Asymmetric synthesis and catalytic activity of 3-methyl-β-proline in enantioselective anti -mannich-type reactions

Article abstract of DOI:10.1021/jo4010316

Enantiomerically pure 3-methyl-β-proline was synthesized using an asymmetric phase-transfer-catalyzed alkylation of a cyanopropanoate to establish the all-carbon stereogenic center. The catalytic activity of 3-methyl-β-proline in the Mannich-type reaction between a glyoxylate imine and ketones/aldehydes was subsequently investigated. The catalyst was designed and found to be more soluble in nonpolar organic solvents relative to the unsubstituted β-proline catalyst, and as a result allowed for added flexibility during optimization efforts. This work culminated in the development of a highly anti-diastereo- and enantioselective process employing low catalyst loading.

Full text of DOI:10.1021/jo4010316

Article
pubs.acs.org/joc
Asymmetric Synthesis and Catalytic Activity of 3‑Methyl-β-proline in
Enantioselective anti-Mannich-type Reactions
Kazuhiro Nagata, Yasushi Kuga, Akinori Higashi, Atsushi Kinoshita, Takuya Kanemitsu, Michiko Miyazaki,
and Takashi Itoh*
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
S
* Supporting Information
ABSTRACT: Enantiomerically pure 3-methyl-β-proline was synthesized using
an asymmetric phase-transfer-catalyzed alkylation of a cyanopropanoate to
establish the all-carbon stereogenic center. The catalytic activity of 3-methyl-β-
proline in the Mannich-type reaction between a glyoxylate imine and ketones/
aldehydes was subsequently investigated. The catalyst was designed and found
to be more soluble in nonpolar organic solvents relative to the unsubstituted β-
proline catalyst, and as a result allowed for added flexibility during optimization
efforts. This work culminated in the development of a highly anti-diastereo-
and enantioselective process employing low catalyst loading.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
β-Amino acids have received much attention due to their
unique characteristics,7,8 which include enhancing proteolytic
stability and the tendency to form stable secondary structures
of peptides. Thus, β-prolines as well as other acyclic β-amino
acids have become sought-after synthetic targets.9 Despite the
fact that several syntheses of β-proline,8b,10 and a few syntheses
of substituted β-prolines,4k,11 have been reported, there were no
general methods disclosed for the synthesis of 3-substituted-β-
prolines.12 Therefore, we targeted our initial efforts on
discovering a general route toward 3-substituted-β-prolines.
The results of these studies are depicted in Scheme 1. Racemic
3-methyl-β-proline was derived from tert-butyl 2-cyanopropa-
noate (1) by first alkylation with ethyl iodoacetate under phase-
transfer-catalyzed conditions to provide the cyanodiester 2 in
97% yield. The chemoselective nitrile reduction (NaBH4,
CoCl2)13 of 2 occurred with spontaneous ring closure to afford
lactam 3. Conversion of 3 into the corresponding thiolactam 4
with Lawesson’s reagent, subsequent reduction of the
thiolactam (Raney-Ni), and N-protection with Z-chloride
provided the N-protected β-proline 5. Removal of the t-butyl
group upon treatment with TFA and subsequent deprotection
of the Cbz group (Pd/C, H2) gave 3-methyl-β-proline (7) in
45% yield over seven steps. The catalytic activity in the
Mannich-type reaction of cyclohexanone was first explored with
racemic 3-methyl-β-proline (7) (Table 1). The previously
reported conditions for Mannich-type reactions using the
unsubstituted β-proline catalyst4l were initially investigated to
explore the feasibility of the substituted catalyst in the racemic
sense (Table 1, entry 1). An excellent anti-selectivity was
obtained in the reaction using 10 equiv of cyclohexanone;
however, reducing the amount of the substrate caused a slight
Mannich reactions that provide access to β-amino carbonyl
compounds are important C−C bond-forming reactions
between an enolizable carbonyl compound and an imine.1
The stereochemical course (e.g., diastereo- and enantioselec-
tivity) of Mannich-type reactions has been extensively studied.
Recently, a lot of direct catalytic asymmetric Mannich-type
reactions have been disclosed.2 With both metal-based
catalysis3 and organocatalysis,4 syn-selective products are
typically obtained. In 2002, the first organocatalytic anti-
selective Mannich-type reaction employing aldehyde donors
was reported by Barbas et al.,4c and then β-proline catalyst was
reported to provide products with high anti-diastereo- and
enantioselectivities in the Mannich-type reactions employing
ketones and hindered aldehydes.4k,l This method, however,
requires the use of polar solvents and relatively high catalyst
loading. In response to the limitations of these methods,
complementary pyrrolidine-based catalysts have been devel-
oped.5 As a part of our ongoing studies on the asymmetric
synthesis of all-carbon quaternary stereocenters,6 we were
drawn to the synthesis of 3-substituted β-prolines. Further-
more, the substituent at the 3-position of β-prolines was
considered to potentially alter the reactive conformation of the
pyrrolidine ring as well as affect the spatial arrangement of
carboxyl group. As a result of these effects, the stereochemical
course of the Mannich-type reaction using these catalysts may
be unique. In addition, the substituent would increase the
lipophilicity of the amino acid and provide for a more organic-
soluble catalyst. This could help to change the transition-state
conformation in a beneficial way and reduce the catalyst
loading. In this Article, we report the asymmetric synthesis of 3-
methyl-β-proline and its application to the anti-diastereose-
lective catalytic asymmetric direct Mannich-type reaction.
Received: May 11, 2013
Published: June 29, 2013
© 2013 American Chemical Society
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Article
Scheme 1. Synthesis of 3-Methyl-β-proline
Table 2. Solvent Effects on the Mannich-type Reaction of
Cyclohexanone
a
entry
solvent
yield (%)
dr (anti/syn)
1
2
3
4
5
6
7
8
2-PrOH
DMSO
AcOEt
THF
87
10
53
56
86
85
54
35
94/6
57/43
67/33
52/48
95/5
CH3CN
CH2Cl2
CHCl3
toluene
98/2
95/5
86/14
a
1
Determined by H NMR of the crude reaction mixture.
Table 3. Mannich-type Reaction of Cyclohexanone in
CH2Cl2 Using Catalyst 7
Table 1. Mannich-type Reaction of Cyclohexanone
Catalyzed by 7
a
entry catalyst (mol %) X (equiv) time (h) yield (%) dr (anti/syn)
1
2
3
4
5
6
7
8
5
2
2
2
2
75
81
86
85
81
77
92
90
53
93
91/9
97/3
98/2
98/2
97/3
95/5
97/3
97/3
96/4
3
2
2
2
1
2
2
a
entry
catalyst (mol %)
X (equiv)
yield (%)
dr (anti/syn)
0.5
0.1
1
2
2
1
2
3
4
5
10
10
5
10
2
80
91
>99/1
94/6
95/5
95/5
93/7
2
40
2
10
5
2
99
1
2
1
2
quant
89
9
1
1
2
0.5
1
2
b
10
1
2
20
98/2
a
Determined by H NMR of the crude reaction mixture.
a
b
Determined by 1H NMR of the crude reaction mixture. The
reaction was carried out at 0 °C.
decrease in the diastereoselectivity (Table 1, entry 2). We were
encouraged by the result that moderately high anti-selectivities
were obtained even with low catalyst loading (Table 1, entries 4
and 5). Because 7 was found to be more soluble in nonpolar
organic solvents, relative to the unsubstituted β-proline, it was
possible to screen additional solvents to optimize the
transformation (Table 2). It bears mentioning that the
increased solubility in less polar organic solvents is a
consequence of the increase in lipophilicity of the substituted
β-proline derivatives, and was an element of the initial catalyst
design, offering added flexibility in the optimization process.
When the reaction was carried out with 1.0 mol % 7 at room
temperature in CH2Cl2 for 2 h, a high yield and anti-
diastereoselectivity was obtained (Table 2, entry 6). Notably,
the catalyst was completely soluble in this case. Reactions
conducted in DMSO or THF afforded almost no diaster-
eoselectivity (Table 2, entries 2 and 4). Further optimization of
the reaction conditions using CH2Cl2 as a solvent was next
studied (Table 3), and 7 was found to catalyze the reaction with
very low catalyst loading. Even using 0.1 mol % of 7, high anti-
diastereoselectivity was obtained (Table 3, entry 6). By
conducting the reaction at 0 °C with 1.0 mol % catalyst, a
high yield (93%) and diastereoselectivity (up to anti/syn = 98/
2) was achieved (Table 3, entry 10). When the unsubstituted β-
proline catalyst was used under the same conditions as in entry
4, the catalyst solubility was an issue.14 As a result, the chemical
yield suffered (25%), and the anti/syn diastereoselectivity was
reduced to 96/4. Because catalyst 7 was found to be effective in
providing high diastereoselectivity with low catalyst loading, we
next investigated the synthesis of enantiomerically pure 7. In
Scheme 2, the asymmetric synthesis of 7 is shown.
Construction of the all-carbon quaternary stereocenter was
carried out using (R,R)-3,5-bistrifluoromethylphenyl-NAS bro-
mide as a chiral phase-transfer catalyst in the alkylation of 1
with ethyl iodoacetate.6b Using this methodology, 2 was
obtained in good enantiopurity (86% ee) and was converted to
6 following the same synthetic sequence as that of racemic 7. In
addition, it was found that the enantio purity of 6 could be
further enriched to 99% ee with a single recrystallization of the
diastereomeric (S)-1-phenylethylamine salts.15 Catalytic hydro-
genation of 6 removed the Cbz group and provided the
enantiomerically pure 3-methyl-β-proline (7). With the
optically active catalyst in hand, the enantioselectivity of the
Mannich-type reaction was investigated and directly compared
to the results obtained with the unsubstituted β-proline (8)
using typical ketones and aldehydes (Table 4). With aldehyde
substrates, even 0.5 mol % of 7 afforded products with high
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required increasing the catalyst loading to 5.0−10 mol % of 7 to
provide a favorable yield. The use of acyclic pentan-3-one
resulted in a decrease in diastereoselectivity. It was also found
that an increase in the yield and enantioselectivity was generally
observed with the substituted β-proline catalyst relative to the
unsubstituted catalyst 8.
Scheme 2. Enantioselective Synthesis of 3-Methyl-β-proline
CONCLUSION
■
We have developed a general asymmetric synthetic route
toward the synthesis of chiral 3-substituted β-prolines bearing
an all-carbon quaternary stereogenic center. Furthermore, the
now accessible chiral 3-substituted β-prolines were demon-
strated to be effective and differential catalysts for use in
Mannich-type reactions of ketones/aldehydes with ethyl
glyoxylate imines. It was found that 7 was more soluble in
nonpolar organic solvents as compared to the unsubstituted β-
proline 8. The catalyst 7 effected Mannich-type reactions with
low catalyst loadings achieving high anti-diastereo- and
enantioselectivities. These results suggest that improvement
in the solubility of amino acid catalysts in nonpolar organic
solvents could lead to the development of more effective
asymmetric organocatalysts. Additional investigations are under
way directed at applying 7 as a catalyst in other asymmetric
transformations.
EXPERIMENTAL SECTION
■
General Information. All reagents were purchased from
commercial suppliers and used without further purification.
Commercially available dehydrated solvents were used for all reactions.
Column chromatography was performed using silica gel (spherical,
neutral, 100−200 μm) or NH silica gel (100−200 mesh). NMR
spectra were recorded on 400 MHz (1H NMR) and 100 MHz (13C
NMR) spectrometers. HRMS were obtained by the FAB technique
with a double sector mass spectrometer. HPLC analysis was conducted
on an HPLC system equipped with chiral stationary-phase columns
(0.46 cm × 25 cm).
Table 4. anti-Selective Mannich-type Reaction
Synthesis of Racemic 3-Methyl-β-proline (7). 1-tert-Butyl 4-
Ethyl 2-Cyano-2-methylbutanedioate (2). To a solution of tert-butyl
2-cyanopropanoate (329 mg, 2.12 mmol) in Et2O (13 mL) were
added ethyl iodoacetate (544 mg, 2.54 mmol), TBAI (39 mg, 0.106
mmol), and powdered KOH (593 mg, 10.59 mmol). The solution was
stirred at rt for 18 h under Ar atmosphere, and then water was added.
After being neutralized with diluted HCl, AcOEt (30 mL) was added.
The organic layer was washed with water (10 mL) and brine (10 mL),
dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (hexane/
AcOEt = 4/1) to give 2 (494 mg, 2.05 mmol) in 97% yield as a
anti
a
b
catalyst
time yield
dr
ee
entry substrate catalyst (mol %)
(h)
(%) (anti/syn)
(%)
1
9a
9a
9b
9b
9c
9c
9d
9d
9e
9e
9f
7
8
7
8
7
8
7
8
7
8
7
8
1.0
1.0
5.0
5.0
1.0
1.0
20
20
72
72
44
44
78
78
20
20
20
20
84
20
53
35
92
42
76
21
99
85
92
56
96/4
97
81
71
62
90
73
72
88
92
82
93
66
2
85/15
c
d
3
79/2
c
d
4
91/9
1
colorless oil: Rf = 0.42 (1:4, hexane/AcOEt). H NMR (400 MHz,
5
98/2
CDCl3) δ 1.28 (3H, t, J = 7.2 Hz), 1.52 (9H, s), 1.62 (3H, s), 2.77
(1H, d, J = 16.8 Hz), 2.98 (1H, d, J = 17.2 Hz), 4.19 (2H, q, J = 7.2
Hz); 13C NMR (100 MHz, CDCl3) δ 14.0, 23.5, 27.5, 41.1, 41.4, 61.3,
84.0, 119.5, 167.3, 168.6; IR (film) ν 2983, 2360, 1739, 1458, 1371,
1157, 1030, 843 cm−1; HRMS (FAB) m/z: calcd for C12H20NO4 [M +
H]+ 242.1392, found 242.1367.
6
90/10
48/52
80/20
98/2
c
d
d
7
10
10
0.5
c
8
9
10
11
12
0.5
0.5
0.5
95/5
95/5
tert-Butyl 3-Methyl-5-oxopyrrolidine-3-carboxylate (3). A mixture
of NaBH4 (1.33 g, 35.3 mmol) and CoCl2 (917 mg, 7.06 mmol) was
added to a solution of 2 (852 mg, 3.53 mmol) in dry MeOH (50 mL)
at 0 °C, and the solution was stirred at rt for 24 h under Ar
atmosphere. After 10% aqueous Rochelle salt (10 mL) was added, the
mixture was stirred for 3 h and filtered. MeOH in the filtrate was
evaporated, and the resulting solution was extracted with AcOEt (15
mL × 4). The combined organic layer was washed with H2O and
brine, and dried over MgSO4. After filtration, the solvent was
evaporated to give 3 (664 mg, 3.34 mmol) in 95% yield as a colorless
9f
92/8
a
b
Determined by 1H NMR of the crude reaction mixture. Determined
by chiral HPLC analysis. The reaction was carried out at rt.
c
d
Determined by HPLC analysis of isolated product.
diastereo- and enantioselectivities in high yields. When the less
reactive cyclohexanone substrate was subjected to the reaction
conditions, a considerable difference in the yield between using
catalyst 7 or 8 was observed, with 7 dramatically outperforming
the unsubstituted catalyst 8. Cycloheptanone and pentan-3-one
1
solid: mp 77−78 °C; H NMR (400 MHz, CDCl3) δ 1.41 (3H, s),
1.46 (9H, s), 2.17 (1H, d, J = 17.2 Hz), 2.84 (1H, d, J = 17.2 Hz), 3.14
(1H, d, J = 10.0 Hz), 3.74 (1H, d, J = 10.0 Hz), 6.00 (1H, brs); 13C
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NMR (100 MHz, CDCl3) δ 24.5, 27.8, 41.1, 46.0, 51.4, 81.4, 174.1,
176.5; IR (KBr) ν 3234, 2929, 1722, 1668, 1254, 1165 779 cm−1. Anal.
Calcd for C10H17NO3: C, 60.28; H, 8.60; N, 7.03. Found: C, 60.63; H,
8.77; N, 7.09.
3423, 2966, 1630, 1571, 1400, 1255, 806, 789 cm−1; HRMS (FAB) m/
z: calcd for C6H12NO2 [M + H]+ 130.0868, found 130.0878.
Synthesis of (R)-3-Methyl-β-proline (7). (R)-1-tert-Butyl 4-Ethyl
2-Cyano-2-methylbutanedioate (2).6b To a solution of tert-butyl 2-
cyanopropanoate (1.55 g, 10.0 mmol) in Et2O (60 mL) at −60 °C
were added ethyl iodoacetate (2.57 g, 12.0 mmol), (R,R)-3,5-
bistrifluoromethylphenyl-NAS bromide (54.0 mg, 0.05 mmol), and
CsOH (6.35 g, 42.4 mmol). The solution was stirred at −60 °C for 1 d
under Ar atmosphere, and then washed with water (10 mL) and brine
(10 mL), and dried over MgSO4. After the solvent was concentrated
under reduced pressure, the resulting residue was purified by column
chromatography on silica gel (hexane/AcOEt = 4/1) to give 2 (2.20 g,
9.13 mmol) in 91% yield with 86% ee as a colorless oil. [α]25D = +15.8
(c 2.0, CHCl3, ee = 86%). The ee was determined by HPLC analysis
(Daicel CHIRALCEL OJ-H, 2-propanol/hexane = 1:75, 1.0 mL/min
retention time: 9.1 min (major enantiomer) and 11.6 min (minor
enantiomer).
tert-Butyl 3-Methyl-5-thioxopyrrolidine-3-carboxylate (4). To a
solution of 3 (2.00 g, 10.1 mmol) in THF (75 mL) was added
Lawesson’s reagent (4.17 g, 10.3 mmol). The solution was stirred at rt
for 17 h under Ar atmosphere. After the solvent was removed under
reduced pressure, the residue was purified by column chromatography
on NH-silica gel (hexane/AcOEt = 2/1) to give 4 (1.63 g, 7.56 mmol)
in 76% yield as a colorless solid: mp 80−81 °C; Rf = 0.42 (2:1,
1
hexane/AcOEt); H NMR (400 MHz, CDCl3) δ 1.41 (3H, s), 1.46
(9H, s), 2.78 (1H, d, J = 18.4 Hz), 3.32 (1H, d, J = 18.0 Hz), 3.39 (1H,
d, J = 11.2 Hz), 4.05 (1H, d, J = 11.2 Hz), 7.70 (1H, brs); 13C NMR
(100 MHz, CDCl3) δ 23.9, 27.8, 48.7, 51.9, 58.1, 81.9, 174.0, 203.8; IR
(KBr) ν 3136, 2968, 1726, 1554, 1369, 1151, 1090, 845, 795 cm−1.
Anal. Calcd for C10H17NO2S: C, 55.78; H, 7.96; N, 6.51. Found: C,
55.97; H, 8.07; N, 6.51.
Optical Resolution of Compound 6. Compound 6 (200 mg, 0.76
mmol), which was prepared from 2 (86% ee) following the same
synthetic sequence as that of racemic 6, and (S)-(−)-1-phenylethyl-
amine (92 mg, 0.76 mmol) were dissolved in warm benzene (1.0 mL).
After being cooled to room temperature, the precipitate was filtered
and recrystallized from EtOH/hexane to yield crystals (114 mg, 0.30
mol). The crystals were dissolved in EtOH (1.0 mL), and a solution of
NaOH (12 mg, 0.30 mol) in H2O (1.0 mL) was added. After the
solution was stirred for 2 h, H2O (2.0 mL) was added, and extracted
with AcOEt (8 mL × 3). The aqueous layer was acidified with diluted
HCl and extracted with AcOEt (10 mL × 3). The latter combined
organic layer was washed with H2O (2.0 mL) and brine (1.0 mL), and
dried over MgSO4. The solvent was concentrated under reduced
tert-Butyl N-Cbz-3-methylpyrrolidine-3-carboxylate (5). In a 100
mL two-necked flask, Raney nickel slurry in water (3 mL) was placed
under Ar atmosphere, then washed two times with H2O (5 mL × 2),
two times with MeOH (5 mL × 2), and two times with THF (5 mL ×
2), respectively, by decantation. After THF (10 mL) was added,
compound 4 (215 mg, 1.0 mmol) in THF (20 mL) was added. The
solution was stirred under an H2 atmosphere for 2 h at rt. The reaction
mixture was filtered through a pad of Celite, and the filtrate was
concentrated to half volume. To the solution was added Z-chloride
(1.02 g, 6.0 mmol). The solution was made weakly basic (pH 8−10)
with 20% aqueous NaOH solution, and stirred at rt for 16 h. After
being neutralized with aqueous HCl, the solution was extracted with
CH2Cl2 (20 mL × 4). The combined organic layer was washed with
brine and dried over MgSO4. After filtration, the solvent was
evaporated, and the residue was purified by column chromatography
on NH-silica gel (hexane/AcOEt = 10/1) to give 5 (223 mg, 0.698
mmol) in 70% yield as a pale yellow oil: Rf = 0.30 (10:1, hexane/
AcOEt); 1H NMR (400 MHz, CDCl3) 5:4 mixture of conformational
isomers: δ 1.29 (3H × 5/9, s), 1.30 (3H × 4/9, s), 1.43 (9H, s), 1.70−
1.76 (1H, m), 2.27−2.32 (1H, m), 3.18 (1H × 5/9, d, J = 10.8 Hz),
3.25 (1H × 4/9, d, J = 10.8 Hz), 3.46−3.52 (2H, m), 3.81 (1H, d, J =
11.2 Hz), 5.13 (2H, s), 7.33−7.36 (5H, m); 13C NMR (100 MHz,
CDCl3) δ 22.2, 27.8, 35.7 (35.0), 45.2 (44.9), 49.5 (48.5), 55.2 (54.7),
66.7, 81.0, 127.82, 127.85, 127.91, 128.4, 136.9, 174.5; IR (film) ν
2976, 1707, 1419, 1363, 1138, 848, 698 cm−1; HRMS (FAB) m/z:
calcd for C18H26NO4 [M + H]+ 320.1862, found 320.1882.
N-Cbz-3-methylpyrrolidine-3-carboxylic Acid (6). To a solution of
5 (160 mg, 0.50 mmol) in CH2Cl2 (3.0 mL) was added TFA (370 μL,
5.0 mmol), and the solution was stirred for 17 h at rt. After the solvent
was evaporated, the residue was purified by column chromatography
on silica gel (hexane/AcOEt = 1/2) to give 6 (127 mg, 0.48 mmol) in
97% yield as a pale yellow solid; mp 113−115 °C; Rf = 0.39 (1:2,
hexane/AcOEt); 1H NMR (400 MHz, CDCl3) 5:4 mixture of
conformational isomers: δ 1.36 (3H × 5/9, s), 1.37 (3H × 4/9, s),
1.76−1.84 (1H, m), 2.32−2.40 (1H, m), 3.24 (1H × 5/9, d, J = 10.8
Hz), 3.29 (1H × 4/9, d, J = 11.2 Hz), 3.47−3.55 (2H, m), 3.87 (1H ×
5/9, d, J = 10.8 Hz), 3.90 (1H × 4/9, d, J = 10.4 Hz), 5.11 (2H, s),
7.28−7.35 (5H, m); 13C NMR (100 MHz, CDCl3) δ 22.11 (22.06),
34.9 (35.7), 45.2 (44.9), 48.7 (47.8), 54.6 (55.1), 67.01 (66.97), 127.9,
128.0, 128.5, 136.6 (136.7), 154.9, 181.0; IR (KBr) ν 3089, 2978,
1730, 1660, 1435, 1369, 1213, 1115, 732, 669 cm−1. Anal. Calcd for
C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.94; H, 6.56; N,
5.32.
pressure to give 6 (78 mg, 0.30 mol) with 99% ee. [α]27 = −28.3 (c
D
0.21, CHCl3, ee = 99%). The ee was determined by HPLC analysis
(Daicel CHIRALCEL AD-H, EtOH/hexane = 1:8, 1.0 mL/min,
retention time: 14.1 min (major enantiomer) and 17.3 min (minor
enantiomer)).
(R)-3-Methyl-β-proline (7). Compound 6 (99% ee) was hydro-
genated in the same manner as that for the hydrogenation of the
racemate 6, and (R)-3-methyl-β-proline (7) was obtained in
quantitative yield as a colorless solid: mp 216 °C (decomp); [α]31
D
= −26.4 (c 0.20, MeOH, ee = 99%). Anal. Calcd for C6H11NO2: C,
55.80%; H, 8.58%; N, 10.84%. Found: C, 55.32%; H, 8.54%; N,
10.54%.
A Typical Procedure for the Asymmetric Mannich-type
Reaction Using N-PMP-Protected Glyoxylate Imine. To a
solution of N-PMP-protected glyoxylate imine (162 mg, 0.78 mmol)
in dry CH2Cl2 (1.5 mL) were added catalyst 7 (99% ee, 1.0 mg, 1.0
mol %) and cyclohexanone (162 μL, 1.57 mmol) at 0 °C. The solution
was stirred for 20 h, and then Et2O was added (15 mL). The organic
layer was washed with H2O (1.0 mL) and brine (0.5 mL), dried over
MgSO4, and evaporated under reduced pressure to give ethyl 2-(p-
methoxyphenylamino)-2-(2′-oxocyclohexyl) acetate as a mixture of
diastereomers. The yield and diastereomeric ratio of the Mannich
product were determined by 1H NMR using mesitylene as an internal
standard. After column chromatography on silica gel (hexane/AcOEt
= 3/1), the enantiomeric excess of the products was determined by
chiral-phase HPLC.
Ethyl (2S,1′R)-2-(p-Methoxyphenylamino)-2-(2′-oxocyclo-
hexyl)acetate.4l,16 1H and 13C NMR spectrum data were in
accordance with those in the literature. HPLC analysis: Daicel
Chiralpak IA, hexane/2-PrOH = 92/8, 0.5 mL/min, retention time,
32.7 min (anti minor enantiomer) and 42.2 min (anti major
enantiomer).
Ethyl (2S,1′R)-2-(p-Methoxyphenylamino)-2-(2′-oxocyclo-
heptyl)acetate.4m 1H and 13C NMR spectrum data were in
accordance with those in the literature. The dr was determined by
HPLC analysis of isolated product. HPLC analysis: Daicel Chiralpak
AD-H, hexane/2-PrOH = 9/1, 1.0 mL/min, retention time, 21.7 min
(anti minor enantiomer) and 28.1 min (anti major enantiomer).
Ethyl (2S,3′S)-2-(p-Methoxyphenylamino)-2-(4′-oxotetra-
hydropyran-3′-yl)acetate.4l 1H and 13C NMR spectrum data were
3-Methyl-β-proline (7). To the solution of 6 (76 mg, 0.29 mmol) in
dry MeOH (5.0 mL) was added 10% Pd/C (31 mg, 10 mol %), and
the solution was stirred under H2 atmosphere for 1 h at rt. The
reaction mixture was filtered through a pad of Celite, and the filtrate
was evaporated to give 7 (37 mg, 0.29 mmol) in quantitative yield as a
1
colorless solid: H NMR (400 MHz, CD3OD) δ 1.35 (3H, s), 1.78
(1H, dt, J = 12.8, 8.8 Hz), 2.40 (1H, dt, J = 13.2, 6.0 Hz), 2.83 (1H, d,
J = 11.2 Hz), 3.32−3.34 (2H, m), 3.70 (1H, d, J = 11.2 Hz); 13C NMR
(100 MHz, CD3OD) δ 22.8, 37.1, 46.0, 51.7, 55.5, 181.8; IR (KBr) ν
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Article
in accordance with those in the literature. HPLC analysis: Daicel
Chiralpak IA, hexane/EtOH = 90/10, 1.0 mL/min, retention time,
33.6 min (anti minor enantiomer) and 53.0 min (anti major
enantiomer).
Ethyl (2S,3R)-2-(p-Methoxyphenylamino)-3-methyl-4-oxo-
hexanoate.4l 1H and 13C NMR spectrum data were in accordance
with those in the literature. The dr was determined by HPLC analysis
of isolated product. HPLC analysis: Daicel Chiralpak AS-H, hexane/2-
PrOH = 99/1, 1.0 mL/min, retention time, 27.9 min (anti major
enantiomer) and 49.3 min (anti minor enantiomer).
Ethyl (2S,3R)-3-Formyl-2-(p-methoxyphenylamino)-hepta-
noate.4k 1H and 13C NMR spectrum data were in accordance with
those in the literature. HPLC analysis: Daicel Chiralpak OJ-H, hexane/
EtOH = 9/1, 1.0 mL/min, retention time, 9.9 min (anti minor
enantiomer) and 12.1 min (anti major enantiomer).
Ethyl (2S,3R)-3-Formyl-2-(p-methoxyphenylamino)-4-meth-
ylpentanoate.4k 1H and 13C NMR spectrum data were in accordance
with those in the literature. HPLC analysis: Daicel Chiralpak AD-H,
hexane/2-PrOH = 8/2, 1.0 mL/min, retention time, 8.0 min (anti
minor enantiomer) and 9.1 min (anti major enantiomer).
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: itoh-t@pharm.showa-u.ac.jp.
Notes
■
(5) (a) Kano, T.; Hato, Y.; Yamamoto, A.; Maruoka, K. Tetrahedron
2008, 64, 1197−1203. (b) Pouliquen, M.; Blanchet, J.; Lasen, M.-C.;
Rouden, J. Org. Lett. 2008, 10, 1029−1032. (c) Zang, H.; Chuan, Y.;
Li, Z.; Peng, Y. Adv. Synth. Catal. 2009, 351, 2288−2294. (d) Gom
Bengoa, E.; Maestro, M.; Mielgo, A.; Otazo, I.; Palomo, C.; Velilla, I.
Chem.-Eur. J. 2010, 16, 5333−5342. (e) Martín-Rapun, R.; Fan, X.;
́
ez-
The authors declare no competing financial interest.
́
Sayalero, S.; Bahramnejad, M.; Cuevas, F.; Pericas
2011, 17, 8780−8783.
́
, M. A. Chem.-Eur. J.
ACKNOWLEDGMENTS
■
This work was supported in part by Grants-in-Aid for Scientific
Research and the High-Technology Research Center Project
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
(6) (a) Nagata, K.; Sano, D.; Itoh, T. Synlett 2007, 547−550.
(b) Nagata, K.; Sano, D.; Shimizu, Y.; Miyazaki, M.; Kanemitsu, T.;
Itoh, T. Tetrahedron: Asymmetry 2009, 20, 2530−2536. (c) Kanemitsu,
T.; Koga, S.; Nagano, D.; Miyazaki, M.; Nagata, K.; Itoh, T. ACS Catal.
2011, 1, 1331−1335.
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1
(1.3 mg) in CD2Cl2 (1.5 mL) was stirred for 1 h. After filtration, H
NMR measurement of the filtrate indicated only the signals of 7, but
the signals of 8 were not observed. Next, dissolving the residue
obtained by the filtration in CD3OD, the 1H NMR was measured, and
both signals of 7 and 8 appeared at the molar ratio of 1:3.7.
(15) Diastereomeric (S)-1-phenylethylamine salts, which were
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solvent (EtOH/hexane) as that applied to the salts prepared from
optically active 6 (86% ee). Using different solvents (AcOEt/hexane)
enabled the recrystallization of the diastereomeric salts; optical purity
of 6 after treatment of the crystals with NaOH solution was 27% ee
with 21% recovery.
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