Catalytic asymmetric synthesis of cyclic α-alkyl-amino acid derivatives by C,N-double alkylation

Article abstract of DOI:10.1016/j.tet.2010.01.105

Catalytic asymmetric synthesis of various cyclic α-alkyl-amino acid derivatives having a tetrasubstituted α-carbon, such as α-alkylprolines has been accomplished by asymmetric phase-transfer C-alkylation of α-alkyl-amino acid derivatives and subsequent intramolecular N-alkylation.

Full text of DOI:10.1016/j.tet.2010.01.105

Tetrahedron 66 (2010) 4900–4904
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic asymmetric synthesis of cyclic
by C,N-double alkylation
a-alkyl-amino acid derivatives
*
Taichi Kano, Ryu Sakamoto, Haruka Mii, Yong-Gang Wang, Keiji Maruoka
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Catalytic asymmetric synthesis of various cyclic
a-alkyl-amino acid derivatives having a tetrasubstituted
Received 14 January 2010
Received in revised form 27 January 2010
Accepted 27 January 2010
Available online 2 February 2010
a
-carbon, such as
alkyl-amino acid derivatives and subsequent intramolecular N-alkylation.
Ó 2010 Elsevier Ltd. All rights reserved.
a-alkylprolines has been accomplished by asymmetric phase-transfer C-alkylation of a-
Keywords:
Asymmetric synthesis
Amino acid
Phase-transfer catalyst
Alkylation
Cyclization
1. Introduction
asymmetric
t
t
Ar
N
CO2Bu
H2N
CO2Bu
C-alkylation
Conformationally constrained
a,a-dialkyl-a-amino acids serve
R
R
1
n
as an important building block in designing a novel peptide.1
hydrolysis
X2
3
Among them, cyclic
a-alkyl-
a-amino acids with the amine group
(Ar = 4-Cl-C6H4)
Intramolecular
N-alkylation
inside the cyclic system, such as
a
-methylproline are applied not
+
only to peptide chemistry but also to organocatalytic reactions as
catalyst,2 and there is a need to expand synthetic approaches for
their preparation. While a number of asymmetric syntheses of such
X1
R
n
X2
n
2
t
N
H
CO2Bu
4
cyclic amino acids via construction of tetrasubstituted
a-carbon
have been reported to date,3–9 general methods for their prepara-
tion based on the catalytic asymmetric construction of tetrasub-
Scheme 1. Asymmetric synthesis of cyclic
double alkylation.
a-alkyl-a-amino acid derivatives by C,N-
stituted
interested in utilization of asymmetric phase-transfer alkylation to
prepare cyclic -alkyl-
-amino acid derivatives.8–10 The asymmet-
ric C-alkylation of -alkyl- -amino acid derivatives 1 with diha-
loalkane 2 would give optically enriched -dialkyl- -amino acid
derivatives 3, which could be readily converted to cyclic -alkyl-
a
-carbon are scarce.7–9 In this context, we have been
2. Results and discussion
a
a
a
a
We first examined the synthesis of
a-alkylproline tert-butyl
a
,
a
a
esters by C,N-double alkylation of C-alkyl-substituted-N-(4-chlor-
obenzylidene)glycine esters 1 using 1-chloro-3-iodopropane as an
alkylating agent. The reaction of 1 (R¼Me) with 1-chloro-3-iodo-
propane (2 equiv) in toluene in the presence of a chiral phase-
transfer catalyst (S)-511 (1 mol %) and CsOH$H2O (5 equiv) at 0 ꢀC
proceeded smoothly to afford the corresponding a-alkylated ala-
nine derivative. Acidic hydrolysis with 1 N HCl and subsequent
ring-closing N-alkylation with an excess amount of Na2CO3 gave
a
a-
amino acid derivatives 4 by the intramolecular N-alkylation
(Scheme 1). Here we wish to report the efficient asymmetric syn-
thesis of
a
-alkylproline,
a-alkylpipecolic acid, a-alkylaziridine-2-
carboxylic acid, and
a
-alkylazetidine-2-carboxylic acid derivatives
based on the asymmetric phase-transfer alkylation.
a
-methylproline tert-butyl ester 6 (R¼Me) in 87% yield. The enan-
tiomeric excess of 6 (R¼Me) was determined to be 99% ee by chiral
HPLC analysis of its N-benzoyl adduct (Table 1, entry 1). Other
C-primary-alkyl-substituted glycine derivatives 1 (R¼i-Bu, allyl,
* Corresponding author. E-mail address: maruoka@kuchem.kyoto-u.ac.jp
(K. Maruoka).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.105

T. Kano et al. / Tetrahedron 66 (2010) 4900–4904
4901
and Bn) were also applicable to this reaction sequence, and the
corresponding
-alkylproline tert-butyl esters 6 (R¼i-Bu, allyl, and
that the ring-closing N-alkylation did not proceed under similar
conditions (Eq.1). Thus the chloro group in the C-alkylation product
was replaced by the better leaving group. When the cyclization was
performed in the presence of TBAI (0.1 equiv), NaI (5.0 equiv), and
K2CO3 (2.0 equiv) in MeCN under reflux overnight, the desired
a
Bn) were obtained in good yield with excellent enantioselectivity
(entries 2–4). The catalyst loading could be reduced without sig-
nificant loss of enantioselectivity, and moderate to good yields of 6
(R¼Bn) were obtained with prolonged reaction time (entries 5 and
6). While the reaction of phenylglycine derivatives 1 (R¼Ph) also
gave the corresponding cyclic amino acid 6 (R¼Ph) in good yield,
a significant decrease in enantioselectivity was observed (entry 7).
Sterically hindered valine derivative 1 (R¼i-Pr) was found to be
unreactive toward 1-chloro-3-iodopropane (entry 8).
a
-alkylpipecolic acid tert-butyl esters 8 (R¼Me, allyl, and Bn) were
obtained in good yield with excellent enantioselectivity (Table 3,
entries 1–3).
Table 3
Asymmetric synthesis of
a
-alkyl-pipecolic acid tert-butyl esters 8
(S)-5 (1 mol%) 1) 1N HCl
CsOH·H2O
2) Na2CO3
Table 1
R
CO2Bu
8
I
1
+
Asymmetric synthesis of
a
-alkylproline tert-butyl esters 6
(S)-5 (1 mol%) 1) 1N HCl
Cl
N
H
t
toluene, 0 °C 3) TBAI, NaI
K2CO3, MeCN
CsOH·H2O
2) Na2CO3
R
I
Cl
1
+
N
H
t
Entry
R
Time (h)
Yielda (%)
eeb (%)
toluene, 0 °C
CO2Bu
1
2
3
Me
allyl
Bn
12
8
8
83
81
84
99c
98c
99
6
Entry
R
Time (h)
Yielda (%)
eeb (%) (config)
1c
2
Me
i-Bu
Allyl
Bn
Bn
Bn
6
12
8
87
94
76
91
81
75
88
0
99d (R)
99d
98d
99
99
98
a
Isolated yield.
b
Determined by HPLC analysis using chiral column (Chiralpak AS-H or Chiralcel
3
4
OD-H, Daicel Chemical Industries, Ltd.).
c
6
ee of the corresponding N-benzoyl adduct.
5e
6f
7
24
40
8
Ph
i-Pr
64
d
8e
30
t
H2N
Me
CO2Bu
Na2CO3
a
Me
CO2Bu
Isolated yield.
(1)
N
H
b
t
toluene, rt
Determined by HPLC analysis using chiral column (Chiralpak AD-H or Chiralcel
OD-H, Daicel Chemical Industries, Ltd.).
Cl
no reaction
c
2 equiv of 1-chloro-3-iodopropane was used.
ee of the corresponding N-benzoyl adduct.
0.5 mol % of (S)-5.
0.1 mol % of (S)-5.
d
e
f
Using diiodomethane as an alkylating agent, a-alkylaziridine-2-
Ar
Br
carboxylic acid tert-butyl esters 9 were also effectively synthesized
(Table 4). In the case of phenylalanine derivative 1 (R¼Bn), the
enantioselectivity was improved by lowering the reaction tem-
perature from 0 ꢀC to ꢁ20 ꢀC (entry 2 vs 3).
Bu
Bu
N
Ar
Table 4
(S)-5
Asymmetric synthesis of a-alkylaziridine-2-carboxylic acid tert-butyl esters 10
(Ar = 3,4,5 -F3C6H2)
(S)-5 (1 mol%)
1) 1N HCl
R
CsOH·H2O (5 eq) 2) Na2CO3
toluene, 0 °C
In a similar manner, using 1,3-dichloro-2-methylenepropane
instead of 1-chloro-3-iodopropane, a variety of a-alkyl-4-methyl-
eneproline tert-butyl esters 7 could be synthesized in moderate
t
I
I
1
+
CO2Bu
N
H
9
yield with excellent enantioselectivity (Table 2).
Entry
R
Time (h)
Yielda (%)
eeb (%)
Table 2
Asymmetric synthesis of
1
i-Bu
Bn
Bn
6
6
12
89
91
87
97c
83
a
-alkyl-4-methyleneproline tert-butyl esters 7
(S)-5 (1 mol%) 1) 1N HCl
2
3d
98
a
CsOH·H2O
2) Na2CO3
Isolated yield.
R
1
+
b
Cl
Cl
Determined by HPLC analysis using chiral column (Chiralcel OJ-H, Daicel
N
H
t
toluene, 0 °C
CO2Bu
Chemical Industries, Ltd.).
c
7
ee of the corresponding N-benzoyl adduct.
The reaction was performed at ꢁ20 ꢀC.
d
Entry
R
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
Me
2
1
0.7
0.75
44
48
64
56
97c
96c
96c
97
The alkylation of 1 (R¼Me) with 1,2-diiodoethane did not pro-
ceed in the presence of TBAB as catalyst, probably due to the de-
composition of 1,2-diiodoethane under basic alkylation conditions,
i-Bu
Allyl
Bn
and the attempted synthesis of
derivative failed (Eq. 2).
a-alkylazetidine-2-carboxylic acid
a
Isolated yield.
b
Determined by HPLC analysis using chiral column (Chiralpak AD-H or Chiralcel
OD-H, Daicel Chemical Industries, Ltd.).
c
ee of the corresponding N-benzoyl adduct.
TBAB (10 mol%)
CsOH·H2O
t
Ar
N
CO2Bu
Based on the above results, we then examined the catalytic
I
1
+
(2)
Me
I
toluene, 0 °C, 12 h
asymmetric synthesis of
a-alkylpipecolic acid tert-butyl esters
(R = Me)
I
0% yield
using 1-chloro-4-iodobutane. Unfortunately, however, it was found

4902
T. Kano et al. / Tetrahedron 66 (2010) 4900–4904
We then examined various dihaloethanes using (S)-5 as catalyst,
ring-closing N-alkylation. Further investigations to expand the
scope of this and related reactions are currently underway.
and the results are summarized in Table 5. When an increased
amount of 1,2-diiodoethane, or 1,2-dichloroethane was used as an
alkylating agent, the desired C-alkylation did not proceed (entries 1
and 2). On the other hand, the reaction using 1-chloro-2-iodoethane
4. Experimental
or 1,2-dibromoethane gave
a-benzylazetidine-2-carboxylic acid tert-
4.1. General information
butyl ester 10 (R¼Bn), albeit in low yield (entries 3 and 4). In both
cases, the ring-closing N-alkylation required the replacement of the
leaving group (chloro or bromo group) with iodo group. In terms of
enantioselectivity, 1,2-dibromoethane was then chosen for further
investigation. The yield of 10 was improved by using an increased
amount of (S)-5 and/or 1,2-dibromomethane (entries 5–7), and the
desired cyclic amino ester 10 was obtained in moderate yield with
excellent enantioselectivity (entry 7).
Infrared (IR) spectra were recorded on a Shimadzu IR Prestige-
21 spectrometer. 1H and 13C NMR spectra were measured on
a JEOL JNM-FX400 NMR instrument (400 MHz for 1H NMR,
100 MHz for 13C NMR) at ambient temperature and calibrated using
SiMe4
(d
¼0 ppm) and the central line of CDCl3 triplet ( ¼77 ppm)
d
as internal references unless otherwise noted. The following ab-
breviations were used to express the multiplicities: s¼singlet;
d¼doublet; t¼triplet; q¼quartet; m¼multiplet; br¼broad
app¼apparent. High performed liquid chromatography (HPLC) was
performed on Shimadzu 10A instruments using Daicel Chiralpak
AD-H, AS-H, Chiralcel OD, OD-H, and OJ-H 4.6 mmꢂ25 mm col-
umns. High-resolution mass spectra (HRMS) were performed on
BRUKER microTOF focus–KR. Optical rotations were measured on
a JASCO DIP-1000 digital polarimeter. All reactions were monitored
by thin-layer chromatography carried out on Merck silica gel plates
(0.25 mm thick, 60F-254), visualization by using UV (254 nm), or
dyes, such as KMnO4, PMA, and CeSO4. The products were purified
by flash column chromatography on silica gel 60 (Merck
1.09386.9025, 230–400 mesh). In experiments requiring dry sol-
vents, ether, and tetrahydrofuran (THF) were purchased from Kanto
Chemical Co. Inc. as ‘Dehydrated’. Toluene was dried over sodium
metal. Dichloromethane (CH2Cl2) was stored over 4 Å molecular
sieves. Other simple chemicals were purchased and used as such.
Table 5
Asymmetric synthesis of a-alkylazetidine-2-carboxylic acid tert-butyl ester 10
1) 1N HCl
2) Na2CO3
(S)-5 (1 mol%)
R
CsOH·H2O
X1
1
+
t
X2
N
H
CO2Bu
10
°
toluene, 0 C, 24 h 3) TBAI, NaI
K2CO3,MeCN
Entry
R
X1, X2
Yielda (%)
eeb (%)
1
2
3
Me
Me
Bn
Bn
Bn
Bn
Bn
I, I (5 equiv)
Cl, Cl
I, Cl
Br, Br
Br, Br
0c
0c
17
15
29
33
39
d
d
59
98
98
98
98
4
5d
6
Br, Br (10 equiv)
Br, Br (10 equiv)
7d
a
Isolated yield.
b
Determined by HPLC analysis using chiral column (Chiralpak AD-H, Daicel
4.2. Representative procedure for synthesis of
proline ester
a-substituted-
Chemical Industries, Ltd.).
c
The C-alkylation did not proceed.
5 mol % of (S)-5.
d
To a mixture of alanine tert-butyl ester aldimine Schiff base 1
(200 mg, 0.747 mmol), PTC (S)-5 (4.3 mg, 1 mol %), and 1-chloro-3-
iodopropane (0.079 mL, 0.747 mmol) in toluene (1.0 mL) was added
CsOH$H2O (314 mg, 1.87 mmol) at 0 ꢀC under an argon atmosphere.
After being stirred vigorously for 6 h at 0 ꢀC, the resulting mixture
was poured into water and extracted with Et2O twice. The com-
bined extracts were dried over Na2SO4 and concentrated. To the
residue dissolved in ethyl acetate (5 mL) was added 1 N HCl (5 mL).
After being stirred at room temperature for 1 h, the aqueous phase
was separated. The organic phase was washed with H2O (3 mL)
twice. The combined aqueous phase was adjusted to pH¼9–10 by
addition of Na2CO3. The mixture was stirred for 2 h at room tem-
perature and extracted by CH2Cl2 for three times. The combined
organic extracts were dried over Na2SO4 and concentrated. The
residual oil was purified by column chromatography on silica gel
(ethyl acetate/hexane¼1:6 as eluent) to give tert-butyl (R)-2-
methylpyrrolidine-2-carboxylate (60 mg, 87%) as an oil.
To enhance the utility of this methodology we further examined
the synthesis of an a-alkylproline derivative through the one-pot
double C-alkylation of N-(4-chlorobenzylidene)glycine ester
1
(R¼H) and the following intramolecular N-alkylation.12 Using
a
-unsubstituted glycine derivative 1 (R¼H), sequential C-alkylations
were performed with allyl bromide (1.0 equiv) and 1-chloro-3-iodo-
propane (2.0 equiv) in one-pot, and the intramolecular N-alkylation
of the resulting
a,a-dialkylated product gave the
a-allylproline tert-
butyl ester in 72% yield with 98% ee (Scheme 2).
5
(S)- (1 mol%)
t
Ar
Ar
N
N
CO2Bu
CsOH·H2O (5 eq)
Br
(1 eq)
1
+
toluene
(R = H)
–10 °C, 3 h
I
Cl
(2 eq)
0 °C, 10 h
1) 1N HCl
2) Na2CO3
28
t
4.2.1. tert-Butyl (R)-2-methylpyrrolidine-2-carboxylate. [
(c 1.8, CHCl3); 1H NMR
1.58 (3H, m), 1.46 (9H, s), 1.34 (3H, s); 13C NMR
46.1, 36.5, 27.7, 25.7, 24.9; IR (neat) 2974, 2357, 2342, 1719, 1155,
a
]
22.6
CO2Bu
D
d
3.03–2.92 (2H, m), 2.20–2.08 (2H, m), 1.88–
176.5, 80.5, 65.9,
N
H
t
CO2Bu
d
Cl
72%, 98% ee
1121 cmꢁ1
; HRMS (ESI-TOF) calcd for C10H20NO2: 186.1489
Scheme 2. Asymmetric synthesis of
a-allylproline tert-butyl ester by C,C,N-triple
([MþH]þ), found: 186.1489 ([MþH]þ); the enantiomeric excess was
determined by HPLC analysis of the corresponding N-benzoyl ad-
duct: Daicel Chiralpak AS-H, 254 nm, hexane/2-propanol¼30:1,
flow rate 0.5 mL/min, retention time: 14.6 min (R) and 15.6 min (S).
alkylation.
3. Conclusion
In summary, we have demonstrated an efficient asymmetric
synthesis of cyclic -alkyl-amino acid derivatives, such as -alkyl-
proline, -alkylpipecolic acid, -alkylaziridine-2-carboxylic acid,
and -alkylazetidine-2-carboxylic acid derivatives by the highly
enantioselective phase-transfer C-alkylation and the following
28
a
a
4.2.2. tert-Butyl (S)-2-isobutylpyrrolidine-2-carboxylate. [
a]
52.2
D
a
a
(c 0.95, CHCl3); 1H NMR
d 3.03–2.92 (2H, m), 2.47 (1H, br s), 2.18–
2.07 (1H, m), 1.82–1.60 (5H, m), 1.51–1.47 (1H, m), 1.47 (9H, s), 0.93
a
(3H, d, J¼6.5 Hz), 0.87 (3H, d, J¼6.5 Hz); 13C NMR
d 176.6, 80.6, 69.3,

T. Kano et al. / Tetrahedron 66 (2010) 4900–4904
4903
48.2, 46.0, 37.3, 27.8, 25.4, 24.1, 24.0, 23.1; IR (neat) 2955, 2359,1717,
1368, 1148 cmꢁ1; HRMS (ESI-TOF) calcd for C13H26NO2: 228.1958
([MþH]þ), found: 228.1953 ([MþH]þ); the enantiomeric excess was
determined by HPLC analysis of the corresponding N-benzoyl ad-
duct: Daicel Chiralpak AS-H, 254 nm, hexane/2-propanol¼50:1,
flow rate 0.5 mL/min, retention time: 12.6 min (S) and 19.4 min (R).
analysis of the corresponding N-benzoyl adduct: Daicel Chiralpak
AD-H, 254 nm, hexane/2-propanol¼20:1, flow rate 0.5 mL/min,
retention time: 17.9 min (S) and 21.4 min (R).
4.3.2. tert-Butyl
(R)-2-allyl-4-methylenepyrrolidine-2-carboxyl-
28
ate. [
a]
ꢁ10.0 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d 5.81–
D
5.70 (1H, m), 5.13–5.07 (2H, m), 4.92 (1H, d, J¼2.0 Hz), 4.88 (1H, d,
J¼2.0 Hz), 3.63 (1H, d, J¼14.4 Hz), 3.57 (1H, d, J¼14.4 Hz), 2.80 (1H,
d, J¼15.2 Hz), 2.55 (1H, dd, J¼14.0, 6.8 Hz), 2.45 (1H, br), 2.45–2.32
28
4.2.3. tert-Butyl (S)-2-allylpyrrolidine-2-carboxylate. [
a
]
64.6
D
(c 0.68, CHCl3); 1H NMR
d
5.84–5.70 (1H, m), 5.19–5.02 (2H, m),
3.05–2.90 (2H, m), 2.54 (1H, dd, J¼13.7, 7.3 Hz), 2.30 (1H, dd, J¼13.7,
(2H, m), 1.45 (9H, s); 13C NMR (100 MHz, CDCl3)
d 177.1, 147.4, 133.4,
7.3 Hz), 2.18–2.05 (2H, m), 1.85–1.62 (3H, m), 1.45 (9H, s); 13C NMR
118.2, 105.5, 81.3, 69.4, 50.4, 43.1, 41.9, 28.0; IR (neat) 2976, 1722,
1367, 1248, 1227, 1149 cmꢁ1; HRMS (ESI-TOF) calcd for C13H22NO2:
224.1645 ([MþH]þ), found: 224.1644 ([MþH]þ); the enantiomeric
excess was determined by HPLC analysis of the corresponding
N-benzoyl adduct: Daicel Chiralpak AD-H, 254 nm, hexane/2-
propanol¼20:1, flow rate 0.5 mL/min, retention time: 16.1 min (S)
and 23.7 min (R).
d
175.5, 133.9, 117.4, 80.6, 69.0, 46.1, 44.0, 35.2, 27.7, 24.6; IR (neat)
2976, 2342, 2330, 1721, 1148 cmꢁ1; HRMS (ESI-TOF) calcd for
C12H22NO2: 222.1645 ([MþH]þ), found: 222.1670 ([MþH]þ); the
enantiomeric excess was determined by HPLC analysis of the cor-
responding N-benzoyl adduct: Daicel Chiralcel OD-H, 254 nm,
hexane/2-propanol¼20:1, flow rate 0.5 mL/min, retention time:
15.7 min (R) and 17.0 min (S).
4.3.3. tert-Butyl (R)-2-Benzyl-4-methylenepyrrolidine-2-carboxyl-
28
28
4.2.4. tert-Butyl (S)-2-benzylpyrrolidine-2-carboxylate. [
(c 0.54, CHCl3); 1H NMR
3.04–2.92 (2H, m), 2.84 (1H, d, J¼13.2 Hz), 2.33 (1H, br s), 2.25–2.12
(1H, m),1.87–1.57 (3H, m),1.37 (9H, s); 13C NMR
175.3,137.7,129.8,
a
]
29.6
ate. [
a
]
ꢁ29.3 (c 1.8, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.28–
D
D
d
7.28–7.16 (5H, m), 3.12 (1H, d, J¼13.2 Hz),
7.18 (5H, m, Ar-H), 4.93 (1H, d, J¼2.0 Hz), 4.87 (1H, d, J¼2.0 Hz), 3.60
(2H, s), 3.15 (1H, d, J¼13.2 Hz), 2.88 (1H, d, J¼13.2 Hz), 2.80 (1H, d,
J¼15.6 Hz), 2.52 (1H, d, J¼15.6 Hz), 2.30 (1H, br), 1.37 (9H, s); 13C
d
127.7, 126.3, 80.8, 70.4, 45.8, 45.1, 36.1, 27.8, 24.2; IR (neat) 2974,
1719, 1367, 1152 cmꢁ1; HRMS (ESI-TOF) calcd for C16H24NO2:
262.1802 ([MþH]þ), found: 262.1802 ([MþH]þ); HPLC analysis:
Daicel Chiralcel OD-H, 254 nm, hexane/2-propanol¼30:1, flow rate
0.5 mL/min, retention time: 8.0 min (R) and 9.5 min (S).
NMR (100 MHz, CDCl3) d 174.4, 147.2, 137.1, 129.9, 128.1, 126.7, 105.5,
81.3, 70.6, 50.3, 44.3, 42.9, 27.9; IR (neat) 2976, 1722, 1367, 1248,
1150 cmꢁ1
; HRMS (ESI-TOF) calcd for C17H24NO2: 274.1801
([MþH]þ), Found: 274.1795 ([MþH]þ); HPLC analysis: Daicel Chir-
alcel OD-H, 254 nm, hexane/2-propanol¼100:1, flow rate 0.5 mL/
min, retention time: 11.4 min (R) and 13.1 min (S).
28
4.2.5. tert-Butyl (S)-2-phenyl-2-pyrrolidinecarboxylate. [
(c 0.97, CHCl3); 1H NMR
(2H, app t), 2.78 (1H, br s), 2.74–2.66 (1H, m), 2.11–1.96 (1H, m),
1.93–1.70 (2H, m), 1.38 (9H, s); 13C NMR
174.7, 143.1. 127.9, 126.8,
126.0, 81.3, 72.6, 45.5, 36.4, 27.7, 24.5; IR (neat) 2974, 1719, 1250,
a
]
D
22.7
d
7.52 (2H, app d), 7.39–7.19 (3H, m), 3.07
4.3.4. tert-Butyl (R)-2-isobutyl-4-methylenepyrrolidine-2-carboxyl-
28
ate. [
a
]
ꢁ13.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d 4.91 (1H,
D
d
s), 4.86 (1H, s), 3.61 (1H, d, J¼14.8 Hz), 3.54 (1H, d, J¼14.4 Hz), 2.80
(1H, d, J¼16.4 Hz), 2.36 (1H, d, J¼13.6 Hz), 2.35 (1H, br), 1.79–1.51
(3H, m),1.45 (9H, s), 0.94 (3H, d, J¼6.0 Hz), 0.89 (3H, d, J¼6.0 Hz); 13C
1150 cmꢁ1
; HRMS (ESI-TOF) calcd for C15H22NO2: 248.1645
([MþH]þ), found: 248.1647 ([MþH]þ); HPLC analysis: Daicel Chir-
alcel OD-H, 210 nm, hexane/2-propanol¼33:1, flow rate 0.5 mL/
min, retention time: 9.5 min (S) and 10.7 min (R).
NMR (100 MHz, CDCl3) d 175.6, 147.6, 105.2, 81.1, 69.7, 50.4, 47.3,
44.0, 27.9, 25.3, 24.1, 23.3; IR (neat) 2955, 1721, 1368, 1234,
1150 cmꢁ1
; HRMS (ESI-TOF) calcd for C14H26NO2: 240.1958
([MþH]þ), found: 240.1965 ([MþH]þ); the enantiomeric excess was
determined by HPLC analysis of the corresponding N-benzoyl ad-
duct: Daicel Chiralpak AD-H, 254 nm, hexane/2-propanol¼19:1,
flow rate 0.5 mL/min, retention time: 13.0 min (S) and 20.3 min (R).
4.3. Determination of the absolute stereochemistry of (R)-a-
methylproline
To a solution of tert-butyl (R)-2-methylproline-2-carboxylate
(38 mg, 0.205 mmol) in CH2Cl2 (2 mL) was added TFA (0.076 mL,
1.03 mmol). The resulting solution was stirred at room temperature
for 3 h and concentrated. To the residue dissolved in EtOH (2 mL)
was added propylene oxide (0.5 mL), and the resulting solution was
heated at reflux for 2 h and concentrated. The residual solid was
4.4. Representative procedure for synthesis of tert-butyl
2-alkylpiperidine-2-carboxylate
To a mixture of alanine tert-butyl ester aldimine Schiff base 1
(80 mg, 0.30 mmol), PTC (S)-5 (2.2 mg, 1 mol %), and 1-chloro-4-
rinsed with ethyl acetate and acetone and dried up to give (R)-
a
-
iodobutane (110 mL, 0.36 mmol) in toluene (1.5 mL) was added
methylproline (20 mg, 76%) as a white solid: 1H NMR
d
3.44–3.37
CsOH$H2O (251 mg, 1.50 mmol) at 0 ꢀC under an argon atmosphere.
After being stirred vigorously for 8 h at 0 ꢀC, the resulting mixture
was poured into water and extracted with Et2O twice. The com-
bined extracts were dried over Na2SO4 and concentrated. To the
residue dissolved in ethyl acetate (5 mL) was added 1 N HCl (5 mL).
After being stirred at room temperature for 1 h, the aqueous phase
was separated. The organic phase was washed with H2O (3 mL)
twice. The combined aqueous phase was adjusted to pH¼9–10 by
addition of Na2CO3 and extracted by CH2Cl2 for three times. The
combined organic extracts were dried over Na2SO4 and concen-
trated. The residual oil was used for the next reaction without
further purification.
(1H, m), 3.31 (1H, s), 3.30–3.22 (1H, m), 2.44–2.38 (1H, m), 2.07–
1.78 (3H, m), 1.56 (3H, s); HRMS (ESI-TOF) calcd for C6H12NO2:
28
130.0863 ([MþH]þ), found: 130.0862 ([MþH]þ); [
a]
80.1 (c 1.0,
D
H2O). The absolute configuration of the obtained a-methylproline
was determined to be R by comparison of the sign of the optical
rotation with the literature data.5b
4.3.1. tert-Butyl
(R)-2-methyl-4-methylenepyrrolidine-2-carbox-
28
ylate. [
a
]
D
ꢁ19.2 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3)
d 4.93
(1H, app dd, J¼2.0, 2.0 Hz), 4.88 (1H, app dd, J¼2.0, 2.0 Hz), 3.63
(1H, d, J¼16.8 Hz), 3.58 (1H, d, J¼16.4 Hz), 2.82 (1H, d, J¼16.0 Hz),
2.38 (1H, br), 2.37 (1H, d, J¼16.0 Hz), 1.46 (9H, s), 1.37 (3H, s); 13C
To a solution of the crude mixture obtained above in MeCN
(5.0 mL) were added TBAI (11 mg, 0.03 mmol), NaI (224 mg,
1.49 mmol), and K2CO3 (83 mg, 0.60 mmol). The resulting mixture
was refluxed overnight and cooled to room temperature. Then the
reaction mixture was filtered through a pad of Celite with ethyl
NMR (100 MHz, CDCl3)
d 175.5, 147.8, 105.5, 81.1, 66.4, 50.5, 43.3,
27.9, 24.6; IR (neat) 2976, 1724, 1367, 1248, 1153 cmꢁ1; HRMS (ESI-
TOF) calcd for C11H20NO2: 198.1489 ([MþH]þ), found: 198.1480
([MþH]þ); the enantiomeric excess was determined by HPLC

4904
T. Kano et al. / Tetrahedron 66 (2010) 4900–4904
acetate. The filtrate was concentrated, and the residue was purified
by column chromatography on silica gel (ethyl acetate/hexane¼1:5
as eluent) to give (R)-tert-butyl 2-methylpiperidine-2-carboxylate
(45 mg, 76%) as an oil.
IR (neat) 2957, 1713, 1368, 1234, 1153 cmꢁ1; HRMS (ESI-TOF) calcd
for C11H22NO2: 200.1645 ([MþH]þ), found: 200.1636 ([MþH]þ); the
enantiomeric excess was determined by HPLC analysis of the cor-
responding N-benzoyl adduct: Daicel Chiralcel OJ-H, 254 nm, hex-
ane/2-propanol¼50:1, flow rate 0.5 mL/min, retention time:
10.2 min (S) and 11.1 min (R).
28
4.4.1. tert-Butyl (R)-2-methylpiperidine-2-carboxylate. [
a
]
ꢁ28.1
D
(c 0.71, CHCl3); 1H NMR
d
2.91–2.83 (1H, m), 2.68 (1H, td, J¼11.7,
28
3.2 Hz), 2.25 (1H, br s), 2.15–2.07 (1H, m), 1.72–1.60 (1H, m), 1.59–
4.4.6. tert-Butyl (R)-2-Benzylazetidine-2-carboxylate. [
(c 1.2, CHCl3); 1H NMR
3.15 (1H, m), 3.09 (2H, dd, J¼18.4, 13.5 Hz), 2.58 (1H, br), 2.53–2.43
(1H, m), 2.43–2.34 (1H, m), 1.39 (9H, s); 13C NMR
175.2, 136.9,
a
]
84.9
D
1.40 (2H, m), 1.48 (9H, s), 1.39–1.26 (2H, m), 1.21 (3H, s); 13C NMR
d
7.30–7.15 (5H, m); 3.49 (1H, app q), 3.24–
d
175.7, 80.5, 59.6, 43.5, 34.0, 27.9, 27.8, 24.9, 22.1; IR (neat) 2932,
2361, 1720, 1368, 1242, 1126 cmꢁ1; HRMS (ESI-TOF) calcd for
C11H22NO2: 200.1645 ([MþH]þ), found: 200.1644 ([MþH]þ); the
enantiomeric excess was determined by HPLC analysis of the cor-
responding N-benzoyl adduct: Daicel Chiralpak AS-H, 254 nm,
hexane/2-propanol¼20:1, flow rate 0.5 mL/min, retention time:
8.6 min (R) and 9.0 min (S).
d
129.5, 128.0, 126.5, 81.3, 68.8, 45.5, 41.5, 31.1, 27.9; IR (neat) 2976,
1722, 1368, 1271, 1155 cmꢁ1; HRMS (ESI-TOF) calcd for C15H22NO2:
248.1645 ([MþH]þ), found: 248.1638 ([MþH]); HPLC analysis:
Daicel Chiralpak AD-H, 210 nm, hexane/2-propanol¼5:1, flow rate
0.5 mL/min, retention time: 9.4 min (S) and 9.8 min (R).
28
4.4.2. tert-Butyl (S)-2-allylpiperidine-2-carboxylate. [
1.4, CHCl3); 1H NMR
a]
ꢁ60.4 (c
D
Acknowledgements
d
5.75–5.62 (1H, m), 5.15–5.05 (2H, m), 2.90–
2.80 (1H, m), 2.73 (1H, td, J¼11.7, 3.1 Hz), 2.36 (1H, dd, J¼13.5,
This work was partially supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas ‘Advanced Molecular Trans-
formation of Carbon Resources’ from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan. H.M. is grateful to
the Japan Society for the Promotion of Science for Young Scientists
for a research fellowship.
6.5 Hz), 2.21 (1H, dd, J¼13.7, 8.6 Hz), 2.16–2.08 (2H, m), 1.48 (9H, s),
1.71–1.62 (1H, m), 1.60–1.26 (4H, m); 13C NMR
d 174.4, 132.3, 118.7,
80.8, 62.3, 45.9, 43.3, 33.2, 28.1, 25.3, 22.1; IR (neat) 2932, 1721,
1250, 1227, 1142 cmꢁ1; HRMS (ESI-TOF) calcd for C13H24NO2:
226.1802 ([MþH]þ), found: 226.1804 ([MþH]þ); the enantiomeric
excess was determined by HPLC analysis of the corresponding
N-benzoyl adduct: Daicel Chiralcel OD-H, 254 nm, hexane/
2-propanol¼50:1, flow rate 0.5 mL/min, retention time: 15.7 min
(R) and 16.9 min (S).
References and notes
´
1. For reviews, see: (a) Cativiela, C.; Dıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 2000, 11, 645; (b) Park, K. H.; Kurth, M. J. Tetrahedron 2002, 58,
8629; (c) Calaza, M. I.; Cativiela, C. Eur. J. Org. Chem. 2008, 3427.
2. (a) Priem, G.; Pelotier, B.; Macdonald, S. J. F.; Anson, M. S.; Campbell, I. B. J. Org.
Chem. 2003, 68, 3844; (b) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450;
28
4.4.3. tert-Butyl (S)-2-benzylpiperidine-2-carboxylate. [
(c 0.8, CHCl3); 1H NMR
a
]
ꢁ11.3
D
d
7.28–7.15 (5H, m), 2.92 (1H, d, J¼13.2 Hz),
´
´
(c) Cordova, A.; Sunden, H.; Engqvist, M.; Ibrahem, I.; Casas, J. J. Am. Chem. Soc.
2004, 126, 8914.
2.91–2.84 (1H, m), 2.77 (1H, d, J¼13.2 Hz), 2.69 (1H, td, J¼11.6,
3.2 Hz), 2.22–2.16 (1H, m), 2.09 (1H, br s), 1.72–1.65 (1H, m), 1.40
3. (a) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc. 1983, 105,
5390; (b) Wang, H.; Germanas, J. P. Synlett 1999, 33; (c) Ferey, V.; Vedrenne, P.;
Toupet, L.; Le Gall, T.; Mioskowski, C. J. Org. Chem. 1996, 61, 7244; (d) Matsu-
mura, Y.; Kinoshita, T.; Yanagihara, Y.; Kanemoto, N.; Watanabe, M. Tetrahedron
Lett. 1996, 37, 8395; (e) Berrien, J.-F.; Royer, J.; Husson, H.-P. J. Org. Chem. 1994,
59, 3769; (f) Hou, D.-R.; Hung, S.-Y.; Hu, C.-C. Tetrahedron: Asymmetry 2005, 16,
3858.
(9H, s),1.60–1.22 (4H, m); 13C NMR
d 174.0,135.8,130.2, 127.8, 126.6,
80.9, 63.3, 47.7, 43.2, 34.0, 27.9, 25.1, 22.0; IR (neat) 2930, 2359,1717,
1366, 1246, 1150, 1123 cmꢁ1; HRMS (ESI-TOF) calcd for C17H26NO2:
276.1958 ([MþH]þ), found: 276.1953 ([MþH]þ); HPLC analysis:
Daicel Chiralpak AS-H, 254 nm, hexane/2-propanol¼100:1, flow
rate 0.5 mL/min, retention time: 8.8 min (R) and 9.1 min (S).
`
4. (a) Bajgrowicz, J.; Achquar, A. E.; Roumestant, M.-L.; Pigiere, C.; Viallefont, P.
Heterocycles 1986, 24, 2165; (b) Chinchilla, R.; Galindo, N.; Na´jera, C. Tetrahe-
dron: Asymmetry 1998, 9, 2769; (c) Chinchilla, R.; Galindo, N.; Na´jera, C. Syn-
thesis 1999, 704; (d) Kedrowski, B. L.; Heathcock, C. H. Heterocycles 2002, 58,
601; (e) Balducci, D.; Grandi, A.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry
2005, 16, 1453; (f) Scho¨llkopf, U.; Hinrichs, R.; Lonsky, R. Angew. Chem., Int. Ed.
Engl. 1987, 26, 143.
5. (a) Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am. Chem. Soc. 2003, 125, 13012;
(b) MacQuarrie-Hunter, S.; Carlier, P. R. Org. Lett. 2005, 7, 5305.
6. (a) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 5473; (b) Risberg,
E.; Fischerb, A.; Somfai, P. Chem. Commun. 2004, 2088.
7. (a) Shao, H.; Zhu, Q.; Goodman, M. J. Org. Chem. 1995, 60, 790; (b) Longmire, J.
M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400; (c) Li, H.; Wang, B.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 732.
8. (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347; (b) Horikawa,
M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843.
9. Ooi, T.; Takeuchi, M.; Maruoka, K. Synthesis 2001, 1716.
28
4.4.4. tert-Butyl (R)-2-benzylaziridine-2-carboxylate. [
(c 1.0, CHCl3); 1H NMR
2.71 (1H, d, J¼14.5 Hz), 2.06 (1H, s), 1.70 (1H, s), 1.54 (1H, br s), 1.33
(9H, s); 13C NMR
172.3, 138.4, 129.2, 127.9, 126.2, 82.0, 39.3, 37.6,
a
]
59.8
D
d
7.36–7.15 (5H, m), 3.26 (1H, d, J¼14.5 Hz),
d
32.6, 27.7; IR (neat) 2978, 2359, 2342, 1713, 1358, 1227, 1152 cmꢁ1
;
HRMS (ESI-TOF) calcd for C14H20NO2: 234.1489 ([MþH]þ), found:
234.1485 ([MþH]þ); HPLC analysis: Daicel Chiralcel OD-H, 254 nm,
hexane/2-propanol¼20:1, flow rate 0.5 mL/min, retention time:
9.2 min (R) and 11.1 min (S).
28
4.4.5. tert-Butyl (R)-2-isobutylaziridine-2-carboxylate. [
(c 0.65, CHCl3); 1H NMR
s), 1.25–1.18 (1H, m), 0.95 (3H, d, J¼5.6 Hz), 0.93 (3H, dd, J¼13.7,
5.9 Hz); 13C NMR
173.0, 81.6, 40.6, 37.9, 33.5, 27.8, 26.4, 22.9, 22.8;
a]
14.1
D
10. Wang, Y.-G.; Mii, H.; Kano, T.; Maruoka, K. Bioorg. Med. Chem. Lett. 2009, 19,
3795.
11. Kitamura, K.; Shirakawa, S.; Maruoka, K. Angew. Chem., Int. Ed. 2005, 44, 1549.
12. Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228.
d
2.00–1.90 (3H, m),1.58 (1H, br s),1.47 (9H,
d