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DOI: 10.1055/s-0028-1087940
Azide-Free Synthesis of Oseltamivir from l-Methionine
Publikationsverlauf
Publikationsdatum:
09. März 2009 (online)
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Abstract
Highly enantioselective synthesis of oseltamivir has been achieved starting from l-methionine, in which Staudinger reaction is utilized for the alignment of three contiguous chiral centers of oseltamivir. The present method would lead to an alternative synthesis of oseltamivir that avoids the use of hazardous azide reagents.
Key words
anti-influenza drugs - tamiflu - Staudinger reaction - hydroformylations - intramolecular aldol condensation
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Wallace GA.Scott RW.Heathcock CH. J. Org. Chem. 2000, 65: 4145 - A mixture of 7b (1.55 g, ca. 3.22 mmol), NaHCO3 (2.70 g, 32.2 mmol), α-pinene (10 mL), and decalins (10 mL) was placed into a 100 mL round-bottomed flask fitted with a reflux condenser. The reaction mixture was deoxygenated by alternate evacuation-argon flush cycles (five iterations) and heated with vigorous stirring at 150-155 ˚C for 6 h under argon atmosphere. After being cooled to r.t., the reaction mixture was partitioned between H2O (30 mL) and EtOAc (30 mL). The organic layer separated was washed with brine (2 × 30 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-EtOAc, 1:0 to 20:1 to 10:1 to 6:1) to give olefin 8a as a white solid (1.09 g, 81% from 7a); [α]D ²6 -93.6 (c 1.03, CHCl3); mp 116.9-117.4 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 7.35 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 5.92 (ddd, J = 7.6, 10.4, 17.0 Hz, 1 H), 5.30 (d, J = 9.5 Hz, 1 H), 5.07 (d, J = 10.4 Hz, 1 H), 5.00 (d, J = 17.0 Hz, 1 H), 4.94 (m, 1 H), 4.78 (d, J = 5.5 Hz, 1 H), 4.38 (dd, J = 5.1, 5.5 Hz, 1 H), 3.79 (s, 3 H), 3.60 (tt, J = 5.5, 5.5 Hz, 1 H), 1.72 (m, 2 H), 1.62 (m, 2 H), 1.45 (br s, 9 H), 0.95 (t, J = 7.5 Hz, 6 H). ¹³C NMR (125 MHz, CDCl3): δ = 165.2, 156.4, 133.8, 130.7, 118.6, 114.5, 106.3, 84.4, 81.0, 79.7, 57.5, 55.5, 52.3, 28.4, 26.5, 25.5, 9.6, 9.3. For thermal elimination of a methionine-derived sulfoxide, see:
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References and Notes
Present address: School of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Sagamiko, Sagamihara, 229-0195, Japan.
12The desired cis-β-lactam 7a was easily purified by trituration in
cold MeOH to remove byproducts such as minor stereoisomers (ca.
5%) and N-(4-methoxyphenyl)-
(3-pentyloxy)acetamide.
Compound 7a: a white solid; [α]D
²² -119
(c 0.99 CHCl3); mp 161.6-162.6 ˚C. ¹H
NMR (500 MHz, CDCl3): δ = 7.39 (br d, J = 8.9 Hz,
2 H), 6.87 (br d, J = 8.9
Hz, 2 H), 5.09 (br d, J = 10.1
Hz, 1 H), 4.78 (d, J = 5.5
Hz, 1 H), 4.56 (m, 1 H), 4.40 (dd, J = 5.5,
5.8 Hz, 1 H), 3.79 (s, 3 H), 3.61 (tt, J = 5.8, 5.8
Hz, 1 H), 2.55 (ddd, J = 4.6,
8.6, 13.1 Hz, 1 H), 2.38 (ddd, J = 7.9,
8.3, 13.1 Hz, 1 H), 1.93 (m, 1 H), 1.87 (s, 3 H), 1.80 (m, 1 H),
1.72 (m, 2 H), 1.62 (m, 2 H), 1.51-1.43 (two br s, 9 H),
1.94 (m, 6 H). ¹³C NMR (125 MHz, CDCl3): δ = 165.3,
156.6, 155.7, 130.6, 118.4, 114.6, 84.5, 81.1, 79.6, 57.3, 55.5,
48.7, 30.9, 28.8, 28.4, 26.6, 25.5, 15.2, 9.6, 9.4. Anal. Calcd
for C24H38N2O5S: C,
61.77; H, 8.21; N, 6.00. Found: C, 61.87; H, 8.31; N, 6.16.
Daicel CHIRALCEL OD-RH; eluent: MeCN-H2O (10:1); λ = 254 nm; flow rate: 0.3 mL/min; t R(7a) = 7.8 min; t R (ent-7a) = 9.9 min.
15Compound 8c: white solid; [α]D ²5 -14.4 (c 0.86 CHCl3); mp 111.6-111.8 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 7.60-7.55 (br s, 4 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.39 (d, J = 8.8 Hz, 2 H), 6.20 (ddd, J = 6.1, 10.0, 17.0 Hz, 1 H), 5.33-5.26 (m, 3 H), 5.03 (dd, J = 5.2, 10.3 Hz, 1 H), 4.89 (d, J = 5.2 Hz, 1 H), 3.65 (tt, J = 5.5, 5.5 Hz, 1 H), 3.45 (s, 3 H), 1.72 (m, 2 H), 1.61 (m, 2 H), 1.02 (t, J = 7.5 Hz, 3 H), 0.92 (t, J = 7.5 Hz, 3 H). ¹³C NMR (125 MHz, CDCl3): δ = 167.8, 166.0, 156.9, 134.2, 133.5, 131.7, 131.4, 128.1, 123.5, 122.8, 122.7, 119.0, 118.5, 114.5, 113.8, 83.3, 80.3, 57.3, 55.1, 53.0, 26.2, 25.3, 9.4, 9.2. Anal. Calcd for C26H28N2O5: C, 69.63, H, 6.29, N, 6.25. Found: C, 69.25; H, 6.10; N, 6.29.
21Compound 12: off-white solid; [α]D ²³.4 -44.0 (c 1.05, CHCl3); mp 198-199.1 ˚C. ¹H NMR (500 MHz, CDCl3, data of a mixture of rotamers): δ = 9.56 (s, 0.15 H), 9.54 (s, 0.85 H), 7.86-7.72 (m, 4 H), 6.68 (s, 0.15 H), 6.67 (s, 0.85 H), 5.58 (d, J = 7.6 Hz, 0.85 H), 5.26 (d, J = 7.6 Hz, 0.15 H), 4.95-4.87 (m, 0.85 H), 4.75-4.71 (m, 0.85 H), 4.50-4.32 (m, 1.15 H), 4.15-4.10 (m, 0.15 H), 3.46-3.33 (m, 1 H), 3.10-2.97 (m, 1 H), 2.76-2.65 (m, 1 H), 2.05 (s, 0.45 H), 1.78 (s, 2.55 H), 1.60-1.50 (m, 4 H), 1.00-0.85 (m, 6 H). ¹³C NMR (125 MHz, CDCl3, data of a mixture of rotamers): δ = 192.2, 170.3, 168.1, 147.5, 138.8, 134.2, 131.6, 123.4, 82.4, 74.6, 54.3, 47.8, 26.3, 25.7, 25.5, 23.3, 9.6, 9.3. Anal. Calcd for C22H26N2O5: C, 66.32, H, 6.58, N, 7.03. Found: C, 66.06; H, 6.72; N, 6.98.