Synthesis of arylated norbornyl amino acid esters

Article abstract of DOI:10.1007/s00706-010-0384-3

Palladium-catalyzed hydroarylation of optically active norbornenimide- protected amino acid esters was studied to stereoselectively synthesize a series of new exo-aryl(hetaryl)-substituted norbornyl amino acid methyl esters.

Full text of DOI:10.1007/s00706-010-0384-3

Monatsh Chem (2010) 141:1237–1243
DOI 10.1007/s00706-010-0384-3
ORIGINAL PAPER
Synthesis of arylated norbornyl amino acid esters
•
Omer Tahir Gunkara Irem Kulu
•
•
Nuket Ocal Dieter E. Kaufmann
Received: 23 January 2010 / Accepted: 9 August 2010 / Published online: 21 September 2010
Ó Springer-Verlag 2010
Abstract Palladium-catalyzed hydroarylation of opti-
cally active norbornenimide-protected amino acid esters
was studied to stereoselectively synthesize a series of new
exo-aryl(hetaryl)-substituted norbornyl amino acid methyl
esters.
development [8, 9]. Dyatkin and coworkers [10] have
developed integrin antagonists by incorporating an azabi-
cyclic amino acid group as a proline-mimetic scaffold. On
the other hand, optically active aromatic a-amino acids are
important molecular fragments in many molecules of bio-
logical importance such as cephalecins, nocardisins, and
glycopeptides of the vancomycin family. Heteroaromatic
a-amino acids are also an interesting and important class of
amino acids, and in particular, naphthyl and biphenyl
derivatives have received increased attention due to the
large number of structural equivalents and synthetic
applications of the heteroaromatic moiety [11]. Saaby and
coworkers [12] have reported that synthesis of optically
active aromatic and heteroaromatic a-amino acids was a
challenge in organic chemistry, and a few research groups
have succeeded in development of a catalytic asymmetric
Strecker reaction or the Sharpless amino-hydroxylation
reaction giving the corresponding hetaryl a-amino cyanides
or alcohols.
Keywords Amino acids Á Aromaticity Á C–C coupling Á
Homogeneous catalysis Á Heterocycles
Introduction
Amino acids are among the simplest optically active
compounds in nature. Polymers, peptides, and proteins
constructed from them show a wide variety of functions
such as electron transfer, information transfer, photoreac-
tivity, and selective catalytic functions, which still can only
partly be imitated by synthetic compounds [1–4]. The use
of both natural (chiral pool) and unnatural a-amino acids
and their derivatives as chiral reagents, auxiliaries, and
ligands for asymmetric catalysis is widespread [5–7]. In
medicinal chemistry, bicyclic amino acids have attracted
general interest as complex, polyfunctional templates for
new drug candidates from bioactive molecules. Conform-
ationally restricted bicyclic amino acids deserve special
interest due to their prominent role in drug design and
Additionally, bi- and tricyclic imides represent an
important class of substrates for biological and chemical
applications [13, 14]. These molecules are reported to
exhibit a wide variety of biological activities such as
antitumor, anti-inflammatory, and antimicrobial effects
[15]. There are few reports in literature on synthesis of
N-substituted chiral maleimides which contain the nor-
bornyl function in their skeleton. Biagini and coworkers
[16] have synthesized some amino acid methyl esters
containing a norbornene unit.
O. T. Gunkara Á I. Kulu Á N. Ocal (&)
Department of Chemistry, Faculty of Art and Sciences,
Yildiz Technical University, Esenler, 34210 Istanbul, Turkey
e-mail: nocal@yildiz.edu.tr
Therefore, we became interested in synthesis of new,
protected chiral amino acid esters, which represent aryl-
modified bicyclic imide systems at the same time, by
reductive Heck reactions. Due to its broad synthetic
potential as a stereoselective C–C coupling method, the
Heck reaction has been the subject of several synthetic and
D. E. Kaufmann
Institute of Organic Chemistry,
Clausthal University of Technology, Leibnizstr. 6,
38678 Clausthal-Zellerfeld, Germany
123

1238
O. T. Gunkara et al.
mechanistic studies over the last 30 years [17–20]. Origi-
nally developed to arylate acyclic alkenes, the reaction
scope was later extended to cyclic compounds too. In
previous work [21–24] it has been demonstrated by the
Kaufmann group that palladium-catalyzed asymmetric
Heck-type hydroarylations of bicyclic and tricyclic alkenes
offer a valuable route to epibatidine analogs. Domino–
Heck applications [25] are also feasible. We then extended
the synthetic scope further by means of reductive Heck
reactions of polyfunctionalized tricyclic molecules with a
strained C=C bond and an acylamino imide or hydrazide
group [26, 27].
exo-arylated heterocycles 7 and 8 in good yields after
chromatographic separation.
We also synthesized 9 and 10 from 3 with 2-iodothio-
phene and 1-chloro-2-iodobenzene and prepared 11 and 12
from 4 with iodobenzene and 2-iodothiophene as new 8-
exo-compounds under the same Heck arylation conditions
(Scheme 3).
We expected to obtain two diastereomers after reductive
Heck reactions due to the unsymmetric structures of 1–4,
but we observed only one set of signals. This was probably
due to a rather long distance between the two chiral cen-
ters. The stereochemistry was inferred from their NMR
spectra including diagnostic spin–spin interactions. The
exo-position of the C-8 substituent was confirmed by the
fact that H8 showed no significant interaction with H1. The
geminal protons at C-9 were identified by vicinal coupling
to H1. Additionally, H–H correlation spectroscopy (COSY)
spectra showed cross peaks between H2 and H6 and
between H8 and H9. We observed diastereotopic methoxy
protons as two singlets in the 1H NMR spectra of 5, 6, and
10–12. In addition to 13C NMR, DEPT, and FT-IR spectral
data and elemental analyses, which were in agreement with
the proposed structures, the mass spectra of all new com-
pounds showed the expected molecular ion peaks.
In conclusion, in presence of triphenylarsine as ligand,
palladium-catalyzed hydroarylation of readily accessible
optically active norbornyl amino acid methyl esters 1–4
was shown to be a stereoselective, versatile, and high-yield
approach to synthesis of aryl and heteroaryl derivatives of
tricyclic amino acid methyl esters 5–12, which proved
useful for construction of novel heterocycles of potential
pharmacological interest.
Results and discussion
In this work, we first prepared optically active (S)-N-endo-
norbornenyl amino acid methyl esters 1–3 and (S)-2-(1,
3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-epoxy-2H-isoindol-
2-yl)-3-(4-hydroxyphenyl)propionic acid methyl ester (4)
as new starting compounds (except 1) in good yields using
North’s procedure (Scheme 1). The new structures were
1
assigned by their H nuclear magnetic resonance (NMR)
data. In addition to 13C NMR, distortionless enhancement
by polarization transfer (DEPT), and Fourier-transform
infrared (FT-IR) spectral data and elemental analyses,
which were in agreement with the proposed structures, the
mass spectra of all new compounds showed the expected
molecular ion peaks.
Treatment of 1 with 1-chloro-4-iodobenzene and 1-iodo-
4-methoxybenzene under reductive Heck conditions gave
the pure products 5 and 6 after chromatographic separation
on silica gel as single diastereomers in isolated yields of
78–80% (Scheme 2).
The same reductive Heck arylation conditions were
successfully applied to the reaction of 2 with 1-iodo-4-
methoxybenzene and 1-iodonaphthalene to give the new
Experimental
All reactions were carried out under nitrogen atmosphere
unless otherwise indicated. Reactions were monitored by
thin-layer chromatography. Visualization of the developed
chromatograms was performed either with ultraviolet (UV)
light or KMnO4 stain. Products were purified by silica gel
chromatography with solvent gradient of ethyl acetate:n-
hexane to afford the title compounds. IR spectra were
obtained with a Perkin Elmer FT-IR instrument, and
absorption frequencies are reported in cm-1. Melting
points were determined with a Gallenkamp digital ther-
mometer. NMR spectra were determined with a Bruker
AC-400 and a Varian-INOVA-500 spectrometer. NMR 2D
experiments were measured with a Bruker AC-400 spec-
trometer. Tetramethylsilane was used as internal standard
and CDCl3 as the solvent. Signal multiplicities in the NMR
spectra are reported as follows: s, singlet; brs, broad sin-
glet; d, doublet; dd, doublet of doublets; m, multiplet. Mass
O
O
H
H
N
O
R
H
Et3N
HCl.H2N
+
R
O
O
Toluene
H
O
O
O
O
1-3
R
1
O
CH3
O
R
H2C
OH
H
O
2, 4
N
O
H
H
O
CH3
3
OH
4
Scheme 1
123

Synthesis of arylated norbornyl amino acid esters
1239
Scheme 2
X
O
H
H
R
H
N
5-7, 10
O
X
I
O
H
O
O
Pd(OAc)2, AsPh3
H
R
DMF
N
+
H
HCOOH, Et3N
O
Ar
O
H
O
O
H
R
N
1-3
H
O
8-9
O
O
Compound
R
X
Ar
CH3
CH3
Cl
5
6
OMe
OMe
7
OH
OH
H2C
H2C
8
9
CH3
OH
S
CH3
OH
Cl
10
Scheme 3
General procedure for synthesis of 1–4
spectra were measured with an Agilent 6890N GC-System-
5973 IMSD. Optical rotation values were determined with
a polarimeter model AA-55 series from Optical Activity
Ltd.
To a solution of endo-bicyclo[2.2.1]hept-5-ene-2,3-dicar-
boxylic anhydride (exo-7-oxabicyclo[2.2.1]hept-5-ene-2,3-
123

1240
O. T. Gunkara et al.
2:1). 1H NMR (500 MHz, CDCl3): d = 1.01 (d,
J = 4.8 Hz, 3H, CH3), 1.53 (d, J = 8.8 Hz, H10a), 1.72 (d,
J = 8.8 Hz, H10s), 3.33–3.66 (m, 4H, H1, H2, H6, H7), 3.68
(s, 3H, OCH3), 3.97 (d, J = 9.3 Hz, 1H, N–CH), 4.38 (brs,
OH), 4.60 (d, J = 4.8 Hz, CH), 6.10 (s, 2H, H8, H9) ppm;
13C NMR (125 MHz, CDCl3): d = 20.45 (CH3), 45.31
(CH2), 45.37 (C2), 46.22 (C6), 46.62 (C1), 52.72 (C7), 52.95
(OCH3), 59.59 (N–CH), 66.55 (C–OH), 135.11 (C8, C9),
167.90 (C=O), 177.91 (C=O), 178.93 (C=O) ppm; FT-IR
dicarboxylic anhydride for 4) (44 mmol) and triethylamine
(80 mmol) in 150 cm3 toluene was added amino acid
methyl ester hydrochloride (40 mmol). The resulting
mixture was heated at reflux for 15 h, then the cooled
reaction mixture was washed with 2 M hydrochloric acid
(3 9 50 cm3), and the aqueous phase back-extracted with
30 cm3 ethyl acetate. The combined organic phase was
washed with saturated ammonium carbonate (2 9 50 cm3)
and 30 cm3 H2O. The organic layer was dried (MgSO4),
and the solvent removed. The residue was submitted to
column chromatography using mixtures of ethyl acetate:
n-hexane or crystallization from a suitable solvent.
ꢀ
(ATR): m = 3,417 (OH), 3,063, 2,984, 2,952, 2,870, 1,743
(C=O), 1,691 (C=O), 1,455, 1,435, 1,384, 1,277,
1,181 cm-1; GC–MS (EI, 70 eV): m/z = 282 (M??2),
264, 235, 220, 154, 137, 66; [a]2D0 = ?15.3° cm2 g-1
(c = 0.018 g cm-3, chloroform).
Methyl [2a(S),3aa,4a,7a,7aa]-2-(1,3,3a,4,7,7a-hexahydro-
1,3-dioxo-4,7-methano-2H-isoindol-2-yl)propanoate
(1, C13H15NO4)
Methyl [2a(2S),3aa,4b,7b,7aa]-2-(1,3,3a,4,7,7a-hexa-
hydro-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-3-
(4-hydroxyphenyl)propanoate (4, C18H17NO6)
The general procedure described above was used with
endo-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride
and (S)-alanine methyl ester to afford 1 (68%) as a
colorless solid identical to the product described in Ref.
[16].
The general procedure described above was used with exo-
7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride
and (S)-tyrosine methyl ester to afford 4 (37%) as a colorless
oil (column chromatography from ethyl acetate:n-hexane
2:1). 1H NMR (400 MHz, CDCl3): d = 2.66 (d,
J = 6.2 Hz, H2), 2.69 (d, J = 6.2 Hz, H6), 3.18 (dd,
J = 5.5, 14.1 Hz, 1H, CH2), 3.34 (dd, J = 5.5, 14.1 Hz,
1H, CH2), 3.68 (s, 3H, OCH3), 4.81 (dd, J = 4.7, 10.9 Hz,
1H, N–CH), 5.02 (s, H1), 5.15 (s, H7), 5.44 (brs, OH), 6.38 (s,
2H, H8, H9), 6.60 (d, J = 8.6 Hz, 2H, Ar), 6.93 (d,
J = 8.6 Hz, 2H, Ar) ppm; 13C NMR (100 MHz, CDCl3):
d = 35.52 (CH2), 46.21 (C6), 46.29 (C2), 51.77 (OCH3),
53.16 (N–CH), 79.74 (C1), 79.77 (C7), 114.36 (ArC), 126.76
(ArC), 129.16 (ArC), 135.48 (C8), 135.73 (C9), 154.22 (C),
161.61 (C), 167.72 (C=O), 174.34 (C=O) ppm; FT-IR
Methyl [2a(S),3aa,4a,7a,7aa]-2-(1,3,3a,4,7,7a-hexahydro-
1,3-dioxo-4,7-methano-2H-isoindol-2-yl)-3-(4-hydroxy-
phenyl)propanoate (2, C19H19NO5)
The general procedure described above was used with
endo-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride
and (S)-tyrosine methyl ester to afford 2 (73%) as a
colorless solid. M.p.: 141–142 °C (recrystallization from
1
ethyl acetate:n-hexane 1:1); H NMR (400 MHz, CDCl3):
d = 1.36 (d, J = 8.6 Hz, H10a), 1.54 (d, J = 8.6 Hz, H10s),
3.05 (dd, J = 4.7, 7.8 Hz, 1H, CH2), 3.11–3.20 (m, 4H, H1,
H2, H6, H7), 3.32 (dd, J = 4.7, 11.7 Hz, 1H, CH2), 3.67 (s,
3H, OCH3), 4.85 (dd, J = 5.5, 11.7 Hz, 1H, N–CH), 5.50
(brs, H8), 5.75 (brs, H9), 6.22 (brs, OH), 6.65 (d,
J = 8.6 Hz, 2H, Ar), 6.92 (d, J = 8.6 Hz, 2H, Ar) ppm;
13C NMR (100 MHz, CDCl3): d = 33.16 (CH2), 44.91
(C7), 45.11 (C1), 45.94 (C6), 46.06 (C2), 52.41 (C10), 52.90
(OCH3), 53.25 (N–CH), 115.44 (ArC), 128.14 (C), 130.37
(ArC), 134.32 (C8), 134.54 (C9), 155.26 (C–OH), 169.12
(C=O), 177.46 (C=O), 177.76 (C=O) ppm; FT-IR (ATR):
ꢀ
(ATR): m = 3,405 (OH), 3,012, 2,956, 1,775 (C=O), 1,738
(C=O), 1,694 (C=O), 1,614, 1,596, 1,516, 1,438, 1,391,
1,245, 1,202, 1,166, 875 cm-1; GC–MS (EI, 70 eV):
m/z = 311 (M??1-OMe), 294, 218, 177, 147, 132, 94;
[a]D20 = -34.4° cm2 g-1 (c = 0.018 g cm-3, chloroform).
General procedure for synthesis of hydroarylation
products of 1–4
ꢀ
m = 3,418 (OH), 3,058, 2,992, 2,952, 2,872, 1,764 (C=O),
1,742 (C=O), 1,687 (C=O), 1,614, 1,596, 1,516, 1,437,
1,387, 1,248, 1,226, 1,165 cm-1; GC–MS (EI, 70 eV):
m/z = 341 (M?), 326, 310, 293, 179, 162, 107, 91, 59;
[a]D20 = ?76.6° cm2 g-1 (c = 0.018 g cm-3, chloroform).
A solution of 5.6 mg Pd(OAc)2 (0.025 mmol) and 33.7 mg
AsPh3 (0.11 mmol) in 3 cm3 dry DMF was stirred in a
Schlenk flask under nitrogen at 65 °C for 15 min in order
to form the catalyst complex. Then, 306 mg aryl iodide
(1.5 mmol), 1 (or 2–4) (1.00 mmol), 354 mg triethylamine
(3.5 mmol), and 138 mg formic acid (3.0 mmol) were
added. The mixture was heated to 65 °C for 24–48 h. After
cooling to rt, 50 cm3 brine was added, the reaction mixture
was extracted with ethyl acetate and dried over MgSO4.
The solvent was evaporated, and the residue purified by
chromatography.
Methyl [2a(2S,3R),3aa,4a,7a,7aa]-2-(1,3,3a,4,7,7a-
hexahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-yl)-
3-hydroxybutanoate (3, C14H17NO5)
The general procedure described above was used with endo-
bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride and
(S)-threonine methyl ester to afford 3 (50%) as a colorless
oil (column chromatography from ethyl acetate:n-hexane
123

Synthesis of arylated norbornyl amino acid esters
1241
10s
10
Methyl [2a(2S),3aa,4a,5a,7a,7aa]-2-[octahydro-5-(4-
methoxyphenyl)-1,3-dioxo-4,7-methano-2H-isoindol-2-yl]-
3-(4-hydroxyphenyl)propanoate (7, C26H27NO6)
a
7
6
2
Ar
9x
O
R
8n
9n
The general procedure described above was used with 2
and 1-iodo-4-methoxybenzene to afford 7 (68%) as a
colorless oil (column chromatography from ethyl acetate:
N
O
1
H
O
O
1
Me
n-hexane 2:1). H NMR (400 MHz, CDCl3): d = 1.43 (d,
J = 10.9 Hz, H10a), 1.48–1.77 (m, 3H, H10s, H9x, H9n),
2.46–2.50 (m, H8n), 2.71–2.76 (m, 2H, CH2), 2.91–3.10
(m, 2H, H1, H7), 3.35–3.49 (m, 2H, H2, H6), 3.76 (s, 3H,
OCH3), 3.77 (s, 3H, OCH3), 5.07 (dd, J = 5.8, 9.7 Hz, 1N–
CH), 5.75 (brs, OH), 6.64 (dd, J = 2.3, 8.6 Hz, 2H, Ar),
6.78–6.82 (dd, J = 2.3, 8.6 Hz, 2H, Ar), 6.96–7.03 (m, 4H,
Ar) ppm; 13C NMR (100 MHz, CDCl3): d = 33.06 (C10),
39.87 (CH2), 40.71 (C9), 41.15 (C7), 45.91 (C1), 46.08
(C8), 48.35 (C6), 48.88 (C2), 53.08 (OCH3), 53.46 (OCH3),
55.49 (N–CH), 113.91 (ArC), 115.65 (ArC), 115.70 (ArC),
128.07 (ArC), 128.12 (ArC), 128.22 (ArC), 128.24 (ArC),
130.25 (ArC), 136.94 (C), 137.06 (C), 155.19 (C), 157.91
(C), 169.19 (C=O), 177.97 (C=O), 178.11 (C=O) ppm;
Methyl [2a(2S),3aa,4a,5a,7a,7aa]-2-[5-(4-chlorophenyl)-
octahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-yl]-
propanoate (5, C19H20ClNO4)
The general procedure described above was used with 1
and 1-chloro-4-iodobenzene to afford 5 (78%) as a
colorless oil (column chromatography from ethyl ace-
tate:n-hexane 2:1). 1H NMR (500 MHz, CDCl3): d = 1.51
(d, J = 7.3 Hz, 4H, CH3, H10a), 1.72–1.85 (m, 3H, H10s
,
H9x, H9n), 2.77–2.84 (m, 2H, H1, H7), 3.06–3.18 (m, 3H,
H2, H6, H8n), 3.65, 3.67 (2s, 3OCH3), 4.76 (dq, J = 0.9,
7.3 Hz, 1H, N–CH), 7.05 (dd, J = 5.9, 8.8 Hz, 2H, Ar),
7.17 (d, J = 8.8 Hz, 2H, Ar) ppm; 13C NMR (125 MHz,
CDCl3): d = 13.48 (CH3), 31.61 (C9), 39.81 (C10), 40.20
(C8), 44.91 (C2), 46.74 (C6), 46.92 (C1), 47.29 (C7), 47.95
(OCH3), 51.63 (N–CH), 127.38 (ArC), 127.54 (ArC),
130.88 (C), 142.32 (C), 168.60 (C=O), 175.80 (C=O),
ꢀ
FT-IR (ATR): m = 3,416 (OH), 3,022, 2,968, 2,838, 1,743
(C=O), 1,690 (C=O), 1,614, 1,595, 1,513, 1,441, 1,384,
1,245, 1,206, 1,174, 1,160, 820, 804 cm-1; GC–MS (EI,
70 eV): m/z = 449 (M?), 403, 327, 310, 270, 239, 218,
204, 107, 59; [a]2D0 = -60.4° cm2 g-1 (c = 0.014 g cm-3
chloroform).
,
ꢀ
176.06 (C=O) ppm; FT-IR (ATR): m = 3,043, 2,955,
2,885, 1,770 (C=O), 1,744 (C=O), 1,698 (C=O), 1,492,
1,455, 1,381, 1,227, 1,118, 820 cm-1; GC–MS (EI,
70 eV): m/z = 361 (M?), 346, 332, 163, 125, 59;
[a]D20 = -13.1° cm2 g-1 (c = 0.018 g cm-3, chloroform).
Methyl [2a(2S),3aa,4a,5a,7a,7aa]-2-[octahydro-5-
(1-naphthyl)-1,3-dioxo-4,7-methano-2H-isoindol-2-yl]-
3-(4-hydroxyphenyl)propanoate (8, C29H27NO5)
The general procedure described above was used with 2
and 1-iodonaphthalene to afford 8 (66%) as a light yellow
solid. M.p.: 172–174 °C (column chromatography from
Methyl [2a(2S),3aa,4a,5a,7a,7aa]-2-[octahydro-5-(4-
methoxyphenyl)-1,3-dioxo-4,7-methano-2H-isoindol-2-
yl]propanoate (6, C20H23NO5)
1
ethyl acetate:n-hexane 2:1); H NMR (500 MHz, CDCl3):
The general procedure described above was used with 1 and
1-iodo-4-methoxybenzene to afford 6 (80%) as a colorless
oil (column chromatography from ethyl acetate:n-hexane
2:1). 1H NMR (400 MHz, CDCl3): d = 1.52–1.55 (m,
d = 1.39 (d, J = 9.8 Hz, H10a), 1.64–1.72 (m, 2H, H9x,
H9n), 1.77 (d, J = 9.8 Hz, H10s), 2.77 (brs, H7), 2.92 (dd,
J = 4.9, 7.8 Hz, H8n), 3.00 (brs, H1), 3.29–3.37 (m, 2H,
CH2), 3.40 (d, J = 5.8 Hz, H2), 3.43 (d, J = 5.8 Hz, H6),
3.75 (s, 3H, OCH3), 5.06 (dd, J = 5.8, 9.7 Hz, 1N–CH),
5.36 (brs, OH), 6.48 (d, J = 7.8 Hz, 2H, Ar), 6.95 (dd,
J = 8.8, 10.7 Hz, 2H, Ar), 7.16 (d, J = 7.8 Hz, 1H, Ar),
7.31 (dd, J = 7.8, 12.7 Hz, 1H, Ar), 7.41 (dd, J = 7.8,
12.7 Hz, 1H, Ar), 7.47–7.50 (m, 1H, Ar), 7.63 (d,
J = 7.8 Hz, 1H, Ar), 7.76 (d, J = 7.8 Hz, 1H, Ar), 8.03
(dd, J = 8.8, 13.9 Hz, 1H, Ar) ppm; 13C NMR (125 MHz,
CDCl3): d = 37.38 (CH2), 38.64 (C10), 39.02 (CH2), 44.39
(C7), 47.35 (C1), 47.51 (C8), 47.53 (C6), 47.72 (C2), 51.83
(OCH3), 52.44 (N–CH), 114.39 (ArC), 114.53 (ArC),
121.03 (ArC), 121.14 (ArC), 123.12 (ArC), 123.89 (ArC),
124.63 (ArC), 125.17 (ArC), 126.01 (ArC), 127.65 (ArC),
129.10 (ArC), 131.04 (C), 133.03 (C), 138.74 (C), 153.74
(C), 167.98 (C), 176.43 (C=O), 176.72 (C=O), 176.87
H
10a), 1.57 (d, J = 7.8 Hz, 3H, CH3), 1.83–1.99 (m, 3H,
10s, H9x,H9n), 2.81–2.90 (m, 2H, H1, H7), 3.12–3.23 (m,
H
3H, H2, H6, H8n), 3.71, 3.73 (2s, 3OCH3), 3.77 (s, 3H,
OCH3), 4.83 (dq, J = 1.9, 7.8 Hz, 1H, N–CH), 6.83 (dd,
J = 2.3, 8.6 Hz, 2H, Ar), 7.09 (dd, J = 2.3, 8.6 Hz, 2H,
Ar) ppm; 13C NMR (100 MHz, CDCl3): d = 14.75 (CH3),
32.77 (CH2), 39.89 (C9), 41.20 (C8), 47.85 (C2), 48.25 (C6),
48.57 (C1), 48.85 (C7), 49.18 (OCH3), 52.89 (OCH3), 55.51
(N–CH), 114.03 (ArC), 128.22 (ArC), 137.04 (C), 158.12
(C), 169.90 (C=O), 177.47 (C=O), 177.51 (C=O) ppm; FT-
ꢀ
IR (ATR): m = 3,014, 2,954, 2,916, 2,838, 1,770 (C=O),
1,746 (C=O), 1,698 (C=O), 1,609, 1,581, 1,511, 1,455,
1,382, 1,243, 1,198, 1,178, 825 cm-1; GC–MS (EI, 70 eV):
m/z = 357 (M?), 326, 298, 268, 253, 172, 134, 59;
[a]D20 = -17.7° cm2 g-1 (c = 0.010 g cm-3, chloroform).
ꢀ
(C=O) ppm; FT-IR (ATR): m = 3,268 (OH), 3,017, 2,979,
123

1242
O. T. Gunkara et al.
2,946, 2,891, 1,737, 1,703, 1,683, 1,615, 1,595, 1,517,
1,440, 1,388, 1,239, 1,199, 1,162, 798, 773 cm-1; GC–MS
(EI, 70 eV): m/z = 469 (M?), 438, 347, 330, 290,
275, 254, 240, 107, 59; [a]2D0 = ?57.8° cm2 g-1 (c =
0.014 g cm-3, chloroform).
Methyl [2a(2S),3aa,4b,5b,7b,7aa]-2-(octahydro-1,3-dioxo-
5-phenyl-4,7-epoxy-2H-isoindol-2-yl)-3-(4-hydroxy-
phenyl)propanoate (11, C24H23NO6)
The general procedure described above was used with 4
and iodobenzene to afford 11 (65%) as a yellow crystals.
M.p.: 168–171 °C (column chromatography from ethyl
acetate:n-hexane 2:1); 1H NMR (500 MHz, CDCl3):
d = 1.78–1.86 (m, H9x), 2.04–2.10 (m, H9n), 2.76–2.88
(m, 3H, H2, H6, H8n), 3.16 (ddd, J = 2.3, 10.9, 11.0 Hz,
1H, CH2), 3.33 (dd, J = 4.7, 14.0 Hz, 1H, CH2), 3.68, 3.69
(2s, 3OCH3), 4.59 (s, H1), 4.68 (s, H7), 4.77–4.81 (m, 1H,
N–CH), 4.89 (d, J = 5.5 Hz, OH), 6.60–6.63 (m, 2H, Ar),
6.91–6.93 (d, J = 6.8 Hz, 2H, Ar), 7.11–7.22 (m, 5H,
Ar) ppm; 13C NMR (125 MHz, CDCl3): d = 33.33 (CH2),
40.50 (CH2), 47.69 (CH), 49.78 (C6), 50.15 (C2), 53.08
(CH3), 54.56 (N–CH), 79.15 (C1), 84.75 (C7), 115.60
(ArC), 127.04 (ArC), 127.35 (ArC), 127.37 (ArC), 128.87
(ArC), 130.50 (ArC), 130.53 (ArC) ppm; FT-IR (ATR):
Methyl [2a(2S,3R),3aa,4a,5a,7a,7aa]-2-[octahydro-1,
3-dioxo-5-(2-thienyl)-4,7-methano-2H-isoindol-2-yl]-
3-hydroxybutanoate (9, C18H21NO5S)
The general procedure described above was used with 3 and
2-iodothiophene to afford 9 (74%) as a colorless oil (column
chromatography from ethyl acetate:n-hexane 2:1). 1H NMR
(400 MHz, CDCl3): d = 1.19 (d, J = 5.5 Hz, 3H, CH3),
1.65 (d, J = 10.9 Hz, H10a), 1.82–1.88 (m, H10s), 1.96–2.03
(m, 2H, H9x, H9n), 2.92 (brs, 2H, H1, H7), 3.22–3.40 (m, 3H,
H2, H6, H8n), 3.78 (s, 3H, OCH3), 3.94 (dd, J = 9.4, 13.3 Hz,
1H, CH), 4.53–4.62 (m, OH), 4.80 (dd, J = 3.1, 4.7 Hz, 1H,
CH), 6.78–6.80 (m, 1H, Ar), 6.91 (ddd, J = 1.6, 5.5, 8.6 Hz,
1H, Ar), 7.13 (dd, J = 1.6, 5.5 Hz, 1H, Ar) ppm; 13C NMR
(100 MHz, CDCl3): d = 20.56 (CH3), 35.35 (CH2), 38.19
(C8), 39.87 (C9), 40.45 (C7), 47.52 (C1), 48.63 (C6), 49.08
(C2), 53.11 (OCH3), 59.65 (CH–OH), 66.41 (N–CH), 123.68
(ArC), 127.01 (ArC), 149.81 (ArC), 168.02 (C), 178.18
(C=O), 179.02 (C=O), 179.21 (C=O) ppm; FT-IR (ATR):
ꢀ
m = 3,437 (OH), 3,015, 2,954, 2,921, 1,775 (C=O), 1,740
(C=O), 1,696 (C=O), 1,614, 1,596, 1,515, 1,494, 1,392,
1,246, 1,203, 1,166, 836, 701, 672 cm-1; GC–MS (EI,
70 eV): m/z = 406 (M?), 391, 362, 345, 327, 313, 283,
172, 146, 129, 112, 57; [a]2D0 = ?88.94° cm2 g-1
(c = 0.013 g cm-3, chloroform).
ꢀ
m = 3,438 (OH), 3,068, 2,970, 2,881, 1,744 (C=O), 1,693
(C=O), 1,455, 1,435, 1,381, 1,277, 1,177, 740, 697 cm-1
;
Methyl [2a(2S),3aa,4b,5b,7b,7aa]-2-[octahydro-1,3-dioxo-
5-(2-thienyl)-4,7-epoxy-2H-isoindol-2-yl]-3-(4-hydroxy-
phenyl)propanoate (12, C22H21NO6S)
GC–MS (EI, 70 eV): m/z = 363 (M?), 346, 319, 304,
281, 215, 165, 148, 66; [a]2D0 = ?7.70° cm2 g-1 (c =
0.018 g cm-3, chloroform).
The general procedure described above was used with 4 and
2-iodothiophene to afford 12 (63%) as a yellow oil (column
chromatography from ethyl acetate:n-hexane 2:1). 1H NMR
(500 MHz, CDCl3): d = 1.87–1.94 (m, H9n), 2.08 (dd,
J = 8.8, 12.7 Hz, H9x), 2.74–2.86 (m, 2H2, H6), 3.14–3.24
(m, 2H, H8n, CH2), 3.32 (dd, J = 4.9, 9.7 Hz, 1H, CH2),
3.67, 3.68 (2s, 3OCH3), 4.67 (brs, H7), 4.76–4.80 (m, 1H,
N–CH), 4.90 (d, J = 5.8 Hz, H1), 5.32 (brs, OH), 6.60–6.63
(m, 2H, Ar), 6.76 (s, 1H, Ar), 6.82–6.84 (m, 1H, Ar),
6.91–6.93 (m, 2H, Ar), 7.07 (d, J = 4.9 Hz, 1H, Ar) ppm;
13C NMR (125 MHz, CDCl3): d = 39.60 (CH2), 41.76
(CH2), 38.82 (C8), 38.90 (C9), 42.00 (CH), 48.26 (C6), 48.34
(C2), 51.83 (OCH3), 53.31 (N–CH), 77.78 (C1), 83.72 (C7),
114.37 (ArC), 122.86 (ArC), 123.05 (ArC), 125.71 (ArC),
127.35 (ArC), 127.38 (ArC), 129.31 (ArC), 146.03 (C),
153.59 (C), 167.56 (C), 174.60 (C=O), 174.91 (C=O),
Methyl [2a(2S,3R),3aa,4a,5a,7a,7aa]-2-[5-(4-chloro-
phenyl)-octahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-
yl]-3-hydroxybutanoate (10, C20H22ClNO5)
The general procedure described above was used with 3
and 1-chloro-2-iodobenzene to afford 10 (67%) as a yellow
oil (column chromatography from ethyl acetate:n-hexane
1
2:1). H NMR (500 MHz, CDCl3): d = 1.18 (dd, J = 3.9,
6.8 Hz, 3H, CH3), 1.60 (d, J = 8.8 Hz, H10a), 1.66–1.75
(m, H10s), 1.83–1.90 (m, H9x), 1.98–2.03 (m, H9n), 2.16
(ddd, J = 1.9, 8.8, 10.7 Hz, H8n), 2.87 (brs, H7), 2.93 (d,
J = 5.8 Hz, H1), 3.16–3.33 (m, 3H2, H6, 1CH), 3.71, 3.72
(2s, 3OCH3), 4.52 (brs, OH), 4.77 (t, J = 4.8 Hz, 1H,
N–CH), 7.06–7.09 (m, 1H, Ar), 7.13–7.18 (m, 2H, Ar),
7.29 (d, J = 6.8 Hz, 1H, Ar) ppm; 13C NMR (125 MHz,
CDCl3): d = 19.45 (CH3), 31.59 (CH2), 38.82 (C8), 38.90
(C9), 39.17 (C7), 43.19 (C1), 47.58 (C6), 407.87 (C2), 51.89
(OCH3), 58.47 (CH–OH), 65.28 (N–CH), 125.52 (ArC),
126.46 (ArC), 129.08 (ArC), 133.68 (ArC), 140.91 (C),
166.89 (C), 176.84 (C=O), 176.93 (C=O), 177.60
ꢀ
174.96 (C=O) ppm; FT-IR (ATR): m = 3,398 (OH), 3,063,
2,987, 2,953, 1,776 (C=O), 1,738 (C=O), 1,696 (C=O),
1,614, 1,596, 1,516, 1,438, 1,392, 1,247, 1,204, 1,166, 830,
701, 657 cm-1; GC–MS (EI, 70 eV): m/z = 429 (M??2),
329, 313, 296, 219, 206, 178, 165, 149, 122, 107; [a]D20
-40.70° cm2 g-1 (c = 0.018 g cm-3, chloroform).
=
ꢀ
(C=O) ppm; FT-IR (ATR): m = 3,426, 3,063, 2,971,
2,881, 1,743, 1,695, 1,436, 1,378, 1,276, 1,190,
751 cm-1; GC–MS (EI, 70 eV): m/z = 391 (M?), 376,
361, 331, 314, 275, 231, 215, 165, 66;
[a]D20 = -8.80° cm2 g-1 (c = 0.013 g cm-3, chloroform).
Acknowledgments We gratefully acknowledge financial support of
this work by the Yildiz Technical University Scientific Research
Projects Coordination Department (project no. 28-01-02-04).
123

Synthesis of arylated norbornyl amino acid esters
1243
14. Kilama JJ, Drauz K, Hong W, Schafer M (1998) Herbicidal
bicyclic and tricyclic imides. US patent US5719104
15. Ferri N, Beccalli EM, Contini A, Corsini A, Antonino M, Radice
T, Pratesi G, Gelmi ML (2008) Bioorg Med Chem 16:1691
16. Biagini SCG, Bush SM, Gibson VC, Mazzariol L, North M,
Teasdale WG, Williams CM, Zagotto G, Zamuner D (1995)
Tetrahedron 51:7247
References
1. Wagner I, Musso H (1983) Angew Chem Int Ed 22:816
2. Gante J (1994) Angew Chem Int Ed 33:1699
3. Serron SA, Aldridge WS, Danell RM, Meyer TJ (2000) Tetra-
hedron Lett 41:4039
4. Sundararajan C, Falyey DE (2006) Photochem Photobiol Sci
5:116
5. Coppola GM, Schuster HF (1987) Asymmetric synthesis: con-
struction of chiral molecules using amino acids. Wiley, New
York
6. Williams RM (1989) Synthesis of optically active a-amino acids.
Pergamon, Oxford
7. Xu LW, Lu Y (2008) Org Biomol Chem 6:2047
8. Urbach H, Henning R, Becker R (1990) Derivatives of bicyclic
amino acids, agents containing them, and their use as hypoten-
sives. US Patent US4920144
9. Trabocchi A, Scarpi D, Guarna A (2008) Amino Acids 34:1
10. Dyatkin AB, Hoekstra WJ, Kinney WA, Kontoyianni M, Santulli
RJ, Kimball ES, Fisher MC, Prouty SM, Abraham WM, Gordon
PA, Hlasta DJ, He W, Hornby PJ, Damiano BP, Maryanoff BE
(2004) Bioorg Med Chem Lett 14:591
17. Heck RF (1985) Palladium reagents in organic synthesis. Aca-
demic, San Diego
18. de Meijere A, Meyer FE (1994) Angew Chem Int Ed 33:2379
19. Tsuji J (1996) Palladium reagents and catalyst. Wiley, New York
20. Cheprakov AV, Beletskaya IP (2000) Chem Rev 100:3009
21. Yao ML, Adiwidjaja G, Kaufmann DE (2002) Angew Chem Int
Ed 41:3375
22. Storsberg J, Yao ML, Ocal N, de Meijere A, Adam AEW,
Kaufmann DE (2005) Chem Commun 45:5665
23. Namyslo JC, Kaufmann DE (1999) Synlett 1999:114–116
24. Namyslo JC, Kaufmann DE (1999) Synlett 1999:804–806
25. Yolacan C, Bagdatli E, Ocal N, Kaufmann DE (2006) Molecules
11:603
26. Bagdatli E, Ocal N, Kaufmann DE (2007) Helv Chim Acta
90:2380
27. Goksu G, Gul M, Ocal N, Kaufmann DE (2008) Tetrahedron Lett
49:2685
11. Jones RCF, Berthelot DJC, Illey JN (2007) ARKIVOC (xi):73
12. Saaby S, Bayon P, Aburel PS, Jorgensen KA (2002) J Org Chem
67:4352
13. Sondhi S, Rani R, Roy P, Agrawal SK, Saxena AK (2009) Bioorg
Med Chem Lett 19:1534
123