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Synlett 2008(19): 2951-2954  
DOI: 10.1055/s-0028-1087351
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Addition of Titanium Enolates to Functionalized Acetals: A Novel Approach to the γ-Amino Acid of Bistramides and FR252921

Erik Gálvez, Ricard Parelló, Pedro Romea*, Fèlix Urpí*
Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Catalonia, Spain
Fax: +34 93 339 78 78; e-Mail: felix.urpi@ub.edu; e-Mail: pedro.romea@ub.edu;
Further Information

Publication History

Received 3 June 2008
Publication Date:
12 November 2008 (online)

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Abstract

Dialkyl acetals containing other functional groups can participate in stereoselective coupling reactions with chiral titanium enolates. Such an approach provides the protected γ-amino acid present in bistramides and FR252921 in a highly efficient manner.

Key words

stereoselective reactions - crossed aldol-like condensation - titanium enolates - acetals - bistramide - FR252921

    References and Notes

  • 1 Misra M. Luthra R. Singh KL. Sushil K. In Comprehensive Natural Products   Vol. 4:  Barton DHR. Nakanishi K. Meth-Cohn O. Pergamon; Oxford: 1999.  p.25 
    Google Scholar
  • For recent reviews on aldol reactions, see:
  • 2a Alcaide B. Almendros P. Eur. J. Org. Chem.  2002,  1595 
    Google Scholar
  • 2b Modern Aldol Reactions   Mahrwald R. Wiley-VCH; Weinheim: 2004. 
    Google Scholar
  • 2c Schetter B. Mahrwald R. Angew. Chem. Int. Ed.  2006,  45:  7506 
    Google Scholar
  • 3 For an overview on the alkylation of alcohols, see: Wuts PGM. Greene TW. In Protective Groups in Organic Synthesis   4th ed.:  John Wiley and Sons; Hoboken: 2007. 
    Google Scholar
  • 4a Cosp A. Romea P. Talavera P. Urpí F. Vilarrasa J. Font-Bardia M. Solans X. Org. Lett.  2001,  3:  615 
    Google Scholar
  • 4b Cosp A. Romea P. Urpí F. Vilarrasa J. Tetrahedron Lett.  2001,  42:  4629 
    Google Scholar
  • 4c Cosp A. Larrosa I. Vilasís I. Romea P. Urpí F. Vilarrasa J. Synlett  2003,  1109 
    Google Scholar
  • 4d Baiget J. Cosp A. Gálvez E. Gómez-Pinal L. Romea P. Urpí F. Tetrahedron  2008,  64:  5637 
    Google Scholar
  • 5 Cosp A. Llàcer E. Romea P. Urpí F. Tetrahedron Lett.  2006,  47:  5819 
    CrossrefGoogle Scholar
  • For the synthesis of bistramides, see:
  • 6a Statsuk AV. Liu D. Kozmin SA. J. Am. Chem. Soc.  2004,  126:  9546 
    Google Scholar
  • 6b Wipf P. Hopkins TD. Chem. Commun.  2005,  3421 
    Google Scholar
  • 6c Crimmins MT. DeBaille AC. J. Am. Chem. Soc.  2006,  128:  4936 
    Google Scholar
  • 6d Lowe JT. Wrona IE. Panek JS. Org. Lett.  2007,  9:  327 
    Google Scholar
  • 6e Yadav JS. Chetia L. Org. Lett.  2007,  9:  4587 
    Google Scholar
  • For the synthesis of FR252921, see:
  • 7a Amans D. Bellosta V. Cossy J. Org. Lett.  2007,  9:  4761 
    Google Scholar
  • 7b Falck JR. He A. Fukui H. Tsutsui H. Radha A. Angew. Chem. Int. Ed.  2007,  46:  4527 
    Google Scholar
  • Dimethyl acetals a and b are commercially available. The other acetals (c-f) have been prepared following standard procedures reported in the literature. See:
  • 8a Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed.:  John Wiley and Sons; New York: 1999. 
    Google Scholar
  • 8b Kocienski PJ. Protecting Groups   Thieme; Stuttgart: 1994. 
    Google Scholar
  • 10 Dibenzyl acetals g-i have been prepared from the corresponding dimethyl acetal, see: Vidal-Pascual M. Martínez-Lamarca C. Hoffmann HMR. Org. Synth.  2005,  83:  61 
    Google Scholar
  • 11 This pattern has been established in preceding reports mentioned in ref. 4 and was supported by structural studies, see: Cosp A. Larrosa I. Anglada JM. Bofill JM. Romea P. Urpí F. Org. Lett.  2003,  5:  2809 
    CrossrefGoogle Scholar
  • Asymmetric anti-aldol reactions were early recognized as more challenging than the syn counterparts. For stereoselective procedures based on chiral auxiliaries, see:
  • 12a Walker MA. Heathcock CH. J. Org. Chem.  1991,  56:  5747 
    Google Scholar
  • 12b Wang Y.-C. Hung A.-W. Chang C.-S. Yan T.-H. J. Org. Chem.  1996,  61:  2038 
    Google Scholar
  • 12c Ghosh AK. Onishi M. J. Am. Chem. Soc.  1996,  118:  2527 
    Google Scholar
  • 12d Abiko A. Liu J.-F. Masamune S. J. Am. Chem. Soc.  1997,  119:  2586 
    Google Scholar
  • 12e Evans DA. Tedrow JS. Shaw JT. Downey CW. J. Am. Chem. Soc.  2002,  124:  392 
    Google Scholar
  • 12f Evans DA. Downey CW. Shaw JT. Tedrow JS. Org. Lett.  2002,  4:  1127 
    Google Scholar
  • 12g Fanjul S. Hulme AN. White JW. Org. Lett.  2006,  8:  4219 
    Google Scholar
  • For examples on the easy removal of thiazolidinethione auxiliaries, see:
  • 13a Crimmins MT. Chaudhary K. Org. Lett.  2000,  2:  775 
    Google Scholar
  • 13b Zhang Y. Phillips AJ. Sammakia T. Org. Lett.  2004,  6:  23 
    Google Scholar
  • 13c Wu Y. Sun Y.-P. Yang Y.-Q. Hu Q. Zhang Q. J. Org. Chem.  2004,  69:  6141 
    Google Scholar
  • 13d Osorio-Lozada A. Olivo HF. Org. Lett.  2008,  10:  617 
    Google Scholar
  • 16 Ok T. Jeon A. Lee J. Lim J.-H. Hong C.-S. Lee H.-S. J. Org. Chem.  2007,  72:  7390 
    CrossrefGoogle Scholar
9

The stoichiometry, the reaction temperature, and time were carefully evaluated.

14

Enantiomeric adducts ent-3 are obtained from ent-1, which in turn is prepared from the commercially available (R)-valinol.

15

Preparation of Methyl Ester 8
Neat TiCl4 (0.12 mL, 1.1 mmol) was added dropwise to a solution of ent-1 (217 mg, 1.0 mmol) in CH2Cl2 (8 mL), at 0 ˚C under N2. The yellow suspension was stirred for 5 min at 0 ˚C, cooled at -78 ˚C, and a solution of i-Pr2NEt (0.19 mL, 1.1 mmol) in CH2Cl2 (1 mL) was added. The dark red enolate solution was stirred for 2 h at -50 ˚C. Then, 1 M SnCl4 in CH2Cl2 (1.1 mL, 1.1 mmol), followed by acetal i (314 mg, 1.1 mmol) in CH2Cl2 (1 mL), was successively added dropwise at -78 ˚C. The resulting mixture was stirred at -78 ˚C for 30 min and kept at -20 ˚C for 2 h. The reaction was cooled at -78 ˚C and quenched by the addition of sat. NH4Cl (8 mL) with vigorous stirring. The layers were separated. The aqueous layer was re-extracted with CH2Cl2, and the combined organic extracts were dried (Na2SO4), filtered, concentrated, and analyzed by HPLC. A solution of the residue and a crystal of DMAP in MeOH (8 mL) was stirred for 3.5 h at r.t. under N2, diluted in Et2O, and washed with 2 M NaOH, 2 M HCl, sat. NaHCO3, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the resultant oil through a pad of SiO2 (CH2Cl2) afforded 141 mg (0.38 mmol, 77% yield) of methyl ester 8. Colorless oil. R f = 0.2 (CH2Cl2). [α]D +16.1 (c 0.95, CHCl3). IR (film): ν = 2948, 1773, 1715, 1395, 1196, 1071 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.79-7.76 (2 H, m, ArH), 7.71-7.67 (2 H, m, ArH), 7.31-7.04 (5 H, m, ArH), 4.57 (1 H, d, J = 11.3 Hz, PhCH xHy), 4.52 (1 H, d, J = 11.3 Hz, PhCHx H y), 4.01 (1 H, ddd, J = 7.3, 5.8, 4.5 Hz, CHOBn), 3.91-3.82 (2 H, m, CH 2N), 3.65 (3 H, s, OCH 3), 2.85-2.76 (1 H, m, COCHCH3), 1.33 (3 H, d, J = 7.0 Hz, COCHCH 3). ¹³C NMR (100.6 MHz, CDCl3): δ = 174.6 (C), 168.2 (C), 137.7 (C), 133.8 (CH), 132.0 (C), 128.1 (2 × CH), 127.5 (CH), 123.2 (CH), 78.3 (CH), 72.7 (CH2), 51.8 (CH3), 42.7 (CH), 38.3 (CH2), 12.6 (CH3). ESI-HRMS: m/z calcd for C21H22NO5 [M + H]+: 368.1492; found: 368.1488.

17

Selected Data for Methyl Ester 11
[α]D +34.6 (c 1.3, CHCl3). IR (film): ν = 2950, 2101, 1737, 1455, 1285, 1262, 1197, 1172, 1098, 1065 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.38-7.25 (5 H, m, ArH), 4.65 (1 H, d, J = 11.3 Hz, PhCH xHy), 4.57 (1 H, d, J = 11.3 Hz, PhCHx H y), 3.83 (1 H, ddd, J = 7.5, 5.7, 3.2 Hz, CHOBn), 3.68 (3 H, s, OCH 3), 3.44 (1 H, dd, J = 13.2, 3.2 Hz, CH xHyN3), 3.30 (1 H, dd, J = 13.2, 5.7 Hz, CHx H yN3), 2.92-2.84 (1 H, m, COCHCH3), 1.13 (3 H, d, J = 7.1 Hz, COCHCH 3). ¹³C NMR (100.6 MHz, CDCl3): δ = 174.6 (C), 137.6 (C), 128.4 (CH), 127.9 (CH), 127.8 (CH), 79.9 (CH), 72.8 (CH2), 51.8 (CH3), 51.2 (CH2), 42.0 (CH), 12.7 (CH3). ESI-HRMS: m/z calcd for C13H17N3NaO3 [M + Na]+: 286.1162; found: 286.1174.