Synthesis of N-phosphonamidothionate derivatives of glutamic acid

Full text of DOI:10.1021/jo991090x

8698
J . Org. Chem. 1999, 64, 8698-8701
residues. Investigations thus far have indicated that
Syn th esis of N-P h osp h on a m id oth ion a te
these enzymes are metallopeptidases with the greatest
information gathered for a form of CPG due to the recent
acquisition of its crystal structure confirming the pres-
ence of zinc(II) in the active site.8 In previous studies with
a partially purified form of CPG, we observed that
N-phosphonamidate derivatives of glutamic acid (1,
Figure 1) were indeed competitive inhibitors, albeit
weak.9 Based on that limited success, we have proposed
the phosphonamidothionates (2) as putative and potent
inhibitors of glutamate carboxypeptidases.
Der iva tives of Glu ta m ic Acid
Haiyan Lu, Karyn L. Mlodnosky, Trang T. Dinh,
Azar Dastgah, Vinh Q. Lam, and Clifford E. Berkman*
Department of Chemistry & Biochemistry, San Francisco
State University, 1600 Holloway Avenue,
San Francisco, California 94132
Received J uly 7, 1999
Resu lts a n d Discu ssion
In tr od u ction
Due to the susceptibility of the phosphorus-nitrogen
bond to acidic conditions, it was desired to use a base-
labile protecting group on phosphorus such as the 2-cya-
noethoxy ligand, which has seen limited use for the
preparation of phosphonamidothionates10 but extensive
use in the synthesis of nucleoside phosphorodithioates.11
Base-labile protecting groups for the carboxylic acids of
glutamic were also chosen with the anticipation that all
the protecting groups could be conveniently removed in
one final step. On the basis of these considerations, the
intermediate targets 4 (Scheme 1) were pursued.
Because we had recently developed a convenient
method for the preparation of the intermediate phospho-
ramidate esters 3 in a one-pot, two-step reaction,12 we
sought to prepare the series of phosphonamidothionate
esters 4 through path A in Scheme 1. Although 3a and
3b could be prepared via this route, their preparation
generally suffered low yields while good yields (greater
than 60%) were obtained for the intermediates 3c and
3d . These intermediates were subsequently thionated
with Lawesson’s reagent to provide the respective phos-
phonamidothionate esters 4c and 4d .
To circumvent the difficulties encountered in path A
for the preparation of 4a , a more direct route was
pursued. Thus, methylphosphonothioic dichloride was
employed in a direct and sequential thiophosphonylation
of 3-hydroxypropionitrile and glutamic acid dimethyl
ester to give the phosphonamidothionate ester 4a (Scheme
1, path B). Due to the ready availability of phenylphospho-
nothioic dichloride, path B was also explored for the
preparation of 4d and was found to be superior to path
A. Alternatively, recent methodology which was success-
ful for the preparation of nucleoside methanephospho-
nothioanilidates was applied to the preparation of 4b
(Scheme 1, path C).13 The results from this three-step,
one-pot sequence provided 4b in good yield. It should be
noted that through all three pathways delineated the
Although N-phosphonothionylamino acids have not
commonly been considered as potential enzyme inhibi-
tors, the analogous phosphonamidates are well-known
to function as potent tetrahedral-intermediate analogue
inhibitors of metallopeptidases.1 With such phosphon-
amidate inhibitors, active-site metal ions, specifically
Zn2+, have been shown to coordinate with the phosphonyl
oxygen ligands analogous to the putative bidentate
complex of the enzymatic transition-state or tetrahedral
intermediate.2 Although the formations of Zn2+-oxygen
complexes are favorable, the coordination of Zn2+ with
sulfur is of a more covalent nature.3 Therefore, the simple
replacement of a phosphonyl oxygen with a sulfur atom
is anticipated to provide more potent inhibitors of met-
allopeptidases due to enhanced chelation of active-site
metals. In addition, N-phosphonothionylamino acids are
unique to their respective phosphonamidate counterparts
as they possess a chiral center at phosphorus that may
be invaluable for probing active-site architecture. Al-
though N-thiophosphonylamino groups have been greatly
overlooked as potentially potent, transition-state ana-
logue, or tetrahedral-intermediate inhibitors of metallo-
proteases, progress toward developing synthetic strate-
gies for phosphonamidothionates has recently been
pioneered.4
Our main objective in this investigation was to syn-
thesize putative inhibitors of glutamate carboxypepti-
dases such as prostate specific membrane antigen (PS-
MA),5 N-acetylated R-linked acidic dipeptidase (NAA-
LADase),6 and carboxypeptidase G (CPG),7 all of which
function to hydrolytically cleave terminal glutamate
(1) Rowsell, S.; Pauptit, R. A.; Tucker, A. D.; Melton, R. G.; Blow,
D. M.; Brick, P. Structure 1997, 5, 337.
(2) Holden, H. M.; Tronrud, D. E.; Monzingo, A. F.; Weaver, L. H.;
Matthews, B. W. Biochemistry 1987, 26, 8542. Christianson, D. W.;
Lipscomb, W. N. J . Am. Chem. Soc. 1988, 110, 5560.
(3) Bell, C. F. In Principles and Applications of Metal Chelation;
Atkins, P. W., et al., Eds.; Oxford University Press: Oxford, 1977.
Prasad, A. S. In Biochemistry of Zinc; Frieden, E., Ed.; Plenum Press:
New York, 1993.
(8) Rowsell, S.; Pauptit, R. A.; Tucker, A. D.; Melton, R. G.; Blow,
D. M., Brick, P. Structure 1997, 5, 337.
(4) Suarez, A. I.; Lin, J .; Thompson, C. M. Tetrahedron 1996, 52,
6117. Thompson, C. M.; Lin, J . Tetrahedron Lett. 1996, 27, 8979.
Wiesler, W. T.; Caruthers, M. H. J . Org. Chem. 1996, 61, 4272.
(5) Carter, R. E.; Feldman, A. R.; Coyle, J . T. Proc. Natl. Acad. Sci.
U.S.A. 1996, 93, 749.
(6) Robinson, M. B.; Blakely, R. D.; Couto, R. Coyle, J . T. J . Biol.
Chem. 1987, 262, 14498.
(7) (a) Goldman, P.; Levy, C. C. Proc. Natl. Acad. Sci. U.S.A. 1967,
58, 1299. (b) Levy, C. C.; Goldman, P. J . Biol. Chem. 1967, 242, 2933.
(c) McCullough, J . L.; Chabner, B. A.; Bertino, J . R. J . Biol. Chem.
1971, 246, 7207. (d) Sherwood, R. F.; Melton, R. G.; Alwan, S. M.;
Hughes, P. Eur. J . Biochem. 1985, 148, 447.
(9) Rodriguez, C. E.; Holmes, H. M.; Mlodnosky, K. L.; Lam, V. Q.;
Berkman, C. E. Bioorg. Med. Chem. Lett. 1998, 8, 1521.
(10) Bartlett, P. A.; J acobsen, N. E. J . Am. Chem. Soc. 1983, 105,
1619.
(11) Beaton, G.; Brill, W. K.-D.; Grandas, A.; Ma, Y.-X.; Nielsen, J .;
Yau, E.; Caruthers, M. H. Tetrahedron 1991, 47, 2377. Grandas, A.;
Robles, J .; Pegroso, E. Nucleosides Nucleotides 1995, 14, 825. Okruszek,
A.; Olesiak, M.; Krajewska, D.; Stec, W. J . Org. Chem. 1997, 62, 2269.
(12) Mlodnosky, K. L.; Holmes, H. M.; Lam, V. Q.; Berkman, C. E.
Tetrahedron Lett. 1997, 38, 8803.
(13) Wozniak, L. A.; Wieczorek, M.; Pyzowski, J .; Majzner, W.; Stec,
W. J . J . Org. Chem. 1998, 63, 5395.
10.1021/jo991090x CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/15/1999

Notes
J . Org. Chem., Vol. 64, No. 23, 1999 8699
UW Medicinal Chemistry Mass Spectrometry Center, Seattle,
WA. High-resolution mass spectra (ESI) were performed by the
UC Berkeley Mass Spectrometry Facility, Berkeley, CA.
Gen er a l P r oced u r e for P a th A (P r oced u r e A). A flask
was charged with 1H-tetrazole (18.2 mg, 0.26 mmol) and benzene
(9 mL) under an Ar(g) atmosphere followed by the dropwise
addition of an alkylphosphonic dichloride (2.86 mmol), and the
temperature was reduced to 4 °C. To the stirring reaction
mixture were sequentially added 3-hydroxypropionitrile (0.19
g, 2.60 mmol) and diisopropylethylamine (0.5 mL, 2.86 mmol)
dropwise via syringe. The reaction mixture was stirred and
allowed to warm to room temperature until 3-hydroxypropioni-
trile was consumed (approximately 2 h) as monitored by TLC.
Glutamic acid dimethyl ester hydrochloride (0.61 g, 2.86 mmol)
and DEA (1.0 mL, 5,72 mmol) were dissolved in benzene (8 mL)
and added dropwise to the reaction mixture, and the resulting
mixture was allowed to stir for an additional 3 h. The reaction
mixture was concentrated in vacuo, and the resulting oil was
directly purified by flash chromatography to give the phospho-
namidate esters 3. The phosphonamidothionate esters 4 were
prepared by refluxing a solution of 3 (0.72 mmol) and Lawesson’s
reagent (0.16 g, 0.4 mmol) in toluene (6 mL) for 3 h. The reaction
mixture was concentrated in vacuo, and the resulting oil was
purified by flash chromatography.
Gen er a l P r oced u r e for P a th B (P r oced u r e B). A solution
of 3-hydroxypropionitrile (0.43 g, 6 mmol) and triethylamine (0.9
mL, 6 mmol) was added via syringe to a stirring solution of an
alkylphosphonothioic dichloride (6 mmol) in methylene chloride
(7 mL) at -5 °C. The resulting solution was warmed to 20 °C
and stirred 3 h. A solution L-glutamic dimethyl ester hydrochlo-
ride (0.14 g, 6.6 mmol) and triethylamine (2.5 mL, 18 mmol) in
methylene chloride (20 mL) was added to the reaction mixture
and stirred for an additional 3 h, after which time the reaction
mixture was diluted with methylene dichloride (20 mL), washed
with 20 mL of 2 M H2SO4, dried with Na2SO4, and concentrated
in vacuo. The resulting crude product was obtained as a viscous
yellow oil that was purified by flash chromatography.
F igu r e 1. Structures of phosphorus-containing glutamate
carboxypeptidase inhibitors.
phosphonamidothionate esters 4 were provided as a
mixture of diastereomeric mixtures, racemic at phospho-
rus. Because chromatographic resolution of diastereo-
meric mixtures of 4 proved to be difficult, further
attempts for the resolution of these compounds have been
postponed.
Although 2-cyanoethyl phosphorus esters are tradi-
tionally removed with aqueous ammonia, we explored the
possibility of removing this group with LiOH, the same
conditions that would be employed to hydrolyze the
C-terminal methyl esters. Indeed, we found that in the
case of our phosphonamidothionate ester intermediates
4 complete deprotection occurred to give the target
phosphonamidothionates 2 as the trilithium salts. It is
noteworthy to mention that of the two cosolvents explored
for this dual deprotection with LiOH, it was found that
in methanol the reaction was complete after 18 h, while
in acetonitrile the reaction was still incomplete after 72
h. It was noted that upon complete deprotection of
phosphonamidothionate esters 4 to the phosphonami-
dothionates 2, the diastereomeric ratios were not altered.
N-[2-Cya n oeth oxy(n -bu tyl)p h osp h in yl]-L-glu ta m ic Acid
Dim eth yl Ester (3c). 3c was prepared using procedure A and
purified by flash chromatography (MeOH/ethyl acetate 2.5:97.5
v/v, Rf ) 0.19) to give a colorless oil (0.52 g, 1.49 mmol, 58%
Ultimately, it is anticipated that these compounds will
prove to be more potent inhibitors of metallopeptidases
than analogous phosphonamidates, and preliminary
results for 1a and 1d with the CPG and PSMA have
indicated as much. More detailed investigations into the
mode and kinetics of inhibition are currently underway,
and the results will be forthcoming. In summary, we have
identified three distinct strategies for the preparation of
simple amino acid-containing phosphonamidothionates.
On the basis of preliminary evidence, such compounds
containing the phosphonamidothionate motif show strong
promise as potent tetrahedral-intermediate analogue
inhibitors of metallopeptidases with the unique value of
probing enzyme active sites with complementary chiral
phosphorus centers.
1
yield). H NMR (CDCl3) δ: 0.91 (t, J ) 7.26 Hz, 3H), 1.40 (dt, J
) 7.2, 14.6 Hz, 2H), 1.52-1.57 (m, 2H), 1.70-1.77 (m, 2H), 1.91-
2.21 (dm, 2H), 2.39-2.45 (m, 2H), 2.67-2.74 (m, 2H), 3.12-3.19
(m, 1H), 3.67 (s, 3H), 3.75 (s, 3H), 4.02-4.21 (dm, 3H). 31P NMR
(CDCl3) δ: 36.27, 37.16.
N-[2-Cya n oeth oxy(p h en yl)p h osp h in yl]-L-glu ta m ic Acid
Dim eth yl Ester (3d ). 3d was prepared using procedure A and
purified by flash chromatography (MeOH/ethyl acetate 10:90 v/v,
Rf ) 0.44) to give a colorless oil (0.43 g, 1.16 mmol, 55% yield).
1H NMR (CDCl3) δ: 1.75-2.12 (dm, 2H), 2.33-2.40 (m, 2H),
2.72-2.79 (m, 2H), 3.60 and 3.66 (s, 3H), 3.62 and 3.67 (s, 3H),
3.86-4.10 (m, 1H), 4.17-4.34 (dm, 2H), 7.43-7.58 (m,3H), 7.74-
7.87 (m, 2H). 31P NMR (CDCl3): δ 19.90, 20.93; 23.07, 23.84.
N-[2-Cya n oet h oxy(m et h yl)p h osp h in ot h ioyl]-L-glu t a m -
ic Acid Dim eth yl Ester (4a ). 4a was prepared using procedure
B and purified by flash chromatography to give a colorless oil
(0.87 g, 2,7 mmol, 45% yield). 1H NMR (CDCl3) δ: 1.83 and 1.86
(d, J ) 15.3 Hz, 3H), 1.91-2.19 (m, 2H,), 2.39-2.48 (m, 2H),
2.66-2.77 (m, 2H), 3.39-3.56 (m, 1H), 3.68 and 3.69 (s, 3H),
3.75 and 3.76 (s, 3H), 4.21-4.24 (dm, 3H). 31P NMR (CDCl3) δ:
86.12, 86.30. Anal. Calcd for C11H19N2O5PS: C, 40.98; H, 5.90;
N, 8.69. Found: C, 40.81; H, 6.00, N, 8.65.
N-[2-Cya n oet h oxy(et h yl)p h osp h in ot h ioyl]-L-glu t a m ic
Acid Dim eth yl Ester (4b; P a th C). A solution of 3-hydrox-
ypropionitrile (0.21 g, 3 mmol) in THF (5 mL) was added via
syringe to a stirring solution of dichloroethylphosphine (0.43 g,
3.3 mmol) and triethylamine (0.5 mL, 3.3 mmol) in THF (15 mL)
at -40 °C. The resulting solution was stirred 0.5 h and then
allowed to warm to ambient temperature. A solution of L-
glutamic acid dimethyl ester (0.7 g, 3.9 mmol) and triethylamine
(1.0 mL, 6.6 mmol) in THF (5 mL) was added to the reaction
mixture, followed by the addition of sulfur (0.15 g, 4.8 mmol).
The solution was stirred overnight, filtered, concentrated in
vacuo, and purified by flash chromatography (hexane/ethyl
acetate/THF 60:40:1 v/v, Rf ) 0.23) to give 4b as a colorless oil
(0.33 g, 0.98 mmol, 33% yield). 1H NMR (CDCl3) δ: 1.62 and
Exp er im en ta l Section
Gen er a l Meth od s. All solvents used in reactions (benzene,
CH2Cl2, THF), 3-hydoxypropionitrile, diisopropylethylamine
(DEA), and triethylamine (TEA) were freshly distilled prior to
use. Sulfur was recrystallized from toluene. All other reagents
were used as supplied unless otherwise stated. Liquid (flash)14
chromatography was carried out using silica gel 60 (230-400
mesh). 1H, 13C, and 31P NMR spectra were recorded on a Bruker
DRX 300 MHz NMR spectrometer. 1H NMR chemical shifts are
relative to TMS (δ ) 0.00 ppm), CDCl3 (δ ) 7.24 ppm), or CD3-
OD (δ ) 4.87 and 3.31 ppm). 13C NMR chemical shifts are
relative to CD3OD (δ ) 49.15 ppm). 31P NMR chemical shifts
are relative to 85% H3PO4 (δ ) 0.00 ppm). Combustion analyses
were performed by Quantitative Technologies Inc., Whitehouse,
NJ . High-resolution mass spectra (FAB) were performed by the
(14) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

8700 J . Org. Chem., Vol. 64, No. 23, 1999
Sch em e 1. Syn th esis of N-P h osp h on a m id oth ion a te Der iva tives of Glu ta m ic Acid
Notes
1
1.24 (dt, J ) 7.6 Hz, 3H), 1.93-2.14 (dm, 4H,), 2.40-2.46 (m,
2H), 2.69-2.74 (m, 2H), 3.36-3.55 (dm, 1H), 3.69 and 3.70 (s,
3H), 3.76 and 3.77 (s, 3H), 4.05-4.30 (dm, 3H). 31P NMR (CDCl3)
δ: 93.47, 93.88. Anal. Calcd for C12H21N2O5PS: C, 42.81; H, 6.29;
N, 8.33. Found: C, 42.88; H, 6.17; N, 8.20.
Tr ilith iu m Sa lt (2a ). Yield: 0.12 g, 0.46 mmol, 93%. H NMR
(CD3OD) δ: 1.29 and 1.30 (d, J ) 14.1 Hz, 3H), 1.54-1.65 (m,
2H), 1.94-2.11 (m, 2H), 3.31-3.4 (m, 1H). 13C NMR (CD3OD)
δ: 25.34 (d, J ) 18.9 Hz), 26.60(d, J ) 20.7 Hz), 33.95, 35.60,
58.42, 58.55, 182.50 and 182.55(d, J ) 3.6 Hz), 183.35, 183.45.
31P NMR (CD3OD) δ: 62.63, 63.35. ESI-HRMS: calcd for C6H9-
Li2NO5PS (M - Li)- 252.0259, found 252.0259.
N-[2-Cya n oeth oxy(n -bu tyl)p h osp h in oth ioyl]-L-glu ta m -
ic Acid Dim eth yl Ester (4c). 4c was prepared using procedure
A and purified by flash chromatography (hexanes/ethyl acetate
5:2 v/v, Rf ) 0.23) to give a colorless oil (0.15 g, 0.42 mmol, 58%
yield). 1H NMR (CDCl3) δ: 0.93(t, J ) 7.2 Hz, 3H), 1.41 (dt, J )
7.2, 14.4 Hz, 2H), 1.58-1.62 (m, 2H), 1.91-2.00 (dm, 4H), 2.39-
2.45 (m, 2H), 2.66-2.72 (m, 2H), 3.47 (m, 1H), 3.68 and 3.69 (s,
3H), 3.75 and 3.76 (s, 3H), 4.18-4.27 (dm, 3H). 31P NMR (300
Hz, CDCl3) δ: 91.82, 92.22. Anal. Calcd for C14H25N2O5PS: C,
46.14; H, 6.87; N, 7.69. Found: C, 46.20; H, 6.96; N, 7.57.
N-[H yd r oxy(et h yl)p h osp h in ot h ioyl]-L-glu t a m ic Acid
1
Tr ilith iu m Sa lt (2b). Yield: 0.12 g, 0.43 mmol, 86%. H NMR
(D2O) δ: 0.99 and 1.06 (dt, J ) 7.6, 4.8 Hz, 3H), 1.69-1.83 (m,
4H), 2.15-2.21 (m, 2H), 3.48 and 3.62 (dt, J ) 6.4, 10.7 Hz, 1H).
13C NMR (D2O) δ: 8.94(d, J ) 5.1 Hz), 9.16(d, J ) 4.4 Hz), 30.33,
31.37, 31.58, 32.63, 33.57, 33.71 (d, J ) 6.0 Hz), 35.36, 35.49,
58.26, 58.36, 183.35, 183.40, 184.58, 184.62. 31P NMR (D2O) δ:
69.87, 71.42. FAB-HRMS: calcd for C7H11Li2NO5PS (M - Li)-
266.0416, found 266.0416.
N-[Hyd r oxy(n -bu tyl)p h osp h in oth ioyl]-L-glu ta m ic Acid
Tr ilith iu m Sa lt (2c). Yield: 0.14 g, 0.46 mmol, 93%. H NMR
N-[2-Cya n oet h oxy(p h en yl)p h osp h in ot h ioyl]-L-glu t a m -
ic Acid Dim eth yl Ester (4d ). 4d was prepared using proce-
dures A and B and purified by flash chromatography (hexanes/
ethyl acetate 2:1 v/v Rf ) 0.24) to give a colorless oil (0.12 g,
0.32 mmol, 44% yield from procedure A; 1.06 g, 2.76 mmol, 46%
yield from procedure B. 1H NMR (CDCl3) δ: 1.89-2.18 (dm, 2H,),
2.29-2.40 (m, 2H), 2.74-2.81 (m, 2H), 3.63 and 3.64 (s, 3H),
3.65 and 3.66 (s, 3H), 3.85-3.98 (m, 1H), 4.23-4.31 (dm, 2H),
7.46-7.54 (m, 3H), 7.85-7.90 (m, 2H). 31PNMR (CDCl3) δ: 78.22,
78.47. Anal. Calcd for C16H21N2O5PS: C, 49.99; H, 5.47; N, 7.29.
Found: C, 50.26; H, 5.51. N, 7.18.
1
(CD3OD) δ: 0.78 and 0.79 (t, J ) 7.3 Hz, 3H), 1.21-1.27 (m,
2H), 1.47-1.52 (m, 2H), 1.54-1.64 (m, 2H), 1.76-1.81 (m, 2H),
2.13-2.19 (m, 2H), 3.50-3.60 (m, 1H). 13C NMR (CD3OD) δ:
14.46, 25.21, 25.46, 27.87, 27.91, 34.13, 34.18, 35.57, 38.44 and
39.71(d, J ) 20.9 Hz), 58.33, 58.37, 182.44, 182.49, 183.36,
183.51. 31P NMR (CD3OD) δ: 68.30, 68.70. ESI-HRMS: calcd
for C9H15Li2NO5PS (M - Li)- 294.0729, found 294.0736.
N-[Hyd r oxy(p h en yl)p h osp h in oth ioyl]-L-glu ta m ic Acid
1
Tr ilith iu m Sa lt (2d ). Yield: 0.15 g, 0.47 mmol, 93%. H NMR
(CD3OD) δ: 1.49-1.61 (m, 2H), 1.78-2.15 (m, 2H), 3.18-3.26
(m, 1H), 6.93-6.98 (m, 3H), 7.50-7.57 (m, 2H). 13C NMR (CD3-
OD) δ: 33.70 and 34.17(d, J ) 5.9 Hz), 35.32, 35.53, 128.49,
128.54, 128.67, 128.72, 128.96, 130.21, 130.38, 131.12, 131.78,
131.92, 132.06, 181.57, 181.65, 183.37, 183.69. 31P NMR (CD3-
OD) δ: 55.58, 56.54. ESI-HRMS: calcd for C11H11Li2NO5PS (M
- Li)- 314.0416, found 314.0415.
Gen er a l P r oced u r e for P h osp h on a m id oth ioic Acid s 2.
Phosphonamidothionate ester 4 (0.5 mmol) was dissolved in
methanol (2 mL) to which was added aqueous lithium hydroxide
(2 mL, 1.0 M). The resulting solution was stirred at room
temperature for 18 h and then filtered. The solvent was
evaporated in vacuo to give 2 as a white residue. The residue
was resuspended in anhydrous methanol, filtered (0.2 µm Teflon
membrane), and concentrated in vacuo to give the trilithium salt
of the desired product 2 as a white solid.
Ack n ow led gm en t . This investigation was sup-
ported in part through a grant from the National
Institutes of Health, MBRS SCORE Program-NIGMS
N-[Hyd r oxy(m eth yl)p h osp h in oth ioyl]-L-glu ta m ic Acid

Notes
J . Org. Chem., Vol. 64, No. 23, 1999 8701
(Grant No. S06 GM52588-04), and a “Research Infra-
structure in Minority Institutions” award from the
National Center for Research Resources with funding
from the Office of Research on Minority Health, Na-
tional Institutes of Health (Grant No. RR11805-02). The
authors would also like to extend their gratitude to the
Department of Defense Science Scholars Program for
support to A. Dastgah (Grant No. 6-93472).
Su p p or t in g In for m a t ion Ava ila b le: NMR spectra of
2a -d and 3c,d . This material is available free of charge via
the Internet at http://pubs.acs.org.
J O991090X