A tandem Michael addition ring-closure route to the metabotropic receptor ligand α-(hydroxymethyl)glutamic acid and its γ-alkylated derivatives

Full text of DOI:10.1021/jo010626n

J . Org. Chem. 2001, 66, 7555-7559
7555
Sch em e 1a
A Ta n d em Mich a el Ad d ition Rin g-Closu r e
Rou te to th e Meta botr op ic Recep tor
Liga n d r-(Hyd r oxym eth yl)glu ta m ic Acid
a n d Its γ-Alk yla ted Der iva tives
J iazhong Zhang,† J udith L. Flippen-Anderson,‡ and
Alan P. Kozikowski*,†
a
Conditions: (a) (i) LDA, THF, -78 °C, 1 h, (ii) ethyl acrylate,
Georgetown University Medical Center,
Drug Discovery Program, 3970 Reservoir Road NW,
Washington, D.C. 20007-2197, and Laboratory for the
Structure of Matter, Code 6030, Naval Research Laboratory,
4555 Overlook Avenue SW, Washington, D.C. 20375-5000
-78 °C, 12 h, 41%; (b) Dess-Martin reagent, CH2Cl2, room
temperature, or PDC, CH2Cl2, room temperature.
Sch em e 2a
kozikowa@georgetown.edu
Received J une 18, 2001
In tr od u ction
L-Glutamate is one of the most abundant excitatory
amino acid neurotransmitters found in the mammalian
brain. This amino acid acts on diverse glutamate recep-
tors, including members of both the ionotropic and the
metabotropic glutamate receptor (mGluR) families.1,2
Because of the possibility of identifying ligands that may
prove useful in disease intervention, considerable atten-
tion has been given to the discovery of both selective
agonists and antagonists of these glutamate receptors
over the past decade.3 As part of our ongoing efforts to
discover subtype-selective mGluR agonists and antago-
nists, we have found that a 2-substituted L-glutamate
analogue, namely, (2S)-R-(hydroxymethyl)glutamate (1,
HMG), is able to act as a relatively potent agonist of the
group 2 receptor mGluR3 while functioning as a weak
antagonist of mGluR2. This compound has, in contrast,
little or no effect on the Group 1 and Group 3 mGluRs.4
Since our first synthetic approach to HMG required 10
synthetic steps, we sought a more practical route to this
molecule, and in particular, a route that could produce
not only the parent structure but its γ-substituted
analogues as well. Herein, we describe a general ap-
proach to such molecules that starts from D-serine.
a
Conditions: (a) (i) LDA, THF, -78 °C, 1 h, (ii) ethyl acrylate,
-78 °C, 12 h, 10%; (b) 6 N HCl, reflux, overnight, 90%.
Sch em e 3a
a
Conditions: (a) (i) LDA, THF, -78 °C, 1 h, (ii) ethyl acrylate,
-78 °C, 12 h, 62%; (b) 6 N HCl, reflux, overnight, 90%.
bring about this oxidation with either PDC or the Dess-
Martin reagent resulted only in formation of the elimina-
tion product 4.
Upon replacement of the N-formyl group of 2 with the
larger, less electrophilic Boc protecting group, the Michael
addition reaction of carbamate 56 with ethyl acrylate was
found to take place, albeit in a very low yield (15% yield
based on 67% conversion). The intermediate 6 was then
hydrolyzed with 6 N HCl to afford the required HMG
(Scheme 2).
Upon consideration of the somewhat disappointing
results stemming from the use of the N-formyl and N-Boc
derivatives, it appeared reasonable to attempt the same
reaction using a methoxycarbonyl group for nitrogen
protection. We believed that the smaller protecting group
might allow the ring closure to the lactam to ensue, thus
providing a means to drive the reaction to completion.
The lactam intermediate might in turn allow for the
stereocontrolled introduction of additional substituents
through further carbanion-based alkylation chemistry.
In the event, the carbamate 77 was converted to its
enolate anion by the use of LDA and the anion reacted
in turn with ethyl acrylate (Scheme 3). The desired
Michael addition ring closure was indeed found to take
place smoothly to provide the bicycle 8 as a single isomer
in 62% yield after recrystallization. The configurations
of the newly formed chiral centers were assigned as
shown on the basis of an X-ray analysis. Adduct 8 was
Resu lts a n d Discu ssion
In our initial efforts to discover an expedient route to
HMG, we first examined a simple Michael addition
reaction of the serine-derived oxazolidine 25 with ethyl
acrylate (Scheme 1). The major product of the reaction
was found to be the bicycle 3, which was formed in 27%
yield, together with the unsaturated ester 4 in 14% yield.
We sought to oxidize intermediate 3 to the corresponding
lactam in order to subsequently effect hydrolysis and
decarboxylation to afford HMG. However, attempts to
† Georgetown University Medical Center.
‡ Naval Research Laboratory.
(1) Bra¨uner-Osborne, H.; Egebjerg, J .; Nielsen, E.; Madsen, U.;
Krogsgaard-Larsen, P. J . Med. Chem. 2000, 43, 2609.
(2) Nakanishi, S. Science 1992, 258, 597. Blasi, A. D.; Conn, P. J .;
Pin, J . P.; Nicoletti, F. Trends Pharmacol. Sci. 2001, 22, 114.
(3) Mukhopadhyaya, J . K.; Kozikowski, A. P.; Grajkowska, W.;
Pshenichkin, S.; Wroblewski, J . T. Bioorg. Med. Chem. Lett. In press.
Kozikowski, A. P.; Steensma, D.; Araldi, G. L.; Pshenichkin, S.; Surina,
S.; Wroblewski, J . T. J . Med. Chem. 1998, 41, 1641.
(4) Kozikowski, A. P.; Zhang, J .; Wroblewski, J . T. Manuscript in
preparation.
(6) Cagnon, J .; Bideau, F.; Marchand-Brynaert, J .; Ghosez, L.
Tetrahedron Lett. 1997, 38, 2291.
(5) Seebach, D.; Aebi, J . D.; Gander-Coquoz, M.; Naef, R. Helv. Chim.
Acta 1987, 70, 1194.
(7) Wuensch, B.; Hoefner, G.; Bauschke, G. Arch. Pharm. 1993, 326,
101.
10.1021/jo010626n CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/05/2001

7556 J . Org. Chem., Vol. 66, No. 22, 2001
Notes
Sch em e 4a
F igu r e 2. Crystal structure of 14d .
Sch em e 5a
a
Conditions: (a) NaH, DMF, MeI or BnBr, room temperature,
overnight; (b) H2, Pd(OH)2/C, t-BuOH, room temperature, over-
night; (c) 220 °C, 5 min; (d) 6 N HCl, reflux, 2 h.
a
Conditions: (a) H2, Pd(OH)2/C, t-BuOH, room temperature,
overnight; (b) 220 °C, 5 min; (c) (i) LDA, THF, -78 °C, 1 h, (ii)
RX, -78 °C, 4 h; (d) 6 N HCl, reflux, 2 h.
HCl under reflux conditions gave the desired 4-alkylated
HMG analogues 15a and 15d . The purity of these
compounds was confirmed by their H NMR spectra.
F igu r e 1. Crystal structure of 13.
1
For the pharmacological studies, we were also inter-
ested in obtaining the 4R-isomers of 15a and 15d in order
to ascertain the contribution of this stereocenter to
mGluR subtype selectivity and potency. To accomplish
this, we chose to explore the alkylation chemistry of
bicycle 17, which was obtained from 9 by hydrogenation
and decarboxylation (Scheme 5). Interestingly, when the
methylation reaction of 17 was carried out using methyl
trifluoromethanesulfonate as the electrophile, only a
single product 14a was obtained. On the other hand,
when either methyl iodide or benzyl bromide was em-
ployed as the electrophile, mixtures of mono- and disub-
stituted products resulted. In the case of methyl iodide,
the ratio of 14a :14b:14c was 32:32:21, while 14d , 14e,
and 14f were formed in a ratio of 57:22:8 in the case of
benzyl bromide. When the larger electrophilic reagent,
4,4-diphenyl-1-bromobutane,10 was used (THF as the
solvent and HMPA as the chelating agent),11 14g was
obtained in 32% yield, together with a small amount of
14h and 14i (both less than 1% yield). The structures of
compounds 14g and 14h were assigned on the basis of
in turn directly hydrolyzed to the final product HMG in
a high yield.
After successfully obtaining the desired parent mol-
ecule, HMG, we examined the possibility of using the
bicycle 8 in the preparation of γ-substituted analogues
of HMG. This was of interest to us as several γ-substi-
tuted glutamate analogues have been shown to exhibit
selective mGluR2 antagonist activity.8 After some ex-
perimentation, we found that the best way to carry out
this chemistry was to use benzyl acrylate in the tandem
reaction to generate the bicycle 9 in 63% yield (Scheme
4). Next, crude 9 was used directly without further
purification in an alkylation reaction with either io-
domethane or benzyl bromide. In both cases, single
isomeric products, 10 and 11, respectively, were gener-
ated. Hydrogenation of the benzyl esters 10 and 11
afforded the crystalline acids 12 and 13, respectively, the
structures of which were established by X-ray analysis.
As is apparent from Figure 1, the crystal structure
analysis of compound 13 shows that the alkyl substituent
has been introduced cis to the methoxycarbonyl group.
Next, decarboxylation was brought about by heating the
intermediates 12 and 13 at 220 °C for several minutes9
to afford 14a and 14d , respectively, as single isomers.
Decarboxylation occurred with maintenance of the sub-
stituent on the convex face of the bicycle as revealed by
X-ray analysis (Figure 2). Finally, hydrolysis with 6 N
1
their H NMR spectra. As can be seen from Table 1, the
proton in the R-position relative to the lactam carbonyl
group (6-H) resonates at lower field when it is situated
on the convex face of the bicycle. This is observed for 14b
and 14e in comparison to 14a and 14d , respectively. As
the stereochemistry of these compounds has been firmly
established by X-ray analysis, we thus conclude that the
(8) Escribano, A.; Ezquerra, J .; Pedregal, C.; Rubio, A.; Yruretagoy-
ena, B.; Baker, S. R.; Wright, R. A.; J ohnson, B. G.; Schoepp, D. D.
Bioorg. Med. Chem. Lett. 1998, 8, 765.
(9) Elsinger, F.; Dauben, W.; Wipke, W. Organic Syntheses; Wiley:
New York, 1973; Collect. Vol. V, 1973, p 76.
(10) N’Goka, V.; Schlewer, G.; Linget, J . M.; Chambon, J . P.;
Wermuth, C. G. J . Med. Chem. 1991, 34, 2547.
(11) Ezquerra, J .; Pedregal, C.; Rubio, A.; Yruretagoyena, B.;
Escribano, A.; Sanchez-Ferrando, F. Tetrahedron 1993, 49, 8665.

Notes
J . Org. Chem., Vol. 66, No. 22, 2001 7557
Ta ble 1. 1H Ch em ica l Sh ifts of 6-H of th e
6-Mon oa lk yla ted Bicycles
min, ethyl acrylate (280 mg, 2.80 mmol) in THF (2.5 mL) was
added, and stirring was continued for 9 h at -78 °C. The reaction
mixture was poured into NH4Cl solution and extracted with
EtOAc three times. The organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated. Purification by
flash column chromatography (SiO2, 1:15 EtOAc/hexane) af-
forded 5 (178 mg, 33% recovery) and product 6 (75 mg, 15%
based on 67% conversion) as a colorless oil: [R]D -50.0° (c 0.5,
CHCl3); IR (film) 2961, 1740, 1711 cm-1; 1H NMR δ 5.13 (s, 1H),
4.26 (d, 1H, J ) 8.7 Hz), 4.13 (q, 2H, J ) 6.9 Hz), 4.02 (d, 1H,
J ) 8.7 Hz), 3.76 (s, 3H), 2.73 (br, 1H), 2.49 (m, 1H), 2.31 (m,
1H), 2.16 (m, 1H), 1.45 (s, 9H), 1.25 (t, 3H, J ) 6.9 Hz), 1.00 (s,
9H); 13C NMR δ 172.76, 171.98, 153.15, 98.12, 81.08, 75.72,
68.10, 60.49, 52.45, 39.49, 30.06, 28.66, 28.01, 26.41, 14.13; MS
m/z (%) 330 (6), 230 (100), 184 (46), 57 (95).
compd
R1
R2
δ(6-H)
14a
14b
14c
14d
14e
14f
14g
14h
14i
Me
H
Me
Bn
H
H
2.75
3.33
Me
Me
H
Bn
Bn
H
3.00
3.51
Bn
Ph2CH(CH2)3
H
Ph2CH(CH2)3
2.58
3.08
Ph2CH(CH2)3
Ph2CH(CH2)3
alkylation reaction using 4,4-diphenyl-1-bromobutane as
the electrophile occurs predominantly on the convex face
of the bicycle. The final HMG analogues were obtained
from the bicyclic precursors by hydrolysis with 6 N HCl
under reflux conditions followed by purification on a C18
column.
In conclusion, we have developed a straightforward
method to synthesize HMG and its γ-substituted ana-
logues starting from D-serine. The method is based on a
tandem Michael addition ring-closure protocol followed
by a stereoselective alkylation reaction that takes place
from the convex face of the bicycle. The biological
evaluation of these novel amino acids as mGluR ligands
will be reported separately.
(3S,7a R)-3-ter t-Bu tyl-1,6,7,7a -tetr a h yd r o-5-oxop yr r olo-
[1,2-c]oxa zole-6,7a -d ica r boxylic Acid 6-Eth yl Ester 7a -
Meth yl Ester (8). To a solution of compound 7 (3.90 g, 15.9
mmol) in 60 mL of THF stirred at -78 °C under nitrogen was
added a 0.61 M solution of lithium diisopropylamide in THF
(31.0 mL, 18.9 mmol, 1.2 equiv). After the reaction mixture had
been stirred at -78 °C for 30 min, ethyl acrylate (2.0 g, 20.0
mmol) in THF (10 mL) was added, and stirring was continued
for 12 h at -78 °C. The reaction mixture was poured into NH4-
Cl solution and extracted with EtOAc three times. The organic
layers were washed with brine, dried over Na2SO4, filtered, and
concentrated. Purification by flash column chromatography
(SiO2, 1:10 EtOAc/hexane) afforded starting material 7 (1.10 g,
28% recovery) and product 8 (2.92 g, 86% based on 72%
conversion). Compound 8: mp 105-107 °C (from acetone/
hexane); [R]D -15.2° (c 1.2, MeOH); IR (KBr) 2977, 1732, 1720
cm-1 1H NMR δ 4.86 (s, 1H), 4.82 (d, 1H, J ) 8.7 Hz), 4.29-
;
Exp er im en ta l Section
4.15 (m, 3H), 3.77 (s, 3H), 3.54 (d, 1H, J ) 8.7 Hz), 2.64 (m,
1H), 2.44 (dd, 1H, J ) 9.0, 13.2 Hz), 1.30 (t, 3H, J ) 7.2 Hz),
0.85 (s, 9H); 13C NMR δ 172.94, 172.17, 168.49, 96.59, 73.84,
70.04, 61.94, 52.88, 51.90, 35.78, 33.16, 24.71, 14.15; MS m/z
(%) 298 (2), 256 (91), 210 (100). Anal. Calcd for C15H23NO6: C,
57.50; H, 7.40; N, 4.47. Found: C, 57.37; H, 7.67; N, 4.41.
(3S,6R,7a R)-3-ter t-Bu tyl-1,6,7,7a -tetr a h yd r o-6-m eth yl-5-
oxop yr r olo[1,2-c]oxa zole-6,7a -d ica r boxylic Acid 6-Ben zyl
Ester 7a -Meth yl Ester (10). To a solution of compound 7 (3.60
g, 14.7 mmol) in THF (40 mL) stirred at -78 °C under nitrogen
was added a solution of LDA in THF (1.5 M, 12.0 mL, 18.0
mmol). After the reaction mixture had been stirred at -78 °C
for 30 min, benzyl acrylate (2.88 g, 17.8 mmol) in THF (10 mL)
was added, and stirring was continued for 12 h at -78 °C. The
reaction mixture was poured into NH4Cl solution and extracted
with EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4, filtered, and concentrated to afford
an inseparable mixture of 7 and 9 (4.80 g).
Gen er a l Meth od s. THF was freshly distilled under N2 from
1
sodium benzophenone. H and 13C NMR spectra were acquired
at a proton frequency of 300 MHz, using CDCl3 as the solvent
unless noted otherwise. 1H chemical shifts (parts per million,
ppm) were obtained using CHCl3 (δ ) 7.26, for CDCl3 as the
solvent) or HDO (δ ) 4.80, for D2O as the solvent) as the internal
standard. 13C chemical shifts (ppm) were determined with CHCl3
(central peak δ ) 77.00, for CDCl3 as the solvent) or MeOH (δ
) 49.15, for D2O as the solvent) as the internal standard. Melting
points were determined in Pyrex capillaries with a Thomas-
Hoover Unimelt apparatus and are uncorrected. Mass spectra
were measured in the EI mode at an ionization potential of 70
eV. X-ray data were collected on a computer-controlled Bruker
P4 automatic four-circle diffractometer. The structures were
solved by direct methods and refined, using all independent data,
with full matrix least-squares on F2 values using the SHELXTL
program package. TLC was performed on Merck silica gel 60F254
glass plates. Optical rotations were measured at room temper-
ature.
(3S,7a R)-3-ter t-Bu tyl-7,7a -d ih yd r o-1H-p yr r olo[1,2-c]ox-
a zole-6,7a -d ica r boxylic Acid 6-Eth yl Ester 7a -Meth yl Ester
(4). To a solution of 2 (350 mg, 1.63 mmol) in THF (6.0 mL)
stirred at -78 °C under nitrogen was added a solution of lithium
diisopropylamide in THF (0.51 M, 3.4 mL, 1.7 mmol). After the
reaction mixture had been stirred at -78 °C for 30 min, ethyl
acrylate (188 mg, 1.88 mmol) in THF (2.6 mL) was added, and
stirring was continued for 1 h at -78 °C. The reaction mixture
was poured into NH4Cl solution and extracted with EtOAc three
times. The organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated. Purification by flash column
chromatography (SiO2, 1:15 EtOAc/hexane) afforded unreacted
compound 2 (113 mg, 32% recovery) and products 3 (135 mg,
39% based on 68% conversion) and 4 (70 mg, 21% based on 68%
conversion) as colorless oils. Compound 4: 1H NMR δ 6.82 (s,
1H), 4.70 (d, 1H, J ) 8.7 Hz), 4.18-4.11 (m, 3H), 3.74 (s, 3H),
3.39 (d, 1H, J ) 8.7 Hz), 2.84 (br, 2H), 1.25 (t, 3H, J ) 6.9 Hz),
0.87 (s, 9H); 13C NMR δ 172.74, 164.76, 149.77, 110.53, 101.88,
75.41, 71.33, 59.88, 52.59, 34.85, 24.19, 14.38.
To a solution of this mixture (95 mg) in DMF (5 mL) was
added NaH (60% in oil, 15 mg, 0.38 mmol) under nitrogen.
Methyl iodide (40 µL, 0.64 mmol) was added 5 min later. The
mixture was stirred overnight, poured into saturated NH4Cl
solution, and extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, filtered, and
concentrated. The crude product was purified by column chro-
matography (SiO2, 1:20 EtOAc/hexane) to afford compound 10
as a colorless oil: [R]D -6.0° (c 0.5, CHCl3); IR (film) 2987, 1745,
1
1718 cm-1; H NMR δ 7.38-7.28 (m, 5H), 5.23 (d, 1H, J ) 9.0
Hz), 5.13 (d, 1H, J ) 9.0 Hz), 4.84 (s, 1H), 4.76 (d, 1H, J ) 8.7
Hz), 3.78 (s, 3H), 3.47 (d, 1H, J ) 8.7 Hz), 2.78 (d, 1H, J ) 14.1
Hz), 2.12 (d, 1H, J ) 14.1 Hz), 1.70 (s, 3H), 0.89 (s, 9H); 13C
NMR δ 178.97, 172.71, 171.36, 135.23, 128.64, 128.43, 128.42,
128.02, 98.21, 73.35, 69.79, 67.65, 56.22, 52.86, 38.73, 35.31,
24.82, 21.90; MS m/z (%) 332 (86), 91 (100), 43 (16).
(3S,6R,7a R)-6-Ben zyl-3-ter t-bu tyl-1,6,7,7a -tetr a h yd r o-5-
oxop yr r olo[1,2-c]oxa zole-6,7a -d ica r boxylic Acid 6-Ben zyl
Ester 7a -Meth yl Ester (11). To a solution of crude compound
9 (480 mg) in DMF (10 mL) was added NaH (60% in oil, 60 mg,
1.5 mmol) under nitrogen. Benzyl bromide (0.20 mL, 1.7 mmol)
was added 5 min later. The mixture was stirred overnight,
poured into saturated NH4Cl solution, and extracted with
EtOAc. After evaporation, the crude oil was purified by column
chromatography (SiO2, 20:1 hexane/EtOAc) to afford compound
11 (300 mg) as a colorless oil: [R]D -7.4° (c 2.0, CHCl3); IR (film)
(2S,4R)-2-ter t-Bu tyl-4-[2-(eth oxyca r bon yl)eth yl]oxa zoli-
d in e-3,4-d ica r boxylic Acid 3-ter t-Bu tyl Ester 4-Meth yl
Ester (6). To a solution of 5 (550 mg, 1.91 mmol) in THF (10
mL) stirred at -78 °C under nitrogen was added a solution of
lithium diisopropylamide in THF (0.53 M, 4.0 mL, 2.1 mmol).
After the reaction mixture had been stirred at -78 °C for 30
1
2956, 1742, 1724 cm-1; H NMR δ 7.40-7.10 (m, 10H), 5.23 (s,

7558 J . Org. Chem., Vol. 66, No. 22, 2001
Notes
2H), 4.81 (s, 1H), 4.68 (d, 1H, J ) 8.4 Hz), 3.56 (s, 3H), 3.52-
3.41 (m, 3H), 2.68 (d, 1H, J ) 8.4 Hz), 2.27 (d, 1H, J ) 8.4 Hz),
0.88 (s, 9H); 13C NMR δ 177.91, 172.59, 170.39, 135.99, 134.96,
130.24, 128.67, 128.56, 128.40, 127.01, 98.63, 73.08, 69.64, 68.03,
61.19, 52.78, 39.53, 35.27, 33.18, 24.91; MS m/z (%) 450 (0.5),
408 (58), 91 (100).
(14b): [R]D -27.1° (c 0.76, CHCl3); IR (film) 2961, 1743, 1718
1
cm-1; H NMR δ 4.87 (s, 1H), 4.82 (d, 1H, J ) 8.7 Hz), 3.78 (s,
3H), 3.40 (d, 1H, J ) 8.7 Hz), 3.33 (m, 1H), 2.54 (dd, 1H, J )
8.7, 13.2 Hz), 1.78 (dd, 1H, J ) 8.7, 13.2 Hz), 1.18 (d, 3H, J )
6.9 Hz), 0.88 (s, 9H); 13C NMR δ 180.01, 172.78, 96.19, 74.71,
69.61, 52.64, 39.85, 39.46, 35.81, 24.75, 14.92; MS m/z (%) 256
(0.3), 198 (100), 138 (40). Anal. Calcd for C13H21NO4: C, 61.16;
H, 8.29; N, 5.49. Found: C, 60.96; H, 8.45; N, 5.27.
(3S,6R,7a R)-3-ter t-Bu tyl-1,6,7,7a -tetr a h yd r o-6-m eth yl-5-
oxop yr r olo[1,2-c]oxa zole-6,7a -d ica r boxylic Acid 7a -Meth yl
Ester (12). To a solution of compound 10 (110 mg, 0.33 mmol)
in tert-butyl alcohol (10 mL) was added 20% Pd(OH)2/C (50 mg),
and the mixture was hydrogenated at 1 bar and room temper-
ature overnight. Filtration from the catalyst and concentration
afforded the product 12: mp >132 °C dec (from EtOAc/hexane);
[R]D -47.4° (c 0.14, CHCl3); IR (KBr) 3118, 2938, 1748, 1716
cm-1; 1H NMR δ 10.0 (br, 1H), 4.85 (s, 1H), 4.82 (d, 1H, J ) 8.7
Hz), 3.82 (s, 3H), 3.49 (d, 1H, J ) 8.7 Hz), 2.81 (d, 1H, J ) 14.4
Hz), 2.25 (d, 1H, J ) 14.4 Hz), 1.76 (s, 3H), 0.90 (s, 9H); 13C
NMR δ 180.10, 174.45, 172.17, 97.88, 73.90, 69.42, 55.33, 53.03,
38.30, 35.33, 24.81, 23.69; MS m/z (%) 255 (0.1), 198 (4), 83 (100).
(3S,6R,7a R)-6-Ben zyl-3-ter t-bu tyl-1,6,7,7a -tetr a h yd r o-5-
oxop yr r olo[1,2-c]oxa zole-6,7a -d ica r boxylic Acid 7a -Meth yl
Ester (13). Compound 11 (250 mg, 0.54 mmol) was dissolved
in tert-butyl alcohol (10 mL); then, 20% Pd(OH)2/C (90 mg) was
added, and the mixture was hydrogenated at 1 bar and room
temperature overnight. The catalyst was filtered off, and the
solvent was removed under vacuum to give product 13 (200 mg,
100%): mp >133 °C dec (from hexane/EtOAc); [R]D +9.1° (c 0.4,
CHCl3); IR (KBr) 3141, 2973, 1736, 1718 cm-1; 1H NMR δ 7.33-
7.14 (m, 5H), 6.5 (br, 1H), 4.84 (s, 1H), 4.80 (d, 1H, J ) 8.7 Hz),
3.77 (s, 3H), 3.54-3.38 (m, 3H), 2.67 (d, 1H, J ) 14.7 Hz), 2.43
(d, 1H, J ) 14.7 Hz), 0.93 (s, 9H); 13C NMR δ 179.77, 172.03,
171.80, 134.52, 130.02, 128.50, 127.70, 97.94, 74.25, 69.22, 60.24,
53.09, 42.94, 35.34, 35.15, 24.93; MS m/z (%) 331 (0.3), 274 (36),
58 (72), 43 (100). Anal. Calcd for C20H25NO6: C, 63.99; H, 6.71;
N, 3.73. Found: C, 64.33; H, 6.47; N, 3.57.
(3S,7a R)-3-ter t-Bu tyl-1,6,7,7a -tetr a h yd r o-5-oxop yr r olo-
[1,2-c]oxa zole-7a -ca r boxylic Acid Meth yl Ester (17). To a
solution of crude compound 9 (1.35 g) in tert-butyl alcohol (15
mL) was added 20% Pd(OH)2/C (0.45 g), and the mixture was
hydrogenated at 1 bar and room temperature for 1 h. Filtration
from the catalyst and concentration afforded the crude acid 16,
which was heated to 220 °C for 5 min. The crude product was
purified by column chromatography (SiO2, 10:1 hexane/EtOAc)
to afford the bicycle 17 (650 mg, 75% over two steps): mp 82-
83 °C (from EtOAc/hexane); [R]D -50.2° (c 2.0, CHCl3); IR (KBr)
2965, 1741, 1708 cm-1; 1H NMR δ 4.87 (s, 1H), 4.81 (d, 1H, J )
8.4 Hz), 3.79 (s, 3H), 3.44 (d, 1H, J ) 8.4 Hz), 3.10 (m, 1H), 2.52
(m, 1H), 2.32 (m, 1H), 2.16 (m, 1H), 0.88 (s, 9H); 13C NMR δ
178.42, 172.77, 96.43, 73.97, 72.01, 52.65, 35.72, 34.40, 29.68,
24.74; MS m/z (%) 226 (0.3), 184 (22), 58 (30), 43 (100). Anal.
Calcd for C13H21NO4: C, 59.73; H, 7.94; N, 5.81. Found: C, 59.62;
H, 7.84; N, 5.61.
Rep r esen ta tive P r oced u r e for th e Alk yla tion of Bicycle
17. To a solution of compound 17 (146 mg, 0.61 mmol) in THF
(7 mL), which was stirred at -78 °C, was added a solution of
LDA in THF (1.0 M, 0.8 mL, 0.8 mmol). After the reaction
mixture had been stirred at -78 °C for 1 h, iodomethane (45
µL, 0.73 mmol) was added, and stirring was continued for 3 h.
The reaction was quenched with saturated NH4Cl solution (20
mL) at -78 °C, and the mixture was extracted with 3 × 20 mL
of diethyl ether. The combined organic phases were dried over
Na2SO4, filtered, and concentrated. Column chromatogaphy
(SiO2, 10:1 hexane/EtOAc) afforded the products 14a (50 mg,
32%), 14b (50 mg, 32%), and 14c (35 mg, 22%).
(3S,6S,7a R)-3-ter t-Bu tyl-1,6,7,7a -tetr a h yd r o-6-m eth yl-5-
oxop yr r olo[1,2-c]oxa zole-7a -ca r boxylic Acid Meth yl Ester
(14a ): mp 107-108 °C (from EtOAc/hexane); [R]D -58.3° (c 0.42,
CHCl3); IR (KBr) 2956, 1738, 1707 cm-1; 1H NMR δ 4.81 (s, 1H),
4.79 (d, 1H, J ) 9.0 Hz), 3.78 (s, 3H), 3.31 (d, 1H, J ) 9.0 Hz),
2.75 (m, 1H), 2.39 (dd, 1H, J ) 10.8, 13.8 Hz), 1.95 (dd, 1H, J )
10.8, 13.8 Hz), 1.43 (d, 3H, J ) 7.8 Hz), 0.89 (s, 9H); 13C NMR
δ 183.32, 173.20, 97.70, 73.52, 70.85, 52.62, 40.19, 35.27, 34.61,
24.82, 18.41; MS m/z (%) 240 (0.6), 198 (40), 58 (72), 43 (100).
Anal. Calcd for C13H21NO4: C, 61.16; H, 8.29; N, 5.49. Found:
C, 61.11; H, 8.31; N, 5.31.
(3S,7a R)-3-ter t-Bu tyl-1,6,7,7a -tetr a h yd r o-6,6-d im eth yl-5-
oxop yr r olo[1,2-c]oxa zole-7a -ca r boxylic Acid Meth yl Ester
(14c): [R]D -28.5° (c 0.80, CHCl3); IR (film) 2965, 1744, 1718
1
cm-1; H NMR δ 4.84 (s, 1H), 4.81 (d, 1H, J ) 8.7 Hz), 3.78 (s,
3H), 3.28 (d, 1H, J ) 8.7 Hz), 2.20 (d, 1H, J ) 14.1 Hz), 2.05 (d,
1H, J ) 14.1 Hz), 1.42 (s, 3H), 1.20 (s, 3H), 0.90 (s, 9H); 13C
NMR δ 184.62, 173.23, 97.52, 75.20, 68.67, 52.60, 44.98, 43.08,
35.34, 27.09, 26.59, 24.90; MS m/z (%) 270 (0.1), 212 (34), 58
(79), 43 (100).
Com p ou n d s 14d-f. Compounds 14d -f were obtained analo-
gously in yields of 57%, 22%, and 8%, respectively. Compound
14d can also be prepared in 91% yield by heating acid 13 to 220
°C under nitrogen for 5 min.
(3S,6S,7a R)-6-Ben zyl-3-ter t-bu tyl-1,6,7,7a -tetr a h yd r o-5-
oxop yr r olo[1,2-c]oxa zole-7a -ca r boxylic Acid Meth yl Ester
(14d ): mp 130-131 °C (from EtOAc/hexane); [R]D +32.9° (c 0.90,
1
CHCl3); IR (KBr) 2977, 1736, 1706 cm-1; H NMR δ 7.39-7.18
(m, 5H), 4.88 (s, 1H), 4.78 (d, 1H, J ) 8.7 Hz), 3.80 (s, 3H), 3.32
(d, 1H, J ) 8.7 Hz), 3.30 (br, 1H), 3.11-2.97 (m, 2H), 2.20-2.02
(m, 2H), 0.94 (s, 9H); 13C NMR δ 181.68, 172.97, 138.69, 128.79,
128.53, 128.36, 126.49, 97.61, 73.53, 70.73, 52.59, 47.13, 37.97,
35.25, 31.31, 24.81; MS m/z (%) 331 (0.1), 316 (1), 274 (48), 43
(100). Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23.
Found: C, 68.55; H, 7.23; N, 4.00.
(3S,6R,7a R)-6-Ben zyl-3-ter t-bu tyl-1,6,7,7a -tetr a h yd r o-5-
oxop yr r olo[1,2-c]oxa zole-7a -ca r boxylic Acid Meth yl Ester
(14e): [R]D -28.8° (c 0.16, CHCl3); IR (film) 2957, 1740, 1705
cm-1; 1H NMR δ 7.32-7.15 (m, 5H), 4.88 (s, 1H), 4.76 (d, 1H, J
) 8.7 Hz), 3.73 (s, 3H), 3.51 (m, 1H), 3.29-3.23 (m, 2H), 2.63
(m, 1H), 2.32 (m, 1H), 1.85 (t, 1H, J ) 12.6 Hz), 0.89 (s, 9H); 13
C
NMR δ 178.67, 172.55, 138.78, 128.87, 128.57, 126.47, 96.29,
74.53, 69.64, 52.65, 46.70, 36.76, 36.25, 35.79, 24.76; MS m/z
(%) 331 (0.4), 274 (100), 91 (29), 43 (32). Anal. Calcd for C19H25
-
NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.51; H, 7.21; N,
3.90.
(3S,7a R)-6,6-Diben zyl-3-ter t-bu tyl-1,6,7,7a -tetr a h yd r o-5-
oxop yr r olo[1,2-c]oxa zole-7a -ca r boxylic Acid Meth yl Ester
(14f): [R]D -5.4° (c 0.28, CHCl3); IR (film) 3028, 2957, 1742, 1712,
1732, 1720 cm-1 1H NMR δ 7.36-7.09 (m, 10H), 4.60 (s, 1H),
;
4.24 (d, 1H, J ) 8.4 Hz), 3.59 (s, 3H), 3.35 (d, 1H, J ) 13.5 Hz),
3.30 (d, 1H, J ) 13.2 Hz), 3.01 (d, 1H, J ) 13.2 Hz), 2.48 (d, 1H,
J ) 13.5 Hz), 2.18 (d, 1H, J ) 14.1 Hz), 2.05 (d, 1H, J ) 14.1
Hz), 1.68 (d, 1H, J ) 8.4 Hz), 0.85 (s, 9H); 13C NMR δ 183.04,
173.34, 137.30, 136.74, 130.86, 130.81, 128.52, 128.25, 127.17,
126.89, 97.31, 72.27, 68.60, 55.43, 52.63, 45.05, 42.13, 35.22,
32.02, 24.93; MS m/z (%) 406 (1), 364 (100), 91 (54), 43 (49).
P r ep a r a tion of Com p ou n d s 14g-i. To a solution of bicycle
17 (260 mg, 1.08 mmol) in THF (7.0 mL) under nitrogen were
successively added solutions of LDA (1.5 M, 1.0 mL) and HMPA
(1.0 mL) at -78 °C. After 1 h, 4-bromo-1,1-diphenylbutane (360
mg, 1.25 mmol) in THF (3.0 mL) was added. After 6 h at -78
°C, the reaction was quenched with saturated NH4Cl solution.
The product was extracted into EtOAc, and the combined organic
layers were washed with brine, dried (Na2SO4), and concentrated
under reduced pressure. Separation by column chromatography
(SiO2, 30:1 hexane/EtOAc) afforded starting material 17 (140
mg, 54% recovery) and compound 14g (70 mg, 31%) besides
traces of 14h (2 mg) and 14i (2 mg).
(3S,6S,7a R)-3-ter t-Bu t yl-6-(4,4-d ip h en ylb u t yl)-1,6,7,7a -
tetr a h yd r o-5-oxop yr r olo[1,2-c]oxa zole-7a -ca r boxylic Acid
Meth yl Ester (14g): colorless oil; [R]D -19.0° (c 0.28, CHCl3);
IR (film) 2954, 1742, 1713 cm-1; 1H NMR δ 7.30-7.15 (m, 10H),
4.80 (s, 1H), 4.76 (d, 1H, J ) 8.4 Hz), 3.92 (t, 1H, J ) 4.8 Hz),
3.73 (s, 3H), 3.26 (d, 1H, J ) 8.4 Hz), 2.58 (m, 1H), 2.28-1.69
(m, 6H), 1.42-1.32 (m, 2H), 0.88 (s, 9H); 13C NMR δ 182.81,
173.18, 144.90, 144.76, 128.41, 127.78, 127.74, 126.13, 126.10,
97.90, 73.39, 70.83, 52.60, 50.93, 45.13, 35.21, 32.70, 32.40, 25.76,
24.86; MS m/z (%) 449 (6), 392 (100), 91 (16), 43 (18).
(3S,6R,7a R)-3-ter t-Bu tyl-1,6,7,7a -tetr a h yd r o-6-m eth yl-5-
oxop yr r olo[1,2-c]oxa zole-7a -ca r boxylic Acid Meth yl Ester

Notes
(3S,6R,7a R)-3-ter t-Bu t yl-6-(4,4-d ip h en ylb u t yl)-1,6,7,7a -
J . Org. Chem., Vol. 66, No. 22, 2001 7559
2.05 (d, 1H, J ) 13.8 Hz), 1.16 (s, 3H), 1.13 (s, 3H); 13C NMR
(D2O) δ 188.10, 179.55, 68.88, 67.42, 43.73, 43.06, 27.66, 27.19.
Anal. Calcd for C8H15NO5‚0.5HCl: C, 43.00; H, 6.99; N, 6.27.
Found: C, 42.72; H, 6.34; N, 6.06.
(2R,4S)-4-Ben zyl-2-(h yd r oxym eth yl)glu ta m ic Acid (15d ):
[R]D +70.4° (c 0.16, CH3OH); IR (KBr) 3363, 1683 cm-1; 1H NMR
(D2O) δ 7.36-7.24 (m, 5H), 3.81 (d, 1H, J ) 11.7 Hz), 3.62 (d,
1H, J ) 11.7 Hz), 3.12-2.92 (m, 2H), 2.77 (m, 1H), 2.23-2.05
(m, 2H). Anal. Calcd for C13H17NO5‚0.7H2O‚0.1HCl: C, 55.07;
H, 6.58; N, 4.94. Found: C, 54.96; H, 6.68; N, 4.49.
tetr a h yd r o-5-oxop yr r olo[1,2-c]oxa zole-7a -ca r boxylic Acid
Meth yl Ester (14h ): colorless oil; [R]D -29.6° (c 0.5, CHCl3);
1H NMR δ 7.30-7.14 (m, 10H), 4.84 (s, 1H), 4.78 (d, 1H, J ) 8.7
Hz), 3.89 (t, 1H, J ) 7.8 Hz), 3.75 (s, 3H), 3.33 (d, 1H, J ) 8.7
Hz), 3.08 (m, 1H), 2.38 (m 1H), 2.11-1.24 (m, 7H), 0.86 (s, 9H);
13C NMR δ 179.48, 172.76, 144.91, 128.44, 127.79, 127.74,
126.16, 126.13, 96.23, 74.67, 69.76, 52.68, 51.07, 44.93, 37.54,
35.83, 35.47, 30.36, 25.66, 24.78; MS m/z (%) 449 (6), 392 (94),
43 (18).
(3S,7a R)-3-ter t-Bu tyl-6,6-bis(4,4-d ip h en ylbu tyl)-1,6,7,7a -
tetr a h yd r o-5-oxop yr r olo[1,2-c]oxa zole-7a -ca r boxylic Acid
Meth yl Ester (14i): colorless oil; [R]D -15.5° (c 1.2, CHCl3); IR
(2R,4R)-4-Ben zyl-2-(h yd r oxym eth yl)glu ta m ic Acid (15e):
[R]D -33.9° (c 0.13, MeOH); IR (KBr) 3386, 1701, 1664 cm-1; 1H
NMR (D2O) δ 7.40-7.27 (m, 5H), 3.77 (d, 1H, J ) 11.7 Hz), 3.24
(d, 1H, J ) 11.7 Hz), 3.09-2.96 (m, 2H), 2.80 (m, 1H), 2.33 (m,
1H), 1.85 (m, 1H); 13C NMR (D2O) δ 184.14, 178.85, 140.94,
131.74, 131.16, 129.20, 69.49, 68.17, 44.39, 37.91, 33.99.
(R)-4,4-Diben zyl-2-(h yd r oxym eth yl)glu ta m ic Acid (15f):
(film) 2953, 1742, 1714 cm-1 1H NMR δ 7.29-7.12 (m, 20H),
;
4.67 (s, 1H), 4.63 (d, 1H, J ) 8.4 Hz), 3.89 (t, 1H, J ) 8.1 Hz),
3.83 (t, 1H, J ) 8.1 Hz), 3.63 (s, 3H), 3.01 (d, 1H, J ) 8.4 Hz),
2.03-0.96 (m, 14H), 0.84 (s, 9H); 13C NMR δ 183.82, 173.26,
144.94, 144.92, 144.74, 144.72, 128.41, 128.40, 127.80, 127.77,
127.75, 126.15, 126.14, 126.07, 97.50, 74.11, 68.67, 52.42, 52.00,
50.85, 50.77, 37.79, 37.30, 35.86, 35.78, 35.74, 35.19, 24.93, 23.03,
22.39; MS m/z (%) 657 (5), 600 (45), 572 (12), 44 (100).
Rep r esen ta tive P r oced u r e for Hyd r olysis: (R)-2-(Hy-
d r oxym eth yl)glu ta m ic Acid (1). A solution of compound 8
(930 mg, 2.97 mmol) in 6 N HCl (20 mL) was stirred under reflux
overnight and then concentrated. Purification by reverse-phase
column chromatography (C18, 125 Å, Waters; H2O as the eluent)
and lyophilization afforded HMG (1; 580 mg, 91%): [R]D -1.6°
(c 1.0, H2O); 1H NMR (D2O) δ 4.02 (d, 1H, J ) 12.3 Hz), 3.75 (d,
1H, J ) 12.3 Hz), 2.61-2.43 (m, 2H), 2.23-2.06 (m, 2H); 13C
NMR (D2O) δ 176.13, 171.58, 64.35, 63.45, 28.15, 26.86. Anal.
Calcd for C6H11NO5‚HCl‚0.5H2O: C, 32.37; H, 5.89; N, 6.29.
Found: C, 32.22; H, 5.74; N, 6.16.
1
[R]D -8.2° (c 0.12, MeOH); IR (film) 3415, 1682 cm-1; H NMR
(CD3OD) δ 7.25-7.13 (m, 10H), 3.16 (d, 1H, J ) 10.5 Hz), 3.15
(d, 1H, J ) 13.5 Hz), 3.01 (d, 1H, J ) 13.2 Hz), 2.65 (d, 1H, J )
13.2 Hz), 2.53 (d, 1H, J ) 13.5 Hz), 2.32 (d, 1H, J ) 14.7 Hz),
2.19 (d, 1H, J ) 10.5 Hz), 1.80 (d, 1H, J ) 14.7 Hz); 13C NMR
(CD3OD) δ 181.92, 175.97, 138.85, 138.02, 131.90, 131.80, 129.56,
129.53, 128.13, 128.11, 69.44, 65.46, 52.65, 45.31, 44.03, 33.25.
Anal. Calcd for C20H23NO5‚1.7HCl: C, 57.28; H, 5.70; N, 3.34.
Found: C, 57.31; H, 5.62; N, 3.03.
(2R,4S)-4-(4,4-Diph en ylbu tyl)-2-(h ydr oxym eth yl)glu tam -
ic Acid (15g): [R]D -9.5° (c 0.2, MeOH); 1H NMR (CD3OD) δ
7.25-7.09 (m, 10H), 3.91 (t, 1H, J ) 7.8 Hz), 3.68 (d, 1H, J )
11.1 Hz), 3.61 (d, 1H, J ) 11.1 Hz), 2.45 (m, 1H), 2.28 (m, 1H),
2.11-2.01 (m, 2H), 1.89-1.78 (m, 2H), 1.42-1.27 (m, 3H); 13C
NMR (CD3OD) δ 181.80, 180.02, 146.82, 146.78, 129.54, 129.52,
129.05, 129.02, 127.18, 127.16, 68.84, 68.52, 52.63, 43.16, 36.77,
35.95, 32.71, 27.01.
The following compounds were obtained analogously.
(2R,4S)-2-(Hydr oxym eth yl)-4-m eth ylglu tam ic Acid (15a):
[R]D -18.2° (c 0.34, CH3OH); IR (KBr) 3407, 1683 cm-1; 1H NMR
(D2O) δ 3.90 (d, 1H, J ) 11.7 Hz), 3.70 (d, 1H, J ) 11.7 Hz),
2.69 (m, 1H), 2.44 (dd, 1H, J ) 9.3, 13.8 Hz), 1.96 (dd, 1H, J )
9.3, 13.8 Hz), 1.14 (d, 3H, J ) 7.2 Hz); 13C NMR (CD3OD) δ
182.62, 176.34, 67.93, 67.05, 37.47, 37.08, 17.16. Anal. Calcd for
C7H13NO5‚1.4HCl: C, 34.71; H, 5.99; N, 5.78. Found: C, 34.70;
H, 5.59; N, 5.57.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (NS 35449) for financial support of this
research and the Office of Naval Research and NIDA
for collection and processing of X-ray crystal data. We
also thank Dr. Werner Tu¨ckmantel for his assistance
in the preparation of the manuscript.
(2R,4R)-2-(Hydr oxym eth yl)-4-m eth ylglu tam ic Acid (15b):
1
[R]D +8.9° (c 0.18, CH3OH); H NMR (D2O) δ 3.94 (d, 1H, J )
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 15a -g together with tables of experimental X-ray
data and ORTEP plots for compounds 8, 12, 13, 14a , 14d , and
17. This material is available free of charge via the Internet
at http://pubs.acs.org.
11.7 Hz), 3.64 (d, 1H, J ) 11.7 Hz), 2.67 (m, 1H), 2.55 (dd, 1H,
J ) 9.0, 12.6 Hz), 1.78 (dd, 1H, J ) 9.0, 12.6 Hz), 1.14 (d, 3H, J
) 7.2 Hz); 13C NMR (D2O) δ 183.82, 177.99, 67.03, 66.20, 35.89,
35.51, 15.55.
(R)-2-(Hyd r oxym eth yl)-4,4-d im eth ylglu ta m ic Acid (15c):
1
[R]D -18.5° (c 0.13, MeOH); H NMR (D2O) δ 3.93 (d, 1H, J )
11.4 Hz), 3.64 (d, 1H, J ) 11.4 Hz), 2.28 (d, 1H, J ) 13.8 Hz),
J O010626N