Asymmetric α-Amination of Chiral Protected β-Hydroxyaldehydes Catalyzed by Proline

Abstract

Proline-catalyzed α-amination of a variety of chiral β-hydroxyaldehydes followed by reduction step afforded the corresponding chiral 2-hydrazino-1,3-diols in good yields, enantioselectivities and diastereoselectivities.

Key words

amination - organocatalysis - diastereoselectivity - β-­hydroxyaldehyde - 2-hydrazino-1,3-diol - azodicarboxylate

References and Notes

• 1 Xu LW. Luo J. Lu X. Chem. Commun.  2009,  1807 
• 2 Mukherjee S. Yang JW. Hoffmann S. List B. Chem. Rev.  2007,  107:  5471 
• 3 For either diastereoselective or organocatalytic electrophilic α-amination, see: Greck C. Drouillat B. Thomassigny C. Eur. J. Org. Chem.  2004,  1377 
• 4 Bogevig A. Juhl K. Kumaragurubaran N. Zhuang W. Jørgensen KA. Angew. Chem. Int. Ed.  2002,  41:  1790 
• 5 List B. J. Am. Chem. Soc.  2002,  124:  5656 
• 6a Vogt H. Vanderheiden S. Bräse S. Chem. Commun.  2003,  2448 
• 6b Baumann T. Vogt H. Bräse S. Eur. J. Org. Chem.  2007,  266 
• 6c Baumann T. Bächle M. Hartmann C. Bräse S. Eur. J. Org. Chem.  2008,  2207 
• 7a Kumaragurubaran N. Juhl K. Zhuang W. Bogevig A. Jørgensen KA. J. Am. Chem. Soc.  2002,  124:  6254 
• 7b Liu T. Cui H. Zhang Y. Jiang K. Du W. He Z. Chen Y. Org. Lett.  2007,  9:  3671 
• 8a Dahlin N. Bøgevig A. Adolfsson H. Adv. Synth. Catal.  2004,  346:  1101 
• 8b Thomassigny C. Prim D. Greck C. Tetrahedron Lett.  2006,  47:  1117 
• 8c Hayashi Y. Arakate S. Imai Y. Hibino K. Chen QY. Yamaguchi J. Uchimaru T. Chem. Asian. J.  2008,  3:  225 
• 9a de Figueiredo RM. Christmann M. Eur. J. Org. Chem.  2007,  2575 ; and references cited therein
• 9b Sudalai A. Tetrahedron  2007,  63:  9758 
• 9c George S. Suryavanshi GS. Sudalai A. Tetrahedron Lett.  2008,  49:  6791 
• 9d Kalch D. De Rycke N. Moreau X. Greck C. Tetrahedron Lett.  2009,  50:  492 
• 9e Nishikawa Y. Kitajima M. Kogure N. Takayama H. Tetrahedron  2009,  65:  1608 
• 11 To determine the relative configuration of anti-2, we synthesized this compound via diastereoselective electro-philic amination method from ethyl (R)-3-hydroxybutyrate using LDA, ZnBr₂ and DBAD. For this reaction, see: Genêt JP. Jugé S. Mallart S. Tetrahedron Lett.  1998,  29:  6765 
• 13 Ait-Youcef R. Kalch D. Moreau X. Thomassigny C. Greck C. Lett. Org. Chem.  2009,  6:  377 
• 14 Franzén J. Marigo M. Fielenbach D. Kjrsgaard A. Jørgensen KA. J. Am. Chem. Soc.  2005,  127:  18296 
• 16 Bourdreux Y. Drouillat B. Greck C. Synlett  2005,  2086 
• 17 Poupardin O. Greck C. Genêt JP. Synlett  1998,  1279 

10

3-tert-Butyldimethylsilyloxybutanal (1) was synthesized in two steps (TBS protection and DIBAL-H reduction of the ester moiety) from ethyl 3-hydroxybutyrate commercially available in both enantiomeric forms.

12

General Procedure for the Organocatalytic α-Amination: Dibenzylazodicarboxylate (1 mmol) and d- or l-proline (0.2 mmol, 20 mol%) in MeCN (10 mL) were treated with an aldehyde (1.5 mmol) at r.t. The reaction mixture was stirred at this temperature until the yellow color of the azodicarboxylate had disappeared. The mixture was treated with EtOH (10 mL) and NaBH₄ (40 mg) and was stirred for 5 min at 0 ˚C. The reaction was worked up with aq NH₄Cl solution and EtOAc. The organic layers were dried (MgSO₄), filtered, and concentrated. Medium-pressure column chromatography on silica gel with EtOAc-pentane mixture (1:4) gave the desired anti- or syn-2-hydrazino-1,3-diol as a single diastereomer.

15

Characterization of Selected Compounds:
Compound 2: ^¹H NMR (300 MHz, CDCl₃): δ = 0.01-0.05 (m, 6 H), 0.86 (s, 9 H), 1.08-1.16 (m, 3 H), 3.51-3.99 (m, 4 H), 4.15-4.33 (m, 1 H), 5.16-5.29 (m, 4 H), 6.54 (s, 1 H), 7.28-7.37 (m, 10 H). ^¹³C NMR (75 MHz, CDCl₃): δ = -5.1, -4.3, 17.7, 21.1, 25.6, 59.1, 59.6, 66.3, 67.0, 67.4, 68.1, 68.3, 68.5, 127.5, 127.7, 128.0, 128.1, 128.3, 128.4, 128.5, 135.0, 135.4, 135.6, 156.0, 157.0, 158.2, 158.9. MS (ESI): m/z = 525.4 [M + Na⁺]. IR: 3409, 3272, 2955, 2856, 1722, 1268, 1097, 833, 777, 696 cm^-¹. Anal. Calcd for C₂₆H₃₈N₂O₆Si: C, 62.12; H, 7.62; N, 5.57. Found: C, 62.06; H, 7.55; N, 5.48. [α]_D ^²5 -25 (c = 1, CH₂Cl₂) for (S,R)-2; [α]_D ^²5 +24 (c = 1, CH₂Cl₂) for (R,S)-2.
Compound 3: ^¹H NMR (300 MHz, CDCl₃): δ = (-0.01)-0.05 (m, 6 H), 0.81-0.82 (m, 9 H), 1.08-1.18 (m, 3 H), 3.48-4.04 (m, 4 H), 4.20-4.38 (m, 1 H), 5.14-5.30 (m, 4 H), 6.69-6.74 (m, 1 H), 7.32-7.37 (m, 10 H). ^¹³C NMR (75 MHz, CDCl₃): δ = -5.3, -5.2, -4.3, -4.2, 17.6, 21.2, 21.3, 25.5, 25.6, 59.7, 59.8, 64.1, 65.8, 68.1, 68.2, 68.5, 68.7, 127.6, 128.0, 128.1, 128.2, 128.4, 128.5, 135.2, 135.5, 135.8, 156.3, 156.9, 157.6, 158.2. MS (ESI): m/z = 525.4 [M + Na⁺]. IR: 3401, 3270, 2953, 2855, 1721, 1256, 1072, 836, 776, 696 cm^-¹. Anal. Calcd for C₂₆H₃₈N₂O₆Si: C, 62.12; H, 7.62; N, 5.57. Found: C, 62.02; H, 7.35; N, 5.55. [α]_D ^²5 -3 (c = 1, CH₂Cl₂) for (R,R)-3; [α]_D ^²5 +3 (c = 1, CH₂Cl₂) for (S,S)-3.