First Examples of a Highly Stereoselective Passerini Reaction: A New Access to Enantiopure Mandelamides

Abstract

Achiral benzaldehydes and isocyanides could be transformed enantioselectively in a Passerini three-component reaction to chiral mandelamides by using a galacturonic acid derivative as chiral inducer.

Key words

α-hydroxy acid derivative - mandelamide - Passerini reaction - multi-component reaction

References

• 2a Coppola GM. Schuster HF. α-Hydroxy Acids in Enantioselective Syntheses   Wiley-VCH; Weinheim: 1997. 
• 2b Seebach D. Hungerbühler E. In Modern Synthetic Methods   Vol. 2:  Scheffold R. Otto Salle Verlag; Frankfurt: 1980.  p.91 
• 3a Su T. Wu Y. Doughan B. Kane-Maguire K. Marlowe CK. Kanter JP. Woolfrey J. Huang B. Wong P. Sinha U. Park G. Malinowski J. Hollenbach S. Scarborough RM. Zhu B.-Y. Bioorg. Med. Chem. Lett.  2001,  11:  2279 
• 3b Mitsuya M. Kobayashi K. Kawakami K. Satoh A. Ogino Y. Kakikawa T. Ohtake N. Kimura T. Hirose H. Sato A. Numazawa T. Hasegawa T. Noguchi K. Mase T. J. Med. Chem.  2000,  43:  5017 
• 4a Zeller M, Jeanguenat A, Lamberth C, and Kunz W. inventors; WO  00/41998.  ; Chem. Abstr. 2000, 133, 104883
• 4b Ort O. Döller U. Reissel W. Lindell SD. Hough TL. Simpson DJ. Chung JP. Pestic. Sci.  1997,  50:  331 
• 5a Pasquier C. Pelinski L. Brocard J. Mortreux A. Agbossou-Niedercorn F. Tetrahedron Lett.  2001,  42:  2809 
• 5b Pasquier C. Eilers J. Reiners I. Martens J. Mortreux A. Agbossou F. Synlett  1998,  1162 
• 5c Pasquier C. Naili S. Pelinski L. Brocard J. Mortreux A. Agbossou F. Tetrahedron: Asymmetry  1998,  9:  193 
• 5d Carpentier J.-F. Mortreux A. Tetrahedron: Asymmetry  1997,  8:  1083 
• 5e Roucoux A. Thieffry L. Carpentier J.-F. Devocelle M. Meliet C. Agbossou F. Mortreux A. Welch AJ. Organometallics  1996,  15:  2440 
• 5f Roucoux A. Devocelle M. Carpentier J.-F. Agbossou F. Mortreux A. Synlett  1995,  358 
• 5g Carpentier J.-F. Agbossou F. Mortreux A. Tetrahedron: Asymmetry  1995,  6:  39 
• 5h Roucoux A. Agbossou F. Mortreux A. Petit F. Tetrahedron: Asymmetry  1993,  4:  2279 
• 5i Hatat C. Kokel N. Mortreux A. Petit F. Tetrahedron Lett.  1990,  31:  4139 
• 6a Chiba T. Miyashita A. Nohira H. Takaya H. Tetrahedron Lett.  1993,  34:  2351 
• 6b Chiba T. Miyashita A. Nohira H. Takaya H. Tetrahedron Lett.  1991,  32:  4745 
• For recent reviews on multi-component reactions see:
• 7a Hulme C. Gore V. Curr. Med. Chem.  2003,  10:  51 
• 7b Ugi I. Pure Appl. Chem.  2001,  73:  187 
• 7c Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
• 7d Dömling A. Curr. Opin. Chem. Biol.  2000,  4:  318 
• 7e Ugi I. Dömling A. Werner B. J. Heterocycl. Chem.  2000,  37:  647 
• 7f Bienayme H. Hulme C. Oddon G. Schmitt P. Chem.-Eur. J.  2000,  6:  3321 
• 7g Weber L. Illgen K. Almstetter M. Synlett  1999,  366 
• 7h Ugi I. J. Prakt. Chem.  1997,  339:  499 
• 7i Armstrong RW. Combs AP. Tempest PA. Brown SD. Keating TA. Acc. Chem. Res.  1996,  29:  123 
• 8a Ross GF. Herdtweck E. Ugi I. Tetrahedron  2002,  58:  6127 
• 8b Oertel K. Zech G. Kunz H. Angew. Chem. Int. Ed.  2000,  39:  1431 
• 8c Linderman RJ. Binet S. Petrich SR. J. Org. Chem.  1999,  64:  336 
• 8d Lehnhoff S. Goebel M. Karl RM. Klösel R. Ugi I. Angew. Chem., Int. Ed. Engl.  1995,  34:  1104 
• 8e Kunz H. Pfrengle W. Rück K. Sager W. Synthesis  1991,  1039 
• 8f Kunz H. Pfrengle W. Sager W. Tetrahedron Lett.  1989,  30:  4109 
• 8g Kunz H. Pfrengle W. J. Am. Chem. Soc.  1988,  110:  651 
• 8h Kunz H. Pfrengle W. Tetrahedron  1988,  44:  5487 
• 9a Demharter A. Ugi I. J. Prakt. Chem.  1993,  335:  244 
• 9b Eberle G. Ugi I. Angew. Chem., Int. Ed. Engl.  1976,  15:  492 
• 10 Moran EJ. Armstrong RW. Tetrahedron Lett.  1991,  32:  3807 
• 11a Ziegler T. Kaisers H.-J. Schlömer R. Koch C. Tetrahedron  1999,  55:  8397 
• 11b Ziegler T. Schlömer R. Koch C. Tetrahedron Lett.  1998,  39:  5957 
• 11c Bock H. Ugi I. J. Prakt. Chem.  1997,  339:  385 
• 12a Herman LW. Sharma V. Kronauge JF. Barbarics E. Herman LA. Piwnica-Worms D. J. Med. Chem.  1995,  38:  2955 
• 12b Westling M. Smith R. Livinghouse T. J. Org. Chem.  1986,  51:  1159 
• 13 Vogel C. Jeschke U. Kramer S. Ott A.-J. Liebigs Ann. Chem.  1997,  737 
• 14 Zeller M, and Lamberth C. inventors; WO  03/41728. 
• 16 Seebach D. Adam G. Gees T. Schiess M. Weigand W. Chem. Ber.  1988,  121:  507 
• 17 Smith MB. March J. Advanced Organic Chemistry   5th Ed.:  Wiley; New York: 2001.  p.1251 
• 18 Cyclohexyl isocyanide and benzyl isocyanide were obtained from Aldrich. For the preparation of o-tolyl isocyanide from commercially available 2-methylformanilide, see: Obrecht R. Herrmann R. Ugi I. Synthesis  1985,  400 

1

Current address: Department of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh, EH9 3JJ, UK.

15

A typical experimental procedure is as follows: A mixture of benzaldehyde (3, 6 mmol), 2-(3,4-dimethoxyphenyl)ethyl isocyanide [12] (4, 6 mmol) and 1,2,3,4-tetra-O-acetyl-α-d-galacturonic acid [13] (5d, 6 mmol) in 15 mL of acetonitrile was stirred for 16 h at r.t. Subsequently, the reaction mixture was diluted with CH₂Cl₂, washed with H₂O, dried over Na₂SO₄ and evaporated. The residue was taken up in a mixture of 1 N NaOH (5 mL) and dioxane (10 mL). This mixture was stirred for 1 h at r.t., acidified to pH 2 with 2 N HCl and extracted with EtOAc. The combined organic layer was dried over Na₂SO₄ and evaporated. The residue was purified by flash chromatography on silica gel (EtOAc/hexane 7:3) to obtain colourless crystals of predominantly (S)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-phenylacetamide (7, 1.2 g, 3.8 mmol, 63%). ¹H NMR (300 MHz, CDCl₃): δ = 2.74 (q, 2 H, NCH₂), 3.49-3.60 (m, 3 H, PhCH₂, OH), 3.83 (s, 3 H, OCH₃), 3.88 (s, 3 H, OCH₃), 5.01 (s, 1 H, CHO), 6.06 (br s, 1 H, NH), 6.57-7.39 (m, 8 H, aromatic H). MS (70 eV): m/z = 315 (M⁺), 316 (M⁺ + 1). Mp: 91-92 °C (Lit. [16] 92-93.5 °C).