Formal total synthesis of (-)-oseltamivir phosphate

Article abstract of DOI:10.1021/jo200698g

An asymmetric synthesis of chiral intermediate 3 for (-)-oseltamivir phosphate has been accomplished from chiral building block 1, which was prepared by catalytic asymmetric synthesis.

Full text of DOI:10.1021/jo200698g

Supporting Information
Formal Total Synthesis of (-)-Oseltamivir Phosphate
Takanori Tanaka†‡, Qitao Tan‡, Hiromu Kawakubo§ and Masahiko Hayashi∗†
†Department of Chemistry, Graduate School of Science, Kobe University, Nada, Kobe 657-501, Japan,
‡Department of Frontier Research and Technology, Headquarters for Innovative Cooperation and Development,
Kobe University, Nada, Kobe 657-8501, Japan, and §API Department, ASAHI KASEI CHEMICALS
CORPORATION, Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan
mhayashi@kobe-u.ac.jp
Table of contents
(1) General Methods and Materials
S1
S2
S4
S5
(2) Experimental Procedures and Compounds Characterization Data
(3) HPLC chart of 3
(4) 1H and 13C NMR spectra
General Methods and Materials
All reactions were performed under argon atmosphere using Schlenk tube techniques and freshly
distilled solvents. All melting points were measured on a Yanaco MP-500D and were uncorrected.
1H and 13C NMR spectra (400 and 100.6 MHz, respectively) were recorded on a JEOL JNM-LA 400
using Me4Si as the internal standard (0 ppm). The following abbreviations are used: s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet. Elemental analyses were performed with a
Yanaco CHN Corder MT-5. Mass spectra were measured on a Thermo Quest LCQ DECA plus.
Optical rotations were measured on a HORIBA SEPA-300 Polarimeter for solution in a 1 dm cell.
Preparative column chromatography was carried out on Fuji Silysia BW-820MH or YMC*GEL
Silica (6 nm I-40—63 ꢀm). Thin layer chromatography (TLC) was carried out on Merck 25 TLC
aluminum sheets silica gel 60 F254. Chiral HPLC was performed on a HITACHI L-2000 series
instrument equipped with an L-2455 Diode Array Detector using chiral columns CHIRALPAC
AD-H (250mm x 4.6mm x 5•m).
S1

Experimental Procedures and Compounds Characterization Data
(1S,2S,3S)-3-methoxymethyl-1,2-epoxycyclohex-4-ene (4):
O
1) MeONa
MeOH,
28 ºC, 8 h
MOMCl
DIPEA
OMOM
O
O
2) AcOH
10 min
CH2Cl2
28 ºC, 10 h
NO2
O
4
1b; >99% ee
To a solution of 1b (1.5 g, 5.8 mmol) in MeOH (15 mL) was added a 0.5 M NaOMe solution (0.6 mL, 0.3
mmol). After stirring at rt for 8 h, the complete disappearance of starting material was indicated by TLC and
acetic acid (18 ꢀL, 0.3 mmol) was added to quench the reaction. Methanol was removed by rotary evaporation
and the residue was purified by chromatography (hexane/EtOAc = 4/1 to 2/1) to give the deprotected compound
as a colorless liquid. To a solution of the deprotected compound in CH2Cl2 (30 mL) was added DIPEA (2.9 mL,
17.3 mmol), followed by addition of MOMCl (1.3 mL, 17.3 mmol). The mixture was stirred for 10 h and H2O
(30 ꢀL) was added to quench the reaction. The aqueous layer was extracted with EtOAc (30 mL x 3). The
combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After evaporation of the
solvent, the residue was purified by chromatography (hexane/EtOAc = 5/1) to give MOM protected compound 4
17
1
as a colorless oil (0.88 g, 99%). Rf = 0.28 (hexane/EtOAc = 3/1); [α]D +118.3 (c 0.5, CHCl3); H NMR (400
MHz, CDCl3): δ 5.6 (br s, 2H), 4.78 (d, J = 7.2 Hz, 1H), 4.75 (d, J = 7.2 Hz, 1H), 4.4 (br s, 1H), 3.40 (s, 3H), 3.2
13
(br s, 1H), 3.3 (br s, 1H), 2.63–2.51 (m, 2H); C NMR (100.6 MHz, CDCl3): δ 125.3, 122.8, 95.9, 68.7, 55.5,
52.4, 50.3, 25.1; MS (ESI) m/z 157 (M + H)+; Anal. calcd. for C8H12O3: C, 61.52; H, 7.74; Found: C, 61.25; H,
7.81.
(1R,2S,3S)-1-azido-3-methoxymethyl-2-(methylsulfonyl)oxycyclohex-4-ene (5):
OMOM
OMOM
NaN3, NH4Cl
MsCl, DIPEA
MsO
N3
O
MeOH, H2O
80 ºC, 24 h
CH2Cl2
26 ºC, 24 h
4
5
To a solution of 4 (440 mg, 2.8 mmol) in MeOH (15 mL) were added NH4Cl (450 mg, 8.4 mmol) and NaN3
(1.27 g, 12.6 mmol) in H2O (5 mL). The mixture was heated to 80 ºC and stirred for 24 h. After cooling to rt,
additional H2O (20 mL) was added to dissolve the solid and MeOH was removed by rotary evaporation. The
aqueous solution was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine
(20 mL) and dried (Na2SO4). After evaporation of the solvent, the residue was dissolved in CH2Cl2 (15 mL). To
the solution, DIPEA (0.70 mL, 4.2 mmol) and MsCl (0.33 mL, 4.2 mmol) were added at 0 ºC. The mixture was
stirred for 24 h and aqueous ammonium chloride solution (15 mL) was added to quench the reaction. The
aqueous layer was extracted with CH2Cl2 (30 mL x 3). The combined organic layers were washed with brine (20
mL) and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography
(hexane/EtOAc = 5/1) to give compound 5 (690 mg, 88%). Rf = 0.17 (hexane/EtOAc = 3/1); m.p. 57–59 ºC;
1
[α]D28 +33.4 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz): δ 5.72 (m, 2H), 4.81 (d, J = 7.2 Hz, 1H), 4.77 (d, J =
7.2 Hz, 1H), 4.65 (dd, J = 10.4, 7.2 Hz, 1H), 4.32 (dd, J = 8.0, 3.6 Hz, 1H), 3.77 (ddd, J = 10.4, 10.4, 6.0 Hz,
1H), 3.43 (s, 3H), 3.18 (s, 3H), 2.63 (m, 1H), 2.27 (m, 1H); 13C NMR (CDCl3, 100.6 MHz): δ 127.3, 125.0, 97.0,
83.5, 76.8, 58.9, 55.9, 39.1, 31.0; MS (ESI) m/z 300 (M + Na)+; Anal. calcd. for C9H15N3O5S: C, 38.98; H, 5.45;
N, 15.15; Found: C, 38.98; H, 5.45; N, 14.76.
S2

(1S,2R,3S)-2-(acetylamino)-1-azido-3-methoxymethylcyclohex-4-ene (6):
1) PPh3, THF NaN3
Ac2O
8% NaHCO3 aq.
OMOM
OMOM
26 ºC, 6 h
NH4Cl
MsO
N3
AcHN
N3
DMF
65 ºC
20 h
hexane, CH2Cl2
20 ºC, 3 h
2) Et3N, H2O
26 ºC, 12 h
5
6
A solution of 5 (430 mg, 1.6 mmol) in THF (10 mL) was stirred at 0 ºC. To the solution, PPh3 (510 mg, 1.95
mmol) was added in three portions. The reaction mixture was stirred at room temperature (20 ºC) for 3 h. After
adding Et3N (0.43 ꢀL, 2.3 mmol) and H2O (0.7 mL), the solution was stirred vigorously for 12 h. Organic
solvent was removed by rotary evaporation, then the residue was extracted with CH2Cl2 (30 mL x 3) and brine
(20 mL). The combined organic layers were dried over Na2SO4. After evaporation of the solvent, P(O)Ph3 and
unreacted PPh3 were removed by chromatography (EtOAc/MeOH = 10/1) to give the aziridine. To a solution of
the aziridine in DMF (15 mL) were added NH4Cl (0.15 g, 2.8 mmol) and NaN3 (450 mg, 6.9 mmol). The mixture
was heated to 65 ºC and stirred for 16 h. After cooling to rt, 5% NaHCO3 aq. (15 mL) was added. The aqueous
solution was extracted with hexane (50 mL x 5) and diethyl ether (50 mL x 5). The combined organic layers
were dried (Na2SO4). After evaporation of the solvent, the residue was dissolved in CH2Cl2 (1.5 mL) and hexane
(1.5 mL). To the solution, 5% NaHCO3 aq. (3.0 mL, 2.8 mmol) and Ac2O (0.13 mL, 1.4 mmol) were added at 0
ºC. The mixture was stirred for 3 h. The aqueous layer was extracted with diethyl ether (30 mL x 3). The
combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After evaporation of the
solvent, the residue was purified by chromatography (hexane/EtOAc = 1/2) to give compound 6 (220 mg, 67%).
1
Rf = 0.48 (EtOAc); m.p. 82–85 ºC; [α]D28 +101.0 (c 0.5, CHCl3); H NMR (CDCl3, 400 MHz): δ 5.53 (m, 2H),
4.87 (d, J = 6.8 Hz, 1H), 4.80 (d, J = 6.8 Hz, 1H), 4.49 (m, 1H), 3.45 (s, 3H), 2.61 (m, 1H), 2.50–2.43 (m, 1H),
2.40–2.31 (m, 2H), 1.26 (br s, 1H); 13C NMR (CDCl3, 100.6 MHz): δ 124.9, 124.0, 95.4, 70.7, 55.5, 33.4, 29.1,
24.7; MS (ESI) m/z 263 (M + Na)+; Anal. calcd. for C10H16N4O3: C, 49.99; H, 6.71; N, 23.32; Found: C, 50.17;
H, 6.85; N, 22.96.
(1S,2R,3S)-2-(acetylamino)-1-(tert-butoxycarbonylamino) -4-cyclohexen-3-one (3):
(Boc)2O
O
OMOM
DMAP
Et3N
(i-PrCO)2O
DMSO
PPh3
H2O
5-10%
HCl/MeOH
AcHN
AcHN
N3
MeOH
18 ºC, 19 h
CH2Cl2
AcO-i-Pr
26 ºC, 24 h 80 ºC, 10 h
BocHN
THF
50 ºC
24 h
6
3
A solution of 6 (230 mg, 0.9 mmol) in MeOH (1 mL) was stirred at 0 ºC. To the solution, 5–10% HCl in
MeOH (5 mL) was added slowly. The reaction mixture was stirred at room temperature (20 ºC) for 20 h.
Organic solvent was removed by rotary evaporation. Further removal of HCl gas was carried out by passing air
over the solution for 1 h. The residue was dissolved in THF (10 mL). To this solution, PPh3 (370 mg, 1.4 mmol)
was added in three portions. The reaction mixture was stirred at room temperature (20 ºC) for 1 h. After adding
H2O (1 mL), the solution was stirred vigorously at 50 ºC for 24 h. Organic solvent was removed by rotary
evaporation and the residue was dissolved in CH2Cl2 (10 mL). To the solution, Boc2O (21 mg, 0.9 mmol) and
Et3N (0.66 mL, 4.8 mmol) were added. After adding 4-dimethylaminopyridine (6.1 mg, 0.05 mmol), the solution
was stirred at 26 ºC for 24 h. Sat. NH4Cl aq. (2 mL) was added to quench the reaction. The aqueous layer was
extracted with CH2Cl2 (30 mL x 3). The combined organic layers were dried over Na2SO4. After evaporation of
the solvent, the residue was purified by chromatography (EtOAc) to give the crude allylic alcohol. This allylic
alcohol was dissolved in i-PrOAc (1.5 mL) and DMSO (135 ꢀL) to which was added isobutyric anhydride (150
ꢀL). The reaction mixture was stirred at 80 ºC for 5 h. The mixture was diluted with 10 mL of EtOAc. The
S3

organic solution was washed with sat. NaHCO3 aq. (10 mL) and brine (10 mL). The combined organic layers
were dried (Na2SO4). After evaporation of the solvent, the residue was purified by chromatography
28
(hexane/EtOAc = 1/1) to give compound 3 (96.7 mg, 40%). Rf = 0.50 (EtOAc); m.p. 142–144 ºC; [α]D -119.6
1
(c 0.14, CHCl3); H NMR (CDCl3, 400 MHz): δ 6.98 (ddd, J = 10.0, 6.4, 2.0 Hz, 1H), 6.36 (br d, J = 6.4 Hz, 1H),
6.15 (dd, J = 10.0, 3.6 Hz, 1H), 5.72 (br d, J = 7.2 Hz, 1H), 4.61 (dd, J = 13.2, 6.8 Hz, 1H), 3.98-3.87 (m, 1H),
2.97 (ddd, J = 19.2, 6.4, 4.8 Hz, 1H), 2.48–2.40 (m, 1H), 2.10 (s, 3H), 1.43 (s, 1H); 13C NMR (CDCl3, 100.6
MHz): δ 194.8, 172.4, 148.7, 132.1, 128.5, 79.5, 59.7, 53.6, 34.2, 28.4, 23.9; MS (ESI) m/z 291 (M + Na)+.
HPLC chart of 3
column, CHIRALPAK AD-H (DAICEL): eluent, hexane–2-propanol (90:10): 0.6 mL/min, detection, 254 nm
S4

1H and 13C NMR spectra
OMOM
MsO
N3
5
S5

OMOM
MsO
N3
5
S6

OMOM
AcHN
N3
6
S7

OMOM
AcHN
N3
6
S8

O
AcHN
BocHN
3
S9

O
AcHN
BocHN
3
S10