Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives

Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Stereoselective and Catalytic Synthesis of

anti β-Alkoxy-α-Azido Carboxylic Derivatives

Javier Fernández-Valparis,† Pedro Romea,*,† Fèlix Urpí,*,† and Mercè Font-Bardia#

† Secció de Química Orgànica, Departament de Química Inorgànica i Orgànica,

and Institut de Biomedicina (IBUB)
Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain

# Unitat de Difracció de RX. CCiTUB.

Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain

Part I. Experimental procedures

1. General Experimental Methods S2

2. (S)-N-Azidoacetyl-4-isopropyl-1,3-thiazolidine-2-thione (2) S2
3. Additions to acetals from aromatic aldehydes. General Procedure S4
4. Physical and Spectroscopic Data for Adducts 4 S4
5. Removal of the Chiral Auxiliary from 4a S10
6. Additions to diethyl acetals from propargylic aldehydes.
General Procedure S13
7. Physical and Spectroscopic Data for Adducts 10 S13
8. Synthesis of derivatives from 10 S18
9. X-Ray of amide 8 S25

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

1. General Experimental Methods

Unless otherwise noted, reactions were conducted in oven-dried glassware under inert atmosphere of
N2 with anhydrous solvents. The solvents and reagents were dried and purified when necessary in
accordance with standard procedures. Commercially available reagents were used as received.
Analytical thin-layer chromatography (TLC) was carried out on Merck silica gel 60 F254 plates and
analyzed by UV (254 nm) and stained with phosphomolybdic acid and p-anisaldehyde; Rf values are
approximate. Column chromatographies were carried out under low pressure (flash) conditions and
performed with SDS silica gel 60 (35–70 µm). Most of the compounds were purified by column
chromatography to be completely identified. Melting points (Mp) were determined with a Gallenkamp
apparatus and are uncorrected. Specific rotations ([α]D) were determined at 20 °C with a Perkin-Elmer
241 MC polarimeter. IR spectra (Attenuated Total Reflectance, ATR) were recorded with a Nicolet
6700 FT-IR Thermo Scientific spectrometer and only the more representative wavenumbers (ν) are
reported in cm–1. 1H NMR (400 MHz) and 13C NMR (100.6 MHz) spectra were recorded with a Varian
Mercury 400. Chemical shifts (δ) are quoted in ppm and referenced to internal TMS (δ 0.00 for 1H
NMR), CDCl3 (δ 77.0 for 13C NMR), or CD3OD (δ 3.34 for 1H NMR or δ 49.9 for 13C NMR); coupling
constants (J) are quoted in Hz; data are reported as follows: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet (and their corresponding combinations); where necessary, 2D techniques (NOESY, COSY,
HSQC) were also used to assist on structure elucidation. High resolution mass spectra (HRMS) were
obtained with an Agilent 1100 spectrometer by the Unitat d’Espectrometria de Masses (CCiTUB),
Universitat de Barcelona.

2. (4S) N-Azidoacetyl-4-isopropyl-1,3-thiazolidine-2-thione (2)

S O
N3
S N

2.1. Acid chloride–mediated acylation of the thiazolidinethione

A solution of bromoacetic acid (2.09 g, 15.0 mmol) in water (5 mL) was added dropwise to a solution
of sodium azide (1.96 g, 30 mmol) in water (15 mL) and the reaction mixture was stirred for 16 h at
room temperature. The solution was carefully acidifed with 2 M HCl until pH 1 and extracted with Et2O
(3 × 25 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford 1.37 g (13.5
mmol, 90% yield) of 2-azidoacetic acid as a colorless oil that was used in the next step without further
purification. IR (ATR) ν 3046, 2104, 1716, 1187 cm–1. 1H NMR (CDCl3, 400 MHz) δ 6.99 (1H, br s,
CO2H), 3.98 (2H, s, CH2N3).1

1 Haridas, V.; Sharma, Y. K.; Sahu, S.; Verma, R. P.; Sadanandan, S.; Kacheshwar, B. G. Tetrahedron 2011, 67, 1873.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Recently distilled oxalyl chloride (1.6 mL, 18.8 mmol) was added dropwise to a solution of 2-
azidoacetic acid (1.52 g, 15.0 mmol) in CH2Cl2 (50 mL) under N2 at 0 °C. A few drops of DMF were
added and the resultant was warmed to room temperature and stirred for 16 h. The volatiles were
removed in vacuo to afford 1.67 g (14.0 mmol, 93% yield) of 2-azidoacetyl chloride as a colorless oil,
which was used in the next step without further purification. IR (ATR) ν 3048, 2100, 1788, 1723, 1406,
1269 cm–1. 1H NMR (CDCl3, 400 MHz) δ 4.29 (2H, s, CH2N3).
CAUTION: The synthesis of the 2-azidoacetyl chloride by treatment of the carboxylic acid with thionyl
chloride has been reported to be potentially dangerous if the acid chloride is distilled at more than 95–
100 °C.2

A solution of (S)-4-isopropyl-1,3-thiazolidine-2-thione3 (1.23 g, 7.6 mmol) and Et3N (1.1 mL, 7.6 mmol)
in CH2Cl2 (30 mL) was stirred at room temperature for 15 min under N2 and cooled to 0 °C. Then, a
solution of azidoacetyl chloride (1.09 g, 9.1 mmol) in CH2Cl2 (5 mL) was added via cannula and the
resultant mixture was stirred at room temperature for 15 h.
It was diluted with Et2O (50 mL) and washed with H2O (3 × 30 mL). The organic layer was dried
(MgSO4), filtered, and concentrated. The resulting oil was purified by column chromatography
(CH2Cl2/hexanes 70:30) to afford 1.47 g (6.0 mmol, 79% yield) of 2 as a yellow oil. Rf (CH2Cl2/hexanes
70:30) 0.45. [α]20D +239.9 (c 1.00, CHCl3). IR (ATR) ν 2961, 2097, 1692, 1467, 1304, 1168, 1037 cm–1.
1H NMR (CDCl3, 400 MHz) δ 5.22–5.17 (1H, m, NCH), 4.92 (1H, d, J = 18.3 Hz, COCHaHb), 4.73 (1H, d, J =
18.3 Hz, COCHaHb), 3.62 (1H, dd, J = 11.6, 8.1 Hz, SCHaHb), 3.10 (1H, dd, J = 11.6, 1.0 Hz, SCHaHb), 2.40–
2.30 (1H, m, CH(CH3)2), 1.08 (3H, d, J = 6.9 Hz, CH3), 0.96 (3H, d, J = 6.9 Hz, CH3). 13C NMR (CDCl3, 100.6
MHz) δ 202.5, 168.7, 71.6, 55.0, 31.1, 30.7, 19.0, 17.5. HRMS (+ESI): m/z calcd. for C8H13N4OS2 [M+H]+:
245.0525; found: 245.0530.

2.2. Carboxylic acid–mediated acylation of the thiazolidinethione

A solution of 2-azidoacetic acid (0.56 g, 5.5 mmol) in CH2Cl2 (20 mL) was added dropwise to a solution
of (S)-4-isopropyl-1,3-thiazolidine-2-thione3 (0.81 g, 5.0 mmol), EDC·HCl (1.17 g, 6.1 mmol), and DMAP
(33.0 mg, 0.3 mmol) in CH2Cl2 (25 mL) at 0 °C under N2. The resultant yellow mixture was stirred at
room temperature for 20 h.
Then, it was washed with 0.5 M HCl (3 × 25 mL), 0.5 M NaOH (3 × 25 mL), and brine (30 mL), dried
(Na2SO4), filtered and concentrated. The residue was purified by column chromatography
(hexanes/EtOAc 80:20) to afford 0.85 g (3.5 mmol, 70% yield) of 2. Rf (hexanes/EtOAc 80:20) 0.40.

2Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K. J. Org. Chem. 1991, 56, 5265.
3For the synthesis of the (S)4-isopropyl-1,3-thiazolidine-2-thione see: Gálvez, E.; Romea, P.; Urpí, F. Org. Synth.
2009, 86, 70.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

3. Additions to acetals from aromatic aldehydes. General Procedure

Solid (Me3P)2NiCl2 (7.0 mg, 25 µmol, 5 mol %) was added to a solution of (S)-N-azidoacetyl-4-
isopropyl-1,3-thiazolidine-2-thione (2, 122 mg, 0.5 mmol) and the corresponding dialkyl acetal (a–j,
0.55 mmol) in CH2Cl2 (1.0 mL) under N2 at room temperature. The resulting solution was cooled to –20
°C. Then, TESOTf (170 µL, 0.75 mmol) and 2,6-lutidine (87 µL, 0.75 mmol) were added dropwise after
3 and 7 min respectively and the reaction mixture was stirred at –20 °C for 15 h.
The reaction mixture was quenched with sat NH4Cl (1.2 mL) and then diluted in H2O (20 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed
with brine (50 mL), dried (MgSO4), and filtered. They were concentrated and filtered through a pad of
silica gel (CH2Cl2); the solvent was removed in vacuo and the resultant oil was purified by column
chromatography to afford the desired product 4.

4. Physical and Spectroscopic Data for Adducts 4

(4S)-N-[(2R,3R)-2-Azido-3-methoxy-3-(4-methoxyphenyl)propanoyl]-4-isopropyl-1,3-
thiazolidine-2-thione (4a)
S O OMe

S N
N3
OMe

4a

Solid (Me3P)2NiCl2 (14.1 mg, 50 µmol, 5 mol %) was added to a solution of 2 (245 mg, 1.0 mmol) and 4-
methoxybenzaldehyde dimethyl acetal (a, 190 µL, 1.1 mmol) in CH2Cl2 (2.0 mL) under N2 at room
temperature. The resulting solution was cooled to –20 °C. Then, TESOTf (340 µL, 1.5 mmol) and 2,6-
lutidine (175 µL, 1.5 mmol) were added dropwise after 3 and 7 min respectively and the reaction
mixture was stirred at –20 °C for 15 h. The reaction mixture was quenched with sat NH4Cl (2.5 mL) and
then diluted in H2O (40 mL). The aqueous layer was extracted with CH2Cl2 (3 × 40 mL). The combined
organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, concentrated, and filtered
through a pad of silica gel (CH2Cl2). The solvent was removed in vacuo to afford a 96:4 anti/syn
diastereomeric mixture as established by 1H NMR analysis of the crude product. Purification of this
crude mixture by column chromatography (CH2Cl2/hexanes 80:20) gave 338 mg (0.86 mmol, 85%
yield) of 4a as a yellow oil. Rf (CH2Cl2/hexanes 80:20) 0.50. [α]20D +90.4 (c 1.0, CHCl3). IR (ATR) ν
2960, 2824, 2095, 1686, 1610, 1360, 1240, 1162 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.40–7.36 (2H, m,
ArH), 6.96–6.93 (2H, m, ArH), 6.50 (1H, d, J = 9.0 Hz, CHN3), 5.33 (1H, ddd, J = 8.4, 5.9, 1.6 Hz, NCH),
4.53 (1H, d, J = 9.0 Hz, CHOMe), 3.83 (3H, s, OCH3), 3.54 (1H, dd, J = 11.5, 8.4 Hz, SCHaHb), 3.15 (3H, s,
OCH3), 3.05 (1H, dd, J = 11.5, 1.6 Hz, SCHaHb), 2.42–2.31 (1H, m, CH(CH3)2), 1.10 (3H, d, J = 6.8 Hz,
CHCH3), 1.03 (3H, d, J = 6.9 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ 203.1 (C), 170.5 (C), 160.2 (C),
129.2 (CH), 129.1 (C), 114.1 (CH), 83.8 (CH), 71.8 (CH), 62.5 (CH), 56.5 (CH3), 55.3 (CH3), 30.4 (CH2),

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

29.8 (CH), 18.9 (CH3), 17.3 (CH3). HRMS (+ESI): m/z calcd. for C16H19N4O2S2 [M–OMe]+: 363.0944;
found: 363.0952.

This reaction has been carried out at other scales with similar results: 0.5 mmol (85% yield), 0.8 mmol
(87% yield), 1.5 mmol (81% yield), and 2 mmol (86%).

(4S)-N-[(2R,3R)-2-Azido-3-methoxy-3-(3-methoxyphenyl)propanoyl]-4-isopropyl-1,3-
thiazolidine-2-thione (4b)
S O OMe
OMe
S N
N3

4b

The reaction was performed from 2 (122 mg, 0.5 mmol), (Me3P)2NiCl2 (14.1 mg, 50 µmol), 3-
methoxybenzaldehyde dimethyl acetal (b, 100 mg, 0.55 mmol), TESOTf (249 µL, 1.10 mmol), and 2,6-
lutidine (88 µL, 0.75 mmol) in CH2Cl2 (1.0 mL) at –20 °C for 15 h to afford a 73:27 anti/syn
diastereomeric mixture established by 1H NMR analysis of the crude product. Purification of this crude
by column chromatography (CH2Cl2/hexanes 80:20) gave 22 mg (56 µmol, 11% yield) of the pure syn
diastereomer and 98 mg of a mixture of the anti diastereomer and 3-methoxybenzaldehyde. Further
purification of such a mixture by column chromatography (hexanes/EtOAc 90:10) afforded 70 mg
(0.18 mmol, 36% yield) of the pure anti diastereomer 4b as a yellow oil. Rf (hexanes/EtOAc 90:10)
0.30. [α]D +127.1 (c 1.0, CHCl3). IR (ATR) ν 2961, 2826, 2095, 1686, 1599, 1359, 1253, 1159 cm–1. 1H
NMR (CDCl3, 400 MHz) δ 7.35–7.31 (1H, m, ArH), 7.05–7.03 (2H, m, ArH), 6.93–6.91 (1H, m, ArH), 6.51
(1H, d, J = 9.1 Hz, CHN3), 5.33 (1H, ddd, J = 8.3, 6.0, 1.6 Hz, NCH), 4.55 (1H, d, J = 9.1 Hz, CHOMe), 3.84
(3H, s, OCH3), 3.54 (1H, dd, J = 11.5, 8.3 Hz, SCHaHb), 3.18 (3H, s, OCH3), 3.05 (1H, dd, J = 11.5, 1.6 Hz,
SCHaHb), 2.43–2.31 (1H, m, CH(CH3)2), 1.10 (3H, d, J = 6.8 Hz, CHCH3), 1.03 (3H, d, J = 7.0 Hz, CHCH3).
13C NMR (CDCl3, 100.6 MHz) δ 203.2 (C), 170.3 (C), 160.0 (C), 138.9 (C), 129.8 (CH), 120.4 (CH), 114.7
(CH), 113.0 (CH), 84.1 (CH), 71.9 (CH), 62.3 (CH), 56.8 (CH3), 55.3 (CH3), 30.5 (CH), 29.8 (CH2), 18.9
(CH3), 17.3 (CH3). HRMS (+ESI): m/z calcd. for C17H22N4NaO3S2 [M+Na]+: 417.1026; found: 417.1036.

(4S)-N-[(2R,3R)-2-Azido-3-methoxy-3-(2-methoxyphenyl)propanoyl]-4-isopropyl-1,3-
thiazolidine-2-thione (4c)
S O OMe OMe

S N
N3

4c

The reaction was performed from 2 (122 mg, 0.5 mmol), TESOTf (249 µL, 1.10 mmol), and 2-
methoxybenzaldehyde dimethyl acetal (c, 100 mg, 0.55 mmol) according to the general procedure to
afford a 82:18 anti/syn diastereomeric mixture established by 1H NMR analysis of the crude product.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Purification of this crude by column chromatography (from CH2Cl2/hexanes 60:40 to CH2Cl2) gave 27
mg (68 µmol, 14% yield) of the pure syn diastereomer and 147 mg (0.37 mmol, 75% yield) of the pure
anti diastereomer 4c as a yellow oil. Rf (CH2Cl2/hexanes 60:40) 0.25 [α]D +135.9 (c 1.0, CHCl3). IR
(ATR) ν 2961, 2828, 2097, 1685, 1600, 1360, 1240, 1159 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.50–7.48
(1H, m, ArH), 7.35–7.31 (1H, m, ArH), 7.04–7.00 (1H, m, ArH), 6.93–6.91 (1H, m, ArH), 6.43 (1H, d, J =
8.9 Hz, CHN3), 5.32 (1H, ddd, J = 8.3, 5.8, 1.4 Hz, NCH), 5.2 (1H, d, J = 8.9 Hz, CHOMe), 3.87 (3H, s, OCH3),
3.53 (1H, dd, J = 11.5, 8.3 Hz, SCHaHb), 3.18 (3H, s, OCH3), 3.05 (1H, dd, J = 11.5, 1.4 Hz, SCHaHb), 2.43–
2.31 (1H, m, CH(CH3)2), 1.09 (3H, d, J = 6.8 Hz, CHCH3), 1.03 (3H, d, J = 7.0 Hz, CHCH3). 13C NMR (CDCl3,
100.6 MHz) δ 202.9 (C), 170.6 (C), 158.4 (C), 129.9 (CH), 128.8 (CH), 125.3 (C), 121.0 (CH), 110.5 (CH),
77.7 (CH), 71.8 (CH), 61.5 (CH), 56.9 (CH3), 55.5 (CH3), 30.5 (CH), 29.8 (CH2), 18.9 (CH3), 17.4 (CH3).
HRMS (+ESI): m/z calcd. C16H19N4O2S2 for [M–OMe]+: 363.0944; found: 363.0946.

(4S)-N-[(2R,3R)-2-Azido-3-(benzo[d][1,3]dioxol-5-yl)-3-methoxypropanoyl]-4-isopropyl-1,3-
thiazolidine-2-thione (4d)
S O OMe

S N O
N3 O

4d

The reaction was performed from 2 (122 mg, 0.5 mmol) and piperonal dimethyl acetal (d, 108 mg,
0.55 mmol) according to the general procedure to afford a 92:8 anti/syn diastereomeric mixture
established by 1H NMR analysis of the crude product. Purification of this crude by column
chromatography (CH2Cl2/hexanes 65:35) afforded 173 mg (0.42 mmol, 84% yield) of the anti
diastereomer 4d as a yellow oil. Rf (CH2Cl2/hexanes 65:35) 0.25. [α]D +124.5 (c 1.0, CHCl3). IR (ATR) ν
2962, 2875, 2095, 1686, 1485, 1359, 1241, 1162 cm–1. 1H NMR (CDCl3, 400 MHz) δ 6.98–6.97 (1H, m,
ArH), 6.92–6.90 (1H, m, ArH), 6.84–6.82 (1H, m, ArH), 6.47 (1H, d, J = 9.1 Hz, CHN3), 6.00 (1H, d, J = 5.2
Hz, OCHaHbO), 5.99 (1H, d, J = 5.2 Hz, OCHaHbO), 5.33 (1H, ddd, J = 8.4, 6.0, 1.6 Hz, NCH), 4.49 (1H, d, J =
9.1 Hz, CHOMe), 3.54 (1H, dd, J = 11.5, 8.4 Hz, SCHaHb), 3.16 (3H, s, OCH3), 3.05 (1H, dd, J = 11.5, 1.6 Hz,
SCHaHb), 2.42–2.30 (1H, m, CH(CH3)2), 1.10 (3H, d, J = 6.8 Hz, CHCH3), 1.03 (3H, d, J = 7.0 Hz, CHCH3).
13C NMR (CDCl3, 100.6 MHz) δ 203.1 (C), 170.3 (C), 148.2 (2 × C), 131.0 (C), 122.1 (CH), 108.3 (CH),
107.7 (CH), 101.2 (CH2), 84.0 (CH), 71.8 (CH), 62.4 (CH), 56.6 (CH3), 30.4 (CH), 29.8 (CH2), 18.9 (CH3),
17.3 (CH3). HRMS (+ESI): m/z calc. for C16H17N4O3S2 [M–OMe]+: 377.0737; found: 377.0742.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

(4S)-N-[(2R,3R)-2-Azido-3-(4-dimethylaminophenyl)-3-methoxypropanoyl]-4-isopropyl-1,3-
thiazolidine-2-thione (4e)
S O OMe

S N
N3
NMe2

4e

The reaction was performed from 2 (122 mg, 0.5 mmol) and 4-(N,N-dimethylamino)benzaldehyde
dimethyl acetal (e, 107 mg, 0.55 mmol) according to the general procedure to afford a 91:9 anti/syn
diastereomeric mixture established by 1H NMR analysis of the crude product. Purification of this crude
by column chromatography (from hexanes/EtOAc 90:10 to 80:20) provided 159 mg (0.39 mmol, 78%
yield) of the anti diastereomer 4e as an orange oil. Rf (hexanes/EtOAc 90:10) 0.25. [α]D +95.4 (c 1.0,
CHCl3). IR (ATR) ν 2961, 2874, 2093, 1686, 1610, 1521, 1347, 1241, 1159 cm–1. 1H NMR (CDCl3, 400
MHz) δ 7.33–7.29 (2H, m, ArH), 6.76–6.73 (2H, m, ArH), 6.49 (1H, d, J = 9.1 Hz, CHN3), 5.34 (1H, ddd, J =
8.3, 5.9, 1.6 Hz, NCH), 4.48 (1H, d, J = 9.1 Hz, CHOMe), 3.52 (1H, dd, J = 11.5, 8.3 Hz, SCHaHb), 3.13 (3H, s,
OCH3), 3.04 (1H, dd, J = 11.5, 1.6 Hz, SCHaHb), 2.97 (6H, s, N(CH3)2), 2.43–2.31 (1H, m, CH(CH3)2), 1.10
(3H, d, J = 6.8 Hz, CHCH3), 1.03 (3H, d, J = 7.0 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ 203.0 (C),
170.9 (C), 150.1 (C), 128.9 (CH), 124.1 (C), 112.2 (CH), 84.1 (CH), 71.8 (CH), 62.4 (CH), 56.3 (CH3), 40.4
(CH3), 30.4 (CH), 29.7 (CH2), 18.9 (CH3), 17.3 (CH3). HRMS (+ESI): m/z calcd. for C17H22N5OS2 [M+H]+:
376.1271, found: 376.1260.

(4S)-N-[(2R,3R)-2-Azido-3-methoxy-3-(4-methylphenyl)propanoyl]-4-isopropyl-1,3-thiazolidi-
ne-2-thione (4f)
S O OMe

S N
N3

4f

The reaction was performed from 2 (122 mg, 0.5 mmol), TESOTf (249 µL, 1.10 mmol), and 4-
methylbenzaldehyde dimethyl acetal (f, 91 mg, 0.55 mmol) according to the general procedure to
afford a 83:17 anti/syn diastereomeric mixture established by 1H NMR analysis of the crude product.
Purification of this crude by column chromatography (hexanes/EtOAc 95:5) provided 30 mg (80 µmol,
16% yield) of the syn diastereomer and 138 mg (0.365 mmol, 73% yield) of the anti diastereomer 4f as
a yellow oil. Rf (hexanes/EtOAc 95:5) 0.20. [α]D +120.4 (c 1.0, CHCl3). IR (ATR) ν 2962, 2824, 2094,
1686, 1359, 1239, 1161 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.36–7.34 (2H, m, ArH), 7.23–7.21 (2H, m,
ArH), 6.50 (1H, d, J = 9.1 Hz, COCH), 5.33 (1H, ddd, J = 8.4, 5.9, 1.7 Hz, NCH), 4.54 (1H, d, J = 9.1 Hz,
CHOMe), 3.54 (1H, dd, J = 11.5, 8.4 Hz, SCHaHb), 3.16 (3H, s, OCH3), 3.05 (1H, dd, J = 11.5, 1.7 Hz,
SCHaHb), 2.38 (3H, s, ArCH3), 2.43–2.31 (1H, m, CH(CH3)2), 1.09 (3H, d, J = 6.8 Hz, CHCH3), 1.03 (3H, d, J
= 7.0 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ 203.1 (C), 170.5 (C), 138.9 (C), 134.1 (C), 129.4 (CH),
127.9 (CH), 84.0 (CH), 71.8 (CH), 62.4 (CH), 56.6 (CH3), 30.4 (CH), 29.8 (CH2), 21.3 (CH3), 18.9 (CH3),

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

17.3 (CH3). HRMS (+ESI): m/z calcd. for C17H23N4O2S2 [M+H]+: 379.1257; found: 379.1258; calcd. for
C17H22N4NaO2S2 [M+Na]+: 401.1076; found: 401.1085.

(4S)-N-[(2R,3R)-2-Azido-3-methoxy-3-phenylpropanoyl]-4-isopropyl-1,3-thiazolidine-2-thione
(4g)
S O OMe

S N
N3

4g

The reaction was performed from 2 (122 mg, 0.5 mmol), (Me3P)2NiCl2 (14.1 mg, 50 µmol),
benzaldehyde dimethyl acetal (g, 83 µL, 0.55 mmol), TESOTf (249 µL, 1.10 mmol), 2,6-lutidine (87 µL,
0.75 mmol) in CH2Cl2 (1 mL) at –20 °C for 15 h to afford a 77:23 anti/syn diastereomeric mixture
established by 1H NMR analysis of the crude product. Purification of this crude by column
chromatography (hexanes/EtOAc 90:10) led to a mixture free of aldehyde, which was further purified
by a column chromatography (CH2Cl2/hexanes 70:30) to give 31 mg (85 µmol, 17% yield) of the syn
diastereomer and 104 mg (0.285 mmol, 57% yield) of anti diastereomer 4g as a yellow oil. Rf
(CH2Cl2/hexanes 70:30) 0.50. [α]D +116.1 (c 1.05, CHCl3). IR (ATR) ν 2964, 2827, 2106, 1689, 1362,
1241, 1166 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.48–7.37 (5H, m, ArH), 6.52 (1H, d, J = 9.1 Hz, CHN3),
5.33 (1H, ddd, J = 8.2, 6.0, 1.6 Hz, NCH), 4.58 (1H, d, J = 9.1 Hz, CHOMe), 3.54 (1H, dd, J = 11.5, 8.2 Hz,
SCHaHb), 3.17 (3H, s, OCH3), 3.06 (1H, dd, J = 11.5, 1.6 Hz, SCHaHb), 2.43–2.31 (1H, m, CH(CH3)2), 1.11
(3H, d, J = 6.8 Hz, CHCH3), 1.04 (3H, d, J = 7.0 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ 203.1 (C),
170.3 (C), 137.2 (C), 129.0 (C), 128.7 (CH), 128.1 (CH), 84.2 (CH), 71.8 (CH), 62.4 (CH), 56.8 (CH3), 30.4
(CH2), 29.8 (CH), 18.9 (CH3), 17.3 (CH3). HRMS (+ESI): m/z calcd. for C16H21N4O2S2 [M+H]+: 365.1100,
found: 365.1099.

(4S)-N-[(2R,3R)-2-Azido-3-(4-chlorophenyl)-3-methoxypropanoyl]-4-isopropyl-1,3-
thiazolidine-2-thione (4h)
S O OMe

S N
N3
Cl

4h

The reaction was performed from 2 (122 mg, 0.5 mmol), (Me3P)2NiCl2 (28.2 mg, 0.1 mmol, 20 mol %),
4-chlorobenzaldehyde dimethyl acetal (h, 103 mg, 0.55 mmol), TESOTf (249 µL, 1.10 mmol), 2,6-
lutidine (88 µL, 0.75 mmol) in CH2Cl2 (1 mL) at –20 °C for 15 h to afford a 83:17 anti/syn
diastereomeric mixture established by 1H NMR analysis of the crude product. Purification of this crude
by column chromatography (from hexanes/EtOAc 95:5 to 90:10) afforded 31 mg (78 µmol, 15% yield)
of anti diastereomer 4h as a yellow oil. Rf (hexanes/EtOAc 95:5) 0.25. [α]D +123.6 (c 1.00, CHCl3). IR
(ATR) ν 2961, 2101, 1689, 1358, 1240, 1163 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.40 (4H, s, ArH), 6.49

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

(1H, d, J = 8.9 Hz, CHN3), 5.31 (1H, ddd, J = 8.3, 6.0, 1.6 Hz, NCH), 4.56 (1H, d, J = 8.9 Hz, CHOMe), 3.54
(1H, dd, J = 11.5, 8.3 Hz, SCHaHb), 3.17 (3H, s, OCH3), 3.06 (1H, dd, J = 11.5, 1.6 Hz, SCHaHb), 2.40–2.32
(1H, m, CH(CH3)2), 1.10 (3H, d, J = 6.8 Hz, CHCH3), 1.03 (3H, d, J = 7.0 Hz, CHCH3). 13C NMR (CDCl3,
100.6 MHz) δ 203.4 (C), 170.1 (C), 135.9 (C), 135.1 (C), 129.5 (CH), 129.1 (CH), 83.6 (CH), 72.0 (CH),
62.5 (CH), 57.1 (CH3), 30.6 (CH), 30.1 (CH2), 19.1 (CH3), 17.5 (CH3). HRMS (+ESI): m/z calcd. for
C16H20ClN4O2S2 [M+H]+: 399.0711, found: 399.0706.

(4S)-N-[(2R,3R)-3-Allyloxy-2-azido-3-(4-methoxyphenyl)propanoyl]-4-isopropyl-1,3-
thiazolidi-ne-2-thione (4i)
S O OAllyl

S N
N3
OMe

4i

The reaction was performed from 2 (122 mg, 0.5 mmol) and 4-methoxybenzaldehyde diallyl acetal (i,
129 mg, 0.55 mmol) according to the general procedure to afford a 96:4 anti/syn diastereomeric
mixture established by 1H NMR analysis of the crude product. Purification of this crude by column
chromatography (CH2Cl2/hexanes 60:40) provided 7 mg (20 µmol, 3% yield) of the syn diastereomer
and 180 mg (0.43 mmol, 85% yield) of the anti diastereomer 4i as a yellow solid. Rf (CH2Cl2/hexanes
60:40) 0.30. Mp 81–83 °C. [α]D +129.9 (c 1.0, CHCl3). IR (ATR) ν 3008, 2958, 2099, 1684, 1682, 1609,
1510, 1358, 1272, 1165 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.42–7.36 (2H, m, ArH), 6.96–6.92 (2H, m,
ArH), 6.49 (1H, d, J = 9.0 Hz, CHN3), 5.81–5.66 (1H, m, OCH2CH=CH2), 5.33–5.28 (1H, m, NCH), 5.17 (1H,
dq, J = 17.2, 1.5 Hz, OCH2CH=CHtHc), 5.10 (1H, dq, J = 10.4, 1.5 Hz, OCH2CH=CHtHc), 4.74 (1H, d, J = 9.1
Hz, CHOAllyl), 3.87 (1H, ddt, J = 6.3, 4.6, 1.5 Hz, OCHaHbCH=CH2), 3.83 (3H, s, OCH3), 3.74 (1H, ddt, J =
12.7, 6.3, 1.5 Hz, OCHaHbCH=CH2), 3.54 (1H, dd, J = 11.5, 8.4 Hz, SCHaHb), 3.04 (1H, dd, J = 11.5, 1.2 Hz,
SCHaHb), 2.42–2.29 (1H, m, CH(CH3)2), 1.08 (3H, d, J = 6.8 Hz, CHCH3), 1.01 (3H, d, J = 6.9 Hz, CHCH3).
13C NMR (CDCl3, 100.6 MHz) δ 203.2 (C), 170.3 (C), 160.3 (C), 134.2 (CH), 129.4 (CH, C), 117.2 (CH2),
114.3 (CH), 81.2 (CH), 72.0 (CH), 69.6 (CH2), 62.6 (CH), 55.4 (CH3), 30.7 (CH), 30.0 (CH2), 19.2 (CH3),
17.7 (CH3). HRMS (+ESI): m/z calc. for C19H24N4NaO3S2 [M+Na]+: 443.1182, found: 443.1188.

(4S)-N-[(2R,3R)-2-Azido-3-benzyloxy-3-(4-methoxyphenyl)propanoyl]-4-isopropyl-1,3-thiazoli-
dine-2-thione (4j)
S O OBn

S N
N3
OMe

4j

The reaction was performed from 2 (122 mg, 0.5 mmol) and 4-methoxybenzaldehyde dibenzyl acetal
(j, 184 mg, 0.55 mmol) according to the general procedure to afford a 95:5 anti/syn diastereomeric
mixture established by 1H NMR analysis of the crude product. Purification of this crude by column

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

chromatography (hexanes/EtOAc 90:10) provided 8 mg (17 µmol, 3% yield) of the syn diastereomer
and 193 mg (0.41 mmol, 82% yield) of the anti diastereomer 4j as a yellow oil. Rf (hexanes/EtOAc
90:10) 0.20. [α]D +95.4 (c 1.0, CHCl3). IR (ATR) ν 2961, 2871, 2095, 1684, 1609, 1510, 1361, 1243,
1163 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.46–7.42 (2H, m, ArH), 7.30–7.19 (5H, m, ArH), 6.98–6.94 (2H,
m, ArH), 6.50 (1H, d, J = 9.0 Hz, CHN3), 5.28 (1H, ddd, J = 8.3, 5.8, 1.3 Hz, NCH), 4.81 (1H, d, J = 9.0 Hz,
CHOBn), 4.41 (1H, d, J = 11.3 Hz, OCHaHbAr), 4.24 (1H, d, J = 11.3 Hz, OCHaHbAr), 3.84 (3H, s, OCH3),
3.51 (1H, dd, J = 11.5, 8.3 Hz, SCHaHb), 2.99 (1H, dd, J = 11.5, 1.3 Hz, SCHaHb), 2.29–2.17 (1H, m,
CH(CH3)2), 0.90 (3H, d, J = 7.0 Hz, CHCH3), 0.88 (3H, d, J = 6.9 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz)
δ 203.0 (C), 169.9 (C), 160.2 (C), 137.6 (C), 129.4 (CH), 129.1 (C), 128.1 (CH), 127.7 (CH), 127.5 (CH),
114.2 (CH), 81.6 (CH), 71.8 (CH), 70.7 (CH2), 62.6 (CH), 55.3 (CH3), 30.6 (CH), 29.6 (CH2), 19.0 (CH3),
17.0 (CH3). HRMS (+ESI): m/z calcd. for C16H19N4O2S2 [M+H]+: 363.0944; found: 363.0941.

5. Removal of the Chiral Auxiliary from 4a

(2S,3R)-2-Azido-3-methoxy-3-(4-methoxyphenyl)propanol (5)
OMe

HO
N3
OMe
5

A solution of 4a (50 mg, 0.13 mmol) in THF (2 mL) was added via cannula to a mixture of NaBH4 (25
mg, 0.65 mmol) in 30:1 THF/H2O (3 mL) at 0 °C under N2. The resultant mixture was stirred at 0 °C for
30 min and at room temperature for 1.5 h. The reaction was quenched with sat NH4Cl (5 mL) and
extracted with CH2Cl2 (3 × 20 mL). The organic extracts were washed with sat NaHCO3 (2 × 30 mL) and
brine (40 mL), dried (MgSO4), and filtered. The volatiles were evaporated and the crude mixture was
purified by column chromatography (from CH2Cl2 to CH2Cl2/EtOAc 90:10) to afford 28 mg (0.12 mmol,
90% yield) of (2S,3R)-2-azido-3-methoxy-3-(4-methoxyphenyl)propanol (5) as a yellowish oil. Rf
(CH2Cl2/EtOAc 90:10) 0.45. [α]D –117.7 (c 1.35, CHCl3). IR (ATR) ν 3412, 2933, 2105, 1610, 1510,
1244, 1173 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.30–7.24 (2H, m, ArH), 6.96–6.91 (2H, m, ArH), 4.25
(1H, d, J = 6.8 Hz, CHOMe), 3.85–3.72 (2H, m, HOCH2), 3.83 (3H, s, ArOCH3), 3.61–3.54 (1H, m, CHN3),
3.24 (3H, s, CHOCH3), 2.25 (1H, t, J = 6.1 Hz, OH). 13C NMR (CDCl3, 100.6 MHz) δ 159.8, 129.6, 128.6,
114.1, 83.9, 67.2, 62.7, 56.8, 55.3. HRMS (+ESI): m/z calcd. for C11H19N4O3 [M+NH4]+: 255.1452; found:
255.1453.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Methyl (2R,3R)-2-azido-3-methoxy-3-(4-methoxyphenyl)propanoate (6)

O OMe

MeO
N3
OMe
6

A solution of 4a (52 mg, 0.13 mmol) and DMAP (130 µL of a 0.05 M solution in MeOH, 6.5 µmol) in
MeOH (5 mL) was stirred at room temperature under N2 for 20 h. Then, it was diluted in Et2O (10 mL).
The organic layer was washed with 0.5 M NaOH (3 × 20 mL), 0.5 M HCl (3 × 20 mL), and brine (40 mL).
It was dried (MgSO4), filtered, and concentrated in vacuo. The crude mixture was purified by column
chromatography (hexanes/EtOAc 85:15) to afford 32 mg (0.12 mmol, 95% yield; 3% epimerization) of
methyl (2R,3R)-2-azido-3-methoxy-3-(4-methoxyphenyl)propanoate (6) as a yellowish oil. Rf
(hexanes/EtOAc 85:15) 0.35. [α]D –43.7 (c 1.0, CHCl3). IR (ATR) ν 2951, 2105, 1736, 1609, 1510, 1356,
1167 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.31–7.25 (2H, m, ArH), 6.95–6.90 (2H, m, ArH), 4.49 (1H, d, J =
7.4 Hz, CHOMe), 4.02 (1H, d, J = 7.4 Hz, CHN3), 3.82 (3H, s, ArOCH3), 3.79 (3H, s, COOCH3), 3.24 (3H, s,
CHOCH3). 13C NMR (CDCl3, 100.6 MHz) δ 169.1, 160.0, 128.7, 128.4, 114.1, 82.6, 66.3, 56.9, 55.2, 52.6.
HRMS (+ESI): m/z calcd. for C12H19N4O4 [M+NH4]+: 283.1401; found: 283.1399.

Ethyl (4R,5R)-4-azido-5-methoxy-5-(4-methoxyphenyl)-3-oxopentanoate (7)

O O OMe

EtO
N3
OMe
7

Freshly distilled EtOAc (37 µL, 0.38 mmol) was added to a solution of 1 M NaHMDS (375 µL, 0.38
mmol) in THF (1 mL) at –78 °C under N2. The resultant mixture was stirred for 1 h at –78 °C and a
solution of 4a (58 mg, 0.14 mmol) in THF (1 mL) was added via cannula. The reaction mixture was
stirred for 2 h at –78 °C and quenched with sat NH4Cl (2 mL). The aqueous layer was extracted with
EtOAc (3 × 10 mL) and the combined organic extracts were dried (MgSO4) filtered, and concentrated in
vacuo. The crude mixture was purified by column chromatography (CH2Cl2/EtOAc 80:20) to afford 30
mg (90 µmol, 63% yield) of ethyl (4R,5R)-4-azido-5-methoxy-5-(4-methoxyphenyl)-3-oxopentanoate
(7) as a 85:15 mixture of the keto and enol forms established by 1H NMR. Yellowish oil. Rf
(CH2Cl2/EtOAc 80:20) 0.45. [α]D –218.9 (c 1.00, CHCl3). IR (ATR) ν 2935, 2104, 1744, 1719 1512, 1247,
1093 cm–1. 1H NMR (CDCl3, 400 MHz) δ keto form 7.29–7.24 (2H, m, ArH), 6.95–6.90 (2H, m, ArH), 4.44
(1H, d, J = 7.1 Hz, CHOMe), 4.28 (1H, d, J = 7.1 Hz, CHN3), 4.19 (2H, q, J = 7.2 Hz, OCH2CH3), 3.83 (3H, s,
ArOCH3), 3.51 (1H, d, J = 16.1 Hz, COCHaHbCO), 3.37 (1H, d, J = 16.1 Hz, COCHaHbCO), 3.21 (3H, s,
CHOCH3), 1.28 (3H, t, J = 7.2 Hz, COCH2CH3). 13C NMR (CDCl3, 100.6 MHz) δ 199.6, 166.6, 160.0, 128.9,
128.8, 114.1, 83.4, 70.9, 61.5, 56.6, 55.2, 48.2, 14.1. HRMS (+ESI): m/z calcd. for C15H23N4O5 [M+NH4]+:
339.1663; found: 339.1661.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

(2R,3R)-2-Azido-3-methoxy-3-(4-methoxyphenyl)-N-[(S)-1-phenyl-1-ethyl]propanamide (8)
O OMe

N
H
N3
OMe
8

Neat (S)-(−)-α-methylbenzylamine (37 µL, 0.29 mmol) was added to a solution of 4a (51 mg, 0.13
mmol) in CH2Cl2 (0.7 mL) at room temperature under N2 and the resultant mixture was stirred for 2.5
h at room temperature. The volatiles were removed and the crude mixture was purified by column
chromatography (from CH2Cl2 to CH2Cl2/EtOAc 90:10) to afford 42 mg (0.13 mmol, 93% yield) of
(2R,3R)-2-azido-3-methoxy-3-(4-methoxyphenyl)-N-[(S)-1-phenyl-1-ethyl]propanamide (8) as a
yellowish solid, which was recrystallized (CH2Cl2/hexane) to provide yellow needles. Rf (CH2Cl2) 0.20.
Mp 108–110 °C. [α]D –218.9 (c 1.0, CHCl3). IR (ATR) ν 3332, 2930, 2122, 1651 1510, 1248, 1132 cm–1.
1H NMR (CDCl3, 400 MHz) δ 7.21–7.13 (5H, m, ArH), 6.84–6.80 (2H, m, ArH), 6.77–6.72 (2H, m, ArH),
6.31 (1H, d, J = 8.1 Hz, NH), 5.01–4.92 (1H, m, PhCHN), 4.84 (1H, d, J = 3.7 Hz, CHOMe), 4.54 (1H, d, J =
3.7 Hz, CHN3), 3.79 (3H, s, ArOCH3), 3.30 (3H, s, CHOCH3), 1.40 (3H, d, J = 7.0 Hz, PhCHCH3). 13C NMR
(CDCl3, 100.6 MHz) δ 165.4, 159.6, 142.1, 129.1, 128.3, 127.4, 127.1, 125.9, 113.6, 83.6, 67.7, 56.8, 55.1,
48.1, 21.5. HRMS (+ESI): m/z calcd. for C19H23N4O3 [M+H]+: 355.1765; found: 355.1762.

(S) Methyl N-[(2R,3R)-2-azido-3-methoxy-3-(4-methoxyphenyl)propanoyl]leucinate (9)

O OMe
MeO
N
H
O N3
OMe
9

A solution of 4a (57 mg, 0.14 mmol), methyl (S) leucinate hydrochloride (28 mg, 0.15 mmol), and
freshly distilled DIPEA (49 µL, 0.28 mmol) in THF (1 mL) was stirred under N2 at 0 °C for 30 min and at
room temperature for 4 h. The volatiles were removed and the crude was diluted in CH2Cl2 (10 mL)
and washed with 1 M NaOH (3 × 10 mL). The combined organic extracts was dried (MgSO4), filtered,
and concentrated. The resulting mixture was purified by column chromatography (from
hexanes/EtOAc 85:15 to 50:50) to afford 51 mg (0.13 mmol, 96% yield) of methyl (S)-N-[(2R,3R)-2-
azido-3-methoxy-3-(4-methoxyphenyl)propanoyl]leucinate (9) as a yellowish oil. Rf (hexanes/EtOAc
85:15) 0.20. [α]D –97.8 (c 1.0, CHCl3). IR (ATR) ν 3308, 2954, 2104, 1743, 1660 1511, 1246, 1173 cm–1.
1H NMR (CDCl3, 400 MHz) δ 7.26–7.22 (2H, m, ArH), 6.89–6.85 (2H, m, ArH), 6.42 (1H, d, J = 8.4 Hz,
NH), 4.73 (1H, d, J = 4.7 Hz, CHOMe), 4.51 (1H, td, J = 8.7, 5.1 Hz, CHNH), 4.36 (1H, d, J = 4.7 Hz, COCH),
3.81 (3H, s, ArOCH3), 3.61 (3H, s, COOCH3), 3.30 (3H, s, CHOCH3), 1.62–1.45 (3H, m, CH2CH(CH3)2),
0.92 (3H, d, J = 6.1 Hz, CHCH3), 0.91 (3H, d, J = 6.2 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ 172.2 (C),
166.7 (C), 159.9 (C), 129.0 (CH), 127.9 (C), 113.8 (C, CH), 83.6 (CH), 67.6 (CH), 57.0 (CH3), 55.3 (CH3),
52.3 (CH3), 50.7 (CH), 41.7 (CH2), 24.8 (CH), 22.9 (CH3), 22.0 (CH3). HRMS (+ESI): m/z calcd. for
C18H27N4O5 [M+H]+: 379.1976; found: 379.1973.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

6. Additions to diethyl acetals from propargylic aldehydes. General Procedure

Solid (Me3P)2NiCl2 (14.1 mg, 50 µmol, 10 mol %) was added to a solution of (S)-N-azidoacetyl-4-
isopropyl-1,3-thiazolidine-2-thione (2, 122 mg, 0.5 mmol) and the corresponding diethyl acetal (k–t,
1.1 mmol) in CH2Cl2 (1.0 mL) under N2 at room temperature. The resulting solution was cooled to –20
°C. Then, TESOTf (250 µL, 1.1 mmol) and 2,6-lutidine (87 µL, 0.75 mmol) were added dropwise after 3
and 7 min respectively and the reaction mixture was stirred at –20 °C for 15 h.
The reaction mixture was quenched with sat NH4Cl (1.2 mL) and then diluted in H2O (20 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed
with brine (50 mL), dried (MgSO4), and filtered. They were concentrated and filtered through a pad of
silica gel (CH2Cl2); the solvent was removed in vacuo and the resultant oil was purified by column
chromatography (from hexanes/EtOAc 95:5 to 80:20) to afford the desired product 10.

7. Physical and Spectroscopic Data for Adducts 10

(4S)-N-[(2R,3S)-Hexacarbonyl{µ-[η 4-(2-azido-3-ethoxy-5-phenyl-4-
pentynoyl)]dicobalt(Co-Co)}-4-isopropyl-1,3-thiazolidine-2-thione (10k)
S O OEt
Co2(CO)6
S N
N3 Ph

10k

Solid (Me3P)2NiCl2 (28.2 mg, 0.1 mmol, 10 mol %) was added to a solution of (S)-N-azidoacetyl-4-
isopropyl-1,3-thiazolidine-2-thione (2, 244 mg, 1.0 mmol) and hexacarbonyl μ-[η4-(1,1-diethoxy-3-
phenyl-2-propyne)dicobalt (k, 1.085 g, 2.2 mmol) in CH2Cl2 (2.0 mL) under N2 at room temperature.
The resulting solution was cooled to –20 °C. Then, TESOTf (0.5 mL, 2.2 mmol) and 2,6-lutidine (175 µL,
1.5 mmol) were added dropwise after 3 and 7 min respectively and the reaction mixture was stirred at
–20 °C for 15 h.
The reaction mixture was quenched with sat NH4Cl (2.5 mL) and then diluted in H2O (40 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 40 mL). The combined organic extracts were washed
with brine (50 mL), dried (MgSO4), and filtered. They were concentrated and filtered through a pad of
silica gel (CH2Cl2). The solvent was removed in vacuo. Analysis of the resultant oil by 1H NMR
established the formation of a single diastereomer. Then, it was purified by column chromatography
(from hexanes/EtOAc 95:5 to 80:20) to afford 506 mg (0.73 mmol, 73% yield) of the desired adduct
10k as a dark oil. Rf (hexanes/EtOAc 95:5) 0.25. IR (ATR) ν 2963, 2089, 2049, 2010, 1694, 1440, 1341,
1240, 1164 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.52–7.50 (2H, m, ArH), 7.36–7.27 (3H, m, ArH), 5.66
(1H, d, J = 2.1 Hz, CHN3), 5.61 (1H, d, J = 2.1 Hz, CHOEt), 5.31 (1H, ddd, J = 9.0, 5.5, 1.1 Hz, NCH), 3.71–
3.59 (2H, m, OCHaHb, SCHaHb), 3.51–3.44 (1H, m, OCHaHb), 3.10 (1H, dd, J = 11.6, 1.1 Hz, SCHaHb), 2.39–

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

2.28 (1H, m, CH(CH3)2), 1.16 (3H, t, J = 7.0 Hz, OCH2CH3), 1.08 (3H, d, J = 6.8 Hz, CHCH3), 1.03 (3H, d, J =
7.0 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ 202.9 (C), 199.1 (CO), 169.0 (C), 138.1 (C), 129.3 (CH),
128.7 (CH), 127.6 (CH), 93.6 (C), 93.1 (C), 80.8 (CH), 72.2 (CH), 68.0 (CH2), 64.1 (CH), 30.8 (CH), 30.4
(CH2), 19.0 (CH3), 17.3 (CH3), 14.9 (CH3). HRMS (+ESI): m/z calcd. for C23H17Co2N4O7S2 [M–OEt]+:
642.9197; found: 642.9195.

This reaction has been carried out at other scales with similar results: 0.5 mmol (73% yield) and 2
mmol (67% yield).

(4S)-N-[(2R,3S)-Hexacarbonyl{µ-[η 4-(2-azido-3-ethoxy-4-pentynoyl)]dicobalt(Co-Co)}-4-
isopropyl-1,3-thiazolidine-2-thione (10m)
S O OEt
Co2(CO)6
S N
N3 H

10m

The reaction was performed from 2 (122 mg, 0.5 mmol) and hexacarbonyl μ-[η4-(1,1-diethoxy-2-
propyne)dicobalt (m, 456 mg, 1.1 mmol) to afford a 60:40 anti/syn diastereomeric mixture as
established by 1H NMR analysis of the crude product. Purification of this crude by column
chromatography (from hexanes/EtOAc 95:5 to 80:20) afforded 84 mg (0.14 mmol, 28% yield) of the
pure syn diastereomer and 149 mg (0.24 mmol, 49% yield) of the anti diastereomer 10m as a dark oil.
Rf (hexanes/EtOAc 90:10) 0.30. IR (ATR) ν 2965, 2093, 2005, 1964, 1342, 1162 cm–1. 1H NMR (CDCl3,
400 MHz) δ 6.05 (1H, d, J = 2.4 Hz, C≡CH), 5.60 (1H, d, J = 2.9 Hz, CHN3), 5.35–5.29 (2H, m, NCH,
CHOEt), 3.84 (1H, dq, J = 8.5, 7.0 Hz, OCHaHbCH3), 3.62 (1H, dd, J = 11.6, 8.4 Hz, SCHaHb), 3.53 (1H, dq, J
= 8.5, 7.0 Hz, OCHaHbCH3), 3.10 (1H, dd, J = 11.6, 1.2 Hz, SCHaHb), 2.42–2.31 (1H, m, CH(CH3)2), 1.23
(3H, t, J = 7.0 Hz, CH2CH3), 1.10 (3H, d, J = 6.8 Hz, CHCH3), 1.04 (3H, d, J = 6.9 Hz, CHCH3). 13C NMR
(CDCl3, 100.6 MHz) δ 203.0 (C), 199.2 (CO), 169.3 (C), 90.2 (C), 79.5 (CH), 73.7 (CH), 72.2 (CH), 67.2
(CH2), 64.4 (CH), 31.0 (CH), 30.6 (CH2), 19.2 (CH3), 17.5 (CH3), 15.1 (CH3). HRMS (+ESI): m/z calcd. for
C17H13Co2N4O7S2 [M–OEt]+: 566.8884; found: 566.8887.

(4S)-N-[(2R,3S)-Hexacarbonyl{µ-[η 4-(2-azido-3-ethoxy-5-trimethylsilyl-4-
pentynoyl)]dicobalt(Co-Co)}-4-isopropyl-1,3-thiazolidine-2-thione (10n)
S O OEt
Co2(CO)6
S N
N3 TMS

10n

The reaction was performed from 2 (122 mg, 0.5 mmol) and hexacarbonyl μ-[η4-(1,1-diethoxy-3-
trimethylsilyl-2-propyne)dicobalt (n, 535 mg, 1.1 mmol) according to the general procedure to afford a
crude material containing a 94:6 mixture of diastereomers (1H NMR analysis). Chromatographic

S14
 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

purification (from hexanes/EtOAc 95:5 to 80:20) of the crude material gave 243 mg (0.37 mmol, 74%
yield) of pure 10n as a dark oil. Rf (hexanes/EtOAc 95:5) 0.20. IR (ATR) ν 2964, 2085, 2008, 1698,
1338, 1241, 1169 cm–1. 1H NMR (CDCl3, 400 MHz) δ 5.53 (1H, d, J = 1.9 Hz, CHOEt), 5.34 (1H, d, J = 1.9
Hz, CHN3), 5.29 (1H, ddd, J = 8.4, 5.4, 1.0 Hz, NCH), 3.83 (1H, dq, J = 14.0, 7.0 Hz, OCHaHbCH3), 3.64 (1H,
dd, J = 11.6, 8.4 Hz, SCHaHb), 3.54 (1H, dq, J = 14.0, 6.9 Hz, OCHaHbCH3), 3.12 (1H, dd, J = 11.6, 1.0 Hz,
SCHaHb), 2.45–2.35 (1H, m, CH(CH3)2), 1.23 (3H, t, J = 7.0 Hz, CH2CH3), 1.11 (3H, d, J = 6.9 Hz, CHCH3),
1.06 (3H, d, J = 6.9 Hz, CHCH3), 0.35 (9H, s, SiC(CH3)3). 13C NMR (CDCl3, 100.6 MHz) δ 202.9 (C), 200.1
(CO), 169.2 (C), 105.6 (C), 81.8 (CH), 79.2 (C), 72.4 (CH), 68.1 (CH2), 63.9 (CH), 30.8 (CH), 30.5 (CH2),
19.1 (CH3), 17.2 (CH3), 14.9 (CH3), 1.1 (CH3). HRMS (+ESI): m/z calcd. for C20H21Co2N4O7S2Si [M–OEt]+:
638.9279; found: 638.9306.

(4S)-N-[(2R,3S)-Hexacarbonyl{µ-[η 4-(2-azido-3-ethoxy-4-nonynoyl)]dicobalt(Co-Co)}-4-
isopropyl-1,3-thiazolidine-2-thione (10o)
S O OEt
Co2(CO)6
S N
N3 Bu

10o

The reaction was performed from 2 (122 mg, 0.5 mmol) and hexacarbonyl μ-[η4-(1,1-diethoxy-2-
heptyne)dicobalt (o, 517 mg, 1.1 mmol) according to the general procedure to afford a crude mixture
containing a single diastereomer (1H NMR analysis). Chromatographic purification (from
hexanes/EtOAc 95:5 to 80:20) of this crude material gave 208 mg (0.31 mmol, 62% yield) of pure 10o
as a dark oil. Rf (hexanes/EtOAc 90:10) 0.30. IR (ATR) ν 2961, 2088, 2001, 1694, 1344, 1241, 1165 cm–
1. 1 H NMR (CDCl3, 400 MHz) δ 5.48 (1H, d, J = 2.4 Hz, CHOEt), 5.43 (1H, d, J = 2.4 Hz, CHN3), 5.29 (1H,
ddd, J = 8.2, 5.7, 1.3 Hz, NCH), 3.81 (1H, dq, J = 8.3, 6.9 Hz, OCHaHbCH3), 3.65–3.52 (2H, m, OCHaHbCH3,
SCHaHb), 3.11 (1H, dd, J = 11.6, 1.0 Hz, SCHaHb), 2.81 (2H, t, J = 8.2 Hz, C≡CCH2), 2.44–2.34 (1H, m,
CH(CH3)2), 1.72–1.58 (2H, m, CCH2CH2), 1.54–1.42 (2H, m, CCH2CH2), 1.23 (3H, t, J = 7.0 Hz, OCH2CH3),
1.11 (3H, d, J = 6.9 Hz, CHCH3), 1.05 (3H, d, J = 6.9 Hz, CHCH3), 0.98 (3H, d, J = 7.3 Hz, CH2CH2CH3); 13C
NMR (CDCl3, 100.6 MHz) δ 203.0 (C), 199.8 (CO), 169.1 (C), 100.1 (C), 92.4 (C), 81.4 (CH), 72.3 (CH),
68.0 (CH2), 63.4 (CH), 34.1 (CH2), 33.2 (CH2), 30.9 (CH), 30.5 (CH2), 22.7 (CH2), 19.0 (CH3), 17.3 (CH3),
15.0 (CH3), 13.9 (CH3). HRMS (+ESI): m/z calcd. for C21H21Co2N4O7S2 [M–OEt]+: 622.9510; found:
622.9505.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

(4S)-N-[(2R,3S)-Hexacarbonyl{µ-[η 4-(2-azido-8-bromo-3-ethoxy-4-octynoyl)]dicobalt(Co-Co)}-
4-isopropyl-1,3-thiazolidine-2-thione (10p)
S O OEt
Co2(CO)6
S N
Br
N3

10p

The reaction was performed from 2 (122 mg, 0.5 mmol) and hexacarbonyl μ-[η4-(1,1-diethoxy-2-
heptyne)dicobalt (p, 589 mg, 1.1 mmol) according to the general procedure to afford a crude mixture
containing a single diastereomer (1H NMR analysis). Chromatographic purification (from
hexanes/EtOAc 95:5 to 80:20) of the crude material gave 272 mg (0.37 mmol, 74% yield) of pure 10p
as a dark oil. Rf (hexanes/EtOAc 90:10) 0.25. IR (ATR) ν 2964, 2089, 2002, 1693, 1468, 1344, 1165 cm–
1. 1 H NMR (CDCl3, 400 MHz) δ 5.48 (1H, d, J = 2.5 Hz, CHN3), 5.43 (1H, d, J = 2.5 Hz, EtOCH), 5.31–5.27
(1H, m, NCH), 3.85–3.78 (1H, m, OCHaHbCH3), 3.66–3.55 (4H, m, SCHaHb, OCHaHbCH3, CH2Br), 3.12 (1H,
dd, J = 11.6, 1.2 Hz, SCHaHb), 3.00 (2H, t, J = 8.1 Hz, C≡CCH2), 2.42–2.36 (1H, m, CH(CH3)2), 2.30–2.17
(2H, m, CH2CH2Br), 1.24 (3H, t, J = 7.0 Hz, CH2CH3), 1.11 (3H, d, J = 6.8 Hz, CHCH3), 1.06 (3H, d, J = 6.9
Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ 203.3 (C), 199.6 (CO), 169.1 (C), 97.8 (C), 92.9 (C), 81.6
(CH), 72.4 (CH), 68.4 (CH2), 63.5 (CH), 34.7 (CH2), 32.9 (CH2), 32.3 (CH2), 31.0 (CH), 30.7 (CH2), 19.2
(CH3), 17.4 (CH3), 15.2 (CH3). HRMS (+ESI): m/z calcd. for C20H18BrCo2N4O7S2 [M–OEt]+: 686.8459;
found: 686.8454.

(4S)-N-[(2R,3S)-Hexacarbonyl{µ-[η 4-(2,8-diazido-3-ethoxy-4-octynoyl)]dicobalt(Co-Co)}-4-
isopropyl-1,3-thiazolidine-2-thione (10r)
S O OEt
Co2(CO)6
S N
N3
N3

10r

The reaction was performed from 2 (122 mg, 0.5 mmol) and hexacarbonyl μ-[η4-(6-azido-1,1-
diethoxy-2-hexyne)dicobalt] (r, 547 mg, 1.1 mmol) according to the general procedure to afford a
crude mixture containing a single diastereomer (1H NMR analysis). Chromatographic purification
(from hexanes/EtOAc 90:10 to 80:20) of the crude material gave 272 mg (0.35 mmol, 70% yield) of
pure 10r as a dark oil. Rf (hexanes/EtOAc 90:10) 0.15. IR (ATR) ν 2964, 2088, 1997, 1693, 1345, 1240,
1164 cm–1. 1H NMR (CDCl3, 400 MHz) δ 5.46 (1H, d, J = 2.4 Hz, CHN3), 5.44 (1H, d, J = 2.4 Hz, EtOCH),
5.29 (1H, ddd, J = 8.2, 5.6, 1.0 Hz, NCH), 3.81 (1H, dq, J = 8.5, 6.9 Hz, OCHaHbCH3), 3.66–3.54 (2H, m,
SCHaHb, OCHaHbCH3), 3.48 (2H, t, J = 6.5 Hz, CH2N3), 3.12 (1H, dd, J = 11.5, 0.9 Hz, SCHaHb), 2.91 (2H, t, J
= 8.2 Hz, C≡CCH2), 2.42–2.35 (1H, m, CH(CH3)2), 2.03–1.90 (2H, m, CHCH2), 1.23 (3H, t, J = 7.0 Hz,
CH2CH3), 1.11 (3H, d, J = 6.9 Hz, CHCH3), 1.06 (3H, d, J = 6.9 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ
203.4 (C), 199.7 (CO), 169.1 (C), 98.2 (C), 92.8 (C), 81.7 (CH), 72.5 (CH), 68.4 (CH2), 63.5 (CH), 51.4

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

(CH2), 31.3 (CH2), 31.03 (CH2), 30.98 (CH), 30.7 (CH2), 19.2 (CH3), 17.4 (CH3), 15.2 (CH3). HRMS (+ESI):
m/z calcd. for C20H18Co2N7O7S2 [M–OEt]+: 649.9368; found: 649.9368.

(4S)-N-[(2R,3S)-Hexacarbonyl{µ-[η 4-(2-azido-3-ethoxy-8-pivaloyloxy-4-octynoyl)]dicobalt(Co-
Co)}-4-isopropyl-1,3-thiazolidine-2-thione (10s)
S O OEt
Co2(CO)6
S N
OPiv
N3

10s

According to the general procedure, the reaction was performed from 2 (122 mg, 0.5 mmol) and
hexacarbonyl μ-[η4-(6-azido-1,1-diethoxy-2-hexyne)dicobalt] (r, 547 mg, 1.1 mmol) to afford a crude
mixture containing a single diastereomer (1H NMR analysis). Further chromatographic purification
(from hexanes/EtOAc 90:10 to 80:20) of the crude material gave 280 mg (0.37 mmol, 74% yield) of
pure 10s as a dark oil. Rf (hexanes/EtOAc 90:10) 0.25. IR (ATR) ν 2965, 2089, 2006, 1725, 1694, 1479,
1345, 1155 cm–1. 1H NMR (CDCl3, 400 MHz) δ 5.45 (2H, s, CHN3, EtOCH), 5.31–5.27 (1H, m, NCH), 4.22
(2H, td, J = 6.0, 1.3 Hz, CH2OPiv), 3.80 (1H, dq, J = 8.3, 7.0 Hz, OCHaHbCH3), 3.66–3.53 (2H, m, SCHaHb,
OCHaHbCH3), 3.12 (1H, dd, J = 11.6, 1.0 Hz, SCHaHb), 2.93–2.89 (2H, m, C≡CCH2), 2.45–2.35 (1H, m,
CH(CH3)2), 2.08–1.96 (2H, m, CHCH2), 1.24–1.21 (12H, m, CH2CH3, CCH3), 1.11 (3H, d, J = 6.9 Hz,
CHCH3), 1.06 (3H, d, J = 6.9 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ 203.3 (C), 199.7 (CO), 178.6 (C),
169.2 (C), 98.8 (C), 92.8 (C), 81.7 (CH), 72.5 (CH), 68.3 (CH2), 63,6 (CH2), 63.4 (CH), 38.9 (C), 31.2
(CH2), 31.0 (CH), 30.7 (CH2), 30.2 (CH2), 27.3 (CH3), 19.2 (CH3), 17.4 (CH3), 15.2 (CH3). HRMS (+ESI):
m/z calcd. for C27H36Co2N5O10S2 [M+NH4]+: 772.0562; found: 772.0568.

(4S)-N-[(2R,3S)-Hexacarbonyl{µ-[η 4-(2-azido-8-tert-butyldiphenylsilyloxy-3-ethoxy-4-
octynoyl)]dicobalt(Co-Co)}-4-isopropyl-1,3-thiazolidine-2-thione (10t)
S O OEt
Co2(CO)6
S N
OTBDPS
N3

10t

According to the general procedure, the reaction was performed from 2 (122 mg, 0.5 mmol) and
hexacarbonyl μ-[η4-(6-tert-butyldiphenylsilyloxy-1,1-diethoxy-2-hexyne)dicobalt] (t, 782 mg, 1.1
mmol) to afford a crude mixture containing a single diastereomer (1H NMR analysis). Further
chromatographic purification (from hexanes/EtOAc 90:10 to 80:20) of the crude material gave 344 mg
(0.38 mmol, 76% yield) of pure 10t as a dark oil. Rf (hexanes/EtOAc 90:10) 0.25. IR (ATR) ν 2930,
2088, 2010, 1964, 1427, 1344, 1240 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.68–7.66 (4H, m, ArH), 7.44-
7.36 (6H, m, ArH), 5.46 (2H, s, COCH, EtOCH), 5.32–5.28 (1H, m, NCH), 3.84–3.77 (3H, m, CH2OTBDPS,
OCHaHbCH3), 3.63 (2H, dd, J = 11.6, 8.3 Hz, SCHaHb), 3.58–3.51 (1H, m, OCHaHbCH3), 3.11 (1H, dd, J =
11.6, 0.9 Hz, SCHaHb), 2.97–2.93 (2H, m, C≡CCH2), 2.43–2.35 (1H, m, CH(CH3)2), 1.97–1.86 (2H, m,

S17
 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

CHCH2), 1.21 (3H, t, J = 7.0 Hz, CH2CH3), 1.10 (3H, d, J = 6.8 Hz, CHCH3), 1.06–1.04 (12H, m, CHCH3,
CCH3). 13C NMR (CDCl3, 100.6 MHz) δ 203.1 (C), 199.8 (CO), 169.3 (C), 135.7 (CH), 134.0 (C), 129.8
(CH), 127.8 (CH), 100.2 (C), 92.6 (C), 81.6 (CH), 72.4 (CH), 68.2 (CH2), 63.6 (CH), 63.4 (CH2), 35.1 (CH2),
31.0 (CH), 30.7 (CH2), 30.3 (CH2), 27.0 (CH3), 19.4 (C), 19.2 (CH3), 17.5 (CH3), 15.2 (CH3). HRMS (+ESI):
m/z calcd. for C38H46Co2N5O9S2Si [M+NH4]+: 926.1165; found: 926.1157.

8. Synthesis of derivatives from 10

(2S,3R)-2-Amino-N-tert-butyloxycarbonyl-3-ethoxy-5-phenyl-4-pentyn-1-ol (11)

S O OEt OEt
Co2(CO)6
S N HO
N3 Ph NHBoc Ph
11
10k

i. PMe3, NaOH, THF, rt

CAN, acetone, –78 °C to rt, 1.5 h
ii. Boc2O, THF, rt, 4 h

S O OEt OEt
NaBH4
S N 50:1 THF/H2O, 0 °C to rt, 1.5 h
HO
N3 Ph N3 Ph
19
18

(4S)-N-[(2R,3R)-2-Azido-3-ethoxy-5-phenyl-4-pentynoyl]-4-isopropyl-1,3-thiazolidine-2-thione (18)
A solution of 10k (768 mg, 1.1 mmol) and ceric ammonium nitrate (2.5 g, 4.5 mmol) in acetone (30
mL) was stirred at –78 °C for 30 min and at room temperature for 1.5 h under N2. It was partitioned in
Et2O (30 mL) and brine (50 mL) and the aqueous layer was extracted with Et2O (2 × 30 mL). The
organic extracts were dried (MgSO4), filtered, and the volatiles were evaporated to obtain a yellow oil,
which was purified by column chromatography (hexanes/EtOAc 90:10) to afford 342 mg (0.85 mmol,
76% yield) of 18 as a yellowish oil. Rf (hexanes/EtOAc 90:10) 0.40. [α]D +245.5 (c 1.0, CHCl3). IR (ATR)
ν 2965, 2111, 1698, 1489, 1240, 1164 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.45–7.43 (2H, m, ArH), 7.33–
7.28 (3H, m, ArH), 6.31 (1H, d, J = 6.0 Hz, CHOEt), 5.31 (1H, ddd, J = 8.3, 5.9, 1.3 Hz, NCH), 5.03 (1H, d, J
= 6.0 Hz, COCH), 3.94 (1H, dq, J = 9.1, 7.0 Hz, OCHaHb), 3.59–3.52 (2H, m, OCHaHb, SCHaHb), 3.04 (1H, dd,
J = 11.6, 1.3 Hz, SCHaHb), 2.34–2.26 (1H, m, CH(CH3)2), 1.27 (3H, t, J = 7.0 Hz, CH2CH3), 0.98 (3H, d, J =
6.8 Hz, CHCH3), 0.95 (3H, d, J = 7.0 Hz, CHCH3). 13C NMR (CDCl3, 100.6 MHz) δ 202.9 (C), 167.9 (C),
132.1 (CH), 128.9 (C), 128.4 (CH), 122.1 (C), 88.4 (C), 84.0 (C), 71.9 (CH), 71.2 (CH), 65.2 (CH2), 63.4
(CH), 30.9 (CH), 30.3 (CH2), 19.1 (CH3), 17.6 (CH3), 15.2 (CH3). HRMS (+ESI): m/z calcd. for
C17H17N4OS2 [M–OEt]+: 357.0838; found: 357.0843.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

(2S,3R)-2-Azido-3-ethoxy-5-phenyl-4-pentyn-1-ol (19)
A solution of 18 (342 mg, 0.85 mmol) and NaBH4 (161 mg, 4.3 mmol) in 50:1 THF/H2O (25 mL) was
stirred at 0 °C under N2 for 30 min and at room temperature for 1.5 h. The reaction was quenched with
sat NH4Cl (15 mL) and was extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were
washed with NaHCO3 (2 × 30 mL) and brine (40 mL), dried (MgSO4), filtered, and concentrated. The
crude mixture was purified by column chromatography (from CH2Cl2 to CH2Cl2/EtOAc 90:10) to afford
168 mg (0.77 mmol, 90% yield) of 19 as a yellowish oil. Rf (CH2Cl2) 0.30. [α]D –101.6 (c 1.1, CHCl3). IR
(ATR) ν 3388, 2975, 2094, 1489, 1258, 1091 cm–1. 1H NMR (CDCl3, 400 MHz) δ 7.47–7.44 (2H, m, ArH),
7.34–7.32 (3H, m, ArH), 4.46 (1H, d, J = 6.9 Hz, CHOEt), 3.97–3.92 (2H, m, CHaHbOH, CHN3), 3.82–3.75
(2H, m, CHaHbOH, OCHaHb), 3.58 (1H, dq, J = 9.1, 6.7 Hz, OCHaHb), 1.96 (1H, t, J = 6.3 Hz, CH2OH), 1.30
(1H, J = 7.0 Hz, CH2CH3). 13C NMR (CDCl3, 100.6 MHz) δ 131.8 (CH), 128.8 (CH), 128.3 (CH), 121.9 (C),
88.1 (C), 84.3 (C), 71.1 (CH), 65.9 (CH), 65.3 (CH2), 62.3 (CH2), 15.0 (CH3). HRMS (+ESI): m/z calcd. for
C13H19N4O2 [M+NH4]+: 263.1503; found: 263.1500.

(2S,3R)-2-Amino-N-tert-butyloxycarbonyl-3-ethoxy-5-phenyl-4-pentyn-1-ol (11)
A 1 M solution of PMe3 in THF (1.1 mL, 1.1 mmol) was added to a solution of 19 (168 mg, 0.77 mmol)
and a degassed aqueous solution of 1 M NaOH (0.85 mL, 0.85 mmol) in THF (2.5 mL) at room
temperature under N2. Such an addition produced the formation of bubbles immediately. When the
bubbles stopped appearing (approximately 5 min), Boc2O (185 mg, 0.8 mmol) was added via cannula
(2 mL) and the resultant mixture was stirred for 4 h at room temperature. The reaction was quenched
with a pH 7 buffer solution of phosphate (5 mL) and the mixture was extracted with CH2Cl2 (3 × 10
mL). The combined organic extracts were dried (MgSO4), filtered, and the volatiles were evaporated.
The crude mixture was purified by column chromatography (from CH2Cl2/EtOAc 90:10 to
CH2Cl2/MeOH 90:10) to afford 170 mg (0.53 mmol, 69% yield; 48% overall yield from 10k) of 11 as a
yellowish oil. Rf (CH2Cl2/EtOAc 90:10) 0.40. [α]D –3.1 (c 1.0, CHCl3). IR (ATR) ν 3436 (br), 2975, 2097,
1692, 1489, 1248, 1162 cm–1. 1H NMR (MeOD-d4, 400 MHz) δ 7.46–7.43 (2H, m, ArH), 7.35–7.33 (3H,
m, ArH), 4.73 (1H, d, J = 4.4 Hz, CHOEt), 3.93–3.85 (2H, m, OCHaHbCH3, CHNHBoc), 3.75 (1H, dd, J =
11.1, 6.2 Hz, CHaHbOH), 3.67 (1H, dd, J = 11.1, 6.5 Hz, CHaHbOH), 3.59–3.51 (1H, m, OCHaHbCH3), 1.46
(9H, s, C(CH3)3), 1.26 (3H, t, J = 6.5 Hz, CH2CH3). 13C NMR (MeOD-d4, 100.6 MHz) δ 158.2 (C), 132.7
(CH), 129.6 (CH), 129.4 (CH), 123.9 (C), 87.4 (C), 87.1 (C), 80.4 (C), 70.3 (CH), 65.9 (CH2), 62.0 (CH2),
57.4 (CH), 28.8 (CH3), 15.4 (CH3). HRMS (+ESI): m/z calcd. for C18H26NO4 [M+H]+: 320.1856; found:
320.1858.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

(2S,3R)-2-Amino-N-tert-butyloxycarbonyl-3-ethoxy-5-phenyl-1-pentanol (12)
OEt

HO Ph
NHBoc
12

A mixture of 11 (40 mg, 0.13 mmol) and 10% Pd/C (6.9 mg) in MeOH (0.3 mL) was stirred at room
temperature under H2 (balloon) for 2 h. The reaction mixture was filtered throught a pad of Celite®
using EtOAc as eluent and the volatiles were evaporated in vacuo. Purification of the resultant crude
mixture by column chromatography (CH2Cl2/EtOAc 90:10) afforded 39 mg (0.12 mmol, 95% yield) of
12 as a colorless oil. Rf (CH2Cl2/EtOAc 90:10) 0.20. [α]D +21.1 (c 1.0, CHCl3). IR (ATR) ν 3443 (br),
2973, 1685, 1410, 1365, 1162 cm–1. 1H NMR (MeOD-d4, 400 MHz) δ 7.28–7.14 (5H, m, ArH), 3.78 (1H,
dt, J = 6.6, 2.5 Hz, CHOEt), 3.66–3.50 (5H, m, OCH2CH3, CHNHBoc, CH2OH), 2.72–2.64 (2H, m, CH2Ph),
1.85–1.73 (2H, m, CH2CH2Ph), 1.46 (9H, s, C(CH3)3), 1.19 (3H, t, J = 7.0 Hz, CH2CH3). 13C NMR (MeOD-d4,
100.6 MHz) δ 158.3 (C), 143.4 (C), 129.39 (CH), 129.37 (CH), 126.8 (CH), 80.2 (C), 78.7 (CH), 67.0
(CH2), 62.4 (CH2), 55.5 (CH), 34.1 (CH2), 33.0 (CH2), 28.8 (CH3), 16.0 (CH3). HRMS (+ESI): m/z calcd. for
C18H30NO4 [M+H]+: 324.2169; found: 324.2170.

(2S,3R,4Z)-2-Amino-N-tert-butyloxycarbonyl-3-ethoxy-5-phenyl-4-penten-1-ol (13)
OEt Ph

HO
NHBoc
13

A mixture of 11 (30 mg, 94 µmol), 5% Lindlar catalyst (10 mg) and quinoline (13 µL, 0.11 mmol) in
EtOAc (1 mL) was stirred under H2 (balloon) at room temperature for 18 h. The reaction mixture was
filtered throught a pad of Celite® using CH2Cl2 as eluent and the volatiles were evaporated in vacuo.
Purification of the resultant crude mixture by column chromatography (CH2Cl2/EtOAc 90:10) afforded
27 mg (84 µmol, 90% yield) of 13 as a colorless oil. Rf (CH2Cl2/EtOAc 90:10) 0.70. [α]D +248.0 (c 1.2,
CHCl3). IR (ATR) ν 3444 (br), 2974, 1689, 1493, 1365, 1162 cm–1. 1H NMR (MeOD-d4, 400 MHz) δ
7.35–7.23 (5H, m, ArH), 6.74 (1H, d, J = 11.9 Hz, CH=CHPh), 5.65–5.59 (1H, m, CH=CHPh), 3.78 (1H, dd,
J = 9.9, 2.6 Hz, CHOEt), 3.81–3.77 (1H, m, CHNHBoc), 3.67 (1H, dd, J = 10.8, 7.1 Hz, CHaHbOH), 3.55 (1H,
dd, J = 10.8, 6.1 Hz, CHaHbOH), 3.52–3.44 (1H, m, OCHaHbCH3), 3.21–3.14 (1H, m, OCHaHbCH3), 1.44
(9H, s, C(CH3)3), 1.06 (3H, t, J = 7.0 Hz, CH2CH3). 13C NMR (MeOD-d4, 100.6 MHz) δ 158.2 (C), 138.0 (C),
134.5 (CH), 131.3 (CH), 129.9 (CH), 129.3 (CH), 128.3 (CH), 80.3 (C), 73.8 (CH), 64.9 (CH2), 62.2 (CH2),
57.5 (CH), 28.8 (CH3), 15.5 (CH3). HRMS (+ESI): m/z calcd. for C18H28NO4 [M+H]+: 322.2013; found:
322.2010.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

(2S,3R,4E)-2-Amino-N-tert-butyloxycarbonyl-3-ethoxy-5-phenyl-4-penten-1-ol (14)
OEt

HO Ph
NHBoc
14

A mixture of 11 (23 mg, 72 µmol) and LiAlH4 (8 mg, 0.22 mmol) in THF (1 mL) was stirred at room
temperature for 15 h under N2. The reaction mixture was cooled at 0 °C and quenched with EtOAc (1
mL), and the resultant mixture was stirred at 0 °C for 5 min. Then, 1 M aqueous solution of sodium and
potassium tartrate (1.5 mL) was added, and stirred at room temperature for 1 h. The mixture was
extracted with CH2Cl2 (3 × 5 mL) and the combined organic extracts were dried (MgSO4), filtered, and
concentrated. Purification of the crude mixture by column chromatography (CH2Cl2/EtOAc 80:20)
permitted to recover 12 mg (38 µmol, 53%) of starting material 11 and afforded 7 mg (22 µmol, E/Z
90:10, 30% yield) of 14 as a colorless oil. Rf (Et2O/EtOAc 80:20) 0.30. [α]D +24.7 (c 1.0, CHCl3).
IR (ATR) ν 3440 (br), 2974, 1686, 1495, 1366, 1162 cm–1. 1H NMR (MeOD-d4, 400 MHz) δ 7.41–7.22
(5H, m, ArH), 6.62 (1H, d, J = 16.0 Hz, CH=CHPh), 6.14 (1H, dd, J = 16.0, 7.4 Hz, CH=CHPh), 4.12 (1H, dd,
J = 7.4, 2.9 Hz, CHOEt), 3.70–3.54 (4H, m, CHNHBoc, CH2OH, OCHaHbCH3), 3.43 (1H, dq, J = 9.5, 7.1 Hz,
OCHaHbCH3), 1.40 (9H, s, C(CH3)3), 1.21 (3H, t, J = 7.0 Hz, CH2CH3). 13C NMR (MeOD-d4, 100.6 MHz) δ
158.3 (C), 138.1 (C), 133.8 (CH), 129.6 (CH), 128.7 (CH), 128.7 (CH), 127.6 (CH), 80.2 (C), 80.0 (CH),
65.6 (CH2), 62.4 (CH2), 57.4 (CH), 28.7 (CH3), 15.6 (CH3). HRMS(+ESI): m/z calcd. for C18H28NO4
[M+H]+: 322.2013; found: 322.2022.

(2S,3R)-2-Amino-N-tert-butyloxycarbonyl-3-ethoxy-4-penten-1-ol (15)

S O OEt 1) CAN, acetone, rt, 2 h OEt H2, Lindlar OEt

2) NaBH4, wet THF, rt, 2 h quinoline
Co2(CO)6
S N HO HO
3) K2CO3, MeOH, rt, 3 h EtOAc, rt,16 h
N3 TMS 4) Me3P, Boc2O, NaOH, THF, rt, 5 h NHBoc NHBoc

10n 20 15

(2S,3R)-2-Amino-N-tert-butyloxycarbonyl-3-ethoxy-4-pentyn-1-ol (20)
A solution of 10n (920 mg, 1.4 mmol) and ceric ammonium nitrate (3.1 g, 5.6 mmol) in acetone (30
mL) was stirred at –78 °C for 30 min and at room temperature for 1.5 h under N2. It was partitioned in
Et2O (30 mL) and brine (50 mL) and the aqueous layer was extracted with Et2O (2 × 30 mL). The
organic extracts were dried (MgSO4), filtered, and the volatiles were evaporated to obtain 547 mg
(1.37 mmol, 98% yield) of the decobaltated adduct as a yellow oil, which was used in the next step
without further purification.
A solution of the former oil (518 mg, 1.3 mmol) and NaBH4 (246 mg, 6.5 mmol) in 50:1 THF/H2O (30
mL) was stirred at 0 °C for 30 min and at room temperature for 1.5 h under N2. The reaction was
quenched with sat NH4Cl (20 mL) and was extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were washed with 1 M NaOH (2 × 30 mL) and brine (40 mL), dried (MgSO4), filtered, and

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

concentrated to afford 297 mg (1.23 mmol, 95% yield) of the expected alcohol, which was used in the
next step without further purification.
A mixture of the former oil (262 mg, 1.1 mmol) and K2CO3 (227 mg, 1.64 mmol) in MeOH (4 mL) was
stirred at room temperature for 3 h under N2. The resultant mixture was quenched with sat NH4Cl (3
mL), diluted in H2O (5 mL) and extracted with Et2O (3 × 10 mL). The combined organic extracts were
washed with brine (40 mL), dried (MgSO4), filtered and the volatiles were evaporated to afford 175 mg
(1.03 mmol, 95% yield) of the deprotected alcohol, which was used in the next step without further
purification.
A 1 M solution of PMe3 in THF (1.32 mL, 1.32 mmol) was added to a solution of the former oil (159 mg,
0.94 mmol) and a degassed aqueous solution of 1 M NaOH (1.0 mL, 1.0 mmol) in THF (3.5 mL) at room
temperature under N2. Such an addition produced the formation of bubbles immediately. When the
bubbles stopped appearing (approximately 5 min), Boc2O (225 mg, 1.0 mmol) was added via cannula
(2 mL) and the resultant mixture was stirred for 4 h at room temperature. The reaction was quenched
with a pH 7 buffer solution of phosphates (5 mL) and the mixture was extracted with CH2Cl2 (3 × 10
mL). The combined organic extracts were dried (MgSO4), filtered, and the volatiles were evaporated.
The crude mixture was purified by column chromatography (from CH2Cl2/EtOAc 90:10 to
CH2Cl2/MeOH 95:5) to afford 156 mg (0.64 mmol, 68% yield) of 20 as a yellowish oil. Rf (CH2Cl2/EtOAc
90:10) 0.25. [α]D +6.3 (c 1.0, CHCl3). IR (ATR) ν 3291 (br), 2976, 1685, 1410, 1163 cm–1. 1H NMR
(MeOD-d4, 400 MHz) δ 4.28 (1H, dd, J = 4.6, 2.0 Hz, CHOEt), 3.86–3.77 (2H, m, CHNHBoc, OCHaHb), 3.70
(1H, dd, J = 11.1, 5.9 Hz, HOCHaHb), 3.63 (1H, dd, J = 11.1, 6.5 Hz, HOCHaHb), 3.48 (1H, dq, J = 9.2, 7.0 Hz,
OCHaHb), 2.88–2.87 (1H, m, C≡CH), 1.47 (9H, s, COC(CH3)3), 1.22 (1H, t, J = 7.0 Hz, CH2CH3). 13C NMR
(MeOD-d4, 100.6 MHz) δ 158.2 (C), 81.6 (C), 80.3 (C), 76.2 (C), 69.6 (CH), 65.8 (CH2), 61.7 (CH2), 57.1
(CH), 28.7 (CH3), 15.3 (CH3). HRMS (+ESI): m/z calcd. for [M–Boc]+ C7H14NO2: 144.1019; found:
144.1018.

Hydrogenation of 20
A mixture of 20 (75 mg, 0.31 mmol), 5% Lindlar catalyst (33.9 mg) and quinoline (44 µL, 0.37 mmol)
in EtOAc (3 mL) was stirred under H2 (balloon) at room temperature for 18 h. The reaction mixture
was filtered through a pad of Celite® using CH2Cl2 as eluent and the volatiles were evaporated in
vacuo. Purification of the resultant crude mixture by column chromatography (Et2O/EtOAc 90:10)
afforded 69 mg (0.28 mmol, 91% yield, 56% overall yield from 10n) of (2S,3R) 2-amino-N-tert-
butyloxycarbonyl-3-ethoxy-4-penten-1-ol (15) as a colorless oil. Rf (Et2O/EtOAc 90:10) 0.75. [α]D
+18.5 (c 1.0, CHCl3). IR (ATR) ν 3448 (br), 2975, 1690, 1612, 1499, 1361, 1166 cm–1. 1H NMR (MeOD-
d4, 400 MHz) δ 5.78 (1H, ddd, J = 17.4, 10.4, 7.1 Hz, CH=CH2), 5.32–5.25 (2H, m, CH=CH2), 3.95 (1H, dd, J
= 6.8, 3.0 Hz, CHOEt), 3.66–3.51 (3H, m, CHNHBoc, CHaHbOH, OCHaHbCH3), 3.55–3.49 (1H, m,
CHaHbOH), 3.39 (1H, dq, J = 9.3, 7.0 Hz OCHaHbCH3), 1.46 (9H, s, C(CH3)3), 1.19 (3H, t, J = 7.0 Hz,
CH2CH3). 13C NMR (MeOD-d4, 100.6 MHz) δ 158.2 (C), 137.4 (CH), 118.1 (CH2), 80.2 (two peaks C, CH),

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

65.4 (CH2), 62.2 (CH2), 57.1 (CH), 28.7 (CH3), 15.5 (CH3). HRMS (+ESI): m/z calcd. for C12H24NO4
[M+H]+: 246.1700; found: 246.1702.

(2S,3R,4E)-2-Amino-N-tert-butyloxycarbonyl-3-ethoxy-4-nonen-1-ol (16)
OEt

HO
NHBoc

16

A mixture of 15 (23 mg, 94 µmol), 1-hexene (117 µL, 0.94 mmol), and Hoveyda-Grubbs 2nd Generation
catalyst (2.9 mg, 0.37 µmol) in toluene (0.5 mL) was stirred at room temperature for 2 h under N2.
Then, more catalyst (2.9 mg, 0.37 µmol) was added in one portion and the reaction was further stirred
for 2 h. It was filtered through a pad of Celite® using CH2Cl2 as eluent and the volatiles were
evaporated in vacuo. Purification of the crude mixture by column chromatography (CH2Cl2/EtOAc
90:10) gave 5 mg (0.20 mmol, 22%) of starting material 15 and afforded 17 mg (0.56 mmol, 61% yield,
77% brsm) of (2S,3R,4E)-2-amino-N-tert-butyloxycarbonyl-3-ethoxy-4-nonen-1-ol (16) as a colorless
oil. Rf (CH2Cl2/EtOAc 90:10) 0.20. [α]D +21.9 (c 1.0, CHCl3). IR (ATR) ν 3439 (br), 2973, 1684, 1406,
1365, 1161 cm–1. 1H NMR (MeOD-d4, 400 MHz) δ 5.78 (1H, dt, J = 15.3, 6.8 Hz, CH=CHCH2), 5.37 (1H,
dd, J = 15.3, 7.8 Hz, CHCH=CH), 3.89 (1H, dd, J = 7.8, 3.4 Hz, CHOEt), 3.64–3.46 (4H, m, CHNHBoc,
CH2OH, OCHaHbCH3), 3.42–3.36 (1H, m, OCHaHbCH3), 2.12–2.07 (2H, m, CH=CHCH2), 1.46 (9H, s,
C(CH3)3), 1.46–1.31 (4H, m, CH2(CH2)2CH3), 1.18 (3H, t, J = 7.0 Hz, CH2CH3), 0.94 (3H, t, J = 7.2 Hz,
(CH2)2CH3). 13C NMR (MeOD-d4, 100.6 MHz) δ 156.8 (C), 134.6 (CH), 127.5 (CH), 78.7 (C), 78.4 (CH),
63.6 (CH2), 60.9 (CH2), 56.0 (CH), 31.6 (CH2), 31.0 (CH2), 27.3 (CH3), 21.8 (CH2), 14.1 (CH3), 12.8 (CH3).
HRMS (+ESI): m/z calcd. for C16H32NO4 [M+H]+: 302.2353, found: 302.2360.

(4S)-N-[(2R,3S)-Hexacarbonyl{µ-[η 4-(3-allyloxy-2-azido-4-decynoyl)]dicobalt(Co-Co)}-4-
isopropyl-1,3-thiazolidine-2-thione (10u)

S O O
Co2(CO)6
S N
N3 C5H11

10u

The reaction was carried out according to the general procedure using 2 (244 mg, 1.0 mmol),
(Me3P)2NiCl2 (28.2 mg, 0.1 mmol), hexacarbonyl μ-[η4-(1,1-bis(allyloxy)oct-2-yne)dicobalt (1.12 g, 2.2
mmol), TESOTf (0.5 mL, 2.2 mmol), and 2,6-lutidine (0.18 mL, 1.5 mmol) in CH2Cl2 (2.0 mL) at –20 °C
for 15 h. This reaction gave a crude mixture containing just a single diastereomer as established by 1H
NMR analysis. Further chromatographic purification (from hexanes/EtOAc 95:5 to 80:20) of the crude
afforded 443 mg (0.64 mmol, 64% yield) of the pure anti diastereomer 10u as a dark oil. Rf
(hexanes/EtOAc 90:10) 0.45. IR (ATR) ν 3008, 2959, 2087, 2004, 1997, 1693, 1466, 1342, 1239, 1165
cm–1. 1H NMR (CDCl3, 400 MHz) δ 5.88 (1H, ddt, J = 17.2, 10.6, 5.4 Hz, CH2CH=CH2), 5.52 (2H, s, COCH,
CHOAllyl), 5.38–5.27 (2H, m, NCH, CH2CH=CHaHb), 5.18 (1H, dq, J = 10.5, 1.3 Hz, CH2CH=CHaHb), 4.30

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

(1H, ddt, J = 12.2, 5.4, 1.3 Hz, CHaHbCH=CH2), 4.06 (1H, ddt, J = 12.2, 5.4, 1.3 Hz, CHaHbCH=CH2), 3.62
(1H, dd, J = 11.6, 8.4 Hz, SCHaHb), 3.11 (1H, dd, J = 11.6, 1.1 Hz, SCHaHb), 2.80 (1H, t, J = 8.5 Hz, C≡CCH2),
2.44–2.34 (1H, m, CH(CH3)2), 1.76–1.60 (2H, m, CH2CH2CH3), 1.49–1.34 (4H, m, (CH2)2CH2CH3), 1.10
(3H, d, J = 6.9 Hz, CHCH3), 1.04 (3H, d, J = 7.0 Hz, CHCH3), 0.93 (3H, t, J = 7.2 Hz, CH2CH3). 13C NMR
(CDCl3, 100.6 MHz) δ 203.2 (C), 199.9 (CO), 169.1 (C), 133.4 (CH), 117.7 (CH2), 100.5 (C), 91.8 (C), 80.8
(CH), 72.9 (CH2), 72.5 (CH), 63.8 (CH), 33,6 (CH2), 31.87 (CH2), 31.84 (CH2), 31.1 (CH), 30.5 (CH2), 22.6
(CH2), 19.2 (CH3), 17.3 (CH3), 14.1 (CH3). HRMS (+ESI): m/z calcd. for C22H23Co2N4O7S2 [M–OAllyl]+:
636.9667; found: 636.9672.

Pauson-Khand
S O O H

S N
N3 O
C5H11

17

A solution of 10u (33 mg, 47 µmol) and NMO (50 mg, 0.43 mmol) in CH2Cl2 (1 mL) was stirred at –20
°C for 1 h under N2. Direct purification of the mixture by column chromatography (CH2Cl2) afforded 12
mg (27 µmol, 57% yield) of a 95:5 diastereomeric mixture of cyclic adduct 17 as a colorless oil. Rf
(CH2Cl2/EtOAc 90:10) 0.20. [α]D +156.7 (c 1.0, CHCl3). IR (ATR) ν 2958, 2113, 1706, 1670, 1466, 1365,
1163 cm–1. 1H NMR (MeOD-d4, 400 MHz) δ 6.13 (1H, d, J = 2.7 Hz, CHN3), 5.50 (1H, br s, CHOCH2), 5.44–
5.40 (1H, m, NCH), 4.45 (1H, t, J = 7.8 Hz, OCHaHbCH), 3.61 (1H, dd, J = 11.6, 8.9 Hz, SCHaHb), 3.41–3.34
(1H, m, CH2CHCH2), 3.24 (1H, dd, J = 11.1, 7.9 Hz, OCHaHbCH), 3.13 (1H, dd, J = 11.6, 1.9 Hz, SCHaHb),
2.72 (1H, dd, J = 17.8, 7.2 Hz, CHaHbCO), 2.44–2.35 (1H, m, CH(CH3)2), 2.31 (1H, t, J = 7.6 Hz, C=CCH2),
2.11 (1H, dd, J = 17.8, 3.5 Hz, CHaHbCO), 1.38–1.24 (6H, m, (CH2)3CH3), 1.06 (3H, d, J = 6.8 Hz, CHCH3),
1.02 (3H, d, J = 7.0 Hz, CHCH3), 0.88 (3H, t, J = 6.7 Hz, CH2CH3). 13C NMR (MeOD-d4, 100.6 MHz) δ 208.6
(C), 203.1 (C), 173.2 (C), 168.7 (C), 139.9 (C), 76.3 (CH), 72.6 (CH), 72.4 (CH2), 62.9 (CH), 42.7 (CH),
39.7 (CH2), 32.1 (CH2), 30.8 (CH), 30.0 (CH2), 28.4 (CH2), 24.7 (CH2), 22.7 (CH2), 19.1 (CH3), 17.0 (CH3),
14.2 (CH3). HRMS (+ESI): m/z calcd. for C20H29N4O3S2 [M+H]+: 437.1676; found: 437.1678.

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

9. X-Ray of amide 8

Asymmetric unit of amide 8 with 50% probability ellipsoid contour

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Crystal Structure Report for Amide 8

A yellow prism-like specimen of C19H20N4O3, approximate dimensions 0.051 mm × 0.095 mm

× 0.400 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured
on a D8 Venture system equipped with a multilayer monochromator and a Mo microfocus (λ = 0.71073
Å).
The total exposure time was 4.79 hours. The frames were integrated with the Bruker SAINT software
package using a narrow-frame algorithm. The integration of the data using an orthorhombic unit cell
yielded a total of 5580reflections to a maximum θ angle of 26.38° (0.80 Å resolution), of
which 3139 were independent (average redundancy 1.778, completeness = 98.4%, Rint = 2.40%,
Rsig = 4.20%) and 2810 (89.52%) were greater than 2σ(F2). The final cell constants
of a = 5.4093(2) Å, b = 17.5992(7) Å, c = 18.7390(7) Å, volume = 1783.94(12) Å 3, are based upon the
refinement of the XYZ-centroids of 7198 reflections above 20 σ(I) with 5.114° < 2θ < 52.76°. Data were
corrected for absorption effects using the multi-scan method (SADABS). The ratio of minimum to
maximum apparent transmission was 0.886. The calculated minimum and maximum transmission
coefficients (based on crystal size) are 0.6606 and 0.7454.

The structure was solved and refined using the Bruker SHELXTL Software Package, using the space
group P 21 21 21, with Z = 4 for the formula unit, C19H20N4O3. The final anisotropic full-matrix least-
squares refinement on F2 with 238 variables converged at R1 = 3.54%, for the observed data and wR2
= 10.79% for all data. The goodness-of-fit was 1.177. The largest peak in the final difference electron
density synthesis was 0.239 e-/Å3 and the largest hole was -0.239 e-/Å3 with an RMS deviation
of 0.064 e-/Å3. On the basis of the final model, the calculated density was 1.320 g/cm3 and
F(000), 752 e-.

Autor cristal.lografic: Mercè Font-Bardia,

Unitat de Difracció de RX. Centres Científics i Tecnològics de la Universitat de Barcelona (CCiTUB).
Universitat de Barcelona. Solé i Sabarís 1-3. 08028-Barcelona

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Table 1. Crystal data and structure refinement for Amide 8.

Identification code mo_o31ub171_0m

Empirical formula C19 H22 N4 O3
Formula weight 354.40
Temperature 100(2) K
Wavelength 0.71073 Å
Crystal system Orthorhombic
Space group P 21 21 21
Unit cell dimensions a = 5.4093(2) Å α= 90°.
b = 17.5992(7) Å β= 90°.
c = 18.7390(7) Å γ = 90°.
Volume 1783.94(12) Å3
Z 4
Density (calculated) 1.320 Mg/m3
Absorption coefficient 0.092 mm-1
F(000) 752
Crystal size 0.590 x 0.090 x 0.084 mm3
Theta range for data collection 2.174 to 26.380°.
Index ranges -6<=h<=6, -21<=k<=21, -22<=l<=23
Reflections collected 5580
Independent reflections 3139 [R(int) = 0.0240]
Completeness to theta = 25.242° 98.6 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.7454 and 0.6606
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3139 / 1 / 238
Goodness-of-fit on F2 1.177
Final R indices [I>2sigma(I)] R1 = 0.0354, wR2 = 0.0924
R indices (all data) R1 = 0.0441, wR2 = 0.1079
Absolute structure parameter -0.4(7)
Extinction coefficient n/a
Largest diff. peak and hole 0.239 and -0.239 e.Å-3

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103)
for amide 8. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
________________________________________________________________________________
x y z U(eq)
________________________________________________________________________________
O(1) 5197(4) 6619(1) 1512(1) 31(1)
O(2) 9574(3) 3252(1) 1813(1) 20(1)
O(3) 11379(3) 3922(1) -285(1) 22(1)
N(1) 7229(4) 3976(1) -471(1) 17(1)
N(2) 6148(4) 3179(1) 656(1) 20(1)
N(3) 5513(4) 2706(1) 1106(1) 18(1)
N(4) 4597(5) 2297(2) 1488(1) 29(1)
C(1) 3258(5) 6717(2) 2023(1) 29(1)
C(2) 6240(5) 5911(2) 1474(1) 21(1)
C(3) 5395(5) 5280(2) 1845(1) 21(1)
C(4) 6614(5) 4590(2) 1766(1) 19(1)
C(5) 8667(5) 4518(2) 1332(1) 17(1)
C(6) 9506(5) 5160(2) 967(1) 20(1)
C(7) 8297(5) 5846(2) 1034(1) 23(1)
C(8) 9901(5) 3756(2) 1222(1) 17(1)
C(9) 10930(5) 3472(2) 2434(1) 24(1)
C(10) 8822(5) 3319(2) 581(1) 17(1)
C(11) 9242(5) 3771(2) -107(1) 16(1)
C(12) 7379(5) 4430(2) -1128(1) 17(1)
C(13) 5384(5) 4166(2) -1647(1) 20(1)
C(14) 7184(5) 5269(2) -960(1) 18(1)
C(15) 9031(5) 5771(2) -1180(1) 26(1)
C(16) 8862(6) 6543(2) -1035(2) 34(1)
C(17) 6836(6) 6819(2) -666(2) 34(1)
C(18) 5004(6) 6330(2) -445(1) 29(1)
C(19) 5158(5) 5557(2) -591(1) 23(1)
________________________________________________________________________________

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Table 3. Bond lengths [Å] and angles [°] for amide 8.

_____________________________________________________
O(1)-C(2) 1.369(3)
O(1)-C(1) 1.432(3)
O(2)-C(8) 1.428(3)
O(2)-C(9) 1.429(3)
O(3)-C(11) 1.232(3)
N(1)-C(11) 1.335(3)
N(1)-C(12) 1.470(3)
N(1)-H(1N) 0.8800
N(2)-N(3) 1.234(3)
N(2)-C(10) 1.474(3)
N(3)-N(4) 1.129(3)
C(1)-H(1A) 0.9800
C(1)-H(1B) 0.9800
C(1)-H(1C) 0.9800
C(2)-C(3) 1.388(4)
C(2)-C(7) 1.390(4)
C(3)-C(4) 1.390(4)
C(3)-H(3) 0.9500
C(4)-C(5) 1.383(4)
C(4)-H(4) 0.9500
C(5)-C(6) 1.396(4)
C(5)-C(8) 1.513(4)
C(6)-C(7) 1.379(4)
C(6)-H(6) 0.9500
C(7)-H(7) 0.9500
C(8)-C(10) 1.542(3)
C(8)-H(8) 1.0000
C(9)-H(9A) 0.9800
C(9)-H(9B) 0.9800
C(9)-H(9C) 0.9800
C(10)-C(11) 1.533(3)
C(10)-H(10) 1.0000
C(12)-C(14) 1.513(4)
C(12)-C(13) 1.526(3)
C(12)-H(12) 1.0000
C(13)-H(13A) 0.9800

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

C(13)-H(13B) 0.9800
C(13)-H(13C) 0.9800
C(14)-C(19) 1.391(4)
C(14)-C(15) 1.396(4)
C(15)-C(16) 1.389(4)
C(15)-H(15) 0.9500
C(16)-C(17) 1.383(5)
C(16)-H(16) 0.9500
C(17)-C(18) 1.376(5)
C(17)-H(17) 0.9500
C(18)-C(19) 1.390(4)
C(18)-H(18) 0.9500
C(19)-H(19) 0.9500

C(2)-O(1)-C(1) 116.5(2)
C(8)-O(2)-C(9) 113.61(18)
C(11)-N(1)-C(12) 122.0(2)
C(11)-N(1)-H(1N) 119.0
C(12)-N(1)-H(1N) 119.0
N(3)-N(2)-C(10) 116.8(2)
N(4)-N(3)-N(2) 170.1(3)
O(1)-C(1)-H(1A) 109.5
O(1)-C(1)-H(1B) 109.5
H(1A)-C(1)-H(1B) 109.5
O(1)-C(1)-H(1C) 109.5
H(1A)-C(1)-H(1C) 109.5
H(1B)-C(1)-H(1C) 109.5
O(1)-C(2)-C(3) 124.5(2)
O(1)-C(2)-C(7) 115.8(2)
C(3)-C(2)-C(7) 119.7(3)
C(2)-C(3)-C(4) 119.3(2)
C(2)-C(3)-H(3) 120.3
C(4)-C(3)-H(3) 120.3
C(5)-C(4)-C(3) 121.6(2)
C(5)-C(4)-H(4) 119.2
C(3)-C(4)-H(4) 119.2
C(4)-C(5)-C(6) 118.4(3)
C(4)-C(5)-C(8) 121.0(2)

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

C(6)-C(5)-C(8) 120.6(2)
C(7)-C(6)-C(5) 120.7(2)
C(7)-C(6)-H(6) 119.7
C(5)-C(6)-H(6) 119.7
C(6)-C(7)-C(2) 120.4(2)
C(6)-C(7)-H(7) 119.8
C(2)-C(7)-H(7) 119.8
O(2)-C(8)-C(5) 113.01(19)
O(2)-C(8)-C(10) 104.35(19)
C(5)-C(8)-C(10) 112.4(2)
O(2)-C(8)-H(8) 109.0
C(5)-C(8)-H(8) 109.0
C(10)-C(8)-H(8) 109.0
O(2)-C(9)-H(9A) 109.5
O(2)-C(9)-H(9B) 109.5
H(9A)-C(9)-H(9B) 109.5
O(2)-C(9)-H(9C) 109.5
H(9A)-C(9)-H(9C) 109.5
H(9B)-C(9)-H(9C) 109.5
N(2)-C(10)-C(11) 108.2(2)
N(2)-C(10)-C(8) 112.4(2)
C(11)-C(10)-C(8) 109.9(2)
N(2)-C(10)-H(10) 108.8
C(11)-C(10)-H(10) 108.8
C(8)-C(10)-H(10) 108.8
O(3)-C(11)-N(1) 124.7(2)
O(3)-C(11)-C(10) 118.6(2)
N(1)-C(11)-C(10) 116.7(2)
N(1)-C(12)-C(14) 110.64(19)
N(1)-C(12)-C(13) 109.2(2)
C(14)-C(12)-C(13) 112.4(2)
N(1)-C(12)-H(12) 108.1
C(14)-C(12)-H(12) 108.1
C(13)-C(12)-H(12) 108.1
C(12)-C(13)-H(13A) 109.5
C(12)-C(13)-H(13B) 109.5
H(13A)-C(13)-H(13B) 109.5
C(12)-C(13)-H(13C) 109.5

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

H(13A)-C(13)-H(13C) 109.5
H(13B)-C(13)-H(13C) 109.5
C(19)-C(14)-C(15) 118.7(3)
C(19)-C(14)-C(12) 120.9(2)
C(15)-C(14)-C(12) 120.4(2)
C(16)-C(15)-C(14) 121.0(3)
C(16)-C(15)-H(15) 119.5
C(14)-C(15)-H(15) 119.5
C(17)-C(16)-C(15) 119.5(3)
C(17)-C(16)-H(16) 120.3
C(15)-C(16)-H(16) 120.3
C(18)-C(17)-C(16) 120.2(3)
C(18)-C(17)-H(17) 119.9
C(16)-C(17)-H(17) 119.9
C(17)-C(18)-C(19) 120.6(3)
C(17)-C(18)-H(18) 119.7
C(19)-C(18)-H(18) 119.7
C(18)-C(19)-C(14) 120.1(3)
C(18)-C(19)-H(19) 120.0
C(14)-C(19)-H(19) 120.0
_____________________________________________________________
Symmetry transformations used to generate equivalent atoms:

S32
 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Table 4. Anisotropic displacement parameters (Å2x 103) for amide 8. The anisotropic
displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]
______________________________________________________________________________
U11 U22 U33 U23 U13 U12
______________________________________________________________________________
O(1) 39(1) 24(1) 30(1) 1(1) 5(1) 7(1)
O(2) 20(1) 24(1) 15(1) 6(1) -4(1) -4(1)
O(3) 15(1) 32(1) 19(1) 3(1) 0(1) 1(1)
N(1) 15(1) 21(1) 14(1) 2(1) 0(1) 1(1)
N(2) 19(1) 21(1) 19(1) 6(1) -4(1) -4(1)
N(3) 20(1) 16(1) 18(1) 0(1) -1(1) -2(1)
N(4) 28(1) 28(1) 30(1) 8(1) -3(1) -6(1)
C(1) 33(2) 30(2) 25(1) -5(1) 1(1) 4(1)
C(2) 25(1) 20(1) 18(1) -2(1) -4(1) 1(1)
C(3) 19(1) 27(2) 18(1) -2(1) 0(1) -1(1)
C(4) 18(1) 22(1) 18(1) 1(1) -1(1) -4(1)
C(5) 16(1) 23(1) 13(1) 0(1) -4(1) -4(1)
C(6) 20(1) 25(1) 14(1) -1(1) 1(1) -4(1)
C(7) 27(1) 23(2) 20(1) 3(1) -1(1) -5(1)
C(8) 15(1) 22(1) 14(1) 4(1) -3(1) -2(1)
C(9) 25(1) 32(2) 14(1) 3(1) -5(1) -7(1)
C(10) 16(1) 17(1) 17(1) 1(1) -4(1) 1(1)
C(11) 17(1) 15(1) 15(1) -3(1) -2(1) 1(1)
C(12) 16(1) 22(1) 12(1) 3(1) 2(1) 2(1)
C(13) 20(1) 24(1) 16(1) 2(1) -2(1) 1(1)
C(14) 17(1) 24(1) 14(1) 4(1) -6(1) 0(1)
C(15) 20(1) 31(2) 27(1) 9(1) -5(1) -2(1)
C(16) 31(2) 27(2) 43(2) 9(1) -14(2) -10(1)
C(17) 43(2) 19(2) 39(2) -1(1) -21(2) 1(1)
C(18) 33(2) 28(2) 25(1) -4(1) -5(1) 8(1)
C(19) 24(1) 25(2) 21(1) 1(1) -3(1) 0(1)
______________________________________________________________________________

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Table 5. Hydrogen coordinates (× 104) and isotropic displacement parameters (Å2x 10 3)

for amide 8.
________________________________________________________________________________
x y z U(eq)
________________________________________________________________________________

H(1N) 5767 3835 -313 20

H(1A) 3827 6545 2493 44
H(1B) 1815 6418 1878 44
H(1C) 2803 7255 2049 44
H(3) 3999 5320 2150 25
H(4) 6022 4158 2016 23
H(6) 10923 5124 670 23
H(7) 8875 6277 778 28
H(8) 11710 3837 1143 20
H(9A) 10472 3990 2570 36
H(9B) 12706 3451 2332 36
H(9C) 10543 3123 2827 36
H(10) 9689 2819 540 20
H(12) 9027 4336 -1353 20
H(13A) 3751 4243 -1433 30
H(13B) 5617 3626 -1753 30
H(13C) 5502 4460 -2090 30
H(15) 10425 5582 -1432 31
H(16) 10127 6880 -1189 40
H(17) 6710 7346 -566 41
H(18) 3622 6523 -190 34
H(19) 3878 5225 -439 28
________________________________________________________________________________

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

Table 6. Torsion angles [°] for amide 8_0m.

________________________________________________________________
C(1)-O(1)-C(2)-C(3) 6.1(4)
C(1)-O(1)-C(2)-C(7) -173.1(2)
O(1)-C(2)-C(3)-C(4) -179.7(2)
C(7)-C(2)-C(3)-C(4) -0.5(4)
C(2)-C(3)-C(4)-C(5) 0.7(4)
C(3)-C(4)-C(5)-C(6) -0.1(3)
C(3)-C(4)-C(5)-C(8) -177.0(2)
C(4)-C(5)-C(6)-C(7) -0.6(3)
C(8)-C(5)-C(6)-C(7) 176.2(2)
C(5)-C(6)-C(7)-C(2) 0.8(4)
O(1)-C(2)-C(7)-C(6) 179.0(2)
C(3)-C(2)-C(7)-C(6) -0.2(4)
C(9)-O(2)-C(8)-C(5) -70.6(3)
C(9)-O(2)-C(8)-C(10) 167.0(2)
C(4)-C(5)-C(8)-O(2) -27.5(3)
C(6)-C(5)-C(8)-O(2) 155.7(2)
C(4)-C(5)-C(8)-C(10) 90.3(3)
C(6)-C(5)-C(8)-C(10) -86.5(3)
N(3)-N(2)-C(10)-C(11) 166.9(2)
N(3)-N(2)-C(10)-C(8) -71.5(3)
O(2)-C(8)-C(10)-N(2) 64.0(3)
C(5)-C(8)-C(10)-N(2) -58.8(3)
O(2)-C(8)-C(10)-C(11) -175.4(2)
C(5)-C(8)-C(10)-C(11) 61.7(3)
C(12)-N(1)-C(11)-O(3) -1.6(4)
C(12)-N(1)-C(11)-C(10) 178.1(2)
N(2)-C(10)-C(11)-O(3) -177.2(2)
C(8)-C(10)-C(11)-O(3) 59.8(3)
N(2)-C(10)-C(11)-N(1) 3.1(3)
C(8)-C(10)-C(11)-N(1) -119.9(2)
C(11)-N(1)-C(12)-C(14) -92.0(3)
C(11)-N(1)-C(12)-C(13) 143.8(2)
N(1)-C(12)-C(14)-C(19) -56.6(3)
C(13)-C(12)-C(14)-C(19) 65.8(3)
N(1)-C(12)-C(14)-C(15) 124.1(2)
C(13)-C(12)-C(14)-C(15) -113.5(3)

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 Stereoselective and Catalytic Synthesis of anti β-Alkoxy-α-Azido Carboxylic Derivatives
Javier Fernández-Valparís, Pedro Romea, Fèlix Urpí, and Mercè Font-Bardia

C(19)-C(14)-C(15)-C(16) 0.0(4)
C(12)-C(14)-C(15)-C(16) 179.3(2)
C(14)-C(15)-C(16)-C(17) 0.2(4)
C(15)-C(16)-C(17)-C(18) 0.0(4)
C(16)-C(17)-C(18)-C(19) -0.3(4)
C(17)-C(18)-C(19)-C(14) 0.5(4)
C(15)-C(14)-C(19)-C(18) -0.3(4)
C(12)-C(14)-C(19)-C(18) -179.6(2)
________________________________________________________________
Symmetry transformations used to generate equivalent atoms:

S36