Efficient Syntheses of Biologically Important (S)-2-Amino-8-oxodecanoic Acid (Aoda) and Homologues

Article abstract of DOI:10.1055/s-2003-41073

The efficient and practical asymmetric syntheses of the biologically important (S)-2-amino-8-oxodecanoic ester and its homologues have been achieved employing the Schoellkopf chiral auxiliary. Carbon-carbon bond formation between the appropriate alkyl bromide and the LDA generated anion of the Schoellkopf auxiliary, followed by hydrolysis provided the desired methyl ester of a long-chained keto amino acid in high yield with high selectivity.

Full text of DOI:10.1055/s-2003-41073

2
194
PAPER
Efficient Syntheses of Biologically Important (S)-2-Amino-8-oxodecanoic Acid
(
Aoda) and Homologues
a
a
a
b
Synthesis of
(
S
a
)-2-Amino
n
-8-oxodecan
g
oic
A
cid hee Kim,* Eun-Young Kim, Hyojin Ko, Young Hoon Jung
a
Natural Products Research Institute, College of Pharmacy, Seoul National University, 28 Yungun, Jongro, Seoul 110-460,
Republic of Korea
Fax 82(2)7628322; E-mail: pennkim@snu.ac.kr
b
College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
Received 20 May 2003; revised 3 July 2003
Abstract: The efficient and practical asymmetric syntheses of the
biologically important (S)-2-amino-8-oxodecanoic ester and its ho-
mologues have been achieved employing the Schöllkopf chiral aux-
iliary. Carbon-carbon bond formation between the appropriate alkyl
bromide and the LDA generated anion of the Schöllkopf auxiliary,
followed by hydrolysis provided the desired methyl ester of a long-
chained keto amino acid in high yield with high selectivity.
O
O
H2N
OH
O
N
H
1
N
N
NH
H
R
O
N
O
(
S)-2-amino-8-oxodecanoic acid
O
O
Key words: alkylation, amino acids, asymmetric synthesis, chiral
auxiliaries, diastereoslectivity
2
3
R = OMe, apicidine
R = H, apicidine A
O
O
N
H
O
H
The unusual keto amino acid, (S)-2-amino-8-oxodecanoic
acid (Aoda, 1), is a biologically important constituent of
the naturally occurring cyclic tetrapeptides, such as
N
NH
N
H
N
H
H
N
O
N
O
5
O
4
O
1
2
apicidins (2 and 3) and 9,10-deepoxy-chlamydocin 4
Figure 1). Apicidins and structurally related cyclic tet-
rapeptides are known to be potent inhibitors of histone
N-acetylated lysine
residue of histone
9
,10-deepoxy-chlamydocin
O
(
Figure 1 Chemical structures of compounds 1–4 and the N-acetyla-
deacetylases, integral nuclear isozymes that regulate ted lysine residue of histone 5.
gene transcription by deacetylating the -N-acetyl lysine
3
,4
5
residues of histones. Structural similarities between the
Aoda moiety of apicidins and N-acetylated lysine residues As part of an ongoing program, aimed at the search for a
of histone (5, Figure 1) suggest that Aoda is a reactive non-cyclic tetrapeptide histone deacetylase inhibitors, we
isostere of N-acetyl lysine and a key pharmacophoric ele- needed to synthesize both the enantiomers of Aoda and
6
–8
ment of these cyclic tetrapeptides. Consequently, ex- their related analogues in large quantities. In this paper,
tensive chemical modifications of the Aoda residue of we wish to report the practical and versatile synthesis of
apicidin were studied, which led to the discovery of a the long-chained keto amino acids in an enantiomerically
semi-synthetic, mechanism-based histone deacetylase in- pure form.
4
,6–8
hibitors with an increased potency.
There are a number of methodologies in the literature con-
Therefore, there has been considerable interest in the de- cerning the synthesis of amino acids containing long alkyl
velopment of a methodology for the efficient preparation side chains.1
2,13
Most synthetic methods have employed
of this unusual keto amino acid. Initially, the asymmetric the homologation of natural amino acids, with the appro-
synthesis of the N- and C-protected Aoda was achieved by
9
Viallefont in 1985. He employed the reaction of the ap-
O
propriate organocuprates with a halogen derivative of L-
homoserin. Very recently, three independent synthetic ap-
proaches of Aoda derivatives were reported for the syn-
thesis of apicidins. Kitahara synthesized the 2-amino-8-
protected hydroxydecanoic acid, using the appropriate
N
N
OMe
H2N
OMe O
MeO
7 a-c
n
n
O
6 a-c
1
0
Grignard reagent and 2-amino- -lactone. Singh accom-
N
N
OMe
a
b
n = 1
n = 2
plished the synthesis of the N- and C-protected Aoda un-
c n = 3
MeO
der photolytic conditions in the presence of n-Bu SnH,
8
3
1
1
using L-glutamic acid. Murray et al. prepared N-Boc-L-
Aoda from the Garner aldehyde in a six step process.12
HO
ref. 17
Br
n
n
O
SYNTHESIS 2003, No. 14, pp 2194–2198
0
2.
1
0
.
2
0
0
3
10 a-c
9 a-c
Advanced online publication: 24.09.2003
DOI: 10.1055/s-2003-41073; Art ID: F04503SS.pdf
Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis of 6.
©

PAPER
Syntheses of (S)-2-Amino-8-oxodecanoic Acid
2195
priate reagents.11–13 However, we felt that these approach- An attempt to improve the diastereoselectivity of the
es were not suitable to the preparation of a series of alkylation was executed by changing the reaction condi-
ketone-containing amino acid derivatives. Consequently, tions. As illustrated in Table 1, when the process was car-
a new enantioselective general synthesis of 6 was de- ried out at a lower temperature (–40 °C), the selectivity
signed utilizing the reaction of alkyl bromides 9 with the was slightly improved (trans/cis 8.0:1). The alkylation of
1
4
Schöllkopf chiral auxiliary 8 (Scheme 1). We chose the 13b with the recently described higher order bislactim
20
popular Schöllkopf auxiliary, bislactim ether 8, derived ether lithium cyanocuprate furnished similar diastereo-
from valine and glycine, since both enantiomers are readi- selectivity (trans/cis 7.8:1), but with a lower yield (68%).
ly available on a large scale and generally afford the alky- However, when the hard base LDA was employed instead
lated products with
diastereoselectivity.
a
high degree of trans- of the soft base n-BuLi, the alkylation process at –50 °C
provided the best trans-diastereoselectivity (trans/
cis 12.3:1) in 82% isolated yield of 14b.21
1
4–16
The requisite -bromoketones 9 could be conveniently
prepared by a retro-Barbier fragmentation, according to Separation of the major trans-isomer could easily be
1
7
established synthetic protocols of Li. Treatment of cy- achieved by flash chromatography with diastereomeric
clic tertiary alcohols 10a–c with bromine and potassium excess higher than 98%. Treatment of the purified bislac-
bicarbonate provided the corresponding fragmentation tim ether product 14b with 0.1 N HCl in THF effected
products 9a–c in high yields (70%, 80%, and 65%, respec- both the hydrolysis14 of the Schöllkopf chiral auxiliary
tively). When the -bromoketone 9b was treated with and the removal of the ketal protecting group to give the
chiral lithiated bislactim ether 11, the tertiary alcohol 12 desired methyl ester of Aoda 6b22 in 98% ee and 87%
was produced with high diastereoface selection in 77% yield (Scheme 3).
1
8
yield (Scheme 2). In this case, the addition of the lithiat-
ed bislactim ether 11 to the carbonyl group of 9b was
much faster than to the primary alkyl bromide functional
group. Therefore, the protection of the carbonyl group of
the -bromoketone 9 was necessary to obtain the desired
product. Using p-TsOH as a catalyst, the keto group of 9
was protected by converting it into the ketal group giving
compound 13 in high yield (80–95%) (Scheme 2).
The syntheses of the methyl ester of Aoda homologues
6a and 6c) was carried out by the same route starting
(
from the corresponding alkyl bromides 13, and the route
is amenable to scale-up to multigram level. Again, high
diastereoselectivities of the alkylation process and high
overall chemical yields were obtained, as summarized in
Table 1 and Scheme 3.
N
N
OMe
MeO
8
see text
N
OMe
N
N
OMe
+
MeO
N
n
O
MeO
n
O
O
O
15 a-c
14 a-c
a
a
b
n = 1
n = 2
O
c n = 3
H2N
OMe O
n
6
a-c
Scheme 2 Reagents and Conditions: (a) ethyleneglycol, p-TsOH,
benzene, reflux, 12 h, 82% for 13a; 80% for 13b; 95% for 13c.
Scheme 3 Reagents and Conditions: (a) 0.1 N HCl, THF, r.t., 12 h,
2% for 6a; 87% for 6b; 98% for 6c.
9
Carbon-carbon bond formation between these alkyl bro-
mides and the anion of the Schöllkopf chiral auxiliary was
investigated (Scheme 3). Initially, the alkylation of 13b
with the lithiated bislactim ether 11, generated in situ from
In conclusion, the efficient and practical asymmetric syn-
theses of the biologically important (S)-2-amino-8-oxode-
canoic ester and its homologues have been achieved in
good overall yields. The absolute stereochemistry was in-
troduced by employing the Schöllkopf chiral auxiliary.
The method presented here should allow access to the
8
and n-BuLi in THF at –78 °C, was carried out at 0 °C,
producing 14b in 84% yield along with its 5-epimer 15b
with modest diastereoselectivity (trans/cis 6.6:1).19
Synthesis 2003, No. 14, 2194–2198 © Thieme Stuttgart · New York

2
196
S. Kim et al.
PAPER
a
Table 1 Reaction Conditions and Product Ratios for the Reaction
of 8 with the Alkyl Bromides 13
7-Bromo-heptan-3-one (9a)
Yield: 70%; colorless oil.
1
H NMR (300 MHz, CDCl ): = 1.04 (t, J = 7.5 Hz, 3 H), 1.66–
.77 (m, 2 H), 1.80–1.90 (m, 2 H), 2.41 (m, 4 H), 3.39 (t, J = 6.6
Baseb
Temp. Time Ratioc Yieldof
3
Entry Alkyl
Bromide 13
1
d
(°C)
(h)
14:15 14 (%)
Hz, 2 H).
1
2
3
4
5
6
13b
n-BuLi
n-BuLi
0
3
6.6:1
8.0:1
7.8:1
84
81
68
13C NMR and IR data are in agreement with published values.23
13b
13b
13b
13a
13c
–40
18
16
16
16
16
8
-Bromo-octan-3-one (9b)
Yield: 80%; colorless oil.
n-BuLi/CuCN –23
1
H NMR (300 MHz, CDCl ): = 1.05 (t, J = 7.2 Hz, 3 H), 1.37–
3
LDA
LDA
LDA
–50
–50
–50
12.3:1 82
12.5:1 80
12.1:1 83
1
.48 (m, 2 H), 1.55–1.65 (m, 2 H), 1.82–1.91 (m, 2 H), 2.43 (m, 4
H), 3.40 (t, J = 6.6 Hz, 2 H).
13C NMR and IR data are in agreement with published values.17
9
-Bromo-nonan-3-one (9c)
a
The reactions were carried out in THF under N2.
Base was added at –78 °C and the reaction stirred for 20 min before
Yield: 65%; colorless oil.
IR (neat): 2936, 2859, 1715, 1458, 1111 cm–1.
b
the addition of alkyl bromide.
1
c
H NMR (300 MHz, CDCl ): = 1.04 (t, J = 7.5 Hz, 3 H), 1.24–
Determined by GC analysis of the crude products.
Isolated yield of 14 after column chromatography.
3
d
1.35 (m, 2 H), 1.38–1.48 (m, 2 H), 1.53–1.63 (m, 2 H), 1.79–1.89
(m, 2 H), 2.41 (m, 4 H), 3.39 (t, J = 6.6 Hz, 2 H).
1
3
C NMR (75 MHz, CDCl ): = 211.58, 42.11, 35.89, 33.80, 32.50,
family of long-chained keto amino acids in either enantio-
meric form.
3
2
8.30, 27.88, 23.57, 7.81.
+
MS (EI): m/z (%) = 221 (M , 5), 191 (24), 141 (33), 83 (60), 72 (71),
7 (100), 55 (66).
5
All chemicals were reagent grade and used as purchased. All reac-
tions were performed under an inert atmosphere of dry argon or ni-
trogen using distilled dry solvents. Reactions were monitored by
TLC analysis using Merck silica gel 60 F-254 thin layer plates.
Flash column chromatography was carried out on Merck silica gel
Preparation of 13a-c; General Procedure
To a stirred solution of -bromoketone 9 (1.1 mmol) in benzene (5
mL) was added ethyleneglycol (0.15 mL, 2.75 mmol) and p-TsOH
(10 mol%, 21 mg). The mixture was heated to reflux in a Dean–
6
0 (230–400 mesh). Optical rotations were measured using sodium
Stark apparatus for 12 h. After being cooled to r.t., the reaction mix-
ture was poured into sat. NaHCO solution, and extracted with Et O
1
light (D line 589.3 nm). H NMR (300 MHz) spectra were measured
on a Varian instrument and chemical shifts were recorded in units
relative to internal tetramethylsilane. IR spectra were measured on
Fourier Transform Infrared spectrometer. Petroleum ether used had
a bp 30–70 °C.
3
2
(
2 × 10 mL). The combined organic layers were washed with brine,
dried (MgSO ) and concentrated. The resultant residue was purified
4
by flash chromatography (silica gel; petroleum ether–EtOAc, 15: 1)
to yield 13.
2
-Benzyloxycarbonylamino-8-oxo-decanoic Acid Methyl
-(4-Bromo-butyl)-2-ethyl-[1,3]dioxlane (13a)24
Yield: 82%; colorless oil.
IR (neat): 2947, 2879, 1460, 1070 cm–1
2
22
Ester
[
18
]D +9.2 (c 0.76, CHCl ); ee 98% (determined by HPLC analysis
3
using a CHIRALCEL OD-H hexanes–i-PrOH, 9:1, flow rate: 10
mL/min), t 21.44 min (S)-isomer, t 26.58 min (R)-isomer (detect-
1
H NMR (300 MHz, CDCl ): = 0.89 (t, J = 7.2 Hz, 3 H), 1.45–
R
R
3
ed at 210 nm).
1.69 (m, 6 H), 1.82–1.92 (m, 2 H), 3.40 (t, J = 6.9 Hz, 2 H), 3.93 (s,
–
1
4 H).
IR (neat): 3347, 1735, 1715, 1528, 1213 cm .
13C NMR (75 MHz, CDCl
9.86, 22.48, 8.11.
): = 111.76, 65.00, 35.68, 33.65, 32.94,
1H NMR (300 MHz, CDCl3): = 1.04 (t, J = 7.5 Hz, 3H), 1.23–
3
2
1
4
7
.37 (m, 4 H), 1.50–1.83 (m, 4 H), 2.35–2.44 (m, 4 H), 3.74 (s, 3 H),
.33–4.40 (m, 1 H), 5.11 (s, 2 H), 5.25 (d, J = 8.1 Hz, 1 H), 7.28–
.38 (m, 5 H).
+
MS (EI): m/z (%) = 237 (7), 236 (M , 5), 209 (59), 207 (68), 135
(14), 101 (100), 57 (56).
13C NMR (75 MHz, CDCl3): = 211.4, 172.88, 155.78, 136.17,
2
-(5-Bromo-pentyl)-2-ethyl-[1,3]dioxlane (13b)24
Yield: 80%; colorless oil.
1
2
28.39, 128.04, 127.96, 66.83, 53.67, 52.20, 41.97, 35.77, 32.35,
8.59, 24.89, 23.39, 7.71.
–
1
IR (neat): 2944, 2880, 1462, 1073 cm .
Preparation of 9a–c; General Procedure17
1
H NMR (300 MHz, CDCl ): = 0.86 (t, J = 7.5 Hz, 3 H), 1.31–
3
To a solution of cyclic tertiary alcohol 10 (3.5 mmol) in CHCl (10
3
1
.44 (m, 4 H), 1.56–1.62 (m, 4 H), 1.78–1.88 (m, 2 H), 3.37 (t,
mL) was added powdered K CO (2.90 g, 21 mmol) at 0 °C (for 9a
2
3
J = 6.9 Hz, 2 H), 3.90 (s, 4 H).
and 9b) or –40 °C (for 9c). The mixture was stirred for 10 min, and
bromine (0.90 mL, 17.5 mmol) was then added dropwise. The reac-
tion mixture was stirred at 0 °C (for 9a and 9b) or –40 °C (for 9c)
for 10 h. The mixture was quenched with sat. Na S O solution (10
1
3
C NMR (75 MHz, CDCl ): = 111.78, 64.89, 36.37, 33.70, 32.70,
3
2
9.77, 28.34, 22.86, 8.04.
+
2
2
3
MS (EI): m/z (%) = 250 (M +1, 3), 221 (37), 101 (100), 69 (30), 57
mL) and extracted with EtOAc (2 × 15 mL). The combined organic
(
34).
layers were washed with brine, dried (MgSO ) and concentrated.
4
The resultant residue was purified by flash chromatography (silica
gel; hexanes–EtOAc, 10: 1) to yield 9.
2
-(6-Bromo-hexyl)-2-propyl-[1,3]dioxlane (13c)
Yield: 95%; colorless oil.
–
1
IR (neat): 2940, 1460, 1072 cm .
Synthesis 2003, No. 14, 2194–2198 © Thieme Stuttgart · New York

PAPER
Syntheses of (S)-2-Amino-8-oxodecanoic Acid
2197
1
1H NMR (300 MHz, CDCl3): = 0.68 (d, J = 6.9 Hz, 3 H), 0.89 (t,
J = 7.2 Hz, 3 H), 1.09 (d, J = 6.9 Hz, 3 H), 1.18–1.33 (m, 8 H),
1.55–1.65 (m, 4 H), 1.72–1.78 (m, 2 H), 2.24–2.29 (m, 1 H), 3.68
(s, 3 H), 3.69 (s, 3 H), 3.92 (s, 4 H), 3.93 (m, 1 H), 3.99–4.04 (m, 1
H).
H NMR (300 MHz, CDCl ): = 0.90 (t, J = 7.5 Hz, 3 H), 1.25–
.49 (m, 6 H), 1.57–1.66 (m, 4 H), 1.81–1.90 (m, 2 H), 3.40 (t,
3
1
J = 6.9 Hz, 2 H), 3.93 (s, 4 H).
13C NMR (75 MHz, CDCl3): = 111.99, 64.98, 36.56, 33.95, 32.71,
2
9.83, 29.02, 28.12, 23.58, 8.13.
13C NMR (75 MHz, CDCl
): = 163.96, 163.47, 112.09, 64.93,
0.66, 55.43, 52.36, 36.64, 34.09, 31.65, 29.83, 29.75, 29.45, 24.37,
3.73, 19.06, 16.54, 8.11.
+
3
MS (EI): m/z (%) = 265 [(M + 1), 3], 235 (13), 101 (100), 83, (11),
5
6
2
7 (47).
+
Preparation of 14a–c; General Procedure
MS (EI): m/z (%) = 368 (M , 20), 339 (30), 281 (32), 183 (62), 141
A solution of LDA (2.2 mL, 0.5 M in THF, 1.1 mmol) was added to
a stirred solution of the bislactim ether 8 (1.0 mmol) in THF (3 mL)
at –78 °C, which was stirred for 20 min. Then, a solution of alkyl
bromide 13 (300 mg, 1.1 mmol) in THF (2 mL) was added drop-
wise. The reaction mixture was warmed to –50 °C and stirred for 16
h. The solution was quenched with phosphate buffer solution (pH
(28), 101 (100), 57 (18).
HRMS (EI): m/z calcd for C H N O , 368.2675; found, 368.2680.
2
0
36
2
4
Preparation of 6a–c; General Procedure
To a solution of alkylated bislactim ether product 14 (1.4 mmol) in
THF (10 mL) was added 0.1 N HCl (1.7 mL). The reaction mixture
was stirred at r.t. for 12 h. Then, the solution was basified to pH 11
with ammonium hydroxide and extracted with EtOAc (2 × 10 mL).
The combined organic layers were washed with brine, dried
7
). The crude reaction mixture was warmed to r.t., and the solvent
was removed in vacuo. The resulting material was diluted with wa-
ter and extracted with EtOAc (2 × 10 mL). The combined organic
layers were washed with brine, dried (MgSO ) and concentrated.
4
(
MgSO ), and concentrated. The residue was purified by flash chro-
4
The residue was purified by flash chromatography (silica gel; hex-
anes–EtOAc, 10: 1) to give pure 14.
matography (silica gel; EtOAc–MeOH, 20: 1) to give pure 6.
2
-Amino-7-oxo-nonanoic acid methyl ester (6a)
2
-[4-(2-Ethyl-[1,3]dioxolan-2-yl)-butyl]-5-isopropyl-3,6-dime-
18
Yield: 92%; colorless oil; [ ]D +15.4 (c 0.98, MeOH).
thoxy-2,5-dihydropyrazine (14a)
Yield: 80%; colorless oil.
–
1
IR (neat): 2932, 2361, 1740, 1200 cm .
1
H NMR (300 MHz, CDCl .): = 1.03 (t, J = 7.5 Hz, 3 H), 1.24–
IR (neat): 2946, 2874, 1696, 1462, 1437, 1238, 1196, 1142, 1076,
1
3
–
1
1.44 (m, 2 H), 1.52–1.67 (m, 2 H), 1.71–1.80 (m, 2 H), 2.40 (m, 4
H), 2.77 (br s, 2 H), 3.52 (dd, J = 7.2, 5.4 Hz, 1 H), 3.72 (s, 3 H).
011 cm .
1
H NMR (300 MHz, CDCl ): = 0.68 (d, J = 6.6 Hz, 3 H), 0.89 (t,
3
1
3
C NMR (75 MHz, CDCl ): = 211.44, 176.34, 54.22, 51.76,
J = 7.2 Hz, 3 H), 1.04 (t, J = 6.9 Hz, 3 H), 1.16–1.40 (m, 4 H),
1
3
4
2.03, 35.73, 34.54, 25.29, 23.51, 7.69.
.56–1.65 (m, 4 H), 1.66–1.86 (m, 2 H), 2.21–2.31 (m, 1 H), 3.68
(s, 3 H), 3.69 (s, 3 H), 3.92 (s, 4 H), 3.93 (m, 1 H), 3.99–4.04 (m, 1
+
MS (EI): m/z (%) = 202 [(M + 1), 23], 172 (13), 142 (100), 124
H).
(
28), 57 (34).
13C NMR (75 MHz, CDCl3): = 163.89, 163.51, 112.02, 64.97,
+
HRMS (CI): m/z calcd for C H NO [M + H ], 202.1443; found,
1
0
20
3
6
1
0.67, 55.38, 52.36, 36.68, 34.11, 31.65, 29.88, 24.78, 23.66, 19.05,
6.54, 8.12.
2
02.1441.
+
2-Amino-8-oxo-decanoic acid methyl ester (6b)
Yield: 87%; colorless oil; [ ]D +16.3 (c 1.01, MeOH).
MS (EI): m/z (%) = 340 (M , 15), 297 (15), 279 (20), 253 (21), 239
(
1
7
28), 183 (22), 141 (30), 101 (100), 57 (35), 55 (20).
–
1
IR (neat): 3384, 2940, 2861, 1736, 1715 cm .
HRMS (EI): m/z calcd for C H N O , 340.2362; found, 340.2362.
1
8
32
2
4
1
H NMR (300 MHz, CDCl ): = 1.01 (t, J = 7.2 Hz, 3 H), 1.23–
3
2
-[5-(2-Ethyl-[1,3]dioxolan-2-yl)-pentyl]-5-isopropyl-3,6-dime-
thoxy-2,5-dihydropyrazine (14b)
1
3
.40 (m, 4 H), 1.47–1.71 (m, 4 H), 1.75 (br s, 2 H) 2.38 (m, 4 H),
.42 (dd, J = 7.5, 5.4 Hz, 1 H), 3.69 (s, 3 H).
Yield: 82%; colorless oil.
1
3
C NMR (75 MHz, CDCl ): = 211.57, 176.35, 54.27, 51.87,
3
IR (neat): 2946, 2874, 1696, 1462, 1462, 1437, 1237, 1196, 1140,
4
2.11, 35.81, 34.55, 28.89, 25.35, 23.58, 7.76.
–
1
1
076, 1013 cm .
+
MS (EI): m/z (%) = 216 [(M + 1), 5], 156 (80), 138 (15), 88 (42),
1H NMR (300 MHz, CDCl3): = 0.66 (d, J = 6.9 Hz, 3 H), 0.87 (t,
J = 7.5 Hz, 3 H), 1.03 (d, J = 6.9 Hz, 3H), 1.18–1.32 (m, 6 H),
.53–1.64 (m, 4 H), 1.65–1.79 (m, 2 H), 2.20–2.30 (m, 1 H), 3.66
74 (20), 57 (100).
+
HRMS (CI): m/z calcd for C H NO [M + H ], 216.1599; found,
1
1
22
3
1
(
2
16.1598.
s, 3 H), 3.67 (s, 3 H), 3.96 (s, 4 H), 3.92 (m, 1 H), 3.98–4.01 (m, 1
H).
2
-Amino-8-oxo-undecanoic acid methyl ester (6c)
13C NMR (75 MHz, CDCl3): = 163.89, 163.42, 112.04, 64.91,
19
Yield: 98%; colorless oil; [ ]D +17.8 (c 1.00, MeOH).
6
1
0.64, 55.38, 52.31, 52.26, 36.59, 34.03, 31.60, 29.76, 24.39, 23.70,
9.03, 16.50, 8.07.
–
1
IR (neat): 3380, 2936, 2859, 1738, 1715 cm .
1H NMR (300 MHz, CDCl
): = 1.03 (t, J = 7.2 Hz, 3 H), 1.24–
.36 (m, 6 H), 1.50–1.75 (m, 4 H), 2.04 (br s, 2 H), 2.35–2.43 (m, 4
+
3
MS (EI) m/z (rel. int.): 354 (M , 23), 339 (15), 311 (22), 267 (43),
1
1
83 (73), 141 (42), 101 (100), 57 (13).
H), 3.45 (dd, J = 7.5, 5.7 Hz, 1 H), 3.71 (s, 3 H).
13
HRMS (EI): m/z calcd for C H N O , 354.2518; found, 354.2516.
1
9
34
2
4
C NMR (75 MHz, CDCl ): = 211.74, 176.26, 54.32, 51.92,
3
4
2.27, 35.84, 34.63, 29.10, 29.01, 25.38, 23.74, 7.81.
2
-[6-(2-Ethyl-[1,3]dioxolan-2-yl)-hexyl]-5-isopropyl-3,6-dime-
+
thoxy-2,5-dihydropyrazine (14c)
MS (EI): m/z (%): 230 [(M + 1), 5)], 170 (100), 88 (14), 57 (73).
Yield: 83%; colorless oil.
+
HRMS (CI): m/z calcd for C H NO [M + H ], 230.1756; found,
1
2
24
3
IR (neat): 2944, 2872, 1696, 1462, 1437, 1236, 1196, 1140, 1076,
230.1759.
–
1
1
013 cm .
Synthesis 2003, No. 14, 2194–2198 © Thieme Stuttgart · New York

2
198
S. Kim et al.
PAPER
(12) Williams, R. M. Synthesis of Optically Active -Amino
Acknowledgment
Acids; Baldwin, J. E.; Magnus, P. D., Eds.; Pergamon: Press
Oxford, 1989.
This study was supported by a grant of the KRRC R&D Project, The
Province of Kyonggi, Republic of Korea.
(13) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
(
4
b) Chakraborty, T. K.; Ghosh, A. Tetrahedron Lett. 2002,
3, 9691; and reference cited therein.
References
(
14) (a) Schöllkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int.
Ed. Engl. 1981, 20, 798. (b) Schöllkopf, U. Top. Curr.
Chem. 1983, 109, 65. (c) Schöllkopf, U.; Busse, U.; Lonsky,
R.; Hinrichs, R. Liebigs Ann. Chem. 1986, 2150.
15) Bull, S. D.; Davies, S. G.; Moss, W. O. Tetrahedron:
Asymmetry 1998, 9, 321.
(
1) Singh, S. B.; Zink, D. L.; Polishook, J. D.; Dombrowski, A.
W.; Darkin-Rattray, S. J.; Schmatz, D. M.; Goetz, M. A.
Tetrahedron Lett. 1996, 37, 8077.
(
(
(
2) Tani, H.; Fujii, Y.; Nakajima, H. Phytochemistry 2001, 58,
305.
(
(
(
16) Both enantiomers of 8 are commercially available.
3) Darkin-Rattray, S. J.; Gurnett, A. M.; Myers, R. M.; Dulski,
P. M.; Crumley, T. M.; Alloco, J.; Cannova, C.; Meinke, P.
T.; Colletti, S. L.; Bednarek, M. A.; Singh, S. B.; Goetz, M.
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17) Zang, W.-C.; Li, C.-J. J. Org. Chem. 2000, 65, 5831.
1
18) Analysis by H NMR spectroscopy of the crude product
indicated that two diastereoisomers of 12 was present in a
1:1 ratio and the desired alkylated bislactim ether 7b was not
produced at all.
(
(
(
4) Colletti, S. L.; Li, C.; Fisher, M. H.; Wyvratt, M. J.; Meinke,
P. T. Tetrahedron Lett. 2000, 41, 7825 and reference cited
therein..
5) Rundlett, S. E.; Carmen, A. A.; Kobayashi, R.; Bavykin, S.;
Turner, B. M.; Grunstein, M. Proc. Natl. Acad. Sci. U.S.A.
(
19) Conversion of each pure diastereoisomers (14b and 15b) to
the thermodynamic mixture was studied. In 0.5 M NaOMe–
MeOH solution the two diastereoisomers slowly
interconvert at r.t. eventually reaching thermodynamic
equilibrium within about 1 week to give a 2.9:1 mixture of
1996, 93, 14503.
14b and 15b.
6) Meinke, P. T.; Colletti, S. L.; Doss, G.; Myers, R. W.;
Gurnett, A. M.; Dulski, P. M.; Darkin-Rattray, S. J.; Allocco,
J. J.; Galuska, S.; Schmatz, D. M.; Wyvratt, M. J.; Fisher, M.
H. J. Med. Chem. 2000, 43, 4919.
(
(
20) Baldwin, J. E.; Adlington, R. M.; Mitchell, M. B.
Tetrahedron 1995, 51, 5193.
21) For a previous example employing LDA as a base see: Ohba,
M.; Nishimura, Y.; Kato, M.; Fujii, T. Tetrahedron 1999, 55,
(
(
(
7) Meinke, P. T.; Colletti, S. L.; Ayer, M. B.; Darkin-Rattray,
S. J.; Myers, R. W.; Schmatz, D. M.; Wyvratt, M. J.; Fisher,
M. H. Tetrahedron Lett. 2000, 41, 7831.
8) Colletti, S. L.; Myers, R. W.; Darkin-Rattray, S. J.; Schmatz,
D. M.; Fisher, M. H.; Wyvratt, M. J.; Meinke, P. T.
Tetrahedron Lett. 2000, 41, 7837.
4999.
(
22) The methyl ester of (S)-Aoda was transformed into the
known N-Cbz and C-OMe protected Aoda. The structural
assignment of 6b was strongly supported by comparing the
spectral data of our synthesized N- and C-protected Aoda
1
1
with those reported by Singh.
9) Bajgrowicz, J. A.; El Hallaoui, A.; Jacquier, R.; Pigiere, C.;
Viallefont, P. Tetrahedron 1985, 41, 1833.
(
(
23) Polivin Yu, N.; Karakhanov, R. A.; Makarashin, S. V. Russ.
Chem. Bull. 1993, 42, 1106.
(
(
10) Kuriyama, W.; Kitahara, T. Heterocycles 2001, 55, 1.
11) Mou, L.; Singh, G. Tetrahedron Lett. 2001, 42, 6603.
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280.
Synthesis 2003, No. 14, 2194–2198 © Thieme Stuttgart · New York