Base-promoted diastereoselective α-alkylation of borane: N -((S)-1′-phenylethyl)azetidine-2-carboxylic acid ester complexes

Article abstract of DOI:10.1039/c8ob01395k

The base-promoted α-alkylation of N-((S)-1-phenylethyl)azetidine-2-carboxylic acid esters 1 was investigated. The use of diastereomerically pure borane complexes 3 as substrates, which are easily prepared from 1, dramatically improved the yields and diastereoselectivities of α-alkylated products 2. For example, the treatment of tert-butyl ester (1S,2S,1′S)-3a with 2.4 equivalents of lithium bis(trimethysilyl)amide (LiHMDS) at 0 °C followed by 2.6 equivalents of benzyl bromide afforded α-benzylated (2S,1′S)-2aa in 90% yield as almost a single diastereomer. Our method enables the production of optically active α-substituted azetidine-2-carboxylic acid esters starting from commercially available (S)-1-phenylethylamine, which is one of the least expensive chiral compounds.

Full text of DOI:10.1039/c8ob01395k

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ARTICLE
Base‐promoted diastereoselective ‐alkylation of borane N‐((S)‐
1’‐phenylethyl)azetidine‐2‐carboxylic acid ester complexes
Eiji Tayama,*a Ryotaro Nishiob and Yoshiaki Kobayashib
Received 00th January 20xx,
Accepted 00th January 20xx
The base‐promoted ‐alkylation of N‐((S)‐1‐phenylethyl)azetidine‐2‐carboxylic acid esters 1 was investigated. The use of
diastereomerically pure borane complexes 3 as substrates, which are easily prepared from 1, dramatically improved the
yields and diastereoselectivities of ‐alkylated products 2. For example, the treatment of tert‐butyl ester (1S,2S,1’S)‐3a with
2.4 equivalents of lithium bis(trimethysilyl)amide (LiHMDS) at 0 °C followed by 2.6 equivalents of benzyl bromide afforded
‐benzylated (2S,1’S)‐2aa in 90% yield as almost a single diastereomer. Our method enables the production of optically
active ‐substituted azetidine‐2‐carboxylic acid esters starting from commercially available (S)‐1‐phenylethylamine, which
is one of the least expensive chiral compounds.
DOI: 10.1039/x0xx00000x
www.rsc.org/
ylide rearrangement starting from (S)‐1‐phenylethylamine
(Scheme 1).3 In this protocol, two diastereomers of N‐((S)‐1‐
Introduction
phenylethyl)azetidine‐2‐carboxylic acid esters, (2S,1’S)‐
1 and
Azetidine‐2‐carboxylic acid, a four‐membered cyclic amino acid
proline analog, is a quite useful building blocks for the synthesis
of various nitrogen‐containing compounds.1 Nucleophilic ring‐
opening of the ring‐strained N‐heterocycle affords
functionalized unnatural amino acid derivatives by electrophilic
activation of the nitrogen atom with a Lewis acid or N‐
quaternization.2 Thus, the development of an efficient
synthetic method for the preparation of functionalized
azetidine‐2‐carboxylic acid derivatives has been developed.
(2R,1’S)‐ , were valuable substrates. A rigid four‐membered
1
ring generated a large difference in polarity between each
diastereomer, which facilitates chromatographic separation.4
The N‐((S)‐1‐phenylethyl) substituent was removed by
hydrogenation to produce enantio‐pure azetidine‐2‐carboxylic
acid derivatives. Furthermore, a steric effect based on
preexisting substituents on the ring allowed stereoselective
functionalizations such as an N‐quaternization5 followed by an
ammonium ylide rearrangement involving N‐to‐C chirality
transfer.6
Scheme 1 Synthesis of optically active
esters from (S)‐1‐phenylethylamine.
‐substituted azetidine‐2‐carboxylic acid
The result described above made us wonder how
diastereoselectivity arises in a base‐promoted ‐alkylation of 1.
However, previous reports on this topic were limited. As an
example, an LDA‐promoted reaction with methyl 3‐
bromopropionate as an electrophile resulted in low yield (22%
yield) with moderate diastereoselectivity (Scheme 2, eqn (1)).7
We surveyed examples of similar reactions by expanding our
search to three‐ and five‐membered cyclic amino acid
derivatives. Interestingly, the
phenylethyl)aziridine‐2‐carboxylic acid esters proceeded via a
configurationally stable chiral anion to afford the ‐alkylated
product with retention of the configuration (eqn (2)).8 On the
‐alkylation of ((R)‐2‐methoxy‐1‐

other hand, a diastereoselective
‐alkylation of an N‐borane
complex of N‐benzylproline ester was reported (eqn (3)).9 The
Recently, we reported a unique asymmetric synthesis of ‐
substituted azetidine‐2‐carboxylic acid esters via an ammonium
complex could be prepared in diastereomerically pure form due
to a steric effect from preexisting substituents.
substituents are in equatorial and the axial lone pair of the
nitrogen atom coordinates to the borane. The
diastereoselective ‐alkylation was achieved by exploiting the
nitrogen chirality of the N‐borane complex. To the best of our
knowledge on the ‐alkylations of N‐substituted azetidine‐2‐
The
a. Department of Chemistry, Faculty of Science, Niigata University, Niigata, 950‐
2181, Japan. E‐mail: tayama@chem.sc.niigata‐u.ac.jp.
b. Graduate School of Science and Technology, Niigata University, Niigata, 950‐
2181, Japan.


† Electronic Supplementary Information (ESI) available: Preparation of substrates (
and ) determination of ee ( and
) and copy of 1H, 13C and 11B NMR spectra. See
DOI: 10.1039/x0xx00000x
1
carboxylic acid esters, analogous successful examples, depicted
in eqns (2) and (3), have never reported. From this foundation,
4
4
6
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we started to investigate the

‐alkylation of N‐((S)‐1‐
) and its borane
) for the synthesis of desired product with high
Table 1 LDA‐promoted ‐benzylation of 1a
View Article Online
DOI: 10.1039/C8OB01395K
phenylethyl)azetidine‐2‐carboxylic acid ester (
complex (
1
3
2
diastereoselectivity.
Scheme 2 Previous examples of diastereoselective

‐alkylations of cyclic amino
acid esters.
Azetidine-2-carboxylic acid ester
1. LDA
CO2Me
CO2Me
Br
2. HMPA,
CO2Me
N
N
(1)
THF
CO2Me
Ph
Ph
22%, 82/18 dr
2aa (%)a
Entry
Temp.
1a
LDA
(eq)
1.2
1.2
2.4
BnBr
(eq)
1.3
1.3
2.6
Aziridine-2-carboxylic acid ester
2R,1’S
35
9
2S,1’S
45
16
CO2tBu
CO2tBu
1
2b
3
4b
5c
2S,1’S
2S,1’S
2S,1’S
2S,1’S
2R,1’S
–78 °C to rt
–78 °C
–78 °C to rt
–78 °C
Br
LDA,
N
N
(2)
THF
19
11
0
11
13
MeO
MeO
Ph
Ph
2.4
1.2
2.6
1.3
64%, >98/2 dr
–78 °C to rt
0
Proline ester
CO2Me
c
a Yield of isolated product. b Recovery of (2S,1’S)‐1a; entry 2: 34%, entry 4: 43%.
Epimerized (2S,1’S)‐1a was obtained in 49% yield.
BH3·SMe2
BH3·SMe2
MeO2C
N
N
Ph
hexane/CH2Cl2
Diastereoselective ‐alkylation of borane N‐((S)‐1‐
phenylethyl)azetidine‐2‐carboxylic acid tert‐butyl ester complexes
Bn
H
(3)
1. LDA
CO2Me
CO2Me
2. HMPA, BnI
THF
With these results in hand, we next examined reactions of N‐
borane complexes (Scheme 3) according to the results of N‐
benzylproline esters depicted in Scheme 2, eqn (3). The N‐
boration of (2S,1’S)‐ with a borane dimethyl sulfide complex in
CH2Cl2 proceeded smoothly, and the desired product,
(1S,2S,1’S)‐ , was obtained in excellent yield as a single
diastereomer. The adjacent 2‐ and N‐substituents, as in
(2S,1’S)‐ , are in equatorial, and the axial lone pair of the
(3)
N
N
Bn
3
H3B Bn
Bn
single diastereomer
74%, 94/6 dr
1
3
1
Results and discussion
LDA‐promoted ‐benzylation of N‐((S)‐1‐phenylethyl)azetidine‐2‐
carboxylic acid tert‐butyl esters (1a)
nitrogen atom coordinates to the borane. This stereoselectivity
would be the same as what was seen in the previous studies on
the N‐quaternization of (2S,1’S)‐1a with methyl triflate.5 The
First, we decided to investigate the selectivity of an
‐
stereochemistry of (1S,2S,1’S)‐
(1S,2S,1’S)‐ was stable as a solid or as a solution in CH2Cl2;
however, it decomposed slowly to (2S,1’S)‐ in THF at room
3 was determined by analogy.
benzylation of tert‐butyl ester 1a (Table 1) based on the result
found with aziridine‐2‐carboxylic acid esters depicted in Scheme
2, eqn (2). A solution of (2S,1’S)‐1a in THF was treated with 1.2
equivalents of LDA at –78 °C for 2 h followed by 1.3 equivalents
of benzyl bromide. After stirring for 3 h at room temperature,
3
1
temperature. For example, a solution of (1S,2S,1’S)‐3a in THF
was stirred for 3 h at room temperature under an argon
atmosphere. Evaporation of the volatiles and 1H NMR analysis
of the residue showed a 65/35 mixture of (1S,2S,1’S)‐3a and
(2S,1’S)‐1a. Epimerization on the nitrogen atom via de‐boration
followed by re‐boration was not observed.10‐12
the corresponding
‐benzylated products, (2R,1’S)‐2aa (35%
yield) and (2S,1’S)‐2aa (45% yield), were obtained with poor
selectivity (entry 1). Even when the reaction was carried out at
a lower temperature and with excess of the reagents, no
improvements were observed (entries 2–4). Although the exact Scheme 3 Stereoselective preparation of N‐borane complex (1S,2S,1’S)‐
3.
reason is unclear at present,
a reaction of another
diastereomeric substrate, (2R,1’S)‐1a, did not afford any 2aa
(entry 5). Epimerized (2S,1’S)‐1a was isolated in 49% yield7b
along with unidentifiable compounds. These results indicated
that azetidine‐2‐carboxylic acid esters 1a cannot generate
configurationally stable chiral anions to produce 2aa with
retention of the configuration.
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We subjected the complex (1S,2S,1’S)‐
conditions (Table 2). First, we examined the reaction of diastereomer (Entry 9). The expected side reactions such as O‐
(1S,2S,1’S)‐3a under the same conditions depicted in Table 1, acylation and hydride reduction by N‐borane were not observed.
ARTICLE
3
to the ‐alkylation produce (2R,1’S)‐2ag in 78% yield as almost a single
View Article Online
DOI: 10.1039/C8OB01395K
entry 1. To our delight, the
‐benzylation proceeded with With this result in hand, we further explored the reaction with
excellent selectivity to give (2S,1’S)‐2aa in 57% yield as the only carbonyl compounds such as benzophenone or cyclohexanone;

‐alkylated product (entry 1). The borane complex derived however, the reactions did not give the corresponding ‐
from product 2aa was not isolated.13 The lower yield could be substituted products.16
caused by borane exchange between (1S,2S,1’S)‐3a and the
Table 2 Optimization of the reaction conditions for the in ‐benzylation of (1S,2S,1’S)‐3a
diisopropylamine generated from LDA before the
De‐borated (2S,1’S)‐1a was isolated in 28% yield, and the
formation of borane diisopropylamine complex was
‐alkylation.
a
observed.14,15 The use of excess of reagents, 2.4 equivalents of
LDA and 2.6 equivalents of benzyl bromide, was unsuccessful
(entry 2). Thus, we shorten the reaction time of the
deprotonation with LDA by 30 min and raised the reaction
Entry
Temp., Time
2aa (%)a
Base
(eq)
BnBr
(eq)
temperature to 0 °C (entry 3) to complete the desired
‐
(deprotonation)
2R,1’S
2S,1’S
alkylation before the undesired borane exchange reaction. As
expected, the yield improved to 79% with the same selectivity
for (2S,1’S)‐2aa. The use of excess reagents lowered the yield
to 64% (entry 4). Further shortening the reaction time of the
deprotonation step (5 min) afforded (2S,1’S)‐2aa in the almost
same yield and selectivity (entry 5). Thus, we attempted to use
bulkier bases, such as lithium 2,2,6,6‐tetramethylpiperidide
(LiTMP) and lithium bis(trimethylsilyl)amide (LiHMDS) to
suppress the undesired borane exchange reaction. Although
the reactions with 1.2 equivalents of the bases and 1.3
equivalents of benzyl bromide did not show any improvements
(entries 6, 7), the use of excess of these reagents improved the
yields to 79% and 90%, respectively (entries 8, 9). When the
1b
2c
3d
4d
5
6
7
8
9
–78 °C, 2 h
–78 °C, 2 h
0 °C, 30 min
0 °C, 30 min
0 °C, 5 min
0 °C, 30 min
0 °C, 30 min
0 °C, 30 min
0 °C, 30 min
0 °C, 30 min
LDA, 1.2
LDA, 2.4
1.3
2.6
1.3
2.6
2.6
1.3
1.3
2.6
2.6
2.6
0
0
0
0
0
0
0
0
0
57
10
79
64
64
60
62
79
90
46
LDA, 1.2
LDA, 2.4
LDA, 2.4
LiTMP, 1.2
LiHMDS, 1.2
LiTMP, 2.4
LiHMDS, 2.4
KHMDS, 2.4
10
26
a
b
Yield of isolated product.
Recovered (1S,2S,1’S)‐3a: 8% yield. De‐borated
(2S,1’S)‐1a: 28% yield. c Recovered (1S,2S,1’S)‐3a: 10% yield. De‐borated (2S,1’S)‐
1a: 17% yield. d Borane diisopropylamine complex was isolated with impurities;
entry 3: 71% yield, entry 4: 59% yield.
reaction
was
carried
out
with
potassium
bis(trimethylsilyl)amide (KHMDS), both diastereomers (2R,1’S)‐
and (2S,1’S)‐2aa were obtained (entry 10).
Table 3 Diastereoselective ‐alkylation of (1S,2S,1’S)‐3 with various electrophilesa
To define the scope and limitations of this diastereoselective

‐alkylation, we investigated different electrophiles and ester
substituents under the optimized conditions (Table 3). The
reaction of (1S,2S,1’S)‐3a with allyl bromide afforded (2S,1’S)‐
2ab in 80% yield with excellent diastereoselectivity (entry 1).
The use of primary ethyl and benzyl esters, (1S,2S,1’S)‐3b and
3c, resulted in approximately 40% yields (entries 2, 3).
Undesirable side reactions, such as a Claisen condensation,
might proceed.8b Reactions of (1S,2S,1’S)‐3a with other allylic
bromides such as 1‐bromo‐3‐methyl‐2‐butene (entry 4) and
trans‐3‐bromo‐1‐phenyl‐1‐propene (entry 5) proceeded well
and afforded (2S,1’S)‐2ac and 2ad in good yields; however, the
diastereomeric ratio (dr) of 2ad was slightly decreased to 94/6.
When the reaction was carried out with iodomethane (MeI),
product 2ae was obtained in only 48% yield with 86/14 dr (entry
6). Reactive alkyl halides such as MeI and trans‐3‐bromo‐1‐
phenyl‐1‐propene may result in lower diastereoselectivities.
Furthermore, excess of sterically less hindered MeI would
decrease the yield because of undesirable N‐quaternization of
the product, 2ae. By adding the MeI at –20 °C, the outcome was
Entry
Temp.
(°C)
0
2b
(%)
80 (2ab)
Drc
R
RX
1
2
3
4
5
6
7
8
9
tBu
Et
BrCH2CH=CH2
BrCH2CH=CH2
BrCH2CH=CH2
BrCH2CH=CMe2
trans‐BrCH2CH=CHPhd
MeI
>97/3
>97/3
96/4
>97/3
94/6
86/14
89/11
>97/3
>97/3
0
0
0
0
0
–20
0
0
44 (2bb)
Bn
37 (2cb
73 (2ac)
80 (2ad)
48 (2ae)
62 (2ae)
68 (2af)
78 (2ag)
)
tBu
tBu
tBu
tBu
tBu
tBu
MeI
EtI
ClCO2Et
a Conditions: 2.4 equivalents of LiHMDS and 2.6 equivalents of electrophile (RX).
b
Yield of isolated product as a mixture of diastereomers. c Determined by 1H NMR.
Entries 1–8: 2S,1’S/2R,1’S, entry 9: 2R,1’S/2S,1’S. d Added as a THF solution.
improved to 62% yield with 89/11 dr (entry 7). The ‐alkylation
with iodoethane (EtI), which is a less reactive electrophile than
MeI, provided desired (2S,1’S)‐2af in 68% yield with excellent
selectivity (entry 8). Interestingly, the reaction with acyl halides
such as ethyl chloroformate also proceeded smoothly to
Next, we examined the

‐alkylation of another
to
diastereomeric N‐borane complex, (1R,2R,1’S)‐3a 17
,
preferentially obtain (2R,1’S)‐2aa; however, this resulted in
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lower yield and diastereoselectivity (Scheme 4). (1R,2R,1’S)‐3a the sterically less hindered secondary amine generated from
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was prepared as a single diastereomer from (2R,1’S)‐1a by the the LiHMDS.13
DOI: 10.1039/C8OB01395K
same procedure that was used for (1S,2S,1’S)‐3a depicted in
Scheme 5 ‐Benzylation of N‐borane complex (1R,2R)‐5.
Scheme 3. The reaction of (1R,2R,1’S)‐3a with benzyl bromide
under the same conditions gave desired (2R,1’S)‐2aa in 44%
yield and (2S,1’S)‐2aa in 9% yield (83/17 dr).
1. LiHMDS
2. BnBr
CO2tBu
CO2tBu
Bn
CO2tBu
BH3·SMe2
N
N
N
CH2Cl2
THF
Scheme 4 ‐Benzylation of N‐borane complex (1R,2R,1’S)‐3a.
Ph
H3B
Ph
Ph
)-6
0 °C to rt
0 °C to rt
(R)-4
97/3 er
(1R,2R)-5
(
R
94%
77%, 84/16 er
(68% ee)
(94% ee)
single diastereomer
[ ]22589 +136.4 (c 1.0 in CHCl3)
LiHMDS THF, 0 °C, 30 min to rt, 3 h
CO2tBu
CO2tBu
CO2tBu
+
+
N
N
N
H
Bn
Ph
Ph
H3B
H3B
(1R,2R)-5
(1R,2S)-5
7
60%
32%
0%
[1,2]
recovery
C-epimerized
[ ]23589 +141.2 (c 1.0 in CHCl3)
To clarify the origin of the diastereoselectivity of the
alkylation of (1S,2S,1’S)‐ , we prepared N‐borane adduct
(1R,2R)‐517 from 97/3 enantiomeric ratio (er) (94% ee) of N‐
benzyl derivative (R)‐418 and subjected it to the
‐benzylation
conditions (Scheme 5). This reaction preferentially occurred on
the side of the N‐benzylic substituent to afford (R)‐ in 77% yield
with an 84/16 er (68% ee). When the reaction was quenched
without the addition of benzyl bromide, recovered (1R,2R)‐
(60% yield) and epimerized (1R,2S)‐ (32% yield) were obtained
without formation of [1,2] rearrangement product
Additionally, when (1R,2R)‐ was stirred in THF without base for
3 h at room temperature, a 98/2 mixture of the substrate
(1R,2R)‐ and N‐epimerized (1S,2R)‐ derived by de‐boration
followed by re‐boration was obtained (Scheme 6).11 These
results indicated that the ‐alkylation of the N‐borane
complexes would proceed via a planar enolate, not an N‐
epimerization of followed by an ‐alkylation of
configurationally stable chiral anion. A combination of C‐ and
N‐chirality, as in (1S,2S,1’S)‐ would allow the
diastereoselective formation of products
With these results in hand, we proposed reaction
intermediates in this diastereoselective ‐alkylation of 3a with
‐
Scheme 6 N‐Epimerization of (1R,2R)‐
5
into (1S,2R)‐
5 in THF.
3
CO2tBu
CO Bu
2t

(1R,2R)-5
+
N
N
THF
Ph
Ph
H3B
H3B
rt, 3 h
6
(1R,2R)-5
(1S,2R)-5
N-epimerized
(1R,2R)/(1S,2R) = 98/2
5
5
7.
5
Scheme 7 Proposed reaction intermediate A’ in the diastereoselective
alkylation of (1S,2S,1’S)‐3a
‐
.
5
5


3
,
2
.

benzyl bromide (Scheme 7). First, two molecules of LiHMDS
would be involved because these conditions produced (2S,1’S)‐
2aa in good yields, as described in Table 2. Moreover, a
reasonably stable conformer related to the N‐((S)‐1‐
phenylethyl) substituent that avoids steric repulsion with the
On the other hand, the reaction of (1R,2R,1’S)‐3a depicted in
Scheme 4 would proceed via conformer or ; however,
would be destabilized by the steric repulsion between the
phenyl and tert‐butyl ester substituents (Scheme 8). Although
one molecule of LiHMDS blocks the Re‐face in the ‐benzylation
B
C
C
azetidinyl methylene is shown in A. Thus, intermediate A’ can
be proposed for the reaction of (1S,2S,1’S)‐3a. One molecule of
LiHMDS interacts with O‐lithium to place itself on the side of the
smaller borane (BH3) group and blocks the Si‐face.19,20 Benzyl
bromide reacts exclusively at the Re‐face to provide (2S,1’S)‐2aa
of intermediate B’ leading to (2R,1’S)‐2aa, a methyl group of the
N‐((S)‐1‐phenylethyl) substituent blocks the Si‐face and the rate
is lowered. Therefore, unfavourable
‐benzylation of
.
After ‐alkylation, the BH3 on the nitrogen of A’ is replaced with
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intermediate B’’ would proceed to afford (2S,1’S)‐2aa, and the careful chromatographic purification.
ARTICLE
ThVeiew AartibclseoOlnulitnee
DOI: 10.1039/C8OB01395K
yield and selectivity would be decreased.
stereochemistry of (1S,2R,1’S)‐8 was assigned by comparison of
the 1H and 13C NMR chemical shifts with those reported
previously for an authentic sample.2b,22
Scheme 8 Proposed reaction intermediate B’ and B’’ in the diastereoselective ‐
alkylation of (1R,2R,1’S)‐3a
.
The stereochemistry of 2ab was confirmed by hydride
reduction (Scheme 11). The reactions of 2ab and (2S,1’S)‐2bb
which were stereochemically defined as shown in Scheme 10,
afforded the same diastereomer of amino alcohol (2S,1’S)‐
The stereochemistries of other ‐alkylated derivatives were
determined by analogy to these compounds.
,
Li NR2
Li NR2
OLi
BH3
BH3
N
(1R,2R,1'S)-3a
+
Ph
H
Me
Ph
OLi
N
9.
2 R2NLi
Me
H

2
OtBu
OtBu
(R = SiMe3)
B
C
BnBr
Bn Br
Scheme 10 Determination of the stereochemistry of 2bb by conversion to 8.
Me
N
Me
(Si-face)
Ph
H
Ph
H
O
O
O
tBu
O
tBu
(Re-face)
Li
N
Bn Br
Li
BH3
BH3
Li
N
Li N
R2
R2
B''
B'
(2R,1'S)-2aa
83/17 dr
(2S,1'S)-2aa
Determination of the absolute stereochemistries of the ‐
alkylated products
The stereochemistries of 2aa and
conversion to 2‐benzylazetidine‐2‐carboxylic acid ester
(Scheme 9). Their N‐benzylic substituents were removed by
hydrogenation of the HCl salts to give (S)‐ and (R)‐ , respectively.
6 were determined after
7,
7
Scheme 11 Determination of the stereochemistry of 2ab
.
The absolute configurations were assigned by comparison of
their specific rotation values with that reported previously for
(R)‐7 21
.
Scheme
9
Removal of the N‐benzylic substituents to produce 7a and
determination of the stereochemistries of 2aa and 6.
Conclusions
In conclusion, we demonstrated a highly stereoselective base‐
promoted ‐alkylation of diastereomerically pure borane N‐
((S)‐1‐phenylethyl)azetidine‐2‐carboxylic acid ester complexes
to produce ‐alkylated azetidine‐2‐carboxylic acid esters

3

2.
Further experimental studies clarified the scope and limitations
of this reaction. The reaction intermediate was proposed. N‐
Borane complexes
phenylethyl)azetidine‐2‐carboxylic acid esters
the steric effects of preexisting substituents. Compounds
3
were prepared from N‐((S)‐1‐
1
by exploiting
1
28
a Lit. for (R)‐
7
(98% ee): [

]
D +84.9 (c 1.2 in CHCl3).21
were also easily prepared in diastereomerically pure form from
(S)‐1‐phenylethylamine.
The stereochemistry of 2bb was determined by the following
procedure (Scheme 10). The ‐allylation of (2S,1’S)‐1b under
Products
2 will serve as valuable building blocks for the

synthesis of nitrogen‐containing compounds such as unnatural
amino acids by nucleophilic ring‐opening reactions. On the
other hand, the N‐((S)‐1‐phenylethyl) substituent, as in (2S,1’S)‐
the same conditions depicted in Table 1, entry 1 provided both
diastereomers (2R,1’S)‐2bb and (2S,1’S)‐2bb. Chromatographic
separation of the diastereomers followed by N‐quaternization
of (2R,1’S)‐2bb with methyl triflate gave two diastereomeric
2aa, was removed by hydrogenation to give optically pure
‐
substituted azetidine‐2‐carboxylic acid ester (S)‐ . Our protocol
7
salts, (1S,2R,1’S)‐8 and (1R,2R,1’S)‐8, which were separable by
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
enables the production of optically active nitrogen‐containing hexane/EtOAc = 20/1 to 10/1 as the eluent, Rf: (2R,1´S) >
View Article Online
DOI: 10.1039/C8OB01395K
fine chemicals starting from commercially available (S)‐1‐ (2S,1´S)] to obtain (2R,1´S)‐2aa (16.7 mg, 11% yield) as a
phenylethylamine, which is one of the least expensive chiral colorless oil and (2S,1´S)‐2aa (19.6 mg, 13% yield) as a colorless
compounds.
oil.
Representative procedure for‐alkylation of (1S,2S,1’S)‐3a with
LiTMP to produce (2S,1´S)‐2aa
Experimental
A 1.6 M nBuLi solution in n‐hexane (0.47 mL, 0.75 mmol) was
General
added to a solution of 2,2,6,6‐tetramethylpiperidine (128 L,
0.758 mmol) in THF (1.0 mL) at 0 °C under an argon atmosphere
and the solution was stirred for 20 min at 0 °C. This solution
was added to a solution of (1S,2S,1’S)‐3a (85.7 mg, 0.311 mmol)
in THF (1.6 mL) at 0 °C under an argon atmosphere and the
solution was stirred for 30 min at 0 °C. The solution was treated
Specific rotations were recorded on a JASCO polarimeter P–
1010. Infrared spectra (IR) were recorded on a Perkin Elmer
1
Spectrum GX FT‐IR. H, 13C and 11B NMR spectra were measured
on a Varian or a Bruker 400 MHz spectrometers (1H: 400 MHz,
13C: 100 MHz, 11B: 128 MHz). As an internal standard in CDCl3,
Me4Si (δ 0 ppm) was used for 1H NMR and CDCl3 (δ 77 ppm) for
13C NMR. As an internal standard in acetone‐d6, the residual
protons were used (δ 2.05 ppm) for 1H NMR and acetone‐d6 (δ
29.92 ppm) for 13C NMR. In 11B NMR, boron trifluoride diethyl
etherate (BF3∙OEt2) was used as an external standard (δ 0 ppm).
The splitting patterns are denoted as follows: s, singlet; d,
doublet; t, triplet; q, quartet; sept., septet; m, multiplet; and br,
broad peak. High‐resolution mass spectra were measured on a
Thermo Fisher Scientific LC/FT‐MS spectrometer. Elemental
analyses were recorded on a J‐Science Lab Micro Corder JM10.
Reactions involving air‐ or moisture‐sensitive compounds were
conducted in appropriate round‐bottomed flasks with a
magnetic stirring bars under an argon atmosphere. Anhydrous
tetrahydrofuran (THF) and borane dimethyl sulfide complex
were purchased from KANTO Chemical Co., Inc., Japan. A 1.0 M
lithium bis(trimethylsilyl)amide (LiHMDS) solution in THF and a
0.5 M potassium bis(trimethylsilyl)amide (KHMDS) solution in
toluene were purchased from Sigma‐Aldrich. For thin layer
chromatography (TLC) analysis throughout this work, Merck TLC
plates (silica gel 60 F254) was used. The products were purified
by preparative column chromatography on silica gel (silica gel
60N, spherical neutral, KANTO Chemical Co., Inc., Japan).
with benzyl bromide (96 L, 0.81 mmol) at 0 °C and allowed to
warm at room temperature. After stirring for 3 h, the resulting
mixture was quenched with saturated aqueous NH4Cl and
extracted with EtOAc. The combined organic extracts were
washed with saturated aqueous NaHCO3 followed by brine,
dried over Na2SO4, and evaporated. Purification of the residue
by chromatography on silica gel (n‐hexane/EtOAc = 20/1 to 10/1
as the eluent) gave (2S,1´S)‐2aa (86.7 mg, 79% yield) as a
colorless oil.
Representative procedure for‐alkylation of (1S,2S,1’S)‐3a with
LiHMDS to produce (2S,1´S)‐2aa
A solution of (1S,2S,1’S)‐3a (100 mg, 0.363 mmol) in THF (2.9
mL) was treated with a 1.0 M LiHMDS solution in THF (0.87 mL,
0.87 mmol) at 0 °C under an argon atmosphere. The solution
was stirred for 30 min at 0 °C and treated with benzyl bromide
(112 L, 0.942 mmol) at the same temperature. The mixture
was allowed to warm at room temperature and stirred for 3 h.
The resulting mixture was quenched with saturated aqueous
NH4Cl and extracted with EtOAc. The combined organic extracts
were washed with saturated aqueous NaHCO3 followed by brine,
dried over Na2SO4, and evaporated. The residue was purified by
chromatography on silica gel (n‐hexane/EtOAc = 20/1, 10/1 to
5/1 as the eluent) to obtain (2S,1´S)‐2aa (115 mg, 90% yield) as
a colorless oil.
Preparation of ca. 0.7 M LDA solution in THF/n‐hexane
A dried 100 mL storage flask with stopcock‐equipped septum‐
inlet (Aldrich) was charged with diisopropylamine (3.00 mL, 21.4
mmol) and THF (13.4 mL) under an argon atmosphere. A 1.6 M
n‐butyllithium solution in n‐hexane (12.75 mL, 20.4 mmol) was
added to the solution at –78 °C. The mixture was stirred for 15
min at the same temperature and allowed to warm to 0 °C
slowly. The resulting pale yellow solution was stored in
refrigerator.
(2
carboxylate [(2
Colorless oil; [α]20589 −104.7 (c 1.0 in EtOH); IR (film)
R
,1´
S
)‐tert‐Butyl 2‐benzyl‐1‐(1’‐phenylethyl)azetidine‐2‐
R
,1´ )‐2aa]
S

max/cm−1
3084, 3061, 3027, 2972, 2930, 2854, 1717, 1602, 1493, 1475,
1453, 1391, 1367, 1302, 1273, 1249, 1217, 1147, 1093, 1075,
1058, 1029, 979, 946, 910, 848, 822, 768, 754, 737, 700; 1H NMR
(400 MHz, CDCl3) δ 7.34‐7.18 (10H, m, Ph), 3.71 (1H, q, J = 6.4
Hz, 1’‐H), 3.35 (1H, d, J = 14.0 Hz, CH2Ph), 3.15 (1H, d, J = 14.0
Hz, CH2Ph), 2.96 (1H, ddd, J = 8.4, 8.2, 6.4 Hz, 4‐H), 2.81 (1H, ddd,
J = 8.6, 6.4, 2.8 Hz, 4‐H), 2.22 (1H, ddd, J = 10.6, 8.2, 2.8 Hz, 3‐
H), 2.05 (1H, ddd, J = 10.6, 8.6, 8.4 Hz, 3‐H), 1.49 (9H, s, tBu),
1.38 (3H, d, J = 6.4 Hz, 1’‐CH3); 13C NMR (100 MHz, CDCl3) δ 171.6,
144.0, 137.6, 130.2, 128.2, 127.9, 127.5, 127.0, 126.2, 81.5, 73.4,
62.4, 48.9, 44.3, 28.2, 25.4, 23.1; HRMS (ESI): calcd for
C23H30NO2 [M + H]+ 352.2271, found 352.2264.
Representative procedure for ‐alkylation of (2S,1’S)‐1a with LDA
to produce 2aa
A solution of (2S,1’S)‐1a (111 mg, 0.425 mmol) in THF (3.2 mL)
was treated with a ca. 0.7 M LDA solution in THF/n‐hexane (1.46
mL, 1.02 mmol) at –78 °C under an argon atmosphere. The
solution was stirred for 2 h at –78 °C and treated with benzyl
bromide (130 L, 1.09 mmol) at the same temperature. After
stirring for 3 h at –78 °C, the resulting mixture was poured into
saturated aqueous NH4Cl and extracted with EtOAc. The
combined organic extracts were washed with saturated NaHCO3
followed by brine, dried over Na2SO4, and evaporated. The
residue was purified by chromatography on silica gel [n‐
(2
carboxylate [(2
Colorless oil; [α]21 −51.8 (c 1.0 in EtOH); IR (film)
S
,1´
S
)‐tert‐Butyl 2‐benzyl‐1‐(1’‐phenylethyl)azetidine‐2‐
S
,1´ )‐2aa]
S

max/cm−1
589
3085, 3062, 3028, 2973, 2929, 2850, 1715, 1603, 1494, 1475,
6 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
1453, 1391, 1367, 1351, 1304, 1274, 1247, 1219, 1150, 1091, (1S,2S,1’S)‐(2‐(Benzyloxycarbonyl)‐1‐(1’‐phenylethyl)VaizeewtAidrtiicnle‐1O‐nline
1
DOI: 10.1039/C8OB01395K
1075, 1029, 951, 910, 848, 787, 763, 737, 700; H NMR (400 ium‐1‐yl)trihydroborate [(1S,2S,1´S)‐3c]
MHz, CDCl3) δ 7.40 (2H, ddd, J = 7.0, 1.6, 1.6 Hz, Ph), 7.30 (2H,
Prepared in 92 % yield from (2S,1’S)‐1c by the same procedure
dddd, J = 7.0, 7.0, 1.6, 1.6 Hz, Ph), 7.23 (1H, tt, J = 7.0, 1.6 Hz,
Ph), 7.17 (2H, dddd, J = 7.0, 7.0, 1.6, 1.6 Hz, Ph), 7.12 (1H, tt, J =
7.0, 1.6 Hz, Ph), 7.06 (2H, ddd, J = 7.0, 1.6, 1.6 Hz, Ph), 3.73 (1H,
q, J = 6.4 Hz, 1’‐H), 3.34‐3.25 (2H, m, 4‐H), 2.94 (1H, d, J = 13.8
Hz, CH2Ph), 2.85 (1H, d, J = 13.8 Hz, CH2Ph), 2.36 (1H, ddd, J =
10.5, 7.7, 4.4 Hz, 3‐H), 2.15 (1H, ddd, J = 10.5, 8.0, 8.0 Hz, 3‐H),
1.38 (9H, s, tBu), 1.23 (3H, d, J = 6.4 Hz, 1’‐CH3); 13C NMR (100
MHz, CDCl3) δ 171.4, 145.1, 137.4, 129.6, 127.89, 127.87, 127.7,
126.9, 126.1, 81.2, 74.1, 60.8, 48.8, 42.1, 28.0, 26.0, 22.5; HRMS
(ESI): calcd for C23H30NO2 [M + H]+ 352.2271, found 352.2262.
(1S,2S,1’S)‐(2‐(tert‐Butoxycarbonyl)‐1‐(1’‐phenylethyl)azetidin‐1‐
with (1S,2S,1´S)‐3a. Colorless crystals; mp 97–100 °C; [α]22
589
−155.3 (c 1.0 in CHCl3); IR (KBr) 
max/cm−1 3063, 3028, 3008,
2970, 2944, 2383, 2336, 2287, 1740, 1495, 1456, 1399, 1384,
1353, 1244, 1222, 1190, 1172, 1157, 1115, 1083, 1073, 1035,
1019, 968, 949, 916, 893, 766, 756, 732, 699; 1H NMR (400 MHz,
CDCl3) δ 7.49‐7.33 (10H, m, Ph), 5.32 (1H, d, J = 12.0 Hz, OCH2),
5.18 (1H, d, J = 12.0 Hz, OCH2), 4.34 (1H, q, J = 7.2 Hz, 1’‐H), 4.09
(1H, dd, J = 9.6, 9.0 Hz, 2‐H), 3.75 (1H, ddd, J = 10.0, 8.4, 8.4 Hz,
4‐H), 3.27 (1H, ddd, J = 9.2, 8.4, 2.8 Hz, 4‐H), 2.98 (1H, dddd, J =
11.2, 10.0, 9.6, 9.2 Hz, 3‐H), 2.50‐1.40 (3H, br., BH3), 1.79 (1H,
dddd, J = 11.2, 9.0, 8.4, 2.8 Hz, 3‐H), 1.64 (3H, d, J = 7.2 Hz, 1’‐
CH3); 13C NMR (100 MHz, CDCl3) δ 167.1, 136.7, 135.2, 130.3,
129.2, 128.8, 128.6, 128.5, 128.4, 68.0, 67.3, 65.0, 51.4, 18.2,
15.2; 11B NMR (128 MHz, CDCl3) δ –13.2 (br.); HRMS (ESI): calcd
for C19H24BNNaO2 [M + Na]+ 332.1792, found 332.1779; Found:
C, 73.7; H, 8.1; N, 4.5. C19H24BNO2 requires C, 73.8; H, 7.8; N,
4.5%.
Borane diisopropylamine complex
Obtained in ca. 71% yield with impurities in the ‐benzylation
of (1S,2S,1´S)‐3a (Table 2, entry 3). A 2nd chromatographic
purification on silica gel (n‐hexane/CH2Cl2 = 1/1.5 to 0/1 as the
eluent) afforded pure borane diisopropylamine complex in 47%
yield as a colorless oil. IR (film) 
max/cm−1 3207, 2976, 2941,
2882, 2387, 2340, 2285, 2102, 1473, 1420, 1388, 1347, 1338,
1308, 1244, 1161, 1124, 1090, 1005, 930, 908, 825, 806; 1H NMR
(400 MHz, CDCl3) δ 3.253 (1H, sept., J = 6.6 Hz, NCH), 3.245 (1H,
sept, J = 6.6 Hz, NCH), 3.04 (1H, br., NH), 1.90‐0.80 (3H, br., BH3),
1.29 (3H, d, J = 6.6 Hz, CH3), 1.28 (3H, d, J = 6.6 Hz, CH3); 13C NMR
(100 MHz, CDCl3) δ 52.0, 20.9, 18.9; 11B NMR (128 MHz, CDCl3)
δ –21.5 (q, J = 97 Hz); HRMS (ESI): calcd for C6H18BNNa [M + Na]+
138.1425, found 138.1420.
ium‐1‐yl)trihydroborate [(1S,2S,1´S)‐3a]
Borane dimethyl sulfide complex (ca. 10 M, 0.32 mL, 3.2 mmol)
was added to a solution of (2S,1’S)‐1a (741 mg, 2.84 mmol) in
CH2Cl2 (14 mL) at 0 °C under an argon atmosphere and the
mixture was stirred for 20 h at room temperature. The resulting
mixture was evaporated to ca. 1/3 volume and the residue was
purified by chromatography on silica gel (n‐hexane/CH2Cl2 = 1/2
to 0/1 as the eluent) to obtain (1S,2S,1´S)‐3a (729 mg, 93% yield)
as colorless crystals. Mp 124–126 °C; [α]24 −143.3 (c 1.0 in
589
CHCl3); IR (KBr) 
max/cm−1 3033, 3001, 2981, 2938, 2394, 2345,
2294, 1731, 1492, 1456, 1370, 1356, 1246, 1227, 1180, 1155,
1117, 1081, 1034, 1018, 892, 844, 777, 757, 731, 697; 1H NMR
(400 MHz, CDCl3) δ 7.48‐7.38 (5H, m, Ph), 4.33 (1H, q, J = 7.2 Hz,
1’‐H), 3.96 (1H, dd, J = 9.6, 8.8 Hz, 2‐H), 3.69 (1H, ddd, J = 10.0,
8.8, 8.6 Hz, 4‐H), 3.23 (1H, ddd, J = 9.2, 8.8, 2.4 Hz, 4‐H), 2.88
(1H, dddd, J = 11.2, 10.0, 9.6, 9.2 Hz, 3‐H), 2.30‐1.30 (3H, br.,
BH3), 1.73 (1H, dddd, J = 11.2, 8.8, 8.6, 2.4 Hz, 3‐H), 1.65 (3H, d,
J = 7.2 Hz, 1’‐CH3), 1.58 (9H, s, tBu); 13C NMR (100 MHz, CDCl3)
δ 166.3, 137.0, 130.4, 129.2, 128.7, 82.7, 68.1, 65.6, 51.4, 28.1,
18.4, 15.3; 11B NMR (128 MHz, CDCl3) δ –13.4 (br.); HRMS (ESI):
calcd for C16H26BNNaO2 [M + Na]+ 298.1949, found 298.1941;
Found: C, 69.5; H, 9.4; N, 5.0. C16H26BNO2 requires C, 69.8; H,
9.5; N, 5.1%.
(2
carboxylate [(2
Colorless oil; [α]23 −55.0 (c 1.0 in EtOH); IR (film)
S
,1’
S
)‐tert‐Butyl 2‐allyl‐1‐(1’‐phenylethyl)azetidine‐2‐
S
,1´ )‐2ab]
S

max/cm−1
589
(1S,2S,1’S)‐(2‐(Ethoxycarbonyl)‐1‐(1’‐phenylethyl)azetidin‐1‐ium‐1‐
3074, 3028, 3003, 2974, 2929, 2853, 1717, 1638, 1492, 1475,
1453, 1391, 1367, 1324, 1304, 1250, 1221, 1174, 1145, 1106,
1090, 1075, 1049, 1029, 991, 913, 848, 762, 702; 1H NMR (400
MHz, CDCl3) δ 7.32 (2H, ddd, J = 7.2, 1.6, 1.6 Hz, Ph), 7.26 (2H,
dddd, J = 7.2, 7.2, 1.6, 1.6 Hz, Ph), 7.20 (1H, tt, J = 7.2, 1.6 Hz,
Ph), 5.68 (1H, dddd, J = 16.8, 10.2, 6.8, 6.8 Hz, CH2CH=CH2), 5.03‐
5.00 (1H, m, CH2CH=CH2), 4.98 (1H, dddd, J = 10.2, 2.4, 1.2, 1.2
Hz, CH2CH=CH2), 3.76 (1H, q, J = 6.4 Hz, 1’‐H), 3.27 (1H, ddd, J =
8.0, 7.2, 6.2 Hz, 4‐H), 3.21 (1H, ddd, J = 8.4, 6.2, 4.4 Hz, 4‐H),
2.34‐2.24 (2H, m, 3‐H and CH2CH=CH2), 2.19 (1H, dddd, J = 13.8,
6.8, 1.2, 1.2 Hz, CH2CH=CH2), 1.99 (1H, ddd, J = 10.8, 8.4, 7.2 Hz,
3‐H), 1.47 (9H, s, tBu), 1.21 (3H, d, J = 6.4 Hz, 1’‐CH3); 13C NMR
(100 MHz, CDCl3) δ 172.2, 144.5, 133.7, 127.9, 127.7, 127.0,
117.6, 80.9, 72.0, 60.5, 48.5, 39.9, 28.1, 25.0, 22.4; HRMS (ESI):
calcd for C19H28NO2 [M + H]+ 302.2115, found 302.2107.
yl)trihydroborate [(1S,2S,1´S)‐3b]
Prepared in 94% yield from (2S,1’S)‐1b by the same procedure
with (1S,2S,1´S)‐3a. Colorless crystals; mp 75–77 °C; [α]22
589
−149.9 (c 1.0 in CHCl3); IR (KBr) 
max/cm−1 3033, 3002, 2984,
2939, 2392, 2343, 2292, 1740, 1496, 1457, 1387, 1368, 1297,
1254, 1217, 1174, 1159, 1119, 1086, 1074, 1057, 1029, 968, 945,
922, 891, 849, 833, 787, 763, 752, 727, 702; 1H NMR (400 MHz,
CDCl3) δ 7.49‐7.38 (5H, m, Ph), 4.37 (1H, q, J = 7.0 Hz, 1’‐H), 4.30
(2H, q, J = 7.2 Hz, OCH2CH3), 4.06 (1H, dd, J = 9.6, 9.0 Hz, 2‐H),
3.73 (1H, ddd, J = 10.0, 8.4, 8.4 Hz, 4‐H), 3.25 (1H, ddd, J = 9.2,
8.4, 2.4 Hz, 4‐H), 2.94 (1H, dddd, J = 11.2, 10.0, 9.6, 9.2 Hz, 3‐H),
2.50‐1.30 (3H, br., BH3), 1.77 (1H, dddd, J = 11.2, 9.0, 8.4, 2.4 Hz,
3‐H), 1.66 (3H, d, J = 7.0 Hz, 1’‐CH3), 1.39 (3H, t, J = 7.2 Hz,
OCH2CH3); 13C NMR (100 MHz, CDCl3) δ 167.2, 136.8, 130.4,
129.2, 128.8, 68.0, 64.9, 61.4, 51.4, 18.3, 15.2, 14.1; 11B NMR
(128 MHz, CDCl3) δ –13.4 (br.); HRMS (ESI): calcd for
C14H22BNNaO2 [M + Na]+ 270.1636, found 270.1625; Found: C,
67.7; H, 9.0; N, 5.6. C14H22BNO2 requires C, 68.0; H, 9.0; N, 5.7%.
(2
carboxylate [(2
Colorless oil; [α]23 −66.8 (c 1.0 in EtOH); IR (film)
S
,1’
S
)‐Ethyl 2‐allyl‐1‐(1’‐phenylethyl)azetidine‐2‐
S
,1´ )‐2bb]
S

max/cm−1
589
3074, 3027, 2974, 2929, 2853, 1720, 1638, 1493, 1453, 1388,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 12
ARTICLE
Journal Name
1366, 1302, 1276, 1249, 1216, 1193, 1148, 1126, 1091, 1076, (2
1048, 1027, 992, 914, 863, 787, 763, 702; H NMR (400 MHz, carboxylate [(2
S
,1’
S
)‐tert‐Butyl 2‐cinnamyl‐1‐(1’‐phenylethyl)azetidine‐2‐
View Article Online
DOI: 10.1039/C8OB01395K
1
S
,1´S
)‐2ad]
CDCl3) δ 7.30‐7.18 (5H,m, Ph), 5.70 (1H, dddd, J = 17.0, 11.2, 7.2, 2S,1´S/2R,1´S = 94/6 [diastereomerically pure (2S,1´S)‐2ad could
7.2 Hz, CH2CH=CH2), 5.03‐5.00 (1H, m, CH2CH=CH2), 4.98 (1H, be obtained by careful chromatography on silica gel]; colorless

dddd, J = 11.2, 2.4, 1.2, 1.2 Hz, CH2CH=CH2), 4.21 (1H, dq, J = oil; [α]25589 −18.9 (c 1.0 in EtOH); IR (film) max/cm−1 3081, 3059,
10.8, 7.2 Hz, OCH2CH3), 4.10 (1H, dq, J = 10.8, 7.2 Hz, OCH2CH3), 3027, 2972, 2929, 2852, 1714, 1599, 1493, 1476, 1451, 1391,
3.65 (1H, q, J = 6.6 Hz, 1’‐H), 3.34‐3.25 (2H, m, 4‐H), 2.33‐2.23 1367, 1302, 1278, 1249, 1219, 1152, 1111, 1076, 1028, 966, 910,
(2H, m, 3‐H and CH2CH=CH2), 2.18 (1H, dddd, J = 13.8, 7.2, 1.2, 847, 825, 761, 738, 700; 1H NMR (400 MHz, CDCl3) δ 7.38‐7.14
1.2 Hz, CH2CH=CH2), 2.06 (1H, ddd, J = 10.8, 8.0, 8.0 Hz, 3‐H), (10H, m, Ph), 6.48 (0.06H, d, J = 15.6 Hz, CH2CH=CHPh), 6.37‐
1.22 (3H, t, J = 7.2 Hz, OCH2CH3), 1.19 (3H, d, J = 6.6 Hz, 1’‐CH3); 6.25 (0.06H, m, CH2CH=CHPh), 6.33 (0.94H, d, J = 15.8 Hz,
13C NMR (100 MHz, CDCl3) δ 172.9, 144.2, 133.6, 127.9, 127.7, CH2CH=CHPh), 6.08 (0.94H, ddd, J = 15.8, 7.4, 7.0 Hz,
127.1, 117.8, 71.6, 61.1, 60.2, 48.8, 40.2, 24.9, 22.0, 14.1; HRMS CH2CH=CHPh), 3.85‐3.74 (0.06H, m, 1’‐H), 3.80 (0.94H, q, J = 6.6
(ESI): calcd for C17H24NO2 [M + H]+ 274.1802, found 274.1795.
(2 ,1’ )‐Benzyl 2‐allyl‐1‐(1’‐phenylethyl)azetidine‐2‐
carboxylate [(2 ,1´ )‐2cb]
Hz, 1’‐H), 3.30 (0.94H, ddd, J = 8.0, 7.4, 6.2 Hz, 4‐H), 3.25 (0.94H,
ddd, J = 8.2, 6.2, 4.2 Hz, 4‐H), 3.11 (0.06H, ddd, J = 8.1, 8.1, 6.4
Hz, 4‐H), 2.94 (0.06H, ddd, J = 8.4, 6.4, 3.4 Hz, 4‐H), 2.86 (0.06H,
S
S
S
S
2S,1´S/2R,1´S = 96/4; colorless oil; [α]22589 −85.4 (c 1.0 in EtOH); ddd, J = 14.2, 7.5, 0.8 Hz, CH2CH=CHPh), 2.73 (0.06H, ddd, J =
IR (film) 
max/cm−1 3065, 3030, 2967, 2928, 2853, 1720, 1680, 14.2, 6.8, 0.8 Hz, CH2CH=CHPh), 2.44 (0.94H, ddd, J = 13.7, 7.4,
1639, 1599, 1493, 1452, 1370, 1296, 1247, 1211, 1191, 1145, 1.0 Hz, CH2CH=CHPh), 2.38‐2.21 (0.12H, m, 3‐H), 2.33 (0.94H,
1
1087, 1048, 1028, 991, 966, 915, 845, 753, 699; H NMR (400 ddd, J = 13.7, 7.0, 1.4 Hz, CH2CH=CHPh), 2.30 (0.94H, ddd, J =
MHz, CDCl3) δ 7.40‐7.27 (5H, m, Ph), 7.24‐7.14 (5H, m, Ph), 5.88 10.7, 8.0, 4.2 Hz, 3‐H), 2.05 (0.94H, ddd, J = 10.7, 8.2, 7.4 Hz, 3‐
(0.04H, dddd, J = 18.0, 9.6, 7.2, 7.0 Hz, CH2CH=CH2), 5.69 (0.96H, H), 1.51 (0.54H, s, tBu), 1.47 (8.46H, s, tBu), 1.26 (0.18H, d, J =
ddt, J = 17.0, 10.2, 7.0 Hz, CH2CH=CH2), 5.26 (0.04H, d, J = 12.0 6.4 Hz, 1’‐CH3), 1.23 (2.82H, d, J = 6.6 Hz, 1’‐CH3); 13C NMR (100
Hz, CH2Ph), 5.21 (0.96H, d, J = 12.6 Hz, CH2Ph), 5.10 (0.04H, d, J MHz, CDCl3) [assigned only (2S,1’S)] δ 172.1, 144.5, 137.6, 132.7,
= 12.0 Hz, CH2Ph), 5.09 (0.96H, d, J = 12.6 Hz, CH2Ph), 5.01‐4.91 128.4, 127.9, 127.7, 127.0, 126.9, 125.9, 125.5, 80.9, 72.3, 60.5,
(2H, m, CH2CH=CH2), 3.64 (0.96H, q, J = 6.4 Hz, 1’‐H), 3.58 (0.04H, 48.6, 39.3, 28.1, 25.3, 22.3; HRMS (ESI): calcd for C25H32NO2 [M
q, J = 6.4 Hz, 1’‐H), 3.35 (0.96H, ddd, J = 8.0, 7.2, 6.2 Hz, 4‐H), + H]+ 378.2424, found 378.2417.
3.30 (0.96H, ddd, J = 8.4, 6.2, 4.0 Hz, 4‐H), 3.13 (0.04H, ddd, J = tert‐Butyl 2‐methyl‐1‐(1’‐phenylethyl)azetidine‐2‐carboxylate
7.9, 7.9, 6.4 Hz, 4‐H), 2.94 (0.04H, ddd, J = 8.5, 6.4, 4.0 Hz, 4‐H), (2ae)
2.74 (0.04H, dddd, J = 13.9, 7.2, 1.0, 1.0 Hz, CH2CH=CH2), 2.62 2S,1´S/2R,1´S = 89/11 (difficult to separate diastereomers by
(0.04H, dddd, J = 13.9, 7.0, 1.2, 1.2 Hz, CH2CH=CH2), 2.35‐2.23 chromatography on silica gel); colorless oil; [α]26589 −98.5 (c 1.0
(1.92H, m, 3‐H and CH2CH=CH2), 2.35‐2.00 (0.08H, m, 3‐H), 2.17 in EtOH); IR (film) 
max/cm−1 3062, 3028, 2973, 2929, 2855, 1719,
(0.96H, dddd, J = 14.2, 7.0, 1.2, 1.2 Hz, CH2CH=CH2), 2.09 (0.96H, 1492, 1477, 1453, 1391, 1368, 1281, 1254, 1235, 1222, 1178,
ddd, J = 10.4, 8.4, 8.0 Hz, 3‐H), 1.16 (2.88H, d, J = 6.4 Hz, 1’‐CH3), 1146, 1075, 1054, 1029, 983, 951, 911, 891, 849, 821, 764, 701;
1.13 (0.12H, d, J = 6.4 Hz, 1’‐CH3); 13C NMR (100 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.36‐7.31 (2H, m, Ph), 7.30‐7.24 (2H,
[assigned only (2S,1’S)] δ 172.8, 144.0, 135.7, 133.5, 128.4, m, Ph), 7.24‐7.17 (0.11H, m, Ph), 7.21 (0.89H, tt, J = 7.2, 1.4 Hz,
128.3, 128.1, 127.9, 127.6, 127.1, 117.9, 71.6, 66.1, 60.9, 48.8, Ph), 3.81‐3.72 (0.11H, m, 1’‐H), 3.76 (0.89H, q, J = 6.4 Hz, 1’‐H),
40.2, 24.9, 21.8; HRMS (ESI): calcd for C22H26NO2 [M + H]+ 3.24 (0.11H, ddd, J = 8.4, 6.6, 6.6 Hz, 4‐H), 3.14 (0.89H, ddd, J =
336.1958, found 336.1944.
(2 ,1’ )‐tert‐Butyl 2‐(3‐methylbut‐2‐en‐1‐yl)‐1‐(1´‐
phenylethyl)azetidine‐2‐carboxylate [(2 ,1´ )‐2ac]
Colorless oil; [α]28 −31.0 (c 1.0 in EtOH); IR (film)
8.5, 6.4, 5.4 Hz, 4‐H), 3.07‐2.96 (0.11H, m, 4‐H), 3.03 (0.89H, ddd,
J = 8.1, 6.4, 6.2 Hz, 4‐H), 2.39‐2.30 (0.11H, m, 3‐H), 2.34 (0.89H,
ddd, J = 10.4, 8.5, 6.2 Hz, 3‐H), 1.89‐1.77 (0.11H, m, 3‐H), 1.81
max/cm−1 (0.89H, ddd, J = 10.4, 8.1, 5.4 Hz, 3‐H), 1.49 (8.01H, s, tBu), 1.453
S
S
S
S

589
3061, 3028, 2972, 2928, 2854, 1716, 1602, 1492, 1476, 1452, (0.99H, s, tBu), 1.446 (0.33H, s, 2‐CH3), 1.25 (2.67H, s, 2‐CH3),
1390, 1367, 1323, 1304, 1248, 1222, 1153, 1110, 1086, 1049, 1.21 (2.67H, d, J = 6.4 Hz, 1’‐CH3), 1.17 (0.33H, d, J = 6.4 Hz, 1’‐
1028, 981, 952, 911, 848, 823, 801, 761, 701; 1H NMR (400 MHz, CH3); 13C NMR (100 MHz, CDCl3) δ 174.0 (2S), 173.4 (2R), 144.2
CDCl3) δ 7.35‐7.30 (2H, m, Ph), 7.30‐7.23 (2H, m, Ph), 7.20 (1H, (2R), 143.8 (2S), 128.1 (2R), 128.0 (2S), 127.9 (2S), 127.5 (2R),
tt, J = 7.0, 1.4 Hz, Ph), 5.01‐4.94 (1H, m, CH2CH=C(CH3)2), 3.75 127.0 (2S), 126.8 (2R), 80.6 (2R), 80.4 (2S), 68.5 (2R), 68.0 (2S),
(1H, q, J = 6.4 Hz, 1’‐H), 3.18 (1H, ddd, J = 8.0, 6.4, 6.4 Hz, 4‐H), 61.3 (2R), 60.3 (2S), 48.5 (2R), 47.9 (2S), 28.7 (2S), 28.6 (2R), 28.1,
3.14 (1H, ddd, J = 8.4, 6.4, 5.2 Hz, 4‐H), 2.40‐2.31 (2H, m, 3‐H 23.3 (2R), 22.3 (2S), 21.8 (2R), 19.9 (2S); HRMS (ESI): calcd for
and CH2CH=C(CH3)2), 2.22 (1H, dd, J = 14.4, 6.8 Hz, C17H26NO2 [M + H]+ 276.1958, found 276.1952.
CH2CH=C(CH3)2), 1.89 (1H, ddd, J = 10.7, 8.4, 6.4 Hz, 3‐H), 1.66 (2
(3H, d, J = 0.8 Hz, CH2CH=C(CH3)2), 1.56 (3H, d, J = 0.4 Hz, carboxylate [(2
CH2C=C(CH3)2), 1.45 (9H, s, tBu), 1.23 (3H, d, J = 6.4 Hz, 1’‐CH3); Colorless oil; [α]23 −77.3 (c 1.0 in EtOH); IR (film)
S
,1’
S
)‐tert‐Butyl 2‐ethyl‐1‐(1’‐phenylethyl)azetidine‐2‐
S
,1´ )‐2af]
S

max/cm−1
589
13C NMR (100 MHz, CDCl3) δ 172.5, 144.7, 133.6, 127.8, 127.7, 3062, 2970, 2930, 2874, 2852, 1717, 1601, 1491, 1453, 1391,
126.8, 118.8, 80.6, 72.6, 60.6, 48.4, 33.4, 28.0, 25.9, 25.2, 22.8, 1367, 1322, 1305, 1251, 1234, 1177, 1145, 1076, 1027, 972, 950,
18.2; HRMS (ESI): calcd for C21H32NO2 [M + H]+ 330.2428, found 909, 848, 831, 801, 760, 701; 1H NMR (400 MHz, CDCl3) δ 7.34‐
330.2419.
7.29 (2H, m, Ph), 7.29‐7.23 (2H, m, Ph), 7.20 (1H, tt, J = 7.2, 1.6
Hz, Ph), 3.72 (1H, q, J = 6.4 Hz, 1’‐H), 3.20 (1H, ddd, J = 8.4, 6.8,
8 | J. Name., 2012, 00, 1‐3
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Organic & Biomolecular Chemistry
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ARTICLE
6.4 Hz, 4‐H), 3.15 (1H, ddd, J = 8.4, 6.4, 4.8 Hz, 4‐H), 2.36 (1H, 3‐H), 1.59 (9H, s, tBu); 13C NMR (100 MHz, CDCl3) δV1ie6w5A.r9ti,cl1e3O2nl.i5ne,
11
DOI: 10.1039/C8OB01395K
dddd, J = 10.7, 8.4, 4.8, 0.4 Hz, 3‐H), 1.88 (1H, ddd, J = 10.7, 8.4, 131.3, 129.3, 129.0, 82.9, 64.2, 62.6, 53.0, 28.1, 18.9; B NMR
6.8 Hz, 3‐H), 1.69‐1.59 (1H, m, CH2CH3), 1.56‐1.45 (1H, m, (128 MHz, CDCl3) δ –12.7 (br.); HRMS (ESI): calcd for
CH2CH3), 1.48 (9H, s, tBu), 1.21 (3H, d, J = 6.4 Hz, 1’‐CH3), 0.73 C15H24BNNaO2 [M + Na]+ 284.1792, found 284.1779; Found: C,
(3H, dd, J = 7.4, 7.4 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3) δ 68.7; H, 9.4; N, 5.35. C15H24BNO2 requires C, 69.0; H, 9.3; N, 5.4%.
172.4, 144.9, 127.8, 127.6, 126.8, 80.6, 73.7, 60.6, 48.3, 28.1,
(
R
)‐tert‐Butyl 1,2‐dibenzylazetidine‐2‐carboxylate [(
R)‐6]
27.7, 24.7, 22.7, 7.9; HRMS (ESI): calcd for C18H28NO2 [M + H]+ A solution of (1R,2R)‐
5
(113 mg, 0.433 mmol) in THF (3.5 mL)
290.2115, found 290.2105.
(2 ,1’ )‐2‐tert‐Butyl 2‐ethyl 1‐(1’‐phenylethyl)azetidine‐2,2‐
dicarboxylate [(2 ,1´ )‐2ag]
Colorless oil; [α]23 −96.9 (c 1.0 in EtOH); IR (film)
was treated with a 1.0 M LiHMDS solution in THF (1.04 mL, 1.04
mmol) at 0 °C under an argon atmosphere. The solution was
stirred for 30 min at 0 °C and treated with benzyl bromide (134
R
S
R
S

max/cm−1
L, 1.13 mmol) at the same temperature. After stirring for 3 h
589
3062, 3026, 2977, 2932, 2864, 1754, 1726, 1602, 1493, 1475, at room temperature, the resulting mixture was quenched with
1454, 1392, 1368, 1283, 1251, 1215, 1190, 1170, 1145, 1116, saturated aqueous NH4Cl and extracted with EtOAc. The
1102, 1077, 1040, 1018, 985, 970, 949, 915, 846, 815, 766, 736, combined organic extracts were washed with saturated
1
701; H NMR (400 MHz, CDCl3) δ 7.38‐7.33 (2H, m, Ph), 7.31‐ aqueous NaHCO3 followed by brine, dried over Na2SO4, and
7.25 (2H, m, Ph), 7.21 (1H, tt, J = 7.2, 1.6 Hz, Ph), 4.27 (1H, dq, J evaporated. The residue was purified by chromatography on
= 10.8, 7.0 Hz, OCH2CH3), 4.21 (1H, dq, J = 10.8, 7.0 Hz, OCH2CH3), silica gel (n‐hexane/EtOAc = 15/1 to 10/1 as the eluent) to
3.75 (1H, q, J = 6.4 Hz, 1’‐H), 3.09 (1H, ddd, J = 8.2, 8.0, 6.4 Hz, obtain (R)‐6
(113 mg, 77% yield) as a colorless oil. [α]21589 −8.7
4‐H), 2.98 (1H, ddd, J = 8.0, 6.4, 4.1 Hz, 4‐H), 2.47 (1H, ddd, J = (c 1.0 in EtOH); 68% ee [determined by HPLC analysis: Daicel
11.1, 8.2, 4.1 Hz, 3‐H), 2.42 (1H, ddd, J = 11.1, 8.0, 8.0 Hz, 3‐H), Chiralcel OJ‐H column (25 cm), n‐hexane/EtOH = 98/2 as the
1.50 (9H, s, tBu), 1.30 (3H, d, J = 6.4 Hz, 1’‐CH3), 1.28 (3H, dd, J = eluent, flow rate = 0.50 mL/min, tR = 9.4 min for (S)‐
6 (16.1%)
7.0, 7.0 Hz, OCH2CH3); 13C NMR (100 MHz, CDCl3) δ 169.8, 169.4, and 10.3 min for (R)‐ max/cm−1 3085, 3062,
6
(83.9%)]; IR (film)

143.2, 128.0, 127.6, 127.0, 81.5, 73.6, 61.8, 61.0, 48.1, 27.8, 3028, 3003, 2974, 2928, 2842, 1717, 1603, 1495, 1476, 1454,
25.6, 22.4, 14.1; HRMS (ESI): calcd for C19H28NO4 [M + H]+ 1391, 1367, 1306, 1252, 1214, 1149, 1095, 1029, 950, 909, 847,
334.2013, found 334.2006.
(1R,2R,1’S)‐(2‐(tert‐Butoxycarbonyl)‐1‐(1’‐phenylethyl)azetidin‐1‐
ium‐1‐yl)trihydroborate [(1R,2R,1´S)‐3a]
790, 770, 734, 699; 1H NMR (400 MHz, CDCl3) δ 7.35‐7.17 (10H,
m, Ph), 3.82 (1H, d, J = 13.0 Hz, NCH2Ph), 3.65 (1H, d, J = 13.0 Hz,
NCH2Ph), 3.26‐3.11 (4H, m, 4‐H and 2‐CH2Ph), 2.49 (1H, ddd, J =
10.4, 7.6, 4.8 Hz, 3‐H), 2.17 (1H, ddd, J = 10.4, 8.0, 8.0 Hz, 3‐H),
1.45 (9H, s, tBu); 13C NMR (100 MHz, CDCl3) δ 171.7, 138.7,
137.0, 129.9, 128.5, 128.2, 128.0, 126.8, 126.3, 81.3, 73.3, 56.0,
50.0, 41.3, 28.2, 26.4; HRMS (ESI): calcd for C22H28NO2 [M + H]+
338.2115, found 338.2108.
Prepared in 83% yield from (2R,1’S)‐1a by the same procedure
with (1S,2S,1´S)‐3a. Colorless crystals; mp 122–125 °C; [α]25
589
+82.8 (c 1.0 in CHCl3); IR (KBr) 
max/cm−1 3032, 2980, 2936, 2411,
2389, 2346, 2297, 1736, 1494, 1453, 1392, 1370, 1352, 1246,
1224, 1174, 1159, 1105, 1073, 1042, 1029, 1007, 988, 948, 917,
884, 845, 779, 757, 739, 697; 1H NMR (400 MHz, CDCl3) δ 7.46‐
7.36 (5H, m, Ph), 4.44 (1H, dd, J = 9.4, 9.2 Hz, 2‐H), 4.05 (1H, q,
J = 7.0 Hz, 1’‐H), 3.54 (1H, ddd, J = 9.4, 9.0, 9.0 Hz, 4‐H), 3.41 (1H,
ddd, J = 9.6, 9.0, 3.4 Hz, 4‐H), 2.92 (1H, dddd, J = 11.3, 9.6, 9.4,
9.4 Hz, 3‐H), 2.30‐1.30 (3H, br., BH3), 1.78 (1H, dddd, J = 11.3,
9.2, 9.0, 3.4 Hz, 3‐H), 1.72 (3H, d, J = 7.0 Hz, 1’‐CH3), 1.44 (9H, s,
tBu); 13C NMR (100 MHz, CDCl3) δ 166.0, 137.2, 130.4, 129.0,
128.6, 82.6, 70.3, 64.0, 56.7, 27.8, 17.4, 17.0; 11B NMR (128 MHz,
CDCl3) δ –14.3 (br.); HRMS (ESI): calcd for C16H26BNNaO2 [M +
Na]+ 298.1949, found 298.1936; Found: C, 69.5; H, 9.7; N, 5.0.
C16H26BNO2 requires C, 69.8; H, 9.5; N, 5.1%.
Epimerization of (1
R
,2
R
)‐5 to (1
R,2S)‐5
A solution of (1R,2R)‐
5
(104 mg, 0.398 mmol) in THF (3.2 mL)
was treated with a 1.0 M LiHMDS solution in THF (0.96 mL, 0.96
mmol) at 0 °C under an argon atmosphere. The solution was
stirred for 30 min at 0 °C and for 3 h at room temperature. The
resulting mixture was quenched with saturated aqueous NH4Cl
and extracted with EtOAc. The combined organic extracts were
washed with saturated aqueous NaHCO3 followed by brine,
dried over Na2SO4, and evaporated. The residue was purified by
chromatography on silica gel (n‐hexane/CH2Cl2 = 1/1, 1/2, to 0/1
as the eluent) to afford (1R,2S)‐
colorless crystals and (1R,2R)‐ (62.3 mg, 60% recovery) as
colorless crystals. (1R,2S)‐
: mp 74–79 °C; [α]24589 –33.4 (c 1.0
in CHCl3); IR (KBr)
max/cm−1 3066, 3037, 3004, 2981, 2936, 2883,
5 (33.3 mg, 32% yield) as
5
(1
yl)trihydroborate [(1
Prepared in 94% yield from (R)‐
procedure with (1S,2S,1´S)‐3a Colorless crystals; mp 131–
137 °C; [α]22589 +136.4 (c 1.0 in CHCl3); IR (KBr) max/cm−1 3090,
R
,2
R
)‐(1‐Benzyl‐2‐(tert‐butoxycarbonyl)azetidin‐1‐ium‐1‐
5
R
,2R)‐5]

4
(94% ee) by the same
2367, 2274, 1729, 1497, 1454, 1392, 1367, 1251, 1226, 1168,
1111, 1057, 1047, 1019, 930, 864, 844, 780, 744, 697; 1H NMR
(400 MHz, CDCl3) δ 7.48‐7.42 (2H, m, Ph), 7.39‐7.31 (3H, m, Ph),
4.50 (1H, dd, J = 8.8, 4.8 Hz, 2‐H), 4.13 (1H, d, J = 11.8 Hz, CH2Ph),
4.03 (1H, d, J = 11.8 Hz, CH2Ph), 4.02 (1H, ddd, J = 9.4, 8.8, 8.8
Hz, 4‐H), 3.39 (1H, dddd, J = 8.8, 8.8, 4.8, 1.2 Hz, 4‐H), 2.79 (1H,
dddd, J = 11.4, 8.8, 8.8, 8.8 Hz, 3‐H), 2.36 (1H, dddd, J = 11.4, 9.4,
.

3067, 3035, 2978, 2943, 2878, 2385, 2290, 1738, 1496, 1479,
1455, 1393, 1368, 1307, 1242, 1172, 1155, 1123, 1093, 1080,
1051, 1035, 1019, 978, 955, 928, 909, 866, 845, 813, 781, 757,
740, 723, 697; 1H NMR (400 MHz, CDCl3) δ 7.51‐7.43 (3H, m, Ph),
7.39‐7.32 (2H, m, Ph), 4.16 (1H, d, J = 14.0 Hz, CH2Ph), 4.15 (1H,
dd, J = 10.0, 8.8 Hz, 2‐H), 3.95 (1H, d, J = 14.0 Hz, CH2Ph), 3.56
(1H, ddd, J = 10.0, 8.4, 8.4 Hz, 4‐H), 3.27 (1H, ddd, J = 8.8, 8.4,
2.4 Hz, 4‐H), 2.95 (1H, dddd, J = 10.8, 10.0, 10.0, 8.8 Hz, 3‐H),
2.40‐1.30 (3H, br., BH3), 1.71 (1H, dddd, J = 10.8, 8.8, 8.4, 2.4 Hz,
4.8, 4.8 Hz, 3‐H), 2.30‐1.30 (3H, br., BH3), 1.54 (9H, s, tBu); 13
C
NMR (100 MHz, CDCl3) δ 168.1, 132.1, 131.7, 128.7, 128.0, 83.4,
72.8, 61.5, 57.8, 28.0, 18.7; 11B NMR (128 MHz, CDCl3) δ –10.1
(br.); HRMS (ESI): calcd for C15H24BNNaO2 [M + Na]+ 284.1792,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 9
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ARTICLE
Journal Name
found 284.1783; Found: C, 69.0; H, 9.6; N, 5.2. C15H24BNO2 by chromatography on silica gel [n‐hexane/EtOAc = 20/1 to 15/1
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requires C, 69.0; H, 9.3; N, 5.4%.
‐Epimerization of (1 ,2 )‐5 to (1
A solution of (1R,2R)‐
stirred for 3 h at room temperature under an argon atmosphere. EtOH); IR (film)
The volatiles were removed under reduced pressure. 1H NMR 1639, 1492, 1453, 1368, 1321, 1296, 1248, 1235, 1217, 1192,
analysis of the residue in CDCl3 showed a (1R,2R)‐ /(1S,2R)‐
1147, 1095, 1076, 1055, 1027, 994, 915, 862, 787, 765, 701; 1H
as the eluent, Rf: (2R,1´S) > (2S,1´S)] to obDtaOinI: 1(02.R10,139´S/C)‐82ObBb0(123945.6K
mg, 18% yield) as a colorless oil and (2S,1´S)‐2bb (45.5 mg, 33%
N
R
5
R
S,2R)‐5
(26 mg, 0.10 mmol) in THF (1.0 mL) was yield) as a colorless oil. (2R,1´S)‐2bb: [α]23 −98.1 (c 1.0 in
589

max/cm−1 3077, 3025, 2976, 2930, 2856, 1722,
5
5 =
98/2 mixture. Isolation of (1S,2R)‐
of small amount.
5
was not performed because NMR (400 MHz, CDCl3) δ 7.32‐7.24 (4H, m, Ph), 7.24‐7.18 (1H,
m, Ph), 5.88 (1H, dddd, J = 17.2, 10.2, 7.2, 7.2 Hz, CH2CH=CH2),
Removal of
by hydrogenation to afford (
carboxylate [( )‐7]
N
‐(1‐phenylethyl) substituent, as in (2
S
,1’
S
)‐2aa,
5.13 (1H, dddd, J = 10.2, 2.0, 1.0, 1.0 Hz, CH2CH=CH2), 5.11‐5.08
S
)‐tert‐butyl 2‐benzylazetidine‐2‐ (1H, m, CH2CH=CH2), 4.24 (1H, dq, J = 10.8, 7.2 Hz, OCH2CH3),
4.14 (1H, dq, J = 10.8, 7.2 Hz, OCH2CH3), 3.66 (1H, q, J = 6.4 Hz,
S
A solution of (2S,1´S)‐2aa (108 mg, 0.307 mmol) in MeOH (3.1 1’‐H), 3.14 (1H, ddd, J = 8.4, 7.6, 6.4 Hz, 4‐H), 2.95 (1H, ddd, J =
mL) was treated with ca. 4 M HCl in cyclopentyl methyl ether 8.4, 6.4, 4.0 Hz, 4‐H), 2.72 (1H, dddd, J = 13.9, 7.2, 1.0, 1.0 Hz,
(CPME) (92 L, 0.37 mmol) at 0 °C. After stirring for 20 min at CH2CH=CH2), 2.61 (1H, dddd, J = 13.9, 7.2, 1.0, 1.0 Hz,
room temperature, the solution was evaporated. A mixture of CH2CH=CH2), 2.28 (1H, ddd, J = 10.7, 8.4, 4.0 Hz, 3‐H), 2.02 (1H,
the residue and Pd‐C (loading: 10 wt.%, 16 mg) in MeOH (3.1 ddd, J = 10.7, 8.4, 7.6 Hz, 3‐H), 1.27 (3H, dd, J = 7.2, 7.2 Hz,
mL) was stirred at room temperature for 24 h under a hydrogen OCH2CH3), 1.20 (3H, d, J = 6.4 Hz, 1’‐CH3); 13C NMR (100 MHz,
atmosphere. The resulting mixture was filtered through a pad CDCl3) δ 172.9, 144.1, 133.7, 128.2, 127.4, 126.9, 117.9, 71.1,
of Celite and the filtrate was evaporated. The residue was 61.5, 60.4, 48.5, 41.0, 24.6, 22.4, 14.3; HRMS (ESI): calcd for
suspended in Et2O and treated with 1 M aqueous NaOH. The C17H24NO2 [M + H]+ 274.1802, found 274.1796. (2S,1´S)‐2bb
:
mixture was extracted with Et2O and the combined extracts see the above section. (Step 2) A mixture of (2R,1´S)‐2bb (47.4
were washed with brine, dried over Na2SO4, and evaporated. mg, 0.173 mmol) and NaHCO3 (73 mg, 0.87 mmol) in CH2Cl2 (1.7
The residue was purified by chromatography on silica gel mL) was treated with methyl triflate (40
(CH2Cl2/MeOH = 15/1 as the eluent) to obtain (S)‐721 (68.3 mg, and stirred for
at room temperature.
90% yield) as a colorless oil. [α]24 −84.2 (c 1.2 in CHCl3); IR chromatographic separation on silica gel [CH2Cl2/MeOH = 15/1
L, 0.35 mmol) at 0 °C
3
h
Careful
589
(film) 
max/cm−1 3325, 3085, 3062, 3029, 2976, 2932, 2875, 1722, to 10/1 as the eluent, Rf: (1S,2R,1´S) > (1R,2R,1´S)] gave
1495, 1475, 1455, 1392, 1367, 1315, 1270, 1210, 1153, 1098, diastereomerically pure (1S,2R,1´S)‐82b (31.9 mg, 42% yield) as
1
1049, 1031, 1003, 944, 926, 847, 811, 763, 745, 700; H NMR a colorless gum and a 1S,2R,1´S/1R,2R,1´S = 4/96 mixture of
8
(400 MHz, CDCl3) δ 7.28‐7.16 (5H, m, Ph), 3.49 (1H, ddd, J = 8.6, (37.3 mg, 49% yield) as colorless crystals.
A 2nd
8.4, 7.5 Hz, 4‐H), 3.22 (1H, ddd, J = 8.6, 7.5, 4.0 Hz, 4‐H), 3.12 chromatographic purification of the 4/96 mixture under the
(1H, d, J = 13.8 Hz, CH2Ph), 3.07 (1H, d, J = 13.8 Hz, CH2Ph), 2.70‐ same conditions afforded (1R,2R,1´S)‐822 (31.5 mg, 42% yield,
2.30 (1H, br., NH), 2.48 (1H, ddd, J = 11.6, 8.6, 8.4 Hz, 3‐H), 2.39 1S,2R,1´S/1R,2R,1´S = 2/98) as colorless crystals. (1S,2R,1´S)‐
8:
(1H, ddd, J = 11.6, 8.6, 4.0 Hz, 3‐H), 1.39 (9H, s, tBu); 13C NMR [α]23 −37.6 (c 1.0 in CHCl3); IR (KBr) max/cm−1 3051, 2987,

589
(100 MHz, CDCl3) δ 175.1, 136.9, 129.5, 128.0, 126.5, 81.3, 68.8, 2935, 1736, 1642, 1457, 1418, 1393, 1371, 1264, 1226, 1157,
1
45.4, 41.5, 31.1, 27.9; HRMS (ESI): calcd for C15H22NO2 [M + H]+ 1060, 1031, 1009, 937, 898, 856, 772, 756, 710; H NMR (400
248.1645, found 248.1640.
Removal of ‐benzyl group, as in (
afford ( )‐7
MHz, CDCl3) δ 7.51‐7.43 (5H, m, Ph), 5.55‐5.42 (1H, m,
CH2CH=CH2), 5.41 (1H, dd, J = 17.2, 2.4 Hz, CH2CH=CH2), 5.27 (1H,
dd, J = 9.2, 2.4 Hz, CH2CH=CH2), 4.57‐4.44 (3H, m, 4‐H and
N
R)‐6, by hydrogenation to
R
Performed by the same procedure with the transformation of OCH2CH3), 4.42 (1H, q, J = 7.0 Hz, 1’‐H), 3.30 (3H, s, NCH3), 3.27‐
(2S,1’S)‐2aa into (S)‐
7
described above. The reaction of (R)‐
6
3.15 and 3.13‐3.02 (4H, m, 3‐H, 4‐H and CH2CH=CH2), 2.81 (1H,
(112 mg, 0.332 mmol, 68% ee) afforded (R)‐721 (81.8 mg, quant.) ddd, J = 12.4, 9.2, 3.0 Hz, 3‐H), 1.75 (3H, d, J = 7.0 Hz, 1’‐CH3),
as a colorless oil. [α]25589 +60.2 (c 1.2 in CHCl3); [α]22589 +64.0 (c 1.45 (3H, t, J = 7.2 Hz, OCH2CH3); 1H NMR (400 MHz, acetone‐d6)
1.0 in EtOH).
δ 7.75‐7.68 (2H, m, Ph), 7.58‐7.49 (3H, m, Ph), 5.64 (1H, dddd, J
= 17.0, 10.1, 6.8, 6.8 Hz, CH2CH=CH2), 5.45 (1H, dddd, J = 17.0,
1.8, 1.0, 1.0 Hz, CH2CH=CH2), 5.29 (1H, dddd, J = 10.1, 1.6, 1.0,
1.0 Hz, CH2CH=CH2), 4.73 (1H, q, J = 7.0 Hz, 1’‐H), 4.73‐4.64 (1H,
Preparation of (1S,2R,1’S)‐ and (1R,2R,1’S)‐2‐allyl‐2‐
(ethoxycarbonyl)‐1‐methyl‐1‐(1’‐phenylethyl)azetidin‐1‐ium
trifluoromethanesulfonate [(1 ,2 ,1’ )‐8 and (1 ,2 ,1’ )‐8]
S
R
S
R
R
S
(Step 1) A solution of (2S,1’S)‐1b (117 mg, 0.501 mmol) in THF m, 4‐H), 4.61 (1H, dq, J = 15.0, 7.2 Hz, OCH2CH3), 4.60 (1H, dq, J
(2.0 mL) was treated with a ca. 0.7 M LDA solution in THF/n‐ = 15.0, 7.2 Hz, OCH2CH3), 3.41 (3H, s, NCH3), 3.40‐3.36 (1H, m,
hexane (1.72 mL, 1.2 mmol) at –78 °C under an argon 4‐H), 3.35 (1H, dddd, J = 12.4, 6.8, 1.0, 1.0 Hz, CH2CH=CH2), 3.23
atmosphere. The solution was stirred for 2 h at –78 °C and (1H, dddd, J = 12.4, 6.8, 1.0, 1.0 Hz, CH2CH=CH2), 3.08 (1H, ddd,
treated with allyl bromide (112 L, 1.29 mmol) at the same J = 12.2, 10.8, 9.0 Hz, 3‐H), 2.91 (1H, ddd, J = 12.2, 9.1, 2.6 Hz, 3‐
temperature. After stirring for 3 h at –78 °C, the resulting H), 1.87 (3H, d, J = 7.0 Hz, 1’‐CH3), 1.47 (3H, dd, J = 7.2, 7.2 Hz,
mixture was poured into saturated aqueous NH4Cl and OCH2CH3); 13C NMR (100 MHz, acetone‐d6) δ 167.0, 132.1, 132.0,
extracted with EtOAc. The combined organic extracts were 131.7, 130.1, 128.6, 123.3, 122.4 (q, J = 320 Hz), 87.1, 72.4, 65.2,
washed with saturated aqueous NaHCO3 followed by brine, 62.0, 40.0, 38.6, 24.5, 15.6, 14.1; HRMS (ESI): calcd for
dried over Na2SO4, and evaporated. The residue was purified C18H26NO2 [M – OTf]+ 288.1958, found 288.1950. (1R,2R,1´S)‐
8:
10 | J. Name., 2012, 00, 1‐3
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Organic & Biomolecular Chemistry
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ARTICLE
1S,2R,1´S/1R,2R,1´S = 2/98; mp 151–153 °C; [α]23589 −19.1 (c 1.0 Performed by the same procedure with the transformation of
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in CHCl3); IR (KBr)

max/cm−1 3048, 2991, 1738, 1645, 1499, 1474, (2S,1’S)‐2ab into (2S,1’S)‐
9. The reaction of (2S,1’S)‐2bb
DOI: 10.1039/C8OB0(143925.1K
1458, 1390, 1372, 1337, 1319, 1268, 1246, 1226, 1151, 1116, mg, 0.154 mmol) afforded (2S,1’S)‐
9
(33.5 mg, 94% yield) as
1052, 1033, 1015, 986, 953, 926, 889, 850, 790, 771, 753, 712; colorless crystals. [α]23589 –10.2 (c 1.0 in CHCl3).
1H NMR (400 MHz, CDCl3) δ 7.56‐7.49 (2H, m, Ph), 7.47‐7.42 (3H,
m, Ph), 5.44‐5.35 (2H, m, CH2CH=CH2), 5.35‐5.25 (2H, m, 1’‐H
Conflicts of interest
There are no conflicts to declare.
and CH2CH=CH2), 4.98 (1H, ddd, J = 10.6, 10.0, 9.6 Hz, 4‐H), 4.04
(1H, ddd, J = 10.6, 10.0, 2.6 Hz, 4‐H), 3.93 (1H, dq, J = 10.8, 7.2
Hz, OCH2CH3), 3.88 (1H, dq, J = 10.8, 7.2 Hz, OCH2CH3), 3.81‐3.73
(1H, m, CH2CH=CH2), 3.33‐3.26 (1H, m, CH2CH=CH2), 3.23 (3H, s,
NCH3), 3.15 (1H, dddd, J = 11.8, 10.6, 10.6, 1.2 Hz, 3‐H), 2.40 (1H,
ddd, J = 11.8, 9.6, 2.6 Hz, 3‐H), 1.68 (3H, d, J = 6.8 Hz, 1’‐CH3),
Acknowledgements
This work was financially supported by The Foundation for
Japanese Chemical Research (2016, 464(R)).
1
0.85 (3H, dd, J = 7.2, 7.2 Hz, OCH2CH3); H NMR (400 MHz,
acetone‐d6) δ 7.80‐7.74 (2H, m, Ph), 7.56‐7.49 (3H, m, Ph), 5.57
(1H, dddd, J = 16.9, 10.0, 7.0, 6.8 Hz, CH2CH=CH2), 5.43 (1H, q, J
= 6.8 Hz, 1’‐H), 5.39 (1H, dddd, J = 16.9, 1.6, 1.2, 1.2 Hz,
CH2CH=CH2), 5.27 (1H, dddd, J = 10.0, 1.6, 0.8, 0.8 Hz,
CH2CH=CH2), 4.95 (1H, ddd, J = 10.6, 10.2, 9.4 Hz, 4‐H), 4.19 (1H,
ddd, J = 10.2, 9.3, 2.4 Hz, 4‐H), 3.96 (1H, dq, J = 10.8, 7.2 Hz,
OCH2CH3), 3.91 (1H, dq, J = 10.8, 7.2 Hz, OCH2CH3), 3.82 (1H, dd,
J = 11.8, 6.8 Hz, CH2CH=CH2), 3.44 (1H, dd, J = 11.8, 7.0 Hz,
CH2CH=CH2), 3.41 (3H, s, NCH3), 3.30 (1H, dddd, J = 12.2, 10.6,
9.3, 1.6 Hz, 3‐H), 2.51 (1H, ddd, J = 12.2, 9.4, 2.4 Hz, 3‐H), 1.74
(3H, d, J = 6.8 Hz, 1’‐CH3), 0.83 (3H, dd, J = 7.2, 7.2 Hz, OCH2CH3);
13C NMR (100 MHz, acetone‐d6) δ 166.4, 134.9, 131.6, 130.9,
129.8, 129.2, 123.2, 122.4 (q, J = 320 Hz), 85.9, 68.2, 63.5, 60.9,
42.3, 37.3, 22.9, 15.8, 13.7; HRMS (ESI): calcd for C18H26NO2 [M
– OTf]+ 288.1958, found 288.1949.
Notes and references
1
For reviews: (a) R. Luisi and L. Degennaro, Chem. Heterocycl.
Compd., 2018, 54, 400; (b) D. Antermite, L. Degennaro and R.
Luisi, Org. Biomol. Chem., 2017, 15, 34; (c) F. Couty, B.
Drouillat, G. Evano and O. David, Eur. J. Org. Chem., 2013,
2045.
Studies on ring‐opening of azetidine‐2‐carboxylic acid
derivatives: (a) K. Wright, B. Drouillat, L. Menguy, J. Marrot
and F. Couty, Eur. J. Org. Chem., 2017, 7195; (b) B. Drouillat,
K. Wright, O. David and F. Couty, Eur. J. Org. Chem., 2012,
6005; (c) D.‐H. Leng, D.‐X. Wang, J. Pan, Z.‐T. Huang and M.‐X.
Wang, J. Org. Chem., 2009, 74, 6077; (d) A. Alex, B. Larmanjat,
J. Marrot, F. Couty and O. David, Chem. Commun., 2007, 2500;
(e) F. Couty, O. David, B. Larmanjat and J. Marrot, J. Org.
Chem., 2007, 72, 1058; (f) F. Couty, O. David and F. Durrat,
Tetrahedron Lett., 2007, 48, 1027. See also, ref. 1c.
2
Reduction of (2
phenylethyl)azetidin‐2‐yl)methanol [(2
S
,1’
S
)‐2ab to (2
S
,1’
S
)‐(2‐allyl‐1‐(1’‐
,1’ )‐9]
S
S
3
4
5
(a) E. Tayama, K. Watanabe and S. Sotome, Org. Biomol.
Chem., 2017, 15, 6668; (b) E. Tayama, K. Watanabe and Y.
Matano, Eur. J. Org. Chem., 2016, 3631.
(a) S.‐h. Ma, D. H. Yoon, H.‐J. Ha and W. K. Lee, Tetrahedron
Lett., 2007, 48, 269; (b) F. Couty, G. Evano, M. Vargas‐Sanchez
and G. Bouzas, J. Org. Chem., 2005, 70, 9028.
Studies on N‐quaternization of N‐benzylic 2‐substituted
azetidine derivatives: (a) F. Couty, O. David, F. Durrat, G.
Evano, S. Lakhdar, J. Marrot and M. Vargas‐Sanchez, Eur. J.
Org. Chem., 2006, 3479; (b) F. Couty, F. Durrat, G. Evano and
D. Prim, Tetrahedron Lett., 2004, 45, 7525; See also ref. 3.
Recent examples of asymmetric and diastereoselective
synthesis of azetidine‐2‐carboxylic acid derivatives: (a) G.
Parisi, E. Capitanelli, A. Pierro, G. Romanazzi, G. J. Clarkson. L.
Degennaro and R. Luisi, Chem. Commun., 2015, 51, 15588; (b)
N. Lensen, J. Marais and T. Brigaud, Org. Lett., 2015, 17, 342;
(c) X. Song, A.‐X. Liu, S.‐S. Liu, W.‐C. Gao and M.‐C. Wang,
Tetrahedron, 2014, 70, 1464; (d) Y.‐Z. Hua, X.‐W. Han, X.‐C.
Yang, X. Song, M.‐C. Wang and J.‐B. Chang, J. Org. Chem., 2014,
79, 11690.
A solution of (2S,1’S)‐2ab (30.3 mg, 0.101 mmol) in THF (0.5 mL)
was added to a suspension of lithium aluminum hydride (8 mg,
0.2 mmol) in THF (0.5 mL) at 0 °C under an argon atmosphere.
The mixture was stirred for 30 min at room temperature and
quenched with H2O at 0 °C. The mixture was extracted with
EtOAc and the combined extracts were washed with brine,
dried over Na2SO4, and evaporated. Purification of the residue
by chromatography on silica gel (n‐hexane/EtOAc = 1/1 to 1/2
as the eluent) afforded (2S,1’S)‐
colorless crystals. Mp 62–63 °C; [α]23589 −10.0 (c 1.0 in CHCl3);
IR (KBr)
max/cm−1 3312, 3076, 3022, 3000, 2972, 2925, 2861,
9 (21.1 mg, 90% yield) as
6

1640, 1599, 1490, 1453, 1440, 1415, 1368, 1356, 1328, 1310,
1294, 1217, 1184, 1171, 1137, 1083, 1059, 1040, 1005, 979, 948,
928, 897, 880, 763, 745, 698; 1H NMR (400 MHz, CDCl3) δ 7.34‐
7.21 (5H, m, Ph), 5.75 (1H, dddd, J = 17.0, 10.0, 7.6, 7.0 Hz,
CH2CH=CH2), 5.19 (1H, dddd, J = 17.0, 2.0, 1.6, 1.6 Hz,
CH2CH=CH2), 5.13 (1H, dddd, J = 10.0, 2.0, 1.0, 1.0 Hz,
CH2CH=CH2), 3.94 (1H, br., OH), 3.75 (1H, q, J = 6.4 Hz, 1’‐H),
3.33 (1H, d, J = 10.6 Hz, CH2O), 3.29 (1H, d, J = 10.6 Hz, CH2O),
2.86‐2.75 (3H, m, 4‐H and CH2CH=CH2), 2.37 (1H, dddd, J = 13.4,
7.6, 1.6, 1.0 Hz, CH2CH=CH2), 2.16 (1H, dddd, J = 10.7, 8.8, 1.2
Hz, 3‐H), 1.69 (1H, ddd, J = 10.7, 8.1, 2.8 Hz, 3‐H), 1.22 (3H, d, J
= 6.4 Hz, 1’‐CH3); 13C NMR (100 MHz, CDCl3) δ 143.2, 132.7,
128.4, 127.3, 127.2, 118.5, 68.3, 65.8, 59.2, 46.8, 34.9, 23.2,
22.2; HRMS (ESI): calcd for C15H22NO [M + H]+ 232.1696, found
232.1689.
7
8
(a) P.‐A. Nocquet, D. Hazelard and P. Compain, Tetrahedron,
2012, 68, 4117. As a related work, a protonation of the
enolate was reported: (b) Y. Futamura, M. Kurokawa, R. Obata,
S. Nishiyama and T. Sugai, Biosci. Biotechnol. Biochem., 2005,
69, 1892.
(a) L. Degennaro, R. Mansueto, E. Carenza, R. Rizzi, S. Florio, L.
M. Pratt and R. Luisi, Chem. Eur. J., 2011, 17, 4992; (b) V.
Alezra, M. Bonin, L. Micouin, C. Policar and H.‐P. Husson, Eur.
J. Org. Chem., 2001, 2589; (c) V. Alezra, M. Bonin, L. Micouin
and H.‐P. Husson, Tetrahedron Lett., 2000, 41, 651. See also
its related works: (d) U. Azzena, G. Dettori, L. Pisano, B. Musio
and R. Luisi, J. Org. Chem., 2011, 76, 2291; (e) A. P.
Patwardhan, V. R. Pulgam, Y. Zhang and W. D. Wulff, Angew.
Reduction of (2S,1’S)‐2bb to (2S,1’S)‐9
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 11
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Organic & Biomolecular Chemistry
Page 12 of 12
ARTICLE
Journal Name
Chem. Int. Ed., 2005, 44, 6169; (f) R. Häner, B. Olano and D.
Seebach, Helv. Chim. Acta., 1987, 70, 1676.
View Article Online
DOI: 10.1039/C8OB01395K
9
(a) V. Ferey, P. Vedrenne, L. Toupet, T. L. Gall and C.
Mioskowski, J. Org. Chem., 1996, 61, 7244. See also the
related work: (b) V. Ferey, L. Toupet, T. L. Gall and C.
Mioskowski, Angew. Chem. Int. Ed., 1996, 35, 430.
10 After N‐boration in CH2Cl2, addition of coordinating solvents
should be avoided to obtain pure (1S,2S,1’S)‐3a
.
11 In ref. 9b and 12, it was noted that N‐borane complex is in
equilibrium between diastereomers in THF at room
temperature.
12 Very recently, a study on N‐borane complexes of 2‐
substituted azetidine derivatives was reported: M. Andresini,
S. D. Angelis, A. Uricchio, A. Visaggio, G. Romanazzi, F. Ciriaco,
N. Corriero, L. Degennaro and R. Luisi, J. Org. Chem., doi:
10.1021/acs.joc.8b01441.
13 N‐Boration of (2S,1’S)‐2aa with the borane dimethyl sulfide
complex was possible. The reaction in CH2Cl2 at room
temperature for 22 h afforded the corresponding N‐borane
complex in 72% yield with 25% recovery of (2S,1’S)‐2aa
.
14 The exact yield of borane diisopropylamine complex could not
be determined because partial decomposition of the complex
occurred during chromatographic purification of product 2aa
on silica gel using n‐hexane/EtOAc as the eluent. However,
the pure complex could be isolated after the 2nd purification
by chromatography on silica gel using n‐hexane/CH2Cl2 as the
eluent.
15 For a review: A. Staubitz, A. P. M. Robertson, M. E. Sloan and
I. Manners, Chem. Rev., 2010, 110, 4023.
16 When carbonyl compounds were used as an electrophile, a
hydride reduction with N‐borane complexes and/or a base‐
promoted aldol reaction would proceed to afford complicated
mixture. In fact, the reaction with benzophenone gave
diphenylmethanol in 87% yield. In the reaction with
cyclohexanone, we could not obtain any identifiable products.
17 The stereochemistries of N‐borane complexes were
determined by analogy with (1S,2S,1’S)‐3a. See ref. 5.
18 The stereochemistry of (R)‐4 was determined in our previous
work. See ref. 3b.
19 Mioskowski’s group described that ligands coordinates to
enolate metal cation improved the diastereoselectivity in the

‐alkylation of borane proline ester complex. See ref. 9a.
20 Studies on LiHMDS‐mediated enolization: (a) K. A. Mack, A.
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21 T. Kano, R. Sakamoto, H. Mii, Y.‐G. Wang and K. Maruoka,
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22 The absolute structure of (1R,2R,1’S)‐8 was clarified by a
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Marrot, Synlett, 2009, 767.
12 | J. Name., 2012, 00, 1‐3
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