Synlett 2010(4): 559-562  
DOI: 10.1055/s-0029-1219182
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Versatile Chiral Pyrrolidine Aldehyde Building-Block for Synthesis and Formal Synthesis of ent-Nakadomarin A

Robert A. Stockman*a,b,c, Paul J. McDermottb, Annabella F. Newtona, Philip Magnus*c
a School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
Fax: +44(115)9513564; e-Mail: Robert.Stockman@Nottingham.ac.uk;
b School of Chemistry, University of East Anglia, Norwich, NR4 7TJ, UK
c Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712-1167, USA
Further Information

Publication History

Received 9 November 2009
Publication Date:
11 January 2010 (online)

Abstract

A stable, simple to synthesise and versatile chiral aldehyde building-block has been developed, its reactivity in Wittig, Horner-Wadsworth-Emmons and Grignard reactions investigated, and its use is demonstrated in a highly efficient synthesis of an intermediate in Dixon’s synthesis of nakadomarin A.

    References and Notes

  • 1a Garner P. Park JM. Org. Synth.  1991,  70:  18 
  • 1b Garner P. Park JM. Malecki E. J. Org. Chem.  1988,  53:  4395 
  • 1c Garner P. Ramakanth S. J. Org. Chem.  1986,  51:  2609 
  • 2 Liang YF. Andersch J. Bols M. J. Chem. Soc., Perkin Trans. 1  2001,  2136 
  • For some recent examples of the use of Garner’s aldehyde in total synthesis, see:
  • 3a Blot V. Jacqemard U. Reissig H.-U. Kleuser B. Synthesis  2009,  759 
  • 3b Guaragna A. D’Alonzo D. Paolella C. Palumbo G. Tetrahedron Lett.  2009,  50:  2045 
  • 3c Ribes C. Falomir E. Carda M. Marco JA. J. Org. Chem.  2009,  73:  7779 
  • 3d Srivastava AJ. Panda G. Chem. Eur. J.  2008,  14:  4675 
  • 3e Passiniemi M. Koskinen AMP. Tetrahedron Lett.  2008,  49:  980 
  • 3f Pearson MSM. Evain M. Mathe-Allainmat M. Lebreton J. Eur. J. Org. Chem.  2007,  27:  4888 
  • 4a Sakai R. Higa T. Jefford CW. Bernardinelli G. J. Am. Chem. Soc.  1986,  108:  6404 
  • 4b Sakai R. Kohmoto S. Higa T. Tetrahedron Lett.  1987,  28:  5493 
  • 5 Koyama H. Oda K. J. Chem. Soc. B  1970,  1330 
  • 6 Petcharee P. Bunyapraphatsara N. Cordell GA. Cowe HJ. Cox PJ. Howie RA. Patt SL. J. Chem. Soc., Perkin Trans. 1  1986,  1551 
  • 7 Stierle AA. Stierle DB. Patacini B. J. Nat. Prod.  2008,  71:  856 
  • 8a Friedman TC. Kline TB. Wilk S. Biochemistry  1985,  24:  3907 
  • 8b Meisch H.-U. Maus R. Z. Naturforsch., C  1983,  38:  563 
  • 9a Rassu G. Pinna L. Spanu P. Ulgheri F. Casiraghi G. Tetrahedron Lett.  1994,  35:  4019 
  • 9b Rassu G. Zanardi F. Battistini L. Gaetani E. Casiraghi G. J. Med. Chem.  1997,  40:  168 
  • 9c Rassu G. Carta P. Pinna L. Battastini L. Zanardi F. Acquotti D. Casiraghi G. Eur. J. Org. Chem.  1999,  1395 
  • 10 Clive DLJ. Yeh VSC. Tetrahedron Lett.  1998,  39:  4789 
  • 11 Jakubec P. Cockfield DM. Dixon DJ. J. Am. Chem. Soc.  2009,  131:  16632 
  • 12 Yoshida Y. Sakakura Y. Aso N. Okada S. Tanabe Y. Tetrahedron  1999,  55:  2183 
  • 13 Compound 18 has also been reported previously in racemic form, see: Martin SF. Chen H.-J. Courtney AK. Liao Y. Patzel M. Ramser MN. Wagman AS. Tetrahedron  1996,  52:  7521.  Data for compound 20: R f = 0.3 (EtOAc); [α]D ²² +86.6 (c 1.0, CHCl3); IR (thin film): 1683 (lactam), 1485 (olefin) cm; ¹H NMR (300 MHz, CDCl3): δ = 5.80 (dt, J = 10.6, 8.5 Hz, 1 H), 5.41 (dd, J = 10.6, 6 Hz, 1 H), 4.26 (dt, J = 6.5, 6 Hz, 1 H), 3.42 (t, J = 5.4 Hz, 2 H), 2.50-2.05 (m, 6 H), 1.91-1.70 (m, 2 H), 1.68-1.49 (m, 2 H); ¹³C NMR (75 MHz, CDCl3): δ = 174.4, 131.9, 130.4, 56.8, 41.0, 30.9, 27.0, 26.4, 25.9, 25.2; MS (CI): m/z (%) = 166 (100) [M + 1]+, 152 (23); HRMS: m/z [M + H]+ calcd for C10H16NO: 166.1232; found: 166.1232. Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.82; H, 9.28; N, 8.51
14

Procedure for the synthesis of chiral aldehyde 2b: A solution of pyroglutamic acid methyl ester (3; 25.7 g, 0.180 mol) in anhydrous CH2Cl2 (500 mL) was cooled to 0 ˚C under an atmosphere of argon. The reaction solution was treated with DMAP (2.19 g, 0.018 mol), Et3N (27.0 mL, 0.198 mol) and (Boc)2O (41.2 g, 0.189 mol). The solution was allowed to warm to r.t. and stirred for 16 h. HCl (1 M, 300 mL) was added, and the organic layer was separated, washed with sat. NaHCO3 (300 mL), dried over Na2SO4, and evaporated in vacuo. Recrystallisation from hexanes-EtOAc gave N-tert-butyloxycarbonylpyroglutamic acid methyl ester (4; 38.74 g, 89%) as colourless needles. Mp 58-65 ˚C; [α]D ²0 -30 (c 2.06, CHCl3); IR (nujol): 1763, 1703 cm; ¹H NMR (400 MHz, CDCl3): δ = 4.61 (dd, J = 9.4, 3 Hz, 1 H), 3.75-3.74 (m, 3 H), 2.65-2.55 (m, 1 H), 2.50-2.42 (m, 1 H), 2.34-2.23 (m, 1 H), 2.04-1.96 (m, 1 H), 1.45-1.41 (m, 9 H); ¹³C NMR (100 MHz, CDCl3): δ = 173.5, 172.1, 149.3, 83.8, 59.0, 52.8, 31.4, 28.1, 21.7; MS: m/z (%) = 261 (98) [M + NH4]+, 144 (100); Anal. Calcd for C11H17NO5 [M + NH4]+: 261.1445. Found: 261.1443. A solution of N-tert-butyloxycarbonylpyroglutamic acid methyl ester (4; 34.12 g, 0.14 mol) in anhydrous THF (350 mL) was cooled to -78 ˚C under an atmosphere of argon. DIBAL-H (1 M in toluene, 150 mL) was added over a period of 1 h. The resulting solution was stirred at -78 ˚C for a further 2 h, before being quenched by the addition of anhydrous MeOH (30 mL). After warming to 0 ˚C, a 1 M aqueous solution of Rochelle’s salt (600 mL) and EtOAc (300 mL) were added and the biphasic solution was stirred vigorously for 2 h. The organic layer was separated, dried over Na2SO4 and evaporated to give 1-(tert-butyloxycarbonyl)-5-(hydroxy)pyrrolidine-2-carboxylic acid methyl ester (5; 33.17 g, 98%) as a 2:1 mixture of diastereomers, as a colourless oil. ¹H NMR (400 MHz, CDCl3): δ = 5.63-5.39 (m, 1 H), 4.60-4.17 (m, 1 H), 3.75-3.66 (m, 3 H), 2.64-1.83 (m, 4 H), 1.45-1.36 (m, 9 H); ¹³C NMR (100 MHz, CDCl3): δ = 82.52-81.20, 70.71, 59.5, 52.5, 33.4, 28.5, 28.1, 27.3; MS: m/z (%) = 263 (5) [M + NH4]+, 245 (40), 128 (100); Anal. Calcd for C11H19NO5 [M + NH4]+: 263.1601. Found: 263.1604. A solution of 1-(tert-butyloxycarbonyl)-5-(hydroxy)pyrrolidine-2-carboxylic acid methyl ester (5; 33.12 g, 0.135 mol) in EtOH (600 mL) was treated with PTSA˙H2O (1.85 g, 9.73 mmol), and the solution was allowed to stand for 18 h. The solvent was then removed under reduced pressure and the resulting residue was partitioned between EtOAc (300 mL) and sat. aq NaHCO3 (300 mL). The organic layer was separated, dried over Na2SO4 and evaporated in vacuo to give 1-(tert-butyloxycarbonyl)-5-(ethoxy)pyrrolidine-2-carboxylic acid methyl ester (6; 35.90 g, 96%) as a 2:1 mixture of diastereo-mers, as a colourless oil. Bp 92˚C (0.15 Torr); IR: 1755, 1703 cm; ¹H NMR (400 MHz, CDCl3): δ = 5.38-5.20 (m, 1 H), 4.37-4.22 (m, 1 H), 3.72 (s, 3 H), 3.66-3.49 (m, 2 H), 2.48-1.76 (m, 4 H), 1.41 (s, 9 H), 1.08 (t, J = 3.6 Hz, 3 H); ¹³C NMR (100 MHz, CDCl3): δ = 87.3, 64.0, 59.0, 52.07, 51.92, 32.5, 30.6, 27.5, 15.3; MS: m/z (%) = 273 (6) [M + H]+, 228 (100); Anal. Calcd for C13H24NO5 [M + H]+: 274.1664. Found: 274.1654. A solution of 1-(tert-butyloxy-carbonyl)-5-(ethoxy)pyrrolidine-2-carboxylic acid methyl ester (6; 16.3 g, 59.7 mmol) in anhydrous toluene (100 mL) was cooled to -78 ˚C under an atmosphere of argon. DIBAL-H (1 M in toluene, 71.6 mL) was added over a period of 30 min by cannula (dribbling down the inside of the flask). The resulting solution was stirred at -78 ˚C for a further 6 h before being quenched by the addition of anhydrous MeOH (10 mL). After warming to 0 ˚C, a 1 M aqueous solution of Rochelle’s salt (300 mL) and EtOAc (100 mL) were added, and the biphasic solution was stirred vigorously for 2 h. The organic layer was separated, dried over Na2SO4, and evaporated in vacuo to give aldehyde 2b (12.95 g, 89%) as a colourless oil after distillation (bp 96-98 ˚C, 0.2 Torr); IR: 1739, 1698 cm; ¹H NMR (300 MHz, CDCl3): δ = 9.55-9.36 (m, 1 H, 5-H), 5.39-5.18 (m, 1 H), 4.35-4.00 (m, 1 H), 3.72-3.48 (m, 2 H), 2.48-2.00 (m, 2 H), 1.98-1.63 (m, 2 H), 1.47-1.38 (m, 9 H), 1.09 (t, J = 7 Hz, 3 H); ¹³C (100 MHz, CDCl3): δ = 200.43, 200.31, 166.70, 88.0, 81.5, 81.2, 65.5, 64.4, 32.0, 28.4, 25.0, 15.5; MS:
m/z (%) = 244 (10) [M + H]+, 198 (62); Anal. Calcd for C12H22NO4 [M + H]+: 244.1549. Found: 244.1552.