Download PDF
Synlett 2008(2): 197-202  
DOI: 10.1055/s-2007-1000934
LETTER
© Georg Thieme Verlag Stuttgart · New York

Formal Mixed Double Addition to N-Glycosylnitrones through Addition-Oxidation-Addition to N-Glycosylhydroxylamines

Marco Bonanni, Marco Marradi, Stefano Cicchi, Andrea Goti*
Dipartimento di Chimica Organica ‘Ugo Schiff’, HeteroBioLab, Università di Firenze, associated with INSTM and ICCOM-C.N.R., via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: +39(055)4573531; e-Mail: andrea.goti@unifi.it;
Further Information

Publication History

Received 2 November 2007
Publication Date:
21 December 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

A protocol for the formal mixed addition of two different C-nucleophiles at C1 and C1′ of N-glycosylnitrones has been developed. Addition of Grignard reagents to N-erythrosyl-N-benzylhydroxylamine 1 affords hydroxylamines 6 almost quantitatively with high diastereoselectivity. These compounds undergo regioselective oxidation to the corresponding C-phenyl nitrones 7, which in turn add a second Grignard reagent to give hydroxylamines 5. Synthetic usefulness of mixed bisadduct 5d has been proved by its enyne ring-closing metathesis to afford the densely functionalized unsaturated piperidine derivative 8.

Key words

nitrones - nucleophilic additions - oxidations - piperidines - enyne metathesis

8

General Procedure for the Addition of Grignard Reagents to C1′-Substituted C1-Phenyl Nitrones 7: A commercially available solution of Grignard reagent (5 equiv) was added dropwise to a 0.1 M solution of nitrone 7 (1.0 mmol) in anhyd THF at 0 °C under a nitrogen atmosphere. The mixture was allowed to heat to r.t., then stirred for 4 h and quenched with a sat. aq solution of NaHCO3 (10 mL). The product was extracted with EtOAc (3 × 10 mL). The organic phase was dried over anhyd Na2SO4, then filtered and concentrated. The product was purified by flash column chromatography.

9

Representative Data for Mixed Double Adducts 5. 5a: oil; [α]D 23 +24 (c = 1.04, CH2Cl2). 1H NMR: δ = 7.43-7.51 (m, 4 H), 7.19-7.37 (m, 6 H), 6.03 (ddt, J = 7.3, 10.3, 17.9 Hz, 1 H), 5.23 (s, 1 H), 5.12 (dd, J = 1.9, 17.9 Hz, 1 H), 5.05 (dd, J = 1.9, 10.3 Hz, 1 H), 4.83 (br s, 1 H), 4.57 (dd, J = 6.2, 9.2 Hz, 1 H), 4.35 (q, J = 6.2 Hz, 1 H), 3.73 (dd, J = 6.2, 11.4 Hz, 1 H), 3.49 (dd, J = 6.2, 11.4 Hz, 1 H), 3.09 (dt, J = 4.7, 9.2 Hz, 1 H), 2.63 (m, 2 H), 1.35 (s, 3 H), 1.33 (s, 3 H). 13C NMR: δ = 139.0 (s, 2 × C), 136.3 (d), 129.0 (d, 2 × C), 128.4 (d, 2 × C), 128.0 (d, 2 × C), 127.6 (d, 2 × C), 127.4 (d, 2 × C), 116.3 (t), 107.6 (s), 77.9 (d), 77.4 (d), 74.6 (d), 61.4 (t), 59.7 (d), 31.0(t), 28.0(q), 25.3 (q). Anal. Calcd for C23H29NO4: C, 72.04; H, 7.62; N, 3.65. Found: C, 71.91; H, 7.75; N, 3.54. 5c: oil; [α]D 24 +8 (c = 0.85, CH2Cl2). 1H NMR: δ = 7.28-7.42 (m, 5 H), 6.70 (br s, 1 H), 6.16 (ddd, J = 7.7, 10.3, 17.2 Hz, 1 H), 5.98 (ddt, J = 7.3, 9.9, 17.0 Hz, 1 H), 5.23 (br d, J = 17.2 Hz, 1 H), 5.19 (br d, J = 10.3 Hz, 1 H), 5.09 (dd, J = 2.1, 17.0 Hz, 1 H), 5.06 (dd, J = 2.1, 9.9 Hz, 1 H), 4.60 (d, J = 7.7 Hz, 1 H), 4.54 (dd, J = 5.9, 9.2 Hz, 1 H), 4.36 (q, J = 5.9 Hz, 1 H), 3.50 (m, 2 H), 2.91 (dt, J = 4.5, 9.2 Hz, 1 H), 2.59 (m, 2 H), 1.29 (s, 6 H). 13C NMR: δ = 140.9 (s), 138.1 (d), 136.6 (d), 129.1 (d, 2 × C), 128.5 (d, 2 × C), 128.2 (d), 118.4 (t), 116.1 (t), 107.5 (s), 78.0(d), 77.6 (d), 73.3 (d), 60.7 (t), 60.1 (d), 30.8 (t), 27.8 (q), 25.0 (q). Anal. Calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20. Found: C, 68.64; H, 8.24; N, 4.09. 5d: waxy solid; [α]D 27 +33 (c = 0.71, CH2Cl2). 1H NMR: δ = 7.47-7.55 (m, 2 H), 7.34-7.43 (m, 3 H), 6.65 (br s, 1 H, exchanging proton), 6.00 (ddt, J = 7.3, 10.3, 17.0 Hz, 1 H), 5.15 (dd, J = 2.0, 17.0 Hz, 1 H), 5.06 (dd, J = 2.0, 10.3 Hz, 1 H), 4.97 (d, J = 2.2 Hz, 1 H), 4.50 (dd, J = 5.9, 8.8 Hz, 1 H), 4.28 (dt, J = 5.9, 7.7 Hz, 1 H), 3.30-3.48 (m, 2 H), 3.03 (ddd, J = 4.4, 5.8, 8.8 Hz, 1 H), 2.67-2.80 (m, 1 H), 2.55-2.63 (m, 1 H), 2.52 (d, J = 2.2 Hz, 1 H), 1.34 (s, 3 H), 1.31 (s, 3 H). 13C NMR: δ = 136.7 (d), 136.1 (s), 129.1 (d, 2 × C), 128.9 (d), 128.8 (d, 2 × C), 116.3 (t), 107.7 (s), 81.8 (d), 77.8 (d), 77.5 (d), 74.7 (d), 61.9 (d), 61.1 (d), 60.7 (t), 31.1 (t), 27.8 (q), 25.1 (q). Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23. Found: C, 68.83; H, 7.54; N, 4.62. 5e: oil; [α]D 28 -47 (c = 1.33, CH2Cl2). 1H NMR: δ = 7.74 (br s, 1 H, exchanging proton), 7.28-7.41 (m, 5 H), 6.13 (dt, J = 9.2, 16.8 Hz, 1 H), 5.29-5.54 (m, 2 H), 4.95 (dd, J = 1.8, 16.8 Hz, 1 H), 4.90 (dd, J = 2.0, 16.8 Hz, 1 H), 4.85 (dd, J = 2.0, 10.3 Hz, 1 H), 4.57 (dd, J = 4.4, 9.2 Hz, 1 H), 4.44 (dt, J = 4.4, 9.9 Hz, 1 H), 3.94 (dd, J = 4.0, 10.3 Hz, 1 H), 3.66 (dd, J = 4.4, 11.7 Hz, 1 H), 3.47 (dd, J = 9.9, 11.7 Hz, 1 H), 3.18 (t, J = 9.2 Hz, 1 H), 3.02-3.13 (m, 1 H), 2.39-2.54 (m, 1 H), 1.29 (s, 3 H), 1.24 (s, 3 H). 13C NMR: δ = 137.9 (s), 134.3 (d), 131.3 (d), 128.9 (d, 2 × C), 128.7 (d, 2 × C), 128.1 (d), 122.1 (t), 117.3 (t), 108.1 (s), 77.6 (d), 77.2 (d), 70.2 (d), 65.8 (d), 60.2 (t), 39.0(t), 27.5 (q), 24.9 (q). Anal. Calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20. Found: C, 68.41; H, 8.49; N, 4.06. 5g: white solid; mp 137-139 °C (Büchi 510); [α]D 26 +9 (c = 0.57, CH2Cl2). 1H NMR: δ = 7.34-7.46 (m, 5 H), 6.04 (dt, J = 9.3, 17.0 Hz, 1 H), 5.57 (br d, J = 9.3 Hz, 1 H), 5.52 (br d, J = 17.0 Hz, 1 H), 5.25 (br s, 1 H, exchanging proton), 4.61 (d, J = 2.6 Hz, 1 H), 4.49 (dd, J = 5.5, 9.3 Hz, 1 H), 4.32 (dt, J = 5.5, 8.0 Hz, 1 H), 4.23 (t, J = 9.3 Hz, 1 H), 3.94 (dd, J = 8.0, 11.4 Hz, 1 H), 3.69 (dd, J = 5.5, 11.4 Hz, 1 H), 2.61 (d, J = 2.6 Hz, 1 H), 1.42 (s, 3 H), 1.35 (s, 3 H). 13C NMR: δ = 137.3 (d), 131.3 (s), 129.2 (d, 2 × C), 128.7 (d, 2 × C), 128.6 (d), 122.3 (t), 108.4 (s), 80.1 (s), 78.1 (d), 76.8 (d), 76.5 (d), 65.9 (d), 61.0 (d, 1 C, and t, 1 C), 27.8 (q), 25.4 (q). Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.11; H, 7.58; N, 4.07.