Facile synthesis of (R,R) and of (R,S) tricarballylic acid anhydride and imide derivatives

Article abstract of DOI:10.3390/50400665

The diastereomeric mixture of (R)-2-(methoxycarbonylmethyl)-N-(R)-1-(1- phenylethyl) succinimide 11s and (S)-2-(methoxycarbonylmethyl)-N-(R)-1-(1- phenylethyl) succinimide 11a was synthesized by reaction of 2-(carboxymethyl) succinic anhydride 6 with (R)-(α)-methylbenzylamine in dry THF/room temperature/24 hrs. The diastereomeric mixture of 1-[(R)-(α)- Methylbenzylamideformyl)]propane-2,3-dicarboxylic acid anhydride 9s and 1-[(R)-(α)-methylbenzylamideformyl)]propane-2,3-dicarboxylic acid anhydride 9a was isolated as an intermediate under the reaction conditions. This diastereomeric mixture 9s/9a was also prepared by a different route via reaction of 1-(chloroformyl)propane-2,3-dicarboxylic acid anydride 12 with (R)-(α)-methylbenzylamine in the presence of DMA at 0°C for 24 hrs.

Full text of DOI:10.3390/50400665

Molecules 2000, 5, 665-673
molecules
ISSN 1420-3049
http://www.mdpi.org
Facile Synthesis of (R,R) and of (R,S) Tricarballylic Acid
Anhydride and Imide Derivatives
Abdel-Sattar S. Hamad Elgazwy
Department of Chemistry, Faculty of Science, University of Ain Shams, Abbassia 11566, Cairo, Egypt
Tel.: (00)202-4831836, Fax: (00)202-4831836, E-mail: hamad@asunet.shams.eun.eg
Received: 17 May 1999; revised form: 23 March 2000 / Accepted: 3 April 2000 / Published: 15 April 2000
Abstract: The diastereomeric mixture of (R)-2-(methoxycarbonylmethyl)-N-(R)-1-(1-
phenylethyl) succinimide 11s and (S)-2-(methoxycarbonylmethyl)-N-(R)-1-(1-phenylethyl)
succinimide 11a was synthesized by reaction of 2-(carboxymethyl)succinic anhydride 6
with (R)-(a)-methylbenzylamine in dry THF/room temperature/24 hrs. The diastereomeric
mixture of 1-[(R)-(a)-Methylbenzylamideformyl)]propane-2,3-dicarboxylic acid anhydride
9s and 1-[(R)-(a)-methylbenzylamideformyl)]propane-2,3-dicarboxylic acid anhydride 9a
was isolated as an intermediate under the reaction conditions. This diastereomeric mixture
9s/9a was also prepared by a different route via reaction of 1-(chloroformyl)propane-2,3-
dicarboxylic acid anydride 12 with (R)-(a)-methylbenzylamine in the presence of DMA at
0oC for 24 hrs.
Keywords: Fumonisin, AAL Toxin TA, Actinoplanic acid, Diastereomers of Tricarballylic
acid, Sphingosine analogs.
Introduction
Tricarballylic acid (TCA) 5 is found as a fragment in several mycotoxin natural products such as
Fumonisin B1 (1a), Fumonisin B2 (2b), and AAL Toxin TA (3) and a macrocyclic polycarboxylic acid
which is an inhibitor of Ras Farnesyl-Protein Transferase (FPTase) [1] like Actinoplanic acid (4),
(Figure 1). Fumonisins and AAL toxins are sphingosine analog mycotoxins characterized by tricar-
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

666
Molecules 2000, 5
ballylic acid side chains.[2] Most notably, fumonisins are known to be natural cancer promoters, and
have been linked to human esophageal cancer in parts of China and southern Africa.[3] The occurrence
and biological activity of the tricarballylic acid molecule has been studied extensively.[4]
O
CO2H
*
CO2H
O
OH OH
14
Me
Me
15
5
3
Me
Me
R
NH2
O
CO2H
*
O
O
CO2H
*
HO2C
Fumonisin B 1 R = OH
Fumonisin B 2 R = H
1a
2b
CO2HO
Tricarballylic acid
5
Me
O
*
CO2H
O
CO2H
*
Me
CO2H
CO2H
OH OH
O
O
O
*
5
11
13
O
14
Me
17
1
O
CO2H
NH2
Me
CO2H
OH
Me
Me
O
*
HO2C
Me
O
Me Me Me
CO2HO
Me
OH
Actinoplanic acid A
4
AAL Toxin T A
3
Figure 1.
It has been established that TCA 5 is produced by rumen bacteria and that it influences ruminant
tissue metabolism.[5,6] Previously [7] we have described the synthesis of the 4-(5-nonyloxycarbonyl)-
3-substituted butanoic acids and methyl esters like those found in Fumonisin B1 (1a), B2 (2b), AAL
Toxin TA (3) and Actinoplanic acid 4 (Figure 1) as a part of sphingosine analogs.
We now report the preparation of the diastereomeric mixture of (R)-2-(methoxycarbonyl-methyl)-
N-(R)-1-(1-phenylethyl)succinimide 11s and (S)-2-(methoxycarbonylmethyl)-N-(R)-1-(1-phenylethyl)-
succinimide 11a.
Results and Discussion
Ring-opening of 2-(carboxymethyl) succinic anhydride 6 with (R)-(a)-methylbenzylamine in dry
THF (RT, 24 h) gave a white sticky material of diastereomeric and regioisomeric mixture of amides
upon concentration (Scheme 1).

667
Molecules 2000, 5
HO C
O
Me
2
HO C
2
N
i
(R)
(R)
H
Me
O
(R)
NH
Hd
Hc
HO C Hd
2
NH
Hd
Hc
Hb
7
Ha
Hc
Hx
HO C
CO H
2
2
+
iv
iii
+
CO H
Hb
2
(R)
Ha
Me
O
O
O
6
Hx
5
Hx
ii
O
NH
CO H
O
O
O
O
(R)
O
O
HO C
(S)
2
2
9s
9a
8
v
R
R
R
R
Me
Me
Me
Me
vi
+
+
O
N
O
N
O
N
O
N
O
O
O
O
MeO C
MeO C
HO C
HO C
2
2
2
2
R
S
R
S
11s
11a
10s
10a
o
o
i) Ac O / 24 h, RT, ii) Ac O at 45 C/ 1h.AcOH at 60 C/ 1h., iii) (R)-( a )-methyl benzylamine/
2
2
0
0
dry THF, RT , 24 hrs. iv) fusion at 129-132 C and then solidified, v) fusion at 158-160
Me NCH(OMe) dry THF, RT, 24 hrs.
C, vi)
2
2,
Scheme 1.
1
The H NMR spectrum allowed us to suggest that the mixture of diastereomeric and regioisomeric
amides were the a-amide and b-amide derivatives 7 and 8, respectively. NMR data for these structures
7 and 8 were consistent with the results described by Hoye et al.[8] for the determination of absolute
configuration of 3-substituted carboxylic acids (b-chiral acids). The resulting products 7 and 8 were
melted at 129-132oC, re-solidified by cooling, transferred into a NMR tube and finally analyzed. The
spectrum shows doublet peaks downfield for (RCHc-R') and (RCHd-R') at d 2.86 (dd, J = 6.86, 16.90
1
Hz) and d 3.30 (dd, J = 9.75, 18.54 Hz) of the compound 9s, respectively. The H NMR spectrum of
9a was virtually the same as for 9s with the following differences: d (RCHc-R') and (RCHd-R') at d
2.75 (dd, J = 9.76, 17.90 Hz) and d 3.22 (dd, J = 9.93, 18.42 Hz) ppm. This was considered to be due
to the anisotropic shielding effect of the aromatic ring of the phenyl group attached to the succinimide.
The major product of the diastereomeric mixture of anhydride was assigned to be 9s (1.3:1). The in-
termediate compounds 9s/9a were re-melted at 158-160oC, and gave the expected assignment of the
diastereomeric mixture of succinimide derivatives 10s/10a in a 1:1 ratio. The product was quite pure
after spectroscopic analysis and no attempt was made to purify this diastereomeric mixture further.
Esterification of the diastereomeric mixture 10s/10a was achieved with N,N'-dimethylformamide di-
methylacetal in dry THF (RT, 24h). Concentration gave a white sticky material of diastereomeric
mixture 11s/11a in a 1.2:1 ratio. The diastereomeric mixture was purified by MPLC (1:9 Hexa-
ne:EtOAc) to provide compounds (R)-2-(methoxycarbonylmethyl)-N-(R)-1-(1-phenylethyl)-succin-

668
Molecules 2000, 5
imide 11s and (S)-2-(methoxycarbonylmethyl)-N-(R)-1-(1-phenyl-ethyl) succinimide 11a in 82%
yield. We have developed a reliable method for determining the absolute configuration of carboxylic
acids containing a stereogenic center at C(3) of the tricarballylic acid derivatives.[8,9]. Figure 2 shows
the application of this method to identify a heterotopic group attached to C(3) that contains readily
1
distinguishable H NMR resonances in the diastereomeric pair of 1-arylethylsuccinimides (e.g. the
methoxycarbonyl methyl group in 11). The C(3)-configuration has been deduced by comparing the
relative shifts of these resonances. For example, in the anti isomer 11 of the CH2CO2Me-succinimide
of generic anti-(3S) diastereomer, the methoxyl resonance will be observed at higher field than in the
syn -(3R) diastereomer.
less
shielded
shielding
MeO2CH2C
MeO2CH2C
(S)
(R)
O
O
N
Me
(R)
N
Me
C(3)
O
(R)
O
11s
11a
rotation
Figure 2.
1
Similarly, the H NMR spectrum of compounds 11s/11a shows the (CO2Me) of 11s as a singlet
downfield (high chemical shift) at d (3.66) and the 11a was a singlet upfield (low chemical shift) at d
(3.62), due to the anisotropic shielding effect of the aromatic ring of the phenyl group attached to the
succinimide derivatives. We attempted to further separate these diastereomers and confirmed the pres-
ent of two diastereomers by using gas chromatography at different temperatures (250, 270oC) and also
with different retention times, but we obtained a broad peak which included a shoulder of the other di-
astereomer. HPLC was used for the separation of those diastereomeric mixture of 11s/11a, unfortu-
nately those diastereomeric mixture was enriched to each other.
The intermediate compounds 9s and 9a were also prepared via a different route as shown in
(Scheme 2), by treatment of the 1-(chloroformyl) propane-2,3-dicarboxylic acid anhydride 12 with
(R)-a-methylbenzylamine in the presence of DMA and CH2Cl2 at 0°C. The reaction mixture was vi-
gorously stirred at room temperature overnight to provide a good yield of the crude product which was
purified further by flash chromatography (2:1 Hexane:EtOAc) to afford the diastereoisomeric mixture
in 60% yield.

669
Molecules 2000, 5
i
Cl
Hd
(R)
Me
O
(R)
NH
HO2C Hd
Hb
Me
O
O
Hb
NH
Ha
Hc
HO2C
CO2H
CO2H
Ha
Hc
Hx
O
iv
iii
Hx
O
+
O
O
(S)
O
(R)
5
O
6
ii
12
O
O
O
O
O
O
9s
9a
o
o
i) Ac2O / 24 hrs, RT; ii) AC 2O at 45 C/1 h., AcOH at 60 C/1 h.; iii) SOCl 2/refluxed for 48
o
hrs.; iv) ( R)-(a)-methylbenzylamine, dry CH Cl2, DMA, 0 C
2
Scheme 2.
Experimental
General
1H and 13C NMR spectra were taken on an IBM NR-200 or IBM NR-300-AF spectrometer. Chemi-
1
cal shifts are given in ppm (d-scale), coupling constants (J) in hertz. H-chemical shifts (300MHz)
13
were referenced to the residual CHCl3 signal (7.24). C-chemical shifts (75 MHz) were referenced to
CDCl3 (77.0). Optical rotations were measured on a Perkin Elmer 1420 ratio recording spectrometer,
1-2% solution in CHCl3. MPLC refers to medium pressure liquid chromatography (25-60 psi) using
hand packed columns of E. Merck silica gel (230-400 mesh) and a Fluid Metering Inc. pump, an ISCO
Model 2361 gradient programmer, and a differential refractive index detector (Waters R401). Flash
column chromatography was performed as described by Still [10] using E. Merck silica gel (230-400
mesh). The R value reported for TLC analysis was determined on Macherey-Nagel 0.25 mm layer
f
fluorescent UV
plates with the indicated solvent system. Infrared IR spectra listed as recorded
254
‘neat’ refer to a thin film of material on NaCl disks. Infrared spectra were recorded on a MIDAC Pros-
pect spectrometer. IR spectrum peaks are reported in cm-1. Elemental analyses were performed by M-
H-W Laboratories (Phoenix, AZ) and the Central Lab.of Ain Shams University, Cairo, Egypt. Tandem
gas chromatography/ low resolution mass spectrometry (GC/LRMS) using electron impact (EI) ioni-
zation was performed on a Hewlett-Packard 5890 series II gas chromatography and 5971A mass se-
lective detector at 70 eV. Gas chromatography retention time is reported along with the capillary col-
umn configuration using the following convention: Column C = DB-5.6 m x 0.1 mm ID x 0.1 m film +
1 guard column with a 1 mL/in flow rate.
Propane-1,2,3-tricarboxylic Acid (1,2-Anhydride) 6
Tricarballylic acid 5 (1.76 g, 0.01 mol) was dissolved in acetic anhydride (1.78 mL, 2.04 g, 0.02

670
Molecules 2000, 5
mol). The reaction mixture was stirred overnight at room temperature, then excess acetic anhydride
was removed under reduced pressure and the product was recrystallized twice from ethyl acetate to
give of the title compound as a white micro-crystalline solid (1.37 g, 0.0087 mol, 77.8% yield) that had
1
mp. 132-133oC, lit.[11]: 132-134oC. H NMR: (200 MHz, acetone-d ): d 2.89 [dd, J = 2.6 and 18.2
6
Hz, 1H, RCHa-R'(ax)], 2.91 [dd, J = 6.6 and 18.6 Hz, 1H, RCHc-R'(ax)], 3.002 [dd, J = 5.4 and 18.2
Hz, 1H, RCHd-R'(eq)], 3.27 [dd, J = 10.4 and 18.2 Hz, 1H, RCHb-R'(eq)], 3.62 [dddd, J = 10.4, 6.6,
13
5.4, and 2.6 Hz, R-CH CHxCH -R'(eq)], 11.3 (s, R-CO H) ppm. C NMR: (50 MHz, acetone-d ): d
2
2
2
6
176.7, 174.2, 173.4 , 38.2, 35.3 and 35.2 ppm. IR: (KBr pellet): 1727 (vs), 1790 (s), and 1833 (m) cm-1
Anal. Calcd for C6H6O5: C, 45.58; H, 3.84; O, 50.59% Found: C, 45.55; H, 4.08.
1-(Chloroformyl)propane-2,3-dicarboxylic anhydride 12
Propane-1,2,3-tricarboxylic acid (1,2-anhydride) 6 (0.01 mol) was refluxed with SOCl2 (1 mol) for
48 hours. The SOCl2 was evaporated and the residue distilled under reduced pressure. Purification of
the fraction collected at b.p. 132-136oC (1.5 mmHg) required the use of a Buchi Kugelrohr apparatus
which afforded the product which later crystallized from CH2Cl2 upon being cooled to room tempera-
1
ture to give the title product (1.58 g, 0.009 mol, 90% yield), m.p. 96-98oC, lit.[12] 97-98oC; H NMR
(200 MHz, acetone-d6): d 2.63 (dd, J = 6.2 and 17 Hz, RCHa-R’), 2.80 (dd, J = 6.8 and 17 Hz, RCHc-
R’), 3.07 (dd, J = 7.2 and 18.6 Hz, RCHd-R’), 3.33 (dd, J = 10 and 18.8 Hz, RCHb-R’), 3.86 (dddd, J =
6.2, 6.8, 7, and 10 Hz, RCH2CHxCH2-R’) ppm. IR (KBr pellet); 1760 (vs) and 1835 (m) cm-1. Anal.
Calcd for C6H5ClO4: C, 40.82; H, 2.85; Cl, 20.08; O, 36.25% Found: C, 45.55; H, 4.08; Cl, 20.93.
3-Carboxypentane-1,5-dioic acid, mono-[1-(R)-(1-phenylethyl)]amide 7, and 3-mono-[(R)-(1-phenyl-
ethyl)]amide pentane-1,5-dioic acid 8
Tricarballylic acid anhydride (TCA) 6 (47.4 mg, 0.3 mmol) was placed into an oven dried culture
tube (25 mL r.b.), dissolved in dry THF (1.2 mL, 0.25 M), and then treated with (R)-(+)-a -
methylbenzyl amine (46.4 mL, 43.6 mg, 0.36 mmol). The resulting solution was stirred overnight at
room temperature. The solvent was removed under reduced pressure to give 84.3 mg (92% mass re-
1
covery) of a white sticky of diastereoisomer 7 and regioisomeric amides 8 as determined by H NMR
analysis and no attempt was made to purify this material further and isolate the diastereoisomers.
Compound 7
1
H NMR (200 MHz, acetone-d6, from the mixture) : d 1.43- 1.40 (d, J = 7.0 Hz, 3H, Ar CHCH ),
3
2.43- 2.54 (m, 2H, RCH -CONH), 2.61-2.68 (m, 2H, RCH -CO H), 3.18-3.22 (m, 1H, RCH CHCH -
2
2
2
2
2
R'), 5.03 (dq, J = 6.8 Hz, ArCH-), 5.34 (d, J = 7.23 Hz, -NH-), 7. 16-7.52 (m, 5H, Ph-H) ppm.

671
Molecules 2000, 5
Compound 8
1
H NMR (200 MHz, acetone-d6, from the mixture) : d 1.62- 1.59 (d, 3H, J = 6.8 Hz, Ar CHCH3),
2.43- 2.54 (m, 2H, RCHaHb-CO H), 2.61- 2.68 (m, 2H, RCHa’Hb’-CO H), 3.2-3.3 (m, 1H, RCHR'),
2
2
5.0-5.08 [dq, J = 6.65 Hz, 1H, ArCHNHMe], 5.63 (d, J = 7.23 Hz, 1H, -NH-), 7.19-7.49 (m, Ph-H)
ppm.
The mixture of compounds 7 and 8, were placed into an oven dried melting point tube, fused (129-
o
135 C), solidified, and then transferred into the NMR tube. The diastereoisomers were determined by
1
H NMR analysis. The structural assignments were made by comparison of the spectral data of com-
pounds 9s/9a which were obtained by the reaction of tricarballylic anhydride acid chloride 12 with (R)-
(+)-a -methylbenzyl amine. The ratio of the distereoisomers was ~1:1 according to the integration. No
1
attempt was made to resolve the diastereoisomers further, m.p. 129-135oC. The H NMR spectra data
was identical consistent with authentic samples 9s/9a in all aspects.
1-[(R)-(a)-methylbenzylamido)formylpropane-(R)-2,3-dicarboxylic-anhydride 9s and 1-[(R)-(a)-me-
thylbenzylamido)formylpropane-(S)-2,3-dicarboxylic anhydride 9a
Into an oven dried flask (50 mL r.b.) equipped with a stirring bar were placed tricarballylic anhy-
dride acid chloride (85.7 mg, 0.5 mmol) in dry CH Cl (20 mL). The reaction mixture was stirred until
2
2
dissolution was complete. (R)-a - methylbenzylamine (60.5 mg, 0.5 mmol) and N,N'-dimethylaniline
(DMA) (70 mL, 66.5 mg, 0.55 mmol) in CH Cl (5 mL) were added dropwise to the acid chloride so-
2
2
o
lution at 0 C with vigorous stirring. The reaction mixture was warmed slowly to RT and stirred over-
night. The solvent was removed under reduced pressure, the residue dissolved in CH Cl , extracted
2
2
-3
three times with cooled dilute HCl (2 mol dm ), and several times with water. The organic layer was
dried on Na SO , filtered, and concentrated under reduced pressure to give the crude product. No at-
2
4
tempts were made to purify this material. The compounds 9s and 9a were obtained as mixture of dias-
tereoisomers in 1:1 ratio (NMR).
Compond 9s
+
1
LRMS (EI): m/z 148 [M -113, (20)], 106 (20), 94 (20), 77 (25), 44 (100). H NMR (200 MHz,
acetone-d ): d 1.62 (d, J = 7.2 Hz, ArCHCH3), 2.65 (dd, J = 6.39 and 16.93 Hz, RCHa-R'), 2.86 (dd, J
6
= 6.86 and 16.90 Hz, RCHc-R'), 3.09 (dd, J = 7.13 and 18.59 Hz, RCHb-R'), 3.30 (dd, J = 9.75 and
18.54 Hz, RCHd-R'), 3.84 (dddd, J = 12.20, 7.31, 5.16, and 2.21 Hz, RCH2CHxCH2-R'), 5.37 (q, J =
7.20 and 14.36 Hz, ArCH-), 7.42 (m, Ar-H) ppm.; Cap gc; t = 7.21 min.; column: DB-5 5 m+ 1m
R
o
o
-1
o
guard ~1 mL / min.; gum temp prog: To = 50 C / 2 min. / 20 C min. / 250 C / 5 min.
1
The H NMR spectrum of 9a was virtually the same as for 9s with the following differences. d 2.75
(dd, J = 9.76 and 17.90 Hz, RCHc-R'), 3.22 (dd, J = 9.93 and 18.42 Hz, RCHd-R') ppm. Anal. Calcd

672
Molecules 2000, 5
for C14H15NO4: C, 64.36; H, 5.79; N, 5.36; O, 24.49% Found: C, 64.03; H, 4.99; N, 5.01.
The solidified materials 9s/9a were again melted at 158-160oC, and transferred into a NMR tube.
1
The H NMR spectral data was identical with those for compounds 10s and 10a. Tlc: R = 0.2 in
f
+
2:1:Hex:EtOAc. LRMS (EI): m/z 275 (M , (100), 260 (<3), 244 (20), 232 (55), 215 (20), 200 (15),
172 (20), 146 (40), 120 (65), 105 (100), 104 (100), 94 (12), 77 (60), 59 (75), and 41 (25). The com-
1
pounds 10s and 10a were obtained as a diastereoisomeric mixture in 1.2:1 ratio (NMR). (10s) H NMR
(500 MHz, CDCl ): d 8.07 (d, 1H, J = 8.5 Hz, Ar-H), 7.87 (d, 1H, J = 8.0 Hz, Ar-H), 7.80 (d, 1H, J = 1
3
and 7 Hz, Ar-Hp), 5.42 (dq, J = 7.5 Hz, Ar-CH-Me), 3.66 (s, RR’CHCOOCH3)2 3.51 (dddd, J = 2.3,
3.6, 3.8, and 9.3 Hz, R CHCO Me), 2.99 (dd, J = 3.73 and 15.31 Hz, RCHaHbCONHCHAr), 2.9-2.75
2
2
(m, 2H, RCHaHbCOOMe), 2.47-2.44 (dd, J = 6.0 and 7.5 Hz, 2H, RCHcHdCONHAr), 2.43-2.41 (dd,
1
J = 5.5 and 7.5 Hz, RCHcHdCONHAr), 1.827 -1.812 (d, J = 7.5 Hz, 3H, ArCH-Me) ppm. The H
NMR spectrum of 10a was virtually the same as that for 10s with the following differences: d 3.62 (s,
3H, RCH COOMe) and 1.821-1.807 (d, J = 7.0 Hz, 3H, ArCH-CH3) ppm.; Cap gc: t = 10.44 min.;
2
R
o
o
-1
column: DB-5 5mL = 1m guard ~ 1mL / min.; gum temp prog: To = 50 C / 2 min. / 20 C min.
/
o
250 C / 5 min.
(R)-2-Carboxymethyl-N-[(R)-1-(phenylethyl)succinimide 11s and (S)-2-Carboxymethyl-N-[(R)-1-
(phenylethyl)succinimide 11a
Diastereomeric acid mixture 10s/10a (115 mg, 0.44 mmol) was dissolved or suspended in dry THF
(1 mL). N,N’-dimethylformamide dimethylacetal (209 mg, 1.76 mmol, 0.5 mL) was added dropwise to
the suspended solution within 20 min. The reaction mixture was allowed to stir overnight at room tem-
perature and then the solvent was removed. The residue was washed with water (15 mL) and then the
product was extracted with ethyl acetate, washed with saturated NaHCO3 solution (2x10 mL), and
brine (10 mL). The organic layer was dried over MgSO4 anhydrous. The solvent was removed, to af-
ford 110.5 mg of crude semi-oily product. The residue was purified by MPLC (with pure EtOAc) to
provide the diastereoisomeric products 11s and 11a (95 mg, 0.35 mmol., 20 mole% and 82% yield).
1
The material proved to be a 1.2:1 mixture of diastereoisomers according to H NMR analysis. TLC; R
f
+
= 0.2 in 2:1:Hex:EtOAc.; LRMS (EI): m/z 275 (M , (100), 260 (<3), 244 (20), 232 (55), 215 (20), 200
(15), 172 (20), 146 (40), 120 (65), 105 (100), 104 (100), 94 (12), 77 (60), 59 (75), and 41 (25).
Compound 11s
1
H NMR (500 MHz, CDCl ) : d 8.07 (d, 1H, J = 8.5 Hz, Ar-H), 7.87 (d, 1H, J = 8.0 Hz, Ar-H),
3
7.80 (d, 1H, J = 1 and 7 Hz, Ar-Hp), 5.42 (dq, J = 7.5 Hz, Ar-CH-Me), 3.66 (s, RR’CHCOOCH3)2
3.51 (dddd, J = 2.3, 3.6, 3.8, and 9.3,Hz, R CHCO Me), 2.99 (dd, J = 3.73 and 15.31 Hz,
2
2
RCHaHbCONHCHAr), 2.9-2.75 (m, 2H, RCHaHbCOOMe), 2.47-2.44 (dd, J = 6.0 and 7.5 Hz, 2H,
RCHcHdCONHAr), 2.43-2.41 (dd, J = 5.5 and 7.5 Hz, RCHcHdCONHAr), 1.827 -1.812 (d, J = 7.5

673
Molecules 2000, 5
Hz, 3H, ArCH-Me) ppm.
1
The H NMR spectrum of 11a was virtually the same as for 11s with the following differences: d
3.62 (s, 3H, RCH COOMe) and 1.821-1.807 (d, J = 7.0 Hz, 3H, ArCH-CH3) ppm.; Cap gc: t = 10.44
2
R
o
o
-1
min.; column: DB-5 5mL = 1m guard ~ 1mL / min; gum temp prog.: To = 50 C / 2 min. / 20 C min.
o
/ 250 C / 5 min. Anal. Calcd for C15H17NO4: C, 66.44; H, 6.22; N, 5.09; O, 23.25% Found: C, 66.55;
H, 6.09; N, 4.99.
Acknowledgment: This work was supported by the Department of Chemistry, Ain Shams University,
Cairo, Egypt and the Egyptian Academy of Science and Technology (ARE). I deeply thank Professor
Thomas R. Hoye, University of Minnesota, MN, USA, for providing spectral data and Prof. Dr. Henry
N.C. Wong, Chinese University of Hong Kong for his generous assistance.
References and Notes
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Sample Availability: Samples not available.
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