)
NaHMDS (50%).
cleaner products and better yields than commercially
available material.
Michael addition of Schiff base, tert-butyl N-(diphe-
nylmethylene)glycinate,8 to 8 in the presence of Cs2CO3
in THF9 gave the target 5-oxo diaminoazelate, 9. This
compound, being very susceptible to acidolysis of the
diphenylmethylene group, was obtained in 74% yield
after rapid neutral alumina chromatography as a mixture
of two inseparable diastereomers with >95% purity.
Hydrogenation with 10% palladium-on-carbon in 9:1
EtOH/AcOH for 24 h accomplished amino group depro-
tection, reductive amination of the ketone, and lactam-
ization to give a 1:1 diastereomeric mixture of fully
protected azabicycloalkane, tert-butyl-2-oxo-3-[N-tert-bu-
toxycarbonylamino]-1-azabicyclo[4.3.0]nonane-9-carboxy-
late 1a and 1b in 70% overall yield. The two diastereo-
mers were readily separated by silica gel chromatography
with 40% EtOAc/hexanes as the eluant.
Crystallization of 1a was fruitless, thus precluding
stereochemical assignment by X-ray crystallography.
However, NMR and optical rotation data were in excel-
lent agreement with that of the (3S,6S,9S) isomer
reported by Scolastico and colleagues.5j Diastereomer 1b
gave good crystals from hexanes-ether, and its structure
was determined by X-ray crystallography to be (3S,6R,9R)
(Figure S1, Supporting Information). The stereochemistry
of the hydrogenation of the five-membered ring of these
mimetics provided cis arrangement of the 2 and 5
substituents, in agreement with that reported by Werf
and Kellog for 1,5-dehydropyrrolidines.9
Our approach to the synthesis of diaminoazelate (2)
is based on a simple Michael addition of glycine ester to
an enone analogue of glutamic acid, derived from com-
mercially available, inexpensive pyroglutamic acid
(Scheme 2). Thus, Michael acceptor 8 was prepared by
ring opening of methyl N-Boc-pyroglutamate 76 with
vinyl Grignard (1.1 equiv).7 The reaction occurred re-
giospecifically to give exclusively the enone amino acid
derivative. Freshly prepared vinyl Grignard reagent gave
The (3S,6R,9S) diastereomer (1c) was prepared by
epimerization of C(9) of 1b using NaHMDS in a 1:1
(6) Gu, Z. Q.; Li, M. Tetrahedron Lett. 2003, 44, 3203-3205.
(7) Ohta, T.; Hosoi, A.; Kimura, T.; Nozoe, S. Chem. Lett. 1987,
2091-2094.
(8) O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663-2666.
(9) Werf, A. V. D.; Kellogg, R. M. Tetrahedron Lett. 1991, 32, 3727-
3730.
J. Org. Chem, Vol. 70, No. 24, 2005 10129

1a: yield 208 mg (33%) [R]20D -12.1 (c 1.32, CHCl3); 1H NMR
(300 Hz, CDCl3) δ 1.44 (s, 9H), 1.46(s, 9H), 1.66-1.72 (m, 3H),
2.00-2.21 (m, 4H), 2.43-2.48 (m, 1H), 3.69 (m, 1H), 4.11 (m,
1H), 4.37 (d, 1H, J ) 7.8 Hz), 5.58 (brs, 1H); 13C NMR (75 MHz,
CDCl3) δ 26.8, 27.1, 27.9, 28.3, 29.1, 32.1, 49.9, 56.3, 59.1, 79.3,
81.4, 155.6, 168.8, 170.7; mass calcd for C18H30N2O5 (M + H+)
355.215, found 355.206; HPLC tR 25.54 (A).
diastereomeric ratio.3c These isomers were inseparable
using standard silica gel chromatography but were
readily separated using C18 reversed-phase HPLC. NMR
and optical rotation were in excellent agreement with the
(3S,6R,9S) diastereomer reported by Scolastico and
colleagues.5j
1b: yield 242 mg (38%); [R]20D 32.7 (c 1.32, CHCl3); 1H NMR
(300 Hz, CDCl3) δ 1.37 (s, 9H), 1.39 (s, 9H), 1.56-2.07 (m, 7H),
2.44 (m, 1H), 3.54 (m, 1H), 3.83 (m, 1H), 4.26 (d, 1H, J ) 9.3
Hz), 5.23 (brs, 1H); 13C NMR (75 MHz, CDCl3) δ 27.8, 27.9, 28.3,
28.5, 31.5, 52.250, 59.6, 60.6, 81.6, 155.9, 168.8, 170. 7; mass
calcd for C18H30N2O5 (M + H+) 355.215, found 355.214; HPLC
tR 22.63 (A).
Each diastereomer of 1 was then converted to the
corresponding N-Fmoc derivative (10) by TFA hydrolysis
of the Boc and tert-butyl ester groups followed by treat-
ment with Fmoc-OSu.10
In conclusion, we have described an efficient route to
synthesize three stereoisomers of azabicyclo[4.3.0]nonane
amino acid ester 1 through a facile pyroglutamate ring
opening, followed by Michael addition, reductive amina-
tion, and lactam cyclization. Further research on asym-
metric synthesis of stereoisomers of 1 and their applica-
tion in a series of azabicyclic dipeptide analogues is in
progress and will be reported in due course.
Synthesis
of
(2S,6R,9S)-tert-Butyl
2-Oxo-3-(tert-
butoxycarbonylamino)-1-azabicyclo[4.3.0]nonane-9-car-
boxylate 1c. To a stirred solution of 1b (400 mg, 1.12 mmol) in
10 mL of dry THF, at -78 °C, was added NaN(SiMe3)2 (2.24
mL, 2.24 mmol, 1 M in THF) over a period of 10 min. Stirring
was continued for 2 h. The reaction was quenched with 1 M
NaH2PO4 (10 mL) followed by 10 mL of EtOAc. The aqueous
portion was extracted with EtOAc (3 × 10 mL). The combined
organic parts were then washed with brine, dried (Na2SO4), and
evaporated. A gummy oil, as a 1:2 ratio of 1b (3S,6R,9R)/1c
(3S,6R,9S), as determined by 1H NMR and by HPLC, was
obtained. Product 1c was then purified by C18 reversed-phase
Experimental Section
Synthesis of Methyl 5-Oxo-2-(tert-butoxycarbonylami-
no)hept-6-enoate 8. Freshly prepared vinylmagnesium bro-
mide (8 mL, 5.0 mmol) in THF was added to methyl N-Boc-
pyroglutamate, prepared as in ref 5 (7, 1.0 g, 4.11 mmol), in dry
THF (20 mL) at -40 °C under argon. After 3 h of stirring, the
reaction was quenched with AcOH-MeOH (1:1, 5.0 mL) and the
mixture diluted with ether. The phases were separated, and the
Et2O layer was washed with water, dried (MgSO4), and evapo-
rated. The residue was purified by silica gel chromatography
HPLC: yield 140 mg (35%); [R]20 -92.1 (c 1.6, CHCl3); mass
D
calcd for C18H30N2O5 (M + H+) 355.215, found 355.22; 1H NMR
(300 Hz, CDCl3) δ 1.44 (s, 9H), 1.47(s, 9H), 1.72-1.82 (m, 3H),
2.05-2.15 (m, 3H), 2.33-2.56 (m, 2H) 3.70(m, 1H), 4.02 (m, 1H),
4.35 (t, 1H, J ) 7.8 Hz), 5.30 (brs, 1H); 13C NMR (75 MHz,
CDCl3) δ 27.5, 27.8, 27.9, 28.3, 28.7, 32.8, 52.1, 58.6, 60.1, 79.4,
81.4, 156.1, 167.6, 171.4; HPLC tR 24.74 (A).
(25% EtOAc-hexane) yielding 890 mg of 8 (80%) as an oil: IR
Synthesis of (2S,6S,9S)-2-Oxo-3-(9-fluorenyloxycarbo-
nylamino)-1-azabicyclo[4.3.0]nonane-9-carboxylic Acid 10a.
Compound 1a (300 mg, 0.85 mmol) was treated with 3.0 mL of
95:5 TFA/:TES in 2.0 mL of dichloromethane for 1 h. The solvent
was removed, and excess TFA was stripped off with toluene (3
× 5 mL). The residue was dissolved in 10 mL of 1,4-dioxane.
Fmoc-OSu (320 mg, 0.94 mmol) was added followed 10 mL of
10% aqueous Na2CO3. Stirring was continued overnight. The
dioxan was removed in vacuo, and the aqueous solution was
extracted with ether (2 × 20 mL). The aqueous solution was
acidified, and the product was extracted with EtOAc (3 × 20
mL). The organic phase was washed with brine, dried (Na2SO4),
and evaporated. Tituration with ether-hexane gave 6a (265 mg,
74%) as white solid: 1H NMR (500 MHz, DMSO-d6) δ 1.52-
1.60 (m, 2H), 1.64-1.70 (m, 1H), 1.91-2.05 (m, 2H), 2.08-2.16
(m, 3H), 3.75 (m, 1H), 4.12 (m, 1H), 4.22-4.44 (m, 4H), 7.32-
7.35 (m, 2H), 7.41-7.45 (m 3H), 7.73-7.76 (m, 2H), 7.895 (d,
2H, J ) 8 Hz); 13C NMR (125 MHz, DMSO-d6) δ 26.2, 27.4, 29.2,
32.1, 47.1, 50.1, 56.5, 58.4, 66.2, 120.5, 125.9, 127.5, 128.1, 141.2,
144.3, 144.4, 156.6, 168.7, 173.5; mass calcd for C24H25N2O5 (M
+ H+) 421.176, found 421.165; HPLC tR 16.81 (B).
10b. Prepared as for 10a: yield 82%; 1H NMR (500 MHz,
DMSO-d6) δ 1.45-1.55 (m, 2H), 1.80-1.87 (m, 2H), 1.97-2.12
(m, 4H), 3.53 (m, 1H), 3.83 (m, 1H), 4.15 (d, 1H, J ) 9.5 Hz),
4.21-4.31 (m, 3H), 7.32-7.35 (m, 2H), 7.38-7.45 (m, 2H), 7.55
(d, 1H, J ) 8.00 Hz), 7.70 (d, 2H, J ) 2.5 Hz), 7.89 (d, 2H, J )
7.5 Hz); 13C NMR (125 MHz, DMSO-d6) δ 26.7, 27.3, 28.5, 31.7,
46.3, 51.2, 56.4, 58.8, 66.0, 120.6, 125.7, 127.5, 128.1, 141.2,
144.3, 144.5, 156.5, 167.8, 173.4; mass calcd for C24H25N2O5 (M
+ H+) 421.176, found 421.170; HPLC tR 17.60 (B).
1
νCH Cl 3300, 1744, 1711, 1680, 1616; H NMR (300 Hz, CDCl3)
δ1.43 (s, 9H), 1.92-1.99 (m, 1H), 2.15-2.22 (m, 1H), 2.66-2.78
(m, 2H), 3.74 (s, 3H), 4.32 (m, 1H), 5.14 (brs, 1H), 5.85 (dd, 1H,
J ) 1.2 and 9.00 Hz), 6.2-6.4 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 26.6, 28.3, 35.4, 52.4, 53.0, 80.0, 128.4, 136.3, 155.4, 172.8,
199.2.
2
2
Synthesis of (2S,8R/S)-Methyl 2-tert-Butoxycarbony-
lamino-5-oxo-8-(diphenylmethylenimino)nonanoate 9. To
a stirred solution of enone 8 (1.0 gm, 3.68 mmol) and tert-butyl
N-(diphenylmethylene)glycinate (1.2gm, 4.05 mmol) in dry THF
(20 mL) was added Cs2CO3 (1.2 gm, 3.68 mmol). The reaction
was monitored by TLC. Upon completion, THF was removed in
vacuo and the residue diluted with 200 mL of ether. The organic
layer was washed with water, followed by brine, and dried (Na2-
SO4), and the solvents were evaporated. Quick neutral alumina
filtration resulted in an equimolar mixture of diasteromers 9
(1.55 gm, 74%) as a viscous oil: 1H NMR (300 Hz, CDCl3) δ 1.42
(s, 9H), 1.43 (s, 9H), 1.79-1.87 (m, 1H), 2.04-2.18(m, 3H), 2.42-
2.56(m, 4H), 3.71 (s, 3H), 3.94 (t, 1H, J ) 6.0 Hz), 4.24 (m, 1H),
5.07 (brs, 1H), 7.15-7.17(m, 2H), 7.31-7.45 (m, 6H), 7.60-7.63
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 26.4, 27.7, 28.0, 28.3, 38.4,
39.0, 52.3, 52.9, 64.7, 79.9, 81.1, 127.7, 128.0, 128.5, 128.6, 128.7,
130.0, 136.4, 139.4, 155.4, 170.5, 170.9, 172.9, 208.8; mass calcd
for C32H42N2O7 566.3, found 566.9.
Synthesis of (2S,6S,9S)/(2S,6R,9R)-tert-Butyl 2-Oxo-3-
(tert-butoxycarbonylamino)-1-azabicyclo[4.3.0]nonane-9-
carboxylate 1a and 1b. A solution of ketone 9 (1.0 gm, 1.76
mmol) in 20 mL of 9:1 EtOH/AcOH was hydrogenated under 30
psi pressure of H2 in the presence of palladium-on-carbon (100
mg, 10 wt %) for 24 h. The reaction mixture then diluted with
20 mL of EtOH, filtered through a pad of Celite, and washed
with additional EtOH. After the solvent was removed, AcOH
was removed azeotropically by adding and evaporating toluene
(3 × 10 mL). The crude mixture of diasteromers was separated
by silica gel chromatography (40% EtOAc-hexane).
10c. Prepared as for 10a: yield 68%; 1H NMR (500 MHz,
DMSO-d6) δ 1.40-1.53 (m, 2H), 1.69-1.73 (m, 1H), 1.76-1.87
(m, 4H), 2.26-2.32 (m, 1H), 3.61 (m, 1H), 4.04 (m, 1H), 4.21-
4.28 (m, 4H), 7.32-7.35 (m, 2H), 7.38-7.45 (m, 2H), 7.55 (d, 1H,
J ) 8.00 Hz), 7.70 (d, 2H, J ) 2.5 Hz), 7.89 (d, 2H, J ) 7.5 Hz);
13C NMR (125 MHz, DMSO-d6) δ 28.0, 28.2, 28.4, 32.6, 47.1, 51.9,
58.7, 59.6, 66.1, 120.5, 125.8, 127.4, 128.0, 141.2, 144.3, 144.4,
156.7, 167.6, 174.2; mass calcd for C24H25N2O5 (M + H+) 421.176,
found 421.210; HPLC tR 17.25 (B).
(10) Belvisi, L.; Bernardi, A.; Checchia, A.; Manzoni, L.; Potenza,
D.; Scolastico, C.; Castorina, M.; Cupelli, A.; Giannini, G.; Carminati,
P.; Pisano, C. Org. Lett. 2001, 3, 1001-1004.
10130 J. Org. Chem., Vol. 70, No. 24, 2005

Supporting Information Available: CIF file and ORTEP
diagram of the X-ray structure of compound 1b, general
experimental methods, 1H and 13C NMR spectra for compounds
8 and 9, 1H and 13C NMR spectra and analytical HPLC
chromatograms for 1a-c, and 1H NMR spectra and analytical
HPLC chromatograms for 10a-c. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the National
Cancer Institute for support of this work (CA096652).
We also acknowledge the NCI Cancer Center Support
Grant CA016672 for the support of our NMR facility
and the Analytical Chemistry Center, which performed
the mass spectrometry. X-ray diffraction of 1b was
performed at the Robert A. Welch Foundation funded
Texas Center for Crystallography at Rice University.
JO0515935
J. Org. Chem, Vol. 70, No. 24, 2005 10131