Ring-opening reactions of 3-aryl-1-benzylaziridine-2-carboxylates and application to the asymmetric synthesis of an amphetamine-type compound

Article abstract of DOI:10.1002/hlca.200790006

Nucleophilic ring-opening reactions of 3-aryl-1-benzylaziridine-2- carboxylates were examined by using O-nucleophiles and aromatic C-nucleophiles. The stereospecificity was found to depend on substrates and conditions used. Configuration inversion at C(3)

Full text of DOI:10.1002/hlca.200790006

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Helvetica Chimica Acta – Vol. 90 (2007)
Ring-Opening Reactions of 3-Aryl-1-benzylaziridine-2-carboxylates and
Application to the Asymmetric Synthesis of an Amphetamine-Type
Compound
by Tomoyuki Manakaa), Shin-Ichiro Nagayamaa), Wannaporn Desadeea), Naoki Yajimaa), Takuya
Kumamotoa), Toshiko Watanabea), Tsutomu Ishikawa*a), Masatoshi Kawahatab), and Kentaro
Yamaguchib)
a) Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522,
Japan (phone: +81-43-290-2910; fax: +81-43-290-2910; e-mail: benti@p.chiba-u.ac.jp)
b) Faculty of Pharmaceutical Sciences, Kagawa Branchi, Tokushima Bunri University, 1314-1 Shido,
Sanuki, Kagawa 769-2193, Japan
Nucleophilic ring-opening reactions of 3-aryl-1-benzylaziridine-2-carboxylates were examined by
usingO-nucleophiles and aromatic C-nucleophiles. The stereospecificity was found to depend on sub-
strates and conditions used. Configuration inversion at C(3) was observed with O-nucleophiles as a
major reaction path in the ring-opening reactions of aziridines carrying an electron-poor aromatic moi-
ety, whereas mixtures containingpreferentially the syn-diastereoisomer were generally obtained when
electron-rich aziridines were used (Tables 1–3). In the reactions of electron-rich aziridines with C-nucle-
ophiles, SN2 reactions yielding anti-type products were observed (Table 4). Reductive ring-opening reac-
tion by catalytic hydrogenation of (+)-trans-(2S,3R)-3-(1,3-benzodioxol-5-yl)aziridine-2-carboxylate
(+)-trans-3c afforded the corresponding a-amino acid derivative, which was smoothly transformed
into (+)-tert-butyl [(1R)-2-(1,3-benzodioxol-5-yl)-1-methylethyl]carbamate((+)-14) with high retention
of optical purity (Scheme 6).
1. Introduction. – Aziridine-2-carboxylates are very versatile synthetic intermedi-
ates [1–3] for the preparation of biologically active N-containing compounds because
they are convertible to a- or b-amino acid derivatives, includingunnatural amino acids,
by regioselective ring-opening reactions [1][4][5] (Scheme 1). Aziridines are classified
into two groups, ꢀactivatedꢁ and ꢀunactivatedꢁ (or nonactivated) aziridines, depending
upon the substituent R1 at the ringN-atom [1][4]; the former category includes elec-
tron-withdrawingsubstituents such as tosyl or acyl functions, whereas a H-atom and
alkyl substituents are typical for the latter one. Although the reactivity of ꢀactivatedꢁ
aziridines has been well investigated, there are only limited reports [6–9] on ꢀunacti-
vatedꢁ aziridines.
Recently, we have reported an atom-economical aziridine synthesis from guanidi-
nium salts 1 (obtained from the ureas 4) and arenecarboxaldehydes 2 [10] (or unsatu-
rated aldehydes [11]) applicable to asymmetric synthesis, in which 1-alkyl-3-arylaziri-
dine-2-carboxylates 3 (or the correspondingunsaturated derivatives) are produced,
as shown in Scheme 2. In this paper, we present the ring-opening reactions of N-benzyl-
aziridine-2-carboxylates, prepared by the above reaction, with O-nucleophiles and aro-
matic C-nucleophiles and application to the asymmetric synthesis of an amphetamine-
type compound from the reductively ring-opened product.
ꢂ 2007 VerlagHelvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 90 (2007)
129
Scheme 1. Schematic Ring-Opening Reactions of Aziridine-2-carboxylates
Scheme 2. Aziridine Synthesis from Guanidinium Salts 1 and Arenecarboxaldehydes 2
2. Results and Discussion. – 2.1. Ring-Opening Reactions with O-Nucleophiles. In
1992, Zwanenburg and co-workers [6] reported the ring-opening reactions of N-unsub-
stituted trans-3-arylaziridine-2-carboxylates with various nucleophiles includingAcOH
and found that regio- and stereoselectivities in the reactions were dependent upon the
characters of either the aziridine substrates or the nucleophiles used. Thus, the reaction
of trans-3-phenylaziridine-2-carboxylate with AcOH quantitatively afforded the 2-
(acetylamino)-3-hydroxy-3-phenylpropanoate with anti-configuration. Recently,
Hruby and co-workers [7] observed the same result. In addition, in the course of the
preparation of a chloramphenicol derivative, Loncaric and Wulff [8] also reported
the formation of the syn-amino alcohol in the reaction of cis-1-benzyl-3-(4-
nitrophenyl)CAHTREUaNG ziridine-2-carboxylate with CF3COOH in CH2Cl2 followed by alkaline
hydrolysis. In these three ring-opening reactions, O-nucleophiles strictly attack at the
C(3) position with inversion of configuration. However, Cardillo et al. [9] reported
that a syn-amino alcohol was stereoselectively formed with retention of configuration
in the Ac2O-triggered ring-opening reaction on using the amide version of Hrubyꢁs
trans-aziridine. This result showed that the stereochemical course in the ring-opening
reaction of 3-arylaziridine-2-carboxylates is partly confusing. Furthermore, there
have been no reports on the ring-opening reaction of 3-arylaziridine-2-carboxylates car-
ryingan electron-rich aromatic substituent with O-nucleophiles. We, therefore, exam-
ined the ring-opening reactions of some racemic 3-aryl-1-benzylaziridine-2-carboxy-
lates 3 [12], includingthe 3-(1,3-benzodioxol-5-yl)- ( 3c), 3-(4-methoxyphenyl)- (3d),

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Helvetica Chimica Acta – Vol. 90 (2007)
and 3-{1-[(tert-butoxy)carbonyl]-1H-indol-4-yl}aziridine-2-carboxylate1) 3e as electron-
rich 3-arylaziridines, in 50% aqueous THF solution in the presence of p-toluenesulfonic
acid monohydrate (TsOH) by usingH O as an O-nucleophile (Table 1).
2
Table 1. Ring-Opening Reaction of 3-Aryl-1-benzylaziridine-2-carboxylates 3 with H2O in the Presence of
TsOHa)
Entry
Startingmaterial
Temp. [ 8]
Time [h]
Product 5
Yield [%]
anti/synb)
1
2
3
4
5
6d)
7
8d)
9d)
10e)
trans-3a
cis-3a
trans-3b
cis-3b
trans-3c
trans-3c
trans-3d
trans-3d
cis-3d
45
45
45
45
2
16.5
9
72
2
97
94
99
72
quant.
88
93
96
quant.
quant.
1:0
0 :1
1:0
0 :1
1:1
1:5
2 :1
1:3
1:3
1:6
r.t.c)
r.t.c)
0
3
0.2
17
15
0.5
r.t.c)
r.t.c)
r.t.c)
trans-3e
a) Conditions: 0.1–0.19M 3/50% aq. THF solution; TsOH, 1.0–1.2 mol-equiv. b) Estimated by 1H-NMR.
c) Room temperature. d) CH2Cl2 was used in place of THF. e) Ethyl ester and MeCN were used as azir-
idine and solvent, respectively.
Examination of the 1H-NMR spectra of the crude reaction products showed that, as
expected, regioselective ring-opening and OH-incorporation at the C(3) position
afforded products 5. The diastereoselectivity was greatly dependent upon the aziridine-
carboxylate used (vide infra). These results were confirmed by the isolation of pure
products from the reactions described in Entries 1–4, 7, and 8 of Table 1. Thus, strict
inversion occurred in the cases of arylaziridinecarboxylates 3a and 3b carryinga Ph sub-
stituent (Table 1, Entries 1 and 2) or an electron-withdrawing-group(EWG)-substituted
aryl substituent (Entries 3 and 4) at C(3). On the other hand, no or low diastereselec-
tivity was observed when arylaziridines 3c and 3d, carrying an electron-donating-group-
ACHTREUNG(EDG)-substituted aryl ring, were used as substrates (Entries 5 and 7). However, dia-
stereoselectivity due to a solvent effect was observed since in CH2Cl2 instead of
THF, syn-amino alcohols were the major ring-opening products (Entries 6 and 8).
The predominance of syn-product was also observed in the ring-opening reaction of
1
)
The preparation of this compound will be reported elsewhere.

Helvetica Chimica Acta – Vol. 90 (2007)
131
the trans-(1H-indol-4-yl)aziridinecarboxylate trans-3e in MeCN (Entry 10). Interest-
ingly, in the reaction of Entry 9 of Table 1, the syn-amino alcohol syn-5d was formed
as the major product from cis-(4-methoxyphenyl)aziridinecarboxylate cis-3d, suggest-
ingthat the openingof the aziridine ringcarryingan electron-rich aryl group at C(3)
is independent of the relative configuration of the starting aziridines.
The configuration of the stereogenic centers in the H2O adducts had been deter-
mined based on the 1H-NMR spectra of known ring-opened products [6][7]; however,
crucial information could not be obtained by this method in some cases. Shiba and co-
workers [13] had assigned the configuration of diastereoisomeric a-amino-b-hydroxy
acids by cyclization to oxazolidinones; the obtained cis-derivative showed a large cou-
plingconstant ( J=9.6 Hz) between HꢀC(4) and HꢀC(5), whereas the trans-isomer
showed a small couplingconstant ( J=5.0 Hz). We have independently determined
the relative configuration of a-amino-b-hydroxy esters derived from 3-vinylaziridine-
2-carboxylates in the synthesis of hydroxyleucinate and sphingosine [11] by application
of Shibaꢁs procedure. This technique was also applied to product 5c obtained in the
reaction of Entry 6 of Table 1 (Scheme 3). Treatment of a ca. 5 :1 mixture 5c with car-
bonylbis[1H-imidazole] ((Im)2CO) in CH2Cl2 afforded an inseparable mixture of iso-
meric oxazolidinone derivatives 6, the ratio of which was determined by 1H-NMR spec-
troscopy (major: 71%, minor: 12% yield). The couplingconstants ( J(4,5)=5.6 Hz in
the major isomer; J(4,5)=9.2 Hz in the minor) indicated that the major isomer had
the trans configuration. In other words, (2RS,3SR)-2-amino-3-aryl-3-hydroxypropa-
noate syn-5c can be assigned to the major isomer formed in the TsOH-catalyzed
ring-opening reaction of trans-3c. This assignment was further supported by the
NOE experiment with the minor oxazolidinone derivative cis-6, in which an NOE en-
hancement (15.3%) was observed between HꢀC(4) and HꢀC(5).
Scheme 3. Derivatization of 5c to Oxazolidinone Derivatives 6 for the Determination of Their Config-
uration
Modification of the ester function to a [(silyloxy)methyl] or (hydroxymethyl) func-
tion in the aziridine derivatives afforded the same tendency of stereoselectivity in the
TsOH-induced ring-opening reactions. syn-Amino alcohols syn-8 were mainly formed
from the reaction of the trans-aziridine derivatives1) carryingthe 4-methoxyphenyl ( 7d)
or 1H-indol-4-yl group (7e; Table 2).
Furthermore, we found that the diastereoselectivity was not influenced by the kind
of nucleophiles (Table 3). Thus, syn-products syn-9 were also obtained as the major
product in the AcOH-induced ring-opening reactions of the EDG-substituted trans-
3-arylaziridine-2-carboxylates trans-3c and trans-3e, by usingeither AcOH or MeOH
as nucleophiles.

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Helvetica Chimica Acta – Vol. 90 (2007)
Table 2. Ring-Opening Reactions of trans-(Silyloxy)methyl]- or trans-(Hydroxymethyl)aziridines 7 with
H2O in the Presence of TsOHa)
Entry Startingmaterial R 1
R2
Solvent Time [h] Product 8
Yield [%] anti/synb)
1
2
3
4
7d
7d
7e
7e
PhCH2
PhCH2
PhCH2
iPr3Si
H
CH2Cl2
CH2Cl2
1
0.2
22
14
97
1:3
1:4
1:20
1:7
quant.
quant.
92
tBuMe2Si MeCN
CH2=CHCH2 tBuMe2Si MeCN
a) The substituent R in 7 corresponds to that in 3 in Table 1 (d: R=4-MeOC6H4; e: R=1-[(tert-butoxy)-
carbonyl]-1H-indol-4-yl). Conditions: 0.09–0.17M 7/solvent; TsOH, 1.1–1.2 mol-equiv. at room temper-
1
b
ature (r.t.). ) Estimated by H-NMR.
Table 3. Ring-Opening Reactions of EDG-substituted trans-3-Aryl-1-benzylaziridine-2-carboxylates with
AcOHa)
Entry Starting
AcOH
Solvent Temp. [8] Time [h] Product 9
material [mol-equiv.]
R1
Yield [%] anti/synb)
1
2
3d)
4e)
trans-3c
trans-3c
trans-3c
trans-3e
81
48
1.2
83
none
0
0.5
2
22
Ac
Ac
88
81
1:3
CH2Cl2
MeOH
none
r.t.c)
r.t.c)
r.t.c)
1:10
1:10
0 :1
Med) 78
4
Ac
quant.
a) The substituent R in 3 corresponds to that in Table 1 (c: R=1,3-benzodioxol-5-yl; e:R=1-[(tert-
carbonyl]-1H-indol-4-yl). b) Estimated by 1H-NMR. c) Room temperature. d) An MeO group was
butoxy)ACHTREUNG
incorporated in place of an AcO group. e) The ethyl ester was used.
Thus, ring-opening reactions of arylaziridinecarboxylates carrying an EDG-substi-
tuted aromatic ringwith O-nucleophiles, except for the reactions in THF, proceed with
the preferred formation of syn-amino alcohol derivatives, independently of the config-
uration of the startingaziridinecarboxylate or the kind of nucleophile. The production
of syn-amino alcohol derivatives as a main course could be reasonably deduced by
application of Cramꢁs model [14] for the transition state as shown in Scheme 4, in
which the ring-opening reactions of cis- and trans-3d with H2O is illustrated. Protona-
tion of the aziridine N-atom followed by ring-opening should give a resonance-stabi-

Helvetica Chimica Acta – Vol. 90 (2007)
133
Scheme 4. Proposed Reaction Path for the Formation of syn-5d as the Major Product of the Ring-
Opening Reactions of cis- and trans-3d with H2O
lized benzyl cationic species (Scheme 4) as a key intermediate, on which the H2O attack
on the less hindered side should give the syn-amino alcohol derivatives.
2.2. Ring-Opening Reactions with Aromatic C-Nucleophiles. Zwanenburg and co-
workers [6] had also examined the ring-opening reactions of N-unsubstituted trans-3-
arylaziridine-2-carboxylates using1 H-indole as a C-nucleophile in the presence of
boron trifluoride etherate (BF3), in which high regio- and stereoselectivities were
observed when phenyl and 4-nitrophenyl groups were used as aromatic moiety, giving
only anti-2-amino-3-aryl-3-(1H-indol-3-yl)propanoates2) as ring-opened products in
53% and 60% yields, respectively. On the other hand, (4-methoxyphenyl)aziridinecar-
boxylate gave, with 1H-indole, a mixture of anti- and syn-adducts at C(3) of the aziri-
dine. Conversion to anti-2-amino-3-(1H-indol-3-yl)-3-phenylpropanoate from trans-3-
phenylaziridine-2-carboxylate in the BF3-induced ring-opening reaction had also
been followed by Hruby and co-workers [7]. In addition, it had been reported that elec-
tron-rich aromatics such as 1H-indole and 1,2-dimethoxybenzene react with tosylazir-
idine, an ꢀactivatedꢁ aziridine, to give ring-opened products in the presence of indium
catalysts such as indium chloride (InCl3) [15] or scandium perchlorate [16].
We examined the InCl3- or BF3-induced ring-opening reactions of ꢀunactivatedꢁ
aziridines with various aromatic C-nucleophiles, usingthe trans-(1,3-benzodioxol-5-
yl)aziridine-2-carboxylate trans-3c (Table 4). Reactions with 1H-indole and 2-methyl-
1H-indole were smoothly catalyzed with InCl3 to afford 3-(1H-indol-3-yl)- and 3-(2-
methyl-1H-indol-3-yl)-2-(benzylamino)propanoates 10a and 10b in 87 and 86% yield,
respectively, as a single stereoisomer (Table 4, Entries 1 and 3). Interestingly, product
10a was formed as a single isomer even in the absence of the catalyst albeit a longer
reaction time was needed (Entry 2). Also 1H-pyrrole and furan reacted as nucleophiles
in the InCl3-catalyzed ring-opening reactions to give the corresponding ring-opened
products 10c and 10d, in which the diastereoselectivity was dependent upon the nucle-
ophile used (Entries 4 and 6). In the BF3-induced reaction with 1H-pyrrole, a similar
diastereoselectivity as with InCl3 was observed (Entry 5).
As benzenoid C-nucleophiles, 1,3-dimethoxybenzene, N,N-dimethylaniline, and
anisole (=methoxybenzene) were also examined. In the presence of InCl3, the former
2
)
The configurational relation between the amino function and the aryl group inserted is adopted.

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Helvetica Chimica Acta – Vol. 90 (2007)
Table 4. Lewis Acid Catalyzed Ring-Opening Reactions of trans-(1,3-Benzodioxol-5-yl)aziridine-2-car-
boxylate (trans-3c) with Aromatic C-Nucleophiles in CH2Cl2
Entry ArH/Lewis acid ([mol-equiv.]) Temp. Time Product 10
[8]
[h]
Ar
Yield d.r.a)
[%]
1
2
3
4
5
6
7
1H-indole/InCl3 (0.1)
1H-indole/–
2-methyl-1H-indole/InCl3 (0.1) 30
r.t.b)
20
a
a
b
c
c
d
e
1H-indol-3-yl
1H-indol-3-yl
2-methyl-1H-indol-3-yl 86
1H-pyrrol-2-yl
1H-pyrrol-2-yl
1H-furan-2-yl
2,4-(MeO)2C6H3
87
73
single
single
single
4 :1
5 :1
10 :1
2 :1
r.t.b) 168
12
5
3
36
12
1H-pyrrole/InCl3 (0.2)
r.t.b)
66
55
60
75
c
1H-pyrrole/BF3 ) (1.0)
0
r.t.b)
30
furan/InCl3 (0.4)
1,3-dimethoxybenzene/InCl3
(0.5)
1,3-dimethoxybenzene/MgBr2 ) 40
(1.1)
N,N-dimethylaniline/InCl3
(0.5)
anisole/InCl3 (0.3)
c
8
9
4
4
n.r.d)
–
–
–
r.t.b)
f
4-(Me2N)C6H4
70
–
3.6 :1
–
10
35
18
mixturee) –
1
c
a) Diastereoisomeric ratio of the crude product estimated by H-NMR. b) Room temperature. ) As an
etherate. d) No reaction. e) A complex mixture was obtained containingthe startinganisole as the main
component.
two satisfactorily reacted with trans-3c to give the ring-opened products 10e and 10f
(Table 4, Entries 7 and 9), but a complex mixture was obtained in the case of anisole
(Entry 10). No reaction occurred when 1,3-dimethoxybenzene was treated with
MgBr2 ·OEt2 (Entry 8). In general, low diastereoselectivity was observed with benze-
noid C-nucleophiles as compared to heterocyclic ones in the InCl3-catalyzed reactions.
Although the configuration of the products formed had been assigned by 1H-NMR
(chemical shift and couplingconstant) in [6][7], this method could not be applied con-
clusively in this case. However, we succeeded in preparinga single crystal of 10a (see
Table 4, Entry 1). The X-ray crystallographic analysis (Fig.) indicated that it was tert-
butyl
(2RS,3SR)-3-(1,3-benzodioxol-5-yl)-2-(benzylamino)-3-(1H-indol-3-yl)propa-
noate with anti-configuration. In other word, inversion of configuration at C(3) of
the aziridine ringoccurred duringthe ring-openingreaction by the aromatic C-nucle-
ophiles, as shown in Scheme 5, in contrast to the reactions with O-nucleophiles men-
tioned above (Scheme 4).
2.3. Ring-Opening by Hydrogenation: Application to Asymmetric Synthesis of an
Amphetamine-Type Compound. In a previous paper [10], we reported the ring-opening
reaction of aziridines by catalytic hydrogenation giving amino acid derivatives. Qua-
gliato et al. [17] had reported the chemical conversion of the a-amino acid function

Helvetica Chimica Acta – Vol. 90 (2007)
135
Scheme 5. Proposed Mechanism for the Ring-Opening Reaction of trans-(1,3-Benzodioxol-5-yl)aziri-
dine-2-carboxylate trans-3c with a C-Nucleophile
Figure. ORTEP Drawing of product 10a
to a a-methylamine system. To show the utility of the 3-aryl-1-benzylaziridine-2-car-
boxylates as chiral tools for synthetic purposes, we independently carried out the asym-
metric synthesis of an amphetamine-type compound (i.e., 1-arylpropan-2-amines) from
tert-butyl (+)-trans-3-(1,3-benzodioxol-5-yl)-1-benzylaziridine-2-carboxylate ((+)-
trans-3c), obtained by the aziridination reaction [12] with (R,R)-guanidinium salt
(R,R)-1 (X=Ph, R1 =Bn, R2 =tBu; see Scheme 2), after a slight modification of the
reported method [17] (Scheme 6). Thus, a solution of (+)-trans-3c (87% ee) in
MeOH was hydrogenated over Pd(OH)2/C in the presence of di(tert-butyl) dicarbonate
((Boc)2O) to give the expected N-Boc-protected amino ester (+)-11 in high yield, as
reported earlier [10]. The absolute configuration of the chiral aziridinecarboxylate
(+)-trans-3c was deduced to be (2S,3R) based on the fact that trans-(2R,3S)- and cis-
(2R,3R)-aziridine derivatives were obtained when the (S,S)-guanidinium salt, the enan-
tiomer of (R,R)-1, was used as a chiral template [10]. Reduction of the ester function in
(+)-11 with lithium borohydride (LiBH4) afforded alcohol (ꢀ)-12, hydrogenolysis of
which was achieved with N-Selectrideꢃ after conversion of the alcoholic function to
an iodide (+)-13. Thus, (+)-tert-butyl [(1R)-2-(1,3-benzodioxol-5-yl)-1-methylethyl]-

136
Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 6. Asymmetric Synthesis of the Amphetamine-Type Compound (+)-14
carbanate ((+)-14) was smoothly and effectively produced in 41% overall yield from
the (2S,3R)-aziridinecarboxylate (+)-trans-3c. The ee of (+)-14 obtained was deter-
mined to be 97%, in spite of the 87% ee of the starting( +)-trans-3c, because of the puri-
fication procedures of crystalline synthetic intermediates by recrystallization.
3. Conclusions. – We found that ring-opening reactions of ꢀunactivatedꢁ 3-aryl-1-
benzylaziridine-2-carboxylates carryingEWG-substituted aryl residues stereospecifi-
cally react with inversion at C(3) of the aziridine ringby an SN2-type reaction, as
reported earlier [6–8]. On the other hand, in the cases of the EDG-substituted aryla-
ziridines, syn-amino alcohol derivatives were obtained as the major component of the
diastereoisomer mixture, independently of the configuration of the starting aziridines3).
These results could reasonably be explained by Cramꢁs transition-state model. In the
reactions with the EDG-substituted arylaziridine-2-carboxylates with aromatic C-
nucleophiles, an SN2 reaction yielding anti-type products was observed as the preferred
reaction. The reductively ring-opened product of (+)-tert-butyl (2S,3R)-trans-3-(1,3-
benzodioxol-5-yl)aziridine-2-carboxylate ((+)-trans-3c) was effectively and smoothly
converted to (+)-tert-butyl [(1R)-2-(1,3-benzodioxol-5-yl)-1-methylethyl]carbamate
((+)-14) with high retention of optical purity.
This work was supported by a Grant-in-Aid for Scientific Research (14370717) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. Dainippon Ink and Chemical Award in the
Society of Synthetic Organic Chemistry, Japan, is acknowledged by T. K.
3
)
Zwanenburg and co-workers [6] had also observed the formation of mixtures of diastereoisomeric
products in the ring-opening reactions of trans-methyl 3-(4-methoxyphenyl)aziridine-2-carboxylate
with hydrogen chloride and thiophenol.

Helvetica Chimica Acta – Vol. 90 (2007)
137
Experimental Part
1. General. Anh. THF and CH2Cl2 were purchased from Wako and Kanto Chemicals, resp. DMF,
Et3N, MeCN, and EtOH were distilled from calcium hydride (CaH2). Startingaziridines were prepared
according to the reported procedure [12]. Column chromatography (CC): silica gel 60 (spherical, 70–230
mesh; Fuji Silysia FL100D or Kanto Chemicals). [a]D: Jasco P-1020. IR Spectra: Jasco FT/IR-300E spec-
trophotometer ATR=attenuated total reflectance; in cmꢀ1. NMR Spectra: Jeol JNM-ECP400 spectrom-
eter; at 400 (1H) and 100 MHz (13C); CDCl3 solns. with SiMe4 as an internal standard (1H) and the middle
resonance of CDCl3 (d 77.0) as an internal standard (13C); d in ppm, J in Hz; dif.=diffused. EI-MS: Jeol
GC-Mate with direct inlet, or Hewlett-Packard-5890 (series II) gas chromatograph and 5971A mass-selec-
tive detector for GC/MS. HR-FAB-MS: JMS-HX110 with 3-nitrobenzyl alcohol as a matrix.
2. Ring-Opening Reactions of Aziridine-2-carboxylates 3 in the Presence of TsOH (Table 1). A soln.
of 3 in 50% THF/H2O in the presence of TsOH was stirred under the conditions given in the footnotes of
Table 1, and in some cases CC (hexane/AcOEt) was carried out for the purification of ring-opened prod-
ucts.
tert-Butyl (2RS,3RS)-2-(Benzylamino)-3-hydroxy-3-phenylpropanoate (anti-5a): From trans-3a
(Entry 1). Colorless needles. M.p. 95–968. IR (KBr): 3290 (NH), 3064 (OH), 1726 (CO). 1H-NMR:
t
1.33 (s, Bu); 2.08 (br. s, NH); 3.57 (d, J=5.1, HꢀC(2)); 3.68, 3.881 (2d, J=12.9, PhCH2); 3.880 (br. s,
OH); 4.95 (d, J=5.1, HꢀC(3)); 7.23–7.35 (m, 10 arom. H). 13C-NMR: 27.9; 52.4; 66.2; 72.9; 81.9;
126.3; 127.2; 127.6; 128.0; 128.3; 128.4; 139.3; 140.3; 171.3. FAB-MS: 328 ([M+H]+). Anal. calc. for
C20H25NO3: C 73.37, H 7.70, N 4.28; found: C 73.59, H 7.68, N 4.24.
tert-Butyl (2RS,3SR)-2-(Benzylamino)-3-hydroxy-3-phenylpropanoate (syn-5a): From cis-3a (Entry
2). Colorless needles. M.p. 45–478. IR (KBr): 3437 (OH); 3287 (NH); 1720 (CO). 1H-NMR: 1.22 (s, tBu);
3.26 (d, J=8.1, HꢀC(2)); 3.67, 3.78 (2d, J=12.9, PhCH2); 4.51 (d, J=8.1, HꢀC(3)); 7.27–7.36 (m, 10
arom. H). 13C-NMR: 27.7; 52.4; 68.3; 74.7; 81.7; 127.1; 127.3; 128.0; 128.1; 128.2; 128.5; 139.2; 140.1;
172.1. FAB-MS: 328 ([M+H]+). Anal. calc. for C20H25NO3: C 73.37, H 7.70, N 4.28; found: C 73.36, H
7.54, N 4.14.
tert-Butyl (2RS,3RS)-2-(Benzylamino)-3-(4-chlorophenyl)-3-hydroxypropanoate (anti-5b): From
trans-3b (Entry 3). Colorless needles. M.p. 124–1258. IR (KBr): 3290 (NH); 3090 (OH); 1726 (CO).
t
1H-NMR: 1.34 (s, Bu); 3.53 (d, J=5.1, HꢀC(2)); 3.67, 3.87 (2d, J=13.0, PhCH2); 4.91 (d, J=5.1, Hꢀ
C(3)); 7.21 (d, J=8.4, 2 arom. H); 7.26–7.35 (m, 7 arom. H). 13C-NMR: 27.9; 52.5; 66.0; 72.3; 82.2;
127.3; 127.7; 128.1; 128.3; 128.5; 133.3; 138.9; 139.1; 171.3. FAB-MS: 364 ([M(37Cl)+H]+), 362
([M(35Cl)+H]+). Anal. calc. for C20H24ClNO3: C 66.38, H 6.69, N 3.87; found: C 66.43, H 6.58, N 3.73.
tert-Butyl (2RS,3SR)-2-(Benzylamino)-3-(4-chlorophenyl)-3-hydroxypropanoate (syn-5b): From cis-
1
3b (Entry 4). Colorless needles. M.p. 86–878. IR (KBr): 3420 (OH); 3281 (NH); 1717 (CO). H-NMR:
t
1.26 (s, Bu); 2.25 (br. s, OH); 3.19 (d, J=7.8, HꢀC(2)); 3.67, 3.78 (2d, J=12.9, PhCH2); 4.16 (br. s,
NH); 4.50 (d, J=7.8, HꢀC(3)); 7.25–7.36 (m, 9 arom. H). 13C-NMR: 27.8; 52.5; 68.2; 73.9; 82.0;
127.3; 128.2; 128.3; 128.47; 128.52; 123.7; 138.8; 139.0; 171.9. FAB-MS: 364 ([M(37Cl)+H]+), 362
([M(35Cl)+H]+). Anal. calc. for C20H24ClNO3: C 66.38, H 6.69, N 3.87; found: C 66.50, H 6.75, N 3.81.
tert-Butyl (2RS,3RS)/(2RS,3SR)-3-(1,3-Benzodioxol-5-yl)-2-(benzylamino)-3-hydroxypropanoate
(anti/syn-5c; anti/syn 1:5): From trans-3c (Entry 6). Colorless prisms. M.p. 68–698. IR (neat): 3422
1
t
t
(OH); 1725 (CO). H-NMR: 1.27 (s, 9 H”5/6, Bu); 1.38 (s, 9 H”1/6, Bu); 3.19 (d, J=8.0, 1 H”5/6,
HꢀC(2)); 3.52 (d, J=5.2, 1 H”1/6, HꢀC(2)); 3.66, 3.88 (2d, J=13.2, 2 H”1/6, PhCH2); 3.68, 3.80 (2d,
J=13.2, 2 H”5/6, PhCH2); 4.42 (d, J=8.0, 1 H”5/6, HꢀC(3)); 4.87 (d, J=5.2, 1 H”1/6, HꢀC(3));
5.93 (s, 2 H”1/6, OCH2O); 5.94 (s, 2 H”5/6, OCH2O); 6.73 (s, 2 H”1/6, arom. H); 6.73–6.76 (m, 2
H”5/6, arom. H); 6.87 (s, 1 H”5/6, arom. H); 6.79 (s, 1 H”1/6, arom. H); 7.27–7.34 (m, 5 H”5/6,
arom. H); 7.28–7.34 (m, 5 H”1/6, arom. H). 13C-NMR (major isomer): 27.8; 52.3; 68.5; 74.4; 81.8;
100.9; 106.8; 107.3; 107.8; 120.7; 127.3; 128.2; 128.5; 139.1; 147.3; 147.6; 172.1. EI-MS: 371 (1, M+),
353 (11), 165 (100). Anal. calc. for C21H25NO5: C 67.91, H 6.78, N 3.77; found: C 67.88, H 6.85, N 3.71.
tert-Butyl (2RS,3RS)-2-(Benzylamino)-3-hydroxy-3-(4-methoxyphenyl)propanoate (anti-5d): From
trans-3d (Entry 7). Colorless needles. M.p. 97–988. Obtained as a major isomer after CC. IR (KBr):
1
t
3420 (OH); 3298 (NH); 1726 (CO). H-NMR: 1.36 (s, Bu); 2.02 (br. s, OH); 3.54 (d, J=5.1, HꢀC(2));
3.66, 3.87 (2d, J=12.9, PhCH2); 3.78 (s, MeO); 3.80 (br. s, NH); 4.90 (br. d, J=5.1, HꢀC(3)); 6.83

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Helvetica Chimica Acta – Vol. 90 (2007)
(dif. d, J=8.5, 2 arom. H); 7.19 (dif. d, J=8.5, 2 arom. H); 7.24–7.35 (m, 5 arom. H). 13C-NMR: 28.0; 52.6;
55.2; 66.3; 72.5; 81.9; 113.5; 127.2; 127.5; 128.3; 128.5; 132.4; 139.4; 159.1; 171.4. Anal. calc. for
C21H27NO4: C 70.56, H 7.61, N 3.92; found: C 70.59, H 7.59, N 3.87.
tert-Butyl (2RS,3SR)-2-(Benzylamino)-3-hydroxy-3-(4-methoxyphenyl)propanoate (syn-5d): From
cis-3d (Entry 9). Colorless needles. M.p. 50–528. Obtained as a major isomer after CC. IR (ATR):
1
t
3427 (OH), 3282 (NH), 1720 (CO). H-NMR: 1.23 (s, Bu); 2.18 (br. s, OH); 3.24 (d, J=8.1, HꢀC(2));
3.68, 3.80 (2d, J=12.9, PhCH2); 3.79 (s, MeO); 4.11 (br. s, NH); 4.45 (d, J=8.1, HꢀC(3)); 6.86 (dif. d,
J=8.8, 2 arom. H); 7.24–7.35 (m, 7 arom. H). 13C-NMR: 27.8; 52.4; 55.3; 68.5; 74.3; 81.6; 113.6;
127.3; 128.3; 128.4; 128.5; 132.1; 139.2; 159.5; 172.2. HR-FAB-MS: 357.1914 (M+, C21H27NO4þ ; calc.
357.1940).
Ethyl
(2RS,3RS)/(2RS,3SR)-2-(Benzylamino)-3-{1-[(tert-butoxy)carbonyl]-1H-indol-4-yl}-3-
hydroxypropanoate (anti/syn-5e; anti/syn 1:6): From trans-3e (Entry 10). Colorless oil. IR (neat): 3338
(NH, OH); 1734 (CO). 1H-NMR: 0.88 (d, J=7.1, 3 H”1/7, MeCH2); 0.95 (t, J=7.2, 3 H”6/7,
t
MeCH2); 1.67 (s, 9 H, Bu); 3.64 (d, J=8.5, 1 H”1/7, HꢀC(2)); 3.76 (d, J=14.9, 2 H”1/7, PhCH2);
3.91 (d, J=3.4, 1 H”6/7, HꢀC(2)); 3.91–3.97 (m, 2 H, MeCH2O); 4.07, 4.22 (2d, J=12.8, 2 H”6/7,
PhCH2); 5.14 (d, J=8.5, 1 H”1/7, HꢀC(3)); 5.78 (d, J=3.4, 1 H”6/7, HꢀC(3)); 6.58 (d, J=3.5, 1
H”1/7, HꢀC(3’)); 6.66 (d, J=3.8, 1 H”6/7, HꢀC(3’)); 7.17–7.29 (m, 5 arom. H); 7.44 (d, J=6.8, 2
arom. H); 7.52 (d, J=3.8, 1 H”6/7, HꢀC(2’)); 8.06 (d, J=6.8, 1 H, HꢀC(7’)). EI-MS: 438 (1, M+), 91
(100).
tert-Butyl (4RS,5SR)/(4RS,5RS)-5-(1,3-Benzodioxol-5-yl)-3-benzyl-2-oxooxazolidine-4-carboxylate
(trans/cis-6). The 5 :1 mixture syn/anti-5c (0.034 g, 0.09 mmol: syn/anti=d.r.=5 :1), obtained as descri-
bed in Entry 6 of Table 1, and (Im)2CO (0.02 g, 0.12 mmol) in CH2Cl2 (1 ml) was stirred at 408 for 3
days. After evaporation of the solvent, purification of the residue by CC (hexane/AcOEt 3 :1) afforded
an inseparable mixture trans/cis-6 as a colorless oil (0.030 g, 83%, trans/cis=d.r.=6 :1). IR (neat): 1763
(CO). 1H-NMR: 1.18 (s, 9 H”1/7, tBu); 1.48 (s, 9 H”6/7, tBu); 3.76 (d, J=5.6, 1 H”6/7, HꢀC(4)); 4.12
(d, J=9.2, 1 H”1/7, HꢀC(4)); 4.24, 4.99 (2d, J=14.8, 2 H”6/7, PhCH2); 4.99, 5.52 (2d, J=14.8, 2 H”1/7,
PhCH2); 5.32 (d, J=5.4, 1 H”6/7, HꢀC(5)); 5.52 (d, J=9.1, 1 H”1/7, HꢀC(5)); 5.94 (s, 2 H”1/7,
OCH2O); 5.96 (s, 2 H”6/7, OCH2O); 6.68 (d, J=1.6, 1 H”6/7, arom. H); 6.72 (dd, J=8.1, 1.6, 1 H”6/
7, arom. H); 6.75 (d, J=8.1, 1 H”6/7, arom. H); 6.80–6.82 (m, 3 H”1/7, arom. H); 7.22–7.37 (m, 5 H,
arom. H). 13C-NMR (major isomer): 27.9; 47.2; 64.1; 77.1; 83.6; 101.4; 105.7; 108.3; 119.4; 128.2;
128.4; 128.9; 131.8; 134.9; 148.17; 148.20; 157.1; 168.1. EI-MS: 397 (28, M+), 252 (54), 91 (100).
3. Ring-Opening Reactions of trans-2-[(Silyloxy)methyl]- or 2-(Hydroxymethyl)aziridine 7 in the
Presence of TsOH (Table 2). trans-2-[(Silyloxy)methyl]- or 2-(hydroxymethyl)aziridine 7 was treated
in either CH2Cl2 or MeCN under the conditions given in Table 2, and in some cases CC (hexane/
AcOEt) was carried out for the purification of ring-opened products.
(1RS,2RS)/(1RS,2SR)-2-(Benzylamino)-3-tris[(isopropylsilyl)oxy]-1-(4-methoxyphenyl)propan-1-ol
(anti/syn-8d; R1 =PhCH2, R2 =iPr3Si; anti/syn 1:3): From trans-7d (R1 =PhCH2; R2 =iPr3Si; Entry 1).
i
Colorless oil. IR (neat): 3419 (NH, OH). 1H-NMR: 0.97–1.13 (m, 21 H, Pr); 2.68 (ddd, J=8.6, 3.6,
3.6, 1 H”3/4, HꢀC(2)); 2.90 (ddd, J=7.2, 5.2, 5.2, 1 H”1/4, HꢀC(2)); 3.46 (dd, J=10.0, 5.2, 1 H”1/4,
CH2(3)); 3.48 (dd, J=10.4, 3.6, 1 H”3/4, CH2(3)); 3.66 (dd, J=10.2, 7.2, 1 H”1/4, CH2(3)); 3.68 (d,
J=12.8, 1 H”3/4, PhCH2); 3.80 (s, 3 H”3/4, MeO); 3.82 (dd, J=10.2, 3.2, 1 H”3/4, CH2(3)); 3.89 (d,
J=12.8, 1 H, PhCH2); 4.51 (d, J=8.0, 1 H”3/4, HꢀC(1)); 4.88 (d, J=4.8, 1 H”1/4, HꢀC(1)); 6.86
(dif. d, J=8.4,
C26H42NO3Si+; calc. 444.2934).
2 arom. H); 7.23–7.36 (m, 8
arom. H). HR-FAB-MS: 444.2918 ([M+H]+,
(1RS,2RS)/(1RS,2SR)-2-(Benzylamino)-1-(4-methoxyphenyl)propane-1,3-diol (anti/syn-8d; R1 =
PhCH2; R2 =H; anti/syn 1:4): From trans-7d (R1 =PhCH2; R2 =H; Entry 2). Colorless oil. IR (neat):
1
3419 (NH, OH). H-NMR: 2.79 (ddd, J=7.6, 3.7, 3.7, 1 H”4/5, HꢀC(2)); 2.86 (ddd, J=5.4, 5.4, 4.4, 1
H”1/5, HꢀC(2)); 3.38 (dd, J=11.2, 3.3, 1 H”4/5, CH2(3)); 3.56 (dd, J=11.2, 4.4, 1 H”1/5, CH2(3));
3.64 (dd, J=11.2, 5.2, 1 H”1/5, CH2(3)); 3.66 (dd, J=11.2, 4.0, 1 H”4/5, CH2(3)); 3.72, 3.84 (2d,
J=13.2, 2 H”4/5, PhCH2); 3.81 (s, 3 H, MeO); 4.63 (d, J=7.6, 1 H”4/5, HꢀC(1)); 4.82 (d, J=5.7, 1
H”1/5, HꢀC(1)); 6.89 (dif. d, J=8.8, 2 arom. H); 7.23–7.35 (m, 8 arom. H). 13C-NMR (major isomer):
51.4; 55.3; 59.7; 64.1; 73.3; 113.8; 127.1; 127.7; 128.1; 128.5; 133.9; 139.9; 159.2. HR-FAB-MS: 288.1600
([M+H]+, C17H22NOþ3 ; calc. 288.1600).

Helvetica Chimica Acta – Vol. 90 (2007)
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tert-Butyl 4-[(1RS,2RS)/(1RS,2SR)-2-(Benzylamino)-3-{[(tert-butyl)dimethylsilyl]oxy}-1-hydroxy-
propyl]indole-1-carboxylate (anti/syn-8e R1 =PhCH2, R2 =tBuMe2Si; anti/syn 1:20). From trans-7e
(R1 =PhCH2, R2 =tBuMe2Si; Entry 3). Colorless oil. IR (neat): 3339 (NH, OH), 1735. 1H-NMR
t
(major isomer): ꢀ0.14, ꢀ0.05 (each s, 3 H, MeSi); 0.78, 1.67 (each s, 9 H, Bu); 3.33 (m, HꢀC(2));
3.63 (dd, J=11.7, 3.1, 1 H, CHCH2O); 4.02 (dd, J=11.7, 7.3, 1 H, CHCH2O); 4.28, 4.42 (2d, J=13.4,
PhCH2); 5.65 (s, HꢀC(1)); 6.39 (d, J=4.0, HꢀC(3’)); 7.21–7.35 (m, 5 arom. H); 7.48 (d, J=4.0, Hꢀ
C(2’)); 7.61 (d, J=6.8, 2 arom. H); 8.05 (d, J=8.0, HꢀC(7’)). EI-MS: 511 (1, [M+H]+), 265 (100), 91 (94).
tert-Butyl
4-{(1RS,2RS)/(1RS,2SR)-3-{[(tert-Butyl)dimethylsilyl]oxy}-2-[(prop-2-enyl)amino]-1-
hydroxypropyl}-1H-indole-1-carboxylate (anti/syn-8e; R1=CH2=CHCH2, R2=tBuMe2Si; anti/syn 1:7):
From trans-7e (R1 =CH2=CHCH2, R2 =tBuMe2Si; Entry 4): Colorless oil. IR (neat): 3337 (NH, OH),
1
t
1735. H-NMR (major isomer): ꢀ0.19, ꢀ0.12 (each s, 3 H, MeSi); 0.75, 1.67 (each s, 9 H, Bu); 3.38
(m, HꢀC(2)); 3.66 (dd, J=12.0, 2.8, 1 H, CHCH2O); 3.81 (dd, J=13.6, 7.2, 1 H, NCH2CH); 3.91 (dd,
J=13.6, 6.4, 1 H, NCH2CH); 3.95 (dd, J=12.0, 7.2, 1 H, CHCH2O); 5.34 (d, J=10.0, 1 H, CH=CH2);
5.44 (d, J=16.8, 1 H, CH=CH2); 5.84 (s, HꢀC(1)); 6.15 (dddd, J=16.8, 10.0, 7.2, 6.4, CH=CH2); 6.85
(d, J=3.6, HꢀC(3’)); 7.14 (d, J=8.2, HꢀC(5’)); 7.26 (dd, J=6.4, 6.4, HꢀC(6’)); 7.55 (d, J=3.6, Hꢀ
C(2’)); 8.07 (d, J=8.2, HꢀC(7’)). EI-MS: 460 (0.1, M+), 214 (100).
4. Ring-Opening Reactions of EDG-Substituted trans-Aziridine-2-carboxylates trans-3 with AcOH
(Table 3). EDG-Substituted trans-aziridine-2-carboxylate trans-3c or trans-3e was treated with AcOH
under the conditions noted in Table 1, and in some cases, CC (hexane/AcOEt) was carried out for the
purification of ring-opened products.
tert-Butyl
(2RS,3RS)/(2RS,3SR)-3-(Acetyloxy)-3-(1,3-Benzodioxol-5-yl)-2-(benzylamino)propa-
noate (anti/syn-9c; R1 =Ac; anti/syn 1:10): From trans-3c in CH2Cl2 (Entry 2). Colorless needles. M.p.
1
74–758. IR (neat): 1733 (CO). H-NMR: 1.38 (s, 9 H”1/11, Me3C); 1.45 (s, 9 H”10/11, Me3C); 2.03 (s,
3 H”10/11, COMe); 2.09 (s, 3 H”1/11, COMe); 3.41 (d, J=5.6, 1 H”1/11, HꢀC(2)); 3.48 (d, J=7.2, 1
H”10/11, HꢀC(2)); 3.58, 3.82 (2d, J=13.6, 2 H”1/11, PhCH2); 3.63, 3.83 (2d, J=13.4, 2 H”10/11,
PhCH2); 5.79 (d, J=7.2, 1 H”10/11, HꢀC(3)); 5.94 (d, J=5.6, 1 H”1/11, HꢀC(3)); 5.95 (s, 2 H,
OCH2O); 6.74 (s, 1 H”1/11, arom. H); 6.76 (s, 1 H”10/11, arom. H); 6.80 (d, J=1.6, 1 H”10/11,
arom. H); 6.82 (d, J=1.6, 1 H”1/11, arom. H); 6.83 (d, J=1.6, 1 H”10/11, arom. H); 6.90 (d, J=1.6,
1 H”1/11, arom. H); 7.19–7.29 (m, 5 arom. H). 13C-NMR (major isomer): 21.0; 28.0; 51.9; 65.0; 75.8;
77.3; 81.7; 101.0; 107.9; 121.3; 128.1; 128.2; 131.0; 139.4; 147.5; 169.5; 171.2. FAB-MS: 414 ([M+H]+).
Anal. calc. for C23H27NO6: C 66.81, H 6.58, N, 3.39: found: C 66.76, H 6.56, N 3.30.
tert-Butyl (2RS,3RS)/(2RS,3SR)-3-(1,3-Benzodioxol-5-yl)-2-(benzylamino)-3-methoxypropanoate
(anti/syn-9c; R1 =Me; anti/syn 1:10): From trans-3c in MeOH (Entry 3). Colorless oil. IR (neat): 1725.
1H-NMR (major isomer): 1.44 (s, tBu); 3.21 (s, MeO); 3.30 (d, J=7.0, HꢀC(2)), 3.59, 3.78 (2d,
J=13.4, PhCH2); 4.22 (d, J=7.0, HꢀC(3)); 5.96 (s, OCH2O); 6.77–6.80 (m, 3 arom. H); 7.16–7.26
(m, 5 arom. H). 13C-NMR (major isomer): 28.0; 51.7; 57.0; 66.7; 75.8; 81.1; 84.6; 100.9; 107.6; 107.8;
121.4; 126.9; 128.1; 128.2; 132.4; 139.6; 147.3; 147.7; 172.4. EI-MS: 385 (1, M+), 165 (100).
Ethyl (2RS,3SR)-3-(Acetyloxy)-2-(benzylamino)-3-[1-[(tert-butoxy)carbonyl]-1H-indol-4-yl}propa-
noate (syn-9e; R1 =Ac): From trans-3e without solvent (Entry 4). Pale yellow oil. IR (neat): 3340
t
(NH), 1736 (CO). 1H-NMR: 1.19 (t, J=7.1, MeCH2); 1.67 (s, Bu); 2.05 (s, MeCO); 3.56, 3.77 (2d,
J=13.6, PhCH2); 3.78 (d, J=7.0, HꢀC(2)); 4.07–4.17 (m, MeCH2O); 6.23 (d, J=7.0, HꢀC(3)); 6.70
(d, J=3.8, HꢀC(3’)); 7.09–7.11 (m, 2 arom. H); 7.18–7.21 (m, 4 arom. H); 7.25–7.29 (m, 1 arom. H);
7.57 (d, J=3.8, HꢀC(2’)); 8.13 (d, J=8.2, HꢀC(7’)). EI-MS: 480 (3, M+), 246 (100).
5. Reactions of 3c with C-Nucleophiles (Table 4). A mixture of trans-3c and a C-nucleophile in CH2Cl2
in either the presence or absence of a catalyst was stirred at r.t., 308, 08, or 408 for an appropriate time
under Ar. Workup followed by purification by CC afforded a 3-aryl-3-(1,3-benzodioxol-5-yl)-2-(benzyl-
amino)propanonate 10.
tert-Butyl (2RS,3SR)-3-(1,3-Benzodioxol-5-yl)-2-(benzylamino)-3-(1H-indol-3-yl)propanoate (anti-
10a): With 1H-indole in the presence of InCl3 (Entry 1). Colorless solid. M.p. 170–1728. IR (neat):
1
t
3418 (NH); 1721, 1706 (CO). H-NMR: 1.25 (s, Bu); 3.64, 3.86 (2d, J=13.2, PhCH2); 3.84 (d, J=7.2,
HꢀC(2)); 4.51 (d, J=7.2, HꢀC(3)); 5.88, 5.89 (2d, J=1.2, OCH2O); 6.68 (d, J=7.9, 1 arom. H); 6.79
(d, J=1.5, 1 arom. H); 6.81 (dd, J=7.9, 1.6, 1 arom. H); 7.02 (dd, J=7.5, 7.1, 1 arom. H); 7.13 (dd,
J=7.5, 7.1, 2 arom. H); 7.22–7.31 (m, 6 arom. H); 7.45 (d, J=7.9, 1 arom. H); 7.99 (br. s, NH). 13C-

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NMR: 27.8; 45.3; 50.6; 52.3; 65.5; 81.0; 100.8; 107.8; 109.2; 110.9; 117.0; 119.2; 119.3; 121.9; 122.0; 126.9;
127.0; 128.2; 128.3; 134.9; 135.9; 139.9; 146.2; 147.4; 173.1. EI-MS: 470 (2, M+); 250 (100), 91 (36). Anal.
calc. for C29H30N2O4: C 74.02, H 6.43, N 5.95; found: C 74.01, H 6.39, N 5.76.
Crystal Data of 10a: C29H30N2O4, Mr 470.55; monoclinic; a=20.4716(12), b=6.0519(4),
c=19.5419(12) Š, b=93.2800(10)8, V=2417.1(3) Š3; T=150 K, space group P21/c (no. 14); Z=4; m
(Mo-Ka)=0.086 mmꢀ1; 13787 reflections measured, 5465 unique (Rint =0.0407); 327 parameters refined;
R1ACHTREUNG
(F2 >2s(F2))=0.0410, wR(F2)=0.1057. CCDC-614921 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
tert-Butyl (2RS,3SR)-3-(1,3-Benzodioxol-5-yl)-2-(benzylamino)-3-(2-methyl-1H-indol-3-yl)propa-
noate (anti-10b): With 2-methyl-1H-indole in the presence of InCl3 (Entry 3). Yellow oil. IR (neat):
1
t
3407 (NH), 1718 (CO). H-NMR: 0.89 (s, Bu); 2.38 (s, MeC); 3.70, 3.86 (2d, J=13.0, PhCH2); 4.18 (d,
J=11.2, HꢀC(2)); 4.24 (d, J=11.2, HꢀC(3)); 5.57, 5.87 (2d, J=1.6, OCH2O); 6.67 (d, J=8.0, 1 arom.
H); 6.81 (dd, J=8.0, 1.6, 1 arom. H); 6.85 (d, J=1.6, 1 arom. H); 6.96–7.05 (m, 2 arom. H); 7.19 (d,
J=8.0, 1 arom. H); 7.27–7.35 (m, 5 arom. H); 7.49 (d, J=8.0, 1 arom. H); 7.70 (br. s, NH). 13C-NMR:
12.2; 27.9; 45.4; 52.3; 63.8; 80.3; 100.7; 107.8; 109.0; 110.0; 112.1; 119.2; 119.8; 120.7; 121.1; 127.1;
127.8; 128.3; 128.6; 131.5; 135.1; 135.8; 139.6; 145.6; 147.4; 173.9. EI-MS: 484 (2, M+), 264 (100), 91
(30). HR-FAB-MS: 485.2488 ([M+H]+, C30H33N2O4þ ; calc. 485.2440).
tert-Butyl (2RS,3RS)/(2RS,3SR)-3-(1,3-Benzodioxol-5-yl)-2-(benzylamino)-3-(1H-pyrrol-2-yl)pro-
panoate (anti/syn-10c; anti/syn 4 :1): With 1H-pyrrole in the presence of InCl3 (Entry 4). Yellow oil. IR
1
t
t
(neat): 3372 (NH); 1719 (CO). H-NMR: 1.22 (s, 9 H”1/5, Bu); 1.45 (s, 9 H”4/5, Bu); 3.60, 3.86 (2d,
J=12.6, 2 H”4/5, PhCH2); 3.65, 3.80 (2d, J=12.8, 2 H”1/5, PhCH2); 3.65 (d, J=9.2, 1 H”1/5, Hꢀ
C(2)); 3.73 (d, J=4.5, 1 H”4/5, HꢀC(2)); 4.04 (d, J=9.2, 1 H”1/5, HꢀC(3)); 4.44 (d, J=4.5, 1 H”4/
5, HꢀC(3)); 5.88, 5.90 (2m, 2 H”4/5, OCH2O); 5.93 (s, 2 H”1/5, OCH2O); 5.95 (br. s, 1 H”4/5, arom.
H); 6.05 (dd, J=2.8, 1 H”1/5, arom. H); 6.10 (d, J=3.0, 1 H”4/5, arom. H); 6.59 (dd, J=7.6, 1.6, 1
H”4/5, arom. H); 6.66–6.68 (m, 2 H”4/5, arom. H); 6.70–6.78 (m, 4 H”1/5, arom. H); 7.28–7.37 (m,
5 arom. H); 9.85 (br. s, 1 H”4/5, NH); 10.02 (br. s, 1 H”1/5, NH). 13C-NMR (major isomer): 28.1;
45.7; 52.5; 65.0; 81.8; 100.9; 106.0; 107.8; 107.9; 109.0; 116.4; 121.7; 127.3; 128.4; 128.6; 132.5; 133.5;
139.4; 146.4; 147.5; 172.3. EI-MS: 420 (4, M+), 200 (100). HR-FAB-MS: 421.2122 ([M+H]+,
C25H29N2Oþ4 ; calc. 421.2127).
tert-Butyl
(2RS,3RS)/(2RS,3SR)-3-(1,3-Benzodioxol-5-yl)-2-(benzylamino)-3-(furan-2-yl)propa-
noate (anti/syn-10d; anti/syn 10 :1). With furan in the presence of InCl3 (Entry 6). Light brown oil. IR
1
t
(neat): 3338 (NH); 1719 (CO). H-NMR (major isomer): 1.20 (s, Bu); 3.60, 3.83 (2d, J=13.4, PhCH2);
3.69 (d, J=8.8, HꢀC(2)); 4.16 (d, J=8.8, HꢀC(3)); 5.90, 5.91 (2d, J=1.2, OCH2O); 6.13 (d, J=3.2,
1 arom. H); 6.29 (dd, J=3.0, 1.7, 1 arom. H); 6.70 (d, J=8.0, 1 arom. H); 6.76 (dd, J=8.0, 1.6, 1 arom.
H); 6.86 (d, J=1.6, 1 arom. H); 7.18–7.32 (m, 6 arom. H). 13C-NMR (major isomer): 27.8; 48.5; 52.1;
64.9; 81.1; 100.9; 107.1; 107.9; 109.4; 110.2; 122.2; 126.9; 128.20; 128.24; 132.8; 139.7; 141.5; 146.5;
147.4; 154.4; 172.6. EI-MS: 421 (2, M+), 220 (51), 164 (100), 91 (55). HR-FAB-MS: 422.1964
([M+H]+, C25H28NOþ5 ; calc. 422.1967).
tert-Butyl (2RS,3SR)/(2RS,3RS)-3-(1,3-Benzodioxol-5-yl)-2-(benzylamino)-3-(2,4-dimethoxyphe-
nyl)propanoate (anti/syn-10e; anti/syn 2 :1): With 1,3-dimethoxybenzene in the presence of InCl3
1
t
(Entry 7): Yellow oil. IR (neat): 3332 (NH); 1718 (CO). H-NMR (major isomer): 1.25 (s, Bu); 3.82,
3.59 (2d, J=13.4, PhCH2); 3.71, 3.78 (2s, 2 MeO); 3.75 (d, J=10.4, HꢀC(2)); 4.47 (d, J=10.4, Hꢀ
C(3)); 5.84, 5.85 (2d, J=1.5, OCH2O); 6.35–6.41 (m, 2 arom. H); 6.63 (d, J=8.4, 1 arom. H);
6.71–6.77 (m, 2 arom. H); 7.01 (d, J=8.4, 1 arom. H); 7.19–7.32 (m, 6 arom. H). 13C-NMR (major iso-
mer): 27.8; 46.3; 51.9; 55.26; 55.29; 64.3; 80.8; 98.6; 100.6; 104.1; 107.7; 109.5; 122.0; 122.3; 126.9; 128.1;
128.4; 128.6; 135.5; 139.7; 145.8; 147.1; 158.2; 159.3; 173.7. EI-MS: 491 (0.2, M+), 271 (100), 135 (33). HR-
FAB-MS: 492.2421 ([M+H]+, C29H33NO6þ ; calc. 492.2308).
tert-Butyl (2RS,3SR)/(2RS,3RS)-3-(1,3-Benzodioxol-5-yl)-2-(benzylamino)-3-[4-(dimethyamino)-
phenyl]propanoate (anti/syn-10f; anti/syn 3.6 :1). With N,N-dimethylaniline in the presence of InCl3
1
t
(Entry 9): Yellow oil. IR (neat): 3394 (NH); 1708 (CO). H-NMR (major isomer): 1.23 (s, Bu); 2.86 (s,
Me2N); 3.62, 3.84 (2d, J=13.2, PhCH2); 3.75 (d, J=9.6, HꢀC(2)); 3.96 (d, J=9.6, HꢀC(3)); 5.88, 5.89
(2d, J=1.5, OCH2O); 6.61 (d, J=8.8, 2 arom. H); 6.68–6.70 (m, 3 arom. H); 7.11 (d, J=8.8, 2 arom.
H); 7.21–7.31 (m, 5 arom. H). 13C-NMR (major isomer): 27.9; 46.3; 51.9; 55.3; 64.2; 80.8; 98.6; 100.6;

Helvetica Chimica Acta – Vol. 90 (2007)
141
104.1; 107.7; 109.4; 122.2; 126.9; 128.1; 128.5; 135.5; 139.7; 145.8; 147.0; 158.2; 159.3; 173.7. EI-MS: 474
(1, M+), 254 (100), 91 (17). Anal. calc. for C29H34N2O4: C 73.39, H 7.22, N 5.90; found: C 73.33, H 7.18, N
5.68.
6. Synthesis of the Amphetamine-Type Compound (+)-14. (+)-tert-Butyl (2S)-3-(1,3-benzodioxol-5-
yl)-2-{[(tert-butoxy)carbonyl]amino}propanoate ((+)-11). A mixture of (+)-trans-3c (0.457 g, 1.29
mmol; 87% ee), Boc2O (0.300 g, 1.37 mmol), and 20% Pd(OH)2/C (0.134 g) in MeOH (8 ml) was stirred
at r.t. for 6.5 h under H2. After filtration of the mixture through a Celite pad, the filtrate was concentrated.
Purification of the residue by CC (hexane/AcOEt 10 :1) afforded (+)-11 (0.457 g, 97%), a part of which
was recrystallized from hexane. Colorless prisms. M.p. 118–1198 [a]2D4 =+26.1 (c=1.0, CHCl3). IR
1
(neat): 3343 (NH), 1720 (CO), 1702 (CO). H-NMR: 1.43 (s, 2 tBu); 2.97 (br. s, CH2(3)); 4.38 (q-like,
J=7.2, HꢀC(2)); 4.97 (br. d, J=8.8, NH); 5.92, 5.93 (2d, J=0.8, OCH2O); 6.61 (dd, J=7.6, 1.6,
1 arom. H); 6.66 (d, J=1.6, 1 arom. H); 6.72 (d, J=7.6, 1 arom. H). EI-MS: 365 (54, M+), 236 (100).
Anal. calc. for C19H27NO6: C 62.45, H 7.45, N 3.83; found: C 62.24, H 7.51, N 3.81.
(ꢀ)-(2S)-3-(1,3-Benzodioxol-5-yl)-2-{[(tert-butoxy)carbonyl]amino}propan-1-ol (=(ꢀ)-tert-Butyl
[(1S)-2-(1,3-Benzodioxol-5-yl)-1-(hydroxymethyl)ethyl]benzylcarbamate; (ꢀ)-12). To a soln. of (+)-11
(0.456 g, 1.25 mmol) and LiBH4 (0.123 g, 5.64 mmol) in THF (6 ml) was added anh. EtOH (0.2 ml,
3.41 mmol). The mixture was stirred at r.t. for 1 h and then refluxed for 17 h. After addition of H2O (1
ml) and 20% NaOH soln. (1 ml), the mixture was extracted with AcOEt (50 ml). The org. soln. was
dried (MgSO4) and concentrated: (ꢀ)-12 (0.325 g, 88%). Colorless prisms. M.p. 76–778 (hexane).
[a]2D4 =ꢀ21.6 (c=1.0, CHCl3). IR (neat): 3357 (NH, OH), 1685 (CO). H-NMR: 1.43 (s, Bu); 2.27 (br.
s, NH or OH); 2.75 (d, J=7.1, CH2(3)); 3.52–3.70 (m, CH2(1)); 3.79 (br. s, HꢀC(2)); 4.71 (br. s, NH
or OH); 5.93 (s, OCH2O); 6.65 (dd, J=8.0, 1.6, 1 arom. H); 6.71 (d, J=1.6, 1 arom. H); 6.74 (d,
J=8.0, 1 arom. H). EI-MS: 295 (100, M+), 239 (100), 178 (99). Anal. calc. for C15H21NO5: C 61.00, H
7.17, N 4.74; found: C 60.93, H 7.27, N 4.60.
1
t
(+)-(2S)-3-(1,3-Benzodioxol-5-yl)-2-{[(tert-butoxy)carbonyl]amino}propyl Iodide (=(+)-tert-Butyl
[(1S)-2-(1,3-Benzodioxol-5-yl)-1-(iodomethyl)ethyl]benzylcarbamate; (+)-13). A soln. of PPh3 (0.582 g,
2.2 mmol), I2 (0.567 g, 2.23 mmol), and 1H-imidazole (0.153 g, 2.2.5 mmol) in CH2Cl2 (5 ml) was stirred
at 08 for 0.5 h. To the soln. was added a soln. of (ꢀ)-12 (0.299 g, 1.01 mmol) in CH2Cl2 (7 ml) at r.t., and
then the mixture was stirred at r.t. for 3 h. After addition of sat. aq. Na2S2O3 soln. (5 ml), the mixture was
extracted with CH2Cl2 (2”5 ml). The org. soln. was dried (Na2SO4) and concentrated. Purification of the
residue by CC (hexane/AcOEt 3 :1) afforded (+)-13 (0.269 g, 66%). Colorless prisms. M.p. 86–878 (hex-
ane). [a]2D4 =+16.2 (c=1.0, CHCl3). IR (neat): 3361 (NH), 1676 (CO). 1H-NMR: 1.44 (s, tBu); 2.68 (dd,
J=13.3, 8.2, 1 H, CH2(3)); 2.82 (dd, J=13.3, 5.6, 1 H, CH2(3)); 3.18 (dd, J=10.0, 3.8, 1 H, CH2(1));
3.35–3.45 (m, HꢀC(2)); 3.52 (br. s, 1 H, CH2(1)); 4.66 (br. s, NH); 5.94 (s, OCH2O); 6.70–6.76 (m, 3
arom. H). EI-MS: 405 (19, M+), 135 (100). Anal. calc. for C15H20INO4: C 44.46, H 4.97, N 3.46; found:
C 44.93, H 5.04, N 3.23.
(+)-(2R)-1-(1,3-Benzodioxol-5-yl)-2-{[(tert-butoxy)carbonyl]amino}propane
(=(+)-tert-Butyl
[(1R)-2-(1,3-Benzodioxol-5-yl)-1-methylethyl]carbamate; (+)-14). N-Selectrideꢃ (0.51 ml, 0.51 mmol)
was added to a soln. of (+)-13 (0.172 g, 0.42 mmol) in THF (5 ml) at ꢀ208, and the mixture was stirred
at ꢀ58 for 1.5 h. After addition of H2O (0.4 ml), followed by a mixture of H2O (3.5 ml), 30% H2O2 soln.
(0.5 ml), and K2CO3 (0.150 g), the mixture was stirred at r.t. for 1 h. After evaporation, the residue was
extracted with CHCl3 (30 ml). The org. soln. was dried (Na2SO4) and concentrated. Purification of the
residue by CC (hexane/AcOEt 30 :1) afforded (+)-14 (0.104 g, 88%). Colorless prisms. M.p. 60–628. Chi-
ral HPLC: Daicel ChiralCel AS-H; hexane/iPrOH 9 :1, 1 ml/min, 254 nm): tR 6.6 (minor) and 10.9 min
(major); 97% ee. [a]2D3 =+5.6 (c=1.0, CHCl3). IR (neat): 3342 (NH), 1701 (CO). 1H-NMR: 1.08 (d,
t
J=6.6, MeꢀC(2)); 1.43 (s, Bu); 2.57 (dd, J=13.4, 7.3, 1 H, CH2(1)); 2.75 (dd, J=13.4, 5.4, 1 H,
CH2(1)); 3.83 (br. s, HꢀC(2)); 4.35 (br. s, NH); 5.93 (s, OCH2O); 6.62 (d, J=7.8, 1 arom. H); 6.68 (s,
1 arom. H); 6.74 (d, J=7.8, 1 arom. H). EI-MS: 279 (32, M+), 162 (32), 135 (100). HR-FAB-MS:
280.1559 ([M+H]+, C15H22NOþ4 ; calc. 280.1548).

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Helvetica Chimica Acta – Vol. 90 (2007)
REFERENCES
[1] A. K. Yudin, in ꢀAziridines and Epoxides in Organic Synthesisꢁ, Wiley-VCH, New York, 2005.
[2] G. Cardillo, L. Gentilucci, A. Tolomelli, Aldrichim. Acta 2003, 36, 39.
[3] W. K. Lee, H.-J. Ha, Aldrichim. Acta 2003, 36, 57.
[4] W. McCoull, F. A.Davis, Synthesis 2000, 1347.
[5] X. E. Hu, Tetrahedron 2004, 60, 2701.
[6] J. Legters, L. Thijs, B. Zwanenburg, Recl. Trav. Chim. Pays-Bas 1992, 111, 16.
[7] C. Xiong, W. Wang, C. Cai, V. J. Hruby, J. Org. Chem. 2002, 67, 1399.
[8] C. Loncaric, W. D. Wulff, Org. Lett. 2001, 3, 3675.
[9] G. Cardillo, L. Gentilucci, A. Tolomelli, Tetrahedron Lett. 1999, 40, 8261.
[10] K. Hada, T. Watanabe, T. Isobe, T. Ishikawa, J. Am. Chem. Soc. 2001, 123, 7705.
[11] W. Disadee, T. Ishikawa, J. Org. Chem. 2005, 70, 9399.
[12] T. Haga, T. Ishikawa, Tetrahedron 2005, 61, 2857.
[13] S. Futagawa, T. Inui, T. Shiba, Bull. Chem. Soc. Jpn 1973, 46, 3308.
[14] F. A. Carey, R. J. Sundberg, in ꢀAdvanced Organic Chemistryꢁ, 4th edn., Part A, Kluwer Academic/
Plenum Publishers, New York, 2000, p. 112.
[15] G. A. Molander, P. J. Stengel, J. Org. Chem. 1995, 60, 6660.
[16] T. Nishikawa, S. Kajii, K. Wada, M. Ishikawa, M. Isobe, Synthesis 2002, 1658.
[17] D. A. Quagliato, P. M. Andrae, E. M. Matelan, J. Org. Chem. 2000, 65, 5037.
Received August 28, 2006