Asymmetric synthesis of all four isomers of an unusual heterocycle- containing amino acid: 2-amino-3-furan-2-yl-pentanoic acid

Article abstract of DOI:10.1002/cjoc.201180489

All four isomers of a novel β-branched unusual amino acid were designed and synthesized with high stereoselectivity (>90% de) and in 33% -44% overall yields by the use of 4(R/S)-5,5-dimethyl-4-phenyl-oxazolidin-2-one as the chiral auxiliary via asymmetric

Full text of DOI:10.1002/cjoc.201180489

NOTE
DOI: 10.1002/cjoc.201180489
Asymmetric Synthesis of All Four Isomers of an Unusual
Heterocycle-Containing Amino Acid:
2-Amino-3-furan-2-yl-pentanoic Acid
Nie, Leia(聂蕾)
Yang, Ruia(杨睿)
Zhang, Conghaia(张从海)
Lin, Jun*,a(林军)
Yin, Haichuanb(尹海川)
Yan, Shengjiaoa(严胜骄)
a Key Laboratory of Medicinal Chemistry for Natural Resource, School of Chemical Science and Technology,
Yunnan University, Kunming, Yunnan 650091, China
b The Education Department of Yunnan Province, Kunming, Yunnan 650091, China
All four isomers of a novel β-branched unusual amino acid were designed and synthesized with high stereose-
lectivity (＞90% de) and in 33%—44% overall yields by the use of 4(R/S)-5,5-dimethyl-4-phenyl-oxazolidin-2-one
as the chiral auxiliary via asymmetric 1,4-Michael addition, direct or indirect azidation, hydrolysis and hydrogena-
tion reactions.
Keywords asymmetric synthesis, unusual amino acid, oxazolidinone, chiral auxiliary, 2-amino-3-furan-2-yl-
pentanoic acid
Introduction
furan-2-yl-pentanoic acid. The synthesis started from
the readily available starting material (E)-3-(furan-2-yl)-
acrylic acid (1), which was coupled with Davies’ “Su-
perQuats” auxiliaries (4R/S)-5,5-dimethyl-4-phenyl-
oxazolidin-2-one[5] to control the diastereoselective re-
actions and yield the imide conjugates 2a and 2b[6]
(Scheme 1).
Incorporation of conformationally constrained novel
β-branched α-amino acids into bioactive peptides pre-
sents a rational approach to the design of highly potent
and selective ligands.[1] Furthermore, the aromatic moie-
ties of peptide side chain groups play an important role
in the molecular recognition processes between peptide
ligands and specific receptors as well as receptor sub-
types. Aromatic ring-substituted amino acids can pro-
vide valuable tools in developing highly selective pep-
tide ligands with specific structural features. In addition,
they can provide a large lipophilic surface for binding to
receptors and for crossing membrane barriers.[2] A gen-
eral approach developed by Hruby et al. which can
produce four pure optical isomers, has synthesized sev-
eral series of specialized β-branched α-amino acids.[2-4]
However, further exploration of various specialized
amino acids, especially heterocycle-containing amino
acids, still remain a central goal for meeting the re-
quirements of peptide molecular design. Therefore, the
design and synthesis of such unusual β-branched amino
acids with lipophilic side chains have been crucial for
the further development of peptides and peptide ana-
logues.
Scheme 1 Preparation of 2a and 2b
Ph
Ph
O
HN
O
a
O
N
O
O
O
Ph
2a (81%)
COOH
O
HN
O
Ph
1
O
O
N
a
O
O
O
2b (83%)
Reagents and conditions: (a) (CH3)3CCOCl, Et3N, n-BuLi, THF, N2,
－78 ℃
The chiral Michael acceptors 2a or 2b were reacted
with EtMgBr via an asymmetric 1,4-Michael addition to
produce the key intermediates 3a or 3b, respectively.
The direct azidation of intermediates 3a or 3b intro-
duced the azido group by stereoselective electrophilic
azidation with trisyl azide[7] to produce α-azido deriva-
tives 4a or 4b, respectively (Scheme 2).
Results and Discussion
We report herein the total asymmetric synthesis of a
novel heterocycle-containing amino acid 2-amino-3-
*
E-mail: linjun@ynu.edu.cn
Received March 24, 2011; accepted August 25, 2011.
460
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Chin. J. Chem. 2012, 30, 460—465

Asymmetric Synthesis of All Four Isomers of an Unusual Heterocycle-Containing Amino Acid
Scheme 2 Preparation of 4a and 4b
Scheme 3 Preparation of 4c and 4d
Reagents and conditions: (b) EtMgBr, CuBr•Me2S, THF, N2, －78
℃; (c) KHMDS/NaH, Trisyl azide; HOAc, THF, N2, －78 ℃
Reagents and conditions: (d) NBS, N2, THF, －78 ℃; (e) NaN3,
DMF, 30—40 ℃
On the other hand, a one-pot tandem asymmetric
1,4-conjugate addition of organocuprates to the pro-
chiral α,β-unsaturated intermediates 2a or 2b, followed
by electrophilic bromination with N-bromosuccinimide
(NBS), yielded the bromo-compounds 3c or 3d. Then,
the bromo group of 3c or 3d was substituted by SN2
displacement with NaN3 which replaced the tetrame-
thylguanidium azide[8] to give α-azido products with
different α configurations, so that 4c or 4d were ob-
tained (Scheme 3) with high chiral selectivity (＞90%
de). Via these two methodologies, we successfully syn-
thesized all four isomers of α-azido products 4a—4d.
The removal of the chiral auxiliary of compounds 4a—
4d was performed using LiOH in the presence of hy-
drogen peroxide to yield azido acids 5a—5d in moder-
ate yields and the chiral auxiliary was recovered for
further use at the same time.[9] The resulting azido acids
5a—5d were subject to catalytic hydrogenation (10%
Pd/C) at 138—207 kPa for 2 h. The crude amino acids
were purified by ion-exchange chromatography to ob-
tain the desired corresponding optically pure target
α-amino acids 6a—6d (Scheme 4).
Scheme 4 Preparation of 6a—6d
Experimental
Reagents and conditions: (f) LiOH/H2O2, THF/H2O, 0 ℃; (g) 138—
207 kPa, hydrogen (H2), 10% Pd/C, MeOH/EtOH, 6 mol•L－1 HCl,
ion exchange resin/column
All reagents were commercially available and used
without further purification. Proton nuclear magnetic
resonance (1H NMR) and carbon nuclear magnetic
resonance (13C NMR) spectra were recorded on Bruker
AM-300 or AM-500 spectrometer in CDCl3 solution
with TMS as the internal standard. Mass spectra were
registered on an Agilent LC/MSD TOF spectrometer
(ESI mode, 70 eV). Optical rotations were measured on
a Perkin Elmer Model 341 Auto Polarimeter. The infra-
red (IR) spectra were recorded on a Shimadzu-450s in-
frared spectrophotometer with a KBr pellet. All melting
points were determined on an XT4A melting point ap-
paratus and were uncorrected. Diastereomeric excesses
(de) were determined on a Bruker AM-500 spectrometer.
THF and ether were freshly distilled from Na before use.
The chiral auxiliary 4(R/S)-5,5-dimethyl-4-phenyl-oxa-
zolidin-2-one was prepared following the Davies
method.[5]
General procedure for the synthesis of compound 2
To a pre-cooled solution of 1 (5 g, 36 mmol) in dry
THF (100 mL) stirred at －78 ℃, triethylamine (5 mL)
was added via a syringe, followed by the addition of
trimethylacetyl chloride (4.5 mL). The resulting white
suspension was stirred at －78 ℃ for 15 min, 0 ℃
for 1 h, and then at －78 ℃ for another 15 min before
transferring a stirred slurry of lithiated (4R/S)-5,5-
dimethyl-4-phenyl-oxazolidin-2-one respectively into it
via a cannula. The lithiated (4R)- or (4S)-5,5-dimethyl-
4-phenyl-oxazolidin-2-one was prepared 15 min in ad-
vance at －78 ℃ by addition of n-butyllithium (22 mL)
into the solution of (4R)- or (4S)-5,5-dimethyl-4-
phenyl-oxazolidin-2-one (5.75 g, 30 mmol) in THF (80
mL) at －78 ℃. The resulting slurry was stirred at
Chin. J. Chem. 2012, 30, 460—465
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461

Nie et al.
NOTE
General procedure for conjugate additions
－78 ℃ for 1 h and then at room temperature for 2 h.
The reaction was always protected under a nitrogen at-
mosphere. The reaction was quenched by the addition of
a saturated aqueous solution of NH4Cl (70 mL). The
organic phase was separated and the aqueous layer was
extracted by ethyl acetate (75 mL×2). The combined
organic phase was washed with saturated bicarbonate
(80 mL×2), brine (80 mL) and water (80 mL), dried
over anhydrous sodium sulfate and then rotary evapo-
rated. The crude product was further purified by recrys-
tallization from ethyl acetate and hexanes to give the
pure product.
To the above mixture of EtMgBr (19.2 mmol, 2
equiv.) and CuBr•SMe2 (1 g, 4.8 mmol, 0.5 equiv.) in
130 mL THF at －78 ℃, a solution of (E)-3-(3-(furan-
2-yl)acryloyl)-5,5-dimethyl-4-phenyl-oxazolidin-2-one
(2) (3 g, 9.6 mmol) in 50 mL of THF was added drop-
wise. The resulting mixture was stirred at －78 ℃ for
15 min, 0 ℃ for 2 h, and then at room temperature for
1 h under nitrogen. The process was monitored by TLC
and the reaction was quenched by adding saturated
ammonium chloride cautiously at 0 ℃. The organic
phase was separated and the aqueous layer was ex-
tracted by ether (50 mL×2). The combined organic
extracts were washed with brine (30 mL×2) and water
(30 mL), dried over anhydrous magnesium sulfate and
rotary evaporated to give the crude product which was
purified by column chromatography.
(R,E)-3-(3-(Furan-2-yl)acryloyl)-5,5-dimethyl-4-
phenyloxazolidin-2-one (2a): Yield 81%; m.p. 137—
1
20
D
138 ℃; [α]
＋83.1 (c 1.21, CHCl3); H NMR
(CDCl3, 500 MHz) δ: 7.86—6.45 (m, 10H, Ar and CH
＝CH), 5.18 (s, 1H, PhCH), 1.61 (s, 3H, CH3), 1.00 (s,
3H, CH3); 13C NMR (CDCl3, 125 MHz) δ: 165.4, 153.6,
151.8, 145.6, 136.8, 132.8, 129.3, 129, 126.8, 116.4,
115.1, 112.9, 82.7, 67.7, 29.4, 24.2; IR (KBr) ν: 3506,
3339, 3112, 3029, 2987, 2935, 2866, 2644, 2359, 2143,
1886, 1765, 1679, 1614, 1551, 1467, 1395, 1331, 1246,
1159, 1108, 1036, 976, 935, 868, 830, 750, 686, 591,
(R)-3-((R)-3-(Furan-2-yl)pentanoyl)-5,5-dimethyl-4-
phenyloxazolidin-2-one (3a): Yield 84%; m.p. 110—
1
20
D
112 ℃; [α]
－70.9 (c 1.00, CHCl3); H NMR
(CDCl3, 500 MHz) δ: 7.37—6.00 (m, 8H, Ar), 5.01 (s,
1H, PhCH), 3.44 (q, J＝8.6 Hz, 1H, furanyl-CH-C2H5),
3.23—3.13 (m, 2H, CH2CO), 1.61 (s, 3H, CH3), 1.67—
1.64 (m, 2H, CHCH2CH3), 0.97 (s, 3H, CH3), 0.79 (t,
J＝7.4 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 125 MHz)
δ: 172.4, 158.0, 154.1, 141.9, 137.2, 129.7, 129.5, 127.2,
110.8, 106.2, 83.3, 68.0, 40.4, 37.4, 29.8, 28.1, 24.5,
12.4; IR (KBr) ν: 3127, 2925, 2861, 1785, 1692, 1597,
1500, 1456, 1384, 1329, 1266, 1222, 1159, 1082, 1016,
975, 944, 856, 807, 738, 699, 631, 599, 527, 467 cm ;
ESI-MS m/z (%): 364 ([M＋Na]＋, 100); HR-MS (TOF
ES＋) calcd for C20H23NO4 [M＋Na]＋ 364.1525, found
364.1519.
－
＋
1
524, 484, 421 cm ; ESI-MS m/z (%): 311 (M , 100);
HR-MS (TOF ES＋) calcd for C18H17NO4 [M＋Na]＋
334.1057, found 334.1050.
(S,E)-3-(3-(Furan-2-yl)acryloyl)-5,5-dimethyl-4-
phenyloxazolidin-2-one (2b): Yield 83%; m.p. 136—
1
20
D
137 ℃; [α]
－81.2 (c 1.29, CHCl3); H NMR
－
1
(CDCl3, 500 MHz) δ: 7.86—6.46 (m, 10H, Ar and CH
＝CH), 5.18 (s, 1H, PhCH), 1.62 (s, 3H, CH3), 1.01 (s,
3H, CH3); 13C NMR (CDCl3, 125 MHz) δ: 165.4, 153.6,
151.8, 145.6, 136.8, 132.8, 129.3, 127.3, 126.8, 116.4,
115.2, 112.9, 82.8, 67.7, 29.4, 24.2; IR (KBr) ν: 3512,
3347, 3031, 3101, 2987, 2939, 2870, 2643, 2554, 2486,
2144, 1956, 1887, 1769, 1679, 1615, 1550, 1467, 1330,
1227, 1159, 1105, 1033, 976, 935, 868, 829, 750, 686,
(S)-3-((S)-3-(Furan-2-yl)pentanoyl)-5,5-dimethyl-4-
phenyloxazolidin-2-one (3b): Yield 81%; m.p. 110—
1
20
D
112 ℃; [α]
＋70.6 (c 1.06, CHCl3); H NMR
(CDCl3, 500 MHz) δ: 7.40—6.02 (m, 8H, Ar), 5.04 (s,
1H, PhCH), 3.50 (q, J＝8.5 Hz, 1H, furanyl-CH-C2H5),
3.29—3.17 (m, 2H, CH2CO), 1.57 (s, 3H, CH3), 1.73—
1.62 (m, 2H, CHCH2CH3), 1.00 (s, 3H, CH3), 0.85 (t,
J＝7.2 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 125 MHz)
δ: 172.4, 158.0, 154.1, 141.9, 136.7, 129.2, 129.8, 126.8,
110.3, 106.2, 83.29, 68.0, 40.4, 37.4, 29.8, 28.1, 24.5,
12.42; IR (KBr) ν: 3129, 1785, 1692, 1602, 1386, 1329,
1265, 1221, 1159, 1080, 1016, 807, 748, 696, 627, 470
－
＋
1
589, 524, 493 cm ; ESI-MS m/z (%): 311 (M , 100);
HR-MS (TOF ES＋) calcd for C18H17NO4 [M＋Na]＋
334.1056, found 334.1050.
General procedure for the preparation of organo-
copper reagents
A three-necked flask with a magnetic bar was placed
with magnesium scraps (500 mg, 20.8 mmol) in dry
ether or THF (50 mL). A few drops of bromoethane and
a bit of iodine were added. When the reaction liquid
showed signs of fading, more bromoethane (1.5 mL)
diluted in THF (30 mL) was added into the reaction
flask dropwise under nitrogen over 30 min and the reac-
tion was stirred at room temperature for 1 h. The Grig-
nard reagent EtMgBr (19.2 mmol) was prepared, then
cooled to 0 ℃ before being transferred via a cannula to
a stirring slurry of copper(I) bromide-dimethyl sulfide
complex (1 g, 4.8 mmol) in THF (50 mL) at －78 ℃.
The grey mixture was warmed to 0 ℃ and stirred for
30 min. The mixture turned black over time, at which
point it was ready for conjugate additions.
－
＋
1
cm ; ESI-MS m/z (%): 364 ([M＋Na] , 100); HR-MS
(TOF ES＋) calcd for C20H23NO4 [M＋Na]＋ 364.1515,
found 364.1519.
General procedure for the direct azidation reaction
Potassium bis(trimethylsilyl) amide (KHMDS) (7.2
mL, 0.91 mol•L－ in THF, 6.6 mmol, 1.5 equiv.) and
1
NaH (280 mg, 60% in oil, 1.5 equiv.) were added via a
syringe to a solution of N-acyloxazolidinone 3a or 3b
(1.5 g, 4.4 mmol) in 50 mL of THF at －78 ℃ under
nitrogen. The mixture was stirred at －78 ℃ under
nitrogen for 30 min. A pre-cooled solution of trisyl azide
(2 g, 6.6 mmol, 1.5 equiv.) in THF (40 mL) was added
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Asymmetric Synthesis of All Four Isomers of an Unusual Heterocycle-Containing Amino Acid
via a cannula. The reaction mixture was stirred at －78
℃ for 15 min and then quenched with acetic acid (1.2
mL, 20.2 mmol, 4.6 equiv.). The reaction flask was
immediately immersed in a water bath at 35 ℃ for 40
min with stirring, and the reaction was monitored by
TLC. When the majority of the starting substance had
been reacted, 100 mL of brine was added and the or-
ganic phase was separated. The aqueous phase was ex-
tracted with ether (50 mL×2). The combined organic
phase was washed with brine (40 mL×2) and water (40
mL×2), and dried over anhydrous magnesium sulfate.
Removal of the solvents gave the crude product as a
light yellow oil, which was purified by silica gel column
chromatography to obtain the α-azido compound 4a or
4b.
(E)-3-(3-(furan-2-yl)acryloyl)-5,5-dimethyl-4-phenyl-
oxazolidin-2-one (2) (3 g, 9.6 mmol) in 50 mL of THF
was added dropwise. The resulting mixture was stirred
at －78 ℃ for 15 min, 0 ℃ for 2 h and then at room
temperature for 1 h under nitrogen atmosphere. The
process was monitored by TLC. When the reaction was
finished, the reaction liquid was cooled to －78 ℃ for
15 min and an excess of NBS (2.65 g, 15 mmol, 2.3
equiv.) was added. As the reaction began to slow down,
the reaction liquid was continually stirred at －78 ℃
for 2 h. After the reaction had finished, the reaction
flask was transferred to an ice bath for 1 h. Then, a liq-
uid of mixture of 0.5 mol•L－ bisulfate and saturated
1
brine (80 mL, V/V＝1∶1) was added to quench the re-
action and the organic phase was separated. The aque-
ous phase was extracted with ether (50 mL×2), the
(R)-3-((2R,3R)-2-Azido-3-(furan-2-yl)pentanoyl)-5,5-
dimethyl-4-phenyloxazolidin-2-one (4a): Yield 85%;
colourless sticky liquid; [α] 2D0 －139.6 (c 0.80, CHCl3);
1H NMR (CDCl3, 500 MHz) δ: 7.38—6.16 (m, 8H, Ar),
5.54 (d, J＝10 Hz, 1H, CHN3), 4.86 (s, 1H, PhCH),
3.27—3.24 (m, 1H, franyl-CH-C2H5), 1.99—1.78 (m,
2H, CHCH2CH3), 1.37 (s, 3H, CH3), 0.95 (s, 3H, CH3),
0.85 (t, J＝7.4 Hz, 3H, CH2CH3); 13C NMR (CDCl3,
125 MHz) δ: 169.6, 153.5, 152.9, 142.5, 142.5, 141.4,
135.9, 129.4, 129, 126.6, 110.8, 109.1, 83.4, 67.5, 61.8,
43.0, 29.0, 24.3, 23.9, 12.0; IR (KBr) ν: 3126, 2104,
1776, 1708, 1496, 1397, 1328, 1267, 1224, 1160, 1098,
combined organic phase was washed with 0.5 mol•L－
1
hyposulphite (40 mL×2), brine (40 mL) and water (40
mL) and dried over anhydrous magnesium sulfate. Re-
moval of the solvents gave the crude product as a light
yellow oil, which was further purified by silica gel
column chromatography.
(R)-3-((2R,3S)-2-Bromo-3-(furan-2-yl)pentanoyl)-
5,5-dimethyl-4-phenyloxazolidin-2-one (3c): Yield 82%;
colourless sticky liquid; [α] 2D0 －82.9 (c 1.20, CHCl3);
1H NMR (CDCl3, 500 MHz) δ: 7.40—6.08 (m, 8H, Ar),
6.05 (d, J＝11 Hz, 1H, CHBr), 4.94 (s, 1H, PhCH), 3.40
(q, J＝10.5 Hz, 1H, CHC2H5), 1.78—1.67 (m, 2H,
CHCH2CH3), 1.44 (s, 3H, CH3), 0.99 (s, 3H, CH3), 0.84
(t, J＝7.1 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 125
MHz) δ: 168.9, 158.0, 154.2, 142.9, 136, 129.8, 127.2,
111.2, 108.7, 106.3, 83.6, 68.3, 67.8, 46.4, 44.1, 29.5,
26.1, 24.5, 11.9; IR (KBr) ν: 3510, 3130, 2967, 2874,
1769, 1597, 1557, 1480, 1398, 1319, 1257, 1217, 1165,
1115, 1039, 932, 884, 850, 809, 752, 702, 657, 566, 471
－
1
1010, 953, 815, 740, 707, 631, 531 cm ; ESI-MS m/z
(%): 405 ([M＋Na]＋, 100); HR-MS (TOF ES＋) calcd
for C20H22N4O4 [M＋Na]＋ 405.1539, found 405.1533.
(S)-3-((2S,3S)-2-Azido-3-(furan-2-yl)pentanoyl)-5,5-
dimethyl-4-phenyloxazolidin-2-one (4b): Yield 76%;
colourless sticky liquid; [α] 2D0 ＋126.4 (c 0.79, CHCl3);
1H NMR (CDCl3, 500 MHz) δ: 7.39—6.00 (m, 8H, Ar),
5.51 (d, J＝10.1 Hz, 1H, CHN3), 5.13 (s, 1H, PhCH),
3.30 (q, J＝6.8 Hz, 1H, CHC2H5), 1.88—1.68 (m, 2H,
CHCH2CH3), 1.62 (s, 3H, CH3), 1.05 (s, 3H, CH3), 0.85
(t, J＝7.3 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 125
MHz) δ: 169.6, 153.5, 152.9, 142.5, 135.9, 129.4, 126.5,
110.7, 108.3, 83.3, 67.5, 61.8, 43, 29, 24, 11.8; IR (KBr)
ν: 3125, 2870, 2105, 1775, 1709, 1601, 1451, 1397,
1330, 1268, 1226, 1161, 1106, 1016, 938, 815, 741, 705,
－
＋
1
cm ; ESI-MS m/z (%): 443 ([M＋Na] , 100); HR-MS
(TOF ES ＋ ) calcd for C20H22NO4Br [M ＋Na] ＋
442.0630, found 442.0624.
(S)-3-((2S,3R)-2-bromo-3-(furan-2-yl)pentanoyl)-5,5-
dimethyl-4-phenyloxazolidin-2-one (3d): Yield 80%;
colourless sticky liquid; [α] 2D0 ＋57.5 (c 1.10, CHCl3);
1H NMR (CDCl3, 500 MHz) δ: 7.35—6.12 (m, 8H, Ar),
6.05 (d, J＝11.1 Hz, 1H, CHBr), 4.90 (s, 1H, PhCH),
3.36 (q, J＝9.8 Hz, 1H, CHC2H5), 1.77—1.69 (m, 2H,
CHCH2CH3), 1.39 (s, 3H, CH3), 0.94 (s, 3H, CH3), 0.80
(t, J＝7.3 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 125
MHz) δ: 168.9, 154.1, 153.1, 142.9, 136, 129.8, 127.2,
111.2, 108.6, 83.6, 68.2, 67.5, 46.4, 44.1, 29.5, 26.0,
24.5, 11.9; IR (KBr) ν: 3129, 1770, 1707, 1621, 1399,
1332, 1271, 1221, 1163, 1099, 1019, 735, 597, 469
－
＋
1
632, 545, 450 cm ; ESI-MS m/z (%): 405 ([M＋Na] ,
100); HR-MS (TOF ES＋) calcd for C20H22N4O4 [M＋
Na]＋ 405.1535, found 405.1533.
General procedure for the asymmetric bromination
of N-acyloxazolidinone
To obtain the two other isomers of 4c and 4d with
different stereochemistry of the α-carbon, an electro-
philic bromination reaction was utilized. This was
achieved by stereoselective halogenation of the
metal-chelated enolate formed by the addition of the
ethylcuprate to the α,β-unsaturated acyloxazolidinones,
namely a one-pot tandem asymmetric conjugation addi-
tion followed by bromination to furnish the α-bromo
products 3c and 3d. To a mixture of EtMgBr (19.2
mmol, 2 equiv.) and CuBr•SMe2 (1 g, 4.8 mmol, 0.5
equiv.) in 130 mL of THF at －78 ℃, a solution of
－
＋
1
cm ; ESI-MS m/z (%): 443 ([M＋Na] , 100); HR-MS
(TOF ES ＋ ) calcd for C20H22NO4Br [M ＋Na] ＋
442.0629, found 442.0624.
General procedure for azide displacement
The bromo-compound 3c or 3d (800 mg, 1.9 mmol)
and NaN3 (200 mg, 1.6 equiv.) were dissolved in DMF
(50 mL). The solution was stirred under nitrogen at
room temperature overnight. A little water was added to
Chin. J. Chem. 2012, 30, 460—465
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
463

Nie et al.
NOTE
1
the reaction flask and stirred for a short period of time
before being extracted with ethyl acetate (30 mL×3).
The combined organic phase was washed with water (30
mL×2) and dried over anhydrous sodium sulfate. Re-
moval of the solvents gave the crude product as a light
yellow oil, which was purified by silica gel column
chromatography.
CHCl3); H NMR (CDCl3, 500 MHz) δ: 10.22 (broad,
1H, COOH), 7.36—6.05 (m, 3H, Ar), 4.18 (d, J＝6.0
Hz, 1H, CHN3), 3.25—3.22 (m, 1H, CHC2H5), 1.89—
1.77 (m, 2H, CHCH2CH3), 0.98 —0.85 (m, 3H,
CH2CH3); 13C NMR (CDCl3, 125 MHz) δ: 178.3, 153.3,
142.4, 110.7, 108.8, 65.7, 43.4, 22.8, 12.1; IR (KBr) ν:
3126, 2112, 1719, 1635, 1400, 1270, 1011, 733, 449
－
＋
1
(R)-3-((2S,3R)-2-Azido-3-(furan-2-yl)pentanoyl)-5,5-
dimethyl-4-phenyloxazolidin-2-one (4c): Yield 74%;
colourless sticky liquid; [α] 2D0 －85.8 (c 0.85, CHCl3);
1H NMR (CDCl3, 500 MHz) δ: 7.41—6.00 (m, 8H, Ar),
5.28 (d, J＝6.6 Hz, 1H, CHN3), 5.13 (s, 1H, PhCH),
3.38 (q, J＝4.2 Hz, 1H, CHC2H5), 1.87—1.68 (m, 2H,
CHCH2CH3), 1.63 (s, 3H, CH3), 1.05 (s, 3H, CH3), 0.86
—0.78 (m, 3H, CH2CH3); 13C NMR (CDCl3, 125 MHz)
δ: 170.4, 153.7, 153.1, 142.8, 136.4, 129.7, 127.8, 111.1,
108.9, 84.3, 68.2, 63.6, 43.7, 29.9, 24.9, 24.6, 12.5; IR
(KBr) ν: 3125, 2972, 2866, 2107, 1774, 1708, 1600,
1457, 1392, 1330, 1268, 1225, 1160, 1106, 1011, 939,
cm ; ESI-MS m/z (%): 210 ([M＋H] , 100).
(2S,3S)-2-Azido-3-(furan-2-yl)pentanoic acid (5b):
Yield 80%; colourless sticky liquid; [α] 2D0 ＋17.5 (c 0.8,
1
CHCl3); H NMR (CDCl3, 500 MHz) δ: 10.31 (broad,
1H, COOH), 7.38—6.06 (m, 3H, Ar), 4.21 (d, J＝6.1
Hz, 1H, CHN3), 3.27—3.23 (m, 1H, CHC2H5), 1.89—
1.79 (m, 2H, CHCH2CH3), 0.95 —0.85 (m, 3H,
CH2CH3); 13C NMR (CDCl3, 125 MHz) δ: 177.0, 155.2,
144.4, 112.7, 110.2, 67.6, 45.3, 24.8, 14.2; IR (KBr) ν:
3126, 2972, 2878, 2112, 1721, 1605, 1504, 1400, 1232,
－
1
1012, 932, 805, 732, 588, 561 cm ; ESI-MS m/z (%):
209 (M＋, 100).
－
1
874, 815, 740, 697, 632, 543, 454 cm ; ESI-MS m/z
(%): 405 ([M＋Na]＋, 100); HR-MS (TOF ES＋) calcd
for C20H22N4O4 [M＋Na]＋ 405.1531, found 405.1533.
(S)-3-((2R,3S)-2-Azido-3-(furan-2-yl)pentanoyl)-5,5-
dimethyl-4-phenyloxazolidin-2-one (4d): Yield 80%;
colourless sticky liquid; [α] 2D0 ＋85.5 (c 1.0, CHCl3);
1H NMR (CDCl3, 500 MHz) δ: 7.38—6.00 (m, 8H, Ar),
5.29 (d, J＝6.6 Hz, 1H, CHN3), 4.86 (s, 1H, PhCH),
3.24—3.28 (m, 1H, franyl-CH-C2H5), 1.99—1.77 (m,
2H, CHCH2CH3), 1.37 (s, 3H, CH3), 0.94 (s, 3H, CH3),
0.85—0.94 (m, 3H, CH2CH3); 13C NMR (CDCl3, 125
MHz) δ: 170.4, 153.7, 153.1, 142.8, 136.4, 129.7, 127.8,
111.1, 109, 84.3, 68.2, 63.6, 43.0, 29.0, 23.9, 23.9, 11.8;
IR (KBr) ν: 3127, 2356, 1773, 1708, 139, 1331, 1266,
(2S,3R)-2-Azido-3-(furan-2-yl)pentanoic acid (5c):
Yield 91%; colourless sticky liquid; [α] 2D0 －59.8 (c 0.5,
1
CHCl3); H NMR (CDCl3, 500 MHz) δ: 10.25 (broad,
1H, COOH), 7.37—6.20 (m, 3H, Ar), 4.11 (d, J＝5.8
Hz, 1H, CHN3), 3.30—3.23 (m, 1H, CHC2H5), 1.94—
1.70 (m, 2H, CHCH2CH3), 0.99 —0.86 (m, 3H,
CH2CH3); 13C NMR (CDCl3, 125 MHz) δ: 174.6, 157.6,
142.1, 112.7, 110.8, 106.2, 65.5, 43.8, 25.0, 12.3; IR
(KBr) ν: 3126, 2113, 1723, 1632, 1400, 1230, 1011, 803,
－
＋
1
733, 452 cm ; ESI-MS m/z (%): 232 ([M＋Na] , 100).
(2R,3S)-2-Azido-3-(furan-2-yl)pentanoic acid (5d):
Yield 83%; colourless sticky liquid; [α] 2D0 ＋58.5 (c
1
0.55, CHCl3); H NMR (CDCl3, 500 MHz) δ: 10.25
(broad, 1H, COOH), 7.37—6.20 (m, 3H, Ar), 4.11 (d,
J＝5.9 Hz, 1H, CHN3), 3.30—3.26 (m, 1H, CHC2H5),
1.94—1.71 (m, 2H, CHCH2CH3), 0.95—0.88 (m, 3H,
CH2CH3); 13C NMR (CDCl3, 125 MHz) δ: 175.9, 152.7,
142.4, 110.7, 108.8, 64.9, 43.3, 24.0, 12.1; IR (KBr) ν:
3125, 2988, 2113, 1723, 1623, 1503, 1399, 1230, 1108,
－
1
1221, 1164, 1099, 1024, 751, 705, 629 cm ; ESI-MS
m/z (%): 405 ([M＋Na]＋, 100); HR-MS (TOF ES＋)
calcd for C20H22N4O4 [M ＋Na] ＋ 405.1541, found
405.1533.
－
1
General procedure for hydrolysis of azido com-
pounds
1011, 805, 738, 612, 547 cm ; ESI-MS m/z (%): 232
([M＋Na]＋, 100).
Into a solution of α-azido compounds 4a—4d (500
mg, 1.3 mmol) in THF (60 mL), 20 mL of H2O was
added. After the solution was cooled to 0 ℃ for 15 min,
0.8 mL of 30% hydrogen peroxide (7.7 mmol, 6 equiv.)
was added dropwise, followed by the dropwise addition
of 370 mg lithium hydroxide monohydrate (8.8 mmol,
6.7 equiv.). The resulting mixture was stirred at 0 ℃
for 4 h. The reaction was quenched by the addition of
saturated sodium sulfite (50 mL) and stirred at room
temperature for 30 min. The aqueous phase was sepa-
rated and extracted with dichloride methane (DCM) (30
mL×3) for the recovery of the auxiliary. Then, the re-
maining aqueous phase was cooled to 0 ℃, acidified
General procedure for reduction of azido acids
A solution of azido acid 5a—5d (100 mg, 0.54 mmol)
in methanol (3 mL) and 6 mol•L－ HCl (0.5 mL) was
1
placed in a hydrogenation vessel. Then, 10% Pd/C (20
mg) was added. The hydrogenation vessel was vac-
uumed and refilled with hydrogen three times and
stirred under 138—207 kPa hydrogen for 2 h. The cata-
lyst was filtered, and the volatile was removed by rotary
evaporation. The residue was loaded on a coolant jack-
eted ion-exchange column filled with Amberlite IR-120
(H＋) resin. The column was washed with deionized wa-
ter until the eluent was neutral. The free amino acid was
washed off the column with a solution (28%
NH3•H2O∶H2O, V/V) in a volume ratio of 2∶3. The
fractions containing the product were combined and
evaporated to remove the NH3, then frozen and lyophi-
lized to give the title compounds 6a—6d.
with 6 mol•L－ HCl to pH 1 and extracted with DCM
1
(30 mL×3). The combined organic phases were dried
over anhydrous magnesium sulfate and evaporated in
vacuo to give the light yellow oils 5a—5d.
(2R,3R)-2-Azido-3-(furan-2-yl)pentanoic acid (5a):
Yield 85%; colourless sticky liquid; [α] 2D0 －17.8 (c 0.5,
(2R,3R)-2-Amino-3-(furan-2-yl)pentanoic acid (6a):
464
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 460—465

Asymmetric Synthesis of All Four Isomers of an Unusual Heterocycle-Containing Amino Acid
Yield 87%; white solid, [α] 2D0 －18.4 (c 0.55, 1 mol•L－
Acknowledgement
1
1
HCl); H NMR (D2O, 500 MHz) δ: 7.39—6.26 (m, 3H,
Project supported by the National Natural Science
Foundation of China (Nos. 20472071, 20562014 and
30860342) and Natural Science Foundation of Yunnan
Province (No. 2009cc017).
Ar), 4.20—4.19 (m, 1H, CHNH2), 3.26—3.25 (m, 1H,
CHC2H5), 0.92—0.74 (m, 5H, C2H5); 13C NMR (D2O,
125 MHz) δ: 171.1, 151.7, 143.9, 111.1, 109.5, 56.7,
42.0, 23.2, 11.7; IR (KBr) ν: 3433, 3136, 1632, 1400,
1118, 600 cm ; ESI-MS m/z (%): 184 ([M＋H] , 100);
HR-MS (TOF ES＋) calcd for C9H13NO3 [M＋H]＋
184.0974, found 184.0972.
－
＋
1
References
[1] (a) Hruby, V. J. Prog. Brain Res. 1992, 92, 215; (b) Hruby, V. J.;
Al-Obedi, F.; Kazmierski, W. Biochem J. 1990, 268, 249; (c) Hruby,
V. J. Life Sci. 1982, 38, 189; (d) Qian, X. H.; Russell, K. C.; Boteju,
L. W.; Hruby, V. J. Tetrahedron 1995, 51, 1033; (e) Qian, X. H.;
Shenderovich, M. D.; Kover, K. E.; Davis, P.; Horvath, R.; Zalewska,
T.; Yammamura, H.; Porreca, F.; Hruby, V. J. J. Am. Chem. Soc.
1996, 118, 7280.
[2] (a) Wang, S. H.; Tang, X. J.; Hruby, V. J. Tetrahedron Lett. 2000, 41,
1307; (b) Wang, W.; Xiong, C. Y.; Yang, J. Q.; Hruby, V. J. Tetrahe-
dron Lett. 2001, 42, 7717; (c) Wang, W.; Zhang, J. Y.; Xiong, C. Y.;
Hruby, V. J. Tetrahedron Lett. 2002, 43, 2137; (d) Wang, W.; Xiong,
C. Y.; Yang, J. Q.; Hruby, V. J. Tetrahedron 2002, 58, 3101.
[3] (a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2000, 11, 645; (b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahe-
dron: Asymmetry 2007, 18, 569; (c) Konno, H.; Aoyama, S.; Nosaka,
K.; Akaji, K. Synthesis 2007, 23, 3666; (d) Cranfill, D. C.; Lipton, M.
A. Org. Lett. 2007, 9, 3511; (e) Cativiela, C.; Ordonez, M. Tetrahe-
dron: Asymmetry 2009, 20, 1; (f) Martens, J. ChemCatChem 2010, 2,
379; (g) Drummond, L. J.; Sutherland, A. Tetrahedron 2010, 66,
5349; (h) Fustero, S.; Mateu, N.; Simon-Fuentes, A.; Acena, J. L.
Org. Lett. 2010, 12, 3014; (i) Radchenko, D. S.; Grygorenko, O. O.;
Komarov, I. V. Amino Acids 2010, 2, 515; (j) Iosub, V.; Haberl, A. R.;
Leung, J.; Tang, M.; Vembaiyan, K.; Parvez, M.; Back, T. G. J. Org.
Chem. 2010, 75, 1612.
(2S,3S)-2-Amino-3-(furan-2-yl)pentanoic acid (6b):
Yield 88%; white solid, [α] 2D0 ＋17.6 (c 0.55, 1 mol•L－
1
1
HCl); H NMR (D2O, 500 MHz) δ: 7.38—6.20 (m, 3H,
Ar), 4.21—4.20 (m, 1H, CHNH2), 3.28—3.24 (m, 1H,
CHC2H5), 0.81—0.76 (m, 5H, C2H5); 13C NMR (D2O,
125 MHz) δ: 171.2, 151.7, 143.8, 111.1, 109.5, 56.7,
41.4, 22.9, 11.6; IR (KBr) ν: 3433, 3136, 1632, 1400,
－
＋
1
1118, 600 cm ; ESI-MS m/z (%): 184 ([M＋H] , 100);
HR-MS (TOF ES＋) calcd for C9H13NO3 [M＋H]＋
184.0974, found 184.0965.
(2S,3R)-2-Amino-3-(furan-2-yl)pentanoic acid (6c):
Yield 86%; white solid, [α] 2D0 －13.6 (c 0.55, 1 mol•L－
1
1
HCl); H NMR (D2O, 500 MHz) δ: 6.90—5.78 (m, 3H,
Ar), 3.74—3.73 (m, 1H, CHNH2), 2.91—2.88 (m, 1H,
CHC2H5), 0.40—0.29 (m, 5H, C2H5); 13C NMR (D2O,
125 MHz) δ: 171.2, 151.7, 143.8, 111.2, 109.5, 56.7,
42.0, 23.2, 11.7; IR (KBr) ν: 3433, 3136, 1632, 1400,
－
＋
1
1118, 600 cm ; ESI-MS m/z (%): 184 ([M＋H] , 100);
HR-MS (TOF ES＋) calcd for C9H13NO3 [M＋H]＋
184.0974, found 184.0973.
(2R,3S)-2-Amino-3-(furan-2-yl)pentanoic acid (6d):
[4] (a) Nicolás, E.; Russel1, K. C.; Knollenberg; Hruby, V. J. J. Org.
Chem. 1993, 58, 7565; (b) Li, G. G.; Keith C; Russel; Jarosinski, M.
A.; Hruby, V. J. Tetrahedron Lett. 1993, 34, 2565 (c) Boteju, L. W.;
Wegner, K.; Qian, X. H.; Hruby, V. J. Tetrahedron 1994, 50, 2391 (d)
Xiang, L.; Wu, H. W.; Hruby, V. J. Tetrahedron: Asymmetry 1995, 6,
83; (e) Liao, S. B.; Hruby, V. J. Tetrahedron Lett. 1996, 37, 1563; (f)
Liao, S. B.; Han, Y. L.; Qiu, W.; Bruck, M.; Hruby, V. J. Tetrahedron
Lett. 1996, 37, 7917; (g) Liao, S. B.; Shenderovich, M. D.; Lin, J.;
Hruby, V. J. Tetrahedron 1997, 53, 16645; (h) Han, Y. L.; Liao, S. B.;
Qiu, W.; Cai, C. Z.; Hruby, V. J. Tetrahedron Lett. 1997, 38, 5135; (i)
Yuan, W.; Hruby, V. J. Tetrahedron Lett. 1997, 38, 3853; (j) Lin, J.;
Liao, S. B.; Hruby, V. J. Tetrahedron Lett. 1998, 39, 3117; (k) Lin, J.;
Liao, S. B.; Han, Y. L.; Qiu, W.; Hruby, V. J. Tetrahedron:
Asymmetry 1997, 8, 3213; (l) Wang, S. H.; Tang, X. J.; Hruby, V. J.
Tetrahedron Lett. 2000, 41, 1307; (m) Lin, J.; Liao, S. B.; Hruby, V.
J. J. Peptide Res. 2005, 65(1), 105.
[5] (a) Davies, S. G.; Sanganee, H. J. Tetrahedron: Asymmetry 1995, 6,
671; (b) Bull, S. G.; Davies, S. G.; Jones, S.; Polywka, M. E. C.;
Prasad, R. S.; Sanganee, H. J. Synlett 1998, 519; (c) Davies, S. G.;
Sanganee, H. J.; Szolcsanyi, P. Tetrahedron 1999, 55, 3337; (d) Bull,
S. D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A. D.
Tetrahedron: Asymmetry 2000, 11, 3475.
[6] (a) Evans, D. A.; Sjogren, B. Tetrahedron Lett. 1986, 26, 3783; (b)
Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757.
[7] Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am.
Chem. Soc. 1990, 112, 4011.
Yield 80%; white solid, [α] 2D0 ＋12.6 (c 0.55, 1 mol•L－
1
1
HCl); H NMR (D2O, 500 MHz) δ: 7.38—6.24 (m, 3H,
Ar), 4.13—4.12 (m, 1H, CHNH2), 3.37—3.36 (m, 1H,
CHC2H5), 0.80—0.75 (m, 5H, C2H5); 13C NMR (D2O,
125 MHz) δ: 171.9, 151.3, 143.9, 111.1, 109.4, 56.9,
41.5, 23.0, 11.6; IR (KBr) ν: 3433, 3136, 1632, 1400,
－
＋
1
1118, 600 cm ; ESI-MS m/z (%): 184 ([M＋H] , 100);
HR-MS (TOF ES＋) calcd for C9H13NO3 [M＋H]＋
184.0974, found 184.0963.
Conclusions
In summary, we have reported stereoselective syn-
thesis of the four individual isomers of the novel
heterocycle-containing amino acid 2-amino-3-furan-2-
yl-pentanoic acid. Davies’ “SuperQuats” chiral auxiliary
4(R/S)-5,5-dimethyl-4-phenyl-oxazolidin-2-one was used
to replace Hruby’s 4(R/S)-4-phenyl-oxazolidin-2-one,
and could control the entire synthesis with high stereo-
selectivity via asymmetric 1,4-Michael addition and
direct or indirect azidation reactions with a greater than
90% de and 33%—44% overall yield. The target com-
pounds represent attractive conformationally con-
strained amino acids that could be incorporated into
peptidomimetic structures with potential biological ac-
tivities. Further application of these compounds for the
preparation of novel non-proteinogenic α-amino acids is
currently underway.
[8] (a) Li, G. G.; Jarosinski, M. A.; Hruby, V. J. Tetrahedron Lett. 1993,
34, 2561; (b) Li, G. G.; Keith, C.; Russel; Jarosinski, M. A.; Hruby, V.
J. Tetrahedron Lett. 1993, 34, 2565; (c) Boteju, L. W.; Wegner, K.;
Hruby, V. J. Tetrahedron Lett. 1992, 33, 7491.
[9] Li, G.; Patel, D.; Hruby, V. J. J. Chem. Soc., Perkin Trans. 1 1994,
3057.
(E1103241 Cheng, B.)
Chin. J. Chem. 2012, 30, 460—465
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
465