Azide-Free Synthesis of Oseltamivir
from l-Methionine

Tetsuta Oshitari; Tadakatsu Mandai

doi:10.1055/s-0028-1087940

LETTER

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;

Abstract

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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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References

References and Notes

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

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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.

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.

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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<A NAME="RU12508ST-14B">14b</A> For our previous protocol of thermal desulfinylation, see also: Mandai T. Matsumoto S. Kohama M. Kawada M. Tsuji J. Saito S. Moriwake T. J. Org. Chem. 1990, 55: 5671

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.

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6,6′-{[3,3′-bis(1,1-dimethylethyl)-5,5′-dimethoxy[1,1′-biphenyl]-2,2′-diyl]bis(oxy)}bis{dibenzo[d,f][1,3,2]dioxa-phosphepine}:

<A NAME="RU12508ST-18A">18a</A> Billig E, Abatjoglou AG, and Bryant DR. inventors; US 4668651.

<A NAME="RU12508ST-18B">18b</A> Billig E, Abatjoglou AG, and Bryant DR. inventors; US 4769498. ; for preparation of BIPHEPHOS, see Supporting Information of ref. 17

<A NAME="RU12508ST-19">19</A> Fukuyama T. Lin S.-C. Li L. J. Am.Chem. Soc. 1990, 112: 7050

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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.