Indium-Induced Addition of Bromomethylacrylates to Phthaloyl-Protected Amino Aldehydes

Abstract

The indium-mediated reaction of phthaloyl-protected α-amino aldehydes 1-4 with methyl 2-(bromomethyl)acrylate in aqueous solvents was investigated. The homoallyl alcohols 5-8 were formed in 72-89% yields, the anti-isomers being the major diastereoisomers (dr 45:55-18:82). Acid-catalyzed esterification (H₂SO₄ in Et₂O) led to α-methylene γ-butyrolactones 9,10 with yields ranging from 88 to 99%. Conjugate addition of cyanide and thiophenolate led to the addition products with improved selectivities compared with additions to carbamate-protected substrates. During the conjugate addition of a cuprate, a trapping of the intermediate enolate by a phthaloyl carbonyl group occurred, leading to tetracycle 11 in 57% yield. The configuration of all diastereo­isomers could be established by three X-ray crystallographic analyses and by NMR spectroscopy.

Key Words

allylation - indium - Michael additions - α-amino aldehydes - α-methylene γ-butyrolactones

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11

The respective isomers could be separated by medium pressure liquid chromatography (MPLC). All new compounds gave satisfactory spectroscopic data (NMR, IR, MS, [α]_D ²⁰ and elemental analyses).

13

Crystal data for 11a: C₂₄H₃₅NO₄Si, M = 429.62 g/mol, orthorhombic, space group P2₁2₁2₁. a = 10.009(2), b = 12.223(2), c = 20.057(3) Å, V = 2453.8(7) ų, Z = 4, D_c = 1.163 Mg/m³, µ (Mo-K_α) = 0.123 mm^-1, F(000) = 928. Data (2735 collected reflections, and 2063 unique reflections [I > 2σ(I)]) were measured on a Nicolet P3 diffractometer with Mo-K_α radiation (graphite monochromator) using 2θ-ω-scans at 293(2) K. The structure was solved by direct methods and the non-hydrogen atoms were refined anisotropically by full-matrix least-squares based on F² to give the agreement factors R₁ = 0.0597, ωR₂ = 0.1289. Computations were carried out using the SHELXTL^TM program. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-179132 (8a), CCDC-179133 (9a), and CCDC-179131 (11a). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, (UK), fax:[phone] or email: [e-mail].