Thiol-Free Synthesis of Oseltamivir and Its Analogues via Organocatalytic Michael Additions of Oxyacetaldehydes to 2-Acylaminonitroalkenes

Abstract

The organocatalytic addition of substituted oxyacetaldehydes to 2-acylaminonitroethenes proceeded with good to high diastereoselectivities and enantioselectivities. The resulting adducts reacted with ethyl 2-(diethoxyphosphoryl) acrylate to afford highly functionalized cyclohexenes. A thiol-free protocol for cyclization has been developed that leads to a separable mixture of two diastereoisomers. The unwanted diastereoisomer can be efficiently epimerized. The resulting cyclohexenes are precursors to oseltamivir and its analogues. The synthesis of the key reagent, 3-pentyloxyaldehyde, was also improved.

Key words

enantioselectivity - Michael addition - cyclization - aminonitroethene - organocatalysis

• References

• 1a Almasi D, Alonso DA, Nájera C. Tetrahedron: Asymmetry 2007; 18: 299
• 1b Vicario JL, Badia D, Carrillo L. Synthesis 2007; 2065
• 1c Tsogoeva SB. Eur. J. Org. Chem. 2007; 1701
• 1d Enders D, Luttgen K, Narine AA. Synthesis 2007; 959
• 1e Enders D, Wang C, Liebich JX. Chem.–Eur. J. 2009; 15: 11058
• 1f Sulzer-Mosse S, Alexakis A. Chem. Commun. 2007; 3123
• 2 Vicario JL, Badía D, Reyes E, Carrillo L. Organocatalytic Enantioselective Conjugate Addition Reactions: A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules. Royal Society of Chemistry; Cambridge: 2010
• 3a García-García P, Ladépęche A, Halder R, List B. Angew. Chem. Int. Ed. 2008; 47: 4719
• 3b Wiesner M, Revell JD, Wennemers H. Angew. Chem. Int. Ed. 2008; 47: 1871
• 3c Belot S, Massaro A, Tenti A, Mordini A, Alexakis A. Org. Lett. 2008; 10: 4557
• 3d Laars M, Ausmees K, Uudsemaa M, Tamm T, Kanger T, Lopp M. J. Org. Chem. 2009; 74: 3772
• 3e Luo R.-S, Weng J, Ai H.-B, Lu G, Chan AS. C. Adv. Synth. Catal. 2009; 351: 2449
• 3f Wu J, Ni B, Headley AD. Org. Lett. 2009; 11: 3354
• 3g Yoshida M, Sato A, Hara S. Org. Biomol. Chem. 2010; 8: 3031
• 4a He T, Qian J.-Y, Song H.-L, Wu X.-Y. Synlett 2009; 3195
• 4b Ma H, Liu K, Zhang F.-G, Zhu C.-L, Nie J, Ma J.-A. J. Org. Chem. 2010; 75: 1402
• 4c Flock AM, Krebs A, Bolm C. Synlett 2010; 1219
• 5 Alcaide B, Almendros P. Angew. Chem. Int. Ed. 2008; 47: 4632
• 6a Quintard A, Alexakis A. Chem. Commun. 2010; 46: 4085
• 6b Reyes E, Vicario JL, Badía D, Carrillo L. Org. Lett. 2006; 8: 6135
• 6c Han B, Xiao Y.-C, He Z.-Q, Chen Y.-C. Org. Lett. 2009; 11: 4660
• 7 Huťka M, Poláčková V, Marák J, Kaniansky D, Šebesta R, Toma Š. Eur. J. Org. Chem. 2010; 6430
• 8a Enders D, Grondal C, Huttl MR. M. Angew. Chem. Int. Ed. 2007; 46: 1570
• 8b Yu X, Wang W. Org. Biomol. Chem. 2008; 6: 2037
• 8c Grondal C, Jeanty M, Enders D. Nat. Chem. 2010; 2: 167
• 9a Vaxelaire C, Winter P, Christmann M. Angew. Chem. Int. Ed. 2011; 50: 3605
• 9b Marques-Lopez E, Herrera RP, Christmann M. Nat. Prod. Rep. 2010; 27: 1138
• 9c de Figueiredo RM, Christmann M. Eur. J. Org. Chem. 2007; 2575
• 10a Shibasaki M, Kanai M, Yamatsugu K. Isr. J. Chem. 2011; 51: 316
• 10b Magano J. Chem. Rev. 2009; 109: 4398
• 10c Shibasaki M, Kanai M. Eur. J. Org. Chem. 2008; 1839
• 10d Farina V, Brown JD. Angew. Chem. Int. Ed. 2006; 45: 7330
• 11a Ishikawa H, Suzuki T, Orita H, Uchimaru T, Hayashi Y. Chem.–Eur. J. 2010; 16: 12616
• 11b Ishikawa H, Suzuki T, Hayashi Y. Angew. Chem. Int. Ed. 2009; 48: 1304
• 12 Zhu S, Yu S, Wang Y, Ma D. Angew. Chem. Int. Ed. 2010; 49: 4656
• 13 Layne SP, Monto AS, Taubenberger JK. Science 2009; 323: 1560
• 14 Krówczyński A, Kozerski L. Synthesis 1983; 489
• 15 Weng J, Li Y.-B, Wang R.-B, Li F.-Q, Liu C, Chan AS. C, Lu G. J. Org. Chem. 2010; 75: 3125
• 16a Marigo M, Wabnitz TC, Fielenbach D, Jørgensen KA. Angew. Chem. Int. Ed. 2005; 44: 794
• 16b Hayashi Y, Gotoh H, Hayashi T, Shoji M. Angew. Chem. Int. Ed. 2005; 44: 4212
• 17 Seebach D, Golinski J. Helv. Chim. Acta 1981; 64: 1413
• 18 Synkola, Slovak Republic, 2011; patent application
• 19 Hon Y.-S, Wong Y.-C, Chang C.-P, Hsieh C.-H. Tetrahedron 2007; 63: 11325
• 20 Yang F, Newsome JJ, Curran DP. J. Am. Chem. Soc. 2006; 128: 14200