Download PDF
Synlett 2002(5): 0711-0714
DOI: 10.1055/s-2002-25358
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of α,α-Disubstituted α-Amino Acid Derivatives in Enantiopure Form via Stereoselective Addition of Grignard Reagents to a Chiral Acyclic Nitrone Derived from l-Erythrulose

Raul Portolésa, Juan Murgaa, Eva Falomira, Miguel Carda*a, Santiago Uriela, J. Alberto Marco*b
Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón, Spain
Fax: +34(964)728214; e-Mail: mcarda@qio.uji.es;
Depart. de Q. Orgánica, Univ. de Valencia, c/D. Moliner, 50, 46100 Burjassot, Valencia, Spain
Fax: +34(96)3864328; e-Mail: alberto.marco@uv.es;
Further Information

Publication History

Received 18 February 2002
Publication Date:
07 February 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

The additions of various Grignard reagents to a chiral nitrone prepared from l-erythrulose take place with variable dia­stereoselectivity. The degree and strength of the facial selectivity can be modified if the reaction is performed in the presence of Lewis acidic additives: zinc bromide enhances attack to the si face whereas diethyl aluminum chloride promotes attack to the re side. The obtained adducts can be then efficiently transformed into protected N-hydroxy α,α-disubstituted α-amino acid derivatives as well as into the corresponding α,α-disubstituted α-amino acids.

Key words

Grignard reagents - chiral nitrone - erythrulose - α,α-di­substituted α-aminoacids - N-hydroxy aminoacids

    References

  • 1a Enders D. Reinhold U. Tetrahedron: Asymmetry  1997,  8:  1895 
    CrossrefGoogle Scholar
  • 1b Bloch R. Chem. Rev.  1998,  98:  1407 
    CrossrefGoogle Scholar
  • 1c Adams JP. Box DS. J. Chem. Soc., Perkin Trans. 1  1999,  749 
    CrossrefGoogle Scholar
  • 2 Gante J. Angew. Chem., Int. Ed. Engl.  1994,  33:  1699 
    CrossrefGoogle Scholar
  • 3a Wirth T. Angew. Chem., Int. Ed. Engl.  1997,  36:  225 
    CrossrefGoogle Scholar
  • 3b Cativiela C. Díaz de Villegas MD. Tetrahedron: Asymmetry  1998,  9:  3517 
    CrossrefGoogle Scholar
  • 3c Cativiela C. Díaz de Villegas MD. Tetrahedron: Asymmetry  2000,  11:  645 
    CrossrefGoogle Scholar
  • For a general review on this class of compounds, see:
  • 4a Ottenheijm HCJ. Herscheid JDM. Chem. Rev.  1986,  86:  697 
    Google Scholar
  • 4b See also: Kolasa T. Sharma SK. Miller MJ. Tetrahedron  1988,  44:  5431 
    Google Scholar
  • 4c Jin Y. Kim DH. Tetrahedron: Asymmetry  1997,  8:  3699 
    Google Scholar
  • 4d Merino P. Castillo E. Franco S. Merchán SL. Tejero T. J. Org. Chem.  1998,  63:  2371 
    Google Scholar
  • 4e N-Hydroxy amino acids have been found as components of depsipeptide antibiotics: Lorca M. Kurosu M. Tetrahedron Lett.  2001,  2431 
    Google Scholar
  • 4f Another N-hydroxy compound which displays useful pharmacological properties is the 5-lipoxygenase inhibitor Zileuton: Brooks DW. Bell RL. Carter GW. Dube LM. Rubin PD. Drugs Future  1993,  18:  616 
    Google Scholar
  • 5a Marco JA. Carda M. Murga J. Rodríguez S. Falomir E. Oliva M. Tetrahedron: Asymmetry  1998,  9:  1679 
    CrossrefGoogle Scholar
  • 5b Carda M. Murga J. Rodríguez S. González F. Castillo E. Marco JA. Tetrahedron: Asymmetry  1998,  9:  1703 
    CrossrefGoogle Scholar
  • 6a Marco JA. Carda M. González F. Rodríguez S. Murga J. Liebigs Ann. Chem.  1996,  1801 
    Google Scholar
  • 6b Carda M. Rodríguez S. Murga J. Falomir E. Marco JA. Röper H. Synth. Commun.  1999,  29:  2601 
    Google Scholar
  • 7a Torssell KBG. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis   VCH; : 1988. 
    CrossrefGoogle Scholar
  • 7b Confalone PN. Huie EM. Org. React.  1988,  36:  1 
    CrossrefGoogle Scholar
  • 7c Enders D. Reinhold U. Tetrahedron: Asymmetry  1997,  8:  1895 
    CrossrefGoogle Scholar
  • 8a Marco JA. Carda M. Murga J. Portolés R. Falomir E. Lex J. Tetrahedron Lett.  1998,  3237 
    CrossrefGoogle Scholar
  • 8b 1,3-Dipolar cycloadditions of this nitrone have also been investigated: Carda M. Portolés R. Murga J. Uriel S. Marco JA. Domingo LR. Zaragozá RJ. Röper H. J. Org. Chem.  2000,  65:  7000 
    CrossrefGoogle Scholar
  • 9 The oximes 1 were obtained as E/Z mixtures, from which only the E isomers showed a good stereoselectivity. Moreover, nitrone 2 was obtained together with a structurally close dioxazine, which was, however, unreactive towards organometallics.
  • See, for example:
  • 14a Chang Z.-Y. Coates RM. J. Org. Chem.  1990,  55:  3464 
    CrossrefGoogle Scholar
  • 14b Dondoni A. Franco S. Merchán SL. Merino P. Tejero T. Synlett  1993,  78 
    CrossrefGoogle Scholar
  • 14c Basha A. Henry R. McLaughlin MA. Ratajczyk JD. Wittenberger SJ. J. Org. Chem.  1994,  59:  6103 
    CrossrefGoogle Scholar
  • 14d Dondoni A. Franco S. Junquera F. Merchán FL. Merino P. Tejero T. Bertolasi V. Chem.-Eur. J.  1995,  1:  505 
    CrossrefGoogle Scholar
  • 14e Merino P. Lanaspa A. Merchán FL. Tejero T. J. Org. Chem.  1996,  61:  9028 
    CrossrefGoogle Scholar
  • 14f Dhavale DD. Desai VN. Sindkhedkar MD. Mali RS. Castellari C. Trombini C. Tetrahedron: Asymmetry  1997,  8:  1475 
    CrossrefGoogle Scholar
  • 15a Marco JA. Carda M. González F. Rodríguez S. Castillo E. Murga J. J. Org. Chem.  1998,  63:  698 
    CrossrefGoogle Scholar
  • 15b Carda M. Castillo E. Rodríguez S. González F. Marco JA. Tetrahedron: Asymmetry  2001,  12:  1417 
    CrossrefGoogle Scholar
  • 16 Oppolzer W. In Comprehensive Organic Synthesis   Vol. 5:  Trost BM. Fleming I. Paquette LA. Pergamon Press; Oxford: 1991.  Chap. 1.2.
    Google Scholar
  • 17a Evans DA. Allison BD. Yang MG. Masse CE. J. Am. Chem. Soc.  2001,  123:  10840 
    CrossrefGoogle Scholar
  • 17b

    The strong chelating ability of Me2AlCl is attributed to a bimolecular interchange where the anion (Me2AlCl2)- is formed together with formal transfer of the chelating, highly Lewis acidic species Me2Al+ to the substrate. Obviously, two equivalents of Me2AlCl are required.
    Crossref
10

A distinct NOE was detected between the N-benzylic hydrogens and the methylene protons of the CH2OTPS group.

11

We have studied the formation of the nitrone with the aid of quantum-mechanical ab initio methods. The non-isolated E nitrone was found to be more stable than the Z isomer by more than 3 kcal/mol. This indicates that the formation of the Z nitrone is subjected to kinetic control. Preliminary results of studies on possible transition states suggest that that leading to the isolated Z nitrone is lower in energy than the alternative transition state leading to the E isomer (unpublished results with S. Safont).

12

Preparation of Nitrone 3. 1-O-t-butyldiphenylsilyl-3,4-O-isopropylidene-l-erythrulose [6] (19.93 g, 50 mmol) and N-benzyl hydroxylamine (6.16 g, 50 mmol) were dissolved in CH2Cl2 (150 mL). Anhyd MgSO4 (10 g) was added to the mixture and the suspension was stirred under Ar for 48 h at r.t. The reaction mixture was then filtered through Celite, and the Celite pad was subsequently washed twice with CH2Cl2 (2 × 30 mL). After complete solvent removal in vacuo, the oily residue was chromatographed on silica gel (hexanes-EtOAc, 7:3). This furnished nitrone 3 as a dense oil (19.65 g, 78%), which could not be induced to crystallize: [α]D 25 -20.6 (CHCl3, c 3.7). IR νmax(film): 3052, 2986, 2934, 2892, 2860, 1577, 1472, 1455, 1428, 1382, 1266, 1212, 1181, 1154, 1112, 1058, 738, 704 cm-1. HRMS (EI): m/z (rel. int.) = 503.2504 (0.5) [M+], 488(10) [M+ - Me], 446(16) [M+ - t-Bu], 388(45), 341(88), 199(100), 101(96). Calcd for C30H37NO4Si, M = 503.2492. 1H NMR (CDCl3, 500 MHz): δ = 7.80-7.20 (15 H, m), 5.27 (1 H, t, J = 7 Hz), 5.06 (2 H, AB system, J = 11 Hz), 4.53 (1 H, dd, J = 8.5 and 7 Hz), 4.46 (2 H, AB system, J = 12.5 Hz), 3.77 (1 H, dd, J = 8.5 and 7 Hz), 1.35 (3 H, s), 1.29 (3 H, s), 1.10 (9 H, s). 13C NMR (CDCl3, 125 MHz): d = 148.1, 133.2, 132.3, 132.2, 109.7, 19.3 (C), 135.7, 135.6, 135.5, 130.0, 129.1, 128.8, 128.6, 128.5, 128.3, 128.2, 127.8, 127.7, 73.2 (CH), 68.3, 64.5, 56.3 (CH2), 27.0, 26.0, 24.7 (CH3).

13

General Reaction Conditions for Grignard Additions to Nitrone 3 with Aqueous Work-up. A solution of 3 (1 mmol) in THF (5 mL) was cooled under Ar to -78 °C and treated with the appropriate Grignard reagent (5 mmol of a commercial solution in THF). After stirring for 5 h at the same temperature, the reaction mixture was quenched with sat. aq NH4Cl (2 mL); the reaction mixture was stirred for further 5 min, poured into brine and extracted with EtOAc. The organic layers were then dried on anhyd Na2SO4 and concentrated in vacuo. Column chromatography of the oily residue on silica gel (hexane-EtOAc mixtures) afforded the corresponding adducts (Table). Additions in the presence of Lewis acid additives were performed in the same way except that the Lewis acid (1 mmol) was added to an ice-cooled solution of 3; the solution was then stirred for 15 min and cooled to -78 °C, prior to addition of the Grignard reagent.
Grignard Additions to Nitrone 3 with acetylating Work-up. For the preparation of amino acid derivatives, the reaction was performed as above except that acetic anhydride (190 µL, 2 mmol) was added dropwise at -78 °C to the reaction mixture. The cooling bath was removed and the mixture was stirred for 30 min at r.t. After quenching with sat. aq NH4Cl (2 mL), the reaction mixture was stirred for further 15 min, poured into brine and worked up as above.
The configuration of the newly formed stereogenic center was determined by straightforward conversion of adducts 4 into oxazolidinones i (Scheme [5] ) and observation of suitable NOE’s in the latter. Additional support was given by X-ray diffraction analyses of 4 (R = Et), 4 (R = allyl) and 6 (R = Ph). The crystallographic data of these three com-pounds have been deposited at the Cambridge Crystallo-graphic Data Centre (deposition numbers, CCDC-177985 to CCDC-177987).

Scheme 5