Download PDF
Synlett 2002(12): 2074-2076
DOI: 10.1055/s-2002-35588
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel Chiral Base Mediated Glutarimide Desymmetrisation: Application to the Asymmetric Synthesis of (-)-Paroxetine

Daniel A. Greenhalgh, Nigel S. Simpkins*
School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
Fax: +44(115)9513564; e-Mail: nigel.simpkins@nottingham.ac.uk;
Further Information

Publication History

Received 3 October 2002
Publication Date:
20 November 2002 (online)

    Permissions and Reprints All articles of this category

Abstract

The asymmetric desymmetrisation of certain 4-aryl substituted glutarimides has been accomplished with high levels of selectivity (up to 97% ee) by enolisation with a chiral bis-lithium amide base. The selectivity of the reaction is shown to be the result of asymmetric enolisation, followed by a kinetic resolution. One of the chiral imides synthesised was converted into the selective seratonin reuptake inhibitor (-)-paroxetine.

Key words

chiral lithium amide - kinetic resolution - asymmetric synthesis - glutarimide - paroxetine

    References

  • 1a Adams DJ. Simpkins NS. Smith TJN. Chem. Commun.  1998,  1605 
    CrossrefGoogle Scholar
  • 1b For our full report of this work, see: Adams DJ. Blake AJ. Cooke PA. Gill CD. Simpkins NS. Tetrahedron  2002,  58:  4603 ; this issue of the journal is dedicated entirely to chiral base chemistry and is an excellent source of leading references in the area
    CrossrefGoogle Scholar
  • For recent asymmetric syntheses of paroxetine, see:
  • 2a de Gonzalo G. Brieva R. Sanchez VM. Bayod M. Gotor V. J. Org. Chem.  2001,  66:  8947 
    CrossrefPubMedGoogle Scholar
  • 2b Cossy J. Mirguet O. Gomez Pardo D. Desmurs J.-R. Tetrahedron Lett.  2001,  42:  7805 
    CrossrefPubMedGoogle Scholar
  • 2c Johnson TA. Curtis MD. Beak P. J. Am. Chem. Soc.  2001,  123:  1004 
    CrossrefPubMedGoogle Scholar
  • 2d Liu LT. Hong P.-C. Huang H.-L. Chen S.-F. Wang C.-LW. Wen Y.-S. Tetrahedron: Asymmetry  2001,  12:  419 
    CrossrefPubMedGoogle Scholar
  • 2e Amat M. Bosch J. Hidalgo J. Canto M. Perez M. Llor N. Molins E. Miravitlles C. Orozco M. Luque J. J. Org. Chem.  2000,  65:  3074 
    CrossrefPubMedGoogle Scholar
  • 3a Rama Rao R. Singh AK. Varaprasad CVNS. Tetrahedron Lett.  1991,  32:  4393 
    CrossrefGoogle Scholar
  • 3b Goehring RR. Greenwood TD. Nwokogu GC. Pisipati JS. Rogers TG. Wolfe JF. J. Med. Chem.  1990,  33:  926 
    CrossrefGoogle Scholar
  • 4 Bambridge K. Begley MJ. Simpkins NS. Tetrahedron Lett.  1994,  35:  3391 
    CrossrefGoogle Scholar
  • 7 Kamikawa T. Hayashi T. Tetrahedron  1999,  55:  3455 
    CrossrefGoogle Scholar
  • 8 Gotov B. Schmalz H.-G. Org. Lett.  2001,  3:  1753 
    CrossrefGoogle Scholar
  • 9 Many syntheses of paroxetine use this approach, see for example: Yu MS. Lantos I. Peng Z.-Q. Yu J. Cacchio T. Tetrahedron Lett.  2000,  41:  5647 ; see also ref. and references therein
    Google Scholar
5

1-Benzyl-4-(4-fluorophenyl)-3-methyl -piperidine-2,6-dione 5e: A solution of the chiral bis-lithium amide base 8 was prepared by dropwise addition of a solution of n-BuLi (1.0 mL, of a 1.6 M in hexanes, 1.60 mmol) to the chiral diamine (342 mg, 0.81 mmol) in THF (4 mL) at -78 °C. The resulting red coloured solution was warmed to room temperature for 20 min before cooling to -78 °C and addition via cannula, to a stirred solution of the starting imide 4 (200 mg, 0.67 mmol) in THF (10 mL) at ca. -78 °C (internal temperature). The mixture was stirred for 45 min at this temperature before being diluted with THF (14 mL). Excess methyl iodide (3 mL) was then added, the mixture warmed to -40 °C (internal temperature) and then stirred at this temperature for 4 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted into Et2O (3 × 20 mL). The extracts were washed sequentially with 2 M HCl (3 × 60 mL), saturated aqueous NaHCO3 (60 mL) and brine (60 mL). The combined extracts were then dried (MgSO4) and concentrated under reduced pressure to yield a crude product which was purified by flash column chromatography on silica gel (40% Et2O in petroleum ether) to give the product as an off white solid (128 mg, 64%), mp 115-118 °C; [α]D 22 -21 (c = 1.02 in CHCl3); IR (CHCl3)/cm-1: 1726 (C=O), 1681 (C=O), 1606 (Ar), 1512 (Ar); δH (400 MHz, CDCl3): 1.11 (3 H, d, J = 7 Hz, CH3), 2.72 (1 H, dq, J = 11 Hz, 7 Hz, CHCH3), 2.78 [1 H, dd, J = 18 Hz, 13 Hz, C(O)CH2ax], 2.94 (1 H, m, CHAr), 2.94 [1 H, dd, J = 18 Hz, 4 Hz, C(O)CH2eq], 4.97 (1 H, d, J = 14 Hz, NCHHPh), 5.02 (1 H, d, J = 14 Hz, NCHHPh), 7.02 (2 H, m), 7.11 (2 H, m), 7.29 (3 H, m) and 7.38 (2 H, m); δC (125 MHz, CDCl3): 14.4 (CH3), 40.8 [C(O)CH2], 41.9 (CHAr), 43.4 (NCH2Ph), 43.5 (CHCH3), 116.1 (J C-F = 21.5 Hz, CH), 127.6 (CH), 128.5 (CH), 128.6 (CH), 128.9 (CH), 136.3 (C), 137.3 (C), 162.1 (d, J C-F = 246 Hz, C), 171.0 (C=O) and 174.5 (C=O); HRMS(EI) Found: [M]+ 311.1334, C19H18NO2F requires 311.1322.
The enantiomeric excess was determined by HPLC analysis using a Chiralcel OD column with 5% i-PrOH in hexane as eluant, at a flow rate of 0.8 mL/min, using UV detection at 215 nm. Retention times were 49.8 min(minor) and 59.5 min(major).
1-Benzyl-4-(4-fluorophenyl)-2,6-dioxo-piperidine-3-carboxylic acid methyl ester 5i:
The reaction was carried out as described above, starting with imide 4 (200 mg, 0.67 mmol) and quenching of the intermediate enolate with excess methyl cyanoformate (0.11 mL). After 30 min at -78 °C the mixture was worked up as described above to give a crude product which was purified by flash column chromatography on silica gel (30% EtOAc in petroleum ether followed by DCM) to give the product 5i as a white solid (168 mg, 71%), mp 137-139 °C; [α]D 28 -31 (c = 0.74 in CHCl3); IR (CHCl3)/cm-1: 1749 (C=O), 1729 (C=O), 1680 (C=O), 1608 (Ar), 1512 (Ar); δH (400 MHz, CDCl3): 2.82 [1 H, dd, J = 17.5 Hz, 11, C(O)CH2ax], 3.02 [1 H, dd, J = 17.5 Hz, 4.5 Hz, C(O)CH2eq], 3.65 (3 H, s, OCH3), 3.68 (1 H, ddd, J = 11 Hz, 11 Hz, 4.5 Hz, CHAr), 3.81 (1 H, d, J = 11 Hz, CHCO2Me), 4.96 (1 H, d, J = 14 Hz, NCHHPh), 5.03 (1 H, d, J = 14, NCHHPh), 7.00 (2 H, m), 7.13 (3 H, m), 7.29 (2 H, m), 7.37 (2 H, m); δC (125 MHz, CDCl3): 37.5 (CHAr), 38.8 [C(O)CH2], 43.5 (NCH2Ph), 52.9 (OCH3), 56.4 (CHCO2Me), 116.2 (d, J C-F = 21.5 Hz, CH), 127.8 (CH), 128.4 (CH), 128.6 (CH), 129.1 (CH), 134.4 (C), 136.5 (C), 163.5 (d, J C-F = 247 Hz, C), 168.1 (C=O), 168.3 (C=O), 170.1 (C=); HRMS(EI): Found: [M]+ 355.1220, C20H18NO4F requires 355.1220.
The enantiomeric excess was determined by HPLC analysis using a Chiralcel OD column with 3% EtOH in hexane as eluant, at a flow rate of 0.8 mL/min, using UV detection at 215 nm. Retention times were 75.8 min(minor) and 88.5 min(major).

6

The use of bis-lithiated base 8 may seem to invite the formation of unwanted products 7 but we achieved much poorer yields of desired compounds 5 by using the base in mono-lithiated form.

10

The reported values for paroxetine include [α]D 20 -75.5 (c = 1.2, MeOH) for >97:3 er, [2c] and [α]D 22 -80.8 (c = 1.25, MeOH) via enantiopure intermediates. [2e]