Asymmetric synthesis of 3,4-disubstituted proline derivatives: Application in synthesis of hepatitis C virus protease inhibitor telaprevir

Article abstract of DOI:10.1002/ejoc.201403069

A practical asymmetric synthesis of 3,4-disubstituted proline derivatives has been realized with high stereoselectivity and moderate yield. The key steps involved are desymmetric ring-opening reaction of commercially available anhydrides, intramolecular Strecker reaction and thermodynamically controlled cyanide hydrolysis. Based on this methodology, the synthesis of HCV protease inhibitor Telaprevir was achieved.

Full text of DOI:10.1002/ejoc.201403069

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FULL PAPER
DOI: 10.1002/ejoc.201403069
Asymmetric Synthesis of 3,4-Disubstituted Proline Derivatives: Application in
Synthesis of Hepatitis C Virus Protease Inhibitor Telaprevir
[a]
[a]
[a]
[a]
Fan Zhang, Xiaoan Wen, Qing-Long Xu,* and Hongbin Sun*
Keywords: Synthetic methods / Asymmetric synthesis / Medicinal chemistry / Antivirus agents / Amino acids
A practical asymmetric synthesis of 3,4-disubstituted proline
derivatives has been realized with high stereoselectivity and
moderate yield. The key steps involved are desymmetric
ring-opening reaction of commercially available anhydrides,
intramolecular Strecker reaction and thermodynamically
controlled cyanide hydrolysis. Based on this methodology,
the synthesis of HCV protease inhibitor Telaprevir was
achieved.
Introduction
Conformationally constrained cyclic proline derivatives
are used widely as modified amino acid building blocks in
peptide synthesis because their exclusive amide bond con-
formation has a dramatic impact on the three-dimensional
structures of peptides and proteins.[ These proline struc-
tural units have been used in many marketed drugs, such as
Trandolapril, Saxagliptin, Telaprevir and Boceprevir (Fig-
ure 1). In particular, Hepatitis C virus (HCV) protease in-
hibitors, Telaprevir and Boceprevir, both contain 3,4-disub-
stituted bicyclic proline units to successfully treat HCV in-
1]
[
2]
fections.
To date, several methods have been reported to synthe-
size optically pure 3,4-disubstituted proline derivatives: (i)
resolution of racemic proline derivatives;[ (ii) asymmetric
Michael addition reactions with a chiral auxiliary, chiral
3]
[4]
Figure 1. Marketed drugs that contain substituted proline moieties.
tion.[9] Although one patent claimed to use this methodol-
phase-transfer catalyst, and chiral Ni complexes; (iii) cata-
lyzed cycloaddition reactions;[ (iv) palladium-catalyzed
intramolecular coupling reactions;[ (v) intramolecular
Pauson–Khand reactions and ring-closing-metathesis reac-
5]
6]
[
10]
ogy to synthesize a Boceprevir intermediate,
we found
[
7]
tions, and (vi) desymmetrization of pyrrolidines through
enzymatic catalysis. A chemical method was also efficient
at synthesizing these compounds.[ Although the described
methods were effective at synthesizing specific structures,
more general and practical methods are needed to construct
optically pure 3,4-disubstituted proline derivatives.
the methodology was not suitable for the Telaprevir inter-
mediate. In this work, we have developed a practical ap-
proach to construct optically pure 3,4-disubstituted proline
derivatives.
8]
We realized that the chiral substituted proline moiety of
Telaprevir could be synthesized from the corresponding an-
hydride through a stereoselective anhydride opening reac-
Results and Discussion
To develop our strategy, we initially synthesized proline
unit 8a in Telaprevir as a model template (Scheme 1).
Asymmetric ring opening of anhydride 1a with methanol in
[
a] Jiangsu Key Laboratory of Drug Discovery for Metabolic
Diseases and Center of Drug Discovery, China Pharmaceutical the presence of quinidine afforded acid 2a with 98% ee.[
9d]
University,
Amidation of 2a with diphenylamine gave amide 3a in 69%
2
4 Tongjia Xiang, Nanjing 210009, China
E-mail: xuqing307@126.com,
yield from 1a. Reduction of 3a with borane dimethylsulfide
BH ·DMS) afforded amino alcohol 4a in 94% yield.
hbsun2000@yahoo.com
(
3
http://yjsc.cpu.edu.cn/dsjj/yaoxueyuan/sunhongbin.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403069.
Hydrogenation of 4a in the presence of di-tert-butyl dicarb-
onate (Boc O) in methanol at room temperature afforded
2
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F. Zhang, X. Wen, Q.-L. Xu, H. Sun
FULL PAPER
alcohol 5a in 89% yield together with trace amounts of the
Based on the above method, we used other anhydrides
double debenzylation product. Oxidation of 5a with pyrid- to construct the corresponding chiral proline derivatives. As
inium chlorochromate (PCC) gave aldehyde 6a. Boc-depro- shown in Table 1, asymmetric ring-opening reaction of an-
tection of 6a with trifluoroacetic acid, followed by intra- hydrides 1 with methanol in the presence of quinidine
molecular Strecker reaction with trimethylsilyl cyanide (Table 1, Entries 1–6,) or quinine (Table 1, Entries 7 and 8,)
(TMSCN) in MeCN provided amino cyanides trans-7a and afforded chiral acids 2 in high enantioselectivity (89–99%
cis-7a (3.6:1) in 49% yield. We tried to separate trans-7a ee). The configuration of 8d (Table 1, Entry 4) was further
and cis-7a by column chromatography, however, they iso- confirmed by NOESY spectroscopy (see the Supporting In-
merized during purification and storage. Thus, the mixture formation).
of trans-7a and cis-7a was used directly in the next step.
Surprisingly, hydrolysis of this mixture in HCl solution at
reflux temperatures afforded near optically pure amino acid Table 1. Asymmetric synthesis of 3,4-disubstituted proline deriva-
8
a in 95% yield. We speculate that unstable cis-7a is quickly tives.
converted into more stable trans-7a through iminium cation
[11]
9,
which leads to dominant formation of trans-8a
(Scheme 2). The absolute configuration of 8a was con-
firmed by debenzylation reaction to give a compound with
known configuration.[
8a]
Scheme 1. Synthesis of 8a.
[
a] The ee was determined by chiral HPLC. [b] The dr was deter-
1
mined by H NMR spectroscopy. [c] Isolated yield over 7 steps.
[d] Ring-opening reaction with quinidine. [e] Ring-opening reaction
with quinine.
Scheme 2. Proposed pathway for stereoselective enrichment of
trans-8a.
2
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Asymmetric Synthesis of 3,4-Disubstituted Proline Derivatives
Scheme 3. Synthesis of HCV protease inhibitor Telaprevir.
When quinine was used as the chiral catalyst, we ob- (Telaprevir) in 70% yield. The spectroscopic data of 18 was
tained proline derivatives 8g and 8h with d-configuration. identical to that reported in the literature.[12]
The total yields were 6–38% for 7 steps.
With 8a in hand, we continued to synthesize HCV prote-
ase inhibitor Telaprevir (Scheme 3). To begin with we devel-
oped a new synthesis of amino alcohol 15 as another key
Conclusions
intermediate of Telaprevir. Sharpless epoxidation of trans-
In conclusion, we have developed a facile asymmetric
2-hexenol 10 afforded epoxide 11 in 89% yield and 91% ee. synthesis of 3,4-disubstituted proline derivatives that is
Oxidation of 11 with NaClO , NaClO, and (2,2,6,6-tet- highlighted by asymmetric ring opening of substituted an-
2
ramethyl-1-piperidinyl)oxidanyl (TEMPO) in buffer (pH = hydrides, intramolecular Strecker reaction, and thermody-
6.9) gave acid 12, which was treated with cyclopropylamine namically-controlled cyanide hydrolysis. High stereoselecti-
to afford amide 13 in 61% yield. Regioselective ring open- vity and moderate yield were achieved for construction of
ing of 13 with NaN3 provided azide 14 in 70% yield. these challenging molecules with several chiral centers.
Hydrogenation of 14, followed by acidification with con. Moreover, a practical synthesis of HCV protease inhibitor
HCl, gave a crude product, which was recrystallized from Telaprevir was achieved in 16% yield over 11 linear steps
2
-propanol to afford 15 in 84% yield and 99% ee. Next, based on the above methodology and new synthesis of
condensation of 8a with 15 furnished dipeptide derivative amino alcohol 15. Further studies are underway to explore
6 in 84% yield. Debenzylation of 16, followed by conden- the utility of these chiral proline building blocks in drug
1
[8c]
sation with acid 17 and Dess–Martin oxidation, gave 18 design and synthesis.
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F. Zhang, X. Wen, Q.-L. Xu, H. Sun
FULL PAPER
+
4
(
5.9, 44.9, 44.6 ppm. MS (ESI): m/z = 376.2 [M + H] . HRMS
Experimental Section
ESI): calcd. for C24H26NO
3
[M + H]+ 376.1913; found 376.1918.
General Information: H and 13C NMR spectra were recorded with
an ACF* 300Q Bruker or ACF* 500Q Bruker spectrometer. Low-
and high-resolution mass spectra were recorded in electron impact
mode. The mass analyzer type used for HRMS measurements was
TOF. Reactions were monitored with TLC on silica gel 60 F254
plates (Qingdao Ocean Chemical Company, China). Column
chromatography was carried out with silica gel (200–300 mesh,
Qingdao Ocean Chemical Company, China). Compounds 2a–2h
were prepared according to the procedure reported.[ The crude
acid was used in the next step without further purification.
1
3
6
d: Eluent petroleum ether/ethyl acetate (6:1). Colorless oil (2.56 g,
3% yield, 99% ee). [Chiralpak IC column (0.46 cmϫ25 cm); n-
hexane/iPrOH = 80:20; flow rate: 0.5 mL/min; detection wave-
length: 254 nm; t = 30.74 min (minor), t = 32.70 min (major)].
OH). H NMR (300 MHz, CDCl ): δ
7.36–7.18 (m, 10 H), 6.18–6.10 (m, 2 H), 4.99 (d, J = 15.0 Hz, 1
R
R
2
5
1
[α]
D
= +49.7 (c = 0.1, CH
3
3
=
H), 4.70 (d, J = 18.0 Hz, 1 H), 4.43 (d, J = 18.0 Hz, 1 H), 4.24 (d,
J = 15.0 Hz, 1 H), 3.70 (t, J = 4.1 Hz, 1 H), 3.57 (s, 3 H), 3.29 (s,
H), 3.00–2.86 (m, 2 H), 2.06–2.03 (m, 1 H), 1.46 (dd, J = 8.6,
9d]
1
1
1
3
3
.4 Hz, 1 H) ppm. C NMR (75 MHz, CDCl ): δ = 174.6, 174.1,
General Procedure for the Preparation of 3: To a solution of crude
137.4, 136.6, 135.9, 128.7, 128.0, 127.5, 126.8, 51.6, 49.9, 48.6, 48.4,
+
acid 2 (10.75 mmol, 1.0 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)- 48.3, 46.7, 45.4, 45.1 ppm. MS (ESI): m/z = 376.1 [M + H] .
HRMS (ESI): calcd. for C H NO [M + H]+ 376.1913; found
carbodiimide (EDCI; 3.06 g, 16.13 mmol), hydroxybenzotriazole
HOBt; 2.3 g, 17.2 mmol) in CH Cl (44 mL) at 0 °C. 4-Methyl-
2
4
26
3
(
2
2
376.1918.
morpholine (NMM; 2.5 mL) was added at 0 °C for 30 min. Then
dibenzylamine (3.2 mL) was added to the mixture. The reaction
mixture was then stirred overnight at room temperature. The sol-
vent was evaporated and the residue was diluted with EtOAc,
3
e: Eluent petroleum ether/ethyl acetate (10:1). Colorless oil
(
(
4.02 g, 96% yield, 99% ee). [Chiralpak IC column
0.46 cmϫ25 cm); n-hexane/iPrOH = 80:20; flow rate: 0.5 mL/min;
detection wavelength: 254 nm; t
4
R
= 43.15 min (minor), t
R
=
washed with HCl (1 n), saturated NaHCO
3
solution, and brine.
25
OH). 1H NMR
9.10 min (major)]. [α]
D
= +37.2 (c = 0.1, CH
): δ = 7.44–7.19 (m, 10 H), 5.08 (d, J = 12.0 Hz,
H), 4.64 (d, J = 18.0 Hz, 1 H), 4.31 (d, J = 15.0 Hz, 1 H), 4.04
3
The combined organic layer was dried with anhydrous sodium sulf-
ate, filtered, and concentrated in vacuo. The crude product was
purified by column chromatography (petroleum ether/ethyl acetate)
to give the product.
(
300 MHz, CDCl
3
1
(
=
d, J = 15.0 Hz, 1 H), 3.70 (s, 3 H), 3.48–3.44 (m, 1 H), 2.64 (d, J
10.6 Hz, 1 H), 2.40–2.28 (m, 1 H), 2.17 (s, 1 H), 1.82–1.76 (m, 2
1
3
3a: Eluent petroleum ether/ethyl acetate (5:1). Colorless oil (2.8 g,
3
H), 1.73–1.38 (m, 6 H) ppm. C NMR (75 MHz, CDCl ): δ =
175.1, 173.7, 138.8, 136.8, 128.8, 128.5, 128.2, 127.6, 127.2, 126.5,
69% yield, 98.7% ee). [Chiralpak IC column (0.46 cmϫ25 cm); n-
hexane/iPrOH = 80:20; flow rate: 0.5 mL/min; detection wave-
length: 254 nm; t = 34.52 min (major), t = 37.82 min (minor)].
OH). H NMR (300 MHz, CDCl ): δ
7.41–7.22 (m, 10 H), 4.72–4.40 (m, 4 H), 3.67 (s, 3 H), 3.49–3.42
m, 1 H), 2.86 (dd, J = 17.4, 8.0 Hz, 1 H), 2.39–2.31 (m, 1 H),
50.9, 49.9, 47.7, 43.4, 43.2, 28.1, 26.1, 24.9, 21.6, 21.3 ppm. MS
+
(ESI): m/z = 392.2 [M + H] . HRMS (ESI): calcd. for C24
H
26NO
3
R
R
2
5
1
[M + H]+ 392.2226; found 392.2232.
[
=
(
α]
D
= +39.9 (c = 0.1, CH
3
3
3f: Eluent petroleum ether/ethyl acetate (5:1). Colorless oil (3.13 g,
86% yield, 99% ee). [Chiralpak IC column (0.46 mmϫ25 cm); n-
13
2
.00–1.94 (m, 4 H), 1.65–1.58 (m, 1 H) ppm. C NMR (125 MHz,
): δ = 174.9, 174.2, 137.6, 136.6, 128.9, 128.5, 128.4, 128.3,
28.2, 127.6, 127.3, 127.0, 126.5, 53.1, 51.5, 49.9, 48.1, 48.0, 43.7,
hexane/iPrOH = 95:5; flow rate: 0.5 mL/min; detection wavelength:
CDCl
1
3
3
25
2
+
7
54 nm; t
43.0 (c = 0.1, CH
.14 (m, 10 H), 4.57 (s, 2 H), 4.42 (s, 2 H), 3.73 (s, 3 H), 2.71 (s, 2
R
= 32.34 min (minor), t
R
= 33.98 min (major)]. [α]
D
=
1
3
OH). H NMR (300 MHz, CDCl ): δ = 7.38–
3
+
0.9, 28.2, 24.4 ppm. MS (ESI): m/z = 352.2 [M + H] . HRMS
+
(ESI): calcd. for C22
H
26NO
3
[M + H] 352.1913; found 352.1915.
13
H), 1.29 (s, 6 H) ppm. C NMR (75 MHz, CDCl
1
4
K] . HRMS (ESI): calcd. for C21
found 378.1477.
3
): δ = 176.2,
75.2, 137.4, 136.5, 128.9, 128.6, 128.2, 127.6, 127.4, 126.4, 51.6,
9.8, 48.3, 43.6, 39.2, 17.1, 16.5 ppm. MS (ESI): m/z = 378.1 [M +
3b: Eluent petroleum ether/ethyl acetate (6:1). Colorless oil (2.68 g,
68% yield, 98% ee). [Chiralpak IC column (0.46 cmϫ25 cm); n-
+
H25NO
3
K [M + K]+ 378.1472;
hexane/iPrOH = 80:20; flow rate: 0.5 mL/min; detection wave-
length: 254 nm; t = 29.70 min(major), t = 32.00 min (minor)].
OH). H NMR (300 MHz, CDCl ): δ
7.41–7.16 (m, 10 H), 4.85 (d, J = 15.0 Hz, 1 H), 4.60 (d, J =
R
R
2
5
1
[α]
D
= +42.0 (c = 0.1, CH
3
3
3g: Eluent petroleum ether/ethyl acetate (5:1). Colorless oil (2.68 g,
66% yield, 94% ee). [Chiralpak IC column (0.46 cmϫ25 cm); n-
8.0 Hz, 1 H), 4.35 (d, J = 18.0 Hz, 1 H), 4.24 (d, J = 15.0 Hz, 1 hexane/iPrOH = 80:20; flow rate: 0.5 mL/min; detection wave-
=
1
H), 3.72 (s, 3 H), 3.39–3.34 (m, 1 H), 2.57–2.53 (m, 1 H), 2.40–2.32
m, 1 H), 2.08–2.04 (m, 1 H), 1.94–1.89 (m, 2 H), 1.69–1.41 (m, 3
length: 254 nm; t = 32.51 min (minor), t = 34.74 min (major)].
R
R
(
[α]25 = –50.9 (c = 0.1, CH OH).
1
H NMR (300 MHz, CDCl ): δ =
D
3
3
13
H), 1.41–1.20 (m, 1 H) ppm. C NMR (75 MHz, CDCl
3
): δ = 7.43–7.22 (m, 10 H), 4.72–4.40 (m, 4 H), 3.67 (s, 3 H), 3.47–3.39
1
5
77.6, 174.2, 140.7, 140.0, 128.8, 128.5, 128.1, 127.6, 127.0, 126.8,
(m, 1 H), 2.89 (dd, J = 17.0, 8.4 Hz, 1 H), 2.42–2.29 (m, 1 H),
1.5, 49.9, 47.2, 43.2, 38.7, 27.6, 25.1, 24.3, 22.2 ppm. MS (ESI):
2.03–1.92 (m, 4 H), 1.69–1.59 (m, 1 H) ppm. 13C NMR (75 MHz,
+
m/z = 366.2 [M + H] . HRMS (ESI): calcd. for C23
H
28NO
3
[M + CDCl ): δ = 174.9, 174.2, 137.5, 136.5, 128.8, 128.5, 128.3, 127.6,
3
+
H] 366.2069; found 366.2073.
127.3, 126.5, 51.5, 49.9, 47.9, 43.6, 30.8, 28.2, 24.4 ppm. MS (ESI):
+
m/z = 352.2 [M + H] . HRMS (ESI): calcd. for C22
H
26NO
3
[M +
3c: Eluent petroleum ether/ethyl acetate (5:1). Colorless oil (2.31 g,
+
H] 352.1913; found 352.1915.
57% yield, 96% ee). [Chiralpak IC column (0.46 cmϫ25 cm); n-
hexane/iPrOH = 80:20; flow rate: 0.5 mL/min; detection wave-
length: 254 nm; t = 33.95 min (major), t = 36.26 min (minor)].
OH). H NMR (300 MHz, CDCl ): δ
3h: Eluent petroleum ether/ethyl acetate (5:1). Colorless oil (2.62 g,
65% yield, 89% ee). [Chiralpak IC column (0.46 cmϫ25 cm); n-
hexane/iPrOH = 80:20; flow rate: 0.5 mL/min; detection wave-
R
R
2
5
1
[α]
D
= +48.1 (c = 0.1, CH
3
3
=
7.42–7.18 (m, 10 H), 6.45–6.42 (m, 1 H), 6.13–6.10 (m, 1 H), length: 254 nm; t
R
= 28.34 min (minor), t
R
= 29.61 min (major)].
OH). H NMR (300 MHz, CDCl ): δ =
7.40–7.14 (m, 10 H), 6.39 (dd, J = 5.5, 3.2 Hz, 1 H), 6.07 (dd, J =
2
5
1
4
.97 (d, J = 15.0 Hz, 1 H), 4.84 (d, J = 18.0 Hz, 1 H), 4.48 (d, J = [α]
8.0 Hz, 1 H), 4.19 (d, J = 15.0 Hz, 1 H), 3.68 (s, 3 H), 3.66–3.63
D
= –56.8 (c = 0.1, CH
3
3
1
(
(
m, 1 H), 3.23–3.10 (m, 3 H), 1.62–1.48 (m, 2 H) ppm. 13C NMR 5.5, 2.8 Hz, 1 H), 4.92 (d, J = 18.0 Hz, 1 H), 4.80 (d, J = 18.0 Hz,
75 MHz, CDCl
3
): δ = 173.8, 173.5, 138.4, 138.3, 137.4, 136.6, 1 H), 4.44 (d, J = 18.0 Hz, 1 H), 4.14 (d, J = 18.0 Hz, 1 H), 3.64
(s, 3 H), 3.61–3.59 (m, 1 H), 3.19 (s, 1 H), 3.09–3.06 (m, 2 H), 1.64–
128.9, 128.8, 128.4, 127.6, 127.4, 126.4, 51.5, 50.1, 48.7, 47.4, 47.2,
4
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Asymmetric Synthesis of 3,4-Disubstituted Proline Derivatives
1
(
.43 (m, 3 H), 1.45 (dd, J = 8.7, 1.5 Hz, 1 H) ppm. 13C NMR
3
75 MHz, CDCl C
): δ = 174.6, 174.1, 137.4, 136.6, 135.9, 128.7, 12.0 Hz, 1 H), 2.08–2.03 (m, 2 H), 1.55–1.24 (m, 11 H) ppm. 13
2 H), 3.40 (t, J = 12.0 Hz, 1 H), 3.22–3.17 (m, 3 H), 2.33 (t, J =
1
4
28.0, 127.5, 126.7, 51.6, 49.9, 48.6, 48.4, 48.3, 46.7, 45.4,
3
NMR (75 MHz, CDCl ): δ = 139.4, 132.5, 131.2, 130.8, 130.1, 65.9,
+
5.0 ppm. MS (ESI): m/z = 376.2 [M + H] . HRMS (ESI): calcd.
61.1, 58.7, 44.7, 37.2, 32.7, 30.8, 29.6, 29.3, 23.7, 23.3 ppm. MS
+
+
for C24
H
26NO
3
[M + H] 376.1913; found 376.1918.
(ESI): m/z = 372.2 [M + Na] . HRMS (ESI): calcd. for
24
C H
31NONa [M + Na]+ 372.2303; found 372.2313.
General Procedure for the Preparation of 4: To a solution of 3
(
5
8.06 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (THF; 4f: Eluent petroleum ether/ethyl acetate (6:1). Colorless oil (1.77 g,
2
5
1
4 mL) at 0 °C under nitrogen was added a solution of BH
3
·DMS
74% yield). [α]
(300 MHz,CDCl
J = 12.0 Hz, 2 H), 3.51 (dd, J = 11.3, 3.7 Hz, 1 H), 3.38–3.28 (m,
D
=
+27.9 (c
=
0.1, CH
3
OH).
H NMR
solution (20.1 mL, 2.0 mol/L, 5.0 equiv.) dropwise. The mixture
was then heated to reflux for 1 h, then quenched with HCl/meth-
3
): δ = 7.34–7.25 (m, 10 H), 5.06 (s, 1 H), 3.82 (d,
anol solution at 0 °C. The solvent was removed, the residue was 3 H), 2.11–2.02 (m, 1 H), 1.96 (dd, J = 12.0, 3.0 Hz, 1 H), 1.76–
diluted with EtOAc, and washed with saturated NaHCO solution 1.70 (m, 1 H), 0.87 (d, J = 9.0 Hz, 3 H), 0.62 (d, J = 9.0 Hz, 3
3
1
3
and brine. The combined organic layer was dried with anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The crude
product was purified by column chromatography (petroleum ether/
ethyl acetate) to give the product.
H) ppm. C NMR (75 MHz, CDCl
3
): δ = 137.4, 129.7, 129.3,
128.2, 127.1, 66.6, 58.8, 55.8, 39.2, 33.8, 18.2, 10.6 ppm. MS (ESI):
+
m/z = 298.2 [M + H] . HRMS (ESI): calcd. for C20
H
28NO [M +
+
H] 298.2171; found 298.2175.
4
(
(
2
1
1
a: Eluent petroleum ether/ethyl acetate (10:1). Colorless oil
4g: Eluent petroleum ether/ethyl acetate (10:1). Colorless oil
2.32 g, 94% yield). [α]2
300 MHz, CDCl ): δ = 7.36–7.29 (m, 10 H), 3.91 (d, J = 12.0 Hz,
H), 3.36–3.11 (m, 1 H), 3.23 (d, J = 15.0 Hz, 2 H), 3.19–3.12 (m, 2 H), 3.36–3.31 (m, 2 H), 3.24 (d, J = 12.0 Hz, 2 H), 3.16 (t, J =
H), 2.78 (t, J = 12.2 Hz, 1 H), 2.58–2.43 (m, 1 H), 2.31–2.25 (m, 12.0 Hz, 1 H), 2.78 (t, J = 12.0 Hz, 2 H), 2.52–2.45 (m, 1 H), 2.35–
5
= +27.9 (c = 0.1, CH
1
25
1
D
3
OH). H NMR
D 3
(2.01 g, 82% yield). [α] = –33.1 (c = 0.1, CH OH). H NMR
3
(300 MHz, CDCl ): δ = 7.33–7.29 (m, 10 H), 3.91 (d, J = 12.0 Hz,
3
1
3
13
H), 2.17 (dd, J = 12.7, 3.2 Hz, 1 H), 1.87–0.89 (m, 6 H) ppm.
C
2.25 (m, 1 H), 2.22–2.15 (m, 2 H), 1.89–0.89 (m, 6 H) ppm.
C
NMR (75 MHz, CDCl
3
): δ = 136.9, 129.7, 128.3, 127.3, 63.1, 58.2,
NMR (75 MHz, CDCl ): δ = 136.8, 127.6, 129.9, 127.4, 62.9, 58.3,
3
5
5.9, 53.1, 44.1, 38.1, 31.8, 28.7, 24.0 ppm. MS (ESI): m/z 310.2 55.9, 53.1, 44.1, 38.1, 31.8, 28.7, 22.1 ppm. MS (ESI): m/z = 310.2
+
+
+
+
[
M + H] . HRMS (ESI): calcd. for C21
H
28NO [M + H] 310.2171;
[M + H] . HRMS (ESI): calcd. for C21
H
28NO [M + H] 310.2171;
found 310.2174.
found 310.2174.
4
b: Eluent petroleum ether/ethyl acetate (15:1). Colorless oil
4h: Eluent petroleum ether/ethyl acetate (16:1). Colorless oil
2.18 g, 84% yield). [α]2
5
= +37.5 (c = 0.1, CH
1
(1.85 g, 70% yield). [α]
(300 MHz, CDCl ): δ = 7.35–7.26 (m, 10 H), 6.02–5.99 (m, 1 H),
5.77–5.74 (m, 1 H), 3.84 (d, J = 12.0 Hz, 2 H), 3.70–3.67 (m, 1 H),
2.0 Hz, 2 H), 2.94–2.84 (m, 2 H), 2.21–2.17 (m, 1 H), 2.02 (dd, J 3.42–3.34 (m, 3 H), 2.76 (s, 1 H), 2.44 (s, 1 H), 2.31 (dd, J = 15.0,
25
1
(
(
D
3
OH). H NMR
D 3
= –37.1 (c = 0.1, CH OH). H NMR
300 MHz, CDCl ): δ = 7.36–7.24 (m, 10 H), 4.99 (s, 1 H), 3.86 (d,
3
3
J = 12.0 Hz, 2 H), 3.34 (dd, J = 11.6, 5.1 Hz, 1 H), 3.22 (d, J =
1
=
12.9, 2.6 Hz, 1 H), 1.86–1.81 (m, 1 H), 1.58–0.96 (m,8 H) ppm.
6.0 Hz, 1 H), 2.07–1.99 (m, 1 H), 1.96–1.89 (m, 1 H), 1.45–1.36 (m,
2 H), 0.85–0.78 (m, 1 H) ppm. C NMR (75 MHz, CDCl ): δ =
3
1
3
13
C NMR (75 MHz, CDCl
3
): δ = 137.7, 129.9, 128.6, 127.4,
6
4.2,58.7, 54.6, 40.6, 33.3, 31.3, 25.6, 24.8, 22.8 ppm. MS (ESI):
137.9, 137.8, 133.3, 129.7, 128.3, 127.2, 66.1, 59.5, 59.2, 49.5, 46.9,
+
+
m/z = 324.2 [M + H] . HRMS (ESI): calcd. for C22
H
30NO [M +
45.9, 44.7, 42.5 ppm. MS (ESI): m/z = 334.21 [M + H] . HRMS
+
H
28NO [M + H]+ 334.2171; found 334.2176.
H] 324.2327; found 324.2330.
(ESI): calcd. for C23
General Procedure for the Preparation of 5: A solution of 4
(7.43 mmol, 1.0 equiv.), Boc O (5.13 g, 11.43 mmol), Pd/C (464 mg,
): δ = 7.33–7.25 (m, 10 H), 6.19–6.17 (m, 2 H), 20% by weight) in methanol (47 mL) was charged with hydrogen
.99 (d, J = 13.0 Hz, 2 H), 3.48 (d, J = 9.0 Hz, 1 H), 3.15–3.08 (m, (1 atm). The mixture was stirred at room temperature for 45 min,
H), 2.80 (t, J = 12.0 Hz, 1 H), 2.40 (d, J = 6.0 Hz, 2 H), 2.33 then filtered and concentrated in vacuo. The crude product was
purified by column chromatography (petroleum ether/ethyl acetate)
H), 1.16 (s, 2 H), 0.88–0.85 (m, 1 H) ppm. C NMR (75 MHz, to give the product.
4
c: Eluent petroleum ether/ethyl acetate (15:1). Colorless oil
2
5
1
(
(
2.09 g, 79% yield). [α]
300 MHz, CDCl
D
= +35.6 (c = 0.1, CH
3
OH). H NMR
2
3
3
3
(dd, J = 12.9, 3.3 Hz, 1 H), 2.07–1.99 (m, 1 H), 1.86–1.81 (m, 1
13
CDCl
3
): δ = 138.2, 136.9, 129.8, 128.4, 127.5, 77.5, 77.0, 76.6, 64.2,
5
a: Eluent petroleum ether/ethyl acetate (5:1). Colorless oil (2.14 g,
58.6, 57.3, 47.7, 46.1, 44.3, 43.8, 37.5 ppm. MS (ESI): m/z = 334.21
2
5
1
8
9% yield). [α]
): δ = 7.33–7.21 (m, 5 H), 4.45 (s, 2 H), 3.63–3.59 (m, 1 H),
.51–3.47 (m, 1 H), 3.34 (s, 1 H), 3.12–3.08 (m, 1 H), 2.32–2.25 (m,
D 3
= +19.3 (c = 0.1, CH OH). H NMR (500 MHz,
+
+
[
M + H] . HRMS (ESI): calcd. for C23
H28NO [M + H] 334.2171;
CDCl
3
found 334.2176.
3
4
(
(
d: Eluent petroleum ether/ethyl acetate (15:1). Colorless oil
1 H), 2.15–2.10 (m, 1 H), 1.98 (s, 1 H), 1.59–1.51 (m, 1 H), 1.49–
1.45 (m, 10 H), 1.40–1.32 (m, 1 H) ppm. C NMR (125 MHz,
2.25 g, 85% yield). [α]2
300 MHz, CDCl ): δ = 7.33–7.25 (m, 10 H), 6.18 (d, J = 6.3 Hz,
H), 5.92 (d, J = 6.3 Hz, 1 H), 3.89 (d, J = 15.0 Hz, 2 H), 3.81 (s,
H), 3.57–3.52 (m, 1 H), 3.31 (d, J = 15.0 Hz, 2 H), 2.96 (t, J =
5
= +56.1 (c = 0.1, CH
1
13
D
3
OH). H NMR
3
CDCl
40.2, 29.6, 28.4, 27.7, 22.5 ppm. MS (ESI): m/z = 320.2 [M + H] .
HRMS (ESI): calcd. for C19
[M + H]+ 320.2226; found
3
): δ = 156.2, 138.5, 128.4, 127.3, 127.1, 79.9, 63.1, 45.9, 44.5,
+
1
1
9
1
H
30NO
3
.0 Hz, 1 H), 2.62 (s, 1 H), 2.49 (s, 1 H), 2.41 (d, J = 6.0 Hz, 2 H), 320.2229.
.43–1.34 (m, 1 H), 1.33–1.26 (m, 2 H), 1.10 (d, J = 9.0 Hz, 1
5
b: Eluent petroleum ether/ethyl acetate (6:1). Colorless oil (1.98 g,
13
H) ppm. C NMR (75 MHz, CDCl
3
): δ = 137.9, 137.8, 133.3,
2
5
1
8
0% yield). [α]
): δ = 9.72 (s, 1 H), 7.33–7.20 (m, 5 H), 4.59 (s, 1 H), 4.30
s, 1 H), 3.61 (s, 1 H), 3.50–3.46 (m, 2 H), 2.98 (s, 1 H), 2.09 (s, 1
H), 1.77 (s, 1 H), 1.55–1.52 (m, 3 H), 1.44 (s, 10 H), 1.40–1.20 (m,
D 3
= +31.4 (c = 0.1, CH OH). H NMR (300 MHz,
1
4
29.7, 128.3, 127.2, 66.1, 59.5, 59.3, 49.5, 46.9, 45.9, 44.7,
2.5 ppm. MS (ESI): m/z = 334.21 [M + H] . HRMS (ESI): calcd.
CDCl
(
3
+
+
for C23
H28NO [M + H] 334.2171; found 334.2176.
1
3
4
e: Eluent petroleum ether/ethyl acetate (15:1). Colorless oil
3
4 H), 0.88 (s, 1 H) ppm. C NMR (75 MHz, CDCl ): δ = 206.7,
2.32 g, 83% yield). [α]2
5
= +13.0 (c = 0.1, CH
OH). H NMR
1
137.6, 127.9, 126.6, 79.5, 51.4, 50.2, 47.3, 35.5, 27.8, 27.6, 25.8,
(
(
D
3
+
300 MHz, CDCl ): δ = 7.33–7.27 (m, 10 H), 3.97 (d, J = 9.0 Hz,
3
24.5, 23.3, 23.2 ppm. MS (ESI): m/z = 356.2 [M + Na] . HRMS
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O43069
/KAP1
Date: 30-10-14 17:33:33
Pages: 10
F. Zhang, X. Wen, Q.-L. Xu, H. Sun
FULL PAPER
(
3
ESI): calcd. for C20
56.2206.
H
31NO
3
Na [M + Na]+ 356.2202; found
General Procedure for the Preparation of 6: To a solution of 5
(6.7 mmol, 1.0 equiv.) in CH Cl (74 mL) at room temperature was
2
2
added PCC (2.89 g, 13.4 mmol), then the mixture was stirred for
1 h, filtered through Celite and concentrated in vacuo to give the
crude aldehyde, which was used in the next step without further
purification.
5
7
c: Eluent petroleum ether/ethyl acetate (6:1). Colorless oil (1.88 g,
3% yield). [α]2
5
1
= +13.9 (c = 0.1, CH OH). H NMR (300 MHz,
D 3
CDCl
3
): δ = 7.32–7.20 (m, 5 H), 4.58 (d, J = 15.0 Hz, 1 H), 4.28
(d, J = 15.0 Hz, 1 H),3.44–3.31 (m, 3 H), 3.08–3.01 (m, 1 H), 2.12–
2
(
.04 (m, 2 H), 1.76–1.68 (m, 3 H), 1.60–1.31 (m, 13 H), 1.23–1.04
General Procedure for the Preparation of 7: To a solution of crude
m, 3 H) ppm. 13C NMR (75 MHz, CDCl
3
): δ = 160.7, 141.5, aldehyde 6 (5.86 mmol, 1.0 equiv.) in CH Cl (37 mL) was added
2
2
1
2
28.4, 127.3, 127.1, 79.8, 67.7, 62.5, 52.3, 46.4, 39.6, 38.8, 37.2,
3 3
CF COOH (6.7 mL) dropwise. After 1 h, the excess CF COOH
+
9.1, 28.4, 22.4 ppm. MS (ESI): m/z = 368.2 [M + Na] . HRMS
and solvent was removed. The residue was diluted with CH CN
3
+
(ESI): calcd. for C21
H
31NO
3
Na [M + Na] 368.2202; found
(37 mL), then TMSCN (2.2 mL) was added. The mixture was
368.2208.
stirred for 3 h. The solvent was removed and the residue was
3
quenched with saturated NaHCO and extracted with EtOAc. The
5
7
d: Eluent petroleum ether/ethyl acetate (6:1). Colorless oil (1.99 g,
7% yield). [α]2
5
1
combined organic layer was dried with anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The crude product was purified
by column chromatography (petroleum ether/ethyl acetate) to give
the product as the mixture of endo and exo.
= +24.0 (c = 0.1, CH OH). H NMR (300 MHz,
D 3
3
): δ = 7.33–7.21 (m, 5 H), 4.54–4.46 (m, 2 H), 3.35 (d, J =
CDCl
.0 Hz, 1 H), 3.18–3.10 (m, 1 H), 2.91 (s, 1 H), 2.27 (s, 1 H), 2.06
s, 1 H), 1.80 (s, 1 H), 1.56–1.34 (m, 15 H), 1.30–1.22 (m, 2 H),
.03 (s, 1 H), 0.90–0.89 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl
):
δ = 156.2, 140.7, 128.4, 127.3, 127.1, 79.8, 64.4, 51.5, 48.3, 46.1,
1.5, 38.2, 36.8, 29.6, 28.4, 22.2 ppm. MS (ESI): m/z = 368.2 [M +
6
(
1
3
7a: Eluent petroleum ether/ethyl acetate (30:1). Colorless oil
2
5
(904.9 mg, 49% yield from 5a, 3.6:1 dr). [α] = +20.2 (c = 0.1,
D
1
4
CH OH); H NMR (300 MHz, CDCl ): δ = 7.35–7.25 (m, 5 H),
3
3
+
+
Na] . HRMS (ESI): calcd. for C21
found 368.2208.
H
31NO
3
Na [M + Na] 368.2202;
4.00 (d, J = 10.0 Hz, 0.25 H), 3.85 (d, J = 10.0 Hz, 0.75 H), 3.66
(d, J = 10.0 Hz, 0.25 H), 3.62 (d, J = 15.0 Hz, 0.75 H), 3.53 (d, J
=
15.0 Hz, 0.25 H), 3.42 (s, 0.75 H), 2.81–2.77 (m, 1 H), 2.75–2.71
5
6
e: Eluent petroleum ether/ethyl acetate (6:1). Colorless oil (1.68 g,
2% yield). [α]2
5
1
(m, 1 H), 2.67–2.61 (m, 1.7 H), 2.36–2.33 (m, 0.25 H), 1.89–1.81
= +13.0 (c = 0.1, CH OH). H NMR (300 MHz,
D 3
(
m, 1.75 H), 1.79–1.77 (m, 1 H), 1.75–1.55 (m, 1 H), 1.47–1.37 (m,
CDCl
3
): δ = 7.34–7.20 (m, 5 H), 4.40 (s, 2 H), 3.77–3.71 (m, 1 H),
.59–3.53 (m, 1 H), 3.42–3.38 (m, 2 H), 2.16–2.08 (m, 1 H), 2.00–
.93 (m, 1 H), 1.78–1.66 (m, 2 H), 1.59–1.55 (m, 4 H), 1.47 (s, 2
1
3
3
1
H) ppm. C NMR (125 MHz, CDCl
3
): δ = 137.9, 128.9, 128.5,
3
1
27.4, 117.6, 59.7, 58.6, 56.7, 55.9, 48.5, 45.5, 42.4, 41.3, 34.4, 33.6,
+
13
30.5, 27.3, 26.8 ppm. MS (ESI): m/z = 227.2 [M + H] . HRMS
H), 1.44 (s, 9 H), 1.36–1.26 (m, 3 H) ppm. C NMR (75 MHz,
CDCl ): δ = 157.3, 139.6, 128.4, 127.2, 126.9, 79.7, 62.5, 49.9, 44.4,
1.2, 36.4, 28.3, 26.5, 26.3, 26.0, 20.7 ppm. MS (ESI): m/z = 382.2
(
ESI): calcd. for C15
19 2
H N
[M + H]+ 227.1548; found 227.1550.
3
4
7b: Eluent petroleum ether/ethyl acetate (40:1). Colorless oil
+
Na [M + Na]+
[M + Na] . HRMS (ESI): calcd. for C22
H
33NO
3
25
(
980.5 mg, 61% yield from 5b, 5.7:1 dr). [α]
D
= +29.0 (c = 0.1,
382.2358; found 382.2368.
1
CH OH). H NMR (500 MHz, CDCl ): δ = 7.53–7.18 (m, 5 H),
3
3
5
8
f: Eluent petroleum ether/ethyl acetate (8:1). Colorless oil (1.94 g,
4.06 (d, J = 13.0 Hz, 0.14 H), 3.96 (d, J = 10.0 Hz, 0.86 H), 3.90
(s, 0.14 H), 3.82 (d, J = 10.0 Hz, 0.86 H), 3.66 (d, J = 13.0 Hz, 0.14
5% yield). [α]2
5
= +23.1 (c = 0.1, CH OH). H NMR (300 MHz,
D 3
1
CDCl
3
): δ = 7.32–7.22 (m, 5 H), 4.57–4.52 (m, 1 H), 4.36–4.29 (m, H), 3.50 (d, J = 5.0 Hz, 0.86 H), 2.90 (t, J = 5.0 Hz,0.14 H), 2.83
H), 3.59–3.49 (m, 2 H), 3.32 (s, 1 H), 2.74 (s, 1 H), 1.93–1.89 (m, (t, J = 10.0 Hz, 0.86 H), 2.80–2.74 (m, 1 H), 2.70–2.66 (m, 0.14 H),
1
1
3
1
H), 1.75 (s, 2 H), 1.45 (s,9 H), 0.91 (d, J = 6.0 Hz, 3 H), 0.80 (s,
2.61–2.52 (m, 0.86 H), 2.41–2.37 (m, 0.86 H), 2.29–2.12 (m, 0.14
H), 1.94–1.87 (m, 1 H), 1.78–1.67 (m, 1 H), 1.64–1.51 (m, 4 H),
27.1, 80.8, 65.4, 51.2, 50.0, 34.0, 28.3,14.5, 13.8 ppm. MS (ESI): 1.49–1.36 (m, 2 H), 1.35–1.26 (m, 1 H) ppm. C NMR (125 MHz,
H) ppm. 13C NMR (75 MHz, CDCl
3
): δ = 156.7, 138.4, 128.4,
1
3
+
m/z = 330.2 [M + Na] . HRMS (ESI): calcd. for C18
H
29NO
3
Na
CDCl
3
): δ = 138.2, 128.7, 128.5, 127.3, 118.9, 58.4, 57.2, 54.9, 43.3,
[
M + Na]+ 330.2045; found 330.2050.
35.5, 26.5, 26.2, 23.2, 20.9 ppm. MS (ESI): m/z = 241.1 [M +
+
21 2
H N
[M + H]+ 241.1705; found
H] . HRMS (ESI): calcd. for C16
241.1707.
5
8
g: Eluent petroleum ether/ethyl acetate (5:1). Colorless oil (2.09 g,
7% yield). [α]2
): δ = 7.43–7.37 (m, 5 H), 4.56 (s, 2 H), 3.73–3.69 (m, 1 H),
.61–3.58 (m, 1 H), 3.45 (s, 1 H), 3.23–3.18 (m, 1 H), 2.41–2.38 (m,
H), 2.25–2.21 (m, 1 H), 2.09 (s, 1 H), 1.81–1.73 (m, 3 H), 1.71– CH
5
1
D 3
= –27.5 (c = 0.1, CH OH). H NMR (300 MHz,
CDCl
3
7c: Eluent petroleum ether/ethyl acetate (40:1). Colorless oil
2
5
3
1
1
(347.9 mg, 21% yield from 5c, 4.9:1 dr). [α]
D
= +38.7 (c = 0.1,
): δ = 7.35–7.28 (m, 5 H),
4.01 (d, J = 12.0 Hz, 0.17 H), 3.89 (d, J = 15.0 Hz, 0.83 H), 3.75
): δ = 156.2, 138.5, 128.5, 127.3, 127.1, 79.9, (d, J = 9.0 Hz, 0.19 H), 3.54 (d, J = 15.0 Hz, 1 H), 3.47 (d, J =
3
1
3
OH). H NMR (300 MHz, CDCl
3
1
3
.64 (m, 1 H), 1.64–1.55 (m, 10 H), 1.50–1.45 (m, 1 H) ppm.
C
NMR (75 MHz, CDCl
6
3
3
3.1, 45.9, 44.5, 40.2, 29.6, 28.4, 27.7, 22.5 ppm. MS (ESI): m/z =
12.0 Hz, 0.2 H), 3.38 (d, J = 3.0 Hz, 0.8 H), 2.85–2.79 (m, 0.8 H),
[M + H]+ 2.76–2.70 (m, 0.2 H), 2.53–2.45 (m, 1 H), 2.40–2.37 (m,1 H), 2.36–
2.19 (m, 2 H), 2.09–2.01 (m, 1 H), 1.92 (d, J = 9.0 Hz, 1 H), 1.58
+
20.2 [M + H] . HRMS (ESI): calcd. for C19
20.2226; found 320.2229.
H30NO
3
(
s, 2 H), 1.52–1.48 (m,2 H), 1.27 (s, 2 H), 1.26–1.06 (m, 3 H) ppm.
5
7
h: Eluent petroleum ether/ethyl acetate (6:1). Colorless oil (2.03 g,
1
3
9% yield). [α]2
5
1
C NMR (75 MHz, CDCl
3
): δ = 139.0, 128.8, 128.4, 127.4, 118.7,
= –24.1 (c = 0.1, CH OH); H NMR (300 MHz,
D 3
5
8.7, 57.5, 56.6, 52.7, 45.9, 41.3, 40.7, 34.3, 28.5, 28.2 ppm. MS
CDCl
3
): δ = 7.36–7.22 (m, 5 H), 4.60 (d, J = 15.0 Hz, 1 H), 4.31
d, J = 15.0 Hz, 1 H), 3.43 (s, 1 H), 3.39–3.33 (m, 1 H), 3.11–3.03
m, 1 H), 2.14 (s, 1 H), 2.07–2.06 (m, 1 H), 1.91 (s, 1 H), 1.80–1.66
+
(
[
ESI): m/z = 226.2 [M – CN] . HRMS (ESI): calcd. for C16
20
H N
(
(
(
M – CN]+ 226.1596; found 226.1599.
m, 1 H), 1.56–1.53 (m, 2 H), 1.48 (s, 9 H), 1.42–1.39 (m, 2 H), 7d: Eluent petroleum ether/ethyl acetate (45:1). Colorless oil
25
1
.30–1.21 (m, 2 H), 1.17–1.09 (m, 2 H) ppm. 13C NMR (75 MHz, (543.2 mg, 53% yield from 5d, 3.0:1 dr). [α]
D
= +18.8 (c = 0.1,
): δ = 7.36–7.30 (m, 5 H),
1
CDCl
3
): δ = 160.6, 141.5, 128.4, 127.3, 127.1, 79.8, 67.7, 62.5, 52.3,
CH
3
OH). H NMR (300 MHz, CDCl
3
4
[
3
6.4, 39.6, 38.9, 37.2, 29.1, 28.4, 22.4 ppm. MS (ESI): m/z = 368.2
4.01 (d, J = 12.0 Hz, 0.25 H), 3.89 (d, J = 15.0 Hz, 0.75 H), 3.75
(d, J = 6.0 Hz, 0.25 H), 3.54 (d, J = 12.0 Hz, 0.75 H), 3.47 (d, J =
12.0 Hz, 0.25 H), 3.38 (d, J = 3.0 Hz, 0.75 H), 2.86–2.79 (m, 0.78
M + Na] . HRMS (ESI): calcd. for C21H31NO
3
Na [M + Na]+
+
68.2202; found 368.2208.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43069
/KAP1
Date: 30-10-14 17:33:33
Pages: 10
Asymmetric Synthesis of 3,4-Disubstituted Proline Derivatives
H), 2.76–2.70 (m, 0.29 H), 2.53–2.47 (m, 1 H), 2.40–2.37 (m, 1 H),
+
m/z = 246.1 [M + H] . HRMS (ESI): calcd. for C15
H
20NO
25
2
[M +
+
2
1
1
1
2
.29–2.02 (m, 3 H), 1.94–1.91 (m, 1 H), 1.59–1.54 (m, 1 H), 1.49–
H] 246.1494; found 246.1496.
.42 (m, 2 H), 1.28 (s, 1 H), 1.19–1.12 (m, 2 H), 1.08 (d, J =
8
(
b: White solid (503 mg, 89%yield), m.p. 269–271 °C. [α]
c = 0.1, CH OH). H NMR (500 MHz, D O): δ = 7.53–7.49 (m,
3 2
H), 4.55 (d, J = 10.0 Hz, 1 H), 4.41 (d, J = 15.0 Hz, 1 H), 4.06–
.99 (m, 2 H), 3.75–3.72 (m, 1 H), 3.35 (t, J = 10.0 Hz, 1 H), 2.48–
.41 (m, 2 H), 1.84–1.81 (m, 1 H), 1.72–1.65 (m, 1 H), 1.60–1.49
D
= +37.1
2.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl
3
): δ = 140.2, 128.7,
1
28.4, 127.3, 114.8, 58.6, 57.5, 56.5, 52.6, 45.8, 41.3, 40.7, 34.3,
5
3
2
+
8.5, 28.1 ppm. MS (ESI): m/z = 226.2 [M – CN] . HRMS (ESI):
+
calcd. for C16
H
20N [M – CN] 226.1596; found 226.1599.
1
3
7
e: Eluent petroleum ether/ethyl acetate (50:1). Colorless oil
(m, 4 H), 1.39–1.37 (m, 1 H) ppm. C NMR (125 MHz, D
= 173.7, 133.1, 132.5, 131.5, 72.6, 62.2, 59.9, 44.3, 38.1, 28.1, 27.1,
2
O): δ
25
(
860.3 mg, 48% yield from 5e, 20:1 dr). [α]
D
= +37.0 (c = 0.1,
): δ = 7.36–7.25 (m, 5 H), 26.1, 23.8 ppm. MS (ESI): m/z = 260.2 [M + H] . HRMS (ESI):
.88 (d, J = 12.9 Hz, 1 H), 3.65 (d, J = 12.9 Hz, 1 H), 3.59 (s, 1
calcd. for C16
[M + H]+ 260.1651; found 260.1653.
H), 2.85 (d, J = 9.6 Hz, 1 H), 2.77–2.71 (m, 1 H), 2.51 (d, J =
1
+
3 3
CH OH). H NMR (300 MHz, CDCl
3
H22NO
2
25
8
+
5
c: White solid (515.8 mg, 88% yield), m.p. 276–277 °C. [α]
OH). H NMR (300 MHz, D O): δ = 7.38 (s,
3 2
H), 4.46 (d, J = 12.8 Hz, 1 H), 4.09 (d, J = 12.8 Hz, 1 H), 3.64–
.59 (m, 1 H), 3.53–3.46 (m, 1 H), 2.32 (s, 1 H), 2.24–2.12 (m, 2
H), 2.07 (s, 1 H), 1.47–1.38 (m, 3 H), 1.15 (d, J = 9.0 Hz, 1 H),
.06–1.01 (m, 2 H) ppm. C NMR (75 MHz, D
33.3, 132.7, 132.3, 131.8, 73.3, 59.9, 59.7, 53.8, 46.6, 42.0, 41.5,
D
=
1
0.3 Hz, 1 H), 2.33–2.27 (m, 1 H), 1.90–1.84 (m, 1 H), 1.74–1.64
1
56.1 (c = 0.1, CH
1
3
(
(
4
m, 1 H), 1.56–1.50 (m, 6 H), 1.37–1.26 (m, 2 H) ppm. C NMR
75 MHz, CDCl ): δ = 137.9, 128.7, 128.4, 127.4, 117.9, 57.8, 56.4,
5.9, 38.2, 28.1, 28.0, 25.8,21.1, 20.7 ppm. MS (ESI): m/z = 240.1
3
3
+
+
[M – CN] . HRMS (ESI): calcd. for C17
H
22N [M – CN] 240.1749;
13
1
2
O): δ = 174.0,
found 240.1745.
1
+
7
7
f: Eluent petroleum ether/ethyl acetate (20:1). Colorless oil (1.06 g,
33.9, 29.5 ppm. MS (ESI): m/z = 272.2 [M + H] . HRMS (ESI):
calcd. for C17
[M + H]+ 272.1651; found 272.1658.
3% yield from 5f, 1.3:1 dr). [α]2
): δ = 7.36–7.28 (m, 5 H), 3.98–3.83 (m, 1
H), 3.74 (d, J = 6.0 Hz, 0.5 H), 3.72–3.61 (m, 1 H), 3.28 (d, J =
.0 Hz, 0.5 H), 3.02–2.84 (m, 1 H), 2.63–2.37 (m, 1 H), 2.12–1.78
5
= +3.25 (c = 0.1, CH
OH). H
1
H22NO
2
D
3
NMR (300 MHz, CDCl
3
25
8
+
5
D
d: White solid (580.3 mg, 99% yield), m.p. 255–256 °C. [α] =
OH). H NMR (300 MHz, D O): δ = 7.43 (s,
3 2
H), 4.50 (d, J = 12.0 Hz, 1 H), 4.12 (d, J = 12.0 Hz, 1 H), 3.61–
.50 (m, 2 H), 2.76–2.69 (m, 1 H), 2.35 (s, 1 H), 2.26–2.15 (m, 2
H), 2.10 (s, 1 H), 1.57–1.51 (m, 3 H), 1.21–0.99 (m, 3 H) ppm.
NMR (75 MHz, D O): δ = 173.8, 154.8, 130.6, 130.0, 129.2,71.2,
7.2, 56.9, 52.1, 44.5, 39.4, 38.8, 31.2, 26.8 ppm. MS (ESI): m/z =
1
24.9 (c = 0.1, CH
6
1
3
(
(
1
1
m, 2 H), 1.20–1.13 (m, 3 H), 1.08–1.00 (m, 3 H) ppm. C NMR
75 MHz, CDCl ): δ = 137.6, 128.8, 128.6, 128.4, 127.3, 127.2,
18.6, 116.3, 60.4, 60.0, 59.7, 58.9, 56.8, 56.7, 46.8, 43.6, 39.9, 38.5,
3
3
13
C
2
+
8.9, 18.4,18.2, 14.6 ppm. MS (ESI): m/z = 188.1 [M – CN] .
5
2
2
+
HRMS (ESI): calcd. for C13
H
18N [M – CN] 188.1439; found
+
+
72.2 [M + H] . HRMS (ESI): calcd. for C17
72.1651; found 272.1658.
H
22NO
2
[M + H]
188.1442.
7
g: Eluent petroleum ether/ethyl acetate (30:1). Colorless oil
25
8
+
5
(
(
e: White solid (576.5 mg, 94% yield), m.p. 285–287 °C. [α]
54.5 (c = 0.1, CH
D
=
25
(859.2 mg, 47% yield from 5 g, 3.1:1 dr). [α]
D
= –23.6 (c = 0.1,
): δ = 7.36–7.28 (m, 5 H),
1
3 2
OH). H NMR (300 MHz, D O): δ = 7.36 (s,
H), 4.50 (d, J = 12.8 Hz, 1 H), 4.14 (d, J = 12.6 Hz, 1 H), 3.87
d, J = 8.8 Hz, 1 H), 3.15 (s, 1 H), 3.11–2.98 (m, 1 H), 2.79–2.38
2
m, 1 H), 1.63–1.31 (m, 9 H) ppm. C NMR (75 MHz, D O, [D4]-
MeOH): δ = 171.0, 144.6, 132.2, 131.6, 130.6, 69.5, 58.6, 56.3, 45.7,
8.4, 26.5, 26.2, 26.1, 26.0, 20.1, 19.9 ppm. MS (ESI): m/z = 308.2
1
CH
3
OH); H NMR (300 MHz, CDCl
3
4
(
1
(
.02 (d, J = 13.0 Hz, 0.25 H), 3.87 (d, J = 13.2 Hz, 0.75 H), 3.68
d, J = 7.9 Hz, 0.25 H), 3.63 (d, J = 13.2 Hz, 0.75 H), 3.54 (d, J =
3.0 Hz, 0.25 H), 3.44 (s, 0.75 H), 2.75–2.62 (m, 3.8 H), 2.38–2.34
m, 0.3 H), 1.90–1.86 (m,2 H),1.76–1.60 (m, 1 H), 1.45–1.42 (m, 3
13
3
13
H) ppm. C NMR (75 MHz, CDCl
3
): δ = 137.9, 128.9, 128.5,
+
+
[M + Na] . HRMS (ESI): calcd. for C18
2
H23NO Na [M + Na]
1
3
27.4, 117.6, 59.7, 58.6, 56.6, 55.9, 48.5, 45.5, 42.4, 41.3, 34.4, 33.6,
0.5, 27.3, 26.8 ppm. MS (ESI): m/z = 227.2 [M + H] . HRMS
308.1626; found 308.1634.
+
2
5
+
8f: White solid (483.4 mg, 96% yield), m.p. 251–252 °C. [α]
D
=
(ESI): calcd. for C15
H
19
N
2
[M + H] 227.1548; found 227.1550.
1
+
3 2
10.0 (c = 0.1, CH OH). H NMR (300 MHz, D O): δ = 7.42–
7.00 (m, 5 H), 4.43–4.30 (m, 2 H), 3.74 (d, J = 12.0 Hz, 1 H), 3.60–
3.53 (m, 1 H), 3.24–3.17 (m, 1 H), 2.18–2.13 (m, 1 H), 1.91–1.84
7
h: Eluent petroleum ether/ethyl acetate (40:1). Colorless oil
2
5
(608.2 mg, 36% yield from 5h, 2.8:1 dr). [α]
D
= –20.1 (c = 0.1,
1
3 3
CH OH). H NMR (300 MHz, CDCl ): δ = 7.36–7.26 (m, 5 H), (m, 1 H), 1.11 (d, J = 6.0 Hz, 3 H), 0.98 (d, J = 6.0 Hz, 3 H) ppm.
3
.89–3.81 (m, 1 H), 3.66 (d, J = 15.0 Hz, 0.72 H), 3.58–3.50 (m, 1
H), 3.36 (s, 0.31 H), 2.88–2.80 (m, 1 H), 2.66–2.64 (m, 1 H), 2.50–
.36 (m, 2 H), 2.35–2.26 (m, 2 H), 2.07–1.90 (m, 1 H), 1.70–1.53
13C NMR (75 MHz, D O): δ = 157.5, 134.8, 130.8, 130.2, 129.2,
2
73.7, 59.6, 46.1, 38.6, 18.5, 14.3, 14.1 ppm. MS (ESI): m/z = 334.1
2
(
(
[M + H]
m, 2 H), 1.47–1.37 (m, 2 H), 1.32–1.26 (m, 1 H) ppm. C NMR found 234.1497.
75 MHz, CDCl ): δ = 140.2, 128.7, 128.4, 127.3, 114.8, 58.6, 57.5,
+
. HRMS (ESI): calcd. for C H NO [M + H] 188.1442;
+
1
4
20
2
1
3
3
2
5
8g: White solid (505 mg, 96% yield), m.p. 270–272 °C. [α]
D
= –30.0
O): δ = 7.50–7.49 (m,
H), 4.56 (d, J = 10.0 Hz, 1 H), 4.23 (d, J = 10.0 Hz, 1 H), 3.85
5
2
2
6.5, 52.6, 45.8, 41.3, 40.7, 34.2, 28.5, 28.1 ppm. MS (ESI): m/z =
26.2 [M – CN] . HRMS (ESI): calcd. for C16
1
(
3 2
c = 0.1, CH OH). H NMR (300 MHz, D
+
20N [M – CN]+
H
5
(
26.1596; found 226.1599.
d, J = 5.0 Hz, 1 H), 3.68–3.66 (m, 1 H), 2.89–2.82 (m, 3 H), 1.86–
General Procedure for the Preparation of 8: A solution of 7, as a
mixture of endo and exo (2.16 mmol, 1.0 equiv.) in con. HCl (m, 1 H) ppm. C NMR (75 MHz, D O): δ = 173.5, 132.9, 132.4,
1.83 (m, 1 H), 1.80–1.74 (m, 2 H), 1.72–1.61 (m, 2 H), 1.60–1.54
1
3
2
(
21 mL) was heated to reflux for 20 h. The solvent was then re-
131.8, 131.5, 74.0, 60.5, 59.8, 49.6, 42.2, 33.3, 32.5, 25.9 ppm. MS
+
moved to give the desired product in excellent optical purity.
(ESI): m/z = 246.1 [M + H] . HRMS (ESI): calcd. for C H NO
1
5
20
2
[M + H]+ 246.1494; found 246.1496.
2
5
8
a: White solid (500 mg, 95% yield), m.p. 275–277 °C. [α]
D
= +28.0
1
25
(c = 0.1, CH
3
OH). H NMR (300 MHz, D
2
O): δ = 7.38 (s, 5 H), 8h: White solid (515.8 mg, 86% yield), m.p. 275–276 °C. [α]
D
=
1
4
.45 (d, J = 12.0 Hz, 1 H), 4.11 (d, J = 12.0 Hz, 1 H), 3.67–3.64 –36.2 (c = 0.1, CH
3
OH). H NMR (300 MHz, D
2
O): δ = 7.43 (s,
(
m, 1 H), 3.57–3.51 (m, 1 H), 2.78–2.69 (m, 3 H), 1.71–1.47 (m, 6
5 H), 4.50 (d, J = 13.0 Hz, 1 H), 4.12 (d, J = 12.8 Hz, 1 H), 3.62–
13
H) ppm. C NMR (125 MHz, D
2
O): δ = 173.5, 132.9, 132.3, 131.8, 3.46 (m, 2 H), 2.85–2.67 (m, 1 H), 2.35 (s, 1 H), 2.19 (dd, J = 14.8,
131.5, 74.0, 60.5, 59.8, 49.6, 42.2, 33.3, 32.5, 25.9 ppm. MS (ESI):
8.8 Hz, 2 H), 2.10 (s, 1 H), 1.69–1.37 (m, 3 H), 1.32–0.90 (m, 3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43069
/KAP1
Date: 30-10-14 17:33:33
Pages: 10
F. Zhang, X. Wen, Q.-L. Xu, H. Sun
FULL PAPER
H) ppm. 13C NMR (75 MHz, D
O): δ = 173.8, 154.8, 130.7, 130.1, the crude product, which was purified by chromatography (petro-
29.2, 71.2, 57.2, 56.9, 52.1, 44.5, 39.4, 38.8, 31.2, 26.8 ppm. MS leum ether/ethyl acetate = 5:1) to give the product as a white pow-
2
1
+
1
(
ESI): m/z = 272.2 [M + H] . HRMS (ESI): calcd. for C17
H
22NO
2
der (83 mg, 69.7% yield). H NMR (500 MHz, [D
6
]DMSO): δ =
[
M + H]+ 272.1651; found 272.1658.
7.88 (s, 1 H), 5.97 (d, J = 5.0 Hz, 1 H), 4.03–4.01 (m, 1 H), 3.44
(
(
2
d, J = 10.0 Hz, 1 H), 2.68–2.65 (m, 1 H), 1.58–1.29 (m, 4 H), 0.88
Procedure for the Preparation of 11: To a solution of dry CH
10 mL) at –23 °C under a N
ide (0.29 mL) was added. After being stirred for 30 min, d-di-
isopropyltartrate (0.286 mL) and (E)-2-hexene-1-ol (100 mg,
2
Cl
2
t, J = 5.0 Hz, 3 H), 0.61 (d, J = 5.0 Hz, 2 H), 0.49 (d, J = 5.0 Hz,
(
2
atmosphere titanium(IV) isopropox-
+
H) ppm. MS (ESI): m/z = 235.1 [M + Na] .
Procedure for the Preparation of 15: A vessel that contained Pd/C
10%, 70 mg) and 14 (693 mg, 3.2 mmol) in methanol (32 mL) was
0
3
CH
1
.99 mmol) in CH
0 min, tert-butyl hydroperoxide (TBHP; 0.37 mL, 5.36 m in
Cl ) was added. The reaction mixture was stirred at –23 °C for
h, before water (5.8 mL) was added, and the reaction warmed to
2 2
Cl (0.33 mL) was added. After being stirred for
(
charged with hydrogen (1 bar) at room temperature for 2.5 h. The
mixture was filtered through a pad of Celite and concentrated un-
der reduced pressure to give the crude product. To a solution of
product in methanol, hydrochloric acid (1.0 equiv.) was added. The
solution was concentrated under reduced pressure to get a crude
product, which was recrystallization from 2-propanol to give a
white powder (516 mg, 84% yield). H NMR (500 MHz, [D
DMSO): δ = 8.14 (s, 3 H), 8.05 (s, 1 H), 6.27 (s, 1 H), 4.22 (s, 1
H), 3.38 (s, 1 H), 2.67 (s, 1 H), 1.48–1.23 (m, 4 H), 0.83 (t, J =
1
2
2
room temperature for 1 h. Next, a saturated solution of sodium
hydroxide (30%) with sodium chloride (0.5 mL) was added and
stirred for 30 min, filtered through Celite to give a clear, colorless
solution and extracted with CH
2
Cl
2
. The organic layer was dried
1
6
]-
with Na SO and concentrated, and the residue was purified by
2
4
chromatography (petroleum ether/ethyl acetate) to give the desired
1
product (103 mg, 89% yield). Colorless oil. H NMR (300 MHz,
0.0 Hz, 3 H), 0.61 (d, J = 5.0 Hz, 2 H), 0.52 (d, J = 5.0 Hz, 2
CDCl
3
): δ = 3.90 (d, J = 12.4 Hz, 1 H), 3.16 (t, J = 6.4 Hz, 1 H),
+
H) ppm. MS (ESI): m/z = 223.0 [M + H] .
2
3
.92 (m, 2 H), 1.83 (s, 1 H), 1.56–1.43 (m, 4 H), 0.96 (t, J = 7.3 Hz,
H) ppm. MS (ESI): m/z = 116.1 [M + H] .
+
Procedure for the Preparation of 16: To a solution of 8 (166.2 mg,
0
1
.68 mmol, 1.0 equiv.), 15 (151.4 mg, 0.68 mmol), EDCI (194 mg,
.02 mmol), and HOBt (145 mg, 1.09 mmol) in dimethylformamide
DMF; 5 mL) at 0 °C was added NMM (0.3 mL) dropwise. The
Procedure for the Preparation of 12: TEMPO (18.69 mg,
.12 mmol) was added to a mixture of 11 (100 mg, 0.86 mmol) in
0
(
acetonitrile (5.16 mL) and sodium phosphate buffer (4.3 mL) at
room temperature. The mixture was heated at 35 °C, then sodium
chlorite (0.311 g) in water (2.4 mL. 3.44 mmol), and bleach
reaction mixture was kept at 0 °C for 30 min. Then the resulting
mixture was stirred overnight at room temperature. The solvent was
removed and the residue was diluted with EtOAc, and washed with
HCl (1N), saturated NaHCO solution, and brine. The combined
3
organic layer was dried with anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The crude product was purified by column
chromatography (petroleum ether/ethyl acetate = 1:1) to give the
product as white powder. (198.6 mg, 80.4% yield). [α]
=
(61.92 μL) in water (1.37 mL) were added into the reaction mixture
simultaneously. The resulting mixture was heated to 100 °C for 2 h.
The mixture was made basic by the addition of NaOH solution
(1N; pH = 8–9), extracted with EtOAc. The organic layer was dis-
carded, and sodium thiosulfate was added to the aqueous layer,
acidified with HCl solution (1N; pH = 2), extracted with EtOAc.
The combined organic layer was dried with Na SO , concentrated
2 4
25
D
= +74.5 (c
1
0.1, CH
3 6
OH). H NMR (500 MHz, [D ]DMSO): δ = 7.83 (s, 1
H), 7.43 (d, J = 10.0 Hz, 1 H), 7.35–7.29 (m, 5 H), 5.69 (s, 1 H),
under reduced pressure to obtain the crude acid , which was used
4
3
2
.18–4.06 (m, 1 H), 3.92 (s, 1 H), 3.89–3.87 (d, J = 10.0 Hz, 1 H),
.09–3.06 (d, J = 15.0 Hz, 1 H), 2.93–2.91 (t, J = 5.0 Hz, 1 H),
.67–2.64 (m, 1 H), 2.44–2.41 (m, 3 H), 1.74–1.72 (t, J = 5.0 Hz, 1
1
in the next step without further purification. H NMR (500 MHz,
[D
6
]DMSO): δ = 12.88 (br. s, 1 H), 3.12 (d, J = 1.8 Hz, 1 H), 3.05–
3
.02 (m, 1 H), 1.57–1.24 (m, 4 H), 0.95 (t, J = 7.3 Hz, 3 H) ppm.
H), 1.52–1.16 (m, 10 H), 0.87–0.78 (m, 3 H), 0.59–0.47 (m, 4
H) ppm. C NMR (125 MHz, [D
+
MS (ESI): m/z = 131.2 [M + H] .
13
6
]DMSO): δ = 172.8, 172.1,
1
3
4
4
38.2, 129.0, 127.9, 126.9, 74.9, 73.4, 59.1, 58.1, 49.9, 49.5, 40.6,
Procedure for the Preparation of 13: To a mixture of 12 (42 mg,
1.4, 30.8, 23.9, 22.1, 18.8, 13.8, 5.4, 5.3 ppm. MS (ESI): m/z =
0.32 mmol), NMM (38.8 μL) in anhydrous THF (1 mL) at –5 °C
+
+
14.3 [M + H] . HRMS (ESI): calcd. for C24
H
36
N
3
O
3
[M + H]
and pivaloylchloride (43.35 μL) was added. The mixture was stirred
for 15 min at this temperature and cyclopropylamine (24.4 μL,
14.2757; found 414.2760.
0
.352 mmol) was added before the reaction mixture was warmed
Procedure for the Preparation of 18: A vessel that contained Pd/C
10%, 12 mg) and 16 (55.7 mg, 0.13 mmol) in methanol (1 mL) was
charged with hydrogen (1 bar) at room temperature overnight. The
mixture was filtered through a pad of Celite and concentrated un-
der reduced pressure to give a crude product, to which was added
to room temperature for 3 h. The reaction was quenched by water,
extracted with EtOAc, and the combined organic layers were
washed with HCl (1N), dried with Na SO , and concentrated under
2 4
reduced pressure to obtain the crude product, which was purified
by chromatography (petroleum ether/ethyl acetate = 5:1) to get the
(
1
7 (40.41 mg, 0.107 mmol) and DIPEA (27.7 μL). The mixture was
dissolved in DMF (1 mL), cooled to 0 °C, and PyBop (72.39 mg,
.139 mmol) was added, before the reaction mixture was warmed
product (29.1 mg, 60.6% yield) as a solid with a low melting point.
1
3
H NMR (300 MHz, CDCl ): δ = 6.17 (s, 1 H), 3.18 (s, 1 H), 2.88–
0
2.75 (m, 1 H), 2.68–2.70 (m, 1 H), 1.63–1.45 (m, 4 H), 0.95 (t, J =
to room temperature and stirred overnight. The solvent was re-
moved and the residue was diluted with EtOAc, and washed with
7.3 Hz, 3 H), 0.77–0.75 (m, 2 H), 0.49–0.45 (m, 2 H) ppm. MS
+
(
ESI): m/z = 192.1 [M + Na] .
HCl (1N), saturated NaHCO
Procedure for the Preparation of 14: A mixture of 13 (95.87 mg, organic layer was dried with anhydrous sodium sulfate, filtered, and
.56 mmol), sodium azide (145.6 mg, 2.24 mmol), and anhydrous concentrated in vacuo. The crude product was dissolved in CH Cl
magnesium sulfate (269.6 mg) in methanol (1.5 mL) was heated to (3 mL), and Dess–Martin reagent (162.08 mg, 0.382 mmol) was
0 °C for 5 h. The mixture was diluted with methanol and filtered added before the mixture was stirred at room temperature for 2 h.
The reaction was quenched with saturated NaHCO and extracted
with CH Cl . The combined organic layer was dried with an-
hydrous sodium sulfate, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography (CH Cl
3
solution, and brine. The combined
0
2
2
7
through a pad of Celite. The solvent was removed under reduced
pressure, the residue was diluted with EtOAc and water, the aque-
ous layer was extracted with EtOAc, and the combined organic
3
2
2
layers were dried with Na
2
SO
4
. The solvent was removed to give
2
2
/
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43069
/KAP1
Date: 30-10-14 17:33:33
Pages: 10
Asymmetric Synthesis of 3,4-Disubstituted Proline Derivatives
MeOH = 70:1) to give the product as a white powder (61.1 mg,
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0% yield). H NMR (500 MHz, [D
6
]DMSO): δ = 9.20 (s, 1 H),
.91 (d, J = 2.2 Hz, 1 H), 8.76 (s, 1 H), 8.67 (d, J = 4.9 Hz, 1 H),
.49 (d, J = 9.1 Hz, 1 H), 8.20 (dd, J = 12.7, 8.0 Hz, 2 H), 4.96 (s,
H), 4.68 (dd, J = 20.1, 11.5 Hz, 1 H), 4.54 (d, J = 9.0 Hz, 1 H),
.28 (d, J = 3.0 Hz, 1 H), 3.74 (d, J = 7.9 Hz, 1 H), 3.68–3.61 (m,
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3
Received: August 12, 2014
Published Online: ᭿
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Job/Unit: O43069
/KAP1
Date: 30-10-14 17:33:33
Pages: 10
F. Zhang, X. Wen, Q.-L. Xu, H. Sun
FULL PAPER
Asymmetric Synthesis
F. Zhang, X. Wen, Q.-L. Xu,*
H. Sun* .......................................... 1–10
Asymmetric Synthesis of 3,4-Disubstituted
Proline Derivatives: Application in Syn-
thesis of Hepatitis C Virus Protease Inhibi-
tor Telaprevir
Asymmetric synthesis of 3,4-disubstituted
proline derivatives was developed through
asymmetric ring opening of substituted an-
hydrides, intramolecular Strecker reaction,
and thermodynamically controlled cyanide
hydrolysis with high stereoselectivity and
moderate yield. HCV protease inhibitor
Telaprevir was synthesized by using the
above methodology.
Keywords: Synthetic methods / Asymmetric
synthesis / Medicinal chemistry / Antivirus
agents / Amino acids
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0