Organocatalytic synthesis of 5-hydroxyisoxazolidine catalyzed by camphor sulfonyl hydrazines through aza-Michael addition/cyclization

Article abstract of DOI:10.1002/chir.23168

A series of chiral 5-hydroxy isoxazolidines has been successfully synthesized through camphor sulfonyl hydrazine-catalyzed asymmetric aza-Michael addition reaction between N,O-protected hydroxyamines and enals. Moderate yields with moderate to good enantioselectivities (up to 96% enantiomeric excess [ee]) were achieved. It provides an alternative asymmetric approach to preparing isoxazolidine derivatives.

Full text of DOI:10.1002/chir.23168

Received: 22 August 2019
DOI: 10.1002/chir.23168
Revised: 11 December 2019
Accepted: 17 December 2019
R E G U L A R A R T I C L E
Organocatalytic synthesis of 5-hydroxyisoxazolidine
catalyzed by camphor sulfonyl hydrazines through
aza-Michael addition/cyclization
Fang-Fang Xu1 | Ling-Yan Chen1
| Peng Sun1 | Yixin Lv2
|
Yan-Xue Zhang1 | Jia-Yu Li1 | Xiaoying Yin1 | Ya Li1
1College of Chemistry and Chemical
Abstract
Engineering, Shanghai University of
Engineering Science, Shanghai, China
A series of chiral 5-hydroxy isoxazolidines has been successfully synthesized
through camphor sulfonyl hydrazine-catalyzed asymmetric aza-Michael addi-
tion reaction between N,O-protected hydroxyamines and enals. Moderate
yields with moderate to good enantioselectivities (up to 96% enantiomeric
excess [ee]) were achieved. It provides an alternative asymmetric approach to
preparing isoxazolidine derivatives.
2College of Pharmacy, Jiangxi University
of Traditional Chinese Medicine,
Nanchang, China
Correspondence
Ling-Yan Chen, College of Chemistry and
Chemical Engineering, Shanghai
University of Engineering Science,
333 Longteng Road, Shanghai 201620,
China.
K E Y W O R D S
5-hydroxyisoxazolidine, aza-Michael addition, camphor sulfonyl hydrazine, organocatalytic
Email: lingyan.chen@hotmail.com
Xiaoying Yin, College of Chemistry and
Chemical Engineering, Shanghai
University of Engineering Science,
333 Longteng Road, Shanghai 201620,
China.
Email: ncyxoy@163.com
Ya Li, College of Chemistry and Chemical
Engineering, Shanghai University of
Engineering Science, 333 Longteng Road,
Shanghai 201620, China.
Email: ya.li@sues.edu.cn
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 81973453;
Natural Science Foundation of Shanghai,
Grant/Award Number: 16ZR1413800;
Students Innovation Program in Shanghai
Universityof Engineering Science, Grant/
Award Number: 18KY0417
1 | INTRODUCTION
anti-HIV properties (Figure 1).2 Isoxazolidines could also
be readily transformed into γ-amino alcohols or β-amino
Isoxazolidines are important skeletons that occur widely
in drugs as well as bioactive compounds.1 For example,
compound A, known as TRINs, has been reported to have
acids.3 As a result, substantial efforts have been devoted
to the synthesis of isoxazolidines, especially those that are
optically active.[1f] Several synthetic methods, including
Chirality. 2020;1–9.
wileyonlinelibrary.com/journal/chir
© 2020 Wiley Periodicals, Inc.
1

2
XU ET AL.
utilization of chiral auxiliaries,4 Lewis acid-catalyzed con-
jugate addition,5 and organocatalytic aza-Michael
addition,6 have been developed and found widespread
use in the asymmetric synthesis of isoxazolidines. Among
these, organocatalytic aza-Michael addition/cyclization
represents an efficient and straightforward approach. In
2006, MacMillan and coworkers reported their pioneering
work on the aza-Michael addition of benzyl tert-
butyldimethylsilyloxycarbamate with enals, using the
imidazolidinone catalyst (now named as MacMillan cata-
lyst). Excellent enantioselectivities (up to 96%) were
achieved. However, the addition product could not
cyclize directly; it could convert to isoxazolidines in two
steps.7 Córdova[6a], 8, Wang9 and Pericàs10 then respec-
tively explored the aza-Michael addition of N-protected
hydroxyamine by different proline-derived catalysts for
the direct synthesis of 5-hydroxyisoxazolidines. Although
considerable progress has been made, developing more
efficient and highly enantioselective approach for the
direct synthesis of isoxazolidine is still highly desirable.
Camphor sulfonyl hydrazines (CaSHs) have emerged
as useful organocatalysts and proved competent in asym-
metric Diels-Alder reaction,11 aza-Micheal addition,12
and Friedel-Crafts alkylation.13 They behave similarly
with primarily and secondary amine organocatalysts
(such as proline derivatives) in terms of catalytic func-
tion. However, CaSHs have enhanced nucleophilicity
because of the α-heteroatom effect, and this accelerates
the formation of the active imine ion intermediate in the
organocatalysis reaction.14 Very recently, we have devel-
oped CaSHs-catalyzed Michael addition reactions
between oxindoles and enals, which enabled us to
synthesize chiral 3,3-disubstituted oxindoles with good
enantioselectivities and diastereoselectivities.15 As part
of our continuing efforts on CaSHs catalysis, herein we
report
the
direct
synthesis
of
chiral
5-hydroxyisoxazolidines through CaSHs-catalyzed aza-
Michael addition/cyclization between N,O-protected
hydroxyamines and enals.
2 | MATERIALS AND METHODS
All reagents were purchased from commercial supplies
and used without further purification. Column chroma-
tography was performed using silica gel (300-400
mesh). Visualization of the compounds was accom-
plished with UV light (254 nm) and iodine. 1H NMR
and 13C NMR spectra were recorded in CDCl3 operat-
ing at 400 and 100 MHz. Proton chemical shifts are
reported relative to the residual proton signals of the
deuterated solvent CDCl3 (7.26 ppm) or DMSO-d6 (2.50
and 3.33 ppm) or TMS. Carbon chemical shifts were
internally referenced to the deuterated solvent signals
in CDCl3 (77.00 ppm) or DMSO-d6 (40.0 ppm). Data
are represented as follows: chemical shift, multiplicity
(bs = broad singlet, s = singlet, d = doublet, t = trip-
let, m = multiplet), coupling constant in hertz (Hz),
and integration. Products were identified by compari-
son with spectral data reported in the literature. High-
performance liquid chromatography (HPLC) was per-
formed using
Chiralpak column (250 mm × 4.6 mm) with n-hexane/
i-PrOH as the eluent.
a chromatograph equipped with a
2.1 | General procedure for
organocatalytic synthesis of
5-hydroxyisoxazolidine
Nα-Methyl CaSH 5b (10 mg, 0.04 mmol) and TCA
(6.5 mg, 0.04 mmol) were mixed in DCM (0.4 mL) for
30 minutes. The respective α,β-unsaturated aldehyde
1 (0.6 mmol) was added. After stirring for another
30 minutes, 2 (0.2 mmol) was added. The resulting
solution was stirred until complete consumption of
2 as determined by thin-layer chromatography (TLC).
The reaction was then quenched with aq. NaHCO3 (0.3
mL) and extracted with EtOAc (3 × 5 mL). The combined
organic solutions were dried over anhydrous Na2SO4.
After the solvent was evaporated and the crude
product was purified by flash chromatography on silica
gel to yield the desired addition product. The enantio-
meric excess of the product was determined by HPLC
analysis. The NMR and HPLC spectra were included in
the Supporting Information.
FIGURE 1 Selected bioactive compound containing the
isoxazolidine skeleton

XU ET AL.
3
SCHEME 1 Strategies for
organocatalytic aza-Michael
addition/cycliztion for
construction of isoxazolidines
2.2 | (3R,5R)-Benzyl-5-hydroxy-
(s, 2H), 2.71-2.65 (m, 1H), 2.26 (s, 3H), 2.23-2.18 (m, 1H).
13C NMR (100 MHz, CDCl3) δ 129.3,128.4, 127.8,126.0,
98.6, 67.9, 45.2, 25.6; Daicel CHIRALPAK AD-H column,
214 nm, n-hexane/i-PrOH = 96/4, 1.0 mL/min, major iso-
mer: tR = 12.0 minutes, minor isomer: tR = 16.0 minutes.
3-methylisoxazolidine-2-carboxylate (3a)9
34.0 mg, 72% yield, 76% enantiomeric excess (ee);
1H NMR (400 MHz, CDCl3) δ 7.36-7.26 (m, 5H), 5.69
(t, J = 4.0 Hz, 1H), 5.24-5.15 (m, 2H), 4.44-4.39 (m, 1H),
2.46-2.41 (m, 1H), 1.93-1.87 (m, 1H), 1.31 (d, J = 8.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 135.8, 128.5,
24
128.2, 127.9, 98.5, 67.9, 54.0, 43.2, 21.4; [α]D = +25.5
(c 0.5 in CHCl3); Daicel CHIRALPAK AD-H column,
2.5 | (3R,5R)-Benzyl-5-hydroxy-
3-(4-methoxyphenyl)isoxazo-lidine-
2-carboxylate (3e)10
214 nm, n-hexane/i-PrOH
=
90/10, 1.0 mL/min,
major isomer: tR
tR = 9.8 minutes.
= 8.4 minutes, minor isomer:
29.6 mg, 41% yield, 63% ee; 1H NMR (400 MHz, CDCl3) δ
7.26-7.21 (m, 3H), 7.17 (d, J = 8.0 Hz, 4H), 6.79
(d, J = 8.0 Hz, 2H), 5.75 (t, J = 4.0 Hz, 1H), 5.28-5.22
(m, 1H), 5.11 (s, 2H), 3.72 (s, 4H), 2.70-2.64 (m, 1H),
2.25-2.19 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 159.2,
135.7, 133.4, 128.4, 128.1, 127.8, 127.3, 114.0, 98.6, 68.0,
60.8, 55.3, 45.1, 29.6. Daicel CHIRALPAK AD-H column,
214 nm, n-hexane/i-PrOH = 96/4, 0.5 mL/min, major iso-
mer: tR = 26.7 minutes, minor isomer: tR = 29.2 minutes.
2.3 | (3R,5R)-Benzyl-5-hydroxy-
3-phenylisoxazolidine-2-carboxylate (3c)9
41.2 mg, 65% yield, 69% ee; 1H NMR (400 MHz, CDCl3) δ
7.32 (d, J = 4.0 Hz, 4H), 7.33-7.25 (m, 8H), 7.23-7.20 (m,
2H), 5.86-5.85 (m, 1H), 5.38 (t, J = 4.1 Hz, 1H), 5.17 (s,
2H), 2.80-2.75 (m, 1H), 2.32-2.26 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 159.2, 141.4, 135.7, 128.6, 128.4,
128.1, 127.8, 127.4, 126.0, 98.6, 68.1, 61.2, 45.2; Daicel
CHIRALPAK AD-H column, 214 nm, n-hexane/i-PrOH
= 97/3, 1.0 mL/min, major isomer: tR = 15.6 minutes,
minor isomer: tR = 18.7 minutes.
2.6 | (3R,5R)-Benzyl-3-(4-chlorophenyl)-
5-hydroxyisoxazolidine-2-carboxylate (3f)9
37.3 mg, 56% yield, 28% ee; 1H NMR (400 MHz, CDCl3) δ
7.30-7.23 (m, 9H), 5.83 (s, 1H), 5.34 (t, J = 4.0 Hz, 1H),
5.17 (s, 2H), 2.79-2.74 (m, 1H), 2.26-2.20 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 159.1, 139.9, 135.4, 133.2,
128.7, 128.4, 128.2, 127.7, 127.4, 98.6, 68.2, 60.7, 45.1;
Daicel CHIRALPAK AD-H column, 214 nm, n-hexane/
2.4 | (3R,5R)-Benzyl-5-hydroxy-3-(p-tolyl)
isoxazolidine-2-carboxylate (3d)10
31.3 mg, 50% yield, 82% ee; 1H NMR (400 MHz, CDCl3) δ
7.23-7.21 (m, 4H), 7.18-7.15 (m, 4H), 7.06 (d, J = 8.0 Hz,
2H), 5.79 (d, J = 4.0 Hz, 1H), 5.27 (t, J = 8.0 Hz, 1H), 5.10
i-PrOH
=
94/6, 1.0 mL/min, major isomer:
tR = 19.4 minutes, minor isomer: tR = 23.1 min.

4
XU ET AL.
2.7 | (3R,5R)-tert-Butyl-5-hydroxy-
(m, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
158.4, 140.4, 132.9, 128.7, 127.5, 98.2, 82.6, 60.7,
45.1, 28.1; Daicel CHIRALPAK OD-H column,
3-methylisoxazolidine-2-carboxylate (3g)9
29.6 mg, 73% yield, 43% ee; 1H NMR (400 MHz,
CDCl3) δ 5.69 (d, J = 8.0 Hz, 1H), 4.33-4.27 (m, 1H),
2.42-2.37 (m, 1H), 1.89-1.83 (m, 1H), 1.47 (s, 9H), 1.28
(d, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
158.7, 98.2, 81.9, 53.9, 43.2, 28.2, 21.5; Daicel
CHIRALPAK AD-H column, 220 nm, n-hexane/i-PrOH
= 96/4, 0.5 mL/min, major isomer: tR =12.6 minutes,
minor isomer: tR = 13.8 minutes.
220 nm, n-hexane/i-PrOH
major isomer: tR = 13.8 minutes, minor isomer: tR
12.6 minutes.
=
96/4, 0.5 mL/min,
=
2.11 | (3R,5R)-Benzyl-3-(2-bromophenyl)-
5-hydroxyisoxazolidine-2-carboxylate (3k)
37.7 mg, 50% yield, 54% ee; 1H NMR (400 MHz, CDCl3) δ
7.54 – 7.49 (m, 2H), 7.31-7.24 (m, 6H), 7.14-7.10 (m,1H),
5.87 (d, J = 4.0 Hz, 1H), 5.76 (t, J = 8.0 Hz, 1H), 5.19
(s, 2H), 3.06-3.00 (m, 1H), 2.13-2.07(m, 1H). 13C NMR
(100 MHz, CDCl3) δ 171.1, 159.0, 140.9, 135.5, 132.2,
128.8, 128.4, 128.1, 127.8, 126.8, 121.6, 98.8, 68.1, 61.2,
60.3, 44.4, 20.9, 14.1; Daicel CHIRALPAK OD-H column,
214 nm, n-hexane/i-PrOH = 94/6, 0.5 mL/min, major iso-
mer: tR = 9.5 minutes, minor isomer: tR = 10.3 minutes.
HRMS (ESI) C17H16NaBrNO4 (M+Na)+ calcd. 400.0155,
found 400.0160.
2.8 | (3R,5R)-tert-Butyl-5-hydroxy-
3-phenylisoxazolidine-2-carboxylate (3h)9
38.0 mg, 72% yield, 96% ee; 1H NMR (400 MHz,
CDCl3) δ 7.33 (d, J = 4.0 Hz, 4H), 7.28-7.24 (m, 1H),
5.90 (d, J = 4.0 Hz, 1H), 5.29 (t, J = 4.0 Hz, 1H),
2.79-2.74 (m, 1H), 2.31-2.25 (m, 1H), 1.42 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 158.6, 142.0, 128.5, 127.2,
126.1, 98.5, 82.4, 61.3, 45.3, 28.1; Daicel CHIRALPAK
OD-H column, 214 nm, n-hexane/i-PrOH = 94/6, 1.0
mL/min, major isomer: tR = 6.6 minutes, minor iso-
mer: tR = 8.3 minutes.
2.12 | (3R,5R)-tert-Butyl-3-(4-tolyl)-
5-hydroxyisoxazolidine-2-carboxylate (3l)
34.5 mg, 62% yield, 95% ee; 1H NMR (400 MHz, CDCl3) δ
7.19-7.14 (m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 5.81 (d, J =
4.0 Hz, 1H), 5.18 (t, J = 8.0 Hz, 1H), 2.69-2.64 (m 1H),
2.26 (s, 3H), 2.22-2.17 (m, 1H), 1.35 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ 158.7, 136.9, 129.2, 126.1, 98.5, 82.2,
61.1, 45.3, 28.1, 21.0; Daicel CHIRALPAK AD-H column,
254 nm, n-hexane/i-PrOH = 98/2, 1 mL/min, major iso-
mer: tR = 23.9 minutes, minor isomer: tR = 30.2 minutes.
HRMS (ESI) C15H21NaNO4 (M+Na)+ calcd.302.1363,
found 302.1361.
2.9 | (3R,5R)-tert-Butyl-
3-(2-bromophenyl)-5-hydroxyisoxazolidine-
2-carboxylate (3i)
1
38.4 mg, 56% yield, 61% ee; H NMR (400 MHz, CDCl3) δ
7.45 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 10Hz, 1H), 7.07-7.03
(m, 1H), 5.81 (d, J = 4.0 Hz, 1H), 5.62 (t, J = 8.0 Hz, 1H),
2.93-2.88 (m, 1H), 2.02-1.96 (m, 1H), 1.36 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ 158.3, 141.6, 132.5, 128.6, 127.8, 127.1,
121.7, 98.7, 82.5, 61.0, 44.5, 28.1; Daicel CHIRALPAK OD-
H column, 214 nm, n-hexane/i-PrOH = 98/2, 1.0 mL/min,
major isomer: tR
=
19.0 minutes, minor isomer:
2.13 | (3R,5R)-Benzyl-3-(furan-2-yl)-
tR = 20.9 minutes. HRMS (ESI) C14H18NaBrNO4 (M +
5-hydroxyisoxazolidine-2-carboxylate (3m)9
Na)+ calcd. 366.0311, found 366.0307.
39.3 mg, 68% yield, 54% ee; 1H NMR (400 MHz,
CDCl3)
δ 7.38 (s, 1H), 7.34-7.29 (m, 5H), 6.32
(s, 1H), 6.26 (s, 1H), 5.87 (d, J = 9.0 Hz, 1H), 5.45
(t, J = 8 Hz, 1H), 5.22 (s, 2H), 2.64-2.56 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 159.3, 152.4, 142.5, 135.6,
128.5, 128.3, 128.0, 110.3, 107.3, 98.7, 68.3, 60.3, 55.1,
40.5, 21.0, 14.1; Daicel CHIRALPAK AD-H column,
2.10 | (3R,5R)-tert-Butyl-
3-(4-chlorophenyl)-5-hydroxyisoxazolidine-
2-carboxylate (3j)9
41.8 mg, 70% yield, 44% ee; 1H NMR (400 MHz,
CDCl3) δ 7.32-7.26 (m, 4H), 5.86 (d, J = 4.0 Hz, 1H),
5.25 (t, J = 4.0 Hz, 1H), 2.78-2.73 (m, 1H), 2.25-2.19
254 nm, n-hexane/i-PrOH
=
97/3,
1
mL/min,
major isomer: tR = 14.5 minutes, minor isomer:
tR = 17.0 minutes.

XU ET AL.
5
3 | RESULTS AND DISCUSSION
desired product 3a but with moderate yield and low
enantioselectivity (41% yield, 17% ee; entry 1, Table 1).
Considering that the O-protecting group may have effects
on the reaction, O-TBS hydroxylamine 2b was tried in
the reaction. To our delight, the reaction proceeded
smoothly and led to the desired product 3a with greatly
improved enantioselectivity (59% ee; entry 2, Table 1),
Initially, trans-crotonaldehyde 1a and N-Cbz hydroxyl-
amine 2a were used as model substrates and the addition
reaction was carried out in the presence of 20 mol%
CaSH 5a and trichloroacetic acid (TCA) as an additive in
CHCl3 at room temperature. The reaction afforded the
TABLE 1 Screening the conditions of aza-Michael additiona
Entry
1d
2
Catalyst
5a
Additive
TCA
Solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Toluene
DCM
Yield,%b
41
Ee, %c
17
59
76
40
61
38
27
7
5a
TCA
60
3
5b
5c
TCA
72
4
TCA
47
5
5d
5e
TCA
42
6
TCA
36
7
5f
TCA
39
8
5g
TCA
37
9
5h
5i
TCA
18
16
19
23
9
10
11
12
13
14
15
16
17
18
19
20
21
22e
23f
TCA
24
5j
TCA
21
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
TsOH
TfOH
TFA
26
39
32
47
81
64
51
57
56
50
60
65
60
61
2-NO2PhCOOH
TCA
32
60
TCA
51
TCA
Dioxane
THF
44
TCA
49
TCA
Et2O
37
TCA
MTBE
CHCl3
CHCl3
45
TCA
51
TCA
50
aUnless otherwise noted, all reactions were carried out using 2b (0.2 mmol), 1a (0.6 mmol), catalyst 5 (0.04 mmol), and additive (0.04 mmol) in solvent (2 mL)
at rt for 24 hours.
bIsolated yield.
cDetermined by HPLC analysis using a chiralpak column.
dN-Cbz protected hydroxylamine 2a was used.
eTCA (0.02 mmol) was used.
f5b (0.02 mmol) was used.

6
XU ET AL.
while product 4a was not observed. We then screened dif-
ferent catalysts 5b-j with different substituents on the Nα-
position. A longer aliphatic chain resulted in lower yield
and enantioselectivity (entries 2-6, Table 1); Catalyst 5b
Under the optimized reaction conditions (Table 1,
entry 2), the scope of current aza-Michael addition pro-
moted by CaSH 5b was examined (Table 2). Different
alkyl or aryl substituted enals were investigated. The
reaction showed strong dependence on the steric hin-
drance of alkyl substituted enals. For N-Cbz hydroxyl-
amine, when R1 was a methyl group, up to 76% ee was
achieved (3a). In contrast, a propyl group substitution
resulted in trace amount of the product (3b). For aryl-
substituted enals, the corresponding product could be
obtained in moderate yields with moderate to good
enantioselectivities. The enal with a 4-methylphenyl
group gave up to 82% ee, while 4-chlorophenyl
substituted enal was used; both the enantioselectivity and
yield were dramatically reduced (3f vs 3d). However,
when phenyl (3c), 4-methoxyphenyl (3e), 2-bromophenyl
(3k), and furyl (3m) substituted enals were used,
enantioselectivities were similar with the range from 54%
to 69%. It seemed hard to explain exactly how substitu-
tions on the aromatic ring of enals dictated the observed
trends in yields and enantioselectivities. For N-Boc
hydroxylamine, phenyl, 4-methylphenyl-substituted enals
gave the corresponding products with excellent
enantioselectivities (96% ee and 95% ee, respectively).
bearing
a
methyl substitution gave the highest
enantioselectivity (79% ee, entry 3, Table 1). Moreover,
when there was a phenyl ring on the catalyst, the results
were even worse (entries 7-11, Table 1). Using CaSH 5b
as the optimal catalyst, the effect of different acid addi-
tives on the reaction was examined (entries 12-15,
Table 1). The use of TsOH, TfOH, or TFA gave dimin-
ished enantioselectivities, whereas the inclusion of
2-nitro benzoic acid led to slightly improved
enantioselectivity, albeit a poor yield. Using CaSH 5b, a
series of solvents (nonpolar solvent [toluene], ethers
[THF, Et2O, and TMBE], or DCM) were also evaluated,
and only moderate yields and enantioselectivities were
obtained (37%-60% yield, 50%-64% ee; entries 16-21,
Table 1). In addition, the loading of the additive acid and
the catalyst were also examined. When the loading of the
additive acid was cut in half, the enantioselectivity
decreased (65% ee; entry 22, Table 1). When the catalyst
loading was decreased to 10 mol%, the reaction needed a
longer time with lower ee and yield (entry 23, Table 1).
TABLE 2 Scope of the aza-Michael additiona, b, c
aAll reactions were carried out using 2 (0.2 mmol), 1 (0.6 mmol), 5b (0.04 mmol), and TCA (0.04 mmol) in CHCl3 (2.0 mL) at rt for 24 hours.
bIsolated yield.
cDetermined by HPLC analysis using a chiralpak column.

XU ET AL.
7
FIGURE 2 Proposed mechanism for the
aza-addition/cyclization
Additionally, N-Ts hydroxylamine was also investigated;
however, it failed to give the desired product.
ACKNOWLEDGMENTS
The authors are grateful for financial support from Natu-
ral Science Foundation of China (81987453), State Educa-
tion Ministry and Natural Science Foundation of
Shanghai (16ZR1413800), and the Students Innovation
Program in Shanghai University of Engineering Science
(18KY0417).
On the basis of our experimental results, a mechanism
is tentatively proposed (Figure 2). The enal 1a was acti-
vated by 5b in the presence of TCA to form iminium ion
intermediate (A). As the Re-face of iminium ion intermedi-
ate was blocked, it was attacked by N-Cbz, O-TBS hydrox-
ylamine (2b) from its Si-face affording the corresponding
aldehyde (B), which cyclized to afford 3a. The absolute
configuration of 3a at C3 was determined by comparison
ORCID
Ling-Yan Chen https://orcid.org/0000-0001-6125-6884
24
with the literature rotation ([α]D = +25.5 (c 0.5 in
CHCl3); lit. [α]D28 = +16.0 (c 1.0 in CHCl3)9,10
.
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15. Cheng WF, Chen LY, Xu FF, Lin WY, Ren X, Li Y.
Organocatalytic asymmetric Michael addition between
3-subsituted oxindoles and enals catalyzed by camphor sulfonyl
hydrazine. Org Biomol Chem. 2019;17(4):885-891.
How to cite this article: Xu F-F, Chen L-Y,
Sun P, et al. Organocatalytic synthesis of 5-
hydroxyisoxazolidine catalyzed by camphor
sulfonyl hydrazines through aza-Michael addition/
cyclization. Chirality. 2020;1–9. https://doi.org/10.
1002/chir.23168
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