Preparation of Spirocyclic β-Proline Esters: Geometrically Restricted Building Blocks for Medicinal Chemistry

Abstract

A series of novel N-Bn-protected spirocyclic β-proline esters were prepared using [3+2] cycloaddition and subsequently converted into their corresponding aldehydes. In addition, two novel N-Cbz-protected spirocyclic β-proline esters were prepared using intramolecular cyclization starting from simple precursors.

Key words

spirocycles - β-proline esters - oxetanes - 1,3-dipolar cy­cloaddition - intramolecular cyclization

• References and Notes

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• 12 General Procedure for the Synthesis of β-Proline Esters Using Cycloaddition To a stirred solution of an unsaturated ester (1 equiv) in toluene (0.4 M w.r.t. the ester) was added N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (1.5 equiv) at 0 °C under argon. After 10 min, a solution of TFA (0.1 equiv) in CH₂Cl₂ (1 M w.r.t. TFA) was added to the mixture, and stirring was continued for 2–18 h while allowing the temperature to slowly reach r.t. Subsequently, the volatiles were removed in vacuo, and the resulting crude residue was purified using silica gel chromatography to provide the desired cycloaddition product 1a–e. Ethyl 6-Benzyl-2-oxa-6-azaspiro[3.4]octane-8-carboxylate (1a) The general procedure A over 12 h provided 1a (5.3 g, 19.25 mmol, 55% yield) as a colorless oil. ¹H NMR (600 MHz, CDCl₃): δ = 7.33–7.29 (m, 4 H), 7.27–7.24 (m, 1 H), 4.72–4.64 (m, 2 H), 4.51–4.43 (m, 2 H), 4.23–4.15 (m, 2 H), 3.66–3.60 (m, 2 H), 3.21 (d, J = 9.2 Hz, 1 H), 3.10–3.02 (m, 2 H), 2.74 (dd, J = 9.3, 0.8 Hz, 1 H), 2.62–2.59 (m, 1 H), 1.30 (t, J = 7.2 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 173.0, 138.5, 128.6, 128.3, 127.1, 84.0, 77.9, 64.3, 60.9, 59.6, 56.5, 50.4, 47.9, 14.3. ESI-HRMS: m/z calcd for C₁₆H₂₂NO₃ [MH⁺]: 276.1594; found: 276.1599.