Enantiopure azetidine-2-carboxamides as organocatalysts for direct asymmetric aldol reactions in aqueous and organic media

Article abstract of DOI:10.1016/j.tet.2013.12.081

A family of enantiopure azetidine-2-caboxamides was asymmetrically synthesized, and was examined as organocatalyst in direct aldol reactions. A well chosen chiral azetidine-2-caboxamide was found to smoothly catalyze the direct aldol reaction of various benzaldehydes with acetone in brine, and β-hydroxy ketones were produced with enantiomeric excess up to 96%. The reaction of benzaldehydes with cyclic ketones also led to the formation of anti-products in diastereomeric ratio up to 99:1 and enantiomeric excess up to 99%.

Full text of DOI:10.1016/j.tet.2013.12.081

Tetrahedron 70 (2014) 1464e1470
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantiopure azetidine-2-carboxamides as organocatalysts for direct
asymmetric aldol reactions in aqueous and organic media
*
Xixi Song, Ai-Xiang Liu, Shan-Shan Liu, Wen-Chao Gao, Min-Can Wang ,
*
Junbiao Chang
The College of Chemistry and Molecular Engineering, Zhengzhou University, No. 75 Daxue Road, Zhengzhou, Henan 450052, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A family of enantiopure azetidine-2-caboxamides was asymmetrically synthesized, and was examined as
organocatalyst in direct aldol reactions. A well chosen chiral azetidine-2-caboxamide was found to
smoothly catalyze the direct aldol reaction of various benzaldehydes with acetone in brine, and b-hy-
droxy ketones were produced with enantiomeric excess up to 96%. The reaction of benzaldehydes with
cyclic ketones also led to the formation of anti-products in diastereomeric ratio up to 99:1 and enan-
tiomeric excess up to 99%.
Received 19 November 2013
Received in revised form 17 December 2013
Accepted 28 December 2013
Available online 4 January 2014
Keywords:
Azetidine
Ó 2014 Elsevier Ltd. All rights reserved.
Azetidine-2-carboxamide
Organocatalysis
Asymmetric
Aldol reaction
1. Introduction
asymmetric addition of various organozinc species (alkylzinc,
arylzinc, and alkynylzinc) to the prochiral aldehydes with excel-
Because of the remarkable biological activities of azetidines,
the interest in the four-membered constrained aza-heterocyclic
compounds in organic syntheses and pharmaceutical chemistry
has increased dramatically over the years.1,2 Although numerous
efficient methodologies have been developed to assemble the
strained ring systems,3 it is still difficult to synthesize enantiopure
forms with general approaches.4 The difficulty renders it un-
common to integrate enantioenriched azetidine scaffold in the
framework of chiral catalysts. As early as in 1998, Zwanenburg and
co-workers successfully applied N-alkyl azetidine-2-tertiary alco-
hols in asymmetric boron catalyzed DielseAlder reactions.5 The
same group also demonstrated enantioselective diethylzinc addi-
tion to aldehydes using the similar azetidine-derived chiral li-
gands.6 Meanwhile, chiral C2-symmetric 2,4-disubstituted
azetidines were developed by Shi and co-workers, and were ex-
amined in the catalytic asymmetric induction reactions.7 Recently,
we highlighted a three-step, one-pot protocol for a facile and
practical preparation of enantiopure N-ferrocenylmethyl azeti-
lent enantioselectivities.8 As illustrated in these examples,
azetidine-based chiral ligands usually afforded improved asym-
metric induction compared with pyrrolidine- or aziridine-based
counterparts. As a result, the enantiopure four-membered aza-
heterocyclic scaffold should be introduced into the building block
arsenal for chiral catalysts, and await broad application and fur-
ther elaboration.
Compared with its higher homologues, such as pyrrolidine and
piperidine, azetidine has found little application as an effective
aminocatalyst.9 In infantile era of organocatalysis, List and co-
workers brought out the concept of enamine catalysis of the
proline-catalyzed direct asymmetric aldol reaction.10 In this pio-
neer work,
ability, but gave an inferior stereoselectivity of 40% ee comparing
with 76% ee of -proline. Interestingly, the higher homologue,
pipecolic acid was ineffective for the reaction. Barbas III and co-
workers also demonstrated the unique catalytic ability of -aze-
tidinecarboxylic acid in the asymmetric Mannich-type reaction.11
The azetidine-based catalyst afforded major syn-product
L-azetidinecarboxylic acid showed similar catalytic
L
L
dine-2-ylmethanol, which served as
a
general ligand for
a
with an enantioselectivity of 80% ee, while its pyrrolidine coun-
terpart induced anti-selectivity. Enders and co-workers de-
veloped an efficient asymmetric syntheses of 3-substituted
azetidine-2-carboxylic acids and 2-substituted azetidine-3-
carboxylic acids, but neither of these amino acids produced
* Corresponding authors. Tel./fax: þ86 371 67769024 (M.-C.W.); tel./fax: þ86 371
67781788 (J.C.); e-mail addresses: wangmincan@zzu.edu.cn (M.-C. Wang), chang-
junbiao@zzu.edu.cn (J. Chang).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.081

X. Song et al. / Tetrahedron 70 (2014) 1464e1470
1465
matchable enantioselectivity in aldol reaction as simple
line.12 In some other cases,
-azetidinecarboxylic acid could pro-
duce similar asymmetric induction comparable to that of
proline.13 Moreover, Greck and co-workers described the asym-
metric -amination of carbonyls, in which -azetidinecarboxylic
acid induced better enantioselectivity than
-proline.14
The proline amides are believed to be one type of the most ef-
fective organocatalysts for stereoselective direct aldol reaction.15
The Gong’s and Singh’s research group have independently de-
L
-pro-
yield. The aza-heterocyclic compound 7 was directly constructed
from acyclic compound 6 via intramolecular nucleophilic sub-
stitution. The cyclization was carried out at an elevated tempera-
ture of 85 ꢀC for 3 days with the efficiency of 52% yield.
The carboxylic acid was obtained after the hydrolysis of the
methyl ester 7, and was stabilized in the form of triethylamine salt
8. The salt could react with various 2-aminoethanol 9 in the pres-
ence of stoichiometric amount of ClCOOEt and triethylamine to give
the corresponding amides 10. Upon the de-protection of N-trityl
group under acidic condition, the chiral azetidine-2-carboxamides
1 were produced in decent yields. Following the similar route, the
chiral amides 2 and 3 were also synthesized.
L
L
-
a
L
L
veloped L-proline amino alcohol amides as catalysts for direct aldol
reactions.16,17 Substitution the pyrrolidine scaffold in proline am-
ides with azetidine would lead to a kindred family of organo-
catalysts. The study of enantiopure azetidine amides would pose
a
useful complement to the five-membered-aza-heterocycle-
2.2. The direct asymmetric aldol reaction of acetone with
aldehydes catalyzed by azetidine-2-carboxamide 1a
dominated aminocatalysis, and gain deeper insight as well as
broader perspective in the organocatalysis. In this paper, we re-
ported the practical asymmetric syntheses of a series of chiral
azetidine-2-caboxamides (Fig. 1, 1, 2, and 3), and the studies of
these compounds in the asymmetric catalysis of direct aldol
reaction.
The aldol reaction of benzaldehydes with acetone was used as
a model reaction to test the catalytic efficiency of various azeti-
dine-2-carboxamides (Table 1). The organocatalyst 1a, which
contains methyl as steric hindrance group on 2-aminoethanol
moiety, was submitted to the model reaction in brine at room
temperature (26 ꢀC), and received 47% yield and 93% ee (Table 1,
entry 1). The dehydration of aldol adduct was observed, and (E)-4-
phenylbut-3-en-2-one was isolated as a major side product. De-
creasing the reaction temperature to 0 ꢀC would increase the yield
to 71% by suppression of dehydration process (Table 1, entry 2).
When azetidine amide 1b or 1c, which bears larger steric hin-
drance group on the side arm, was used as catalyst, decreased
enantioselectivity was observed (Table 1, entries 3 and 4). The
observation was contrary to our expectation. In Singh’s work, the
pyrrolidine counterpart of 1b was found as the optimal catalyst.17e
Similar effect was also observed with chiral amides 2 and 3 (Table
1, entries 5 and 6). Keeping 1a as the optimal catalyst, when other
organic solvents were screened, both reaction yield and stereo-
selectivity were decreased (Table 1, entries 7e12). When the cat-
alyst loading was decreased from 5% mol to 3%, 2%, or even 1% mol,
the catalytic efficiency was diminished, and decreased yield
as well as extended reaction time was observed (not shown in
Table 1).
Fig. 1. Azetidine-2-carboxamides used for direct aldol reactions in this study.
2. Results and discussion
2.1. Preparation of azetidine-based novel organocatalysts
The synthetic route leading to chiral azetidine-2-carboxamides
(1, 2, and 3), was based on our previously developed approach to
the enantiopure azetidine-2-carboxylate (Scheme 1).8b
Starting from the cheap and commercially available
L
-(þ)-me-
thionine 4, which contained the source of chirality, the methyl
L
-2-
amino-4-bromobutanoate 5 was obtained in the overall yield of
47% after three-steps. After the treatment of compound 5 with
triethylamine and triphenylmethyl (trityl, or Trt) chloride in
dichloromethane at room temperature for two days, the amino
group was protected with trityl to afford the compound 6 in 89%
Table 1
Direct aldol reaction of benzaldehyde with acetone catalyzed by 1e3a
Entry
Catalyst (mol %)
Solvent
Yield (%)b
ee (%)c,d
1e
2
3
4
5
1a
1a
1b
1c
2
Brine
Brine
Brine
Brine
Brine
Brine
Neat
i-PrOH
MeOH
CH2Cl2
CHCl3
THF
47
71
72
67
49
63
45
55
40
57
53
42
93
93
84
86
69
53
90
92
26
87
90
69
6
3
7f
8
1a
1a
1a
1a
1a
1a
9
10
11
12
a
Unless specified, aldehyde 11a (1 mmol), acetone 12 (5 mmol), and catalyst
(5 mol %) were dissolved in solvent (2 mL, 0.5 M) and stirred at 0 ꢀC for 1e2 days.
b
Isolated yield calculated based on benzaldehyde.
The ee values were determined by HPLC using the Chiralcel AD column.
The absolute configuration of 13a was assigned as R by comparison of retention
c
d
times of known compounds.
e
The reaction was carried out at the room temperature of 26 ꢀC.
The reaction was carried out in neat acetone with a concentration of 0.5 M.
Scheme 1. Representative asymmetric synthetic route of chiral azetidine-2-
carboxamide 1.
f

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X. Song et al. / Tetrahedron 70 (2014) 1464e1470
The substrate scope and limitation of the aldol reaction were
decreased from 93% ee of benzaldehyde to 78% ee (Table 2, entry
8). The bulkier 1-naphthaldehyde did not gain improved stereo-
control, and retained the enantioselectivity of 79% ee (Table 2,
entry 9).
scrutinized (Table 2). A wide range of aromatic aldehydes reacted
with acetone in brine under the optimal conditions, and the aldol
adducts were produced with moderate to good yields (from 38% to
88%) and good to excellent enantioselectivities (from 67% to 96%
ee). When aliphatic aldehydes, such as butanal and pentanal, were
used as substrate, no desired aldol product was observed (not
shown in Table 2). This might be the formation of aldehyde hydrate
in the aqueous media.
2.3. The direct asymmetric aldol reaction of cyclohexanone
with aldehydes catalyzed by azetidine-2-carboxamide 1a
The donor of the aldol reaction was extended from acyclic ace-
tone to cyclohexanone in order to further explore the catalytic
ability of azetidine-2-carboxamide 1a. Under the previously opti-
mized reaction conditions, the aldol adduct 15a was obtained with
excellent diastereoselectivity favoring anti-product but in moder-
ate enantioselectivity of 81% ee (Table 3, entry 1). The reaction
conditions were screened to gain better results (Table 3). In the
enamine catalysis, the presence of additional proton might pro-
mote the rapid formation of reactive enamine species and
strengthen the intramolecular hydrogen bonding in transition
state, and subsequently accelerate the reaction speed and elevate
the stereoselectivity.18 As a result, different proton source was used
as additive, but no improved result was observed (Table 3, entries 2
and 3). Various solvents were encouragingly screened, and im-
proved results were noticed in some of the cases (Table 3, entries 4,
5, and 6). When the reaction temperature was decreased to ꢁ20 ꢀC,
a boost in enantioselectivity from 86% to 97% ee was identified
(Table 3, entry 7).
Table 2
Direct aldol reaction of various aldehydes with acetone catalyzed by 1aa
Entry
Ar
Product
Yield (%)b
ee (%)c,d
1
2
3
4
5
6
7
8
Ph
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
13m
13n
13o
13p
13q
13r
71
85
78
69
42
71
47
73
88
80
88
62
82
75
70
<5
38
71
93
83
90
89
83
82
67
78
79
95
86
86
83
93
93
n.d.e
90
96
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
2,3,4-(MeO)3C6H2
2-Naphthyl
1-Naphthyl
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
9
10
11
12
13
14
15
16
17
18
Table 3
Direct aldol reaction of benzaldehyde with cyclohexanone catalyzed by 1aa
2-BrC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
a
Unless specified, aldehyde 11 (1 mmol), acetone 12 (5 mmol), and catalyst 1a
(5 mol %) were dissolved in brine (2 mL, 0.5 M) and stirred at 0 ꢀC for 2e3 days.
b
Entry
Solvent
Additive
Yield (%)b
d.r.c
e.e. (%)c
Isolated yield calculated based on aldehyde 11.
The ee values were determined by HPLC using chiral columns.
The absolute configuration of 13 was assigned as R by comparison of retention
c
1
2
3
4
5
6
7e
Brine
Brine
Brine
i-PrOH
CH2Cl2
CHCl3
CHCl3
d
75
<5
84
76
83
87
68
99:1
n.d.d
99:1
94:6
95:5
93:7
99:1
81
d
TFA
TsOH
d
n.d.d
54
times of known compounds.
e
Not determined.
86
86
86
97
d
d
d
Comparing the enantioselective outcomes of para-substituted
benzaldehydes (Table 2, entries 2, 5, 10, 13, and 16), a weak elec-
tronic effect was observed. The substrates 11 bearing electronic
donating groups on para-position (Table 2, entries 2 and 5) pro-
duced diminished stereoselectivities comparing with unsub-
stituted benzaldehyde (Table 2, entry 1). Among weak electronic
withdrawing groups, only chloro brought out elevated enantiose-
lectivity of 95% ee (Table 2, entry 10), while bromo gave the same ee
of 83% as electronic donation groups (Table 2, entry 13). Surpris-
ingly, when para-nitrobenzaldehyde was used as substrate, no
desired aldol product was observed (Table 2, entry 16). For instead,
the (E)-4-(4-nitrophenyl)but-3-en-2-one was isolated as a major
product, because of fast dehydration of the aldol adduct.
A strong steric hindrance effect was identified by comparing the
stereoselective outcomes of the same substituent group at different
substituted positions on benzaldehyde. The ortho- and meta-
methyl benzaldehydes rendered better stereocontrol over para-
substituted one (Table 2, entries 3 and 4 vs 2). The benzaldehydes
bearing bromo (Table 2, entries 13, 14, and 15) and nitro (Table 2,
entries 16, 17, and 18) substituents, also demonstrated the same
effect. But the steric effect did not prevail in methoxy substituted
benzaldehydes (Table 2, entries 6 and 7 vs 5) or chloro substituted
ones (Table 2, entry 10, 11, and 12).
a
Unless specified, aldehyde 11a (1 mmol), cyclohexanone 14 (5 mmol), catalyst
1a (5 mol %), and additive (1 mmol) were dissolved in solvent (2 mL, 0.5 M) and
stirred at the room temperature of 26 ꢀC for 2e3 days.
b
Isolated yield calculated based on aldehyde 11.
The d.r. values and the ee values of the major anti-isomers were determined by
c
HPLC using the Chiralcel OD column. The d.r. value as anti/syn, and the major isomer
was the anti-isomer. The configuration of 15 was assigned by comparison of re-
tention times of known compounds.
d
Not determined.
The experiment was carried out at ꢁ20 ꢀC.
e
Furthermore, a variety of aromatic aldehydes were reacted with
cyclohexanone under the refined reaction conditions (Table 4).
Catalyzed by azetidine-2-carboxamide 1a, the direct aldol reaction
produced the anti-products in diastereomeric ratio up to 99:1 and
enantiomeric excess up to 99%.
By comparison of the enantioselectivities of para-substituted
benzaldehydes (Table 4, entries 2, 5, 9,12, and 15), a strong reversed
electronic effect was disclosed, which was contrary to the effect in
the abovementioned aldol reaction with acetone as nucleophile
(Table 2). While benzaldehydes bearing electronic donating groups
produced similar enantioselectivities as unsubstituted benzalde-
hyde (Table 4, entries 2 and 5), electronic withdrawing groups
afforded decreased stereoselectivities in two cases (Table 4, entries
12 and 15).
Although 2-naphthaldehyde reacted smoothly with acetone to
generate aldol adduct in 73% yield, the enantioselectivity

X. Song et al. / Tetrahedron 70 (2014) 1464e1470
1467
Table 4
Direct aldol reaction of benzaldehyde with cyclohexanone catalyzed by 1aa
Entry
Ar
15
Yield (%)b
d.r.c
e.e.c
1
2
3
4
5
6
7
8
Ph
15a
15b
15c
15d
15e
15f
15h
15i
15j
68
46
69
63
69
65
39
79
61
44
80
56
88
71
63
55
71
99:1
77:23
99:1
84:16
80:20
81:19
88:12
87:13
93:7
82:18
96:4
92:8
89:11
98:2
75:25
94:6
97
>99
91
89
96
93
96
99
99
83
96
75
99
99
52
44
97
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-Naphthyl
1-Naphthyl
4-ClC6H4
Scheme 3. Proposed transition states for aldol reaction of benzaldehyde.
9
10
11
12
13
14
15
16
17
3-ClC6H4
2-ClC6H4
15k
15l
about 2 kcal/mol lower in energy than the most populated transi-
tion state TS-1 of -proline. As a result, the abilities of stereocontrol
4-BrC6H4
3-BrC6H4
2-BrC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
15m
15n
15o
15p
15q
15r
L
of the five-membered aza-heterocycle and the four-membered
counterpart should be on the same level.19
Based on a formally developed transition state TS-3 of Singh’s
organocatalyst,18 the transition state TS-4 of the azetidine-2-
carboxamide 1a was proposed to explain the stereochemical out-
come of the asymmetric aldol reaction. The benzaldehyde was ac-
tivated by hydrogen bonding with the NH and OH of the amide
branch of the catalyst 1a, and was attacked from its re-face by
acetone-derived enamine species, which was synergetically acti-
vated by the azetidine moiety of the same catalyst 1a. Likewise, the
transition state of 1a catalyzed aldol reaction of benzaldehyde with
cyclohexanone was also proposed in model TS-5, which explained
the preferential formation of the anti-diastereoisomer.
75:25
a
Unless specified, aldehyde 11 (1 mmol), cyclohexanone 14 (5 mmol), and cat-
alyst 1a (5 mol %) were dissolved in chloroform (2 mL, 0.5 M) and stirred at 0 ꢀC for
2e3 days.
b
Isolated yield calculated based on aldehyde 11.
The d.r. values and the ee values of the major anti-isomers were determined by
c
HPLC using chiral columns. The d.r. value as anti/syn, and the major isomer was the
anti-isomer. The configuration of 15 was assigned by comparison of retention times
of known compounds.
When bromo and nitro were used as substituent groups of
benzaldehyde (Table 4, entries 12e14, entries 15e17, respectively),
the similar steric effect was clearly received, which was consistent
with the trend observed in Table 2. But the effect did not persist for
methyl, methoxy, or chloro substituted benzaldehydes (Table 4,
entries 2e4, entries 5e6, entries 9e11, respectively). This might be
an overall outcome of the domination of electronic effect over steric
effect in these cases. In addition, the bulkier 1-naphthaldehyde did
induce a better enantioselectivity of 99% ee than 96% ee of 2-
napthaldehyde (Table 4, entries 7 and 8).
3. Conclusion
In summary, a family of enantiopure azetidine-2-carboxamides
was asymmetrically synthesized, and was examined as organo-
catalyst in direct aldol reactions. The azetidine-2-caboxamide 1a,
with methyl as steric hindrance group on 2-aminoethanol moiety,
was found as the optimal catalyst. The presence of 5 mol % 1a could
smoothly catalyze the direct aldol reaction of various benzalde-
The five-membered cyclopentanone 16 was also employed as
a donor in the asymmetric aldol reaction (Scheme 2). Catalyzed by
azetidine-based organocatalyst 1a, the aldol reaction was carried
out without impediment, but the isolated yield was as low as 30%.
The aldol adduct 17 was identified with an anti versus syn ratio of
66:34, and the enantiomeric excess of the major anti-isomer was
99%.
hydes with acetone in brine, to afford b-hydroxy ketones with
enantioselectivities up to 96% ee. The aldol reaction of benzalde-
hydes with cyclohexanone produced anti-products as major iso-
mers in diastereomeric ratio up to 99:1 and enantioselectivities of
more than 90% ee in most cases. In addition, cyclopentanone also
reacted with benzaldehyde to afford the major anti-adduct in 99%
ee. The unprecedented application of enantiopure azetidine-2-
carboxamides as organocatalysts in asymmetric aldol reaction
posed a useful complement to the five-membered-aza-heterocycle-
dominated aminocatalysis. The chiral azetidine scaffold was dem-
onstrated as an efficient chiral unit for organocatalysis. The tran-
sition states of 1a catalyzed aldol reaction were proposed to gain
insight for further development of the azetidine-based
organocatalysts.
Scheme 2. Direct aldol reaction of benzaldehyde with cyclopentanone catalyzed by 1a.
4. Experimental
4.1. General methods
2.4. Proposition and consideration of transition states
NMR Spectra (1H and 13C) were performed on a commercial
spectrometer (400 MHz for 1H and 100 MHz for 13C) using solution
in CDCl3 (referenced internally to Me4Si); J values are given in
Hertz. IR Spectra were determined on a commercial spectropho-
tometer. TLC was performed on dry silica gel plates developed with
petroleum (60e90 ꢀC) and ethyl acetate. Mass spectra were
The transition states for aldol reaction of benzaldehyde with
acetone catalyzed by L-proline, L-azetidinecarboxylic acid, and
Singh’s organocatalyst were proposed previously on the bases of
the DFT calculation (TS-1, TS-2, and TS-3 in Scheme 3).16,17,19 The
calculated transition state TS-2 of L-azetidinecarboxylic acid was

1468
X. Song et al. / Tetrahedron 70 (2014) 1464e1470
obtained using a commercial instrument with an electrospray
ionization source (ESIMS). All the ESIMS spectra were performed
using MeOH as the solvent. Methanol was dried with Mg(OCH3)2.
The ionization method for HRMS is electrospray ionization (ESI),
and the mass analyzer type is the time of flight (TOF). Melting
points were determined using melting point apparatus. Optical
rotations were measured on a commercial polarimeter at 20 ꢀC in
CHCl3. All other reagents were commercially available and used as
received.
the treatment of triethylamine, white solid precipitated again. The
solid was collected by vacuum filtration, and was submitted to
following reaction without purification. The triethylamine (S)-1-
tritylazetidine-2-carboxylate 8 was received in quantitative yield
(0.59 g).
The compound 8 obtained from abovementioned reaction was
dissolved in 30 mL dichloromethane, and was treated with 3 equiv
triethylamine. The ClCOOEt (1 equiv) was added dropwise at 0 ꢀC,
and the mixture was stirred for 1 h. The corresponding amino al-
cohol 9 (1.2 equiv) was added, and the mixture was stirred at rt for
10 h. After reactants were totally consumed (determined by TLC
analysis), the solvent was evaporated and the residue was purified
by column chromatography, eluting with a mixture of ethyl acetate
and petroleum. The compound 10 was received as solid with iso-
lated yield ranging from 42% to 63%.
The mixture of compound 10 (1 mmol), 8 mL distilled water,
3 mL concentrated sulfuric acid, and 60 mL MeOH was stirred at rt
for 3 days. After reactant 10 was totally consumed, 40 mL water was
added, and white solid was filtrated. The pH of the filtrate was
tuned to basic using 25% NaOH aqueous solution. The mixture was
extracted three times by ethyl acetate. The combined organic phase
was washed by saturated NaCl, and was concentrated before pu-
rification by column chromatography, eluting with a mixture of
ethyl acetate and petroleum. After the de-protection process, the
azetidine-based organocatalysts 1e3 were isolated as white solids.
For copies of 1H and 13C NMR spectra of the synthetic key in-
termediate 10 and catalysts 1e3, please refer to Supplementary
data.
4.2. Procedure of preparation of catalysts 1a, 1b, 1c, 2, and 3
4.2.1. Synthesis of
L
-homoserine.
L
-(þ)-Methionine 4 (75 g, 0.5 mol)
was suspended in H2O/MeOH (1400 mL/200 mL), and methyl io-
dide (75 mL, 1.21 mol) was added. The resulting two-phase system
was stirred vigorously for 48 h. The volume of the solvent was then
reduced to one-third by evaporation to remove excess amount of
methyl iodide. Water was added to reach a total volume of 1.0 L, and
NaHCO3 (42 g, 0.5 mol) was added. This solution was refluxed for
15 h and cooled, and the solvent was evaporated under reduced
pressure to yield thick syrup. This residue was dissolved in a mini-
mum quantity of water (140 mL), with heating. The addition of
acetone (270 mL) and ethanol (3.0 L) caused immediate pre-
cipitation of
L-homoserine as a white solid (37 g, 62%);
20
mp¼202e203 ꢀC (dec.) [lit.: mp¼203 ꢀC (dec.)]; [
a
]
¼8.2 (c 3.08,
D
26
H2O) [lit.: [
a
]
¼8.0 (c 5, H2O)]; 1H NMR (400 MHz, D2O)
d ppm:
D
3.66 (dd, J¼7.4, 4.8 Hz, 1H), 3.54e3.58 (m, 2H), 1.92e2.01 (m, 1H),
1.79e1.87 (m, 1H).
4.2.2. Synthesis of
L
-2-amino-4-bromobutanoic acid hydro-
4.3. Characterization of the synthetic key intermediate 10 and
bromide. -Homoserine (1.6 g, 13.3 mmol) and AcOH (36 mL, sat-
L
catalysts 1e3
urated with HBr) were placed in an autoclave, which was immersed
in an oil bath, and then the temperature was raised to 75e80 ꢀC.
After stirring for 5 h, the temperature was gradually lowered to
room temperature overnight. The precipitated was collected by
4.3.1. (S)-N-((S)-1-Hydroxy-1,1-diphenylpropan-2-yl)-1-
tritylazetidine-2-carboxamide (10a). Light yellow solid, 0.38 g, yield
51%; mp¼94e96 ꢀC; [
a
]
25 ꢁ63.7 (c 0.85, CHCl3); 1H NMR (400 MHz,
D
€
suction filtration on a Buchner funnel and was washed with Et2O.
CDCl3)
d
ppm: 7.82 (d, J¼8.9 Hz, 1H), 7.60e7.58 (m, 2H), 7.56e7.54
Recrystallization of the product from C2H5OHeEt2O afforded
L-2-
(m, 2H), 7.30e7.19 (m, 9H), 7.18e7.17 (m, 11H), 4.87 (m, 1H), 4.74 (s,
1H), 4.09 (m, 1H), 3.73 (m, 1H), 3.40 (m, 1H), 3.02e2.98 (m, 1H),
amino-4-bromobutanoic acid hydrobromide (3.1 g, 85%);
20
mp¼187e188 ꢀC [lit.: mp¼188e190 ꢀC]; [
a
]
D
þ11.8 (c 0.21, DMF)
1.68e1.63 (m, 1H), 1.09 (d, 3H); 13C NMR (100 MHz, CDCl3)
d
ppm:
174.5, 146, 145.1, 143.3, 129.2, 128.3, 128.2, 126.8, 126.7, 125.9, 125.7,
80.3, 75.6, 61.7, 53.5, 47.5, 21.8, 15.1; IR (KBr pellet)
cmꢁ1: 3388,
[lit.: [
a
]
D þ11.8 (c 0.20, DMF)]; 1H NMR (400 MHz, DMSO-d6)
d ppm:
8.57 (s, 1H), 8.33 (s, 3H), 4.00 (d, J¼5.6 Hz, 1H), 3.59e3.71 (m, 2H),
n
2.22e2.41 (m, 2H).
2924, 2854, 1654, 1525, 1494, 1448, 1381, 1062, 747, 700; MS (EI) m/
z: 553.4 (MþH)þ, 243.4 (CPh3)þ; HRMS (ESI-TOF) m/z: (MþNa)þ
calcd for C38H36N2O2Na 575.2674, found 575.2680.
4.2.3. Synthesis of methyl
L-2-amino-4-bromobutanoate hydrochlo-
ride (5). -2-Amino-4-bromobutanoic acid hydrobromide (4.2 g,
L
15.6 mmol) was suspended in methanol (120 mL), dry HCl was
passed for 2 h at such a rate that the temperature of the reaction
mixture was maintained at 35e40 ꢀC. The solution was evaporated
to dryness, the residue was dissolved in methanol and the solution
was again evaporated to dryness; the same procedure was repeated
once more, the residual oil was dried in vacuo over sodium hy-
droxide and the resulting crystals were triturated with ether, col-
lected, and washed with diethyl ether. Recrystallization of the
4.3.2. (S)-N-((S)-1-Hydroxy-1,1-diphenylpropan-2-yl)azetidine-2-
carboxamide (1a). Light yellow solid, 126 mg, yield 60%;
25
mp¼151e153 ꢀC; [
a
]
ꢁ129.3 (c 1.60, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d
ppm: 7.78 (d, J¼9.0 Hz, 1H), 7.54e7.51 (m, 4H), 7.30e7.23
(m, 4H), 7.18e7.14 (m, 2H), 4.91 (m, 1H), 3.99 (m, 1H), 3.48 (m, 1H),
3.05 (m, 1H), 2.34 (m, 1H), 1.77 (m, 1H), 1.20 (m, 3H); 13C NMR
(100 MHz, CDCl3)
d ppm: 173.8, 145.8, 145.0, 128.1, 127.9, 126.7,
126.6, 125.8, 125.6, 80.2, 58.8, 51.8, 43.3, 26.0, 15.5; IR (KBr pellet)
product from C2H5OHeEt2O gave methyl
L-2-amino-4-
n
cmꢁ1: 3324, 2927, 1650, 1529, 1493, 1449, 1375, 1178, 1127, 750,
bromobutanoate hydrochloride 5 as white solid (3.3 g, 89%);
701, 642; MS (EI) m/z: 311.4 (MþH)þ, 293.5 (MꢁOH)þ; HRMS (ESI-
TOF) m/z: (MþNa)þ calcd for C19H22N2O2Na 333.1579, found
333.1582.
20
mp¼100.3e102.1 ꢀC [lit.: mp¼98e99 ꢀC]; [
a
]
þ29.1 (c 0.83,
D
CH3OH).
4.2.4. Representative procedure for the synthesis of catalysts 1e3. In
a 100 mL round bottom flask, a reaction mixture of 0.5 g
4.3.3. (S)-N-((S)-1-Hydroxy-4-methyl-1,1-diphenylpentan-2-yl)-1-
tritylazetidine-2-carboxamide (10b). Light yellow solid, 0.44 g, yield
25
(1.33 mmol) (S)-methyl 1-tritylazetidine-2-carboxylate
7
and
55%; mp¼98e100 ꢀC;
[
a
]
D
ꢁ74.0 (c 1.56, CHCl3); 1H NMR
0.213 g (5.33 mmol) sodium hydroxide was dissolved in 40 mL
methanol and 10 mL distilled water, and was stirred at 50 ꢀC for
12 h. When MeOH was distilled out, white solid precipitated. The
solid was dissolved in about 50 mL THF, and the pH was tuned to
3e4 by addition of 1 M HCl. When the pH was tuned to 9e10 with
(400 MHz, CDCl3) d ppm: 7.64 (m, 2H), 7.55 (m, 2H), 7.31e7.15 (m,
21H), 4.81 (m, 1H), 4.11 (m, 1H), 3.70 (m, 1H), 3.30 (m, 1H), 2.92 (m,
1H),1.90e1.91 (m,1H), 1.51e1.60 (m, 2H),1.09 (m, 2H), 0.92 (m, 3H),
0.86 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
ppm: 174.8, 146.1, 145.6,
145.5, 145.1, 143.1, 129.1, 128.7, 128.2 (ꢂ3), 128.0, 127.9, 127.7, 126.7,

X. Song et al. / Tetrahedron 70 (2014) 1464e1470
1469
126.6 (ꢂ2), 125.9, 125.8, 125.5, 125.4, 81.1, 60.4, 55.4, 47.1, 38.5, 26.9,
24.7, 24.0, 21.4; IR (KBr pellet)
cmꢁ1: 3354, 2954, 2868, 1649, 1519,
1492, 1468, 1447, 1369, 1262, 1170, 1097, 1060, 772, 746, 703, 657;
MS (EI) m/z: 594.7 (MþH)þ, 242.8 (CPh3)þ; HRMS (ESI-TOF) m/z:
(MþNa)þ calcd for C41H42N2O2Na 617.3144, found 617.3150.
2923, 2853, 1652, 1524, 1452, 1382, 1098, 1061, 761, 703; MS (EI) m/
z: 296.8 (MþH)þ, 279.0 (MꢁOH)þ; HRMS (ESI-TOF) m/z: (MþNa)þ
calcd for C18H20N2O2Na 319.1422, found 319.1437.
n
4.3.9. (S)-N-((1R,2S)-2-Hydroxy-1,2-diphenylethyl)-1-
tritylazetidine-2-carboxamide (10e). Light yellow solid, 0.30 g, yield
4.3.4. (S)-N-((S)-1-Hydroxy-4-methyl-1,1-diphenylpentan-2-yl)aze-
42%; mp¼76e79 ꢀC; [
a
]
25 ꢁ76.3 (c 0.85, CHCl3); 1H NMR (400 MHz,
D
tidine-2-carboxamide (1b). Light yellow solid, 152 mg, yield 59%;
CDCl3) d ppm: 7.27e7.04 (m, 25H), 5.33e5.30 (m, 1H), 4.99 (m, 1H),
25
mp¼136e138 ꢀC; [
a
]
D
ꢁ64.2 (c 1.28, CHCl3); 1H NMR (400 MHz,
3.87 (m, 1H), 3.57 (m, 1H), 3.08 (m, 1H), 1.90e1.80 (m, 2H); 13C NMR
(100 MHz, CDCl3)
ppm: 174.0, 143.1, 139.5, 137.6, 129.3, 129.2 (ꢂ2),
128.3, 127.9, 127.8, 127.7 (ꢂ2), 127.6 (ꢂ2), 126.9, 126.7, 77.3, 75.7,
61.8, 58.9, 47.5, 21.8; IR (KBr pellet)
cmꢁ1: 3376, 2978, 2934, 1645,
CDCl3)
d
ppm: 7.72 (d, J¼8.9 Hz, 2H), 7.55 (m, 4H), 7.31e7.13 (m, 6H),
d
4.76 (m, 1H), 4.01 (m, 1H), 3.49 (m, 1H), 3.02 (m, 1H), 2.35 (m, 1H),
1.79 (m, 1H), 1.60e1.69 (m, 2H), 1.21 (m, 2H), 0.88 (m, 3H), 0.86 (m,
n
3H); 13C NMR (100 MHz, CDCl3)
d
ppm: 174.5, 146.2, 144.5, 128.2,
127.8, 126.7, 126.5, 125.8, 125.6, 80.8, 58.9, 55.6, 43.3, 38.1, 26.2,
25.2, 23.8, 21.5; IR (KBr pellet)
cmꢁ1: 3323, 2953, 2926, 2871,1652,
1522, 1447, 1373, 1130, 1072, 764, 702, 643; MS (EI) m/z: 539.4
(MþH)þ, 243.5 (CPh3)þ; HRMS (ESI-TOF) m/z: (MþNa)þ calcd for
n
C37H34N2O2Na 561.2518, found 561.2529.
1527, 1447, 1367, 1316, 1167, 1063, 744, 700; MS (EI) m/z: 353.8
(MþH)þ, 334.8 (MꢁOH)þ, 378.8 (MþNa)þ; HRMS (ESI-TOF) m/z:
(MþNa)þ calcd for C22H28N2O2Na 375.2048, found 375.2061.
4.3.10. (S)-N-((1R,2S)-2-Hydroxy-1,2-diphenylethyl)azetidine-2-car-
boxamide (3). Light yellow solid, 124 mg, yield 75%; mp¼74e75 ꢀC;
25
[a
]
ꢁ12.0 (c 0.32, CHCl3); 1H NMR (400 MHz, CDCl3)
d ppm:
D
4.3.5. (S)-N-((2S,3R)-1-Hydroxy-3-methyl-1,1-diphenylpentan-2-yl)-
7.19e6.92 (m, 10H), 5.23e5.15 (m, 1H), 5.01 (m, 1H), 4.01 (m, 1H),
3.20e3.10 (m, 1H), 3.04e3.02 (m, 1H), 2.06 (m, 1H), 1.96e1.94 (m,
1-tritylazetidine-2-carboxamide (10c). Light yellow solid, 0.48 g,
25
yield 61%; mp¼115e118 ꢀC; [
a
]
ꢁ105.5 (c 1.26, CHCl3); 1H NMR
1H); 13C NMR (100 MHz, CDCl3)
d
ppm: 172.9, 136.7, 136.6, 127.2,
D
(400 MHz, CDCl3) d ppm: 7.42 (m, 4H), 7.30e7.03 (m, 21H), 4.93 (m,
127.0 (ꢂ2), 126.9 (ꢂ2), 126.8 (ꢂ2), 126.7, 126.6, 126.5, 78.9, 61.8,
1H), 3.99e3.95 (m, 1H), 3.18e3.12 (m, 1H), 2.02 (m, 1H), 1.90 (m,
1H), 1.60e1.53 (m, 2H), 1.07 (m, 1H), 0.91 (m, 3H), 0.75 (m, 3H); 13
NMR (100 MHz, CDCl3) ppm: 174.1, 147.0, 146.1, 143.5, 129.1, 128.6,
128.2, 127.7, 127.0, 126.7, 126.6, 126.4, 125.6, 81.8, 75.5, 62.0, 58.5,
47.9, 36.6, 23.6, 23.0, 18.5, 12.2; IR (KBr pellet)
cmꢁ1: 3377, 2961,
59.4, 43.6, 25.2; IR (KBr pellet) n
cmꢁ1: 3392, 2923, 2853,1647,1520,
C
1455, 1280, 1054, 698, 601, 529; MS (EI) m/z: 296.5 (MþH)þ, 279.2
(M-OH)þ; HRMS (ESI-TOF) m/z: (MþNa)þ Calcd for C18H20N2O2Na
319.1422, found 319.1435.
d
n
2929, 2873, 1654, 1512, 1446, 1376, 1063, 746, 703, 631; MS (EI) m/z:
595.5 (MþH)þ, 243.4 (CPh3)þ, 617.5 (MþNa)þ; HRMS (ESI-TOF) m/z:
(MþNa)þ calcd for C41H42N2O2Na 617.3144, found 617.3153.
4.4. Representative procedure for the direct aldol reaction of
aldehydes with acetone in brine catalyzed by azetidine-based
organocatalyst 1a
4.3.6. (S)-N-((2S,3R)-1-Hydroxy-3-methyl-1,1-diphenylpentan-2-yl)
An aldehyde (1.0 mmol) was added to a mixture of acetone
(5 mmol) and the catalyst 1a in brine at 0 ꢀC. The reaction mixture
was stirred, and the progress of the reaction was monitored by TLC.
After the completion of the reaction, the reaction mixture was di-
luted and extracted with ethyl acetate. The combined organic layer
was dried over anhydrous sodium sulfate. The solvent was evapo-
rated and the residue was purified by column chromatography,
eluting with a mixture of ethyl acetate and petroleum ether. The
enantiomeric excess (ee) of the aldol adduct was determined by
chiral HPLC analysis. For HPLC spectra of compounds 13aer, please
refer to Supplementary data.
azetidine-2-carboxamide (1c). Light yellow solid, 217 mg, yield 76%;
25
mp¼112e113 ꢀC; [
a
]
ꢁ104.8 (c 0.83, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d ppm: 7.55e7.52 (m, 4H), 7.30e7.12 (m, 6H), 4.76 (m, 1H),
4.01 (m, 3H), 3.53 (m, 1H), 3.16e3.14 (m, 1H), 2.44e2.39 (m, 1H),
1.86e1.76 (m, 3H),1.09e1.05 (m, 1H), 0.83 (m, 3H), 0.78 (m, 3H); 13
NMR (100 MHz, CDCl3) ppm: 174.3,147.2,145.8,128.3,128.2,128.1,
126.6, 125.9, 125.6, 125.5, 81.6, 59.7, 59.1, 43.6, 35.8, 26.5, 24.7, 18.8,
12.0; IR (KBr pellet)
cmꢁ1: 3352, 2960, 2927, 2873, 1638, 1526,
C
d
n
1448, 1377, 1283, 1178, 1065, 747, 701, 642; MS (EI) m/z: 353.4
(MþH)þ, 335.5 (MꢁOH)þ; HRMS (ESI-TOF) m/z: (MþNa)þ calcd for
C
22H28N2O2Na 375.2048, found 375.2057.
4.3.7. (S)-N-((1S,2R)-2-Hydroxy-1,2-diphenylethyl)-1-
4.5. Representative procedure for the direct aldol reaction of
aldehydes with cyclohexanone or cylcopentanone in Chloro-
form catalyzed by azetidine-based organocatalyst 1a
tritylazetidine-2-carboxamide (10d). Light yellow solid, 0.45 g, yield
25
63%; mp¼214e216 ꢀC; [
a]
ꢁ78.6 (c 1.35, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d ppm: 7.36e7.02 (m, 25H), 5.21e5.18 (m, 1H),
4.92 (m, 1H), 4.16 (m, 1H), 3.68 (m, 1H), 3.28 (m, 1H), 1.90e1.80 (m,
2H); 13C NMR (100 MHz, CDCl3)
ppm: 173.7, 143.5, 139.8, 137.3,
129.5, 128.0, 127.9 (ꢂ2), 127.7 (ꢂ2), 126.6 (ꢂ2), 127.5, 126.9, 126.5,
126.4, 126.3, 76.2, 75.5, 62.1, 58.7, 48.2, 21.7; IR (KBr pellet)
cmꢁ1
3318, 2987, 2882, 1646, 1529, 1492, 1448, 1344, 1159, 1033, 998, 895,
772, 701, 641; MS (EI) m/z: 539.6 (MþH)þ, 243.7 (CPh3)þ; HRMS
(ESI-TOF) m/z: (MþNa)þ calcd for C37H34N2O2Na 561.2518, found
561.2523.
An aldehyde (1.0 mmol) was added to a mixture of cyclohexa-
none or cyclopentanone (5 mmol) and the catalyst 1a in chloroform
at ꢁ20 ꢀC. The reaction mixture was stirred, and the progress of the
reaction was monitored by TLC. After the completion of the re-
action, the solvent was evaporated and the residue was purified by
column chromatography, eluting with a mixture of ethyl acetate
and petroleum ether. The diastereomeric ratio (d.r.) and the en-
antiomeric excess (ee) of the aldol adduct were determined by
chiral HPLC analysis. For HPLC spectra of compounds 15aer and 17,
please refer to Supplementary data.
d
n
:
4.3.8. (S)-N-((1S,2R)-2-Hydroxy-1,2-diphenylethyl)azetidine-2-
carboxamide (2). Light yellow solid, 104 mg, yield 42%;
25
mp¼94e97 ꢀC; [
a
]
ꢁ123.0 (c 0.27, CHCl3); 1H NMR (400 MHz,
D
CDCl3)
d
ppm: 7.36e7.30 (m, 10H), 5.29e5.17 (m, 1H), 4.96 (m, 1H),
Acknowledgements
4.07 (m, 1H), 3.37e3.28 (m, 1H), 3.07e3.05 (m, 1H), 2.29e2.23 (m,
1H), 2.06e2.03 (m, 1H); 13C NMR (100 MHz, CDCl3)
ppm: 173.1,
137.7, 137.0, 128.2, 128.1 (ꢂ2), 128.0 (ꢂ2), 127.9, 127.8, 127.7 (ꢂ2),
127.4 (ꢂ2), 77.4, 61.8, 60.4, 45.3, 23.1; IR (KBr pellet)
cmꢁ1: 3396,
d
We are grateful to the National Natural Sciences Foundation of
China (NNSFC: 21272216, 20972140, and 21172202) and the Min-
istry of Education of China for the financial supports.
n

1470
X. Song et al. / Tetrahedron 70 (2014) 1464e1470
ꢀ
Talance, V.; Schmidt, G.; Lubin, H.; Comesse, S.; Dechoux, L.; Hamon, L.; Ka-
Supplementary data
douri-Puchot, C. Eur. J. Org. Chem. 2007, 2007, 4517e4524.
5. Starmans, W. A. J.; Walgers, R. W. A.; Thijs, L.; de Gelder, R.; Smits, J. M. M.;
Zwanenburg, B. Tetrahedron 1998, 54, 4991e5004.
6. Hermsen, P. J.; Cremers, J. G. O.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 2001,
42, 4243e4245.
7. Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10, 1673e1679.
8. (a) Niu, J.-L.; Wang, M.-C.; Lu, L.-J.; Ding, G.-L.; Lu, H.-J.; Chen, Q.-T.; Song, M.-P.
Tetrahedron: Asymmetry 2009, 20, 2616e2621; (b) Wang, M. C.; Zhang, Q. J.;
Zhao, W. X.; Wang, X. D.; Ding, X.; Jing, T. T.; Song, M. P. J. Org. Chem. 2008, 73,
168e176; (c) Song, M.-P.; Wang, M.-C.; Zhao, W.-X.; Wang, X.-D. Synlett 2006,
3443e3446.
Copies of 1H and 13C NMR spectra of 1aec, 3, 10a, and 10c, and
copies of chiral HPLC spectra of 13aer, 15aer, and 17 are available.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.12.081.
References and notes
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