Electrochemical deallylation of α-allyl cyclic amines and synthesis of optically active quaternary cyclic amino acids

Article abstract of DOI:10.1002/chem.200903512

Electrochemical oxidation of α-allylated and α-betizylated N-acylated cyclic amines by using a graphite anode easily affords the corresponding α-methoxylated products with up to 76% yield. Ease of oxidation was affected by the type of electrode, the size

Full text of DOI:10.1002/chem.200903512

DOI: 10.1002/chem.200903512
Electrochemical Deallylation of a-Allyl Cyclic Amines and Synthesis of
Optically Active Quaternary Cyclic Amino Acids
Peter G. Kirira, Masami Kuriyama, and Osamu Onomura*[a]
Abstract: Electrochemical oxidation of a-allylated and a-benzylated N-acylated
cyclic amines by using a graphite anode easily affords the corresponding a-me-
Keywords: alkylation · allylation ·
thoxylated products with up to 76% yield. Ease of oxidation was affected by the
amino acids · diastereoselectivity ·
type of electrode, the size of cyclic amine, and the nature of the protecting group.
electrochemical oxidation
This method was successfully applied to the synthesis of optically active N-acylated
a-alkyl-a-amino acid esters with up to 99% ee.
Introduction
ternary amino acid esters with up to 99% enantiomeric
excess (ee).
Electrochemical oxidation of N-acyl-a-amino acids 1 or N-
acyl-b-hydroxyl amines 2 in methanol has already been re-
ported to afford a-methoxylated amines 4 via acyliminium
ion intermediates 3 [Eq. (1)].[1]
Results and Discussion
Anodic deallylation: Initially we studied the electrochemical
deallylation of a-allyl-N-acyl cyclic amines. Several a-allyl
cyclic amines 5a–j were synthesized and subjected to elec-
trochemical deallylation. Our initial investigation began
with finding suitable electrodes from platinum, glassy
carbon, and graphite capable of supporting the electrochem-
ical oxidation of a-allyl-N-methoxycarbonylpyrrolidine (5a)
as a model substrate.
We observed that when the platinum anode was paired
with a graphite cathode, deallylated derivative a-methoxy-
N-methoxycarbonylpyrrolidine (4a) was obtained in a better
yield relative to the glassy carbon and platinum cathodes
(Table 1, entries 1–3). On the other hand, the glassy carbon
anode demanded relatively high electric loading and afford-
ed almost the same yields with any cathodes (entries 4–6).
The graphite anode required relatively less electricity and
gave an optimum yield of 4a when paired with the platinum
cathode (entries 7–9).
Tetraethylammonium p-toluenesulfonate (Et4NOTs) as a
supporting electrolyte did not improve this reaction
(Table 1, entry 10). The optimized reaction conditions were
applicable to the anodic deallylation of some a-allyl-N-acy-
lated amines 5a–k (Table 2).
These a-methoxylated compounds 4 have been utilized as
starting materials in the synthesis of cyclic lactams,[2] alka-
loids,[3] d-threo-methylphenidate,[4] and even the antimalarial
agent, isofebrifugine.[5] We report for the first time electro-
chemical deallylation and debenzylation of N-acyl-a-allylat-
ed and a-benzylated cyclic amines. We have also successfully
applied this method to the synthesis of optically active qua-
[a] P. G. Kirira, Dr. M. Kuriyama, Prof. Dr. O. Onomura
Graduate School of Biomedical Sciences
Nagasaki University, 1-14 Bunkyo-machi
Nagasaki 852-8521 (Japan)
Relatively bigger a-allylated cyclic amines were then in-
vestigated. Deallylation of a-allyl-N-methoxycarbonylpiperi-
dine (5b) proceeded with 72% yield to give the correspond-
ing a-methoxy-N-methoxycarbonylpiperidine (4b) (Table 2,
Fax : (+81)95-819-2476
E-mail: onomura@nagasaki-u.ac.jp
3970
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3970 – 3982

FULL PAPER
Table 1. Determination of electrodes for the deallylation of a-allyl-N-
methoxycarbonylpyrrolidine (5a).[a]
carbonylpyrrolidine (5e) gave the desired product albeit
with a slightly improved yield relative to N-methoxycarbo-
nylated pyrrolidine 5a (entries 1 and 5). In addition, a-allyl-
N-benzyloxycarbonylpiperidine (5 f), a-allyl-N-benzyloxy-
carbonylazepane (5g), and a-allyl-N-benzyloxycarbonylazo-
cane (5h) efficiently yielded the corresponding a-methoxy-
lated compounds, 4 f–h (entries 6–8). Finally, a-allyl-N-ben-
zoylpyrrolidine (5i) and a-allyl-N-benzoylazepane (5j), as
expected, furnished the corresponding a-methoxylated com-
pounds 4i and 4j in appreciable yields (entries 9 and 10). A
change of solvent to EtOH/MeCN though low yielding gave
the anticipated a-ethoxylated compound 4k (entry 11).
Entry
Electrode
cathode
Electricity
[FmolÀ1
Yield
4a [%]
Anode
G
]
1
2
3
4
5
6
7
8
platinum
platinum
platinum
glassy carbon
glassy carbon
glassy carbon
graphite
graphite
graphite
platinum
glassy carbon
graphite
glassy carbon
platinum
graphite
graphite
glassy carbon
platinum
2.5
3.0
2.5
3.0
3.0
3.0
2.0
3.0
2.0
3.0
51
47
56
53
48
51
52
51
68
36
Deallylation mechanism: Initially, we determined whether
the reaction intermediate was a radical species, by carrying
out deallylation of a-allyl-N-methoxycarbonylpyrrolidine
(5a) with a large excess (10 equiv) of butyl acrylate as a
free-radical scavenging additive. The reaction proceeded
smoothly to yield the expected a-methoxylated pyrrolidine
4a and butyl acrylate was recovered. This result implied
that the reaction did not proceed through an allyl radical,
but probably through an allyl cationic intermediate. To test
the feasibility of such a hypothesis, we prepared a-(1-myris-
tylallyl)-N-benzyloxycarbonylpiperidine (6) with (2-heptade-
cenyl)trimethylsilane[6] and carried out electrochemical deal-
lylation. A plausible reaction pathway based on the ob-
served results is outlined in Scheme 1. We propose that
9
10[b]
graphite
platinum
[a] The substrate 5a (0.5 mmol) and Et4NBF4 (0.1 mmol) were placed in
a beaker-type cell containing a stirring bar. Methanol (2 mL) and aceto-
nitrile (8 mL) were added and the mixture was stirred at 08C. The elec-
trodes were fitted and appropriate electricity was passed through.
[b] Et4NOTs (0.5 equiv) was used as a supporting electrolyte.
Table 2. Anodic deallylation of a-allyl-N-acylated amines 5a–j.[a]
Entry
PG
n
Substrate
Product
Yield [%]
1
2
3
4
5
6
7
8
CO2Me
CO2Me
CO2Me
CO2Me
CO2CH2Ph
CO2CH2Ph
CO2CH2Ph
CO2CH2Ph
COPh
1
2
3
4
1
2
3
4
1
3
5a
5b
5c
5d
5e
5 f
5g
5h
5i
4a
4b
4c
4d
4e
4 f
4g
4h
4i
68
72
66
70
70
76
61
64
65
69
9
10
Scheme 1. Plausible electrochemical deallylation route.
COPh
5j
4j
11[b]
CO2Me
1
5a
51
under a constant electrical current, electron absorption
takes place at the anode, which brings about the carbon–
carbon (C–C) bond cleavage between the a and b carbon
atoms to generate an acyliminium ion and allylic cation ꢀ6ꢁ
(Scheme 1)[7] similar to those anodically generated from
amino acids and alcohols.[1] These ions are then trapped
with nucleophiles, such as methoxide, to afford 47% of a-
methoxy cyclic amine 4 f. The methyl ether 7a and its regio-
isomer 7b as side products (sum up ~80% yield) were de-
tected by GCMS confirming this hypothesis.
[a] The substrates 5a–j (0.5 mmol) and Et4NBF4 (0.1 mmol) were placed
in a beaker-type cell containing a stirring bar. Methanol (2 mL) and ace-
tonitrile (8 mL) were added and the mixture was stirred at 08C. The
graphite anode and platinum cathode were fitted and 2.0 FmolÀ1 of elec-
tricity was passed through. [b] Ethanol (2 mL) and acetonitrile (8 mL)
were added and the mixture was stirred at 08C.
entry 2). Further, a-allyl-N-methoxycarbonylazepane (5c)
and a-allyl-N-methoxycarbonylazocane (5d) led to the cor-
responding a-methoxylated compounds 4c and 4d with
good yields, respectively (entries 3 and 4). A change of N-
acyl groups was tolerated. For instance, a-allyl-N-benzyloxy-
Chemical deallylation: We unsuccessfully attempted to carry
out chemical deallylation by using lead(IV) acetate[8] in
methanol at 08C [Eq. (2)].
Chem. Eur. J. 2010, 16, 3970 – 3982
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3971

O. Onomura et al.
anticipated a-ethoxylated compound 4k (entry 10) albeit in
a low yield.
Debenzylation mechanism: Electrochemical oxidation of a-
(4-tert-butyl)benzyl-N-benzyloxycarbonylpyrrolidine (9) pro-
ceeded smoothly to yield the corresponding a-methoxypyr-
rolidine 4e and a mixture of p-methoxymethyl-tert-butylben-
zene (10a)[9] and p-dimethoxymethyl-tert-butylbenzene
(10b).[9] This implies that under a constant electrical current,
absorption of electrons takes place at the anode, which
brings about the carbon–carbon (C–C) bond cleavage be-
tween the a and b carbon atoms to generate the acylimini-
um ion and benzylic cation ꢀ9ꢁ similar to those anodically
generated during electrochemical deallylation (Scheme 2).
The acyliminium ion is then trapped with methoxide to
afford 57% of a-methoxylated cyclic amine 4e. Similarly,
trapping of a benzylic cation with methoxide afforded
methyl ether 10a and dimethyl acetal 10b, generated by fur-
ther oxidation of 10a, isolated as side products (sum up
~71% yield).
Anodic debenzylation: a-Benzyl-N-acyl cyclic amines 8a–h
were then investigated. Electrochemical oxidation of a-
benzyl-N-methoxycarbonylpyrrolidine (8a) afforded a-me-
thoxylated product 4a in 67% yield. The reaction required
a low temperature, À108C (Table 3, entries 1 and 2), and a
high electric loading (4 FmolÀ1) for optimum yield.
Table 3. Anodic debenzylation of a-benzyl-N-protected amines 8a–h.[a]
Entry
PG
n
Substrate
Product
Yield [%]
1
CO2Me
CO2Me
CO2Me
CO2Me
1
1
2
3
4
1
2
3
4
8a
8a
8b
8c
8d
8e
8 f
8g
8h
4a
4a
4b
4c
4d
4e
4 f
4g
4h
67
57
62
66
71
57
65
72
74
2[b]
3
4
5
6
7
8
9
CO2Me
CO2CH2Ph
CO2CH2Ph
CO2CH2Ph
CO2CH2Ph
10[c]
CO2Me
1
8a
47
Scheme 2. Plausible electrochemical debenzylation route.
[a] The substrate (0.5 mmol) and Et4NBF4 (0.1 mmol) were placed in a
beaker-type cell containing a stirring bar. Methanol (2 mL) and acetoni-
trile (8 mL) were added and the mixture was stirred at À108C. The
graphite anode and platinum cathode were fitted and 4.0 FmolÀ1 of elec-
tricity was passed through. [b] The reaction was carried out at 08C.
[c] Ethanol (2 mL) and acetonitrile (8 mL) were added and the mixture
was stirred at À108C.
Oxidation potentials: Oxidation peak potentials of four
cyclic amines were measured by cyclic voltammetry. The re-
sults are shown in Table 4. The most oxidizable compound
as expected was nonsubstituted N-methoxycarbonyl amine
11 (entry 1), whereas a-hydroxymethylated amine 12 was
hardly oxidizable (entry 4). The amine with an a-allyl sub-
stituent (5a, entry 2) was more oxidizable than that with a
a-benzyl substituent (8a, entry 3).
Debenzylation of a-benzyl-N-methoxycarbonylpiperidine
(8b) proceeded smoothly, yielding the corresponding a-me-
thoxypiperidine 4b (Table 3, entry 3). Similarly, debenzyla-
tion of a-benzyl-N-methoxycarbonylazepane (8c) and a-
benzyl-N-methoxycarbonylazocane (8d) proceeded with
good yields, 66 and 71%, respectively (entries 4 and 5). A
change of N-acyl group was well tolerated. For instance, a-
benzyl-N-benzyloxycarbonylpyrrolidine (8e) yielded its cor-
responding a-methoxypyrrolidine 4e in average yield
(entry 6). Bigger a-benzyl-N-benzyloxycarbonyl cyclic
amines 8 f–h underwent anodic cleavage with improved
yields, 65, 72, and 74%, for a-methoxypiperidine 4 f, a-me-
thoxyazepane 4g, and a-methoxyazocane 4h, respectively
(entries 7–9). A change of solvent to EtOH/MeCN gave the
Synthetic application to optically active quaternary cyclic
amines via a-allylated intermediates: In view of the biologi-
cal importance of optically active a-alkyl-a-amino acids,[10]
several synthetic methods have been reported.[11] However,
the development of new methods with the use of easily
available starting materials and convenient procedures is
still very important. We have previously demonstrated
Shono-type a’-allylation of amino acids.[12] In this study, dia-
stereoselective a’-allylation of methyl 6-methoxy-N-benzy-
loxycarbonyl-d-pipecolinate (15) derived from d-pipecoli-
nate 13 was carried out after N-acylation and electrochemi-
3972
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3970 – 3982

a-Allyl Cyclic Amines and Quaternary Cyclic Amino Acids
FULL PAPER
Table 4. Oxidation peak potentials observed by cyclic voltammetry.
a’-Allylated compound 16 underwent a-methylation after
treatment with 1.2 equivalents of sodium hexamethyldisila-
zide (NaHMDS) and three equivalents of methyl iodide at
À788C in THF to afford a’-allyl-a-methyl-a-amino acid
ester 21 [Eq. (3)]. Removal of the a’-allyl auxiliary from 21
was accomplished by using two steps involving electrochemi-
cal deallylation at 5 FmolÀ1 in methanol by using a graphite
anode followed by methoxy-group cleavage with Et3SiH and
MeSO3H to afford methyl N-benzyloxycarbonyl-(2R)-meth-
ylpipecolinate (19) with >99% ee [Eq. (4)]. Solvent and
base effects on a-methylation of 16 were then determined
(Table 5).
Entry
Substrate
Oxidation potential [V][a]
1
1.7
2
3
4
2.0
2.4
>3.0
[a] Cyclic voltammograms were recorded on each substrate solution
(10 mm) in MeCN containing Et4NBF4 (0.1m): Glassy carbon disk as a
working electrode 1.6 mm); scan rate=0.05 VsÀ1; Ag/AgNO3 as a refer-
ence electrode.
cal oxidation (Scheme 3). Com-
pound 15 could also be inex-
pensively obtained from d-
lysine-derivative 17 via 18 by
electrochemical oxidation.[12b]
Methyl (6S)-allyl-N-benzyloxy-
carbonyl-d-pipecolinate
(16)
was obtained from 15 after
treatment with allyltrimethylsi-
lane in the presence of a Lewis acid as a single cis isomer in
excellent yield.
Similar levels of enantioselectivity were obtained regard-
less of the base used (Table 5). Toluene and THF gave high
yields for a-methylation and >99% ee (entries 1 and 6).
NaHMDS and potassium hexamethyldisilazide (KHMDS)
gave good yields, whereas lithium diisopropylamide (LDA)
and lithium hexamethyldisilazane (LiHMDS) gave moderate
yields (entries 1–4). The reaction carried out from À608C
gave a lower yield (entry 5). Dimethyl formamide (DMF)
The direct introduction of an alkyl group to N-benzyloxy-
carbonyl-d-pipecolinate (14) at the a-position afforded N-
benzyloxycarbonyl-a-methylpipecolinate 19 as a racemic
mixture.[13] Further, 19 obtained from the alkylation of 15
followed by acidic cleaveage of the methoxy group was race-
mic [Eq. (3)]. In our preliminary study, we sought to achieve
asymmetric induction through the use of an a’-allyl group.
gave
a
moderate yield, but low enantiomeric excess
(entry 7). DMF undergoes de-
composition with strong bases,
such as NaHMDS, and the de-
composition products may have
hampered the reaction.[15] Ben-
zene was a poor solvent for this
reaction. Even though it gave
high enantiomeric excess, the
yield was poor (entry 8). This
may be due to the possibility
that since the reaction was car-
ried out at room temperature,
the intermediates formed after
the addition of the base were
unstable and may have disinte-
Scheme 3. Preparation of methyl (6S)-allyl-N-benzyloxycarbonyl-d-pipecolinate (16).
Chem. Eur. J. 2010, 16, 3970 – 3982
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3973

O. Onomura et al.
Table 5. Solvent and base effects on the a-methylation of 16.[a]
EtBr had little effect (entry 2).
In addition, an allyl group was
also tolerated and yielded the
desired a-allyl product 24b in
85% yield and with >99% ee
(entry 3). In the case of propyn-
yl bromide, the alkylating reac-
tion gave the desired product
22c in a high yield, which un-
derwent electrochemical deally-
lation and chemical demethoxy-
lation to yield methyl N-benzy-
loxycarbonyl-(2S)-(2-propynyl)-
pipecolinate 24c with 75% ee
(entry 4). Surprisingly, any at-
tempts to introduce a propyl
group at the a-position were
futile (entry 5). Even though
the 2-butenyl and 2-butynyl
group were easily introduced at
the a-position of 16 to yield
22d and 22e, respectively, con-
sequent deallylation hardly pro-
ceeded (entries 6 and 7). As ob-
served in the case of the propyl
group, any attempts to intro-
Entry
Solvent
Base
Yield [%]
ee [%] of 19[c]
21
20[b]
19
1
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
THF
NaHMDS
LDA
88
56
85
69
77
81
57
23
78
77
74
76
73
78
79
67
69
66
87
85
84
80
89
90
80
72
69
>99
>99
>99
>99
>99
>99
19
KHMDS
LiHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
DMF
benzene
>99
>99
THF[d]
[a] Other than benzene (RT), DMF (from À608C), and entry 5 (from À608C), all other reactions were carried
out from À788C. [b] Electrochemical oxidation was carried out in methanol by using a graphite anode and
platinum cathode. [c] ee was determined by using a Daicel chiralcel OJ column (254 nm) and the absolute con-
figuration was assigned by comparison of the specific rotation to the literature value, see: ref. [14]. [d] Other
than THF containing the base, no other solvent was added.
Table 6. a-Alkylation of 16.
duce
a
butyl group failed
Entry
R
Yield [%]
ee [%] of 24[b]
(entry 8). Methyl (6S)-allyl-N-
methoxycarbonyl-d-pipecoli-
22
23[a]
24
1[c]
2
3
4
5
Et
Et
allyl
2-propynyl
propyl
2-butenyl
2-butynyl
butyl
22a
22a
22b
22c
22d
22e
22 f
22g
22h
79
78
76
80
0
79
73
0
23a
23a
23b
23c
–
23e
23 f
–
79
76
70
80
–
24a
24a
24b
24c
–
24e
24 f
–
87
89
85
84
–
–
–
–
79
>99 (R)
>99 (R)
>99 (R)
75 (R)
–
nate (16h) was prepared ac-
cording to our recently report-
ed method.[12b] This compound
underwent a-alkylation, deally-
lation, and consequent deme-
thoxylation to yield the quater-
nary amino acid 24h in up to
79% yield and with 97% ee
(entry 9). Removal of the N-
acyl groups from the quaternary
amino acid esters 19 and 24h
6
7
trace[d]
n.d.[e]
trace[d]
–
80
n.d.[e]
8
–
9[f]
Me
77
23h
24h
97[g] (R)
[a] Electrochemical oxidation was carried out in methanol by using a graphite anode and platinum cathode.
[b] ee was determined by using a Daicel chiralcel OJ column (254 nm) and the absolute configuration was de-
duced on the basis of retention of configuration as observed in compound 19. [c] EtI was used. [d] Reaction
hardly proceeded and decomposition of the starting material was observed. [e] Not determined. [f] a’-Allyl-N-
methoxycarbonyl-d-pipecolinate (16h) was used instead of 16 as a starting substrate. [g] ee was determined by
using chiral GC.
yielded
amine
25
with
>99% ee [Eq. (5)].
grated. When the reaction was carried out with only THF
containing the base, the reaction cleanly afforded the de-
sired product with a high yield and >99% ee (entry 9).
With regard to substrate scope, selected alkyl substituents
were investigated (Table 6).
To our delight, we successfully introduced other alkyl sub-
stituents with good yields and enantioselectivities. For in-
stance, an ethyl group was introduced at the a-position of 16
in up to 79% yield. The electrochemical removal of the a’-
allyl group followed by demethoxylation of 23a gave the de-
sired quaternary amino acid ester, methyl N-benzyloxycar-
bonyl-(2R)-ethylpipecolinate (24a) with >99% ee (Table 6,
entry 1). A change of the alkylating reagent from EtI to
Lastly, we attempted the preparation of a-alkylated l-pro-
line. Diastereoselective a’-allylation of ethyl 5-methoxy-N-
benzyloxycarbonyl-l-prolinate (28)[16] derived from 27
through N-acylation and electrochemical oxidation of 26
3974
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3970 – 3982

a-Allyl Cyclic Amines and Quaternary Cyclic Amino Acids
FULL PAPER
gave two diastereomers 29 with the cis isomer as the major
product in high yield [Eq. (6)].
ty gave an unexpected inversion of the stereoselectivity
(entry 10). The reaction in entry 4 gave the best result and
was selected for optimization of
the solvent (Table 8).
Nonpolar solvents, fluoroben-
zene (PhF), benzene, xylene,
toluene, and chloroform, gave
the desired compound 29 with
moderate to good de (Table 8,
entries 1–5). The use of polar
aprotic solvents gave mixed re-
sults. While ethyl acetate, ether,
and THF had good to moderate
selectivities, acetonitrile had
Table 8. Optimization of the diastereoselective a’-allylation of 28.
Attempts were made to improve the diastereoselectivity
of compound 29 through the careful tuning of the reaction
parameters: Lewis acids, allylating agents, solvents, and tem-
perature (Table 7).
The allylation reaction with BF3·OEt2 and allyltrimethylsi-
lane (allyl-TMS) gave 29 in 86% yield and with 42% diaste-
reomeric excess (de; Table 7, entry 1). The use of allyltriiso-
propylsilane (allyl-TiPS) and a catalytic amount (20%) of
triisopropylsilyl trifluoromethanesulfonate (TiPSOTf) im-
proved the diastereomeric excess (entry 2). Dichlorome-
thane was found to be unfavourable (entry 3). An increase
of the catalyst loading to 60% somewhat improved the yield
and diastereoselectivity (entry 4). The use of bulkier allyltri-
phenylsilane or allyltripentafluorophenylsilane[17] resulted in
decreased yields (entries 5 and 6). Further tuning of the cat-
alyst loading, temperature, and reaction time improved the
diastereoselectivity with lower yields (entry 8). Interestingly,
a change of Lewis acid to BF3·OEt2 leading to low selectivi-
Entry
Solvent
T [oC]
t [h]
29
yield [%]
de [%]
1
2
3
4
5
6
7
8
PhF
0
RT
RT
0
0
0
0
0
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
5
55
56
50
54
35
46
52
38
42
36
50
47
46
52
48
35
65
53
73
84
62
60
81
74
66
32
64
85
79
92
82
62
78
72
94
94
90
80
benzene
xylene
toluene
CHCl3
AcOEt
MeCN
THF
ether
ether
toluene
PhF
ether
toluene
PhF
toluene
toluene
toluene
toluene
9
0
10
11
12
13[a]
14[a]
15[a]
16
17
18[b]
19
À78 to RT
À78 to RT
À78 to RT
À78 to RT
À78 to RT
À78 to RT
À78 to 0
À78 to 0
À78 to 0
À78 to 0
Table 7. Diastereoselective a’-allylation of ethyl 5-methoxy-N-benzyloxy-
carbonyl-l-prolinate (28).
12
5
36
[a] TMSTFMS was used as a Lewis acid. [b] 2.0 equivalents of Lewis acid
were used.
Entry
Lewis acid [equiv]
R
29
yield [%]
de[a] [%]
poor selectivity (entries 6–9). The reaction from À788C to
room temperature in toluene improved the diastereoselec-
tivity with a moderate yield (entry 11). However, low selec-
tivities were obtained in ether or fluorobenzene from À78
to 08C (entries 10 and 12). Trimethylsilyltrifluoromethane-
sulfonate (TMSTFMS) as a Lewis acid did not improve re-
sults (entries 13–15). The reaction in toluene from À78 to
08C improved selectivity to 94% though a low yield was ob-
tained (entry 16). However, the reaction from À78 to 08C
overnight dramatically improved the yield to 65%
(entry 17). Attempts to improve this result by the use of two
equivalents of Lewis acid or maintaining the reaction at 08C
for longer periods were unsuccessful (entries 18–19). Conse-
1
2
BF3·OEt2 (1.2)
TiPSOTf (0.3)
TiPSOTf (0.3)
TiPSOTf (0.6)
TiPSOTf (0.6)
TiPSOTf (0.6)
TiPSOTf (0.1)
TiPSOTf (0.3)
TiPSOTf (0.1)
BF3·OEt2 (1.0)
Me
iPr
iPr
iPr
Ph
PhF5
iPr
iPr
iPr
iPr
86
60
53
62
41
trace
47
30
30
45
42
82
68
83
91
–
89
91
3[b]
4
5
6
7[c]
8[c,d]
9[c,d]
10[d,e]
76
À38[f]
[a] Determined by using a Daicel chiralpak AD column (254 nm). [b] Re-
action was carried out in dichloromethane. [c] Reaction was carried out
at constant temperature of 08C. [d] Reaction was carried out for 36 h.
[e] Reaction was carried out from 08C. [f] trans-29 was the major isomer.
Chem. Eur. J. 2010, 16, 3970 – 3982
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3975

O. Onomura et al.
quently, for the purpose of this study, compound 29 was pre-
pared in 65% yield and with 94% de (entry 17).
Next, we attempted to introduce an alkyl group at the a-
position of 29 by using previously discussed reaction condi-
tions. Compound 29 underwent a-methylation after treat-
ment with 1.2 equivalents of NaHMDS and three equiva-
lents of methyl iodide at À788C in toluene to afford ethyl
(5S)-allyl-N-benzyloxycarbonyl-(2R)-methylprolinate (30) as
a mixture of diastereomers (Table 9).
Table 9. a-Methylation of ethyl (5S)-allyl-N-benzyloxycarbonyl-l-proli-
nate (29).
Conclusion
We have presented a novel approach to the deallylation of
a-allyl-N-acylated cyclic amines by using an electrochemical
method. We have also applied the method to the debenzyla-
tion of a-benzyl-N-acylated cyclic amines. We have demon-
strated a generalization of this method by changing the size
of the cyclic amines and the N-acyl groups. In all the cases,
the yields were moderate to high. We have also shown the
methods for diastereoselective a’-allylation of N-benzyloxy-
carobonylpipecolinate and N-benzyloxycarobonylprolinate.
Whereas pipecolinate requires allyl-TMS to yield only the
cis diastereomer, prolinate requires a bulky Lewis acid and
allylating reagents to give good selectivity. This information
is important for chemists interested in the diastereoselective
allylation of amino acid esters since they are important
building blocks for asymmetric synthesis. Finally, by using
an allyl group to achieve asymmetric induction,[19] we have
successfully prepared optically active cyclic quaternary
amino acid esters with up to 99% ee.
Entry
T [oC]
Base
28
yield [%]
de [%][a]
1
À78 to RT
À78 to 0
À78 to 0
À78
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
LiHMDS
KHMDS
78
41
83
60
69
41
70
40
50
70
72
76
76
76
72
80
84
74
40
–
2[b]
3
4
5[c]
6
À70
À78
7
8
À78 to RT
À78
KHMDS
9[d]
10[e]
11[f]
12[g]
À78 to RT
À78
NaHMDS
NaHMDS
NaHMDS
NaHMDS
50
trace
trace
À78 to RT
À78 to RT
–
[a] Determined by using a GC column. [b] The reaction was carried out
in THF. [c] MeI was added before the base. [d] Dimethylsulfate was used
as the methylating agent. [e] DME was used as an additive. [f] Methyl p-
toluenesulfonate was used as a methylating agent. [g] Methyl trifluorome-
thanesulfonate was used as a methylating agent.
The reaction from À78 to 08C in toluene and THF gave
an improvement in both yield and selectivity (Table 9, en-
tries 1–4). Addition of the electrophile before the base gave
no observable improvement (entry 5). KHMDS improved
selectivity though the yields were somewhat low, whereas
LiHMDS gave poor yields and selectivities (entries 6–8). A
change of methylating agents to the more reactive dimethyl
sulfate gave an average yield and comparable selectivity,
whereas methyl p-toluenesulfonate and methyl trifluorome-
thanesulfonate gave only trace amounts of products (en-
tries 9, 11, and 12). Addition of 1,2-dimethoxyethane
(DME)[11i] had detrimental effects on selectivity (entry 10).
With consideration to yield and selectivity, 30 was pre-
pared according to conditions in entry 3. Electrochemical a-
deallylation and chemical demethoxylation of 30 yielded
ethyl N-benzyloxycarbonyl-(2R)-methylprolinate (34)[18a]
with 72% ee. A change of the electrophile to ethyl iodide
gave the resultant quaternary amine, ethyl N-benzyloxycar-
bonyl-(2R)-ethylprolinate (35)[18c] with 64% ee [Eq. (7)].
Experimental Section
General: All commercial materials, reagents and solvents, were used
without further purification unless stated otherwise. Electrochemical re-
actions were carried out by the use of the DC Power Supply (GP 050–2)
of Takasago Seisakusho. HPLC analyses were achieved by using LC-
10AT VP and SPD-10A VP of Shimadzu Seisakusho. 1H NMR spectra
were measured at 500, 400, or 300 MHz with TMS as an internal stan-
dard. 13C NMR spectra were measured at 125, 100, or 75 MHz. IR spectra
were obtained on Shimadzu FTIR-8100A. Mass spectra were obtained
on a JEOL JMS-DX 303 instrument. A cyclic voltammogram was mea-
sured in 0.1m Et4NBF4/MeCN solution by using glassy-carbon as a work-
ing electrode, platinum as a counter electrode, and Ag/0.01m AgNO3 as a
reference electrode. Silica-gel column chromatography was performed by
using a mixed solvent of hexane and ethyl acetate. Analytical TLC was
performed on Merck silica gel 60 F254 plates (0.25 mm). Electrochemical
oxidation was carried out by using the DC Power Supply (GP 050–2) of
Takasago Seikakusho. Reactions were carried out in an undivided glass
cell by using platinum plate electrodes (10ꢁ20 mm), glassy carbon elec-
trodes (50ꢁ12ꢁ2 mm), or graphite electrodes (50ꢁ12ꢁ2 mm).
General procedure for the preparation of a-allyl-N-acyl amino acids 5a–
j: BF3·OEt2 (6 mmol) was added dropwise to a flask (50 mL) containing
a-methoxy-N-acyl cyclic amine 4a–j[20] (5 mmol) and allyltrimethylsilane
(6 mmol) in CH2Cl2 (10 mL) at À788C. The mixture was stirred and the
3976
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3970 – 3982

a-Allyl Cyclic Amines and Quaternary Cyclic Amino Acids
FULL PAPER
reaction temperature elevated gradually to room temperature over 6 h.
Progress was monitored by TLC. After completion of the reaction, water
(10 mL) was added and the mixture was extracted by using CHCl3 (3ꢁ
10 mL). The combined organic layers were dried with anhydrous MgSO4
and filtered. The filtrate was concentrated in vacuo. The residue was pu-
rified through silica-gel column chromatography to give a quantitative
yield of the a-allyl amines.
using anhydrous magnesium sulfate and filtered. The filtrate was concen-
trated in vacuo and the concentrate was purified by using silica-gel
column chromatography to give 9 (2.8 mmol). Colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.39–7.15 (m, 9H), 5.16 (s, 2H), 4.10–4.03 (m,
1H), 3.43–3.39 (m, 2H), 3.18 and 2.30 (dd, J=12.8 Hz, 1H), 2.57–2.48
(m, 1H), 1.76 (br s, 4H), 1.30 ppm (s, 9H); 13C NMR (75 MHz, CDCl3):
d=154.89, 154.74 (1C), 148.99, 148.90 (1C), 135.75, 129.14, 128.95,
128.41 (3C), 127.88 (2C), 125.16 (2C), 66.80, 66.39 (1C), 59.24, 58.76
(1C), 46.74, 46.51 (1C), 39.98, 39.66 (1C), 38.80, 34.29, 31.32 (2C), 27.71,
28.83 (1C), 23.35, 22.54 ppm (1C); IR (neat): n˜ =3090, 3030, 2966, 2874,
2361, 1609, 1588, 1498, 1456, 1336, 1269, 1115, 978, 916, 698 cmÀ1; HR-
FAB : m/z: calcd for C23H30NO2: 352.2290 [M+H]+; found: 352.2292.
Compounds 5a,[21] 5b,[22] 5c,[23] 5e,[24] 5 f,[25] 5g[26], and 5i[27] are known and
their spectroscopic datas is available in the literature.
a-Allyl-N-methoxycarbonylazocane (5d): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=5.81–5.67 (m, 1H), 5.01 (d, J=4.8 Hz, 1H), 4.97
(s, 1H), 4.14–3.07 (m, 0.5H), 3.94–3.90 (m, 0.5H), 3.70 (d, J=3.9 Hz,
3H), 3.54–3.39 (m, 1H), 2.98–2.88 (m, 1H), 2.19–2.13 (m, 2H), 1.67–
1.45 ppm (m, 10H); 13C NMR (100 MHz, CDCl3): d=157.18, 156.60
(1C), 135.35, 135.03 (1C), 116.84, 116.64 (1C), 55.79, 52.20, 52.09 (1C),
39.52, 39.31 (1C), 28.88, 27.90, 26.90, 26.29, 26.57, 24.41 ppm; IR (neat):
n˜ =3077, 2926, 2857, 1642, 1478, 1441, 1404, 1347, 1244, 1146, 1069, 994,
914 cmÀ1; HR-FAB: m/z: calcd for C12H22NO2: 212.1669 [M+H]+; found:
212.1671.
a-Allyl-N-benzyloxycarbonylazocane (5h): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.36–7.35 (m, 5H), 5.86–5.63 (m, 1H), 5.14 (d, J=
6.9 Hz, 2H), 5.01–4.94 (m, 2H), 4.19–4.13 (m, 0.5H), 4.08–4.03 (m,
0.5H), 3.80–3.42 (m, 1H), 3.02–2.89 (m, 1H), 2.21–2.10 (m, 2H), 1.90–
1.70 (m, 1H), 1.67–1.47 ppm (m, 9H); 13C NMR (100 MHz, CDCl3): d=
156.46, 155.84 (1C), 137.16, 137.08 (1C), 135.29, 135.01 (1C), 128.30,
127.75, 127.71, 127.61, 127.54, 116.91, 116.70 (1C), 66.66, 66.61 (1C),
55.87, 39.49, 39.31 (1C), 28.95, 27.97, 26.81, 26.57, 26.16, 24.37 ppm; IR
(neat): n˜ =3069, 2926, 2857, 1705, 1642, 1497, 1474, 1416, 1343, 1181,
1144, 1061, 914, 698 cmÀ1; HR-FAB: m/z: calcd for C18H26NO2: 288.1669
[M+H]+; found: 288.1969.
a-Allyl-N-benzoylazepane (5j): Colorless oil; 1H NMR (300 MHz,
CDCl3): d=7.36–7.32 (m, 5H), 5.91–5.85 (m, 0.5H), 5.50–5.44 (m, 0.5H),
5.13–4.92 (m, 2H), 4.66–4.71 (m, 0.5H), 4.32 (br d, J=13.5 Hz, 0.5H),
3.72–3.67 (m, 0.5H), 3.49 (brd, J=16.2 Hz, 0.5H), 3.02–2.98 (m, 0.5H),
2.81–2.72 (m, 0.5H), 2.35 (t, J=6.9 Hz, 1H), 2.21–1.78 (m, 5H), 1.48–
1.25 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=172.42, 171.34 (1C),
137.90, 137.59 (1C), 135.13, 133.95 (1C), 128.50, 128.45, 128.27, 126.25,
126.00, 117.64, 116.87 (1C), 57.10, 52.99 (1C), 44.08, 40.39 (1C), 40.13,
39.10 (1C), 34.18, 32.99 (1C), 30.51, 30.07 (1C), 28.99, 27.62 (1C), 24.93,
24.65 ppm (1C); IR (neat): n˜ =2928, 2855, 1636, 1578, 1495, 1445, 1422,
1375, 1347, 1283, 1177, 1138, 1119, 1075, 972, 914, 779, 704 cmÀ1; HR-
FAB : m/z: calcd for C16H22NO: 244.1707 [M+H]+; found: 244.1708.
General procedure for electrochemical deallylation of a-allyl-N-acyl
amino acids 5a–j: The substrate (0.5 mmol) and Et4NBF4 (0.1 mmol)
were placed in a beaker-type cell containing a stirring bar. Methanol
(2 mL) and acetonitrile (8 mL) were added and the mixture was stirred
at 08C. The graphite anode and platinum cathode were fitted and
2 FmolÀ1 of electricity were passed through. The reaction mixture was
transferred into a flask (25 mL) and the solvent was evaporated. Water
(10 mL) was added, the mixture was extracted with AcOEt (3ꢁ8 mL),
and the combined organic layer was dried by using anhydrous MgSO4
and filtered. The solvent was removed under vacuo to give the methoxy
compounds 4a–k.[20]
a-Methoxy-N-methoxycarbonylazocane (4d): Colorless oil; 1H NMR
(400 MHz, CDCl3): d=5.21–5.18 (m, 0.5H), 5.01–4.95 (m, 0.5H), 3.64
and 3.58 (s, 3H), 3.29–3.20 (m, 2H), 3.08, 3.05 (s, 3H), 1.70–1.32 ppm
(m, 10H); 13C NMR (100 MHz, CDCl3): d=157.68, 156.47 (1C), 85.73,
85.64 (1C), 54.29, 53.92 (1C), 52.31, 52.05 (1C), 48.18, 47.21 (1C), 39.81,
39.29 (1C), 29.28, 28.98 (1C), 27.36, 26.74 (1C), 25.74, 25.58 (1C), 23.43,
22.66 ppm (1C); IR (neat): n˜ =2936, 2859, 1479, 1445, 1408, 1277, 1192,
1028, 885, 773 cmÀ1
; HR-FAB: m/z: calcd for C9H16NO2: 170.1194
[MÀOMe]+; found: 170.1195.
a-Methoxy-N-benzyloxycarbonylazocane (4h): Colorless oil; 1H NMR
(400 MHz, CDCl3): d=7.35 (brs, 5H), 5.35–5.30 (m, 1H), 5.19, 5.15 (dd,
J=9.28 Hz, 2H), 3.55–3.36 (m, 2H), 3.19, 3.11 (s, 3H), 1.82–1.43 ppm (m,
10H); 13C NMR (100 MHz, CDCl3): d=157.04, 155.80 (1C), 137.02,
136.54 (1C), 128.30, 128.22, 127.78, 127.57, 127.51, 85.71, 66.87, 66.54
(1C), 55.38, 54.04 (1C), 48.33, 47.26 (1C), 39.90, 39.37 (1C), 29.31, 29.08
(1C), 27.46, 26.77 (1C), 26.06, 25.59 (1C), 23.43, 22.68 ppm (1C); IR
(neat): n˜ =3034, 2934, 2860, 1709, 1478, 1416, 1275, 1190, 1144, 1084,
1028, 885, 698 cmÀ1
; HR-FAB: m/z: calcd for C15H20NO2: 246.1481
[MÀOMe]+; found: 246.1480.
General procedure for the preparation of a-benzyl-N-acyl amino acids
8a–h: Freshly prepared benzylmagnesium chloride (7.5 mmol) was added
with a syringe under a nitrogen atmosphere to a two-neck flask (50 mL)
containing a-methoxy-N-acyl cyclic amine (5 mmol) in CH2Cl2 (10 mL)
at À788C. The solution was stirred at À788C for 1 h and BF3·OEt2
(6 mmol) was added dropwise. The reaction was stirred for a further 2 h
and the reaction progress was monitored by TLC. After completion of
the reaction, saturated ammonium chloride solution was added (30 mL)
and the resulting mixture was extracted by using CHCl3 (3ꢁ10 mL). The
combined organic layer was washed with brine (2ꢁ10 mL), dried using
anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo.
The residue was purified through silica-gel column chromatography to
give a quantitative yield of the a-benzylated amines 8a–h.
a-(1-Myristylallyl)-N-benzyloxycarbonylpiperidine (6): Trimethyl-1-tetra-
decylallylsilane (10.0 mmol) was added to a solution of 4 f (5.0 mmol) in
CH2Cl2 (60 mL) and the mixture was stirred at À788C for 10 min.
BF3·OEt2 (6.0 mmol) was added dropwise and the temperature was al-
lowed to rise gradually to room temperature over 4 h. Water (30 mL)
was added and the mixture was extracted with CHCl3 (3ꢁ20 mL). The
organic layer was dried by using anhydrous magnesium sulfate and fil-
tered. The filtrate was concentrated in vacuo and the concentrate was pu-
rified by using silica-gel column chromatography to give 6 (2.6 mmol).
Colorless oil; 1H NMR (300 MHz, CDCl3): d=7.36–7.34 (m, 5H), 5.47–
5.40 (m, 0.5H), 5.33–5.29 (m, 0.5H), 5.18–5.11 (m, 4H), 4.30 (brs, 1H),
4.04 (brd, J=11.1 Hz, 1H), 2.89–2.80 (m, 1H), 2.33–2.17 (m, 1H), 1.94–
1.90 (m, 1H), 1.61–1.55 (m, 5H), 1.25 (brs, 26H), 0.88 ppm (t, J=6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=155.53, 137.11, 133.15, 128.54,
128.38 (2C), 127.75, 127.66, 126.30, 66.76, 50.72, 39.23, 33.07, 32.54, 31.90,
29.67–29.16 (m, 10C), 27.40, 25.45, 22.66, 18.71, 14.09 ppm; IR (neat): n˜ =
3032, 2936, 2855, 1707, 1609, 1498, 1468, 1421, 1211, 1170, 1140, 1044,
968, 696 cmÀ1; HR-FAB: m/z: calcd for C30H50NO2: 456.3842 [M+H]+;
found: 456.3841.
Compounds 8a[28] and 8b[28] are known and their spectroscopic data is
available in the literature.
a-Benzyl-N-methoxycarbonylazepane (8c): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.25–7.14 (m, 5H), 4.28–4.38 (m, 0.5H), 4.15–4.01
(m, 0.5H), 3.74–3.70 (m, 3H), 3.53–3.47 (m, 2H), 2.74–2.58 (m, 2H),
1.90–1.14 ppm (m, 8H); 13C NMR (100 MHz, CDCl3): d=156.92, 138.77,
138.70 (1C), 129.42, 129.25, 128.13, 126.08, 126.05, 62.69, 57.46, 57.26
(1C), 52.31, 52.12 (1C), 41.98, 41.45 (1C), 33.65, 32.77 (1C), 29.82, 29.69
(1C), 28.90, 28.16 (1C), 22.43 ppm; IR (neat): n˜ =3027, 2930, 2855, 1603,
a-(4-tert-Butylbenzyl)-N-benzyloxycarbonylpyrrolidine (9): Freshly pre-
pared 4-tert-butylbenzyl magnesium chloride (10.0 mmol) in THF (5 mL)
was added to a solution of 4e (5.0 mmol) in CH2Cl2 (60 mL) and the mix-
ture was stirred at À788C for 10 min. BF3·OEt2 (6.0 mmol) was added
dropwise and the temperature was allowed to rise gradually to room tem-
perature over 4 h. Saturated NH4Cl (30 mL) was added and the mixture
was extracted with CHCl3 (3ꢁ20 mL). The organic layer was dried by
1495, 1474, 1437, 1406, 1375, 1279, 1207, 1103, 1011, 970, 774, 702 cmÀ1
;
HR-FAB: m/z: calcd for C15H22NO2: 248.1653 [M+H]+; found: 248.1653.
a-Benzyl-N-methoxycarbonylazocane (8d): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.24–7.11 (m, 5H), 4.41–4.11 (m, 0.5H), 4.08–4.01
Chem. Eur. J. 2010, 16, 3970 – 3982
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3977

O. Onomura et al.
(m, 0.5H), 3.67 (d, J=9.0 Hz, 3H), 3.44–3.32 (m, 2H), 3.30–2.90 (m,
0.5H), 2.89 (dd, J=6.0 Hz, 0.5H), 2.63 (dddd, J=7.7 Hz, 1H), 1.75–
1.53 ppm (m, 10H); 13C NMR (100 MHz, CDCl3): d=156.85, 156.45
(1C), 138.91, 138.87 (1C), 129.34, 129.18 (1C), 129.01, 128.98 (1C),
128.13, 128.12 (1C), 127.58, 126.24 (1C), 126.08, 126.03 (1C), 58.02, 57.96
(1C), 52.18, 51.93 (1C), 42.12, 41.90 (1C), 41.39, 41.02 (1C), 28.16, 27.98
(1C), 26.97, 26.89 (1C), 26.23, 26.12 (1C), 26.08, 25.89 (1C), 24.71,
24.59 ppm (1C); IR (neat): n˜ =3027, 2930, 2857, 1709, 1603, 1480, 1441,
1437, 1404, 1348, 1223, 1190, 1146, 1069, 1030, 974, 774, 700 cmÀ1; HR-
FAB : m/z: calcd for C16H24NO2: 262.1814 [M+H]+; found: 262.1815.
a-Benzyl-N-benzyloxycarbonylpyrrolidine (8e): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.39–7.34 (m, 5H), 7.25–7.21 (m, 5H), 5.17 (s,
2H), 4.09 (brs, 1H), 3.40 (brs, 2H), 3.19 (brd, J=12.6 Hz, 0.5H), 3.03
(brd, J=10.5 Hz, 0.5H), 2.65–2.57 (m, 1H), 1.77–1.67 ppm (m, 4H);
13C NMR (100 MHz, CDCl3): d=154.89, 138.80, 129.51, 129.31, 128.41
(2C), 128.28 (2C), 128.07, 127.99, 127.93, 127.75, 126.15, 66.87, 66.43
(1C), 59.20, 58.74 (1C), 46.79, 46.53 (1C), 40.55, 39.37 (1C), 29.67, 28.83
(1C), 23.39, 22.58 (1C) ppm; IR (neat): n˜ =3029, 2878, 1713, 1603, 1586,
1497, 1455, 1418, 1360, 1279, 1213, 1188, 1030, 916, 768, 700 cmÀ1; HR-
FAB : m/z: calcd for C19H22NO2: 296.1665 [M+H]+; found: 296.1667.
a-Benzyl-N-benzyloxycarbonylpiperidine (8 f): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.31–7.18 (m, 10H), 5.18–4.96 (m, 2H), 4.49 (brs,
1H), 4.12 (brd, J=12.0 Hz, 1H), 3.04–2.87 (m, 3H), 1.71–1.46 ppm (m,
6H); 13C NMR (100 MHz, CDCl3): d=155.45, 138.94, 136.88, 129.13
(2C), 128.33 (2C), 128.31 (2C), 127.76 (2C), 127.73, 126.15, 66.82, 52.53,
39.52, 36.10, 25.41 (2C), 18.77 ppm; IR (neat): n˜ =3029, 2942, 2861, 1709,
1586, 1603, 1497, 1269, 1198, 1167, 986, 912, 702 cmÀ1; HR-FAB: m/z:
calcd for C20H24NO2: 310.1829 [M+H]+; found: 310.1831.
a-Benzyl-N-benzyloxycarbonylazepane (8g): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.35–7.18 (m, 10H), 5.18–4.91 (m, 2H), 4.41–4.26
(m, 0.5H), 4.19–4.10 (m, 0.5H), 3.87 (brd, J=14.1 Hz, 0.5H), 3.74 (brd,
J=15.0 Hz, 1H), 3.52–3.38 (m, 0.5H), 2.87–2.61 (m, 2H), 1.91–1.16 ppm
(m, 8H); 13C NMR (100 MHz, CDCl3): d=156.08, 138.68, 138.61 (1C),
137.21, 136.91 (1C), 129.41, 129.33 (1C), 129.25, 128.70 (1C), 128.43,
128.37, 128.33 (1C), 128.17, 128.13 (1C), 127.83, 127.77, 127.69 (1C),
127.62, 127.57 (1C), 127.52, 127.38 (1C), 126.10, 126.05 (1C), 66.87, 66.63
(1C), 57.43, 57.37 (1C), 42.12, 42.01 (1C), 41.52, 40.87 (1C), 33.56, 32.90
(1C), 29.79, 29.58 (1C), 29.50, 28.21 (1C), 25.07 ppm; IR (neat): n˜ =3031,
2928, 2855, 1709, 1603, 1586, 1603, 1497, 1420, 1306, 1269, 1204, 1103,
1086, 1001, 770, 698 cmÀ1; HR-FAB: m/z: calcd for C21H26NO2: 324.1955
[M+H]+; found: 324.1956.
ing electrode, and platinum wire was the counter electrode. The scan rate
was 50 mVsÀ1
.
Synthesis of methyl (6S)-allyl-N-benzyloxycarbonyl-d-pipecolinate
(16):[12b] HCl/MeOH solution (1n 100 mL) was added to d-pipecolinic
acid (20 mmol) in a round-bottomed flask (500 mL) and the solution was
stirred at 508C for 6 h. Then the solvent was evaporated. The resulting
ester (20 mmol) in dichloromethane (100 mL) was treated with triethyla-
mine (50 mmol), 4-dimethylaminopyridine (DMAP) (2 mmol), and car-
boxybenzyl chloride (Cbz-Cl) (24 mmol), and the mixture was stirred at
room temperature for 12 h. Water (100 mL) was added to quench the re-
action and the mixture was extracted by using AcOEt (3ꢁ50 mL). The
organic layer was dried by using anhydrous magnesium sulphate, filtered,
and concentrated in vacuo. The resulting concentrate was purified by
silica-gel column chromatography to yield N-benzyloxycarbonyl-d-pipe-
colinate (14; 19.6 mmol). Electrochemical oxidation (2 FmolÀ1) of 14
(10 mmol) in methanol (50 mL) by using an undivided cell graphite
anode at 08C yielded a’-methoxy derivative 15 (9.2 mmol).
Allyltrimethylsilane (10.8 mmol) was added to a solution of 15 (9 mmol)
in CH2Cl2 (30 mL) and the mixture was stirred at À788C for 10 min.
BF3·OEt2 (10.8 mmol) was added dropwise and the temperature allowed
to rise gradually to room temperature over 4 h. Water (30 mL) was
added and the mixture was extracted with CHCl3 (3ꢁ20 mL). The organ-
ic layer was dried by using anhydrous magnesium sulfate and filtered.
The filtrate was concentrated in vacuo and the concentrate was purified
by using silica-gel column chromatography to give 16 (7.9 mmol).
Methyl (6S)-allyl-N-benzyloxycarbonyl-d-pipecolinate (16): The de value
was determined to be >99% by gas chromatography (Shinwa Chemical
Industries, HR-1, 0.25 mmØꢁ25 m) at a constant temperature of 1708C
and a retention time of 32.82 min. Colorless oil; [a]2D8 =77.75 (c=1.0 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.35–7.33 (m, 5H), 5.79–5.65
(m, 1H), 5.18 (s, 2H), 5.05–5.03 (d, J=6 Hz, 1H), 4.99 (s, 1H), 4.89 (brs,
1H), 4.24 (t, J=5.7 Hz, 1H), 3.66 (s, 3H), 2.47–2.14 (m, 3H), 1.73–
1.50 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=172.99, 156.15 (br),
136.58, 135.92, 128.34 (2C), 127.85, 127.69 (2C), 116.87, 67.24, 55.52,
51.97, 50.89, 38.12 (br), 25.79 (2C), 15.31 ppm; IR (neat): n˜ =3069, 3033,
2950, 2867, 1640, 1499, 1412, 1211, 1152, 1071, 1003, 916, 698 cmÀ1; HR-
FAB : m/z: calcd for C18H24NO4: 318.1721 [M+H]+; found: 318.1723.
General a-alkylation protocol for a’-allyl-N-acyl-a-amino acid esters:
NaHMDS (0.6 mmol) was added to the substrate (0.5 mmol) in dry sol-
vent (2 mL) under a nitrogen atmosphere at À788C. The temperature
was elevated to À208C and the mixture stirred for 30 min. The reaction
temperature was restored to À788C and alkyl iodide or bromide
(1.5 mmol) was gradually added. The temperature was then gradually al-
lowed to rise and the reaction was monitored by using TLC. Saturated
ammonium chloride solution (10 mL) was added and the mixture was ex-
tracted by using AcOEt (3ꢁ10 mL). The organic extract was washed
with brine (3ꢁ5 mL), dried by using anhydrous magnesium sulfate, and
filtered. The filtrate was concentrated under reduced pressure and the
concentrate was purified by using silica-gel column chromatography to
yield a’-allyl-N-acyl-a-alkyl-a-amino acid esters 21, 22a–h, 30, and 31.
a-Benzyl-N-benzyloxycarbonylazocane (8h): Colorless oil; 1H NMR
(300 MHz, CDCl3): d=7.32–7.05 (m, 10H), 5.11–5.02 (m, 2H), 4.44–4.22
(m, 0.5H), 4.19–4.08 (m, 0.5H), 3.53 (brd, J=15.6 Hz, 0.5H), 3.40 (brd,
J=14.1 Hz, 0.5H), 3.04–2.92 (m, 1H), 2.83–2.55 (m, 2H), 1.69–1.44 ppm
(m, 10H); 13C NMR (100 MHz, CDCl3): d=156.17, 155.78 (1C), 138.86,
137.21, 136.98 (1C), 129.35, 129.20 (1C), 128.35, 128.31, 128.20, 128.15,
127.79, 127.72, 127.67, 127.57, 127.51 (1C), 126.12, 126.06 (1C), 66.68,
66.57 (1C), 58.12, 58.05 (1C), 41.39, 40.97 (1C), 28.49, 28.06 (1C), 26.93,
26.84, 26.72, 26.21, 24.75, 24.61 ppm (1C); IR (neat): n˜ =3031, 2932,
Methyl (6S)-allyl-N-benzyloxycarbonyl-(2R)-methylpipecolinate (21):
The de value was determined to be >99% by gas chromatography
(Shinwa Chemical Industries, HR-1, 0.25 mmØꢁ25 m) at a constant tem-
perature of 1708C and a retention time of 68.83 min. Colorless oil;
[a]3D2 =11.46 (c=1.25 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.35–
7.34 (m, 5H), 5.80–5.77 (m, 1H), 5.11 (s, 2H), 5.09 (s, 0.5H), 5.03 (t, J=
9.8 Hz, 1.5H), 4.13 (t, J=7.0 Hz, 1H), 3.54 (brs, 3H), 2.59–2.57 (m, 1H),
2.34–2.31 (m, 1H), 2.20–2.18 (m, 1H), 1.83–1.82 (m, 2H), 1.75–1.66 (m,
3H), 1.59 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=175.47, 155.12,
136.51, 135.80, 128.36 (3C), 128.00, 127.92, 116.78, 67.05, 60.29, 52.13,
51.20, 40.22, 30.99, 22.19, 21.67, 12.35 ppm; IR (neat): n˜ =2950, 2361,
1742, 1736, 1698, 1638, 1541, 1509, 1499, 1458, 1401, 1341, 1271, 1227,
1134, 1065, 698 cmÀ1; HR-FAB: m/z: calcd for C19H26NO4: 332.1863
[M+H]+; found: 332.1863.
2857, 1709, 1605, 1586, 1603, 1497, 1418, 1146, 1061, 1030, 970, 702 cmÀ1
;
HR-FAB: m/z: calcd for C22H28NO2: 338.2123 [M+H]+; found: 338.2123.
General procedure for electrochemical debenzylation of a-benzyl-N-acyl
amino acids 8a–h: The substrate (0.5 mmol) and Et4NBF4 (0.1 mmol)
were placed in a beaker-type cell containing a stirring bar. Alcohol
(2 mL) and acetonitrile (8 mL) were added and the mixture was stirred
at À108C. The graphite anode and platinum cathode were fitted and
4 FmolÀ1 of current was passed through. The reaction mixture was trans-
ferred into a flask (25 mL) and the solvent was evaporated. Water
(10 mL) was added and the mixture was then extracted with AcOEt (3ꢁ
8 mL) and the combined organic layer was dried by using anhydrous
MgSO4 and filtered. The solvent was removed under vacuo to give the
methoxy compounds 4a–h and 4k.
Measurement of oxidation potentials: BAS CV-50W was used as a volta-
metric analyzer. A solution of substrate (0.1 mmol) in MeCN (5 mL) con-
taining Et4NBF4 (0.1m) was measured. The reference electrode was Ag/
AgNO3 in saturated aqueous KCl, whereas glassy carbon was the work-
Methyl (6S)-allyl-N-benzyloxycarbonyl-(2R)-ethylpipecolinate (22a): The
de value was determined to be >99% by gas chromatography (Shinwa
Chemical Industries HR-1, 0.25 mmØꢁ25 m) at a constant temperature
of 1708C and a retention time of 70.83 min. Colorless oil; [a]3D2 =36.26
3978
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3970 – 3982

a-Allyl Cyclic Amines and Quaternary Cyclic Amino Acids
FULL PAPER
(c=2.85 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.35–7.31 (m, 5H),
5.78–5.70 (m, 1H), 5.23–4.95 (m, 4H), 4.23–4.08 (m, 1H), 3.57 (brs, 3H),
2.57–2.51 (m, 1H), 2.39–2.31 (m, 1H), 2.10–2.07 (m, 3H), 1.82–1.63 (m,
5H), 0.95 ppm (t, J=7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
175.31, 155.62, 136.04, 128.36, 128.32, 128.01, 127.98, 127.94, 127.89,
116.70, 67.00, 66.54, 63.16, 51.92, 51.86, 39.36, 29.74, 29.46, 22.90, 13.38,
9.41 ppm; IR (neat): n˜ =3069, 3034, 2951, 2880, 1748, 1744, 1640, 1588,
Chemical Industries, HR-1, 0.25 mmØꢁ25 m) at a constant temperature
of 1708C and a retention time of 7.70 (minor) and 8.33 min (major). Col-
orless oil; [a]2D8 =17.38 (c=1.82 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=5.70–5.58 (m, 1H), 4.96–4.87 (m, 2H), 3.93–3.88 (m, 1H), 3.54 (s,
3H), 3.51 (s, 3H), 2.42–2.37 (m, 1H), 2.19–2.03 (m, 2H), 1.66–1.50 (m,
4H), 1.42 (s, 3H), 1.36–1.33 ppm (m, 1H); 13C NMR (125 MHz, CDCl3):
d=175.58, 155.75, 135.81, 134.67 (1C), 117.91, 116.67 (1C), 60.21, 59.64
(1C), 52.53, 52.25 (1C), 51.09, 41.25, 40.13 (1C), 34.83, 30.94, 30.65 (1C),
21.13, 21.66 (1C), 18.38, 12.32 ppm; IR (neat): n˜ =2953, 1642, 1449, 1273,
1096, 997, 918, 776, 735 cmÀ1; HR-FAB: m/z: calcd for C13H22NO4:
256.1551 [M+H]+; found: 256.1551.
1499, 1456, 1402, 1341, 1256, 1219, 1134, 1090, 1030, 1001, 916, 698 cmÀ1
;
HR-FAB: m/z: calcd for C20H28NO4: 346.2032 [M+H]+; found: 346.2034.
Methyl (2S,6S)-diallyl-N-benzyloxycarbonylpipecolinate (22b): The de
value was determined to be >99% by gas chromatography (Shinwa
Chemical Industries, HR-1, 0.25 mmØꢁ25 m) at a constant temperature
of 2008C and a retention time of 29.80 min. Colorless oil; [a]3D2 =9.45 (c=
0.82 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.35–7.29 (m, 5H),
6.01–5.92 (m, 1H), 5.78–5.70 (m, 1H), 5.22–5.00 (m, 6H), 4.16–4.10 (m,
1H), 3.57 (brs, 3H), 2.89 (dd, J=6.4 Hz, 1H), 2.80–2.72 (m, 1H), 2.68–
2.51 (m, 1H), 2.38–2.32 (m, 1H), 2.13–2.05 (m, 1H), 1.86–1.50 ppm (m,
5H); 13C NMR (100 MHz, CDCl3): d=175.03, 155.51, 135.94, 134.88,
128.50, 128.41, 128.08, 127.93, 127.76, 117.69, 116.85, 67.11, 62.65, 52.05,
51.82, 39.68, 29.75, 25.85, 22.59, 15.37, 12.66 ppm; IR (neat): n˜ =2950,
1744, 1701, 1640, 1499, 1456, 1402, 1339, 1314, 1277, 1223, 1001, 916, 769,
698 cmÀ1; HR-FAB: m/z: calcd for C21H28NO4: 358.2032 [M+H]+; found:
358.2033.
Ethyl (5S)-allyl-N-benzyloxycarbonyl-(2S)-methylprolinate (30): The de
value was determined to be 76% by gas chromatography (Shinwa Chem-
ical Industries, HR-1, 0.25 mmØꢁ25 m) at a constant temperature of
2008C and a retention time of 16.17 (minor) and 17.25 min (major). Col-
orless oil; [a]2D8 =8.14 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.35–7.32 (m, 5H), 5.87–5.60 (m, 1H), 5.20–4.92 (m, 4H), 4.22–3.90
(m, 3H), 2.79–2.73 (m, 0.5H), 2.64–2.55 (m, 0.5H), 2.27–2.22 (m, 2H),
2.18–1.93 (m, 1H), 1.85–1.75 (m, 2H), 1.52 (d, J=17.7 Hz, 3H), 1.23,
1.09 ppm (2t, J=7.2, 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
174.41, 174.24 (1C), 153.48, 136.74, 136.37 (1C), 135.40, 135.26 (1C),
128.36, 127.98, 127.88, 127.82, 127.72, 117.09, 66.78, 66.59 (1C), 61.09,
61.05 (1C), 59.32, 58.52 (1C), 37.38, 36.69 (1C), 27.17, 26.15 (1C), 22.27,
20.94 (1C), 18.61, 14.00, 13.85 (1C), 10.91 ppm; IR (neat): n˜ =2979, 1742,
1499, 1406, 1352, 1273, 1179, 1067, 916, 698 cmÀ1; HR-FAB: m/z: calcd
for C19H26NO4: 332.1876 [M+H]+; found: 332.1878.
Methyl
(6S)-allyl-N-benzyloxycarbonyl-(2S)-(2-propynyl)pipecolinate
(22c): The de value was determined to be 81% by gas chromatography
(Shinwa Chemical Industries, HR-1, 0.25 mmØꢁ25 m) at a constant tem-
perature of 2008C and a retention time of 30.00 (major) and 32.67 min
(minor). Colorless oil; [a]3D2 =À5.33 (c=1.00 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.34–7.30 (m, 5H), 5.76–5.71 (m, 1H), 5.13 (s,
2H), 5.07–5.00 (m, 2H), 4.16–4.13 (m, 1H), 3.59 (brs, 3H), 3.05 (s, 2H),
2.59–2.53 (m, 1H), 2.39–2.22 (m, 1H), 2.19–2.12 (m, 2H), 2.03–2.01 (m,
1H), 1.84–1.63 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=174.07,
155.53, 135.83, 128.41, 128.32, 128.03, 127.93, 127.76, 116.95, 80.89, 70.57,
67.29, 62.01, 52.32, 51.78, 39.77, 30.31, 27.04, 25.85, 22.65, 12.97 ppm; IR
(neat): n˜ =2951, 2120, 1742, 1698, 1640, 1456, 1402, 1339, 1312, 1296,
1219, 1159, 1069, 916, 698 cmÀ1; HR-FAB: m/z: calcd for C21H26NO4:
356.1858 [M+H]+; found: 356.1857.
Ethyl (5S)-allyl-N-benzyloxycarbonyl-(2S)-ethylprolinate (31): The de
value was determined to be 68% by gas chromatography (Shinwa Chem-
ical Industries, HR-1, 0.25 mmØꢁ25 m) at a constant temperature of
1708C and a retention time of 63.39 (minor) and 65.42 min (major). Col-
orless oil; [a]2D7 =9.60 (c=0.59 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=7.35–7.31 (m, 5H), 5.80–5.64 (m, 1H), 5.20–5.01 (m, 4H), 4.18–3.91
(m, 3H), 2.83 (brd, J=12 Hz, 0.5H), 2.62 (brd, J=12 Hz, 0.5H), 2.35–
1.98 (m, 6H), 1.78–1.73 (m, 1H), 1.22, 1.10 (2t, J=7.32, 6.84 Hz, 3H),
0.87–0.82 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=175.43, 155.32,
135.62, 135.49, 128.37, 128.01, 127.89, 127.74, 126.45, 117.02, 66.81, 66.62
(1C), 60.96, 60.32 (1C), 59.43, 57.80 (1C), 38.24, 36.89 (1C), 35.30, 33.89
(1C), 28.32, 28.01 (1C), 27.17, 26.88 (1C), 14.03, 13.90 (1C), 8.64, 8.56
(1C), 6.35 ppm; IR (neat): n˜ =3069, 2979, 1748, 1640, 1499, 1456, 1412,
1084, 1030, 916, 700 cmÀ1; HR-FAB: m/z: calcd for C20H28NO4: 346.2025
[M+H]+; found: 346.2026.
Methyl
(6S)-allyl-N-benzyloxycarbonyl-(2S)-(2-butenyl)pipecolinate
(22e): A 3:1 (E/Z) mixture of geometric isomers was determined by gas
chromatography (Shinwa Chemical Industries, HR-1, 0.25 mmØꢁ25 m)
at a constant temperature of 2008C and a retention time of 38.17 (major)
and 41.33 min (minor). Colorless oil; [a]2D8 =À15.08 (c=0.81 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.35–7.30 (m, 5H), 5.82–5.60 (m, 1H),
5.57–5.43 (m, 2H), 5.16–5.00 (m, 4H), 4.14–4.11 (m, 1H), 3.57 (brs, 3H),
2.86–2.71 (m, 2H), 2.58–2.54 (m, 1H), 2.39–2.28 (m, 1H), 2.12–2.01 (m,
1H), 1.87–1.61 ppm (m, 8H); 13C NMR (100 MHz, CDCl3): d=175.22,
155.51, 136.02, 128.38 (2C), 128.27, 128.08, 127.94, 127.19, 126.19, 126.10,
116.81, 116.78 (1C), 67.11, 67.06 (1C), 62.88, 52.05, 52.00 (1C), 51.92,
51.83 (1C), 39.65, 39.51 (1C), 29.77, 22.64, 18.03, 13.22, 12.97 (1C),
12.77 ppm; IR (neat): n˜ =2949, 1744, 1640, 1499, 1456, 1402, 1339, 1312,
1217, 1130, 976, 914, 769, 698 cmÀ1; HR-FAB: m/z: calcd for C22H30NO4:
372.2179 [M+H]+; found: 372.2180.
General procedure for electrochemical deallylation of a’-allyl-N-acyl-a-
alkyl-a-amino acid esters 21, 22a–h, 30, and 31: The substrate (0.5 mmol)
and Et4NBF4 (0.1 mmol) were placed in a beaker-type cell containing a
stirring bar. Methanol (2 mL) and acetonitrile (8 mL) were added and
the mixture was stirred at À108C. The graphite anode and platinum cath-
ode were fitted and 5 FmolÀ1 of electricity was passed through. The reac-
tion mixture was transferred into a flask (25 mL) and the solvent was
evaporated. Water (10 mL) was added and the mixture was then extract-
ed with AcOEt (3ꢁ8 mL). The combined organic layer was dried by
using anhydrous MgSO4 and filtered. The solvent was removed under
vacuo. The resultant oil was purified through silica-gel column chroma-
tography to give the methoxy derivatives 20, 23a–c, 23 f, 32, and 33.
Methyl
(6S)-allyl-N-benzyloxycarbonyl-(2S)-(2-butynyl)pipecolinate
(22 f): The de value was determined to be 99% by gas chromatography
(Shinwa Chemical Industries, HR-1, 0.25 mmØꢁ25 m) at a constant tem-
perature of 2008C and a retention time of 43.17 min. Colorless oil;
[a]2D8 =10.42 (c=5.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.35–
7.34 (m, 5H), 5.80–5.68 (m, 1H), 5.18–5.00 (m, 4H), 4.20–4.13 (m, 1H),
3.57 (brs, 3H), 2.97 (brs, 1H), 2.64–2.11 (m, 3H), 1.86–1.78 (m, 5H),
1.59 (s, 3H), 1.52–1.50 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
175.31, 172.96 (m, 1C), 155.44, 136.56, 136.34 (1C), 135.89, 128.31,
128.30, 127.92, 127.87, 127.66, 116.85, 116.76 (1C), 75.39, 67.22, 67.05
(1C), 62.19, 52.50, 52.11 (1C), 51.95, 51.68 (1C), 39.65, 30.48, 27.28,
25.77, 15.29, 13.05, 3.54 ppm; IR (neat): n˜ =3069, 2951, 2235, 2051, 1640,
1588, 1499, 1003, 916, 804, 777, 700 cmÀ1; HR-FAB: m/z: calcd for
C22H28NO4: 370.2016 [M+H]+; found: 370.2016.
Methyl 6-methoxy-N-benzyloxycarbonyl-(2R)-methylpipecolinate (20):
Colorless oil; 1H NMR (300 MHz, CDCl3): d=7.34–7.33 (m, 5H), 5.42
(brs, 1H), 5.14 (brs, 2H), 3.68 (brs, 3H), 3.41 (brs, 3H), 2.49–2.41 (m,
1H), 2.21–1.96 (m, 1H), 1.80–1.66 (m, 4H), 1.56 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=175.14, 174.06 (1C), 154.16, 135.87, 128.37, 128.35,
128.19, 128.13, 124.17, 81.64, 67.58, 67.33 (1C), 60.52, 60.23 (1C), 52.20,
51.99 (1C), 43.24, 32.11, 25.47, 17.83, 12.12 ppm; IR (neat): n˜ =2151,
1744, 1709, 1657, 1500, 1399, 1339, 1273, 1117, 1092, 909, 700 cmÀ1; HR-
FAB : m/z: calcd for C16H20NO4: 290.1415 [MÀOMe]+; found: 290.1417.
Methyl 6-methoxy-N-benzyloxycarbonyl-(2R)-ethylpipecolinate (23a):
1
Colorless oil; H NMR (300 MHz, CDCl3): d=7.35–7.34 (m, 5H), 5.45 (s,
1H), 5.19–5.08 (m, 2H), 3.55 (brs, 3H), 3.38 (s, 3H), 2.42–2.35 (m, 2H),
2.01–1.68 (m, 6H), 1.06 ppm (t, J=7.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=175.01, 156.20, 136.05, 128.45 (2C), 128.37 (2C), 128.19,
82.05, 67.42, 63.15, 55.08, 51.80, 28.01, 26.92, 26.10, 12.77, 10.43 ppm; IR
Methyl (6S)-allyl-N-methoxycarbonyl-(2R)-methylpipecolinate (22h):
The de value was determined to be 98% by gas chromatography (Shinwa
Chem. Eur. J. 2010, 16, 3970 – 3982
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3979

O. Onomura et al.
(neat): n˜ =3065, 2838, 1588, 1499, 806, 702 cmÀ1; HR-FAB: m/z: calcd for
C17H22NO4: 304.1645 [MÀOMe]+; found: 304.1647.
Methyl N-benzyloxycarbonyl-(2R)-methylpipecolinate (19): Compound
19 was prepared from methyl 6-methoxy-N-benzyloxycarbonyl-(2R)-
methylpipecolinate (20) according to the general procedure and purified
by silica-gel column chromatography (hexane/ethyl acetate 15:1). HPLC
analysis of 19 was carried out by using Daicel Chiralcel OJ (0.46 cmØꢁ
Methyl 6-methoxy-N-benzyloxycarbonyl-(2S)-allylpipecolinate (23b):
Colorless oil; 1H NMR (300 MHz, CDCl3): d=7.35–7.34 (m, 5H), 6.10–
6.00 (m, 1H), 5.45 (s, 1H), 5.17–5.02 (m, 4H), 3.56 (brs, 3H), 3.84 (s,
3H), 3.10–3.04 (m, 1H), 2.54–2.38 (m, 2H), 2.04–1.68 ppm (5H);
13C NMR (100 MHz, CDCl3): d=174.66, 155.48, 135.85, 135.25, 128.37
(2C), 128.31, 128.15, 128.00, 117.34, 81.96, 67.39, 62.52, 54.96, 51.87,
39.90, 27.82, 25.83, 11.88 ppm; IR (neat): n˜ =3066, 2950, 1576, 1499, 1402,
25 cm): n-hexane/isopropanol 10:1, l=254 nm, flow rate=0.5 mLminÀ1
retention time=17.7 (R), 21.6 min (S), >99% ee; colorless oil; [a]D30
,
=
À16.00 (c=2.50 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.34–7.32
(m, 5H), 5.13 (d, J=12.0 Hz, 1H), 5.07 (d, J=12.0 Hz, 1H), 3.94–3.88
(m, 1H), 3.65 (brs, 3H), 3.11–3.04 (m, 1H), 1.93–1.86 (m, 1H), 1.77–1.57
(m, 5H), 1.49 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=175.09,
156.20, 136.35, 128.37 (3C), 127.96 (2C), 67.21, 60.65, 52.04, 41.29, 34.84
(2C), 23.59, 18.31 ppm; IR (neat): n˜ =2951, 2869, 1962, 1750, 1609, 1588,
1499, 1456, 1406, 1350, 1291, 1200, 1144, 1038, 1003, 889, 855, 826, 777,
916, 769, 698 cmÀ1
; HR-FAB: m/z: calcd for C18H22NO4: 316.1550
[MÀOMe]+; found: 316.1550.
Methyl
6-methoxy-N-benzyloxycarbonyl-(2S)-(3-propynyl)pipecolinate
(23c): Colorless oil; 1H NMR (400 MHz, CDCl3): d=7.26–7.19 (m, 5H),
5.45 (brs, 1H), 5.12–5.03 (m, 2H), 3.62 (brd, J=13.2 Hz, 3H), 3.31 (s,
3H), 3.05 (brs, 1H), 2.81 (brs, 1H), 2.43–2.37 (m, 1H), 1.97–1.64 ppm
(6H); 13C NMR (100 MHz, CDCl3): d=173.87, 156.10, 135.20, 128.50
(3C), 128.30 (2C), 82.11, 70.58, 67.69, 64.50, 63.10, 55.13, 52.26, 37.50,
28.63, 25.99, 12.38 ppm; IR (neat): n˜ =3287, 1499, 1402, 1339, 1310, 1296,
1215, 1132, 1080, 918, 700 cmÀ1; HR-FAB: m/z: calcd for C18H20NO4:
314.1410 [MÀOMe]+; found: 314.1411.
737, 700, 608 cmÀ1
; HR-FAB: m/z: calcd for C16H22NO4: 292.1568
[M+H]+; found: 292.1570.
Methyl N-benzyloxycarbonyl-(2R)-ethylpipecolinate (24a): Compound
24a was prepared from methyl 6-methoxy-N-benzyloxycarbonyl-(2R)-
ethylpipecolinate (23a) according to the general procedure and purified
by silica-gel column chromatography (hexane/ethyl acetate 15:1). HPLC
analysis of 24a was carried out by using Daicel Chiralcel OJ (0.46 cmØꢁ
25 cm): n-hexane/isopropanol 10:1, l=254 nm, flow rate=0.5 mLminÀ1
retention time=13.4 (R), 16.1 min (S), >99% ee; colorless oil; [a]D32
,
=
Methyl 6-methoxy-N-methoxycarbonyl-(2R)-methylpipecolinate (23h):
Colorless oil; 1H NMR (300 MHz, CDCl3): d=5.45–5.39 (m, 1H), 3.72–
3.70 (m, 6H), 3.32–3.27 (m, 3H), 2.49–2.41 (m, 0.5H), 2.39–2.30 (m,
0.5H), 1.93–1.78 (m, 5H), 1.60, 1.56 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=175.14, 174.86 (1C), 156.38, 82.89, 82.27 (1C), 60.35, 60.07
(1C), 54.92, 54.59 (1C), 52.39, 52.29 (1C), 51.96, 51.69 (1C), 33.79, 30.31,
30.15 (1C), 25.37, 13.54, 12.04 ppm (1C); IR (neat): n˜ =2836, 1869, 1686,
1541, 1456, 1051, 1015, 939, 810, 779, 654 cmÀ1; HR-FAB: m/z: calcd for
C10H16NO4: 214.1094 [MÀOMe]+; found: 214.1095.
Ethyl 5-methoxy-N-benzyloxycarbonyl-(2S)-methylprolinate (32): Color-
less oil; 1H NMR (300 MHz, CDCl3): d=7.36–7.31 (m, 5H), 5.36–5.06
(m, 3H), 4.23–3.95 (m, 2H), 3.44 (d, J=4.2 Hz, 1.5H), 3.29 (d, J=9.9 Hz,
1.5H), 2.47–2.36 (m, 1H), 1.95–1.86 (m, 3H), 1.65–1.51 (m, 3H), 1.28–
1.07 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=174.13, 154.78,
136.10, 128.43, 128.36, 128.10, 128.06, 127.99, 89.67, 88.96 (1C), 67.24,
67.18 (1C), 61.21, 61.01 (1C), 56.01, 55.41 (1C), 37.26, 35.87 (1C), 30.21,
30.06 (1C), 28.14, 27.04 (1C), 22.14, 20.79 (1C), 13.97, 13.89 ppm (1C);
IR (neat): n˜ =3651, 2975, 1742, 1539, 1499, 1458, 1353, 1134, 1065,
698 cmÀ1; HR-FAB: m/z: calcd for C16H20NO4: 290.1398 [MÀOMe]+;
found: 290.1398.
À5.42 (c=0.50 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.34 (s, 5H),
5.13 (d, J=12.7 Hz, 1H), 5.07 (d, J=12.7 Hz, 1H), 3.94–3.88 (m, 1H),
3.61 (brs, 3H), 3.18–3.10 (m, 1H), 2.19–2.11 (m, 1H), 1.97–1.52 (m, 7H),
0.91 ppm (t, J=7.32 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=174.67,
156.26, 128.37 (4C), 127.95 (2C), 67.17, 63.71, 51.87, 41.63 (2C), 31.32
(2C), 18.09, 8.56 ppm; IR (neat): n˜ =2950, 2878, 1779, 1701, 1499, 1456,
1341, 1267, 1194, 1167, 824, 735, 698 cmÀ1; HR-FAB: m/z: calcd for
C17H24NO4: 306.1719 [M+H]+; found: 306.1721.
Methyl N-benzyloxycarbonyl-(2S)-allylpipecolinate (24b): Compound
24b was prepared from methyl 6-methoxy-N-benzyloxycarbonyl-(2S)-al-
lylpipecolinate (23b) according to the general procedure and purified by
silica-gel column chromatography (hexane/ethyl acetate 15:1). HPLC
analysis of 24b was carried out by using Daicel Chiralcel OJ (0.46 cmØꢁ
25 cm): n-hexane/isopropanol 10:1, l=254 nm, flow rate=0.5 mLminÀ1
retention time=12.7 (R), 14.1 min (S), >99% ee; colorless oil; [a]D32
,
=
À56.81 (c=1.67 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.26 (brs,
5H), 5.84–5.79 (m, 1H), 5.03 (d, J=35 Hz, 2H), 5.00 (d, J=34 Hz, 2H),
3.84 (brs, 1H), 3.55 (brs, 3H), 3.08–3.01 (m, 1H), 2.81–2.76 (m, 1H),
2.59–2.52 (m, 1H), 1.82–1.50 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=174.30, 156.12, 136.42, 133.94, 128.36 (3C), 127.95 (2C), 118.25, 67.17,
62.99, 51.96, 41.41, 31.77 (2C), 28.87, 17.72 ppm; IR (neat): n˜ =2950,
2870, 1744, 1709, 1638, 1499, 1453, 1404, 1347, 1266, 1192, 1163, 1136,
1005, 918, 824, 781, 733, 698 cmÀ1; HR-FAB: m/z: calcd for C18H24NO4:
318.1709 [M+H]+; found: 318.1709.
Ethyl 5-methoxy-N-benzyloxycarbonyl-(2S)-ethylprolinate (33): Colorless
oil; 1H NMR (300 MHz, CDCl3): d=7.35–7.32 (m, 5H), 5.48–5.08 (m,
3H), 4.20–3.67 (m, 2H), 3.46, 3.40 (s, 1.5H), 3.31, 3.27 (s, 1.5H), 2.46–
1.72 (m, 6H), 1.26–1.06 (m, 3H), 0.92–0.78 ppm (m, 3H); 13C NMR
(100 MHz, CDCl3): d=174.27, 173.92 (1C), 155.00, 153.56 (1C), 136.24,
135.98 (1C), 129.62, 129.28 (1C), 128.29, 128.22 (1C), 128.00, 127.91
(1C), 127.89, 127.77 (1C), 127.42, 126.68 (1C), 90.56, 89.82 (1C), 69.10,
68.45 (1C), 67.04, 66.80 (1C), 60.94, 56.03, 55.35 (1C), 35.12, 33.54 (1C),
31.43, 30.93 (1C), 28.48, 26.96 (1C), 13.91, 13.81 (1C), 8.27 ppm; IR
(neat): n˜ =3649, 2980, 2361, 1732, 1541, 1499, 1456, 1401, 1354, 1204,
1165, 1075, 955, 698 cmÀ1; HR-FAB: m/z: calcd for C17H22NO4: 304.1591
[MÀOMe]+; found: 304.1591.
General procedure for a’-methoxy-group cleavage of a’-methoxy-N-acyl-
a-alkyl-amino acid esters 20, 23a–g, 32, and 33: Triethylsilane
(0.375 mmol) was added to a stirred solution of the substrate (0.25 mmol)
in CH2Cl2 (5 mL) under nitrogen at À788C. The temperature was elevat-
ed to 08C over 30 min. Methane sulfonic acid (0.30 mmol) was then
added dropwise and the mixture was stirred at room temperature for a
further 8 min. Water (10 mL) was added and the solution was extracted
by using CHCl3 (3ꢁ10 mL). The organic layer was dried by using anhy-
drous magnesium sulfate and filtered. The filtrate was concentrated in
vacuo and the concentrate was purified by using silica-gel column chro-
matography to give N-acyl-a-alkyl-amino acid esters 19, 24a–c, 24h, 34,
and 35.
Methyl N-benzyloxycarbonyl-(2S)-(2-propynl)pipecolinate (24c): Com-
pound 24c was prepared from methyl 6-methoxy-N-benzyloxycarbonyl-
(2S)-(3-propynyl)pipecolinate (23c) according to the general procedure
and purified by silica-gel column chromatography (hexane/ethyl acetate
15:1). HPLC analysis of 24c was carried out by using Daicel Chiralpak
AD (0.46 cmØꢁ25 cm): n-hexane/isopropanol 20:1, l=254 nm, flow
rate=0.5 mLminÀ1, retention time=25.9 (S), 28.4 min (R), 75% ee; col-
orless oil; [a]3D2 =À50.05 (c=1.25 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=7.37–7.32 (m, 5H), 5.15 (d, J=9.2 Hz, 1H), 5.10 (d, J=
9.2 Hz, 1H), 3.92 (brs, 1H), 3.69 (brs, 3H), 3.38–3.31 (m, 1H), 2.81 (d,
J=17.08 Hz, 1H), 2.33–2.28 (m, 1H), 1.99–1.98 (m, 1H), 1.81–1.64 ppm
(m, 6H); 13C NMR (100 MHz, CDCl3): d=173.47, 155.89, 128.41 (3C),
127.98 (2C), 127.77, 80.01, 70.63, 67.27, 62.21, 52.22, 41.44, 31.37 (2C),
22.10, 17.13 ppm; IR (neat): n˜ =3289, 2951, 2874, 2120, 1744, 1499, 1456,
1412, 1345, 1264, 1194, 1161, 1129, 1063, 980, 777, 700, 652 cmÀ1; HR-
FAB : m/z: calcd for C18H22NO4: 316.1555 [M+H]+; found: 316.1556.
Methyl (2R)-methylpipecolinate (25): Me3SiI (2.0 mmol) was added to
24h (0.5 mmol) in dichloromethane (5 mL), and the solution refluxed at
608C for 3 h. NaOH (1n, 5 mL) was added to achieve a pH value of 10,
then saturated Na2S2O3 (4 mL) was added and the mixture was extracted
in chloroform (3ꢁ10 mL). The organic layer was dried by using anhy-
Compound 24h[29] is known and the spectroscopic data is available in the
literature.
3980
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3970 – 3982

a-Allyl Cyclic Amines and Quaternary Cyclic Amino Acids
FULL PAPER
drous magnesium sulfate and filtered. The filtrate was concentrated in
vacuo to yield compound 25 (1.14 mmol).
Weintraub, J. S. Sabol, J. M. Kane, D. R. Borcherding, Tetrahedron
2003, 59, 2953–2989.
[3] Representative reviews: a) W. N. Speckamp, M. J. Moolenaar, Tetra-
hedron 2000, 56, 3817–3856; b) A. Yazici, S. G. Pyne, Synthesis
2009, 339–368; c) A. Yazici, S. G. Pyne, Synthesis 2009, 513–541;
representative literatures: T. Shono, Y. Matsumura, K. Tsubata, J.
Am. Chem. Soc. 1981, 103, 1172–1176; d) T. Shono, Y. Matsumura,
T. Kanazawa, Tetrahedron Lett. 1983, 24, 4577–4580; e) T. Shono, Y.
Matsumura, K. Uchida, T. Tagami, Chem. Lett. 1987, 912–922; f) Y.
Matsumura, J. Terauchi, T. Yamamoto, T. Konno, T. Shono, Tetrahe-
dron 1993, 49, 8503–8512; g) N. Yamazaki, T. Eto, C. Kibayashi,
Synlett 1999, 37–40.
[4] a) Y. Matsumura, Y. Kanda, K. Shirai, O. Onomura, T. Maki, Org.
Lett. 1999, 1, 175–178; b) Y. Matsumura, Y. Kanda, K. Shirai, O.
Onomura, T. Maki, Tetrahedron 2000, 56, 7411–7422.
[5] M. Sugiura, S. Kobayashi, Org. Lett. 2001, 3, 477–480.
[6] K. Koumaglo, T. H. Chan, Tetrahedron Lett. 1984, 25, 717–720.
[7] J. Yoshida, S. Suga, Chem. Eur. J. 2002, 8, 2650–2658.
By starting from 19 (0.5 mmol) in methanol (5 mL), deprotection was
achieved by using Pd/C (5%) and hydrogen (1 atm.) for 6 h. The solution
was filtered under pressure by using Celite (Celite 545RVS, Nacalai
tesque), and the filtrate concentrated to yield compound 25 (1.64 mmol).
The ee value was determined to be >99% by gas chromatography (TCI
Chemical Industries, Chiraldex B-DA, 0.25 mm (i.d)ꢁ30 mꢁ0.25 mm) at
a constant temperature of 1208C and a retention time of 10.33 min (R).
Colorless oil; [a]2D1 =À41.86 (c=1.0 in CHCl3); lit.:[14] (S)-25; 95% ee;
[a]2D0 =+8.0 (c=5.0 in CHCl3).
Ethyl N-benzyloxycarbonyl-(2S)-methylprolinate (34): Compound 34 was
prepared from ethyl 5-methoxy-N-benzyloxycarbonyl-(2S)-methylproli-
nate (32) according to the general procedure and purified by silica-gel
column chromatography (hexane/ethyl acetate 15:1). HPLC analysis of
34 was carried out by using Daicel Chiralpak AD (0.46 cmØꢁ25 cm): n-
hexane/isopropanol 30:1, l=254 nm, flow rate=0.5 mLminÀ1, retention
time=24.4 (R), 27.8 min (S), 72% ee; colorless oil; [a]2D4 =À11.76 (c=1.0
À
[8] Lead(IV) acetate mediated oxidative C C bond cleavage of N-acyl-
1
in CHCl3); H NMR (300 MHz, CDCl3): d=7.35–7.32 (m, 5H), 5.20–5.05
a-amino acid 1 proceeded, albeit with low yields and a longer reac-
tion time, see: Y. Matsumura, G. N. Wanyoike, O. Onomura, T.
Maki, Electrochim. Acta 2003, 48, 2957–2966.
(m, 2H), 4.17 (q, J=7.2 Hz, 1H), 4.00–3.87 (m, 1H), 3.69–3.56 (m, 2H),
2.21–2.15 (m, 1H), 1.99–1.85 (m, 3H), 1.61, 1.54 (s, 3H), 1.21, 1.08 ppm
(2t, J=7.2, 7.2H, 3H); 13C NMR (125 MHz, CDCl3): d=174.33, 174.14
(1C), 154.21, 154.12 (1C), 136.92, 136.36 (1C), 128.31, 127.93, 127.84,
127.74, 127.61, 66.86, 66.43 (1C), 65.62, 64.89 (1C), 61.03, 60.99 (1C),
48.46, 47.68 (1C), 40.40, 36.13 (1C), 23.21, 23.08 (1C), 22.68, 22.01 (1C),
14.01, 13.90 ppm (1C); IR (neat): n˜ =3065, 2982, 2878, 1748, 1609, 1588,
1541, 1499, 1420, 1362, 1184, 1140, 1073, 914, 864, 770, 700 cmÀ1; HR-
FAB : m/z: calcd for C16H22NO4: 292.1545 [M+H]+; found: 292.1544.
[9] I. Barba, M. Tornero, Tetrahedron 1992, 48, 9967–9977.
[10] a) B. W. Metcalf, P. Bey, C. Danzin, M. J. Jung, P. Casara, J. P.
Vevert, J. Am. Chem. Soc. 1978, 100, 2551–2553; b) M. J. Jung,
Chemistry and Biochemistry of the Amino Acids (Ed.: B. G. C. Bar-
rett), Chapman and Hall, London, 1985, pp. 227–245.
[11] Recent representative reviews: a) C. Cativiela, M. D. Dꢃaz-de-Ville-
gas, Tetrahedron: Asymmetry 2007, 18, 569–623; b) M. I. Calaza, C.
Cativiela, Eur. J. Org. Chem. 2008, 3427–3448; c) C. Cativiela, M.
Ordonez, Tetrahedron: Asymmetry 2009, 20, 1–63; recent represen-
tative literature: d) T. Kawabata, K. Moriyama, S. Kawakami, K.
Tsubaki, J. Am. Chem. Soc. 2008, 130, 4153–4157; e) S. Cabrera, E.
Reyes, J. Aleman, A. Milelli, S. Kobbelgaard, K. A. Jørgensen, J.
Am. Chem. Soc. 2008, 130, 12031–12037; f) M. Kitamura, S. Shira-
kawa, Y. Arimura, X. Wang, K. Maruoka, Chem. Asian J. 2008, 3,
1702–1714; g) M. Terada, H. Tanaka, K. Sorimachi, J. Am. Chem.
Soc. 2009, 131, 3430–3431; h) F. R. Bou-Hamdan, J. L. Leighton,
Angew. Chem. 2009, 121, 2439–2442; Angew. Chem. Int. Ed. 2009,
48, 2403–2406; i) M. Branca, S. Pena, R. Guillot, D. Gori, V. Alezra,
C. Kouklovsky, J. Am. Chem. Soc. 2009, 131, 10711–10718; j) V.
Lupi, M. Penso, F. Foschi, F. Gassa, V. Mihali, A. Tagliabue, Chem.
Commun. 2009, 5012–5014; k) P. Tuzina, P. Somfai, Org. Lett. 2009,
11, 919–921.
[12] a) T. Shono, Y. Matsumura, K. Tsubata, K. Uchida, J. Org. Chem.
1986, 51, 2590–2592; b) Y. Demizu, H. Shiigi, H. Mori, K. Matsumo-
to, O. Onomura, Tetrahedron: Asymmetry 2008, 19, 2659–2665.
[13] Recently, Kawabata and co-workers prepared quaternary cyclic
amino acid derivatives by starting from acyclic N-w-bromoalkyl-N-
tert-butoxycarbonyl-a-amino acid derivatives in up to 99% ee, see:
reference [11d].
Ethyl N-benzyloxycarbonyl-(2S)-ethylprolinate (35): Compound 35 was
prepared from ethyl 5-methoxy-N-benzyloxycarbonyl-(2S)-ethylprolinate
(33) according to the general procedure and purified by silica-gel column
chromatography (hexane/ethyl acetate 15:1). HPLC analysis of 35 was
carried out by using Daicel Chiralpak AD (0.46 cmØꢁ25 cm): n-hexane/
isopropanol 10:1, l=254 nm, flow rate=0.5 mLminÀ1, retention time=
24.3 (R), 28.3 min (S), 64% ee; colorless oil, [a]2D4 =À16.41 (c=1.25 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.54–7.45 (m, 5H), 5.39–5.21
(m, 2H), 4.39–4.32 (q, J=7.2 Hz, 1H), 4.24–3.90 (m, 2H), 3.73–3.64 (m,
1H), 2.58, 2.38 (2sexlet, 7.2, 7.2 Hz, 1H), 2.30–2.00 (m, 5H), 1.40, 1.29
(2t, J=7.2, 7.2 Hz, 3H), 1.05, 1.03 ppm (2t, J=7.5, 7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=174.66, 174.44 (1C), 154.56, 154.26
(1C), 137.00, 136.38 (1C), 128.32, 127.95, 127.86, 127.73, 127.52, 68.90,
68.05 (1C), 66.92, 66.44 (1C), 60.93, 60.89 (1C), 49.31, 48.50 (1C), 36.87,
35.36 (1C), 27.42, 26.27 (1C), 23.13, 22.69 (1C), 14.03, 13.95 (1C), 7.84,
7.68 ppm; IR (neat): n˜ =3034, 2979, 2880, 1740, 1713, 1499, 1456, 1406,
1356, 1273, 1173, 1075, 1028, 698 cmÀ1
; HR-FAB: m/z: calcd for
C17H24NO4: 306.1701 [M+H]+; found: 306.1700.
Acknowledgements
[14] J. Bajgrowicz, A. El Achquar, M. Roumestant, C. Pigiere, P. Vialle-
font, Heterocycles 1986, 24, 2165–2167.
This work was supported by the presidentꢂs discretion fund of Nagasaki
University.
[15] J. Muzart, Tetrahedron 2009, 65, 8313–8323.
[16] TiCl4-mediated a’-allylation of methyl a’-methoxy-N-methoxycar-
bonyl-l-prolinate with allyl-TMS proceeded with moderate diaste-
reoselectivity (46% de): O. Onomura, P. G. Kirira, T. Tanaka, S. Tsu-
kada, Y. Matsumura, Y. Demizu, Tetrahedron 2008, 64, 7498–7503.
[17] Prepared in 34% yield according to A. D. Dilman, D. E. Arkhipov,
A. A. Korlyukov, V. P. Ananikov, V. M. Danilenko, V. A. Tartakov-
sky, J. Organomet. Chem. 2005, 690, 3680–3689.
[18] a) To determine absolute configuration, 34 (0.25 mmol) in methanol
(5 mL) was deprotected by using Pd/C (5%) and hydrogen (1 atm.)
for 6 h. The solution was filtered under pressure by using Celite
(Celite 545RVS, Nacalai tesque), and the filtrate concentrated under
reduced pressure to yield ethyl l-methylprolinate[18b] (0.20 mmol) as
a colorless oil. [a]1D8 =À20.66 (c=0.1 in EtOH) (ref. [18b]: ethyl l-
methylprolinate: [a]2D0 =À30.0 (c=1.0 in EtOH)]; b) Sandoz Ltd,
Netherland Patent No. 6609202, 1967; [Chem. Abstr. 1967, 82297];
[1] a) T. Iwasaki, H. Horikawa, K. Matsumoto, M. Miyoshi, J. Org.
Chem. 1979, 44, 1552–1554; b) T. Shono, Y. Matsumura, O. Ono-
mura, M. Sato, J. Org. Chem. 1988, 53, 4118–4121; c) A. Zietlow, E.
Steckhan, J. Org. Chem. 1994, 59, 5658–5661; d) Y. Matsumura, Y.
Shirakawa, Y. Satoh, M. Umino, T. Tanaka, T. Maki, O. Onomura,
Org. Lett. 2000, 2, 1689–1691; e) G. Ng’ang’a Wanyoike, O. Ono-
mura, T. Maki, Y. Matsumura, Org. Lett. 2002, 4, 1875–1877;
f) G. N. Wanyoike, Y. Matsumura, O. Onomura, Heterocycles 2009,
79, 339–345.
[2] a) O. Loures, M. Gertjan, P. J. T. Floris, W. N. Speckamp, H. Hiem-
stra, Org. Lett. 1999, 1, 1331–1334; representative reviews: b) M. D.
Groaning, A. I. Meyers, Tetrahedron 2000, 56, 9843–9873; c) P. M.
Chem. Eur. J. 2010, 16, 3970 – 3982
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3981

O. Onomura et al.
c) the absolute configuration of 35 was deduced on the basis of re-
tention of configuration as observed in compound 34.
[21] J. Yoshida, S. Suga, S. Suzuki, N. Kinomura, A. Yamamoto, K. Fuji-
wara, J. Am. Chem. Soc. 1999, 121, 9546–9549.
[19] For some selected literature on 1,3-asymmetric induction, see:
a) Y. F. Wang, T. Izawa, S. Kobayashi, M. Ohno, J. Am. Chem. Soc.
1982, 104, 6465–6466; b) M. T. Reetz, A. Jung, J. Am. Chem. Soc.
1983, 105, 4833–4835; c) G. A. Molander, J. B. Etter, L. S. Harring,
P. J. Thorel, J. Am. Chem. Soc. 1991, 113, 8036–8045; d) D. A.
Evans, M. J. Dart, J. L. Duffy, M. G. Yang, J. Am. Chem. Soc. 1996,
118, 4322–4343; e) B. Bret, Eur. J. Org. Chem. 1998, 1123–1134;
f) R. Lazzaroni, S. Rocchiccioli, A. Luliano, L. Cipolla, F. Nicotra,
Tetrahedron: Asymmetry 2005, 16, 3661–3666.
[20] Compounds 4a–j were prepared by electrochemical oxidation from
their respective N-acyl cyclic amines; for 4a,b: a) T. Shono, H. Ha-
maguchi, Y. Matsumura, J. Am. Chem. Soc. 1975, 97, 4264–4268; for
4c: reference [4]; for 4d: see the Experimental Section; b) for 4e–g:
T. Shono, Y. Matsumura, T. Kanazawa, M. Habuka, K. Uchida, K.
Toyoda, J. Chem. Res. 1984, 2873–2889; for 4h: see the Experimen-
tal Section; for 4i: c) T. Shono, Y. Matsumura, T. Kanazawa, Tetra-
hedron Lett. 1983, 24, 1259–1262; for 4j: d) T. Nishitani, H. Horila-
wa, T. Iwasaki, K. Matsumoto, I. Inoue, M. Miyoshi, J. Org. Chem.
1982, 47, 1706–1712; for 4k: e) T. Nagasaka, H. Tamano, F. Hama-
guchi, Heterocycles 1986, 24, 1231–1232.
[22] T. Shono, Y. Matsumura, O. Onomura, M. Ogaki, T. Kanazawa, J.
Org. Chem. 1987, 52, 536–541.
[23] S. Young-Ger, K. Seok-Ho, J. Jae-Kyung, S. Dong-Yun, Tetrahedron
Lett. 2002, 43, 3165–3168.
[24] M.-J. Tranchant, C. Moine, R. B. Othman, T. Bousquet, M. Othman,
V. Dalla, Tetrahedron Lett. 2006, 47, 4477–4480.
[25] S. S. Libendi, Y. Demizu, Y. Matsumura, O. Onomura, Tetrahedron
2008, 64, 3935–3942.
[26] A. Boto, D. Hernandez, R. Hernandez, A. Montoya, E. Suarez, Eur.
J. Org. Chem. 2007, 325–334.
[27] T. Shono, J. Terauchi, K. Kitayama, Y. Takeshima, Y. Matsumura,
Tetrahedron 1992, 48, 8253–8262.
[28] D. Minato, Y. Nagasue, Y. Demizu, O. Onomura, Angew. Chem.
2008, 120, 9600–9603; Angew. Chem. Int. Ed. 2008, 47, 9458–9461.
[29] Y. Matsumura, T. Kinoshita, Y. Yanagihara, N. Kanemoto, M. Wata-
nabe, Tetrahedron Lett. 1996, 37, 8395–8398.
Received: December 22, 2009
Published online: February 19, 2010
3982
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3970 – 3982