Organocatalytic Asymmetric Conjugate Nucleophilic Glyoxylation

Abstract

Organocatalytic nucleophilic glyoxylation reactions have been developed for the first time in asymmetric Michael additions of aminonitriles to α,β-unsaturated aldehydes employing iminium activation with a diphenylprolinol catalyst. After reduction and TBS protection or conversion into camphanoyl derivatives of the resulting alcohols, the final 3-substituted 2-ketoesters were ­obtained in acceptable yields over four steps (ee = 83-87%, de = 49-88%). Recrystallisation of the camphanoyl derivatives ­afforded the pure diastereomers (de ³ 98%)

Key words

organocatalysis - aminonitriles - glyoxylation - iminium activation - umpolung

References and Notes

• 1a Hanessian S. Total Synthesis of Natural Products: The Chiron Approach   Pergamon Press; New York: 1983. 
• 1b Nakamura S. Hirata Y. Kurosaki T. Anada M. Kataoka O. Kitagaki S. Hashimoto S. Angew. Chem. Int. Ed.  2003,  42:  5351 
• 1c Rodrigues JAR. Moran PJS. Milagre CDF. Ursini CV. Tetrahedron Lett.  2004,  45:  3579 
• 1d Pollex A. Hiersemann M. Org. Lett.  2005,  7:  5705 
• 2a Dewick PM. Medicinal Natural Products   John Wiley and Sons; New York: 1997.  p.147 
• 2b Marshall WJ. Bangert SK. Clinical Biochemistry   Churchill Livingstone; New York: 1995.  p.611 
• 3a Ocain TD. Rich DH. J. Med. Chem.  1992,  35:  451 
• 3b Patel DV. Rielly-Gauvin K. Ryono DE. Free CA. Smith SA. Petrillo EW. J. Med. Chem.  1993,  36:  2431 
• 3c Adang AEP. de Man APA. Vogel GMT. Grootenhuis PDJ. Smit MJ. Peters CAM. Visser A. Rewinkel JBM. van Dinther T. Lucas H. Kelder J. van Aelst S. Meuleman DG. van Boeckel CAA. J. Med. Chem.  2002,  45:  4419 
• 4a Yuan W. Wong C.-H. Haeggström JZ. Wetterholm A. Samuelsson B. J. Am. Chem. Soc.  1992,  114:  6552 
• 4b Yuan W. Munoz B. Wong C.-H. Haeggström JZ. Wetterholm A. Samuelsson B. J. Med. Chem.  1993,  36:  211 
• 5 Berzelius JJ. Ann. Phys.  1835,  36:  1 
• Reviews:
• 6a Cooper AJL. Ginos JZ. Meister A. Chem. Rev.  1983,  83:  321 
• 6b Kovacs L. Recl. Trav. Chim. Pays-Bas  1993,  112:  471 
• 7a Enders D. Dyker H. Raabe G. Angew. Chem., Int. Ed. Engl.  1992,  31:  618 
• 7b Enders D. Dyker H. Raabe G. Angew. Chem., Int. Ed. Engl.  1993,  32:  421 
• 7c Enders D. Dyker H. Leusink FR. Chem. Eur. J.  1998,  4:  311 
• 8 Tyrell E. Skinner GA. Janes J. Milsom G. Synlett  2002,  1073 
• 9a Abraham L. Körner M. Schwab P. Hiersemann M. Adv. Synth. Catal.  2004,  346:  1281 
• 9b Abraham L. Körner M. Hiersemann M. Tetrahedron Lett.  2004,  45:  3647 
• 10a Asymmetric Organocatalysis   Berkessel A. Gröger H. Wiley-VCH; Weinheim: 2005. 
• 10b Dalko PI. Moinsan L. Angew. Chem. Int. Ed.  2004,  43:  5138 
• 10c Seayad J. List B. Org. Biomol. Chem.  2005,  3:  719 
• 11 Lelais G. MacMillan DWC. Aldrichimica Acta  2006,  39:  79 
• 12a Paras NA. MacMillan DWC. J. Am. Chem. Soc.  2001,  123:  4370 
• 12b Austin JF. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  1172 
• 12c Paras NA. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  7894 
• 12d Brown SP. Goodwin NC. MacMillan DWC. J. Am. Chem. Soc.  2003,  125:  1192 
• 13a Prieto A. Halland N. Jørgensen KA. Org. Lett.  2005,  7:  3897 
• 13b Knudsen KR. Mitchell CET. Ley SV. Chem. Commun.  2006,  66 
• 14 Gotoh H. Masui R. Ogino H. Shoji M. Hayashi Y. Angew. Chem. Int. Ed.  2006,  45:  6853 
• 15 Enders D. Bonten MH. Raabe G. Angew. Chem., Int. Ed.  2007,  46:  2314 
• 16a Seebach D. Angew. Chem., Int. Ed. Engl.  1969,  8:  639 
• 16b Seebach D. Synthesis  1969,  17 
• 17a Taylor MS. Jacobsen EN. J. Am. Chem. Soc.  2003,  125:  11204 
• 17b Balskus EP. Jacobsen EN. J. Am. Chem. Soc.  2006,  128:  6810 
• 17c Poulsen TB. Alemparte C. Saabe S. Bella M. Jørgensen KA. Angew. Chem. Int. Ed.  2005,  44:  2896 
• 17d Li H. Song J. Liu X. Deng L. J. Am. Chem. Soc.  2005,  127:  8948 
• 17e Wu F. Hong R. Khan J. Liu X. Deng L. Angew. Chem. Int. Ed.  2006,  45:  4301 
• 18a Marigo M. Franzén J. Poulsen TB. Zhuang W. Jørgensen KA. J. Am. Chem. Soc.  2005,  127:  6954 
• 18b Franzén J. Marigo M. Fielenbach D. Wabnitz TC. Kjærsgaard A. Jørgensen KA. J. Am. Chem. Soc.  2005,  127:  18296 
• 18c Hayashi Y. Gotoh H. Hayashi T. Shoji M. Angew. Chem. Int. Ed.  2005,  44:  4212 
• 18d Chi Y. Gellman SH. Org. Lett.  2005,  7:  4253 
• 18e Review: Palomo C. Mielgo A. Angew. Chem. Int. Ed.  2006,  45:  7876 
• 19 Enders D. Hüttl MRM. Grondal C. Raabe G. Nature (London)  2006,  441:  861 
• 20a Enders D. Kipphardt H. Gerdes P. Breña-Valle LJ. Bhushan V. Bull. Soc. Chim. Belg.  1988,  97:  691 
• 20b Franzén J. Marigo M. Fielenbach D. Wabnitz TC. Kjaersgaard A. Jørgensen KA. J. Am. Chem. Soc.  2005,  127:  18296 
• 21 Enders D. Dyker H. Raabe G. Runsink J. Synlett  1992,  901 
• 22a Bunnage ME. Chernega AN. Davies SG. Goodwin JC. J. Chem. Soc., Perkin Trans. 1  1994,  2373 
• 22b Davies SG. Hughes DG. Nicholson RL. Smith AD. Wright AJ. Org. Biomol. Chem.  2004,  2:  1549 
• 24a Enders D. Lotter H. Nouv. J. Chim.  1984,  8:  747 
• 24b Raabe G. Zobel E. Fleischhauer J. Gerdes P. Mannes D. Müller E. Enders D. Z. Naturforsch., A: Phys. Sci.  1991,  46:  275 
• 24c Enders D. Mannes D. Raabe G. Synlett  1992,  837 
• 24d Enders D. Kirchhoff J. Mannes D. Raabe G. Synthesis  1995,  659 
• 24e Enders D. Kirchhoff J. Lausberg V. Liebigs Ann.  1996,  1361 
• 24f Enders D. Kirchhoff J. Gerdes P. Mannes D. Raabe G. Runsink J. Boche G. Marsch M. Ahlbrecht H. Sommer H. Eur. J. Org. Chem.  1998,  63 
• 24g Enders D. Shilvock JP. Raabe G. J. Chem. Soc., Perkin Trans. 1  1999,  1617 
• 24h Enders D. Shilvock JP. Chem. Soc. Rev.  2000,  29:  359 
• 24i Enders D. Lausberg V. Signore GD. Berner OM. Synthesis  2002,  4:  515 
• 24j Enders D. Moser M. Tetrahedron Lett.  2003,  44:  8479 
• 24k Enders D. Signore GD. Berner OM. Chirality  2003,  15:  510 
• 24l Gröger H. Chem. Rev.  2003,  103:  2795 
• 24m Enders D. Milovanovic M. Voloshina E. Raabe G. Fleischhauer J. Eur. J. Org. Chem.  2005,  1984 
• 24n Enders D. Milovanovic M. Z. Naturforsch., B: Chem. Sci.  2007,  62:  117 
• 24o North M. Introduction of the Cyanide Group by Addition to C=O, In Science of Synthesis   Vol. 19:  Murahashi S.-I. Georg Thieme Verlag; Stuttgart: 2004.  p.285 

23

CCDC 631143 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.

25

All new compounds were fully characterised (IR, NMR, MS, elemental analysis, optical rotation, melting point).
Organocatalytic Asymmetric Nucleophilic Glyoxylation to 8a - Typical Procedure To a solution of the aminonitrile 1 (840 mg, 4 mmol) in toluene (4.0 mL) were added the aldehyde 3a (280 mg, 0.33 mL, 4 mmol) and the catalyst (S)-2 (293 mg, 20 mol%). The reaction mixture was stirred at r.t. for 2 d, quenched with brine and extracted three times with Et₂O (10 mL). The organic layer was dried over MgSO₄ and concentrated in vacuo. The crude product 4a was dissolved in anhyd THF (8.0 mL), cooled to 0 °C and NaBH₄ (453 mg, 12 mmol) was added. The suspension was slowly treated with MeOH (2 mL), using a syringe pump. After stirring for 1 h, the mixture was quenched with sat. NH₄Cl solution, the organic phase separated and the aqueous phase extracted three times with Et₂O (10 mL). The combined organic phases were washed with brine and H₂O, respectively, dried over MgSO₄ and the solvent was evaporated. The crude product 5a was subsequently dissolved in anhyd THF (32 mL) and TBSCl (0.9 g, 6.0 mmol) was added. The mixture was cooled to 0 °C and slowly treated with a solution of imidazole (0.54 g, 8 mmol) in anhyd THF (8.0 mL). After stirring for 15 min, the mixture was quenched with brine and extracted three times with Et₂O (10 mL). The combined organic phases were washed with H₂O, dried over MgSO₄, and the solvent was evaporated. The crude product 6a was dissolved in THF (40 mL) and aq 2 N AgNO₃ (2.72 g, 16 mmol) was added. After stirring for 2 h, Et₂O (40 mL) was added and the mixture stirred for an additional 30 min. The Ag residues were removed by filtration and washed with Et₂O and H₂O. The aqueous phase was extracted three times with Et₂O (10 mL). The combined organic layers were subsequently washed with brine, dried over MgSO₄ and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (Et₂O-n-pentane, 1:10) to yield 8a (480 mg, 38%) as a colourless oil; ee 83% (determined by ¹H-shift NMR); [α]_D ²⁰ -4.3 (c 0.65, CHCl₃). IR (CHCl₃): 2933, 2886, 2859, 1724, 1558, 1465, 1370, 1290, 1257, 1168, 1099, 1027, 837, 779 cm^-1. ¹H NMR (300 MHz, CDCl₃, TMS): δ = 0.03 [s, 6 H, Si(CH₃)₂], 0.88 [s, 9 H, SiC(CH₃)₃], 1.14 (d, 3 H, J = 7.10 Hz, CHCH ₃), 1.55 [s, 9 H, OC(CH₃)₃], 1.63 (m, 1 H, CH ₂CH₂O), 1.94 (m, 1 H, CH ₂CH₂O), 3.32 (m, 1 H, CHCH₃), 3.65 (t, 3 H, J = 7.05 Hz, CH₂O). ¹³C NMR (75 MHz, CDCl₃): d = -5.42 [Si(CH₃)₂], 15.24 (CHCH₃), 18.32 [SiC(CH₃)₃], 25.94 [SiC(CH₃)₃], 27.88 [OC(CH₃)₃], 34.76 (CH₂CH₂O), 38.93 (CHCH₃), 60.34 (CH₂O), 83.67 [OC(CH₃)₃], 161.28 (CO₂ t-Bu), 198.50 (COCH). MS (CI): m/z (%) = 316 (0.7) [M⁺], 295 (9), 261 (54), 259 (3), 215 (2) [M⁺ - C₅H₉O₂]. Anal. Calcd for C₁₆H₃₂O₄Si: C, 60.72; H, 10.19. Found: C, 60.91; H, 10.08.