Supporting Information

Palladium-Catalyzed Asymmetric Allylic Alkylation of

4-Substituted Isoxazolidin-5-ones: Straightforward Access to
b2,2-Amino Acids
Marllon Nascimento de Oliveira,[a] Stellios Arseniyadis,*[a, b] and Janine Cossy*[a]

chem_201800641_sm_miscellaneous_information.pdf
 Table of Contents

1. General experimental methods 3

2. Optimization tables 4

3. Synthesis of precursors of 1 6

3.1. Preparation of N-hydroxycarbamate sulfone (A) 6

3.2. Synthesis of 5-aryl-2,2-dimethyl-1,3-dioxane-4,6-diones (B1-B9) 7

4. Synthesis of allyl acetates (C1-C6) 18

5. Synthesis of 4-substituted isoxazolidin-5-ones (1a-1i) 23

6. Synthesis of α-quaternary isoxazolidin-5-ones (2a-2o) 31

7. Post-functionalization 51

7.1. Synthesis of β2,2-amino acid 3 51

7.2. Synthesis of β-lactam 4 52

1
8. H and 13C NMR spectra copies 55
1. General experimental methods

All reactions were run under an argon atmosphere in oven-dried glassware unless otherwise
specified. All commercially available compounds were purchased from Aldrich Chemical Co. and used
as received. Dichloromethane (CH2Cl2) was distilled from calcium hydride. Tetrahydrofuran (THF) and
diethyl ether (Et2O) were distilled from sodium/benzophenone.
Analytical thin layer chromatography (TLC) was performed on silica gel plates (Merck 60F254)
visualized either with a UV lamp (254 nm) or by using solutions of p-anisaldehyde/sulfuric acid/acetic
acid in ethanol or KMnO4/K2CO3 in H2O followed by heating. Flash chromatography was performed on
silica gel (230-400 mesh).
Infrared spectra (IR) were recorded on a Bruker TENSOR™ 27 (IR-FT) with attenuated total
reflectance (ATR) and wavenumbers are indicated in cm-1.
1
H NMR spectra were recorded on a Bruker AVANCE 400 at 400 MHz in CDCl3 (unless
otherwise specified) and the observed signals are reported as follows: chemical shift in parts per
million from tetramethylsilane with the solvent as an internal indicator (CDCl3 δ 7.26 ppm, DMSO δ
2.50 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quintet = quint, m = multiplet
or overlap of non-equivalent resonances), integration. 13C NMR spectra were recorded at 100 MHz in
CDCl3 (unless otherwise specified) and the observed signals were reported as follows: chemical shift in
parts per million from tetramethylsilane with the solvent as an internal indicator (CDCl3 δ 77.16 ppm,
DMSO δ 39.52 ppm), multiplicity on respect to proton. Coupling constants (J) are reported in Hertz
(Hz). All NMR spectra were obtained at rt unless otherwise specified.
Mass spectra with electronic impact (EI–MS) were recorded with a Shimadzu GCM-QP 2010S
gas chromatography-mass spectrometer. High-resolution mass spectra (HRMS) were performed by
"Groupe de Spectrométrie de masse de l'Université Pierre et Marie Curie (Paris)".
Optical rotations were determined using a Perkin Elmer 343 polarimeter. The enantiomeric
excesses were determined by supercritical fluid chromatography (SFC) analysis on a chiral stationary
phase using a Minigram Berger SFC-Mettler Toledo apparatus.
2. Optimization tables

Table 1: Optimization study with bases and additives.[a]

Pd 2(dba) 3 (5 mol %)
O (R,R)-L1 (10 mol %) O O
O
Base (2 equiv) Ph 2P NH HN PPh 2
O + OAc
O
N Additive, THF, rt, 20 h
N
Boc 1a Boc 2a (R,R)-L1

Entry Base Additive (equiv) Yield[b] (%) ee[c] (%)

1 Li2CO3 − 90 87
2 Na2CO3 − 95 90
3 Cs2CO3 − 83 82
4 NaH − 96 87
5 BSA[d] − 85 80
6 DBU − 14 86
7 Na2CO3 LiCl (1) NR −
8 Na2CO3 15-Crown-5 (2) 90 88
[a]
Unless otherwise indicated, all reactions were performed on a 0.19 mmol scale employing 5 mol % of Pd2(dba)3 and
[b] [c] [d]
10 mol % of (R,R)-L1. Isolated yield. Determined by SFC analysis. 20 mol % KOAc were used.

Table 2: Influence of the palladium source.[a]

O [Pd 2], (R,R)-L1 O O

O
Na 2CO 3 (2 equiv) Ph 2P NH HN PPh 2
O + OAc
O
N THF, rt, 20 h
N
Boc 1a Boc 2a (R,R)-L1

Entry [Pd2] (mol %) (R,R)-L1 (mol %) Yield[b] (%) ee[c] (%)

1 Pd2(dba)3 (5) 10 95 90
2 Pd2(dba)3 (1.25) 10 83 79
3 Pd2(dba)3 (0) 10 0 −
4 [Pd(allyl)Cl]2 (5) 10 43 70
5 [Pd(cinnamyl)Cl]2 (5) 10 40 80
6 Pd(OAc)2 (5) 20 10 78
[a] [b] [c]
All reactions were performed on a 0.19 mmol scale. Isolated yield. Determined by SFC analysis.
Table 3: Optimization study with solvents.[a]

Pd 2(dba) 3 (5 mol %)
O (R,R)-L1 (10 mol %) O O
O
Na 2CO 3 (2 equiv) Ph 2P NH HN PPh 2
O + OAc
O
N Solvent (0.1 M), T, 20 h
N
Boc 1a Boc 2a (R,R)-L1

Entry Solvent T Yield[b] (%) ee[c] (%)

1 THF rt 95 90
2 MeCN rt 92 42
3 NMP rt 78 82
4 PhMe rt 99 66
5 MTBE rt 99 89
6 1,4-Dioxane rt 85 83
7 THF (0.033 M) rt 90 89
8 THF 0 °C 95 91
9 THF −10 °C 94 92
[a]
Unless otherwise indicated, all reactions were performed on a 0.19 mmol scale employing 5 mol % of Pd2(dba)3 and
[b] [c]
10 mol % of (R,R)-L1. Isolated yield. Determined by SFC analysis.
3. Synthesis of precursors of 1
3.1. Preparation of N-hydroxycarbamate sulfone (A)

tert-Butyl ((phenylsulfonyl)methyl)-N-hydroxycarbamate (A)1

Me O
Me
OH 4
Me 2 O 3 N
1 O
5 O
S
6
7
8
9
A
C12H17NO 5S
MW = 287.33 g/mol

Sodium benzenesulfinate (15.5 g, 93.9 mmol, 2.50 equiv) was dissolved in H2O/MeOH 2:1 (111 mL).
To this solution was added sequentially tert-butyl-N-hydroxycarbamate (5.00 g, 37.6 mmol,
1.00 equiv), formaldehyde (5.6 mL, 37% wt in H2O, 75 mmol, 2.0 equiv) and formic acid 95% (1.8 mL,
45 mmol, 1.2 equiv). This mixture was stirred for 24 h at rt. The resulting precipitate was collected by
filtration, washed with H2O and pentane, and then purified by trituration in hexane/EtOAc = 3:1. The
sulfone was obtained as a white solid (9.90 g, 92%).1

Mp = 138-139 °C
IR (ATR): 3362, 3009, 2985, 2931, 1707, 1476, 1448, 1394, 1368, 1309, 1287, 1223, 1140, 1094, 1082,
1032, 999, 904 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.97-7.92 (m, 2H), 7.68 (m, 1H), 7.60-7.54 (m, 2H), 4.90 (s, 2H), 1.32 (s,
9H).
Note: The signal corresponding to the OH moiety was not observed.
13
C NMR (100 MHz, CDCl3): δ 154.3, 138.3, 134.3, 129.5 (2C), 128.9 (2C), 83.9 (C), 71.2, 28.0 (3C).
HRMS (ESI) m/z: calcd for C12H17NO5SNa [M+Na]+: 310.0720, found: 310.0720.

1
Guinchard, X.; Vallée, Y.; Denis, J. -N. Org. Lett. 2007, 7, 5147.
 3.2. Synthesis of 5-aryl-2,2-dimethyl-1,3-dioxane-4,6-dione (B1-9)

General procedures for the synthesis of 5-substituted Meldrum’s acid from diethyl malonate

O 1. NaOH O
O O Cross-coupling Ar H 2O, Et 2O, rt, 20 h Ar
EtO O
EtO OEt Method A, B or C 2. Acetone, H 2SO 4 Me
EtO O O O
Ac2O, rt, 12 h Me
B

Cross-coupling Method A: To a flame-dried flask containing a dispersion of NaH (751 mg, 60% in
mineral oil, 18.8 mmol, 1.10 equiv) in THF (17 mL) was added diethyl malonate (2.85 mL, 18.8 mmol,
1.10 equiv) dropwise. Upon evolution of hydrogen (approximately 2 min), aryl bromide (17.1 mmol,
1.00 equiv) and Pd(t-Bu3P)2 (174 mg, 0.340 mmol, 0.020 equiv) and THF (34 mL) were added.
The reaction mixture was stirred at 70 °C. After 48 h, the reaction was cooled to rt and an aqueous
solution of HCl (1 M) was added. The layers were separated, and the aqueous layer was extracted
with EtOAc (2 x 100 mL). The combined organic extracts were washed with a saturated aqueous brine
solution (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude
residue was purified by flash column chromatography on silica gel (PE/EtOAc) to afford the arylated
diethyl malonate.2

Cross-coupling Method B: A flame-dried flask was charged with aryl iodide (21.0 mmol, 1.00 equiv),
CuI (400 mg, 2.10 mmol, 0.100 equiv), L-proline (484 mg, 4.20 mmol, 0.200 equiv) and Cs2CO3 (27.4 g,
84.0 mmol, 4.00 equiv). Then diethyl malonate (3.80 mL, 25.2 mmol, 1.20 equiv) and DMSO (42 mL)
were added under argon. The reaction mixture was stirred at 40 °C. After 48 h, the cooled mixture
was partitioned between EtOAc and a saturated aqueous solution of NH4Cl, the organic layer was
washed with a saturated aqueous brine solution, dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by flash column chromatography on silica gel (PE/EtOAc)
to provide the arylated diethyl malonate.3

2
Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
3
Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693.
Cross-coupling Method C: A flame-dried flask was charged with CuI (132 mg, 0.695 mmol, 0.05 equiv),
2-picolinic acid (171 mg, 1.39 mmol, 0.100 equiv) and Cs2CO3 (13.6 g, 41.7 mmol, 3.00 equiv).
1,4-Dioxane (14 mL), diethyl malonate (4.20 mL, 27.8 mmol, 2.00 equiv) and aryl iodide (13.9 mmol,
1.00 equiv) were added under argon. The reaction mixture was stirred at rt. After 48 h, the cooled
mixture was partitioned between EtOAc and a saturated aqueous solution of NH4Cl, the organic layer
was washed with a saturated aqueous brine solution, dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by flash column chromatography on silica gel
(PE/EtOAc) to provide the arylated diethyl malonate.4

Saponification: The the arylated diethyl malonate (8.00 mmol, 1.00 equiv) was dissolved in Et2O
(8.0 mL) and then added to a flask containing a solution of NaOH (1.28 g, 32.0 mmol, 4.00 equiv) in
H2O (26 mL) at 0 °C over a period of 10 min. The resulting mixture was stirred at rt for 20 h. The
aqueous layer was separated and washed with EtOAc (2 x 100 mL), acidified to pH 2 with an aqueous
solution of HCl (6 M), and extracted with EtOAc (2 x 200 mL). The combined organic extracts were
washed with a saturated aqueous brine solution (100 mL), dried over MgSO4, filtered and
concentrated under reduced pressure to produce the corresponding arylated malonic acid.5

Synthesis of Meldrum’s acid: To a suspension of arylmalonic acid (50 mmol, 1.00 equiv) in Ac2O (2 M)
was added concentrated H2SO4 (20 mmol, 0.40 equiv) dropwise. After complete dissolution of the
arylmalonic acid, acetone (80 mmol, 1.60 equiv) was added. The reaction mixture was stirred for 12 h,
cooled, and filtered. The precipitate was washed thoroughly with ice-cold H2O and then dissolved in
CH2Cl2 (200 mL). The resulting solution was washed with a saturated brine solution, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude solid was purified by trituration in
hexane/EtOAc = 7:3 to give B.

4
Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469.
5
Chidipudi, S. R.; Khan, I.; Lam, H. W. Angew. Chem. Int. Ed. 2012, 51, 12115.
2,2-Dimethyl-5-phenyl-1,3-dioxane-4,6-dione (B1)6

O 8
O Acetone 3
4 5 7
Ac2O, H 2SO 4 O
HO 6
2
1
rt, 10 min Me O O
HO O 1'
Me
B1
C12H12 O4
MW = 220.22 g/mol

B1 was synthesized according to method aforementioned starting from the commercially available
phenylmalonic acid (9.00 g, 50.0 mmol, 1.00 equiv). After complete dissolution of the malonic acid,
the mixture was stirred for 10 min. The titled compound was obtained after trituration in
hexane/EtOAc = 7:3 as a white solid (7.07 g, 64%).

Mp = 143-145 °C
IR (ATR): 2884, 1780, 1735, 1503, 1457, 1387, 1349, 1319, 1284, 1261, 1217, 1068, 1014, 922 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.46-7.35 (m, 3H), 7.33-7.25 (m, 2H), 4.79 (s, 1H), 1.84 (s, 3H), 1.74 (s,
3H).
13
C NMR (100 MHz, CDCl3): δ 164.9 (2C), 130.7, 129.3 (2C), 129.2 (2C), 128.9, 105.8, 52.9, 28.6, 27.5.
HRMS (ESI) m/z: calcd for C12H12O4Na [M+Na]+: 243.0628, found: 243.0627.

2,2-Dimethyl-5-(4-methylphenyl)-1,3-dioxane-4,6-dione (B2)

9
Me Me
Me Pd(t-Bu3P) 2 (4 mol %) O 1. NaOH O 8
O O 3
+ NaH (1.1 equiv) H 2O, Et 2O, rt, 20 h 4 5 7
EtO O 6
EtO OEt Br 2
THF, 70 ºC, 48 h 2. Acetone, H 2SO 4 1
Me
EtO O O O
Ac2O, rt, 12 h 1'
Me
B2
C13H14 O4
MW = 234.25 g/mol

The arylated malonic ester was synthesized according to Method A from 4-bromotoluene (2.10 mL,
17.1 mmol, 1.00 equiv). The crude residue was purified by flash column chromatography on silica gel

6
Crooy, P.; Neys, R. De; Eliaers, J.; Liveyns, R.; Simonet, G.; Vandevelde, J. Bull. Soc. Chim. Belg. 1977, 86, 991.
(PE/EtOAc = 9:1) to afford a clear oil (2.10 g, 49%) which was engaged in the next step without further
purification or characterization.

The corresponding malonic acid was prepared following the saponification procedure using
1,3-diethyl 2-(4-methylphenyl)propanedioate (2.00 g, 8.00 mmol, 1.00 equiv) to afford a white solid
(1.21 g, 77%) that was used in the next step without further purification or characterization.

The desired Meldrum’s acid was synthesized according to the general procedure, using
2-(4-methylphenyl)propanedioic acid (1.00 g, 5.20 mmol, 1.00 equiv). The crude solid was purified by
trituration in hexane/EtOAc = 7:3 to give B2 as a white solid (374 mg, 31%).

Mp = 141-143 °C
IR (ATR): 2918, 2892, 1773, 1735, 1707, 1519, 1430, 1385, 1346, 1319, 1288, 1260, 1223, 1210, 1192,
1064, 1014, 945, 017, 895 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.25-7.15 (m, 4H), 4.73 (s, 1H), 2.36 (s, 3H), 1.87 (s, 3H), 1.75 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 165.0 (2C), 138.9, 130.0 (2C), 129.0 (2C), 127.6, 105.8, 52.6, 28.7, 27.7,
21.3.
HRMS (ESI) m/z: calcd for C13H14O4 Na[M+Na]+: 257.0784, found: 257.0784.

2,2-Dimethyl-5-(4-methoxyphenyl)-1,3-dioxane-4,6-dione (B3)

9
CuI (10 mol %) OMe
OMe
OMe L-proline (20 mol %) O 1. NaOH O 8
O O 3
+ Cs2CO 3 (4 equiv) H 2O, Et 2O, rt, 20 h 4 5 7
EtO O 6
EtO OEt I 2
DMSO, 40 ºC, 48 h 2. Acetone, H 2SO 4 1
Me
EtO O O O
Ac2O, rt, 12 h 1'
Me
B3
C13H14 O5
MW = 240.25 g/mol

The arylated malonic ester was synthesized according to Method B from 4-iodoanisole (5.00 g,
21.3 mmol, 1.00 equiv). The crude residue was purified by flash column chromatography on silica gel
(PE/EtOAc = 9:1) to provide a clear oil (3.34 g, 59%) which was engaged in the next step without
further purification or characterization.
The corresponding malonic acid was prepared following the saponification procedure using
1,3-diethyl 2-(4-methoxyphenyl)propanedioate (3.00 g, 11.3 mmol, 1.00 equiv) to afford a white solid
(1.70 g, 72%) that was used in the next step without further purification or characterization.

The desired Meldrum’s acid was synthesized according to the general procedure, using
2-(4-methoxyphenyl)propanedioic acid (1.50 g, 7.10 mmol, 1.00 equiv). The crude solid was purified
by trituration in hexane/EtOAc = 7:3 to give B3 as a white solid (1.16 g, 65%).

Mp = 129-130 °C
IR (ATR): 2930, 2850, 2830, 1750, 1737, 1615, 1518, 1430, 1410, 1340, 1320, 1299, 1251, 1217, 1179,
1066, 1013, 893, 820, 757, 652 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.23-7.16 (m, 2H), 6.97-6.89 (m, 2H), 4.74 (s, 1H), 3.81 (s, 3H), 1.85 (s,
3H), 1.75 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 165.2 (2C), 159.9, 130.4 (2C), 122.5, 114.7 (2C), 105.7, 55.4, 52.2, 28.6,
27.5.
HRMS (ESI) m/z: calcd for C13H15O5 [M+H]+: 251.0914, found: 251.0914.

2,2-Dimethyl-5-(4-fluorophenyl)-1,3-dioxane-4,6-dione (B4)

CuI (5 mol %) F
F
F 2-picolinic acid (10 mol %) O 1. NaOH O 8
O O 3
+ Cs2CO 3 (3 equiv) H 2O, Et 2O, rt, 20 h 4 5 7
EtO O 6
EtO OEt I 2
dioxane, rt, 48 h 2. Acetone, H 2SO 4 1
Me
EtO O O O
Ac2O, rt, 12 h 1'
Me
B4
C12H11FO 4
MW = 238.21 g/mol

The arylated malonic ester was synthesized according to Method C from 1-fluoro-4-iodobenzene
(1.60 mL, 14.0 mmol, 1.00 equiv). The crude residue was purified by flash column chromatography on
silica gel (PE/EtOAc = 9:1) to provide a yellow oil (2.84 g, 81%) which was engaged in the next step
without further purification or characterization.
The corresponding malonic acid was prepared following the saponification procedure using
1,3-diethyl 2-(4-fluorophenyl)propanedioate (2.70 g, 10.6 mmol, 1.00 equiv) to afford a white solid
(2.05 g, 97%) that was used in the next step without further purification or characterization.

The desired Meldrum’s acid was synthesized according to the general procedure, using
2-(4-fluorophenyl)propanedioic acid (1.80 g, 9.10 mmol, 1.00 equiv). The crude solid was purified by
trituration in hexane/EtOAc = 7:3 to give B4 as a beige solid (909 mg, 42%).

Mp = 143-144 °C
IR (ATR): 3003, 2891, 1783, 1737, 1606, 1515, 1393, 1383, 1347, 1310, 1294, 1261, 1218, 1159, 1098,
1072, 1017, 940, 898 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.30-7.23 (m, 2H), 7.15-7.07 (m, 2H), 4.75 (s, 1H), 1.88 (s, 3H), 1.78 (s,
3H).
13
C NMR (100 MHz, CDCl3): δ 164.7 (2C), 163.0 (d, 1JC-F = 247 Hz), 131.3 (d, 3JC-F = 8.1 Hz, 2C), 126.4 (d,
4
JC-F = 3.6 Hz), 116.4 (d, 2JC-F = 21.9 Hz, 2C), 105.9, 52.3, 28.7, 27.5.
HRMS (ESI) m/z: calcd for C12H12FO4 [M+H]+: 239.0714, found: 239.0713.

2,2-Dimethyl-5-(4-(trifluoromethyl)phenyl)-1,3-dioxane-4,6-dione (B5)

9
CF 3 CF 3
CF 3 Pd(t-Bu3P) 2 (4 mol %) O 1. NaOH O 8
O O 3
+ NaH (1.1 equiv) H 2O, Et 2O, rt, 20 h 4 5 7
EtO O 6
EtO OEt Br 2
THF, 70 ºC, 48 h 2. Acetone, H 2SO 4 1
Me
EtO O O O
Ac2O, rt, 12 h 1'
Me
B5
C13H11F 3O4
MW = 288.22 g/mol

The arylated malonic ester was synthesized according to Method A from 4-bromobenzotrifluoride
(1.20 mL, 8.53 mmol, 1.00 equiv). The crude residue was purified by flash column chromatography on
silica gel (PE/EtOAc = 95:5) to afford a colorless oil (1.15 g, 44%) which was engaged in the next step
without further purification or characterization.
The corresponding malonic acid was prepared following the saponification procedure using
1,3-diethyl 2-(4-(trifluoromethyl)phenyl)propanedioate (1.00 g, 3.29 mmol, 1.00 equiv) to afford a
white solid (792 mg, 97%) that was used in the next step without further purification or
characterization.

The desired Meldrum’s acid was synthesized according to the general procedure, using
2-(4-(trifluoromethyl)phenyl)propanedioic acid (750 mg, 3.00 mmol, 1.00 equiv). The crude solid was
purified by trituration in hexane/EtOAc = 7:3 to give B5 as a beige solid (472 mg, 54%).

Mp = 155-156 °C
IR (ATR): 2891, 1701, 1619, 1514, 1414, 1396, 1326, 1295, 1208, 1238, 1227, 1164, 1123, 1110, 1068,
1020, 917, 904 cm-1.
Note: After trituration, the presence of the corresponding substituted malonic acid (B5’) of B5 was
noticed in a ratio B5’/B5 = 1 :4 by NMR. B5 is reported.
1
H NMR (400 MHz, (CD3)2CO): δ 7.79-7.71 (m, 2H), 7.65-7.59 (m, 2H), 5.72 (s, 1H), 2.02 (s, 3H), 1.80 (s,
3H).
13
C NMR (100 MHz, (CD3)2CO): δ 165.1 (2C), 137.9, 132.4 (2C), 130.5 (q, 2JC-F = 32.4 Hz), 126.0 (q,
3
JC-F = 3.9 Hz, 2C), 125.3 (q, 1JC-F = 272 Hz), 106.3, 53.6, 28.8, 26.5.
HRMS (ESI) m/z: calcd for C13H12F3O4 [M+H]+: 289.0682, found: 289.0683.

General procedures for the synthesis of 5-substituted Meldrum’s acid from aryl acetic acid

1. H 2SO 4 (3 equiv) O 1. NaOH O

O MeOH, reflux, 12 h Ar H 2O, Et 2O, rt, 20 h Ar
MeO O
Ar
HO 2. (MeO) 2CO (3 equiv) 2. Acetone, H 2SO 4 Me
MeO O O O
NaH, THF, reflux, 5 h Ac2O, rt, 12 h Me
then reflux → rt, 48 h
B

Esterification: A flame-dried flask was charged with aryl acetic acid (17.6 mmol, 1.00 equiv),
MeOH (30.0 mL) and H2SO4 (55 mmol, 3.1 equiv) and the reaction mixture was heated to reflux. After
12 h, the reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting
residue was partitioned between H2O (30 mL) and Et2O (30 mL), and the aqueous phase was extracted
with Et2O (3 × 30 mL). The organic layers were combined, washed with a saturated aqueous solution
of NaHCO3 (3 × 30 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford
the methyl aryl acetate.7

C-acylation: To a solution of methyl aryl acetate (15 mmol, 1.00 equiv) in THF (75 mL) was added
NaH (1.45 g, 60% in mineral oil, 36 mmol, 2.4 equiv), followed by dimethyl carbonate (3.8 mL,
45 mmol, 3.0 equiv). The mixture was heated of reflux for 5 h and then cooled to rt. After 48 h, a
saturated aqueous solution of NH4Cl was carefully added to quench the reaction. The organic layer
was extracted with EtOAc (3 x 30 mL), dried over MgSO4, filtered and concentrated under reduced
pressure to afford the corresponding dimethyl malonate.8

2,2-Dimethyl-5-(4-chlorophenyl)-1,3-dioxane-4,6-dione (B6)

Cl Cl
Cl 1. H 2SO 4 (3 equiv) O 1. NaOH O 8
O MeOH, reflux, 12 h H 2O, Et 2O, rt, 20 h 3
4 5
O 7
MeO 6
HO 2. Acetone, H 2SO 4 2
2. (MeO) 2CO (3 equiv) 1
Me
MeO O O O
NaH, THF, reflux, 5 h Ac2O, rt, 12 h 1'
Me
then reflux → rt, 48 h B6
C12H11 ClO4
MW = 254.67 g/mol

Methyl 4-chlorophenylacetate was synthesized according to the esterification procedure starting from
4-chlorophenylacetic acid (3.00 g, 17.6 mmol, 1.00 equiv). The titled compound was obtained as a
slightly yellow oil (2.78 g, 86%), which was engaged in the next step without further purification.

The synthesis of the corresponding dimethyl malonic ester was accomplished following the
C-acylation procedure, using methyl 4-chlorophenylacetate (2.78 g, 15.1 mmol, 1.00 equiv). The titled
compound was isolated as a yellow solid (3.50 g, 96%) which was engaged in the saponification step
without further purification or characterization.

The corresponding malonic acid was prepared following the saponification procedure, using
1,3-dimethyl 2-(4-chlorophenyl)propanedioate (3.50 g, 14.4 mmol, 1.00 equiv) to afford a slightly
yellow solid (2.87 g, 93%) that was used in the next step without further purification or
characterization.

7
Ringstrand, B.; Oltmanns, M.; Batt, J. A.; Jankowiak, A.; Denicola, R. P.; Kaszynsk, P. Beilstein J. Org. Chem. 2011, 7, 386.
8
Zi, W.; Toste, F. D. Angew. Chem. Int. Ed. 2015, 54, 14447.
The desired Meldrum’s acid was synthesized according to the general procedure, using
2-(4-chlorophenyl)propanedioic acid (2.80 g, 13.1 mmol, 1.00 equiv). The crude solid was purified by
trituration in hexane/EtOAc = 7:3 to give B6 as a white pale solid (2.71 g, 82%).

Mp = 145-147 °C
IR (ATR): 3100, 2888, 1739, 1496, 1414, 1393, 1383, 1344, 1311, 1282, 1260, 1222, 1090, 1072, 1015,
946, 895 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 4.74 (s, 1H), 1.87 (s, 3H),
1.78 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 164.5 (2C), 135.2, 130.8 (2C), 129.5 (2C), 129.1, 105.9, 52.4, 28.7, 27.5.
HRMS (ESI) m/z: calcd for C12H11ClO4Na [M+Na]+: 277.0238, found: 277.0240.

2,2-Dimethyl-5-(4-bromophenyl)-1,3-dioxane-4,6-dione (B7)

Br Br
Br 1. H 2SO 4 (3 equiv) O 1. NaOH O 8
O MeOH, reflux, 12 h H 2O, Et 2O, rt, 20 h 3
4 5
O 7
MeO 6
HO 2. Acetone, H 2SO 4 2
2. (MeO) 2CO (3 equiv) 1
Me
MeO O O O
NaH, THF, reflux, 5 h Ac2O, rt, 12 h 1'
Me
then reflux → rt, 48 h B7
C12H11BrO 4
MW = 299.12 g/mol

The methyl 4-bromophenylacetate was synthesized according to the esterification procedure from
4-bromophenylacetic acid (3.00 g, 14.0 mmol, 1.00 equiv). The titled compound was obtained as a
clear oil (3.07 g, 96%) which was engaged in the next step without further purification or
characterization.

The synthesis of the corresponding dimethyl malonic ester was accomplished following the
C-acylation procedure, using methyl 4-bromophenylacetate (3.00 g, 13.1 mmol, 1.00 equiv). The titled
compound was isolated as a yellow solid (3.74 g, 99%) which was engaged in the saponification step
without further purification or characterization.
The corresponding malonic acid was prepared following the saponification procedure, using
1,3-dimethyl 2-(4-bromophenyl)propanedioate (3.74 g, 13.0 mmol, 1.00 equiv) to afford an off-white
solid (3.32 g, 98%) that was used in the next step without further purification or characterization.

The desired Meldrum’s acid was synthesized according to the general procedure, using
2-(4-bromophenyl)propanedioic acid (3.32 g, 12.8 mmol, 1.00 equiv). The crude solid was purified by
trituration in hexane/EtOAc = 7:3 to give B7 as a white solid (2.76 g, 72%).

Mp = 137-139 °C
IR (ATR): 1786, 1745, 1494, 1411, 1394, 1384, 1340, 1312, 1280, 1259, 1216, 1189, 1176, 1074, 1055,
1008, 948, 917, 894 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.59-7.53 (m, 2H), 7.20-7.13 (m, 2H), 4.72 (s, 1H), 1.88 (s, 3H), 1.78 (s,
3H).
13
C NMR (100 MHz, CDCl3): δ 164.4 (2C), 132.5 (2C), 131.1 (2C), 129.6, 123.4, 105.9, 52.5, 28.7, 27.5.
HRMS (ESI) m/z: calcd for C12H11BrO4Na [M+Na]+: 320.9733 found: 320.9736.

2,2-Dimethyl-5-(3,4-dichlorophenyl)-1,3-dioxane-4,6-dione (B8)

9
Cl 10
Cl
Cl 1. H 2SO 4 (3 equiv) O 1. NaOH O 8
O MeOH, reflux, 12 h H 2O, Et 2O, rt, 20 h 3
4 5
MeO Cl O 6
7 Cl
HO Cl 2. Acetone, H 2SO 4 2
2. (MeO) 2CO (3 equiv) 1
Me
MeO O O O
NaH, THF, reflux, 5 h Ac2O, rt, 12 h 1'
Me
then reflux → rt, 48 h B8
C12H10 Cl2O4
MW = 289.11 g/mol

The methyl 3,4-dichlorophenylacetate was synthesized according to the esterification procedure from
3,4-dichlorophenylacetic acid (3.00 g, 14.6 mmol, 1.00 equiv). The titled compound was obtained as a
clear oil (3.20 g, 99%) which was engaged in the next step without further purification or
characterization.

The synthesis of the corresponding dimethyl malonic ester was accomplished following the
C-acylation procedure, using methyl 3,4-dichlorophenylacetate (3.20 g, 14.5 mmol, 1.00 equiv). The
titled compound was isolated as a yellow solid (4.00 g, 99%) which was engaged in the saponification
step without further purification or characterization.

The corresponding malonic acid was prepared following the saponification procedure, using
1,3-dimethyl 2-(3,4-dichlorophenyl)propanedioate (4.00 g, 14.4 mmol, 1.00 equiv) to afford a beige
solid (3.20 g, 89%) that was used in the next step without further purification or characterization.

The desired Meldrum’s acid was synthesized according to the general procedure, using
2-(3,4-dichlorophenyl)propanedioic acid (3.20 g, 12.8 mmol, 1.00 equiv). The crude solid was purified
by trituration in hexane/EtOAc = 7:3 to give B8 as a white solid (2.20 g, 59%).

Mp = 157-158 °C
IR (ATR): 2891, 1785, 1743, 1732, 1475, 1395, 1384, 1344, 1284, 1258, 1227, 1160, 1129, 1077, 1022,
980, 910, 773, 679, 639 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 8.3, 2.2 Hz,
1H), 4.71 (s, 1H), 1.90 (s, 3H), 1.81 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 163.9 (2C), 133.7, 133.5, 131.8, 131.2, 130.5, 128.9, 106.1, 52.1, 28.8,
27.4.
HRMS (ESI) m/z: calcd for C12H10Cl2O4Na [M+Na]+: 310.9848, found: 310.9851.

2,2-Dimethyl-5-(thiophen-3-yl)-1,3-dioxane-4,6-dione (B9)9

S O 8 S
O Acetone 3 7
4 5
Ac2O, H 2SO 4 O
HO 6
1 2
rt, 24 h Me O O
HO O 1'
Me
B9
C10H10 O4S
MW = 226.25 g/mol

To a suspension of 3-thiophenemalonic acid (1.00 g, 5.37 mmol, 1.00 equiv) in Ac2O (1.0 mL) was
added concentrated H2SO4 (22 µL, 0.4 mmol, 0.08 equiv) dropwise. The resulting suspension was
stirred for 30 min and then diluted with acetone (1.0 mL, 14 mmol, 2.5 equiv). The reaction was
quenched by adding cold H2O (20 mL), the precipitate was filtered and washed with cold H2O

9
Dandala, R.; Sarma, M. S. P.; Chaudhary, H.; Sivakumaran, M. An improved process for the preparation of penicillin
derivatives. Indian Pat. Appl. IN 2004CH01095, 2006.
(3 x 15 mL). The resulting solid was suspended in (iPr)2O (4 mL) and stirred for 30 min then filtered to
furnish B9 as an off-white (beige) solid (962 mg, 79%).

Mp = 129-130 °C
IR (ATR): 2893, 1781, 1739, 1392, 1387, 1341, 1268, 1216, 1210, 1075, 1022, 900, 840 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.40 (dd, J = 5.1, 3.0 Hz, 1H), 7.34 (m, 1H), 7.09 (dd, J = 5.0, 1.4 Hz, 1H),
4.91 (s, 1H), 1.84 (s, 3H), 1.67 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 164.5 (2C), 129.1, 127.3, 127.2, 125.0, 106.2, 48.2, 28.6, 27.7.
HRMS (ESI) m/z: calcd for C10H10O4SNa [M+Na]+: 249.0192, found: 249.0193.

4. Synthesis of allyl acetates (C1-6)

General acetylation procedure

Ac2O (1 equiv), Et 3N (1 equiv)

R DMAP (10 mol %) R
OH OAc
CH2Cl2, 0 ºC → rt, 2 h

To a flame-dried round bottom flask equipped with a magnetic stirring bar was added 2-substituted
allyl alcohol (88 mmol, 1.0 equiv) and Ac2O (8.3 mL, 88 mmol, 1.0 equiv). The flask was cooled to 0 °C
and DMAP (108 mg, 0.880 mmol, 0.010 equiv) was quickly added. A solution of Et3N (12.2 mL,
88.0 mmol, 1.00 equiv) in CH2Cl2 (7.0 mL) was prepared in a separate flame-dried flask, then added
dropwise to the first flask. The reaction mixture was allowed to stir while warming to rt. After 2 h, the
reaction mixture was poured into a flask containing an aqueous solution of HCl (2 M) and ice. The
layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The combined
organic extracts were washed with a saturated aqueous solution of NaHCO3 and then with a saturated
aqueous brine solution, dried over MgSO4, filtered and carefully concentrated under reduced
pressure to afford the 2-substituted allyl acetate.10

10
Xi, Z.; Hao, W.; Wang, P.; Cai, M. Molecules 2009, 14, 3528.
2-Methylallyl acetate (C1)

Ac2O 4
Me Me
DMAP, Et 3N 6
OH O 5 Me
CH2Cl2, 0 ºC → rt, 2 h 2
1 3
O
C1
C6H10 O2
MW = 114.14 g/mol

C1 was synthesized according to the aforementioned method from 2-methallyl alcohol (7.4 mL,
88 mmol, 1.0 equiv). The crude residue was purified by flash column chromatography on silica gel
(PE/Et2O = 95:5) to afford the 2-methylallyl acetate as a clear oil (9.74 g, 97%).10

Rf: 0.18 (PE/Et2O = 95:5)

IR (ATR): 2978, 2942, 1738, 1660, 1450, 1373, 1224, 1053, 1026, 957, 904 cm-1.
1
H NMR (400 MHz, CDCl3): δ 4.96 (m, 1H), 4.91 (m, 1H), 4.47 (s, 2H), 2.08 (s, 3H), 1.75 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 170.8, 140.0, 113.0, 67.8, 21.0, 19.6.
HRMS (ESI) m/z: calcd for C6H10O2Na [M+Na]+: 137.0573, found: 137.0573.

2-(Trimethylsilyl)allyl acetate (C2)

Me 4
Me 1. t-BuLi (1.2 equiv) Me Ac2O Me Me
Me Me Me Me Si
Si 2. CH2O Si DMAP, Et 3N 6
O 5 Me
Et 2O, −78 ºC → rt, 20 h OH 2
Br CH2Cl2, 0 ºC → rt, 2 h 1 3
O
C2
C8H16 O2Si
MW = 172.30 g/mol

To a solution of (1-bromovinyl)trimethylsilane (1.00 g, 5.58 mmol, 1.00 equiv) in Et2O (56 mL) at
−78 °C was added t-BuLi (3.95 mL, 1.7 M in pentane, 6.7 mmol, 1.2 equiv). The resulting mixture was
stirred at −78 °C for 3 h. Dry paraformaldehyde (168 mg, 1.86 mmol, 0.33 equiv) was then added, and
the mixture was allowed to warm slowly to rt. After 18 h, H2O was carefully added and the organic
layer was separated and the aqueous layer was extracted with Et2O. The combined organic layers
were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was engaged
in the acetylation step following the general procedure to afford the 2-(trimethylsilyl)allyl acetate C2,
without further purification, as a clear oil (903 mg, 94%).11

IR (ATR): 2930, 1780, 1741, 1372, 1240, 1232, 1147, 1031, 900, 839, 759 cm-1.
1
H NMR (400 MHz, CDCl3): δ 5.77 (dt, J = 2.8, 1.8 Hz, 1H), 5.46 (dt, J = 2.7, 1.4 Hz, 1H), 4.69 (tapp,
J = 1.6 Hz, 2H), 2.09 (s, 3H), 0.13 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 170.9, 146.6, 125.7, 68.2, 21.1, −1.51 (3C).
HRMS (ESI) m/z: calcd for C8H16O2SiNa[M+Na]+: 195.0812, found: 195.0813.

2-Phenylallyl acetate (C3)

7
6
CuI (15 mol %) Ac2O
5
OH PhMgBr (2.5 equiv) DMAP, Et 3N
4 9
Et 2O, rt → reflux, 24 h OH CH2Cl2, 0 ºC → rt, 2 h O 8 Me
2 3
1
O
C3
C11H12 O2
MW = 176.22 g/mol

To a solution of PhMgBr (50 mL, 1.0 M in THF, 50 mmol, 2.5 equiv) in Et2O (120 mL) was added CuI
(571 mg, 3.00 mmol, 0.150 equiv). The mixture was stirred at rt for 30 min, and then a solution of
propargyl alcohol (1.20 mL, 20.0 mmol, 1.00 equiv) in Et2O (20 mL) was added dropwise. The reaction
mixture was heated of reflux and, after 24 h, cooled to rt. Then a saturated aqueous solution of NH4Cl
was added slowly. The organic layer was separated and the aqueous layer was extracted with Et2O.
The combined organic layers were dried over MgSO4, filtered and concentrated under reduced
pressure.12 The resulting residue was engaged in the acetylation step following the general procedure.
The crude was purified by flash column chromatography on silica gel (PE/Et2O = 95:5) to afford the
2-phenylallyl acetate as a yellow oil (3.02 g, 86%).13

Rf: 0.35 (PE/Et2O = 9:1)

IR (ATR): 3058, 1736, 1634, 1575, 1496, 1444, 1373, 1222, 1035, 1027, 979, 907, 843 cm-1.
11
Amat, M.; Arioli, F.; Perez, M.; Molins, E.; Bosch, J. Org.Lett. 2013, 15, 2470.
12
Duan, Z. -C.; Hu, X. -P.; Zhang, C.; Wang, D. -Y.; Yu, S. -B.; Zheng, Z. J. Org. Chem. 2009, 74, 9191.
13
Ruan, J.; Li, X.; Saidi, O.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 2424.
1
H NMR (400 MHz, CDCl3): δ 7.47-7.40 (m, 2H), 7.39-7.28 (m, 3H), 5.56 (m, 1H), 5.37 (m, 1H), 4.99-
4.97 (m, 2H), 2.08 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 170.9, 142.6, 138.1, 128.6 (2C), 128.2, 126.1 (2C), 115.4, 65.9, 21.1.
HRMS (ESI) m/z: calcd for C11H12O2Na [M+Na]+: 199.0730, found: 199.0731.

2-Chloroallyl acetate (C4)

Ac2O
Cl Cl
DMAP, Et 3N 5
OH O 4 Me
CH2Cl2, 0 ºC → rt, 2 h 2
1 3
O
C4
C5H 7ClO2
MW = 134.56 g/mol

C4 was synthesized according to the general procedure from 2-chloroallyl alcohol (1.00 mL,
11.3 mmol, 1.00 equiv). The titled compound was obtained, without further purification, as a clear oil
(1.37 g, 90%).

IR (ATR): 2910, 1744, 1640, 1450, 1371, 1218, 1170, 1125, 1038, 895, 758, 665 cm-1.
1
H NMR (400 MHz, CDCl3): δ 5.47 (m, 1H), 5.41 (m, 1H), 4.65 (s, 2H), 2.13 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 170.2, 136.0, 115.1, 66.2, 20.9.
HRMS (ESI) m/z: calcd for C5H7ClO2Na [M+Na]+: 157.0027, 158.9997, found: 157.0835, 159.0652.

Methyl 2-(acetoxymethyl)acrylate (C5)

5
O OMe Ac2O O 4 OMe
DMAP, Et 3N 7
OH O 6 Me
CH2Cl2, 0 ºC → rt, 2 h 2
1 3
O
C5
C7H10 O4
MW = 158.15 g/mol

C5 was synthesized according to the general procedure from 2-(hydroxymethyl)acrylate (1.00 g,

8.61 mmol, 1.00 equiv). The titled compound was obtained, without further purification, as a clear oil
(912 mg, 67%).
IR (ATR): 2955, 1720, 1641, 1438, 1369, 1309, 1273, 1227, 1197, 1153, 1049, 990, 951, 913 cm-1.
1
H NMR (400 MHz, CDCl3): δ 6.36 (dd, J = 2.0, 1.1 Hz, 1H), 5.85 (dd, J = 2.7, 1.4 Hz, 1H), 4.80 (tapp,
J = 1.2 Hz, 2H), 3.79 (s, 3H), 2.10 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 170.5, 165.8, 135.4, 127.7, 62.6, 52.2, 21.0.
HRMS (ESI) m/z: calcd for C7H10O4Na [M+Na]+: 181.0471, found: 181.0470.

2-(Methoxy)allyl acetate (C6)

1. LiAlH 4 (2.4 equiv)

Br 4
MeONa (3 equiv) OMe Et 2O, 0 ºC, 10 min OMe
Br OMe 6
MeOH, 0 ºC → rt, 6 days OMe O 5 Me
2. Ac2O, DMAP, Et 3N 2
O CH2Cl2, 0 ºC → rt, 2 h 1 3
O O
C6
C6H10 O3
MW = 130.14 g/mol

NaOMe (15.3 g, 268 mmol, 3.0 equiv) was dissolved in MeOH (120 mL) at 0 °C. Then, methyl
2,3-dibromopropanoate (11.7 mL, 89.5 mmol, 1.00 equiv) was added dropwise and reaction mixture
was allowed to stir at rt. After 6 days, the reaction mixture was quenched by addition of dry-ice until
reaching pH 7. The resulting white suspension was diluted with CH2Cl2 (100 mL) and washed with H2O
(2 x 120 mL). The organic layer was dried over Na2SO4, filtered and carefully concentrated under
reduced pressure. The remaining product was purified by distillation under reduced pressure (30 bar,
50 °C) to give the ester (4.67 g, 45%) as a colorless liquid which was engaged in the next step without
further purification or characterization.14

The methyl 2-methoxy acrylate (1.00 g, 8.61 mmol, 1.00 equiv) was added dropwise to a solution of
LiAIH4 (785 mg, 20.7 mmol, 2.4 equiv) in Et2O (18 mL) at 0 °C over 10 min. The reaction mixture was
quenched carefully by dropwise addition of H2O (0.35 mL), followed by the addition of an aqueous
solution of NaOH (15%, 0.35 mL) and H2O (1.0 mL). The white precipitate was filtered and washed
with CH2Cl2. The organic phase was dried over Na2SO4 and filtered.15 This resulting solution was
cooled to 0 °C and then treated with Ac2O (0.80 mL, 8.6 mmol, 1.0 equiv), DMAP (11 mg, 0.86 mmol,

14
Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 11505.
15
Coates, R. M.; Rogers, B. D.; Hobbs, S. J.; Peck, D. R.; Curran, D. P. J. Am. Chem. Soc. 1987, 109, 1160.
0.010 equiv) and a solution of Et3N (1.3 mL, 8.6 mmol, 1.0 equiv) in CH2Cl2 (7.0 mL). The reaction
mixture was warmed up to rt. after 2 h, the reaction mixture was poured into a flask containing an
aqueous solution of HCl (2 M) and ice. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 x 10 mL). The combined organic extracts were washed with a saturated
aqueous solution of NaHCO3 and then with a saturated aqueous brine solution, dried over MgSO4,
filtered and carefully concentrated under reduced pressure. The crude residue was purified by flash
column chromatography on silica gel (PE/Et2O = 95:5) to afford the 2-methoxyallyl acetate C6 as a
clear oil (425 mg, 38%).

Rf: 0.32 (PE/Et2O = 95:5)

IR (ATR): 2943, 1738, 1669, 1638, 1452, 1373, 1304, 1221, 1080, 1032, 977, 947, 916, 825, 733,
605 cm-1.
1
H NMR (400 MHz, CDCl3): δ 4.50 (s, 2H), 4.21 (dapp, J = 2.5 Hz, 1H), 4.12 (d, J = 2.6 Hz, 1H), 3.59 (s,
3H), 2.10 (s, 3H).
13
C NMR (100 MHz, CDCl3): δ 170.7, 158.3, 84.7, 64.7, 55.3, 21.1.
HRMS (ESI) m/z: calcd for C6H10O3Na [M+Na]+: 153.0522, found: 153.0522.

5. Synthesis of 4-aryl isoxazolidin-5-ones (1a-i)

General procedure

O O
Boc OH R K 2CO 3 (2.5 equiv)
R
N
+ O O
Me THF, rt, 24 h N
SO2Ph O O
Me Boc
A B 1

To a mixture of N-hydroxy carbamate sulfone A (1.0 equiv), Meldrum’s acid B (1.1 equiv) and K2CO3
(2.5 equiv) was added THF (0.1 M) at rt. The reaction mixture was stirred for 24 h and filtrated. The
solid was washed with Et2O and the filtrate was concentrated under reduced pressure. The crude
product was purified by flash column chromatography on silica gel using Et2O/PE as eluent to afford
the desired isoxazolidin-5-one 1.16

tert-Butyl 5-oxo-4-phenylisoxazolidine-2-carboxylate (1a)16

O
10
O 6 5 7 9
8
N
3 4
1 2
O
Me O
Me Me
1a
C14H17NO4
MW = 263.29 g/mol

1a was synthesized according to the general procedure from tert-butyl ((phenylsulfonyl)methyl)-N-

hydroxycarbamate A1 (1.19 g, 4.13 mmol, 1.00 equiv) and 2,2-dimethyl-5-phenyl-1,3-dioxane-4,6-
dione B1 (1.00 g, 4.54 mmol, 1.10 equiv). 1a was obtained after flash column chromatography on
silica gel (PE/Et2O = 9:1) as a colorless viscous oil (755 mg, 70%).

Rf: 0.16 (PE/Et2O = 8:2)

IR (ATR): 2981, 1798, 1745, 1718, 1498, 1476, 1456, 1394, 1369, 1341, 1318, 1258, 1216, 1137, 975,
919 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.43-7.33 (m, 3H), 7.32-7.27 (m, 2H), 4.56 (m, 1H), 4.14-4.06 (m, 2H),
1.52 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 173.5, 156.1, 133.4, 129.4 (2C), 128.6, 128.0 (2C), 84.5, 55.8, 46.5, 28.2
(3C).
MS m/z (relative intensity): 264 ([M+H]+.,1), 248 (1), 204 (3), 163 (10), 135 (8), 118 (6), 104 (9), 91 (4),
77 (3), 57 (100).

16
Tite, T.; Sabbah, M.; Levacher, V.; Brière, J.-F. Chem. Commun. 2013, 49, 11569.
tert-Butyl 5-oxo-4-(p-tolyl)isoxazolidine-2-carboxylate (1b)

11
O Me
10
O 6 5 7 9
8
N
3 4
1 2
O
Me O
Me Me
1b
C15H19NO4
MW = 277.32 g/mol

1b was synthesized according to the general procedure from tert-butyl ((phenylsulfonyl)methyl)-N-

hydroxycarbamate A1 (279 mg, 0.970 mmol, 1.00 equiv) and 2,2-dimethyl-5-(4-methylphenyl)-1,3-
dioxane-4,6-dione B2 (250 mg, 1.07 mmol, 1.10 equiv). 1b was obtained after flash column
chromatography on silica gel (PE/Et2O = 9:1) as a colorless oil (169 mg, 63%).

Rf: 0.26 (PE/Et2O = 8:2)

IR (ATR): 2980, 2919, 1796, 1745, 1718, 1517, 1475, 1458, 1394, 1370, 1316, 1258, 1217, 1138, 975,
904 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.22-7.16 (m, 4H), 4.54 (dd, J = 12.3, 2.6 Hz, 1H), 4.10-4.02(m, 2H), 2.35
(s, 3H), 1.52 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 173.6, 156.1, 138.5, 130.4, 130.0 (2C), 127.9 (2C), 84.5, 55.8, 46.2, 28.2
(3C), 21.2.
HRMS (ESI) m/z: calcd for C15H19NO4Na [M+Na]+: 300.1206, found: 300.1208.

tert-Butyl 4-(4-methoxyphenyl)-5-oxoisoxazolidine-2-carboxylate (1c)

11
O OMe
10
O 6 5 7 9
8
N 4
3
1 2
O
Me O
Me Me
1c
C15H19NO5
MW = 293.32 g/mol
1c was synthesized according to the general procedure from tert-butyl ((phenylsulfonyl)methyl)-N-
hydroxycarbamate A1 (1.04 g, 3.63 mmol, 1.00 equiv) and 2,2-dimethyl-5-(4-methoxyphenyl)-1,3-
dioxane-4,6-dione B3 (1.00 g, 4.00 mmol, 1.10 equiv). 1c was obtained after flash column
chromatography on silica gel (PE/Et2O = 7:3) as a colorless oil (628 mg, 59%).

Rf: 0.51 (PE/Et2O = 1:1)

IR (ATR): 3050, 2910, 1796, 1730, 1719, 1613, 1515, 1450, 1369, 1250, 1138, 1100, 1031, 905 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.21 (m, 2H), 6.91 (m, 2H), 4.53 (m, 1H), 4.10-3.99 (m, 2H), 3.80 (s, 3H),
1.52 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 173.8, 159.7, 156.1, 129.2 (2C), 125.3, 114.8 (2C), 84.5, 55.9, 55.5, 45.8,
28.2 (3C).
HRMS (ESI) m/z: calcd for C15H19NO5Na [M+Na]+: 316.1155, found: 316.1156.

tert-Butyl 4-(4-fluorophenyl)-5-oxoisoxazolidine-2-carboxylate (1d)

O F
10
O 6 5 7 9
8
N 4
3
1 2
O
Me O
Me Me
1d
C14H16FNO4
MW = 281.28 g/mol

1d was synthesized according to the general procedure from tert-butyl ((phenylsulfonyl)methyl)-N-

hydroxycarbamate A1 (548 mg, 1.91 mmol, 1.00 equiv) and 2,2-dimethyl-5-(4-fluorphenyl)-1,3-
dioxane-4,6-dione B4 (500 mg, 2.10 mmol, 1.10 equiv). 1d was obtained after flash column
chromatography on silica gel (PE/Et2O = 8:2) as a colorless oil (398 mg, 74%).

Rf: 0.16 (PE/Et2O = 8:2)

IR (ATR): 2982, 1796, 1750, 1718, 1607, 1512, 1459, 1395, 1370, 1320, 1258, 1227, 1137, 1016, 977,
907 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.32-7.26 (m, 2H), 7.12-7.05 (m, 2H), 4.56 (dd, J = 10.4, 7.8 Hz, 1H),
4.14-4.00 (m, 2H), 1.52 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 173.2, 162.8 (d, 1JC-F = 249 Hz), 156.0, 129.8 (d, 3JC-F = 8.3 Hz, 2C), 129.1
(d, 4JC-F = 3.4 Hz), 116.4 (d, 2JC-F = 21.8 Hz, 2C), 84.7, 55.7, 45.8, 28.2 (3C).
HRMS (ESI) m/z: calcd for C14H16FNO4Na [M+Na]+: 304.0956, found: 304.0959.

tert-Butyl 5-oxo-4-(4-(trifluoromethyl)phenyl)isoxazolidine-2-carboxylate (1e)

11
O CF 3
10
O 6 5 7 9
8
N 4
3
1 2
O
Me O
Me Me
1e
C15H16F 3NO4
MW = 331.29 g/mol

1e was synthesized according to the general procedure from tert-butyl ((phenylsulfonyl)methyl)-N-

hydroxycarbamate A1 (287 mg, 0.552 mmol, 1.00 equiv) and 2,2-dimethyl-5-
(4-(trifluoromethyl)phenyl)-1,3-dioxane-4,6-dione B5 (175 mg, 0.607 mmol, 1.10 equiv). 1e was
obtained after flash column chromatography on silica gel (PE/Et2O = 9:1) as a colorless oil (141 mg,
75%).

Rf: 0.33 (PE/Et2O = 8:2)

IR (ATR): 2983, 1798, 1720, 1622, 1459, 1422, 1396, 1371, 1325, 1260, 1126, 1069, 1019, 909 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 4.61 (dd, J = 11.0, 8.3 Hz,
1H), 4.19 (tapp, J = 8.7 Hz, 1H), 4.09 (dd, J = 11.0, 9.1 Hz, 1H), 1.53 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 172.6, 155.9, 137.2, 131.1 (q, 2JC-F = 32.9 Hz), 128.6 (2C), 126.4 (q,
3
JC-F = 3.7 Hz, 2C), 123.9 (q, 1JC-F = 273 Hz), 84.9, 55.4, 46.2, 28.2 (3C).
HRMS (ESI) m/z: calcd for C15H16F3NO4Na [M+Na]+: 354.0924, found: 354.0926.
tert-Butyl 5-oxo-4-(4-chlorophenyl)isoxazolidine-2-carboxylate (1f)

O Cl
10
O 6 5 7 9
8
N 4
3
1 2
O
Me O
Me Me
1f
C14H16 ClNO4
MW = 297.74 g/mol

1f was synthesized according to the general procedure from tert-butyl ((phenylsulfonyl)methyl)-N-

hydroxycarbamate A1 (1.03 g, 3.57 mmol, 1.00 equiv) and 2,2-dimethyl-5-(4-chlorophenyl)-1,3-
dioxane-4,6-dione B6 (1.00 g, 3.93 mmol, 1.10 equiv). 1f was obtained after flash column
chromatography on silica gel (PE/Et2O = 8:2) as an off-white solid (736 mg, 69%).

Mp = 87-89 °C
Rf: 0.21 (PE/Et2O = 8:2)
IR (ATR): 2981, 1796, 1755, 1716, 1494, 1477, 1459, 1395, 1370, 1321, 1258, 1217, 1138, 1090, 1016,
977, 906 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.40-7.34 (m, 2H), 7.27-7.22 (m, 2H), 4.56 (dd, J = 10.3, 7.6 Hz, 1H),
4.14-3.99 (m, 2H), 1.52 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 173.0, 155.9, 134.8, 131.7, 129.6 (2C), 129.4 (2C), 84.7, 55.5, 45.9, 28.2
(3C).
HRMS (ESI) m/z: calcd for C14H16ClNO4Na [M+Na]+: 320.0660, found: 320.0663.

tert-Butyl 5-oxo-4-(4-bromophenyl)isoxazolidine-2-carboxylate (1g)

O Br
10
O 6 5 7 9
8
N
3 4
1 2
O
Me O
Me Me
1g
C14H16BrNO4
MW = 342.19 g/mol
1g was synthesized according to the general procedure from tert-butyl ((phenylsulfonyl)methyl)-N-
hydroxycarbamate A1 (500 mg, 1.74 mmol, 1.00 equiv) and 2,2-dimethyl-5-(4-bromophenyl)-1,3-
dioxane-4,6-dione B7 (573 mg, 1.91 mmol, 1.10 equiv). 1g was obtained after flash column
chromatography on silica gel (PE/Et2O = 8:2) as a white solid (386 mg, 65%).

Mp = 88-89 °C
Rf: 0.20 (PE/Et2O = 8:2)
IR (ATR): 2980, 1795, 1718, 1491, 1458, 1394, 1370, 1320, 1258, 1217, 1139, 1073, 1012, 998, 905
cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.55-7.50 (m, 2H), 7.21-7.16 (m, 2H), 4.57 (m, 1H), 4.11-3.99 (m, 2H),
1.52 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 172.9, 155.9, 132.5 (2C), 132.3, 129.7 (2C), 122.9, 84.7, 55.4, 45.9, 28.2
(3C).
HRMS (ESI) m/z: calcd for C14H16BrNO4Na [M+Na]+: 364.0155, found: 364.0157.

tert-Butyl 5-oxo-4-(3,4-dichlorophenyl)isoxazolidine-2-carboxylate (1h)

11
O 12
Cl
10
O 6 5 7
8 9 Cl
N 4
3
1 2
O
Me O
Me Me
1h
C14H15 Cl2NO4
MW = 332.18 g/mol

1h was synthesized according to the general procedure from tert-butyl ((phenylsulfonyl)methyl)-N-

hydroxycarbamate A1 (500 mg, 1.74 mmol, 1.00 equiv) and 2,2-dimethyl-5-(3,4-dichlorophenyl)-1,3-
dioxane-4,6-dione B8 (553 mg, 1.91 mmol, 1.10 equiv). 1h was obtained after flash column
chromatography on silica gel (PE/Et2O = 8:2) as a white solid (236 mg, 41%).

Mp = 113-114 °C
Rf: 0.15 (PE/Et2O = 8:2)
IR (ATR): 2981, 1797, 1745, 1719, 1475, 1395, 1370, 1319, 1258, 1136, 1033, 936 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.17 (dd, J = 8.4, 2.2 Hz,
1H), 4.56 (m, 1H), 4.11-4.00 (m, 2H), 1.53 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 172.4, 155.9, 133.6, 133.3, 133.2, 131.3, 130.1, 127.4, 85.0, 55.2, 45.5,
28.2 (3C).
HRMS (ESI) m/z: calcd for C14H15Cl2NO4Na [M+Na]+: 354.0270, found: 354.0273.

tert-Butyl 5-oxo-4-(thiophen-3-yl)isoxazolidine-2-carboxylate (1i)

O 10
S
O 6 9
5 7
8
N
3 4
1 2
O
Me O
Me Me
1i
C12H15NO4S
MW = 269.32 g/mol

1i was synthesized according to the general procedure from tert-butyl ((phenylsulfonyl)methyl)-N-

hydroxycarbamate A1 (693 mg, 2.41 mmol, 1.00 equiv) and 2,2-dimethyl-5-(thiophen-3-yl)-1,3-
dioxane-4,6-dione B9 (600 mg, 2.65 mmol, 1.10 equiv). 1i was obtained after flash column
chromatography on silica gel (PE/Et2O = 8:2) as a yellowish oil (515 mg, 79%).

Rf: 0.25 (PE/Et2O = 8:2)

IR (ATR): 2980, 1798, 1730, 1715, 1465, 1458, 1394, 1370, 1319, 1259, 1220, 1136, 985, 958 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.38 (dd, J = 5.0, 2.9 Hz, 1H), 7.30 (m, 1H), 7.08 (dd, J = 5.1, 1.4 Hz, 1H),
4.53 (dd, J = 10.3, 7.6 Hz, 1H), 4.22-4.08 (m, 2H), 1.50 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 173.0, 156.1, 132.7, 127.4, 126.6, 123.5, 84.6, 55.1, 41.9, 28.1 (3C).
HRMS (ESI) m/z: calcd for C12H15NO4SNa [M+Na]+: 292.0614, found: 292.0617.
6. Synthesis of α-quaternary isoxazolidin-5-ones (2a-o)

General procedure for asymmetric allylic alkylation

Pd 2(dba) 3 (5 mol %)
O (R,R)-L1 (10 mol %) O O O
R
R1 Na 2CO 3 (2 equiv) R1 Ph 2P NH HN PPh 2
R
O + OAc O
N THF, 0 ºC N
Boc Boc
1 C 2 (R,R)-L1

To a solution of Pd2(dba)3 (0.01 mmol, 0.05 equiv) in THF (2.0 mL) at rt was added (R,R)-DACH phenyl
Trost ligand (0.02 mmol, 0.10 equiv). After 30 min, this solution was cooled to 0 °C and transferred via
cannula to a flask containing 4-substituted isoxazolidin-5-one (0.2 mmol, 1 equiv) and Na2CO3 (0.4
mmol, 2 equiv), followed by the addition of allyl acetate (0.2 mmol, 1 equiv). Stirring was continued at
0 °C until complete consumption of the starting material (confirmed by TLC). The reaction mixture
was filtered through a plug of Celite® and concentrated under reduced pressure to afford a crude
residue, which was purified by flash column chromatography on silica gel to afford the corresponding
allylated isoxalidin-5-one.

General procedure for the synthesis of the racemic compounds

To a flask containing 4-substituted isoxazolidin-5-one (0.2 mmol, 1 equiv) and Na2CO3 (0.4 mmol,
2 equiv) in THF (2 mL) at rt was added Pd(PPh3)4 (0.01 mmol, 0.05 equiv). Followed by the addition of
allyl acetate (0.2 mmol, 1 equiv) and stirring was continued at rt until complete consumption of the
starting material (confirmed by TLC). The reaction mixture was filtered through a plug of Celite® and
concentrated under reduced pressure to afford a crude residue, which was purified following the
same procedure described for the corresponding enantioenriched compound.
tert-Butyl (S)-4-allyl-5-oxo-4-phenylisoxazolidine-2-carboxylate (2a)

10

O 9

7 8
O 65 12
N 4 11 13
3
1 2
O
Me O
Me Me
2a
C17H 21NO4
MW = 303.36 g/mol

2a was synthesized according to the general procedure from tert-butyl 5-oxo-4-phenylisoxazolidine-2-

carboxylate 1a (55 mg, 0.21 mmol, 1.0 equiv) and allyl acetate (23 µL, 0.21 mmol, 1.0 equiv). 2a was
obtained after flash column chromatography on silica gel (PE/Et2O = 95:5) as a white solid (60 mg,
95%).

Mp = 94-95 °C
Rf: 0.49 (PE/Et2O = 8:2)
[α]20 D = +118 (c 0.50, CHCl3)
ee = 91% (determined by SFC)
SFC: AD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 98:2, Flow rate = 3 mL/min, detection
wavelength = 220 nm. tR = 4.98 min (major) and tR = 5.62 min (minor).
IR (ATR): 2981, 2933, 1796, 1747, 1721, 1497, 1450, 1394, 1370, 1342, 1258, 1145, 1112, 1080, 1033,
994, 929 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.47-7.29 (m, 5H), 5.61 (m, 1H), 5.19-5.09 (m, 2H), 4.61 (d, J = 11.8 Hz,
1H), 4.16 (d, J = 11.7 Hz, 1H), 2.71 (m, 1H), 2.69 (m, 1H), 1.33 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 175.7, 156.1, 136.5, 131.5, 129.1 (2C), 128.4, 126.6 (2C), 120.8, 84.1,
57.6, 52.2, 41.9, 27.9 (3C).
HRMS (ESI) m/z: calcd for C17H21NO4Na [M+Na]+: 326.1363, found: 326.1362.
tert-Butyl (S)-4-allyl-5-oxo-4-(p-tolyl)isoxazolidine-2-carboxylate (2b)

11
Me
10
O 9

7 8
O 65 13
N 12 14
3 4
1 2
O
Me O
Me Me
2b
C18H 23NO4
MW = 317.39 g/mol

2b was synthesized according to the general procedure from tert-butyl 5-oxo-4-(p-tolyl)isoxazolidine-

2-carboxylate 1b (50 mg, 0.18 mmol, 1.0 equiv) and allyl acetate (20 µL, 0.19 mmol, 1.0 equiv). 2b was
obtained after flash column chromatography on silica gel (PE/Et2O = 9:1) as a colorless oil (52 mg,
91%).

Rf: 0.45 (PE/Et2O = 8:2)

[α]20 D = +65.2 (c 0.65, CHCl3)
ee = 90% (determined by SFC)
SFC: AD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 98:2, Flow rate = 3 mL/min, detection
wavelength = 220 nm. tR = 4.93 min (major) and tR = 5.86 min (minor).
IR (ATR): 2980, 2918, 2850, 1795, 1746, 1719, 1515, 1458, 1370, 1343, 1327, 1257, 1144, 1079, 1035,
995, 928 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.33-7.28 (m, 2H), 7.21-7.15 (m, 2H), 5.61 (m, 1H), 5.18-5.08 (m, 2H),
4.57 (d, J = 11.7 Hz, 1H), 4.14 (d, J = 11.7 Hz, 1H), 2.69 (m, 1H), 2.67 (m, 1H), 2.33 (s, 3H), 1.34 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 175.5, 156.1, 138.2, 133.4, 131.6, 129.7 (2C), 126.5 (2C), 120.6, 84.0,
57.7, 51.9, 41.8, 27.9 (3C), 21.0.
HRMS (ESI) m/z: calcd for C18H23NO4Na [M+Na]+: 340.1519, found: 340.1520.

tert-Butyl (S)-4-allyl-4-(4-methoxyphenyl)-5-oxoisoxazolidine-2-carboxylate (2c)

11
OMe
10
O 9

7 8
O 65 13
N 4 12 14
3
1 2
O
Me O
Me Me
2c
C18H 23NO5
MW = 333.38 g/mol

2c was synthesized according to the general procedure from tert-butyl 4-(4-methoxyphenyl)-5-

oxoisoxazolidine-2-carboxylate 1c (50 mg, 0.17 mmol, 1.0 equiv) and allyl acetate (18 µL, 0.17 mmol,
1.0 equiv). 2c was obtained after flash column chromatography on silica gel (PE/Et2O = 8:2) as a
colorless oil (49 mg, 86%).

Rf: 0.26 (PE/Et2O = 8:2)

[α]20 D = +35.5 (c 0.22, CHCl3)
ee = 87% (determined by SFC)
SFC: AD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 95:5, Flow rate = 5 mL/min, detection
wavelength = 220 nm. tR = 1.96 min (major) and tR = 2.95 min (minor).
IR (ATR): 2980, 1794, 1745, 1719, 1610, 1581, 1515, 1459, 1370, 1300, 1253, 1187, 1142, 1031, 994,
928 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.37-7.31 (m, 2H), 6.92-6.86 (m, 2H), 5.60 (ddt, J = 16.6, 10.4, 7.3 Hz, 1H),
5.20-5.08 (m, 2H), 4.56 (d, J = 11.8 Hz, 1H), 4.12 (d, J = 11.7 Hz, 1H), 3.79 (s, 3H), 2.73-2.59 (m, 2H),
1.35 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 175.6, 159.6, 156.1, 131.6, 128.2, 127.8 (2C), 120.6, 114.4 (2C), 84.0,
57.6, 55.5, 51.6, 41.9, 27.9 (3C).
HRMS (ESI) m/z: calcd for C18H23NO5Na [M+Na]+: 356.1468, found: 356.1470.

tert-Butyl (S)-4-allyl-4-(4-fluorophenyl)-5-oxoisoxazolidine-2-carboxylate (2d)

F
10
O 9

7 8
O 65 12
N 11 13
3 4
1 2
O
Me O
Me Me
2d
C17H 20FNO4
MW = 321.35 g/mol
2d was synthesized according to the general procedure from tert-butyl 4-(4-fluorophenyl)-5-
oxoisoxazolidine-2-carboxylate 1d (50 mg, 0.18 mmol, 1.0 equiv) and allyl acetate (20 µL, 0.19 mmol,
1.0 equiv). 2d was obtained after flash column chromatography on silica gel (PE/Et2O = 8:2) as a
colorless oil (56 mg, 97%).

Rf: 0.41 (PE/Et2O = 8:2)

[α]20 D = +41.5 (c 0.20, CHCl3)
ee = 92% (determined by SFC)
SFC: AD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 96:4, Flow rate = 4 mL/min, detection
wavelength = 220 nm. tR = 1.98 min (minor) and tR = 2.30 min (major).
IR (ATR): 2981, 1794, 1730, 1719, 1606, 1511, 1459, 1370, 1323, 1236, 1167, 1143, 1105, 1035, 995,
929 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.42 (ddapp, J = 5.1, 3.7 Hz, 2H), 7.07 (tapp, J = 8.7 Hz, 2H), 5.57 (m, 1H),
5.19-5.09 (m, 2H), 4.56 (d, J = 11.8 Hz, 1H), 4.17 (d, J = 11.8 Hz, 1H), 2.68 (m, 1H), 2.66 (m, 1H), 1.36 (s,
9H).
13
C NMR (100 MHz, CDCl3): δ 175.2, 162.6 (d, 1JC-F = 248 Hz), 156.1, 132.1 (d, 4JC-F = 3.5 Hz), 131.1,
128.5 (d, 3JC-F = 8.1 Hz, 2C), 121.0, 116.0 (d, 2JC-F = 21.6 Hz, 2C), 84.3, 57.5, 51.7, 42.0, 28.0 (3C).
HRMS (ESI) m/z: calcd for C17H20FNO4Na [M+Na]+: 344.1269, found: 344.1268.
tert-Butyl (S)-4-allyl-5-oxo-4-(4-(trifluoromethyl)phenyl)isoxazolidine-2-carboxylate (2e)

11
CF 3
10
O 9

7 8
O 65 13
N 12 14
3 4
1 2
O
Me O
Me Me
2e
C18H 20F 3NO4
MW = 371.36 g/mol

2e was synthesized according to the general procedure from tert-butyl 4-(4-(trifluoromethyl)phenyl)-

5-oxoisoxazolidine-2-carboxylate 1e (50 mg, 0.15 mmol, 1.0 equiv) and allyl acetate (16 µL,
0.15 mmol, 1.0 equiv). 2e was obtained after flash column chromatography on silica gel
(PE/Et2O = 8:2) as a colorless oil (53 mg, 95%).

Rf: 0.48 (PE/Et2O = 8:2)

[α]20 D = +57.0 (c 0.68, CHCl3)
ee = 86% (determined by SFC)
SFC: OD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 98:2, Flow rate = 3 mL/min, detection
wavelength = 220 nm. tR = 3.28 min (minor) and tR = 3.52 min (major).
IR (ATR): 2918, 2850, 1798, 1730, 1722, 1459, 1414, 1371, 1328, 1168, 1146, 1129, 1073, 1017, 995,
931 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 5.57 (m, 1H), 5.23-5.10
(m, 2H), 4.58 (d, J = 11.8 Hz, 1H), 4.22 (d, J = 11.8 Hz, 1H), 2.72 (m, 1H), 2.70 (m, 1H), 1.35 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 174.7, 156.0, 140.5, 130.8 (dapp, 2JC-F = 32.5 Hz), 130.7, 127.2 (2C), 126.0
(q, 3JC-F = 3.7 Hz, 2C), 123.9 (q, 1JC-F = 273 Hz), 121.4, 84.5, 57.3, 52.3, 41.8, 27.9 (3C).
HRMS (ESI) m/z: calcd for C18H20F3NO4Na [M+Na]+: 394.1237, found: 394.1238.
tert-Butyl (S)-4-allyl-4-(4-chlorophenyl)-5-oxoisoxazolidine-2-carboxylate (2f)

Cl
10
O 9

7 8
O 65 12
N 11 13
3 4
1 2
O
Me O
Me Me
2f
C17H 20ClNO4
MW = 337.80 g/mol

2f was synthesized according to the general procedure from tert-butyl 4-(4-chlorophenyl)-5-

oxoisoxazolidine-2-carboxylate 1f (50 mg, 0.17 mmol, 1.0 equiv) and allyl acetate (18 µL, 0.17 mmol,
1.0 equiv). 2f was obtained after flash column chromatography on silica gel (PE/Et2O = 8:2) as a white
solid (52 mg, 92%).

Mp = 58-60 °C
Rf: 0.42 (PE/Et2O = 8:2)
[α]20 D = +88.9 (c 1.40, CHCl3)
ee = 90% (determined by SFC)
SFC: AD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 96:4, Flow rate = 4 mL/min, detection
wavelength = 220 nm. tR = 3.13 min (minor) and tR = 3.34 min (major).
IR (ATR): 2981, 1794, 1746, 1720, 1496, 1458, 1395, 1370, 1324, 1258, 1144, 1096, 1034, 1014, 994,
929 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.40-7.33 (m, 4H), 5.57 (m, 1H), 5.21-5.08 (m, 2H), 4.54 (d, J = 11.8 Hz,
1H), 4.17 (d, J = 11.8 Hz, 1H), 2.68 (m, 1H), 2.66 (m, 1H), 1.37 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 174.9, 156.0, 134.9, 134.6, 131.0, 129.2 (2C), 128.1 (2C), 121.2, 84.4,
57.3, 51.8, 41.8, 27.9 (3C).
HRMS (ESI) m/z: calcd for C17H20ClNO4Na [M+Na]+: 360.0973, found: 360.0975.

tert-Butyl (S)-4-allyl-4-(4-bromophenyl)-5-oxoisoxazolidine-2-carboxylate (2g)

Br
10
O 9

7 8
O 65 12
N 11 13
3 4
1 2
O
Me O
Me Me
2g
C17H 20BrNO4
MW = 382.25 g/mol

2g was synthesized according to the general procedure from tert-butyl 4-(4-bromophenyl)-5-

oxoisoxazolidine-2-carboxylate 1g (50 mg, 0.15 mmol, 1.0 equiv) and allyl acetate (16 µL, 0.15 mmol,
1.0 equiv). 2g was obtained after flash column chromatography on silica gel (PE/Et2O = 8:2) as a clear
solid (51 mg, 91%).

Rf: 0.42 (PE/Et2O = 8:2)

[α]20 D = +24.7 (c 1.84, CHCl3)
ee = 89% (determined by SFC)
SFC: OJ-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 96:4, Flow rate = 4 mL/min, detection
wavelength = 220 nm. tR = 2.20 min (major) and tR = 3.44 min (minor).
IR (ATR): 2981, 1795, 1746, 1720, 1493, 1458, 1397, 1370, 1324, 1257, 1145, 1079, 1010, 929 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.54-7.48 (m, 2H), 7.35-7.28 (m, 2H), 5.57 (m, 1H), 5.21-5.08 (m, 2H),
4.53 (d, J = 11.8 Hz, 1H), 4.16 (d, J = 11.8 Hz, 1H), 2.68 (m, 1H), 2.66 (m, 1H), 1.37 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 174.9, 156.0, 135.5, 132.2 (2C), 131.0, 128.4 (2C), 122.7, 121.2, 84.4,
57.3, 51.9, 41.8, 28.0 (3C).
HRMS (ESI) m/z: calcd for C17H20BrNO4Na [M+Na]+: 404.0468, found: 404.0468.

tert-Butyl (S)-4-allyl-4-(3,4-dichlorophenyl)-5-oxoisoxazolidine-2-carboxylate (2h)

Cl
11
10
12
O Cl
9
7 8
O 65 14
N 13 15
3 4
1 2
O
Me O
Me Me
2h
C17H19 Cl2NO4
MW = 372.24 g/mol
2h was synthesized according to the general procedure from tert-butyl 4-(4-chlorophenyl)-5-
oxoisoxazolidine-2-carboxylate 1h (50 mg, 0.15 mmol, 1.0 equiv) and allyl acetate (16 µL, 0.15 mmol,
1.0 equiv). 2h was obtained after flash column chromatography on silica gel (PE/Et2O = 8:2) as a white
solid (52 mg, 93%).

Mp = 114-115 °C
Rf: 0.28 (PE/Et2O = 8:2)
[α]20 D = +22.5 (c 0.08, CHCl3)
ee = 85% (determined by SFC)
SFC: OJ-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 96:4, Flow rate = 4 mL/min, detection
wavelength = 220 nm. tR = 2.41 min (major) and tR = 4.09 min (minor).
IR (ATR): 2981, 1796, 1735, 1722, 1476, 1371, 1340, 1259, 1144, 1031, 995, 930 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.4 Hz,
1H), 5.56 (m, 1H), 5.22-5.10 (m, 2H), 4.50 (d, J = 11.9 Hz, 1H), 4.18 (d, J = 11.9 Hz, 1H), 2.68 (m, 1H),
2.66 (m, 1H), 1.40 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 174.4, 155.9, 136.6, 133.4, 132.9, 131.0, 130.6, 128.8, 126.2, 121.5, 84.6,
57.1, 51.7, 41.7, 28.0 (3C).
HRMS (ESI) m/z: calcd for C17H19Cl2NO4Na [M+Na]+: 394.0583, found: 394.0586.
tert-Butyl (S)-4-allyl-5-oxo-4-(thiophen-3-yl)isoxazolidine-2-carboxylate (2i)

S
10 9
O
7 8
O 65 12
N 11 13
3 4
1 2
O
Me O
Me Me
2i
C15H19NO4S
MW = 309.38 g/mol

2i was synthesized according to the general procedure from tert-butyl 5-oxo-4-(thiophen-3-

yl)isoxazolidine-2-carboxylate 1i (50 mg, 0.19 mmol, 1.0 equiv) and allyl acetate (20 µL, 0.19 mmol,
1.0 equiv). 2i was obtained after flash column chromatography on silica gel (PE/Et2O = 9:1) as an off-
white solid (57 mg, 97%).

Mp = 75-77 °C
Rf: 0.47 (PE/Et2O = 8:2)
[α]20 D = +86.9 (c 1.76, CHCl3)
ee = 89% (determined by SFC)
SFC: OD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 98:2, Flow rate = 3 mL/min, detection
wavelength = 220 nm. tR = 5.62 min (major) and tR = 6.36 min (minor).
IR (ATR): 2918, 2850, 1795, 1718, 1458, 1394, 1370, 1345, 1322, 1226, 1142, 1080, 995, 925 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.36 (dd, J = 5.1, 3.0 Hz, 1H), 7.28 (dd, J = 3.0, 1.5 Hz, 1H), 7.13 (dd,
J = 5.1, 1.5 Hz, 1H), 5.61 (ddt, J = 16.7, 10.5, 7.3 Hz, 1H), 5.20-5.10 (m, 2H), 4.53 (d, J = 11.7 Hz, 1H),
4.14 (d, J = 11.7 Hz, 1H), 2.79 (ddt, J = 7.2, 7.0, 1.0 Hz, 1H), 2.64 (ddt, J = 7.3, 6.8, 1.1 Hz, 1H), 1.39 (s,
9H).
13
C NMR (100 MHz, CDCl3): δ 175.1, 156.2, 136.9, 131.3, 127.2, 126.0, 122.9, 120.7, 84.2, 57.7, 49.8,
41.4, 28.0 (3C).
HRMS (ESI) m/z: calcd for C15H19NO4SNa [M+Na]+: 332.0927, found: 332.0930.
tert-Butyl (S)-4-(2-methylallyl)-5-oxo-4-phenylisoxazolidine-2-carboxylate (2j)

9 10
8
O
7
13
O 65 12
14
N
3 4 11 Me
1 2
O
Me O
Me Me
2j
C18H 23NO4
MW = 317.39 g/mol

2j was synthesized according to the general procedure from tert-butyl 5-oxo-4-phenylisoxazolidine-2-

carboxylate 1a (50 mg, 0.19 mmol, 1.0 equiv) and 2-methylallyl acetate C1 (190 µL, 1.0 M in THF,
0.19 mmol, 1.0 equiv). 2j was obtained after flash column chromatography on silica gel
(PE/Et2O = 9:1) as a white solid (53 mg, 88%).

Mp = 91-92 °C
Rf: 0.24 (PE/Et2O = 9:1)
[α]20 D = +110 (c 0.29, CHCl3)
ee = 95% (determined by SFC)
SFC: OD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 98:2, Flow rate = 3 mL/min, detection
wavelength = 220 nm. tR = 5.04 min (major) and tR = 5.46 min (minor).
IR (ATR): 2980, 2934, 1795, 1748, 1719, 1645, 1498, 1449, 1370, 1341, 1255, 1230, 1142, 1082, 1050,
989, 967, 904 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.50-7.44 (m, 2H), 7.40-7.28 (m, 3H), 4.89 (quint, J = 1.5 Hz, 1H), 4.73 (d,
J = 11.8 Hz, 1H), 4.71 (m, 1H), 4.19 (d, J = 11.9 Hz, 1H), 2.74 (dapp, J = 14.1 Hz, 1H), 2.69 (dapp,
J = 14.1 Hz, 1H), 1.49 (br sapp, 3H), 1.33 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 175.7, 156.1, 140.1, 136.3, 129.0 (2C), 128.4, 126.7 (2C), 116.9, 84.1,
57.1, 52.1, 45.6, 27.9 (3C), 23.8.
HRMS (ESI) m/z: calcd for C18H23NO4Na [M+Na]+: 340.1519, found: 340.1518.

tert-Butyl (S)-5-oxo-4-phenyl-4-(2-(trimethylsilyl)allyl)isoxazolidine-2-carboxylate (2k)

9 10
8
O
7
13
O 65 12 14
3
N 4 11 Si Me
1 O
Me
2 Me Me
O
Me Me
2k
C20H 29NO4Si
MW = 375.54 g/mol

2k was synthesized according to the general procedure from tert-butyl 5-oxo-4-phenylisoxazolidine-2-

carboxylate 1a (50 mg, 0.19 mmol, 1.0 equiv) and 2-(trimethylsilyl)allyl acetate C2 (190 µL, 1.0 M in
THF, 0.19 mmol, 1.0 equiv). 2k was obtained after flash column chromatography on silica gel
(PE/Et2O = 95:5) as a white solid (54 mg, 76%).

Mp = 40-42 °C
Rf: 0.41 (PE/Et2O = 9:1)
[α]20 D = +73.6 (c 1.12, CHCl3)
ee = 93% (determined by SFC)
SFC: OD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 98:2, Flow rate = 3 mL/min, detection
wavelength = 220 nm. tR = 3.88 min (major) and tR = 4.31 min (minor).
IR (ATR): 2955, 1794, 1751, 1719, 1449, 1394, 1370, 1342, 1248, 1142, 1034, 990, 943 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.48-7.40 (m, 2H), 7.40-7.25 (m, 3H), 5.54 (d, J = 13.2 Hz, 2H), 4.73 (d,
J = 11.8 Hz, 1H), 4.16 (d, J = 11.8 Hz, 1H), 2.84 (s, 2H), 1.32 (s, 9H), −0.01 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 175.8, 156.1, 146.4, 136.6, 130.2, 129.1 (2C), 128.4, 126.8 (2C), 84.0,
57.4, 53.0, 41.3, 27.9 (3C), −1.52 (3C).
HRMS (ESI) m/z: calcd for C20H29NO4SiNa [M+Na]+: 398.1758, found: 398.1759.

tert-Butyl (S)-4-(2-(trimethylsilyl)methyl)-5-oxo-4-phenylisoxazolidine-2-carboxylate (2l)

9 10

8
O
7
13
O 65 12
N 11 CH2TMS
3 4 14
1 O
2
Me O
Me Me
2l
C18H23NO4
MW = 317.39 g/mol
2l was synthesized according to the general procedure from tert-butyl 5-oxo-4-phenylisoxazolidine-2-
carboxylate 1a (70 mg, 0.27 mmol, 1.0 equiv) and 2-[(trimethylsilyl)methyl]allyl acetate (57 µL,
0.27 mmol, 1.0 equiv). Interestingly, after flash column chromatography on silica gel (PE/Et2O = 9:1),
compound 2j was isolated (81 mg, 94%) instead of the expected compound 2l.

Mp = 91-92 °C
Rf: 0.24 (PE/Et2O = 9:1)
[α]20 D = +109 (c 0.25, CHCl3)
ee = 90% (determined by SFC)
SFC: OD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 98:2, Flow rate = 3 mL/min, detection
wavelength = 220 nm. tR = 5.28 min (major) and tR = 5.80 min (minor).
Note: for full characterization see compound 2j.

tert-Butyl (S)-5-oxo-4-phenyl-4-(2-phenylallyl)isoxazolidine-2-carboxylate (2m)

9 10
8
O
7
13
O 65 12
N 4 11 14
3
1 2
O
Me O
15
16 17
Me Me
2m
C23H 25NO4
MW = 379.46 g/mol
2m was synthesized according to the method aforementioned from tert-butyl 5-oxo-4-
phenylisoxazolidine-2-carboxylate 1a (50 mg, 0.19 mmol, 1.0 equiv) and 2-phenylallyl acetate C3
(190 µL, 1.0 M in THF, 0.19 mmol, 1.0 equiv). 2m was obtained after flash column chromatography on
silica gel (PE/Et2O = 9:1) as a colorless oil (51 mg, 71%).

Rf: 0.38 (PE/Et2O = 9:1)

[α]20 D = +81.6 (c 0.17, CHCl3)
ee = 95% (determined by SFC)
SFC: OD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 95:5, Flow rate = 5 mL/min, detection
wavelength = 220 nm. tR = 3.31 min (major) and tR = 3.76 min (minor).
IR (ATR): 2980, 1794, 1748, 1718, 1625, 1494, 1448, 1394, 1370, 1344, 1311, 1257, 1232, 1142, 1108,
1079, 1030, 990, 908 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.39-7.20 (m, 10H), 5.25 (m, 1H), 4.94 (m, 1H), 4.43 (d, J = 12.2 Hz, 1H),
3.87 (d, J = 12.2 Hz, 1H), 3.22 (d, J = 14.2 Hz, 1H), 3.17 (d, J = 14.3 Hz, 1H), 1.22 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 175.7, 156.0, 143.0, 141.0, 135.4, 128.8 (2C), 128.7 (2C), 128.4, 128.0,
126.9 (2C), 126.5 (2C), 119.1, 83.9, 57.1, 53.1, 43.0, 27.8 (3C).
HRMS (ESI) m/z: calcd for C23H25NO4Na [M+Na]+: 402.1676, found: 402.1678.
tert-Butyl (S)-4-(2-chloroallyl)-5-oxo-4-phenylisoxazolidine-2-carboxylate (2n)

9 10
8
O
7
13
O 65 12
N
3 4 11 Cl
1 2
O
Me O
Me Me
2n
C17H 20ClNO4
MW = 337.80 g/mol

2n was synthesized according to the general procedure from tert-butyl 5-oxo-4-phenylisoxazolidine-2-

carboxylate 1a (50 mg, 0.19 mmol, 1.0 equiv) and 2-chloroallyl acetate C4 (18 µL, 0.19 mmol,
1.0 equiv). 2n was obtained after flash column chromatography on silica gel (PE/Et2O = 9:1) as a
colorless oil (14 mg, 22%).

Rf: 0.19 (PE/Et2O = 9:1)

[α]20 D = +10.7 (c 0.15, CHCl3)
ee = 74% (determined by SFC)
SFC: AD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 98:2, Flow rate = 3 mL/min, detection
wavelength = 220 nm. tR = 5.39 min (minor) and tR = 8.41 min (major).
IR (ATR): 2919, 2850, 1795, 1749, 1720, 1634, 1458, 1394, 1371, 1346,1313, 1239, 1145, 1082, 1034,
993, 900 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.48-7.41 (m, 2H), 7.40-7.29 (m, 3H), 5.19 (d, J = 1.6 Hz, 1H), 5.05 (d,
J = 12.4 Hz, 1H), 4.97 (tapp, J = 1.3 Hz, 1H), 4.26 (d, J = 12.4 Hz, 1H), 3.05 (d, J = 14.7 Hz, 1H), 2.96 (dd,
J = 14.7, 1.1 Hz, 1H), 1.26 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 175.2, 155.9, 135.7, 134.3, 129.0 (2C), 128.6, 126.7 (2C), 118.4, 84.0,
57.7, 52.3, 46.8, 27.7 (3C).
HRMS (ESI) m/z: calcd for C17H20ClNO4Na [M+Na]+: 360.0973, found: 360.0974.
tert-Butyl (S)-4-(2-(methoxycarbonyl)allyl)-5-oxo-4-phenylisoxazolidine-2-carboxylate (2o)

9 10
O 8
10 O
7
O 6 5 7 9
13
N 4 8 O 65 12
3 N O
1 O 4 11 14
Me
2
O + 1
Me
2
O
3

O
O 15
Me Me Me
Me Me
1a
2o
C14H17NO4
MW = 263.29 g/mol C19H 23NO6
MW = 361.39 g/mol

2o was synthesized according to the method aforementioned from tert-butyl 5-oxo-4-

phenylisoxazolidine-2-carboxylate 1a (50 mg, 0.19 mmol, 1.0 equiv) and methyl
2-(acetoxymethyl)acrylate C5 (190 µL, 1.0 M in THF, 0.19 mmol, 1.0 equiv). 2o was obtained after
flash column chromatography on silica gel (PE/Et2O = 9:1) in an inseparable mixture of 1a/2o in a ratio
of 65:35 as a colorless viscous oil (48 mg, 23%).

Rf: 0.16 (PE/Et2O = 8:2)

ee = 20% (determined by SFC)
SFC: AD-H column, Pressure = 100 bar, eluent = sc CO2/MeOH = 95:5, Flow rate = 5 mL/min, detection
wavelength = 220 nm. tR = 1.65 min (minor) and tR = 1.85 min (major).
IR (ATR): 2970, 2919, 2850, 1797, 1737, 1724, 1456, 1371, 1229, 1217, 1144, 909 cm-1.
Note: the mixture of 1a/2o = 65:35. The spectrum of 2o is only described.
1
H NMR (400 MHz, CDCl3): δ 7.44-7.27 (m, 5H), 6.24 (d, J = 1.1 Hz, 1H), 5.52 (qapp, J = 1.0 Hz, 1H), 4.70
(d, J = 12.2 Hz, 1H), 4.10 (d, J = 12.3 Hz, 1H), 3.69 (s, 3H), 3.09 (dapp, J = 14.1 Hz, 1H), 2.90 (dd, J = 14.0,
0.9 Hz, 1H), 1.26 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 175.4, 167. 5, 136.0, 134.6, 131.1, 129.1 (2C), 128.6, 126.9 (2C), 84.0,
57.9, 53.5, 52.3, 38.9, 27.8 (3C).
Note: one quaternary carbon was not observed.
HRMS (ESI) m/z: calcd for C19H23NO6Na [M+Na]+: 384.1418, found: 384.1417.
7. Post-functionalization

1. TMSCHN2
O 2. TFA
Na/Naphthalene 3. Et 3N, TMSCl O
O H
THF, −78 ºC N 4. t-BuMgCl
N HO 2C Boc N
5. Boc 2O, DMAP, Et 3N Boc
Boc
2a 3 4

7.1. Synthesis of β2,2-amino acid

(S)-2-[(tert-Butoxycarbonyl)amino)methyl]-2-phenylpent-4-enoic acid (3)

10 9 13
8 12
7 11
H 1
HO 6 5 N 3 O 2 Me
4
O O Me
Me
3
C17H 23NO4
MW = 305.37 g/mol

To a solution of recrystallized naphthalene (960 mg, 7.50 mmol, 1.00 equiv) in THF (15.0 mL) at rt was
added finely chopped Na (190 mg, 8.25 mmol, 1.10 equiv) and the mixture was stirred for 2 h, to
provide the dark green solution of sodium naphthalenide (0.5 M). To a second flask, containing a
solution of tert-butyl (S)-4-allyl-5-oxo-4-phenylisoxazolidine-2-carboxylate 2a (100 mg, 0.33 mmol,
1.0 equiv) in THF (11.0 mL) at −78 °C, was added dropwise, via syringe, the freshly prepared sodium
naphthalenide solution until the dark green color remained. The reaction was quenched, at −78 °C, by
the addition of H2O (10 mL) and the reaction mixture was warmed to rt. The pH was adjusted to 2
with an aqueous solution of HCl (1 M). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude residue was purified by flash column
chromatography on silica gel (CH2Cl2/MeOH = from 95:5 to 90:10) to afford amino acid 3 as a clear oil
(91 mg, 90%).17

17
Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40, 6181.
Rf: 0.45 (CH2Cl2/MeOH = 9:1)
[α]20 D = −2.65 (c 0.98, CHCl3)
IR (ATR): 2978, 2929, 1703, 1653, 1507, 1448, 1404, 1368, 1344, 1248, 1167, 1075, 1029, 993,
921 cm-1.
1
H NMR (400 MHz, DMSO-d6): δ 12.62 (br s, 1H, OH), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 6.32 (t,
J = 6.1 Hz, 1H, NH), 5.66 (m, 1H), 5.12 (dapp, J = 17.2 Hz, 1H), 5.01 (dapp, J = 10.2 Hz, 1H), 3.60 (dd,
J = 13.8, 6.8 Hz, 1H), 3.48 (dd, J = 13.6, 5.7 Hz, 1H), 2.76 (dd, J = 13.8, 7.5 Hz, 1H), 2.68 (dd, J = 13.8,
7.5 Hz, 1H), 1.27 (s, 9H).
13
C NMR (100 MHz, DMSO-d6): δ 175.2, 155.5, 140.6, 134.0, 128.0 (2C), 126.7 (2C), 126.6, 118.7, 77.7,
54.1, 43.7, 37.5, 28.1 (3C).
HRMS (ESI) m/z: calcd for C17H23NO4Na [M+Na]+: 328.1519, found: 328.1521.

7.2. Synthesis of β-lactam

tert-Butyl (S)-3-allyl-2-oxo-3-phenylazetidine-1-carboxylate (4)

9 10
8
O 7
6
1 12
Me 5 13
2 O 3 N 11
4
Me
Me O

4
C17H 21NO3
MW = 287.36 g/mol

To a solution of (S)-2-(((tert-butoxycarbonyl)amino)methyl)-2-phenylpent-4-enoic acid 4 (174 mg,

0.57 mmol, 1.0 equiv) in toluene (3.0 mL) and MeOH (7.5 mL) at 0 °C was added dropwise TMSCHN2
(2 M in Et2O) until the yellow color persisted. The solution was stirred for an additional 20 min and
quenched with a drop of acetic acid. The reaction mixture was concentrated under reduced pressure
to afford the crude methyl ester (180 mg, 99%) as a clear oil which was engaged in the next step
without further purification or characterization.18

18
Gianelli, C.; Sambri, L.; Carlone, A.; Bartoli, G.; Melchiorre, P. Angew. Chem. Int. Ed. 2008, 47, 8700.
The abovementioned methyl ester (180 mg, 0.56 mmol, 1.0 equiv) was dissolved in CH2Cl2 (5.6 mL).
The resulting solution was cooled to 0 °C and TFA (840 µL, 11.3 mmol, 20.0 equiv) was added. The
reaction mixture was stirred at rt. After 2 h, the mixture was cooled to 0 °C and a saturated aqueous
solution of NaHCO3 (20 mL) was added. The layers were separated and the aqueous layer was
extracted CH2Cl2 (2 x 10 mL). The organic layers were combined and washed with H2O (20 mL), dried
over MgSO4, filtered and concentrated under reduced pressure, affording the crude β-amino ester
(120 mg, 98%) as a brownish oil which was engaged in the next step without further purification or
characterization.19

A solution of the aforementioned β-amino ester (50 mg, 0.23 mmol, 1.0 equi) in CH2Cl2 (1.2 mL) was
cooled to 0 °C, and then treated with Et3N (35 µL, 0.25 mmol, 1.1 equiv) and TMSCl (32 µL,
0.25 mmol, 1.1 equiv). After 30 min at rt, t-BuMgCl (1.50 mL, 1 M in THF, 1.50 mmol, 6.6 equiv) was
added dropwise. The reaction mixture was stirred at rt for 18 h and H2O (2 mL) was added. The layers
were separated and the aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic
extracts were dried over MgSO4, filtered and concentrated under reduced pressure.19 The resulting
residue was then dissolved in CH2Cl2 (1.0 mL), cooled to 0 °C and treated with Et3N (38 µL, 0.27 mmol,
1.2 equiv), Boc2O (128 mg, 0.60 mmol, 2.6 equiv) and DMAP (34 mg, 0.27 mmol, 1.2 equiv).
The mixture was stirred overnight at rt. The reaction was acidified with an aqueous solution of HCl
(1M), the layers were separated and the aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The
combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure.
The crude residue was purified by flash column chromatography on silica gel (PE/Et2O = 9:1) to afford
the desired β-lactam 5 as a clear oil (21 mg, 32%).

Rf: 0.36 (PE/Et2O = 8:2)

[α]20 D = +16.4 (c 0.32, CHCl3)
IR (ATR): 2980, 2919, 1798, 1723, 1448, 1370, 1345, 1258, 1202, 1146, 1051, 993, 924, 850, 771,
701 cm-1.
1
H NMR (400 MHz, CDCl3): δ 7.42-7.33 (m, 4H), 7.32-7.26 (m, 1H), 5.11 (m, 1H), 5.18-5.08 (m, 2H),
3.83 (d, J = 6.7 Hz, 1H), 3.77 (d, J = 6.7 Hz, 1H), 2.76-2.62 (m, 2H), 1.52 (s, 9H).
13
C NMR (100 MHz, CDCl3): δ 167.9, 148.4, 138.3, 132.0, 128.8 (2C), 127.7, 126.7 (2C), 119.9, 83.6,
61.3, 49.4, 42.2, 28.2 (3C).
HRMS (ESI) m/z: calcd for C17H21NO3Na [M+Na]+: 310.1414, found: 310.1416.
8. 1H and 13C NMR spectra copies
 Me O
Me
OH
Me O N
O
O
S

A
 Me O
Me
OH
Me O N
O
O
S

A
 O

O
Me O O
Me
B1
 O

O
Me O O
Me
B1
 Me
O

O
Me O O
Me
B2
 Me
O

O
Me O O
Me
B2
 OMe
O

O
Me O O
Me
B3
 OMe
O

O
Me O O
Me
B3
 F
O

O
Me O O
Me
B4
 F
O

O
Me O O
Me
B4
 CF 3
O

O
Me O O
Me
B5
 CF 3
O

O
Me O O
Me
B5
 Cl
O

O
Me O O
Me
B6
 Cl
O

O
Me O O
Me
B6
 Br
O

O
Me O O
Me
B7
 Br
O

O
Me O O
Me
B7
 Cl
O

O Cl
Me O O
Me
B8
 Cl
O

O Cl
Me O O
Me
B8
 O S

O
Me O O
Me
B9
 O S

O
Me O O
Me
B9
Me
O Me

O
C1
Me
O Me

O
C1
 Me
Me Me
Si
O Me

O
C2
 Me
Me Me
Si
O Me

O
C2
O Me

O
C3
O Me

O
C3
Cl
O Me

O
C4
Cl
O Me

O
C4
O OMe

O Me

O
C5
O OMe

O Me

O
C5
OMe
O Me

O
C6
OMe
O Me

O
C6
 O

O
N
O
Me O
Me Me
1a
 O

O
N
O
Me O
Me Me
1a
 O Me
O
N
O
Me O
Me Me
1b
 O Me
O
N
O
Me O
Me Me
1b
 O OMe
O
N
O
Me O
Me Me
1c
 O OMe
O
N
O
Me O
Me Me
1c
 O F
O
N
O
Me O
Me Me
1d
 O F
O
N
O
Me O
Me Me
1d
 O CF 3
O
N
O
Me O
Me Me
1e
 O CF 3
O
N
O
Me O
Me Me
1e
 O Cl
O
N
O
Me O
Me Me
1f
 O Cl
O
N
O
Me O
Me Me
1f
 O Br
O
N
O
Me O
Me Me
1g
 O Br
O
N
O
Me O
Me Me
1g
 O Cl
O
N Cl
O
Me O
Me Me
1h
 O Cl
O
N Cl
O
Me O
Me Me
1h
 O S
O
N
O
Me O
Me Me
1i
 O S
O
N
O
Me O
Me Me
1i
 O

O
N
O
Me O
Me Me
2a
 O

O
N
O
Me O
Me Me
2a
 Me

O
N
O
Me O
Me Me
2b
 Me

O
N
O
Me O
Me Me
2b
 OMe

O
N
O
Me O
Me Me
2c
 OMe

O
N
O
Me O
Me Me
2c
 F

O
N
O
Me O
Me Me
2d
 F

O
N
O
Me O
Me Me
2d
 CF 3

O
N
O
Me O
Me Me
2e
 CF 3

O
N
O
Me O
Me Me
2e
 Cl

O
N
O
Me O
Me Me
2f
 Cl

O
N
O
Me O
Me Me
2f
 Br

O
N
O
Me O
Me Me
2g
 Br

O
N
O
Me O
Me Me
2g
 Cl

O Cl

O
N
O
Me O
Me Me
2h
 Cl

O Cl

O
N
O
Me O
Me Me
2h
 S
O

O
N
O
Me O
Me Me
2i
 S
O

O
N
O
Me O
Me Me
2i
 O

O
N Me
O
Me O
Me Me
2j
 O

O
N Me
O
Me O
Me Me
2j
 O

O
N Si Me
O
Me Me Me
O
Me Me
2k
 O

O
N Si Me
O
Me Me Me
O
Me Me
2k
 O

O
N
O
Me O
Me Me
2m
 O

O
N
O
Me O
Me Me
2m
 O

O
N Cl
O
Me O
Me Me
2n
 O

O
N Cl
O
Me O
Me Me
2n
 O
O
O
N O
O N O
Me O
O Me O
Me Me O Me
Me Me
1a
2o
 O O

O O
N N O
O O
Me O
Me O O Me
Me Me Me
Me
1a 2o
 H
HO N O Me
O O Me
Me
3
 H
HO N O Me
O O Me
Me
3
 O

Me O N
Me
Me O

4
 O

Me O N
Me
Me O