A new chiral synthesis of a bicyclic enedione containing a seven-membered ring mediated by a combination of chiral amine and Bronsted acid

Article abstract of DOI:10.3987/COM-08-S(N)81

Several chiral amines bearing a heterocyclic moiety such as pyrrolidine, piperazine or tetrazole were prepared from l-phenylalanine. The enantioselectivity of the intramolecular asymmetric aldol reaction mediated by a combination of the synthetic chiral a

Full text of DOI:10.3987/COM-08-S(N)81

HETEROCYCLES, Vol. 76, No. 2, 2008
1191
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1191 - 1204. © The Japan Institute of Heterocyclic Chemistry
Received, 31st March, 2008, Accepted, 28th May, 2008, Published online, 2nd June, 2008. COM-08-S(N)81
A
NEW CHIRAL SYNTHESIS OF
A
BICYCLIC ENEDIONE
CONTAINING A SEVEN-MEMBERED RING MEDIATED BY A
COMBINATION OF CHIRAL AMINE AND BRØNSTED ACID
Takashi Nagamine, Kohei Inomata,* and Yasuyuki Endo*
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai
981-8558, Japan, E-mail: inomata@tohoku-pharm.ac.jp
This paper is dedicated to Professor Ryoji Noyori on the occasion of his 70th
birthday.
Abstract – Several chiral amines bearing a heterocyclic moiety such as
pyrrolidine, piperazine or tetrazole were prepared from L-phenylalanine. The
enantioselectivity of the intramolecular asymmetric aldol reaction mediated by
a combination of the synthetic chiral amine and a Brønsted acid to construct an
enedione containing a seven-membered ring was examined in detail. A
remarkable increase of enantioselectivity depending on the amount of Brønsted
acid was observed.
Wieland-Miescher ketone (1a) and its homologues (1b) and (2), which include carbobicyclic enediones,
have been highly useful synthons in the total synthesis of a variety of natural products (Figure 1).1-4 These
useful enediones have been easily prepared from corresponding triones (4) by amino acid-mediated
asymmetric intramolecular aldol reactions.5-7 This asymmetric aldol reaction was first reported by Hajos
et al and has been widely recognized to involve an enamine-based mechanism.8, 9 In a variety of amino
acids, the aldol reaction of 4a and 4c was mediated by L-proline (L-Pro, 5) to afford 1a and 2a in high
yield and high ee, respectively.5 The reaction of 4a and 4c mediated by L-phenylalanine (L-Phe, 6) has
also been reported and shown to be accompanied by a lower ee.5c Uda and Hagiwara successfully
extended the reaction of 4d using L-Phe (6) in the presence of a Brønsted acid such as camphorsulfonic
acid (CSA) to construct a Wieland-Miescher ketone homologue (1b) bearing a methyl substituent at
C-1.7e Although the reactions of 4b and 4d to prepare enediones (1b, 2b) have been successfully mediated
by a variety of primary amino acids such as L-Phe, L-valine and L-alanine,5c,7d the attempt using L-Pro
containing a secondary amine moiety has hardly been successful. Those reactions of trione 4 mediated by
L-amino acid afforded the products 1 or 2 whose absolute configurations at the quaternary carbon were

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HETEROCYCLES, Vol. 76, No. 2, 2008
invariably S (Scheme 1).5, 10 However, there has been little development of this reaction for the purpose of
constructing new ring systems such as enedione (3) encompassing a 7-membered carbocycle.11-14 Since
many pharmaceutically important natural products containing a 7-membered carbocycle have been
isolated,15 enedione (3) has been attractive as a potential chiral synthon to achieve total synthesis of these
products.
O
O
O
*
*
*
O
O
O
R
R
R
1a
2a
: R = H
2b: R = Me
: R = H
1b: R = Me
3a: R = H
3b
: R = Me
Figure 1
NH2
CO2H
O
O
O
O
CO2H
N
6
H+
H
5
*
*
*
For R = H
For R = Me
R
n
n
n
O
O
O
4a: n = 0, R = H
4b
: n = 1, R = H
4d: n = 1, R = Me
: n = 0, R = Me
1a
(S)- : n = 1
1b
(S)- : n = 1
2b
(S)- : n = 0
4c
2a
(S)- : n = 0
Scheme 1
Recently, we reported the L-Methionine (L-Met, 8)- or L-Phe-mediated asymmetric intramolecular aldol
reaction of trione (7) in the presence of CSA or trifluoroacetic acid (TFA) as a Brønsted acid to prepare a
new bicyclic enedione [(R)-3b] containing a 7-membered ring.14 Strikingly, the process was characterized
by an inversion of enantioselectivity when compared with the similar reaction using the trione (4d).
However, the ee value of the reaction to afford (R)-3b was only moderate (Scheme 2). In addition to the
moderate ee value, a catalytic process of the reaction was not successful due to the easy decarboxylation
of L-Met during the reaction to afford an achiral primary amine (9).16 This result means that an amino
acid is not always a suitable mediator for this type of reaction. In connection with an ongoing synthetic
project, we need to improve this method.
On the other hand, in the area of organocatalysis,17 chiral amines, especially based on an L-Pro structure,
have been employed as new catalysts to achieve highly efficient asymmetric reactions, including intra-
19
and intermolecular aldol reactions.18,
Amine-Brønsted acid catalysis has also been utilized in
asymmetric cycloaddition20 and 1,4-addition reactions21, 22 to construct new chiral centers. In those
studies, the authors reported that an ammonium moiety produced from amine and Brønsted acid plays a
key role in stabilizing the transition state as a result of hydrogen bonding between the catalyst and the

HETEROCYCLES, Vol. 76, No. 2, 2008
1193
substrate. This means that an ammonium counterpart in the chiral amine catalysts becomes a powerful
hydrogen bonding donor working like a carboxylic acid in an amino acid catalyst to stabilize a transition
state in important asymmetric reactions. However, to our knowledge, there have been few attempts to use
amine catalysts in the intramolecular aldol reaction to construct Wieland-Miescher ketone and its
homologues,23 so our goal was to use some known or new chiral amines (10) based on a structure of
L-Phe to synthesize 3b more efficiently. Specifically, we attempted to use chiral amines such as 1120a, 24
and 12,25 which were easily prepared from L-Phe, containing pyrrolidine, piperazine and tetrazole
heterocycles for the aldol reaction of 7 in the presence of a Brønsted acid (Figure 2). We report here the
new reaction conditions mediated by a combination of Brønsted acid and several amines 11 and 12 to
afford (R)-3b with higher ee than those reported previously.
O
O
O
6 or 8
NH2
TFA or CSA
DMSO, 90oC
+
MeS
O
O
7
(R)-3b
9 (for using
L
-Met 8)
(91-95% yield, up tp 61% ee)
NH2
MeS
CO2H
8
Scheme 2
NH2
N
H
10
hydrogen bond donor
Me
NH2
NH2
N
NH2
N
N
N
N
HN
N
11b
12
11a
Figure 2
In a similar synthesis reported by Seto,26b chiral amines (11) were prepared from N-tert-butyloxy-L-Phe
(N-Boc-L-Phe, 13). Thus, 13 was converted to corresponding amide (14)26 by the use of a standard
coupling reaction with pyrrolidine or 1-methylpiperazine in the presence of 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide (EDC) in high yield, respectively. After deprotection of the
Boc-moiety in an acidic condition, the resulting amide (15) was reduced by lithium aluminium hydride
(LAH) to afford a known diamine (11a) and a new one (11b), respectively (Scheme 3).

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HETEROCYCLES, Vol. 76, No. 2, 2008
Preparation of 12 bearing tetrazole was achieved in a similar way with the synthesis of
(S)-5-pyrrolidine-2-yl-1H-tetrazole.27 N-Cbz-L-Phe (16) was first converted to amide (17)28 by the
coupling reaction in the presence of di-tert-butyldicarbonate (Boc2O) in 94% yield.28b The dehydration of
an amide using phosphorus (V) oxychloride in the presence of pyridine afforded nitrile (18) in 87%
yield.29 According to Sharpless’s method,30b 1,3-dipolar cycloaddition of sodium azide to construct a
tetrazole unit was easily achieved to afford known 19,30 which was next deprotected by a hydrogenolysis
condition using a palladium carbon catalyst, to afford the desired 12 at 53% yield in 2 steps (Scheme 4).
pyrrolidine
or
1-methylpiperazine
EDC-HC
l, HOBt
NHBoc
CO2H
i-Pr
NHBoc
O
2NEt
NH2
TFA
X
THF
CH2Cl2
NR1R2
NR1R2
: X = O
14a
14b
13
(93%)
(100%)
15a 15b
,
LAH
THF
a: R1 = R2 = -(CH2)4-
: R1 = R2 = -(CH2)2N(Me)(CH2)2-
11a 11b
,
: X = H2
b
(11a
: 75%, 2 steps)
(11b: 83%, 2 setps)
Scheme 3
Boc2O
(NH4)2CO3
pyridine
POCl3
pyridine
NHCbz
O
NHCbz
CO2H
CH2Cl2
(87%)
MeCN
(94%)
NH2
17
16
18
NaN3
ZnBr2
NHR
N
NH2
CN
i-PrOH
H2O
N
HN
N
19
: R = Cbz
Pd-C, H2
MeOH
12: R = H (53%, 2 steps)
Scheme 4
We examined the effects of prepared chiral amines (11) and (12) on the aldol reaction of the trione (7).
All of the reactions were carried out under the same conditions in the presence of a stoichiometric amount
of amine with or without TFA in DMSO at 90oC. The results are compiled in Table 1. First of all, the
aldol reaction mediated by an amine 11 or 12 without Brønsted acid afforded 3b at a moderate or slightly
high yield accompanied with quite low ee (entries 1, 6, and 10). The reaction using 11a in the presence of
1.0 equivalent of TFA as a Brønsted acid showed a slightly improved yield and better enantioselectivity
for (S)-3b (entry 2).31 We next examined the amount effects of TFA on the reaction using 11a. The

HETEROCYCLES, Vol. 76, No. 2, 2008
1195
reactions of 11a in the presence of 1.5 equiv. or 2.0 equiv. of TFA, respectively, inverted the
enantioselectivity of the resulting 3b and increased the ee value, depending on the amount of TFA. The
use of (+)-camphorsulfonic acid (CSA) as an additive was not successful, because a slower reaction and
lower ee than entry 4 were observed (entry 5). The absolute configuration of the product (3b) in entry 4
was assigned as R by comparison with the optical rotation of (R)-3b reported previously.14 Specifically,
the optical rotation of product (R)-3b in entry 4 was [α]D –59.8 (CHCl3, 70% ee), lit.14a [α]D –83.4
(CHCl3, >99% ee). In the case of 11b, the addition of 2.0 equiv. of TFA greatly improved both the yield
and ee of 3b compared to entry 6, but a prolonged reaction time was observed (entry 8). Since 11b had a
triamine structure, we also examined the condition in the presence of 3.0 equiv. of TFA. However, the
reaction proceeded very slowly and a remarkable improvement of the enantioselectivity was not observed
(entry 9). In the case of using 12, the reaction proceeded very smoothly to afford (R)-3b at high yield
accompanied with moderate ee (entries 11-13).
11 or 12
(1.0 equiv.)
additive
DMSO, 90oC
7
3b
Additive
(equiv.)
Time
Yielda, b
(%)
Eec
Entry Amine
Config.d
(h)
32
17
10
10
72
39
24
123
96
6
(%)
1
2
11a
11a
11a
11a
11a
none
65
1.5
S
S
TFA (1.0)
TFA (1.5)
TFA (2.0)
(+)-CSA (2.0)
85
95
18
34
70
45
3
3
R
R
R
R
S
4
91
5
71 (82)
67
6
11b none
7
11b TFA (1.0)
11b TFA (2.0)
11b TFA (3.0)
85
7
8
88
69
67
18
38
57
56
56
84
R
R
S
9
71 (78)
86
10
11
12
13
14 e
15 g
12
12
none
TFA (0.5)
TFA (1.0)
TFA (1.5)
TFA (0.6)f
TFA (2.0)
8
91
R
R
R
R
R
12
9
95
12
24
21
138
89
11a
11a
90
93
a Isolated yield.
b Yields in parentheses were based on the recovery of starting 7.
c Determined by HPLC equipped with a chiral stationary phase column.
d Absolute configuration of a major enantiomer of 3b.
e Catalytic amount of 11a (0.3 equiv.) was used as a mediator.
f 2.0 equiv. of TFA to amine (11a) was used.
g Reaction was carried out at 50oC.
Table 1

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HETEROCYCLES, Vol. 76, No. 2, 2008
Next, we tried to extend this process to a catalytic version. The reaction using 0.3 equiv of 11a in the
presence of 0.6 equiv of TFA in DMSO at 90 oC afforded (R)-3b in high yield but accompanied by lower
ee than that of entry 4 (entry 14). This result means that the catalytic reaction using 11a was not very
effective. Finally, we examined the reaction temperature. Although the reaction using 11a at 50oC
prolonged the reaction time, using this temperature we succeeded in improving the enantioselectivity
greatly, accompanied by a high yield (entry 15). The 84% ee observed in entry 15 was the highest
enantioselectivity to afford 3b in our present and previous experiments. A reaction temperature less than
50oC was not practical because the reaction hardly proceeded. Since we previously reported that we could
obtain optically pure material of 3b by fractional recrystallization from (R)-3b over 68% ee, the achieved
84% ee of 3b was enough optical purity to provide an enantiopure material as a chiral synthon. Based on
these results, we considered our chiral synthesis of (R)-3b to be better than the methods reported
previously by us.14
In the aldol reaction of 7, there exists the possibility of producing eight stereoisomers as a result of three
newly generated stereogenic centers. Since we could not isolate the initially formed β-hydroxy ketones
under the conditions using a chiral amine 11 or 12, dehydration to afford 3b must occur rapidly. The
transition states predicted for the stereoisomers are shown in Figure 3. In the presence of enough Brønsted
acid such as a condition using 2.0 equiv. of TFA, the amino moiety in 11 would be protonated to generate
a corresponding ammonium salt. We think that this hydrogen in the ammonium salt could form a
hydrogen bond to the β-oxygen atom originating from ketone functionality and a nitrogen atom in the
enamine moiety to stabilize the transition state. Among these hydrogen-bonding models, two of the syn
(syn, anti: conformation between olefinic and ammonium moieties) transition states (25) and (27), which
will afford aldol products (21) and (23), respectively, are considered to be slightly higher in energy
because of relatively unstable chair-boat conformations in the 6,6-fused-bicycle, resembling
bicyclo[3.3.1]nonane, while the anti transition states (24) and (26), which will afford 20 and 22,
respectively, have chair-chair conformations. Kwon et al. reported that a chair-chair conformation in
bicyclo[3.3.1]nonane is more stable than a chair-boat conformation.32,33 They also showed that the free
energy difference between those two conformers in bicyclo[3.3.1]nonane is 2.3-2.5 kcal/mol by means of
ab initio and density functional theory (DFT) calculations. Thus, the aldol reaction should proceed
through anti transition states, (24) and/or (26). In comparison with the trans-anti (cis, trans: cis- or
trans-fused carbocycles) transition state (24) and the cis-anti one (26), 26 appears to be disfavored
because of steric repulsion between the methyl enamine and a 7-membered carbocycle in 26.
Consequently, the trans-anti transition state (24) should be most favored, affording the aldol product (20),
which would give rise to (R)-3b after dehydration (Figure 3).
When no or poor Brønsted acid was used, lower ee of the resulting 3b was noted (Table 1). This result
indicates that the reaction with a poor acid could not generate hydrogen bonds and the amino moiety in a

HETEROCYCLES, Vol. 76, No. 2, 2008
1197
side chain would be oriented away from the C-C bond forming site. Since the three favorable transition
states (28), (29), and (31), which would afford 20, 21, and 23, respectively, might have very similar
potential energy, no or lower enantioselectivity was observed (Figure 4). Among the proposed transition
states, the cis-anti one (30) is considered to be slightly higher energy due to the same steric repulsion
described above. To date, we have no evidence to suggest which transition state is more stable. Further
investigations into the effects of Brønsted acids, and calculations of the energy differences of our
proposed transition states are currently under way.
R1
R2
Ph
with enough H+
Ph
chair-chair
H
O
O
O
5
chair-boat
O
N
R1
R2
N
H
HN
N
O
H
O
4a
9a
O
O
1
OH
21
OH
24
25
trans-anti:
cis-syn:
20
R1
Ph
Ph
H
N
O
O
O
R2
N
H
R1
R2
HN
O
N
O
O
H
O
O
OH
OH
27
22
trans-syn:
cis-anti: 26
23
Figure 3
R1
N R2
with no or poor H+
R1
Ph
H
Ph
N
R2
N
HN
O
O
O
20
21
O
28
trans-anti:
29
cis-syn:
R1
R2
R1
R2
N
O
Ph
H
N
O
Ph
N
HN
O
O
22
23
31
trans-syn:
cis-anti: 30
Figure 4

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HETEROCYCLES, Vol. 76, No. 2, 2008
In conclusion, we have established a procedure to prepare new and known chiral amines based on a
structure of L-Phe. We also have established an alternative chiral route to provide (R)-3b by using the
combination of synthetic chiral amine and Brønsted acid. In the reaction, an interesting inversion of
enantioselectivity depending on the amount of a Brønsted acid was observed. Furthermore, under
optimized conditions, we have achieved the synthesis of (R)-3b with over 80% ee for the first time. These
results may enable the creation of efficient organocatalysts for a wide variety of asymmetric reactions.
Further work on a detail of the reaction mechanism and the development of a more efficient mediator for
the reactions is currently in progress.
EXPERIMENTAL
1
Melting points are uncorrected. IR spectra were recorded on a JASCO FT−IR 5000 spectrometer. H
NMR spectra and 13C NMR spectra were recorded on a JEOL AX−400 (1H 400 MHz, 13C 100 MHz)
spectrometer and calibrated using trimethysilane as the internal standard. Mass spectra were recorded on a
JEOL DX−303 or a JEOL JMS-MS700 spectrometer. Elemental analysis was done with a Perkin Elmer
CHN-2400 II. Enantiomeric excesses were determined with a Waters HPLC 600 instrument equipped
with a chiral stationary phase column. Optical rotations were measured with a JASCO DIP−370 digital
polarimeter.
Typical procedure of coupling reaction
To a stirred solution of the N-Boc-L-Phe (13) (3 g, 11.3 mmol), 1-hydroxybenzotriazole (HOBt) (1.83 g,
13.5 mmol), EDC hydrochloride (2.60 g, 13.6 mmol) and diisopropylethylamine (i-Pr2NEt) (2.36 mL,
13.6 mmol) in THF (30 mL) was added pyrrolidine (0.67 mL, 13.6 mmol) at 0oC and the mixture was
stirred at rt for 24h. H2O (10 mL) was added to the mixture to quench the reaction. The mixture was
extracted with ethyl acetate (AcOEt), was washed with brine, and was dried (Na2SO4). The solvent was
removed under reduced pressure. The residue was chromatographed on silica gel (AcOEt/hexane = 1/2)
to afford 14a 3.3 g (93%) as colorless oil.
tert-Butyl (S)-1-oxo-3-phenyl-1-(pyrrolidin-1-yl)propan-2-carbamate (14a)
20
25
1
[α]D +37.5 (c 1.0, CHCl3), lit.,26a [α]D +39.3 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
7.28-7.20 (m, 5 H), 5.42 (d, J = 8.8 Hz, 1 H), 4.59 (q, J = 8.5 Hz, 1 H), 3.46-3.26 (m, 3 H), 3.00 (dd, J =
6.0, 12.8 Hz, 1 H), 2.94 (dd, J = 9.4, 12.6 Hz, 1 H), 2.59-2.52 (m, 1 H), 1.77-1.47 (m, 4 H), 1.42 (s, 9 H);
13C NMR (100 MHz, CDCl3) δ 169.9, 155.0, 136.6, 129.4, 128.3, 126.8, 79.5, 53.6, 46.2, 45.6, 40.2, 28.3,
25.7, 23.9; EI MS: m/z 318 (M+), 120 (100%); HRMS calcd for C18H26N3O3: 318.1943, found: 318.1947.
tert-Butyl (S)-1-oxo-3-phenyl-1-(4-methylpiperazin-1-yl)propan-2-carbamate (14b)
21
Yield 100% (colorless oil); [α]D +4.7 (c 1.1, MeOH); IR (film) ν cm-1 3432, 3296, 3062, 3029, 2977,
2938, 2798, 1708, 1643, 1523, 1496, 1455, 1392, 1367, 1293, 1250, 1171, 1051, 1024, 1003, 867, 753,
1
701; H NMR (400 MHz, CDCl3) δ 7.30-7.17 (m, 5 H), 5.43 (d, J = 8.8 Hz, 1 H), 4.82 (q, J = 7.9 Hz, 1

HETEROCYCLES, Vol. 76, No. 2, 2008
1199
H), 3.62-3.46 (m, 2 H), 3.33-3.27 (m, 1 H), 3.02-2.09 (m, 3 H), 2.34-2.12 (m, 3 H) 2.22 (s, 3 H),
1.77-1.73 (m, 1 H), 1.42 (s, 9 H); 13C NMR (100MHz, CDCl3) δ 169.8, 154.9, 136.4, 129.5, 128.4, 126.8,
79.5, 54.3, 54.2, 50.8, 45.7, 45.2, 41.7, 40.3, 28.2, EI MS: m/z 347 (M+, 100%); HRMS calcd for
C19H29N3O3: 347.2209, found: 347.2200.
Typical procedure of deprotection of 14 and reduction of amide (15)
To a stirred solution of 14a (3.33 g, 10.4 mmol) in CH2Cl2 (20 mL) was added TFA (10 mL, 57.1 mmol)
at 0oC. After stirring the mixture for 1h, the solvent was removed under reduced pressure. The residue
was dissolved to CH2Cl2, and then the mixture was washed with brine and was dried (Na2SO4). The
solvent was removed under reduced pressure to afford crude 15a, which was used in the next reaction
without further purification. To a stirred suspension of LAH (0.7 g, 18.5 mmol) in THF (10 mL) was
added a solution of the crude 15a in THF (20 mL) over 10 min at 0oC. The mixture was heated to reflux
for 13h and then quenched with H2O at 0oC. After stirring the mixture at rt for 2h, it was filtered through
a Celite pad and the filtrate was evaporated under reduced pressure. The residue was chromatographed
(CHCl3/MeOH/NH4OH = 200/10/1 to 100/10/1) to afford 11a 1.6 g (75%) as pale yellow oil.
(S)-1-Phenyl-3-(pyrroidin-1-yl)propyl-2-amine (11a)
[α]D21 +15.4 (c 1.0, CHCl3), lit.,20a [α]D27 +16.2 (c 1.1, CHCl3); IR (film) ν cm-1 3370, 3305, 2963, 2927,
1
2875, 2785, 1602, 1584, 1495, 1454, 746, 701; H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 2 H),
7.23-7.19 (m, 3 H), 3.15 (m, 1 H), 2.78 (dd, J = 4.6, 13.4 Hz, 1 H), 2.62-2.39 (m, 6 H), 2.31 (dd, J = 4.2,
11.8 Hz, 1 H), 1.81-1.70 (m, 4 H) 1.43 (br s, 2 H, D2O exchangeable); 13C NMR (100 MHz, CDCl3) δ
139.5, 129.3, 128.4, 126.1, 63.2, 54.4, 51.3, 42.6, 23.5; EI MS: m/z 204 (M+), 84 (100%); HRMS calcd
for C13H20N2: 204.1626, found: 204.1624.
(S)-1-(4-Methylpiperazin-1-yl)-3-phenylpropyl-2-amine (11b)
Yield 83% (pale yellow oil); [α]D21 +16.1 (c 1.0, CHCl3); IR (film) ν cm-1 3366, 3084, 3061, 3026, 2937,
2795, 1602, 1495, 1457 1283, 1166, 1014, 747, 701; 1H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 2 H),
7.23-7.20 (m, 3 H), 3.19 (m, 1 H), 2.74 (dd, J = 4.4, 13.2 Hz, 1 H), 2.68-2.21 (br m, 8 H), 2.47 (dd, J =
8.8, 13.2 Hz, 1 H), 2.34-2.21 (m, 2 H), 2.28 (s, 3 H), 1.53 (br s, 2 H, D2O exchangeable); 13C NMR (100
MHz, CDCl3) δ 139.1, 129.1, 128.2, 126.0, 64.6, 55.1, 53.3, 49.0, 45.9, 42.0; EI MS: m/z 233 (M+), 133
(100%); HRMS calcd for C14H23N3: 233.1892, found: 233.1888.
(S)-N-Benzyloxycarbonylphenylalanine amide (17)
To a stirred solution of N-Cbz-L-Phe (5 g, 16.7 mmol) and pyridine (0.85 mL, 10.5 mmol) in MeCN (50
ml) was added Boc2O (5 ml, 21.7 mmol) and anmmonium carbonate 1.66 g (21.1 mmol) at 0oC. After
stirring the mixture at rt for 22h, H2O was added to it at 0oC. The mixture was extracted with Et2O, was
washed with brine and was dried (Na2SO4). The solvent was removed under reduced pressure. The
residue was chromatographed (hexane/AcOEt = 1/1 to 1/3) to afford 17 4.67 g (94%) as a colorless solid.

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22
25
Mp 162-163oC (colorless needles from AcOEt); [α]D -6.5 (c 1.0, MeOH), lit.,28a [α]D -6.8 (c 1.0,
1
MeOH); IR (KBr), ν, cm-1 3419, 3319, 3201, 1692, 1659, 1610, 1535, 748, 699; H NMR (400 MHz,
CDCl3) δ 7.38-7.20 (m, 10 H), 5.64 (br s, 1 H), 5.33 (br s, 2 H), 5.09 (s, 2 H), 4.50-4.35 (m, 1 H), 3.14
(dd, J = 6.2, 13.4, 1 H), 3.05 (dd, J = 7.3, 13.4, 1 H); 13C NMR (100 MHz, CDCl3) δ 173.1, 156.0, 136.3,
136.0, 129.3, 128.8, 128.6, 128.3, 128.0, 127.2, 67.1, 55.8, 38.4; EI MS: m/z 298 (M+), 91 (100 %);
HRMS calcd for C17H18N2O3: 298.1317, found: 298.1315; Anal. Calcd for C17H18N2O3: C, 68.44; H,
6.08; N, 9.39. Found: C, 68.45; H, 6.03; N, 9.42.
(S)-1-Benzyloxycarbonylamino-2-phenylpropionitrile (18)
To a stirred solution of 17 (1 g, 3.36 mmol) in pyridine (4.2 mL) and CH2Cl2 (0.8 mL) was added
phosphorus (V) oxychloride (0.42 mL, 4.47 mmol) at -10oC. After stirring the mixture for 1h at the same
temperature, it was poured into H2O and was extracted with AcOEt. The combined organic layer was
washed with brine and was dried (Na2SO4). The solvent was removed under reduced pressure. The
residue was chromatographed (hexane/AcOEt = 5/1) to afford 18 820 mg (87%).
Mp 132-133 oC (Colorless needles from hexane/CH2Cl2); [α]D25 -66.4 (c 0.75, DMF), lit.,30a [α]D27 -66 (c
0.95, DMF); IR (KBr), ν, cm-1 3326, 1697, 1535, 743, 695; 1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m,
8 H), 7.27-7.25 (m, 2 H), 5.13 (s, 2 H), 5.06 (br s, 1 H), 4.95-4.83 (m, 1 H), 3.13 (dd, J = 5.8, 13.8, 1 H),
3.06 (dd, J = 7.0, 13.8, 1 H); 13C NMR (100 MHz, CDCl3) δ 154.9, 135.5, 133.6, 129.4, 128.9, 128.6,
128.4, 128.2, 127.9, 118.0, 67.6, 43.7, 38.9; EI MS: m/z 280 (M+), 91 (100 %); HRMS calcd for
C17H16N2O2: 280.1212, found: 280.1216; Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found:
C, 72.81; H, 5.72; N, 10.09.
(S)-1-Amino-2-phenylethyl-1-2H-tetrazole (12)
To a stirred solution of 18 (2 g, 7.14 mmol) in 2-propanol (15 mL) and H2O (30 mL) were added sodium
azide (930 mg, 14.3 mmol) and zinc bromide (804 mg, 3.57 mmol) at rt. The mixture was heated to reflux
for 18h. After cooling, 10% HCl was added to the mixture at 0oC, and the mixture was extracted with
AcOEt. The combined organic layer was washed with brine and was dried (Na2SO4). The solvent was
removed under reduced pressure to afford crude 19, which was used in the next reaction without further
purification. A suspension of crude 19 and 10% Pd-C (470 mg) in MeOH (40 mL) was stirred vigorously
under hydrogen gas at rt for 20h. The mixture was filtered through a Celite pad and the filtrate was
evaporated under reduced pressure. The residue was recrystalized from MeOH to afford 12 713 mg (53%,
2 steps) as colorless cubes.
Mp 271oC (decomposition); [α]D23 +47.4 (c 0.75, DMSO), lit.,25 [α]D27 +46.4 (c 0.74, DMSO); IR (KBr),
1
ν, cm-1 2823, 2634, 2173, 1633, 1536, 752, 699; H NMR (400 MHz, DMSO-d6) δ 8.30 (br s, 2 H),
7.23-7.10 (m, 5 H), 4.66 (t, J = 7.2 Hz, 1 H), 3.40 (br s, 1 H), 3.33 (dd, J = 8.4, 13.6 Hz, 1 H), 3.17 (dd, J
= 5.6, 13.6 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) δ 158.5, 136.4, 129.4, 128.2, 126.6, 48.7; EI MS:

HETEROCYCLES, Vol. 76, No. 2, 2008
1201
m/z 189 (M+), 98 (100 %); HRMS calcd for C9H11N5: 189.1014, found: 189.1011.
Typical procedure of aldol reaction of 7
To a stirred solution of TFA (104 mg, 1.78 mmol) in DMSO (0.5 mL) were added 11a (182 mg, 0.89
mmol) in DMSO (1.0 mL) and 7 (200 mg, 0.89 mmol) in DMSO (0.5 mL) at rt. The mixture was heated
at 90oC for 10h. After cooling, the mixture was dissolved to AcOEt, was washed with saturated aqueous
NaHCO3 and brine, and was dried (MgSO4). The solvent was removed under reduced pressure. The
residue was chromatographed (hexane/AcOEt = 7/1) to afford 3b 167 mg (91%) as pale yellow crystals.
The optical purity was determined to be 70% ee by HPLC with a chiral stationary phase column. HPLC
conditions: Chiralpak AS-H (Daicel Chemical Industries, LTD), ethanol/hexane = 10/90 (v/v), flow rate
1.0 mL/min. detected at 254 nM, tR = 9.9 min for (R)-3b, 11.1 min for (S)-3b.
[α]D23 -59.8 (c 1.0, CHCl3, 70% ee), lit.,14a [α]D27 -83.4 (c 1.0, CHCl3, >99% ee). All of the spectroscopic
data were identical to those reported by us previously.14
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