Asymmetric synthesis of non-natural amino acid derivatives: (2R/3S) and (2S/3R) 2-(tert-butoxycarbonylamino)-3-cyclohexyl-3-phenyl propanoic acids

Article abstract of DOI:10.3184/174751915X14219405044187

Highly conformationally-constrained novel α-amino acid derivatives ((2R/3S ) and (2S/3R )-2-(tert-butoxycarbonylamino)-3- cyclohexyl-3-phenylpropanoic acids) have been synthesised with high stereoselectivity (> 90% de) and in 36-37% overall yields. In the synthesis, Evans' auxiliary (4(R/S )-4-phenyl-oxzaolidin-2-one) was used to control the stereoselectivity via the key reactions of asymmetric Michael addition, azidation and catalytic hydrogenolysis.

Full text of DOI:10.3184/174751915X14219405044187

86 RESEARCH PAPER
VOL. 39 FEBRUARY, 86–89
JOURNAL OF CHEMICAL RESEARCH 2015
Asymmetric synthesis of non-natural amino acid derivatives: (2R/3S) and
(2S/3R) 2-(tert-butoxycarbonylamino)-3-cyclohexyl-3-phenyl propanoic acids
Rui Yanga,b, Ya-Fei Guoa, Zhan-Yong Gaob, Qian Zhaoa, Qian-Yang Zhangb and Jun Linb*
aFaculty of Science, Kunming University of Science and Technology, Kunming 650500, P.R. China
bKey Laboratory of Medicinal Chemistry for Natural Resource (Ministry of Education), School of Chemical Science and Technology, Yunnan
University, Kunming 650091, P.R. China
Highly conformationally-constrained novel α-amino acid derivatives ((2R/3S) and (2S/3R)-2-(tert-butoxycarbonylamino)-3-
cyclohexyl-3-phenylpropanoic acids) have been synthesised with high stereoselectivity (> 90% de) and in 36–37% overall
yields. In the synthesis, Evans’ auxiliary (4(R/S)-4-phenyl-oxzaolidin-2-one) was used to control the stereoselectivity via the
key reactions of asymmetric Michael addition, azidation and catalytic hydrogenolysis.
Keywords: non-natural amino acid, oxazolidinone, asymmetric synthesis, chiral auxiliary, β-cyclohexylphenylalanine
Peptides and proteins, along with their receptors/targets,
are important chemical couriers because they affect all vital
processes of human and animal biology. A central objective in
modern peptide chemistry, as well as medicinal and organic
chemistry, is to develop efficient approaches to understand
the relationships between structure, conformation, dynamics,
and biological activities so as to design receptor type-
selective and subtype-selective peptide and peptidomimetic
ligands with specific conformational and topographical
features.1 Incorporation of conformationally-constrained novel
β-branched α-amino acids into bioactive peptides introduces
conformational constraints that have been used to obtain
important information on receptor-site structure and to optimise
therapeutic activity.2–6 This has resulted in the development
of a vast number of methods for the asymmetric synthesis of
non-proteinogenic α-amino acids.5–8 Among them, Hruby and
colleagues developed an asymmetric synthetic methodology for
the synthesis of highly conformationally-constrained α-amino
acids that contain two chiral centres, and a series of specialised
α-amino acids were synthesised (Fig. 1).2–6,9–17 Aromatic and
acyclic derivatives are among the numerous types of amino
acids that constitute these groups. Aromatic ring-substituted
amino acids act as valuable tools in developing highly selective
peptide ligands with specific structural features. In addition,
they can provide a large lipophilic surface for binding to
receptors and for crossing membrane barriers.9–12 Therefore,
the design and synthesis of such unusual β-branched amino
acids with lipophilic and cyclic side-chain groups have been
critical for the development of peptides and peptide analogues
(Fig. 1).
peptide ligands with a receptor/acceptor. Thus, peptide ligands
containing these unusual chimeric amino acids may possess
unique physico-chemical and conformational properties,
improve binding affinity and provide useful information about
the stereochemical requirements for peptide ligand–receptor
interactions. We now describe the details of the asymmetric
synthesis of the novel sterically constrained amino acid
derivatives,
2-(tert-butoxycarbonylamino)-3-cyclohexyl-3-
phenylpropanoic acids 5a and 5b.
Results and discussion
As shown in Scheme 1, the synthesis started from a readily
available starting material, trans-cinnamic acid, which was
coupled with optically pure Evans’ auxiliaries (4R) or (4S)-
4-phenyl-oxazolidin-2-one to yield the imide conjugates 1a
and 1b. In this step, phosphorus oxychloride was found to be
the best reagent for the coupling reaction, which proceeded
conveniently under mild conditions with excellent yields.19
Then, the chiral Michael acceptors 1a or 1b were reacted with
cyclohexyl-MgBr under catalysis by the copper(I) bromide-
dimethyl sulfide complex via an asymmetric conjugate
addition to produce the key intermediates 2a or 2b using
the reported optimised conditions.13–17,20 In the asymmetric
1,4-Michael addition reactions, Hruby and colleagues found
that different 4-substituted compounds were obtained in
good yield and optical purity. They studied the mechanism
using an NMR method and they also demonstrated the crystal
structure by X-ray analysis.9 However, in our reaction the
1
selectivity was not as good (de –85%, as determined by H
NMR spectroscopy). It was presumed that this was due to
the conformational flexibility of cyclohexyl.21 As a result, we
had to purify the products by column chromatography to give
the desired corresponding optically pure 2a or 2b (de> 90%),
which led to lower yields.
As illustrated in Fig. 1, our target amino acids contain
two side chain groups, a phenyl and an alicyclic group. The
combination of 4-substituted phenyl and alicyclic groups
may significantly increase the hydrophobic interactions of
OH
Boc
NH2
R
HO
NH
NH2
NH2
*
*
COOH
*
*
COOH
*
H
COO
COOH
*
*
*
Hruby's -branched α-amino acids
R
β
This work
Fig. 1 Highly conformationally-constrained α-amino acids.
* Correspondent. E-mail: linjun@ynu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 87
Ph
HN
O
Ph
Ph
O
iii
ii
O
O
N
O
N
N
87%
56%
91
%
O
O
O
1a
Ph
HN
i
2a
COOH
O
Ph
O
Ph
O
ii
O
iii
O
N
O
92
%
86%
55
%
O
O
2b
1b
Ph
N3
Boc
Boc
Ph
NH
NH
Ph
HN
iv
v
O
O
N
H
O
N
+
93%
90%
O
O
O
O
O
O
3a
O
a
4
a
5
oc
B
Ph
N3
Boc
Ph
NH
NH
Ph
HN
iv
91%
v
91%
O
O
N
N
H
O
+
O
O
O
O
O
O
O
3b
5b
4b
Scheme 1 Reagents and conditions: (i) POCl3, 70 °C; (ii) cyclohexyl-MgBr, CuBr·Me2S, THF, N2, –78 °C; (iii) (a) KHMDS/NaH, Trisyl azide; THF, N2, –78 °C;
(b) HOAc, KOAc, 35–40 °C; (iv) hydrogen (H2), 10%Pd/C, EtOAc, (Boc)2O; (v) LiOH/H2O2, THF/H2O, 0 °C.
Our target amino acid has two chiral centres which generated
four stereo isomers. In order to synthesise all four isomers, we
used Hruby’s approach as a guide. Introduction of the azido
group to β-aryl derivatives can be accomplished either by
direct or indirect azidation which led to diastereoselective
syntheses of (R)- and (S)-α-azido carboxylic acids.9 Following
this procedure, the α-azido derivatives 3a and 3b with high
diastereoselectivity were produced by direct azidation
of intermediates 2a or 2b with trisyl azide according to
the literatures.15,16 However, we failed to synthesise the
other two isomers, 4c and 4d. We originally expected to
perform stereoselective bromination of 2a and 2b with NBS
followed by SN2 displacement of the bromo group with
tetramethylguanidium azide to give α-azido products with
a different α-configuration. Unfortunately, the bromination
reaction with NBS did not work under any conditions just as
indicated by our previous work,15,16 and the reason is still not
clear. Next, the azido acids 3a or 3b were subjected to catalytic
hydrogenation (H2, Pd/C, 2.5 h) and the resulting amines were
protected as Boc derivatives in situ.22 The removal of the
chiral auxiliary from compounds 4a or 4b was effected by
using LiOH in the presence of hydrogen peroxide to produce
final amino acids 5a or 5b respectively. At the same time, the
chiral auxiliary was recovered in 73% yield and >90% ee.
We have not been able to obtain the other pair of amino acid
derivatives, (2R/3R) and (2S/3S) 2-(tert-butoxycarbonylamino)-
3-cyclohexyl-3-phenylpropanoic acids (5c and 5d) (Scheme 2).
In summary, the stereoselective synthesis of a pair of
individual isomers of novel alicyclic-substituted constrained
phenylalanine analogues has been achieved. The Evans’ chiral
auxiliary 4(R/S)-4-phenyloxazolidin-2-one provides highly
stereoselective control of the whole synthesis via asymmetric
1,4-Michael addition, direct azidation, one-pot hydrogenolysis,
amine protection and hydrolysis reactions with a greater than
90% de and 36–37% overall yields. The target compounds
represent attractive conformationally-constrained amino acids
that may be incorporated into peptidomimetic structures with
potential biological activities. Further application of these
compounds for the preparation of novel non-proteinogenic
α-amino acids is currently underway.
Experimental
All reactions were monitored by TLC; TLC was performed on silica
gel GF254. Flash column chromatography was performed on silica
gel (200–300 mesh). Melting points were measured on a XT4A
temperature apparatus and were uncorrected. Optical rotations were
measured on a JASCO DIP-370 polarimeter. NMR spectra were
recorded on a Bruker DRX 500 NMR spectrometer and chemical
shifts were expressed in ppm (δ) relative to TMS as the internal
standard; J values are given in Hz. The IR spectra were recorded on
a FTIR EQUNOX 55 IR spectrophotometer with KBr pellets. High-
resolution mass spectra (HRMS) were determined on VG Auto Spec-
3000 spectrometer. Diastereometric excesses (de) were determined
on Bruker AM-500 spectrometer. All reagents were commercially
available and used without further purification. THF was freshly
distilled from Na before use.

88 JOURNAL OF CHEMICAL RESEARCH 2015
Boc
Ph
Br
Ph
N3
NH
O
O
OH
N
N
2a
O
O
O
O
O
3c
4c
5c
Boc
Ph
Ph
N3
NH
r
B
OH
O
O
N
N
2b
O
O
O
O
O
3d
4d
5d
Scheme 2
Synthesis of compounds 1a–b; general procedure
1H, oxazolidinone, –CH2); 3.52–3.47 (m, 1H, –CβH–), 3.24–3.19
(m, 1H, –CαH2–), 2.97–2.92 (m, 1H, –CαH2–), 1.79–0.52 (m, 11H,
cyclohexyl proton); 13C NMR (CDCl3, 125 MHz) δ 172.4, 154.1, 143.5,
139.4, 129.5, 129.0, 128.9, 128.7, 128.4, 126.6, 126.5, 125.3, 70.2,
58.0, 48.0, 43.3, 39.1, 31.4, 31.3, 26.8; IR (KBr) ν: 3035, 2923, 1784,
1701, 1450, 1391, 1387, 1240, 1172, 695 cm–1; HRMS for C24H27NO3:
[M + Na]+; calcd: 400.1883; found: 400.1880.
A mixture of (4R or 4S)-4-phenyl-oxazolidin-2-one (6.5 g, 41.4 mmol),
trans-cinnamic acid (6.8 g, 46 mmol), and phosphorus oxychloride
(13 mL) was heated at 70 °C for 2.5 h. The process was monitored by
TLC. The reaction mixture was slowly cooled to room temperature
and quenched by the addition of ice water (80 mL). Ice water (50 mL)
was added again when the bubbles vanished, and the mixture was
stirred at 0 °C for 1 h. The precipitate was filtered off and this crude
product was purified by recrystallisation (ethyl acetate: hexane=1:1)
to give the pure product.
(R)-3-((S)-3-Cyclohexyl-3-phenylpropanoyl)-4-phenyloxazolidin-
2-one (2b): White solid; yield 55%; m.p. 117.8–118.6 °C; [α]D20= –99.5
1
(c 0.38, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.37–7.12 (m, 10H,
aromatic protons), 5.18 (q, J=3.4 Hz, 1H, oxazolidinone, PhCH–),
4.44 (t, J=8.7 Hz, 1H, oxazolidinone, –CH2), 4.17 (q, J= 3.5 H z,
1H, oxazolidinone, –CH2); 3.54–3.48 (m, 1H, –CβH–), 3.25–3.20
(m, 1H, –CαH2–), 2.98–2.94 (m, 1H, –CαH2–), 1.81–0.73 (m, 11H,
cyclohexyl proton); 13C NMR (CDCl3, 125 MHz) δ 172.4, 154.1, 143.5,
139.4, 129.5, 129.0, 128.9, 128.4, 126.6, 126.3, 125.6, 70.2, 58.0, 48.1,
43.3, 39.1, 31.4, 31.3, 26.7; IR (KBr) ν: 3035, 2922, 1785, 1702, 1451,
1390, 1327, 1214, 702 cm–1; HRMS for C24H27NO3: [M+Na]+; calcd:
400.1883; found: 400.1876.
(S)-4-Phenyl-3-((E)-3-phenylacryloyl)oxazolidin-2-one (1a): White
specula; yield 91%; m.p. 170–171.5 °C (lit.23 170 °C); [α]D20= +0.8
(c 0.64, CHCl3); 1H NMR(CDCl3, 500 MHz) δ 7.96–7.27 (m,
12H, aromatic protons and –CH=CH–), 5.57 (q, J=3.8 Hz, 1H,
oxazolidinone PhCH–), 4.74 (t, J=8.8 Hz, 1H, oxazolidinone –CH2),
4.32 (q, J=3.9 Hz, 1H, oxazolidinone –CH2); 13C NMR (CDCl3,
125 MHz) δ 165.2, 154.2, 147.1, 139.5, 134.9, 131.1, 129.6, 129.3, 129.1,
126.4, 117.3, 70.1, 58.3; IR (KBr) ν: 3080, 2987, 1774, 1681, 1624,
1390, 1332, 1226, 712 cm–1; HRMS for C18H15NO3: [M+Na]+ (calcd.:
316.0944; Found: 316.0938).
Direct azidation reaction; general procedure
(R)-4-Phenyl-3-((E)-3-phenylacryloyl)oxazolidin-2-one (1b): White
specula; yield 92%; m.p. 169.2–170.9 °C (lit.24 172–174 °C); [α]
CAUTION: Due to the possibility of explosion, the azides were
handled with appropriate precautions at <40 °C.
20=–2.4 (c 0.60, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.95–7.26
1
D
Potassium bis(trimethylsilyl)amide (KHMDS) (5 mL, 0.91 M in THF,
3 mmol, 1.5 equiv.) and NaH (280 mg, 60% in oil, 1.5 equiv.) was added
using a syringe to a solution of 2a or 2b (800 mg, 2 mmol) in THF
(15 mL) at −78 °C under N2. The mixture was stirred at −78 °C under N2
for 30 min. A precooled solution of trisyl azide (980 mg, 3 mmol,
1.5 equiv.) in THF (15 mL) was added via a cannula. The reaction
mixture was stirred at −78 °C for 15 min and then quenched with acetic
acid (1.75 mL, 9.2 mmol, 4.6 equiv.) and potassium acetate (30 mg,
0.3 mmol, 0.15 equiv.). The reaction flask was immediately immersed in
a water bath at 35–40 °C for 10 h with stirring. The reaction was
monitored by TLC and the reaction was quenched by addition of brine
(20 mL). The organic phase was separated. The aqueous phase was
extracted with ether (2×20 mL). The combined organic phases were
washed with brine (2×20 mL) and water (2×20 mL), then dried over
anhydrous MgSO4. Removal of the solvents gave the crude product as a
light yellow oil, which was purified by silica gel column
chromatography (ethyl acetate:hexane=1:15) to get the α-azido
compound 3a or 3b.
(S)-3-((2S,3R)-2-Azido-3-cyclohexyl-3-phenylpropanoyl)-4-
phenyloxazolidin-2-one (3a): yield 87%; white solid; m.p. 159–160 °C;
[α]D20=+225.3 (c 0.72, CHCl3); 1H NMR (CDCl3, 500 MHz) δ
7.33–7.15 (m, 10H, aromatic protons), 5.66 (d, J=11.0 Hz, 1H, –CαH–);
4.78–4.77. (m, 1H, oxazolidinone, PhCH–), 4.12 (t, J=8.4 Hz, 1H,
oxazolidinone, –CH2–), 4.06–4.03 (m, 1H, oxazolidinone, –CH2–);
3.10–3.08 (m, 1H, –CβH–), 1.94–0.86 (m, 11H, cyclohexyl proton);
13C NMR (CDCl3, 125 MHz) δ 169.9, 153.6, 138.6, 138.6, 129.9, 129.7,
129.2, 128.6, 127.6, 126.0, 70.4, 59.9, 58.1, 53.0, 39.8, 32.2, 29.1, 27.1,
26.8, 26.7; IR (KBr) ν: 3032, 2930, 2857, 2098, 1781, 1701, 1493,
(m, 12H, aromatic protons and –CH=CH–), 5.56 (q, J=3.9 Hz, 1H,
oxazolidinone PhCH–), 4.75 (t, J=8.8 Hz, 1H, oxazolidinone –CH2),
4.32 (q, J=3.8 Hz, 1H, oxazolidinone –CH2); 13C NMR (CDCl3,
125 MHz) δ:165.2, 154.2, 147.1, 139.5, 134.9, 131.1, 129.6, 129.3, 129.1,
129.0, 126.4, 117.3, 70.4, 58.3; IR (KBr) ν: 3080, 2987, 1773, 1681,
1624, 1390, 1332, 1212, 712 cm–1; HRMS for C18H15NO3: [M+Na]+;
calcd: 316.0944; found: 316.0946.
General procedure for the conjugate additions
A solution of 1a or 1b (3 g, 9.6 mmol) in 30 mL THF under N2 was
added dropwise to a mixture of freshly prepared cyclohexyl MgBr
(19.2 mmol, 2 equiv.) and copper (I) bromide-dimethyl sufide complex
(1 g, 4.8 mmol, 0.5 equiv.) in 50 mL THF at −78 °C. The resulting
mixture was stirred at −78 °C for 15 min and 0 °C for 2 h, and then
slowly warmed to room temperature for 1 h under N2. The process
was monitored by TLC and the reaction was quenched by addition of
saturated ammonium chloride solution (20 mL) cautiously at 0 °C. The
organic phase was separated and the aqueous layer was extracted by
ether (2×ꢀ20 mL). The combined organic extracts were washed with
brine (2×ꢀ30 mL) and water (30 mL), dried over anhydrous magnesium
sulfate and concentrated under reduced pressure to give the crude
product which was purified by silica gel chromatography (ethyl
acet ate: hexane = 1 : 15).
(S)-3-((R)-3-Cyclohexyl-3-phenylpropanoyl)-4-phenyloxazolidin-2-
one (2a): White solid; yield 56%; m.p. 119.5–120.2 °C; [α]D20= +92.2
1
(c 0.43, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.33–7.11 (m, 10H,
aromatic protons), 5.15 (q, J=3.2 Hz, 1H, oxazolidinone, PhCH–),
4.43–4.40 (t, J=8.7 Hz, 1H, oxazolidinone, –CH2), 4.15 (q, J= 3.4 H z,

JOURNAL OF CHEMICAL RESEARCH 2015 89
1389, 1232, 1196, 707 cm–1; HRMS for C24H26N4O3: [M+Na]+ (calcd.:
441.1897; Found: 441.1893).
[α]D20=+0.70; (c 0.22, CHCl3); H NMR (CDCl3, 500 MHz) δ 10 (s,
1
1H, COOH), 7.33–7.12 (m, 5H, aromatic protons), 4.92–4.87 (m,
2H, –CαH– and –NH), 2.81–2.79 (m, 1H, –CβH–), 2.24–0.75 (m, 20H,
cyclohexyl proton and –C(CH3)3); 13C NMR (CDCl3, 125 MHz) δ 178.1,
156.5, 140.2, 130.3, 129.7, 128.5, 81.4, 56.9, 55.7, 39.4, 32.8, 32.7, 29.7,
27.7, 27.5; IR (KBr) ν: 3438, 3327, 2976, 2928, 2852, 2537, 1720, 1658,
1497, 1453, 1399, 1388, 1236, 1162, 1055, 1028, 771, 703 cm–1; HRMS
for C20H29NO4: [M]+; calcd: 347.2097; found: 347.2098.
(2R,3S)-2-(tert-Butoxycarbonylamino)-3-cyclohexyl-3-phenyl-
propanoic acid (5b): White solid; yield 91%; m.p. 126.8–127.6 °C;
[α]D20=–0.74 (c 0.20, CHCl3); H NMR (CDCl3, 500 MHz) δ 9.5 (s,
1H, COOH), 7.29–7.02 (m, 5H, aromatic protons), 4.89–4.87 (m,
2H, –CαH– and –NH), 2.78–2.76 (m, 1H, –CβH–), 2.21–0.70 (m, 20H,
cyclohexyl proton and –C(CH3)3); 13C NMR (CDCl3, 125 MHz) δ 177.1,
155.5, 139.3, 129.4, 128.8, 127.6, 80.5, 56.0, 54.8, 38.5, 31.8, 28.8, 26.8,
26.6; IR (KBr) ν: 3438, 3326, 2976, 2928, 2852, 2538, 1720, 1658, 1497,
1453, 1399, 1388, 1236, 1162, 1055, 1028, 772, 703 cm–1; HRMS for
C20H29NO4: [M]+; calcd: 347.2097; found: 347.2103.
( R)-3-((2R,3S)-2-Azido-3-cyclohexyl-3-phenylpropanoyl)-
4-phenyloxazolidin-2-one (3b): White solid; yield 86%; m.p.
162.1–162.5 °C; [α]D20=–236.5 (c 0.59, CHCl3); 1H NMR (CDCl3,
500 MHz,) δ 7.34–7.15 (m, 10H, aromatic protons), 5.66 (d, J= 11.2 H z,
1H, –CαH–); 4.79–4.77 (m, 1H, oxazolidinone, PhCH–), 4.12 (t,
J=8.5 Hz, 1H, oxazolidinone, –CH2–), 4.05 (q, J= 2.8 H z, J= 8.6 H z,
1H, oxazolidinone, –CH2–); 3.10–3.07 (m, 1H, –CβH–), 1.94–0.84
(m, 11H, cyclohexyl proton); 13C NMR (CDCl3, 125 MHz) δ 169.9,
153.7, 138.6, 138.5, 129.9, 129.7, 129.2, 128.7, 127.7, 126.0, 70.4, 59.9,
58.1, 53.0, 39.8, 32.2, 29.0, 27.1, 26.9, 26.7; IR (KBr) ν: 3032, 2930,
2857, 2098, 1781, 1701, 1494, 1390, 1232, 1196, 707 cm–1; HRMS for
C24H26N4O3: [M+Na]+; calcd: 441.1897; found: 441.1895.
1
One-pot reduction and Boc protection of azido compounds; general
procedure
A solution of azido compound 3a or 3b (1.8 g, 4.3 mmol) in ethyl
acetate (40 mL) and Boc anhydride (1.9 g, 8.7 mmol) was placed
in a flask with a balloon, and then 10% Pd/C (450 mg, 25%w) was
added. The balloon was emptied and refilled with H2 three times,
and stirred under H2 for 4 h. The catalyst was filtered off, and the
volatile material was removed by rotary evaporation. The remaining
material was purified by silica gel column chromatography (ethyl
acetate:hexane=1:10) to yield the compound 4a or 4b.
Electronic Supplementary Information
The spectral data are available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data.
This work was supported by National Natural Science
Foundation of China (NSFC) (nos 21062009, 20562014),
the Natural Science Foundation of Yunnan Province (no.
2011FZ059), and the Science and Technology Planning
Project of Yunnan Province (no. KKSY201207140), which are
gratefully acknowledged.
tert-Butyl(1R,2S)-1-cyclohexyl-3-oxo-3-((S)-2-oxo-4-phenyl-
oxazolidin-3-yl)-1-phenylpropan-2-ylcarbamate
solid; yield 93%; m.p. 156.5–157 °C; [α]D20=+99.5 (c 0.71, CHCl3);
1H NMR (CDCl3, 500 MHz)
7.27–7.08 (m, 10H, aromatic
(4a):
White
δ
protons), 6.18 (t, J=9.8 Hz, 1H, –CαH–); 5.10 (s, 1H, –NH); 4.69
(t, J=5.4 Hz, 1H, oxazolidinone, PhCH–); 3.97 (d, J=7.2 Hz, 2H,
oxazolidinone, –CH2–); 2.81 (d, J=7.3 Hz, 1H, –CβH–); 2.03–0.77 (m,
20H, cyclohexyl proton and –C(CH3)3); 13C NMR (CDCl3, 125 MHz)
δ 173.4, 155.3, 153.4, 138.9, 138.7, 130.3, 129.7, 129.5, 128.8, 128.3,
127.5, 126.3, 126.0, 80.4, 70.3, 58.1, 56.5, 54.0, 39.6, 39.2, 32.6, 29.1,
28.7, 27.5, 27.3, 27.1, 26.7; IR (KBr) ν: 3357, 3251, 2979, 2929, 2857,
1782, 1705, 1522, 1455, 1380, 1254, 1184, 1043, 757, 708 cm–1; HRMS
for C29H36N2O5: [M+Na]+; calcd: 515.2516; found: 515.2524.
Received 12 September 2014; accepted 8 January 2015
Paper 1402880 doi: 10.3184/174751915X14219405044187
Published online: 13 February 2015
References
1
A.-X. Yan, G.-L. Tian and Y.-H. Ye, Chin. J. Org. Chem., 2000, 102, 299; (in
Chinese).
V.J. Hruby, Prog. Brain Res., 1992, 92, 215.
V.J. Hruby, F. Al-Obedi and W. Kazmierski, Biochem. J., 1990, 268, 249.
V.J. Hruby, Life Sci., 1982, 38, 189.
X.H. Qian, K.C. Russell, L.W. Boteju and V.J. Hruby, Tetrahedron, 1995,
51, 1033.
X.H. Qian, M.D. Shenderovich, K.E. Kover, P. Davis, R. Horvath, T.
Zalewska, H. Yammamura, F. Porreca and V.J. Hruby, J. Am. Chem. Soc.,
1996, 118, 7280.
I. Ortin and D.J. Dixon, Angew. Chem. Int. Ed., 2014, 53, 3462.
S. Sugiyama, S. Imai and K. Ishii, Tetrahedron: Asymmetry, 2013, 24, 1069.
S. Liao, M.D. Shenderovich, J. Lin and V.J. Hruby, Tetrahedron, 1997, 53,
16645.
tert-Butyl(1S,2R)-1-cyclohexyl-3-oxo-3-((R)-2-oxo-4-phenyl-
oxazolidin-3-yl)-1-phenylpropan-2-ylcarbamate (4b): White solid;
yield 91%; m.p. 156.2–157 °C; [α]D20=–111.9 (c 0.46, CHCl3);
2
3
4
5
1H NMR (CDCl3, 500 MHz)
δ 7.25–7.07 (m, 10H, aromatic
protons), 6.18 (t, J=9.9 Hz, 1H, –CαH–); 5.11 (s, 1H, –NH); 4.68
(d, J=4.2 Hz, 1H, oxazolidinone, PhCH–); 3.97 (d, J=7.3 Hz, 2H,
oxazolidinone, –CH2–); 2.81 (d, J=7.2 Hz, 1H, –CβH–); 2.02–0.80 (m,
20H, cyclohexyl proton and –C(CH3)3); 13C NMR (CDCl3, 125 MHz)
δ 173.4, 155.4, 153.4, 138.9, 138.7, 130.3, 129.4, 128.8, 128.3, 127.6,
126.5, 126.0, 80.3, 70.3, 58.1, 56.4, 54.0, 39.6, 32.6, 29.1, 28.7, 27.2,
27.1, 26.7; IR (KBr) ν: 3358, 3252, 2979, 2929, 2856, 1792, 1706, 1522,
1455, 1381, 1254, 1185, 1043, 757, 708 cm–1; HRMS for C29H36N2O5:
[M + Na]+; calcd: 515.2516; found: 515.2509.
6
7
8
9
10 W. Wang, C.Y. Xiong, J.Q. Yang and V.J. Hruby, Tetrahedron Lett., 2001,
42, 7717.
11 W. Wang, J.Y. Zhang, C.Y. Xiong and V.J. Hruby, Tetrahedron Lett., 2002,
43, 2137.
12 W. Wang, C.Y. Xiong, J.Q. Yang and V.J. Hruby, Tetrahedron, 2002, 58,
3101.
13 S. Liao, Y.L. Han, W. Qiu, M. Bruck and V.J. Hruby, Tetrahedron Lett.,
1996, 37, 7917.
14 W. Yuan and V.J. Hruby, Tetrahedron Lett., 1997, 38, 3853.
15 J. Lin, S. Liao and V.J. Hruby, Tetrahedron Lett., 1998, 39, 3117.
16 J. Lin, S. Liao and V.J. Hruby, J. Peptide Res., 2005, 65, 105.
17 B.S. Lou, G.G. Li, F.D. Lung and V.J. Hruby, J. Org. Chem., 1995, 60, 5509.
18 B.C. Wilkes and P.W. Schiller, Biopolymers, 1994, 34, 1213.
19 N.J. Cusack, B.J. Hildick, D.H. Robinson, P.W. Rugg and G. Shaw, J. Chem.
Soc. Perkin Trans I, 1973, 1720.
20 L. Nie, R. Yang, C.H. Zhang, H.C. Yin, S.J. Yan and J. Lin, Chin. J. Chem.,
2012, 30, 460.
21 J. Zhu, S.-Q. Pan, C.-H. Zhang, S.-J. Yan, J. Lin, Chin. J. Org. Chem., 2010,
30, 98 (in Chinese).
Hydrolysis of azido compounds; general procedure
Into a solution of α-azido compound 4a or 4b (600 mg, 0.6 mmol)
in THF (40 mL), water was added (10 mL). After the solution was
cooled at 0 °C for 15 min, 0.6 mL 30% hydrogen peroxide (3.6 mmol,
6 equiv.) was added dropwise, followed by the dropwise addition
of 75 mg of lithium hydroxide monohydrate (1.8 mmol, 3 equiv.).
The resulting mixture was stirred at 0 °C for 2.5 h. The reaction
was quenched by the addition of saturated sodium sulfite (20 mL)
and stirred at room temperature for 30 min. The aqueous phase was
separated and extracted with ethyl acetate (3×ꢀ20 mL) for recovery
of the auxiliary, then the remaining aqueous phase was cooled to
0 °C and acidified with acetic acid, then extracted with ethyl acetate
(3 ×ꢀ20 mL). The combined organic phases were dried over anhydrous
magnesium sulfate and after solvent removal under reduced
pressure, purified by silica gel column chromatography (acetic
acid:acetone:hexane=2:1:40) to give 5a or 5b as a white solid.
(2S,3R)-2-(tert-Butoxycarbonylamino)-3-cyclohexyl-3-phenyl-
propanoic acid (5a): White solid; yield 90%; m.p. 126.2–127.8 °C;
22 D.A. Evans, T.C. Britton, J.A. Ellman and R.L. Dorow, J. Am. Chem. Soc.,
1990, 112, 4011.
23 D.S. Maxwell, D. Sun, Z.-H. Peng, D.V. Martin, B.A. Bhanu Prasad and
W.G. Bornmann, Tetrahedron Lett., 2013, 54, 5799.
24 N. Kise, Y. Hamada and T. Sakurai, Org. Lett., 2014, 16, 3348.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.