Highly enantioselective synthesis of 5-phenyl-2-alkylprolines using phase-transfer catalytic alkylation

Article abstract of DOI:10.1039/c3ob27089k

An efficient enantioselective synthetic method for the synthesis of (2R)-5-phenyl-2-alkylproline tert-butyl esters was reported. The phase-transfer catalytic alkylation of tert-butyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate in the presence of chiral

Full text of DOI:10.1039/c3ob27089k

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Highly enantioselective synthesis of 5-phenyl-2-
alkylprolines using phase-transfer catalytic alkylation†
Cite this: DOI: 10.1039/c3ob27089k
Myungmo Lee,a Young-Ju Lee,a Eunyoung Park,a Yohan Park,b Min Woo Ha,a
Suckchang Hong,a Yeon-Ju Lee,c Taek-Soo Kim,a Mi-hyun Kima and
Hyeung-geun Park*a
An efficient enantioselective synthetic method for the synthesis of (2R)-5-phenyl-2-alkylproline tert-butyl
esters was reported. The phase-transfer catalytic alkylation of tert-butyl-5-phenyl-3,4-dihydro-2H-pyrrole-
2-carboxylate in the presence of chiral quaternary ammonium catalysts gave the corresponding alkylated
products (up to 97% ee). The following diastereoselective reductions afforded chiral 5-phenyl-2-alkylpro-
lines which can be applied to asymmetric synthesis as organocatalysts or synthesis of biologically active
proline based compounds, such as chiral α-alkylated analogues of (+)-RP66803, as potential CCK
antagonists.
Received 22nd August 2012,
Accepted 21st January 2013
DOI: 10.1039/c3ob27089k
www.rsc.org/obc
Introduction
Since the first application of proline to enantioselective
Robinson annulation, proline and proline analogues have been
widely applied in asymmetric synthesis as efficient organocata-
lysts.1 They were generally prepared from proline itself by
chemical derivatization. According to the dramatic increase of
newly developed organic reactions, new synthetic methods of
diverse substituted prolines as efficient organocatalysts are in
need via direct enantioselective construction of a pyrroline
skeleton. Notably, the nonnatural substituted proline ana-
logues can be considered as conformationally constrained
amino acids and have actually been applied in biologically
active peptidomimetics for structure–activity relationship
studies.2–5 Among the important proline analogues in medic-
inal chemistry, cis-5-phenylproline (1) has been applied as an
element of nonpeptide cholecystokinin (CCK) antagonist
(+)-RP66803.6,7 In this article, we would like to report a new
efficient catalytic synthesis of chiral 5-phenyl-2-alkylproline (1)
as a new element of chiral proline derivatives which can be
applied to asymmetric synthesis and medicinal chemistry via
enantioselective phase-transfer catalysis.8–12
Results and discussion
A number of enantioselective synthetic methods for 5-phenyl-
2-alkylprolines have been reported so far.13–26 Most of these
methods are based on the diastereoselective 1,3-dipolar cyclo-
addition, Pictet–Spengler reaction, and intramolecular iodo-
cyclization. However, their total synthetic steps are relatively long
or have low total chemical yields for large-scale production.
Very recently, we reported a series of new synthetic methods
for optically active α-alkylserines (3),27 α-alkylcysteines (5)28,29
and α-alkyl-α,β-diaminopropionic acids (7)30 by the catalytic
enantioselective α-alkylation of tert-butyl 2-phenyloxazoline-4-
carboxylate (2), tert-butyl 2-phenylthiazoline-4-carboxylate (4),
and N(1)-Boc-2-phenyl-2-imidazoline-4-carboxylic acid tert-
butyl ester (6) under phase-transfer conditions, respectively
(Scheme 1). These works demonstrated that the phase-transfer
catalytic conditions are very efficient for the α-alkylation of the
oxazoline-4-carboxylate, the thiazoline-4-carboxylate and the
imidazoline-4-carboxylate systems. Based on our previous
results, we attempted to apply the phase-transfer catalytic
alkylation of tert-butyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-car-
boxylate (8) for the enantioselective synthesis of chiral
5-phenyl-2-alkylproline tert-butyl esters (1), as shown in the
synthetic strategy (Scheme 2).
aResearch Institute of Pharmaceutical Science and College of Pharmacy,
Seoul National University, Seoul 151-742, Korea. E-mail: hgpk@snu.ac.kr;
Fax: +82-2-872-9129; Tel: +82-2-880-8264
bCollege of Pharmacy, Inje University, 607 Obang-dong, Gimhae,
Gyeongnam 621-749, Korea
cMarine Natural Products Chemistry Laboratory, Korea Ocean Research and
Development Institute, Ansan 426-744, Korea
†Electronic supplementary information (ESI) available. CCDC 897225. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob27089k
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Scheme 1 Previous chiral phase-transfer catalysis of 5-membered heterocyclic
carboxylates.
Fig. 1 Chiral phase-transfer catalysts (13–16).
Table 1 Optimization of PTC reaction conditions
Scheme 2 Synthetic strategy for optically active chiral 5-phenyl-2-alkylproline
tert-butyl esters via enantioselective phase-transfer catalysis.
Catalyst
Entry (mol%)
Base
T [°C] t [h] Yielda [%] eeb [%]
1
2
3
4
5
6
7
8
9
13 (5.0)
14 (5.0)
15 (5.0)
16 (5.0)
16 (5.0)
16 (2.5)
16 (2.5)
16 (2.5)
16 (2.5)
s-KOH
s-KOH
s-KOH
s-KOH
s-KOH
s-KOH
s-CsOH
50% KOH
0
0
0
2.5 79
2.0 92
3.5 92
83
43
86
93
97
97
78
86
89
0
20
78
92
94
64
50
51
−20
−20
−20
−20
25
25
48
72
72
50% CsOH −20
a Isolated yields. b The enantiomeric excess was determined by HPLC
analysis of 9c using a chiral column (Chiralcel OD-H) with hexanes–2-
propanol as eluents.
Scheme 3 Preparation of tert-butyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carbox-
ylate (8).
First, we needed to prepare the substrate 8 for PTC alkyl-
ation. In 2010, the Lygo group reported the efficient diastereo-
selective reduction of (S)-8 to synthesize cis-5-phenylproline,
the precursor of (+)-RP66803.31 We adopted their synthetic
method for the preparation of ( )-8. tert-Butyl-5-phenyl-3,4-
dihydro-2H-pyrrole-2-carboxylate (8) was prepared from com-
mercially available benzophenone imine of glycine tert-butyl
ester (10) in 2 steps. Michael addition of 10 to phenylvinyl-
ketone (11), followed by intramolecular transimination using
15% citric acid afforded tert-butyl-5-phenyl-3,4-dihydro-2H-
pyrrole-2-carboxylate (8) (Scheme 3). For the phase-transfer cata-
lytic alkylation, we used our previously reported reaction
conditions.27–30 The phase-transfer catalytic benzylation of 8
was performed using 5 mol% of the representative catalysts
(13,32 14,33 15,34 1635) along with benzyl bromide (5.0 equiv.)
and solid KOH (5.0 equiv.) in toluene at 0 °C (Fig. 1).
enantioselectivity, and all of the cinchona derived catalysts
(13–15) afforded lower enantioselectivities compared to that of
catalyst 16, which was in accordance with previous results
(entries 1–4).27–30 Notably, aqueous 50% alkali bases showed
longer reaction times with lower chemical yields than those of
solid bases (entries 6–9). Lower temperature afforded higher
enantioselectivity with higher chemical yields (entries 4–5).
A decrease in the amount of catalyst 16 preserved the enantio-
selectivity and chemical yield until 2.5 mol% (entries 5 and 6).
Best enantioselectivity was observed in the case of solid KOH
base conditions at −20 °C (entry 6, 94%, 97% ee) in the presence
of 2.5 mol% of (S,S)-3,4,5-trifluorophenyl-NAS bromide 16.
Further investigation on the scope and limitation in enantio-
selective PTC alkylation with various alkyl halides under the
optimal reaction conditions (entry 6 in Table 1) was per-
formed. As shown in Table 2, very high chemical yields (up to
98%) and enantioselectivities (up to 97% ee) were observed in
As shown in Table 1, (S,S)-3,4,5-trifluorophenyl-NAS
bromide 16 (entry 4, 93% ee) gave the highest
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Table 2 Enantioselective phase-transfer alkylation of
8
with various alkyl
Table 3 Diastereoselective reductions of imine of 9a and 9c with various redu-
halides
cing agents
Entry
RX
t [h]
Yielda [%]
eeb [%] ([α]2D5
)
Yielda
[%]
a
b
24
36
61
82
92 (+)
96 (+)
Entry
R (9)
Reduction conditions t [h]
17 18
c
25
95
97 (+)
1
2
3
PhCH2 (9c)
CH2vCHCH2 (9a)
PhCH2 (9c)
CH2vCHCH2 (9a)
PhCH2 (9c)
PhCH2 (9c)
NaCNBH3, AcOH,
MeOH, RT
L-Selectride, THF, RT
1
0.6
24
24
24
24
48
50 22
43 21
0
2
—
52
24
—
d
23
98
96 (+)
4
5b
6
Na2S2O4, DMF, reflux
Pt/C, H2, EtOH, RT
19 77
e
f
30
48
30
68
96
95
95 (+)
7
PhCH2 (9c)
0
20
91 [(+)-R]c
90 (+)d
DPP, CH2Cl2, 40 °C
8
CH2vCHCH2 (9a)
48
1
19
g
a Isolated yields. b No reaction was observed.
a Isolated yields. b The enantiomeric excess was determined by HPLC
analysis of 9 using a chiral column (Chiralcel OD-H, Chiralpak AD-H,
Chiralpak AS-H) with hexanes–2-propanol as eluents. c The absolute
configuration was assigned by X-ray crystallographic structure of 9f
and the other absolute configurations were tentatively assigned as (R)
based on the absolute configuration of 9f. d The enantiomeric excess
was determined by HPLC analysis of the methyl ester analogue of 9g
due to the low resolution of 9g in chiral HPLC analysis.
Scheme 4 Conversion of 9c to amino acid 19.
Interestingly, L-selectride and Hantzsch ester39 in the presence
of the catalytic amount of diphenyl phosphate (DPP) afforded
only 18c (entry 3, 52%; entry 7, 20%), which is opposite to that
of NaCNBH3. Hydrogenation of 9c with Pt/C under atmo-
spheric H2 also provided 18c as a major diastereoisomer (entry
6, 17c : 18c = 19% : 77%). However, no reaction was observed in
the case of Na2S2O4 (entry 5). We speculate that the bulky reduc-
ing agents such as L-selectride and Hantzsch ester together
with catalytic hydrogenation (Pt/C) can approach to the less
sterically hindered β-face of 9c, affording 18c (entries 3, 6, 7)
as a major diastereomer. In the case of NaCNBH3, the chela-
tion of NaCNBH3 with oxygen of tert-butyl ester might let the
hydride approach to the α-face of 9c, affording 17c as a major
diastereomer. The allylated product 9a also showed compar-
able results under the reduction conditions of NaCNBH3
(entry 2, 17a : 18a = 43% : 21%), L-selectride (entry 4, 17a : 18a =
2% : 24%), and Hantzsch ester (entry 8, 17a : 18a = 1% : 19%).
Hydrogenolysis of 9c (97% ee) using Pd/C under atmospheric
H2 followed by hydrolysis with 6 N HCl provided nonnatural
amino acid 19 (Scheme 4).
Fig. 2 X-ray crystallographic structure of 9f.
allylic, propargylic and benzylic halides, but unactivated alkyl
halide such as methyl iodide provided poor chemical yield
(CH3I, 32%). The absolute configuration of 9f was confirmed
as (R) by X-ray crystallographic analysis (Fig. 2).36
Next, the diastereoselective reduction of an imine moiety of
9 was investigated. As shown in Table 3, the diastereoselecti-
vities were quite variable depending upon the reducing agents.
The reduction of 9c with NaCNBH3 in the presence of acetic
acid provided a separable diastereomeric mixture of 17c
(2R,5S)37 and 18c (2R,5R)37 (entry 1, 17c : 18c = 50% : 22%).38
Conclusion
We developed
a very efficient enantioselective synthetic
methodology for the synthesis of (2S)-5-phenyl-2-alkylproline
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tert-butyl ester by the phase-transfer catalytic alkylation of tert-- dichloromethane, washed with brine, dried over anhydrous
butyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate (8), fol- MgSO4, filtered, and concentrated in vacuo. The residue was
lowed by diastereoselective reduction. The easy preparation of purified by column chromatography (hexane–EtOAc = 10 : 1) to
the substrate, the high enantioselectivity, and the very mild afford 5-tert-butyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxy-
reaction conditions could make this method very practical for late (8) (244 mg, 88% yield) as a yellow oil. 1H-NMR (300 MHz,
large scale processes of the versatile synthetic intermediate, CDCl3) δ 7.87–7.35 (m, 5H), 4.82–4.76 (m, 1H), 3.16–2.88 (m,
chiral 5-phenyl-2-alkylprolines, which can be applied to asym- 2H), 2.36–2.02 (m, 2H), 1.47 (s, 9H) ppm; 13C-NMR (100 MHz,
metric synthesis as organocatalysts or synthesis of biologically CDCl3) δ 175.8, 172.3, 134.0, 130.8, 128.3, 128.0, 81.1, 75.3,
active proline based compounds.
35.3, 28.0, 26.7 ppm; IR (KBr) 2978, 1733, 1614, 1576, 1449,
1392, 1367, 1256, 1213, 1153, 1030, 846, 764, 693 cm−1; HRMS
(FAB+): Calcd for [M + H]+ [C15H20NO2]+ 246.1494; Found
246.1512.
Experimental section
General methods
General procedure for asymmetric phase-transfer catalytic
alkylation
All reagents bought from commercial sources were used as
sold. As the commercially available KOH was a pellet type,
KOH should be ground to the powder form for successful
phase-transfer catalytic reaction and high enantiopurity. The
phase-transfer catalyst 16, (S,S)-3,4,5-trifluorophenyl-NAS
bromide, was purchased from the commercial source (Wako).
Flash column chromatography was carried out using silica gel
(230–400 mesh). Nuclear magnetic resonance spectra were
Alkyl halide (0.41 mmol) was added to a solution of 5-tert-
butyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate (8, 20 mg,
0.082 mmol) and (S,S)-3,4,5-trifluorophenyl-NAS bromide 16
(phase-transfer catalyst, 1.9 mg, 0.0021 mmol) in toluene
(0.3 mL) at −20 °C. After weighing of the powdered KOH
(23 mg, 0.41 mmol), it was quickly added to the reaction
mixture. The reaction mixture was stirred for specified time,
then diluted with EtOAc, washed with brine, dried over anhy-
drous MgSO4, filtered, concentrated in vacuo, and purified by
column chromatography (hexane–EtOAc = 25 : 1).
1
measured on a 300 MHz or 400 MHz instrument. All H-NMR
spectra were reported in ppm relative to CHCl3 (δ 7.24). All
13C-NMR spectra were reported in ppm relative to the central
CDCl3 (δ 77.23) or CD3OD (δ 49.15). All HPLC analyses were
performed using a 4.6 mm × 250 mm chiral column as the
stationary phase.
tert-Butyl 2-allyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxy-
late (9a). The general procedure was employed. After stirring
for 24 h, 9a was obtained by column chromatography as a
yellow oil (14 mg, 64% yield). The enantioselectivity was deter-
Preparation of the phase-transfer catalysis substrate
tert-Butyl-2-(diphenylmethylene-amino)-5-oxo-5-phenyl- mined by chiral HPLC analysis (DIACEL Chiralpak AD-H,
pentanoate (12).31 tert-Butyl 2-(diphenylmethylene-amino)- hexane–2-propanol = 99 : 1), flow rate = 1.0 mL min−1, λ =
acetate 10 (413 mg, 1.40 mmol), solid KOH (157 mg, 254 nm, retention time: 5.1 min (minor), 6.3 min (major), 92%
1
2.8 mmol) and tetrabutylammonium bromide (45 mg, ee. H-NMR (300 MHz, CDCl3) δ 7.86–7.35 (m, 5H), 5.83–5.69
0.14 mmol) were added to a 25 mL round bottom flask. (m, 1H), 5.15–5.04 (m, 2H), 3.11–2.96 (m, 2H), 2.68 (d, J =
Dichloromethane (4 mL) was added, then 1-phenyl-propenone 3.4 Hz, 2H), 2.68–2.29 (m, 1H), 2.02–1.92 (m, 1H), 1.44 (s, 9H)
11 (277 mg, 2.1 mmol) in dichloromethane (4 mL) was added ppm; 13C-NMR (100 MHz, CDCl3) δ 133.5, 130.8, 129.0, 128.4,
slowly to the reaction mixture over 2 h. After stirring for 0.5 h, 128.1, 124.6, 118.5, 83.3, 81.2, 42.6, 35.8, 30.8, 28.4, 28.0 ppm;
the reaction mixture was washed with brine, dried over anhy- IR (KBr) 3074, 2978, 2931, 1726, 1640, 1615, 1576, 1496, 1450,
drous MgSO4, filtered, and concentrated in vacuo. The residue 1392, 1368, 1343, 1254, 1151, 1062, 1029, 996, 919, 848, 763,
was purified by column chromatography (hexane–EtOAc = 693 cm−1; HRMS (FAB+): Calcd for [M + H]+ [C18H24NO2]+
25 : 1) to afford tert-butyl-2-(diphenylmethylene-amino)-5-oxo- 286.1807; Found: 286.1799; [α]2D0 = +68.94 (c 1.0, CHCl3).
5-phenylpentanoate (12) (506 mg, 85% yield) as a yellow oil.
tert-Butyl 5-phenyl-2-(prop-2-yn-1-yl)-3,4-dihydro-2H-pyrrole-
1H-NMR (300 MHz, CDCl3) δ 7.94–7.10 (m, 15H), 4.05 (t, J = 6.1 2-carboxylate (9b). The general procedure was employed. After
Hz, 1H), 3.17–2.94 (m, 2H), 2.34–2.26 (m, 2H), 1.43 (s, 9H) stirring for 36 h, 9b was obtained by column chromatography
ppm; 13C-NMR (100 MHz, CDCl3) δ 199.7, 171.1, 170.6, 132.9, as a pale yellow solid (19 mg, 82% yield). The enantioselectivity
132.4, 130.3, 130.0, 128.8, 128.6, 128.5, 128.4, 128.3, 128.1, was determined by chiral HPLC analysis (DIACEL Chiralpak
128.0, 127.7, 81.1, 64.8, 34.7, 28.2, 28.0 ppm; IR (KBr) 2972, AD-H, hexane–2-propanol = 99 : 1), flow rate = 1.0 mL min−1
,
1733, 1686, 1622, 1598, 1578, 1447, 1367, 1278, 1217, 1150, λ = 254 nm, retention time: 9.6 min (minor), 11.6 min (major),
1075, 1001, 848, 745, 686 cm−1; HRMS (FAB+): Calcd for 96% ee. 1H-NMR (300 MHz, CDCl3) δ 7.87–7.35 (m, 5H),
[M + H]+ [C28H30NO3]+ 428.2226; Found 428.2237.
3.15–3.08 (m, 2H), 2.86 (ddd, J = 18.3 Hz, J = 16.7 Hz, J =
5-tert-Butyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate 1.2 Hz, 2H), 2.51–2.40 (m, 1H), 2.22–2.12 (m, 1H), 1.90–1.88
(8).31 To the mixture of tert-butyl-2-(diphenylmethylene- (m, 1H), 1.44 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3) δ 175.5,
amino)-5-oxo-5-phenylpentanoate (12) (481 mg, 1.1 mmol) in 171.7, 130.9, 129.0, 128.4, 128.2, 82.7, 81.7, 80.4, 70.1, 36.5,
THF (9.6 mL) was added 15% citric acid (4.8 mL). The reaction 30.9, 28.1, 27.9 ppm; IR (KBr) 3295, 2978, 2930, 1727, 1614,
mixture was stirred for 2 h, then the reaction mixture was 1576, 1496, 1451, 1426, 1392, 1368, 1344, 1273, 1254, 1223,
concentrated in vacuo. The residue was diluted with 1157, 1071, 942, 846, 763, 693 cm−1; HRMS (FAB+): Calcd for
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[M + H]+ [C18H22NO2]+ 284.1651; Found 284.1645; m.p. = Chiralpak AS-H, hexane–2-propanol = 99 : 1), flow rate = 1.0 mL
96.4–96.7 °C; [α]2D5 = +39.76 (c 0.5, CHCl3). min−1, λ = 254 nm, retention time: 4.8 min (minor), 5.7 min
tert-Butyl-2-benzyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxy- (major), 91% ee. 1H-NMR (300 MHz, CDCl3) δ 7.80–7.77
late (9c). The general procedure was employed. After stirring (m, 2H), 7.45–7.27 (m, 5H), 7.12–7.10 (m, 2H), 3.23 (dd, J =
for 25 h, 9c was obtained by column chromatography as a pale 25.7 Hz, J = 6.9 Hz, 2H), 2.93–2.82 (m, 1H), 2.48–2.22 (m, 2H),
yellow solid (26 mg, 95% yield). The enantioselectivity was 2.00–1.90 (m, 1H), 1.44 (s, 9H) ppm; 13C-NMR (100 MHz,
determined by chiral HPLC analysis (DIACEL Chiralcel OD-H, CDCl3) δ 174.6, 172.9, 136.1, 134.0, 132.4, 130.8, 130.7, 128.3,
hexane–2-propanol = 99 : 1), flow rate = 1.0 mL min−1, λ = 127.8, 120.4, 83.7, 81.3, 42.8, 35.6, 31.0, 27.9 ppm; IR (KBr)
254 nm, retention time: 6.1 min (major), 7.3 min (minor), 97% 3429, 3060, 3030, 2977, 2930, 1901, 1725, 1615, 1576,
1
ee. H-NMR (300 MHz, CDCl3) δ 7.88–7.23 (m, 10H), 3.29 (dd, 1488, 1450, 1403, 1392, 1367, 1344, 1270, 1253, 1153,
J = 41.2 Hz, J = 6.8 Hz, 2H), 2.98–2.86 (m, 1H), 2.43–2.29 (m, 1108, 1071, 1059, 1033, 1012, 922, 846, 803, 761, 719, 693,
2H), 2.17–2.07 (m, 1H), 1.54 (s, 9H) ppm; 13C-NMR (100 MHz, 637 cm−1; HRMS (FAB+): Calcd for [M + H]+ [C22H25BrNO2]+
CDCl3) δ 174.6, 173.3, 136.9, 134.2, 130.8, 130.6, 128.3, 127.9, 414.0990; Found 414.1066; m.p. = 91.2–92.8 °C; [α]2D5 = +20.07
127.8, 126.3, 84.0, 81.2, 43.4, 35.6, 30.8, 28.0 ppm; IR (KBr) (c 1.0, CHCl3).
3029, 2928, 1725, 1615, 1576, 1496, 1453, 1391, 1367, 1343,
tert-Butyl-2-(naphthalene-2-ylmethyl)-5-phenyl-3,4-dihydro-
1254, 1154, 1083, 1057, 846, 762, 695 cm−1; HRMS (FAB+): 2H-pyrrole-2-carboxylate (9g). The general procedure was
Calcd for [M + H]+ [C22H26NO2]+ 336.1964; Found 336.1971; employed. After stirring for 30 h, 9g was obtained by column
m.p. = 98.4–100.6 °C; [α]2D5 = +11.06 (c 1.0, CHCl3).
tert-Butyl
chromatography as a yellow oil (30 mg, 95% yield). 1H-NMR
2-(4-methylbenzyl)-5-phenyl-3,4-dihydro-2H- (300 MHz, CDCl3) δ 7.79–7.36 (m, 12H), 3.23 (dd, J = 20.4 Hz,
pyrrole-2-carboxylate (9d). The general procedure was J = 6.8 Hz, 2H), 2.90–2.77 (m, 1H), 2.35–2.26 (m, 2H), 2.12–2.03
employed. After stirring for 23 h, 9d was obtained by column (m, 2H), 1.46 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3) δ 174.7,
chromatography as a pale yellow solid (28 mg, 98% yield). The 173.2, 134.7, 134.2, 133.2, 132.1, 130.6, 129.3, 129.2, 128.3,
enantioselectivity was determined by chiral HPLC analysis 127.9, 127.6, 127.5, 127.1, 125.7, 125.3 ppm; IR (KBr) 3057,
(DIACEL Chiralpak AD-H, hexane–2-propanol = 99 : 1), flow 2974, 2928, 1724, 1614, 1576, 1508, 1451, 1391, 1367, 1343,
rate = 1.0 mL min−1, λ = 254 nm, retention time: 10.4 min 1252, 1153, 1064, 848, 822, 758, 693 cm−1; HRMS (FAB+): Calcd
1
(minor), 11.7 min (major), 96% ee. H-NMR (300 MHz, CDCl3) for [M + H]+ [C26H28NO2]+ 386.2120; Found 386.2132; [α]2D5
=
δ 7.81–6.96 (m, 9H), 3.23 (dd, J = 17.3 Hz, J = 6.8 Hz, 2H), +132.65 (c 1.0, CHCl3).
2.89–2.77 (m, 1H), 2.38–2.27 (m, 2H), 2.27 (s, 3H), 2.06–1.96
Methyl-2-(naphthalene-1-ylmethyl)-5-phenyl-3,4-dihydro-2H-
(m, 1H), 1.45 (s, 9H) ppm; 13C-NMR (100 MHz, CDCl3) δ 175.5, pyrrole-2-carboxylate (9ga, methyl ester analogue of 9g). To
171.7, 130.9, 129.0, 128.4, 128.2, 82.7, 81.7, 80.4, 70.1, 36.5, the mixture of tert-butyl 2-(naphthalene-2-ylmethyl)-5-phenyl-
30.9, 28.1, 27.9 ppm; IR (KBr) 2976, 2926, 2857, 1725, 1615, 3,4-dihydro-2H-pyrrole-2-carboxylate (9g) (20 mg, 0.052 mmol)
1576, 1514, 1454, 1392, 1368, 1343, 1274, 1254, 1154, 1059, in dichloromethane (0.5 mL) was added trifluoroacetic acid
847, 762, 693 cm−1; HRMS (FAB+): Calcd for [M + H]+ (0.5 mL) and triethylsilane (0.02 mL, 0.13 mmol). The reaction
[C23H28NO2]+ 350.2120; Found 350.2119; m.p. = 80.9–81.2 °C; mixture was stirred for 1 h, then the reaction mixture was con-
[α]2D5 = +65.17 (c 1.0, CHCl3).
centrated in vacuo. To the mixture of residue in toluene
tert-Butyl 2-(4-fluorobenzyl)-5-phenyl-3,4-dihydro-2H-pyrrole- (0.25 mL) and methanol (0.1 mL) was added TMS-diazo-
2-carboxylate (9e). The general procedure was employed. After methane in 2 M diethyl ether (0.1 mL, 0.17 mmol). The reac-
stirring for 30 h, 9e was obtained by column chromatography tion mixture was stirred for 0.5 h, then the reaction mixture
as a yellow oil (20 mg, 68% yield). The enantioselectivity was was diluted with EtOAc, washed with water, washed with
determined by chiral HPLC analysis (DIACEL Chiralcel OD-H, brine, dried over anhydrous MgSO4, filtered, and concentrated
hexane–2-propanol = 99 : 1), flow rate = 1.0 mL min−1, λ = in vacuo. The residue was purified by column chromatography
254 nm, retention time: 7.1 min (major), 8.0 min (minor), 95% (hexane–EtOAc = 25 : 1) to afford methyl 2-(naphthalene-1-
ee. 1H-NMR (300 MHz, CDCl3) δ 7.80–6.83 (m, 9H), 3.23 (dd, ylmethyl)-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate (9ga)
J = 25.7 Hz, J = 6.9 Hz, 2H), 2.91–2.79 (m, 1H), 2.41–2.22 (m, (16 mg, 90% yield) as a yellow oil. The enantioselectivity was
2H), 2.02–1.93 (m, 1H), 1.44 (s, 9H) ppm; 13C-NMR (100 MHz, determined by chiral HPLC analysis (DIACEL Chiralpak AD-H,
CDCl3) δ 162.9, 160.5, 132.6, 132.2, 132.1, 128.6, 128.4, 128.0, hexane–2-propanol = 99 : 1), flow rate = 1.0 mL min−1, λ =
114.7, 114.5, 42.6, 35.6, 30.9, 29.7, 28.0, 27.8 ppm; IR (KBr) 254 nm, retention time: 22.4 min (minor), 32.3 min (major),
1
2927, 2854, 1726, 1606, 1576, 1509, 1451, 1368, 1345, 1255, 90% ee. H-NMR (300 MHz, CDCl3) δ 7.79–7.30 (m, 12H), 3.76
1223, 1155, 1100, 1059, 846, 761, 693 cm−1; HRMS (FAB+): (s, 3H), 3.46 (dd, J = 23.8 Hz, J = 6.8 Hz, 2H), 2.91–2.81
Calcd for [M + H]+ [C22H25FNO2]+ 354.1869; Found 354.1856; (m, 1H), 2.44–2.10 (m, 3H) ppm; 13C-NMR (100 MHz, CDCl3)
[α]2D5 = +81.31 (c 1.0, CHCl3).
δ 174.7, 134.0, 133.2, 132.2, 131.0, 129.4, 129.0, 128.4, 128.1,
(2R,5S)-tert-Butyl 2-(4-bromobenzyl)-5-phenyl-3,4-dihydro- 127.6, 127.5, 127.3, 125.8, 125.5 ppm; IR (KBr) 3057, 2924,
2H-pyrrole-2-carboxylate (9f). The general procedure was 2853, 1733, 1614, 1576, 1508, 1449, 1367, 1344, 1250, 1157,
employed. After stirring for 48 h, 9f was obtained by column 1062, 899, 859, 823, 758, 693 cm−1; HRMS (FAB+): Calcd for
chromatography as a white solid (33 mg, 96% yield). The enan- [M + H]+ [C23H22NO2]+ 344.1651; Found 344.1653; [α]2D5
tioselectivity was determined by chiral HPLC analysis (DIACEL +133.87 (c 0.5, CHCl3).
=
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Reduction of 9c
EtOAc, dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. The residue was purified by column chromatography
(hexane–EtOAc = 20 : 1) to afford (2R,5R)-tert-butyl-2-benzyl-5-
(2R,5S)-tert-Butyl-2-benzyl-5-phenylpyrrolidine-2-carboxylate
(17c) via NaCNBH3. To the mixture of tert-butyl-2-benzyl- phenylpyrrolidine-2-carboxylate (18c) (35 mg, 52% yield) as a
5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate (9c) (168 mg, colorless oil.
0.50 mmol) in methanol (5 mL) was added sodium cyanoboro-
(2R,5R)-tert-Butyl-2-benzyl-5-phenylpyrrolidine-2-carboxylate
hydride (375 mg, 6.0 mmol) and acetic acid (342 μL, (18c) via Hantzsch ester. To the tert-butyl-2-benzyl-5-phenyl-
6.0 mmol). The reaction mixture was stirred for 1 h, the reac- 3,4-dihydro-2H-pyrrole-2-carboxylate (9c) (84 mg, 0.25 mmol)
tion mixture was diluted with EtOAc, washed with water, in a screw-capped vial was added a dichloromethane solution
washed with brine, dried over anhydrous MgSO4, filtered, and (2 mL) of Hantzsch ester (95 mg, 0.38 mmol) and diphenyl
concentrated in vacuo. The residue was purified by column phosphate (3 mg, 0.13 mmol). The vial was flushed with
chromatography (hexane–EtOAc = 20 : 1) to afford (2R,5S)-tert- argon gas and the reaction mixture was stirred for 48 h at
butyl-2-benzyl-5-phenylpyrrolidine-2-carboxylate (17c) (82 mg, 40 °C. The reaction solvent was removed under reduced
50% yield) as a colorless oil and (2R,5R)-tert-butyl-2-benzyl-5- pressure and the residue was purified by column chromato-
phenylpyrrolidine-2-carboxylate (18c) (37 mg, 22% yield) as a graphy (hexane–EtOAc = 20 : 1) to afford (2R,5R)-tert-butyl-2-
colorless oil. Compound 17c: 1H-NMR (300 MHz, CDCl3) benzyl-5-phenylpyrrolidine-2-carboxylate (18c) (16 mg, 20%
δ 7.48–7.17 (m, 10H), 4.25 (t, 1H), 3.08 (dd, J = 67.3 Hz, J = yield) as a colorless oil.
13.0 Hz, 2H), 2.64 (s, 1H), 2.30–2.19 (m, 1H), 2.13–1.94 (m,
Reduction of 9a
2H), 1.65–1.52 (m, 1H), 1.42 (s, 9H) ppm; 13C-NMR (100 MHz,
CDCl3) δ 176.1, 145.6, 137.7, 130.3, 128.1, 127.8, 126.64,
(2R,5S)-tert-Butyl-2-allyl-5-phenylpyrrolidine-2-carboxylate
126.60, 126.4, 81.0, 70.3, 61.4, 46.1, 35.4, 34.3, 28.0 ppm; IR (17a) via NaCNBH3. To the mixture of tert-butyl-2-allyl-5-
(KBr) 3352, 3084, 3061, 3029, 3003, 2975, 2931, 2871, 1947, phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate (9a) (83 mg,
1878, 1807, 1721, 1603, 1584, 1494, 1475, 1454, 1412, 1392, 0.29 mmol) in methanol (3 mL) was added sodium cyanoboro-
1367, 1324, 1299, 1255, 1213, 1152, 1080, 1058, 1030, 983, 939, hydride (219 mg, 3.49 mmol) and acetic acid (200 μL,
911, 896, 847, 744, 700, 664, 636 cm−1; HRMS (FAB+): Calcd for 3.49 mmol). The reaction mixture was stirred for 40 min, the
[M + H]+ [C22H28NO2]+ 338.2120; Found 338.2124; [α]2D5
−99.33 (c 1.0, CHCl3).
=
reaction mixture was diluted with EtOAc, washed with water,
washed with brine, dried over anhydrous MgSO4, filtered, and
(2R,5R)-tert-Butyl-2-benzyl-5-phenylpyrrolidine-2-carboxylate concentrated in vacuo. The residue was purified by column
(18c) via hydrogenation. To the mixture of tert-butyl-2-benzyl- chromatography (hexane–EtOAc = 30 : 1 > 10 : 1) to afford
5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate (9c) (144 mg, (2R,5S)-tert-butyl-2-allyl-5-phenylpyrrolidine-2-carboxylate (17a)
0.43 mmol) and Pt/C (14 mg) in methanol (3 mL), H2 gas was (36 mg, 43% yield) as a colorless oil and (2R,5R)-tert-butyl-2-
added. The reaction mixture was stirred for 24 h, the reaction allyl-5-phenylpyrrolidine-2-carboxylate (18a) (17.5 mg, 21%
mixture was filtered by Celite 545, washed with methanol, and yield) as a colorless oil. Compound 17a: 1H-NMR (400 MHz,
concentrated in vacuo. The residue was purified by column CDCl3) δ 7.42–7.18 (m, 5H), 5.94–5.84 (m, 1H), 5.14–5.06 (m,
chromatography (hexane–EtOAc = 20 : 1) to afford (2R,5R)-tert- 2H), 4.26 (t, J = 7.44 Hz, 1H), 2.74 (s, 1H), 2.61–2.56 (m, 1H),
butyl-2-benzyl-5-phenylpyrrolidine-2-carboxylate (18c) (111 mg, 2.46–2.41 (m, 1H), 2.22–2.05 (m, 2H), 1.91–1.85 (m, 1H),
77% yield) as a colorless oil and (2R,5S)-tert-butyl-2-benzyl-5- 1.71–1.62 (m, 1H), 1.47 (s, 9H) ppm; 13C-NMR (100 MHz,
phenylpyrrolidine-2-carboxylate (17c) (28 mg, 19% yield) as a CDCl3) δ 176.2, 145.3, 134.3, 128.1, 126.7, 126.5, 117.6, 80.9,
colorless oil. Compound 18c: 1H-NMR (300 MHz, CDCl3) δ 69.2, 61.5, 45.0, 34.6, 34.3, 28.1 ppm; IR (KBr) 3353, 3077,
7.41–7.17 (m, 10H), 4.19–4.14 (m, 1H), 3.29 (dd, J = 17.3 Hz, J = 3027, 2977, 2932, 2871, 1723, 1641, 1604, 1493, 1475, 1455,
6.6 Hz, 2H), 2.42–2.35 (m, 1H), 2.12–2.03 (m, 1H), 1.99–1.89 1393, 1368, 1323, 1295, 1254, 1227, 1145, 1081, 1059, 1029,
(m, 1H), 1.68–1.52 (m, 3H), 1.37 (s, 9H) ppm; 13C-NMR 1000, 915, 849, 755, 700, 666 cm−1; HRMS (FAB+): Calcd for
(100 MHz, CDCl3) δ 175.4, 143.7, 137.8, 130.2, 128.4, 127.9, [M + H]+ [C18H26NO2]+ 288.1964; Found 288.1964; [α]2D0
127.1, 126.8, 126.4, 81.3, 71.0, 63.2, 45.3, 37.4, 34.9, 27.9 ppm; −70.16 (c 1.0, CHCl3).
=
IR (KBr) 3356, 3086, 3062, 3030, 2975, 2929, 2857, 1720, 1604,
(2R,5S)-tert-Butyl-2-allyl-5-phenylpyrrolidine-2-carboxylate
1494, 1454, 1392, 1367, 1323, 1257, 1218, 1153, 1089, 1031, (18a) via L-selectride. To the tert-butyl-2-allyl-5-phenyl-3,4-
982, 913, 848, 760, 744, 700 cm−1; HRMS (FAB+): Calcd for dihydro-2H-pyrrole-2-carboxylate (9a) (70 mg, 0.25 mmol) was
[M + H]+ [C22H28NO2]+ 338.2120; Found 338.2113; [α]2D5 = −9.95 added L-selectride solution, 1.0 M in THF (2.9 mL, 2.9 mmol).
(c 1.0, CHCl3).
The reaction mixture was stirred for 24 h. The reaction mixture
(2R,5R)-tert-Butyl-2-benzyl-5-phenylpyrrolidine-2-carboxylate was quenched with water and 1 M HCl, then the water layer
(18c) via L-selectride. To the tert-butyl-2-benzyl-5-phenyl-3,4- was saturated with NaCl. The mixture was extracted with
dihydro-2H-pyrrole-2-carboxylate (9c) (67 mg, 0.20 mmol) was EtOAc, dried over anhydrous MgSO4, filtered, and concentrated
added L-selectride solution, 1.0 M in THF (2.4 mL, 2.4 mmol). in vacuo. The residue was purified by column chromatography
The reaction mixture was stirred for 24 h. The reaction mixture (hexane–EtOAc = 30 : 1 > 10 : 1) to afford (2R,5S)-tert-butyl-
was quenched with water and 1 M HCl, then the water layer 2-allyl-5-phenylpyrrolidine-2-carboxylate (17a) (1.5 mg, 2%
was saturated with NaCl. The mixture was extracted with yield) as
a
colorless oil and (2R,5R)-tert-butyl-2-allyl-5-
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phenylpyrrolidine-2-carboxylate (18a) (17 mg, 24% yield) as a Medicine Center, Korea Institute of Science and Technology)
colorless oil. Compound 18a: 1H-NMR (400 MHz, CDCl3) for the X-ray crystallography of 9f.
δ 7.40–7.19 (m, 5H), 5.87–5.77 (m, 1H), 5.08 (t, J = 15.08 Hz,
2H), 4.26 (dd, J1 = 9.78 Hz, J2 = 5.8 Hz, 1H), 2.58–2.53 (m, 2H),
2.42–2.31 (m, 2H), 2.15–2.07 (m, 1H), 1.88–1.81 (m, 1H),
1.70–1.60 (m, 1H), 1.46 (s, 9H) ppm; 13C-NMR (100 MHz,
CDCl3) δ 175.6, 143.8, 134.3, 128.4, 127.1, 126.8, 117.8, 81.1,
Notes and references
69.7, 63.3, 44.6, 36.8, 35.3, 28.0 ppm; IR (KBr) 3356, 3073,
3029, 3004, 2977, 2932, 2871, 1950, 1875, 1828, 1720, 1640,
1604, 1526, 1495, 1476, 1454, 1436, 1412, 1392, 1368, 1320,
1 For recent reviews on proline based enamine catalysis, see:
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2 G. C. Barrett, in Amino Acids, Peptides and Proteins, The
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3 S. Hunt, in Chemistry and Biochemistry of the Amino
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6 R.-P. Rarer, WO 9301167-A, 1993.
7 F. Manfré and J. P. Pulicani, Tetrahedron: Asymmetry, 1994,
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1254, 1229, 1151, 1030, 1000, 988, 915, 849, 759, 700 cm−1
;
HRMS (FAB+): Calcd for [M + H]+ [C18H26NO2]+ 288.1964;
Found 288.1961; [α]2D0 = −14.58 (c 1.0, CHCl3).
(2R,5R)-tert-Butyl-2-allyl-5-phenylpyrrolidine-2-carboxylate
(18a) via Hantzsch ester. To the tert-butyl-2-allyl-5-phenyl-3,4-
dihydro-2H-pyrrole-2-carboxylate (9a) (68 mg, 0.24 mmol) in a
screw-capped vial was added a dichloromethane solution
(2 mL) of Hantzsch ester (85 mg, 0.33 mmol) and diphenyl
phosphate (3 mg, 0.01 mmol). The vial was flushed with argon
gas and the reaction mixture was stirred for 48 h at 40 °C. The
reaction solvent was removed under reduced pressure and the
residue was purified by column chromatography (hexane–
EtOAc = 30 : 1 > 10 : 1) to afford (2R,5S)-tert-butyl-2-allyl-5-
phenylpyrrolidine-2-carboxylate (17a) (0.8 mg, 1% yield) as a
8 For recent reviews on the phase-transfer catalysis, see:
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9 M. J. O’Donnell, Acc. Chem. Res., 2004, 37, 506.
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2-carboxylate (18a) (13 mg, 19% yield) as a colorless oil. 518.
2-Amino-2-benzyl-5-phenylpentanoate (19). To the mixture 11 T. Hashimoto and K. Maruoka, Chem. Rev., 2007, 107,
of tert-butyl-2-benzyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxy- 5656.
late (9c) (147 mg, 0.44 mmol) and Pd/C (74 mg) in methanol 12 S.-s. Jew and H.-g. Park, Chem. Commun., 2009, 7090.
(3 mL), H2 gas was added. The reaction mixture was stirred for 13 P. W. R. Harris, M. A. Brimble, V. J. Muir, M. Y. H. Lai,
24 h, the reaction mixture was filtered by Celite 545, washed
with methanol, and concentrated in vacuo. To the mixture of 14 T. Tsubogo, S. Saito, K. Seki, Y. Yamashita and
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reaction mixture was cooled to room temperature and concen- W. S. S. Suganthan, Tetrahedron, 2000, 56, 4063.
trated in vacuo. The residue was purified by ion-exchange 16 C. Nájera, M. de Gracia Retamosa, J. M. Sansano, A. de
column chromatography with a DOWEX® 50WX8-100 ion- Cózar and F. P. Cossio, Eur. J. Org. Chem., 2007, 5038.
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(19) (68 mg, 54% yield) as a white solid. 1H-NMR (300 MHz,
CDCl3) δ 7.27–7.08 (m, 10H), 2.98 (dd, J = 47.3 Hz, J = 7.2 Hz),
J. Yu, L. Ren and L.-Z. Gong, J. Am. Chem. Soc., 2011, 133,
13504.
2.58–2.53 (m, 2H), 1.89–1.81 (m, 1H), 1.66–1.50 (m, 3H) ppm; 18 L. N. Goswami, S. Srivastava, S. K. Panday and
13C-NMR (100 MHz, CD3OD) δ 1752, 142.0, 134.1, 130.1, 129.0,
D. K. Dikshit, Tetrahedron Lett., 2001, 42, 7891.
128.7, 127.9, 126.2, 65.7, 48.9, 41.8, 35.4, 34.7, 24.9 ppm; IR 19 M. Amjad and D. W. Knight, Tetrahedron Lett., 2006, 47,
(KBr) 3436, 3061, 3028, 2925, 2854, 1603, 1496, 1454, 1392, 2825.
1330, 1172, 1097, 1032, 781, 745, 700 cm−1; HRMS (FAB+): 20 M. Haddad, H. Imogaï and M. Larchevêque, J. Org. Chem.,
Calcd for [M + H]+ [C18H22NO2]+ 284.1651; Found 284.1648;
1998, 63, 5680.
m.p. = 252.2–254.2 °C; [α]2D5 = +7.05 (c 0.5, MeOH).
21 F. A. Davis, T. Fang and R. Goswami, Org. Lett., 2002, 4,
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22 E. A. Severino, E. R. Costenaro, A. L. L. Garcia and
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23 A. C. Rudolph, R. Machauer and S. F. Martin, Tetrahedron
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Acknowledgements
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MEST) 24 B. C. J. van Esseveldt, P. W. H. Vervoort, F. L. van Delft and
(2012-002956) and the National Research Foundation (NRF) F. P. J. T. Rutjes, J. Org. Chem., 2005, 70, 1791.
grant funded by the Korea government (MEST) (No. 25 D. Stead, P. O’Brien and A. Sanderson, Org. Lett., 2008, 10,
201000017). We specially thank Dr Jae Kyun Lee (Neuro-
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Paper
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35 T. Ooi, M. Kameda and K. Maruoka, J. Am. Chem. Soc.,
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36 CCDC 897225 contains the supplementary crystallographic
data for compound 9f.
37 The relative stereochemistry of diastereomers (17c, 18c)
could be assigned by nOe spectroscopic analysis.
38 J. R. Goodell, J. P. McMullen, N. Zaborenko, J. R. Maloney,
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Org. Biomol. Chem.
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