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Synlett 2009(5): 787-789  
DOI: 10.1055/s-0028-1087940
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Azide-Free Synthesis of Oseltamivir from l-Methionine

Tetsuta Oshitari, Tadakatsu Mandai*
Department of Life Science, Kurashiki University of Science & the Arts, 2640, Nishinoura, Tsurajima, Kurashiki 712-8505, Japan
Fax: +81(86)4401062; e-Mail: ted@chem.kusa.ac.jp;
Further Information

Publication History

Received 11 December 2008
Publication Date:
09 March 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

    References and Notes

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1

Present address: School of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Sagamiko, Sagamihara, 229-0195, Japan.

12

The 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.

13

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.

15

Compound 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.

21

Compound 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.