Azide-Free Synthesis of Oseltamivir from l-Methionine

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.

anti-influenza drugs - tamiflu - Staudinger reaction - ­hydroformylations - intramolecular aldol condensation

References and Notes

1

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

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4l Satoh N. Akiba T. Yokoshima S. Fukuyama T. Tetrahedron  2009,  in press

4m Yamatsugu K. Yin L. Kamijo S. Kimura Y. Kanai M. Shibasaki M. Angew. Chem. Int. Ed.  2009,  48:  1070 

4n Ishikawa H. Suzuki T. Hayashi Y. Angew. Chem. Int. Ed.  2009,  48:  1304 

5 For a recent review on the synthesis of oseltamivir (1), see: Shibasaki M. Kanai M. Eur. J. Org. Chem.  2008,  1839 ; see also ref. 3

6 Mandai T. Oshitari T. Synlett  2009,  783 

For previously reported azide-free syntheses, see:

7a Karpf M. Trussardi R. J. Org. Chem.  2001,  66:  2044 

7b Harrington PJ. Brown JD. Foderaro T. Hughes RC. Org. Process Res. Dev.  2004,  8:  86 

For preparation of cis-β-lactams, see:

8a Palomo C. Cabré F. Ontoria JM. Tetrahedron Lett.  1992,  33:  4819 

8b Palomo C. Cossío FP. Cuevas C. Lecea B. Mielgo A. Román P. Luque A. Martinez-Ripoll M. J. Am. Chem. Soc.  1992,  114:  9360 

For reviews of Staudinger reaction, see:

9a Palomo C. Aizpurua JM. Ganboa I. Oiarbide M. Eur. J. Org. Chem.  1999,  3223 

9b Palomo C. Aizpurua JM. Ganboa I. Oiarbide M. Curr. Med. Chem.  2004,  11:  1837 

For reviews of β-lactams as chiral synthetic building blocks, see:

10a Alcaide B. Almendros P. Curr. Med. Chem.  2004,  11:  1921 

10b Alcaide B. Almendros P. Aragoncillo C. Chem. Rev.  2007,  107:  4437 

11 Wallace GA. Scott RW. Heathcock CH. J. Org. Chem.  2000,  65:  4145 

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.

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:

14a Ohfune Y. Kurokawa N. Tetrahedron Lett.  1984,  25:  1071 

14b 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 

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.

16 Kronenthal DR. Han CY. Taylor MK. J. Org. Chem.  1982,  47:  2765 

17 Cuny GD. Buchwald SL. J. Am. Chem. Soc.  1993,  115:  2066 

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}:

18a Billig E, Abatjoglou AG, and Bryant DR. inventors; US  4668651. 

18b Billig E, Abatjoglou AG, and Bryant DR. inventors; US  4769498.  ; for preparation of BIPHEPHOS, see Supporting Information of ref. 17

19 Fukuyama T. Lin S.-C. Li L. J. Am.Chem. Soc.  1990,  112:  7050 

20a Corey EJ. Danheiser RL. Chandrasekaran S. Siret P. Keck GE. Gras J.-L. J. Am. Chem. Soc.  1978,  100:  8031 

20b Snyder SA. Corey EJ. Tetrahedron Lett.  2006,  47:  2083 

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.