Enantioselective Synthesis of a (1R,5R,9R)-2-Azabicyclo[3.3.1]nonane-9-carboxylic Acid with an Embedded Morphan Motif: A Multipurpose Product

Abstract

A convenient asymmetric synthesis of (1R,5R,9R)-2-aza­bicyclo[3.3.1]nonane-9-carboxylic acid is described, starting from (2E,7E)-dimethyl nonadienedioate. The route involves a stereo­selective domino Michael–Dieckman process that furnishes a 1,2,3-trisubstituted cyclohexane derivative bearing three adjacent stereocenters with full stereochemical control. A subsequent chemoselective transformation of one of the side-chain ester groups allows an effective second cyclization leading to the morphan motif. The versatility of this novel amino acid for the generation of molecular complexity was tested by elaborating a tripeptide in homogeneous phase.

Key words

β-amino acids - asymmetric synthesis - Michael addition - morphan - GABA uptake inhibitors

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This review updates the scope and applications of the conjugate addition of enantiomerically pure lithium amides published in:
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• 18 Typical Procedure Mesylate 18 (18 mg, 0.047 mmol) was dissolved in CH₂Cl₂–TFA 1:1 (5 mL) and stirred 2 h at r.t. Solvent was evaporated, and the crude was further dissolved in EtOH–Et₃N 1:1 (5 mL). The mixture was refluxed at 80 °C for 20 h. The solvent was again evaporated and the crude dissolved in EtOAc (30 mL) and extracted with HCl (0.5 M, 30 mL). The aqueous phase was basified to pH 8 with NaOH (1 M) and extracted with EtOAc. The organic phase was dried over Na₂SO₄, filtered, and the solvent was removed at reduced pressure. Purification of the crude product by flash chromatography (CHCl₃–MeOH, 9:1) provided 21 (7.1 mg, 84%) as an oil. [α]_D ²⁰ = –4.01 (c 0.71, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.65–2.24 (m, 8 H, H-4, H-6, H-7, H-8), 2.52 (s, 1 H, H-5), 3.06 (s, 1 H, H-9), 3.27 (dd, J = 13.5, 7.3 Hz, 1 H, H-3_eq), 3.44 (dt, J = 13.5, 8.0 Hz, 1 H, H-3_ax), 3.73 (s, 3 H, OCH₃), 3.91 (br s, 1 H, H-1), 5.51 (br s, 1 H, NH). IR (neat): 3396, 2931, 2858, 1733, 1426, 1384, 1287, 1203, 1124, 1405, 1023 cm^–1. ¹³C NMR (50 MHz, CDCl₃): δ = 19.8, 23.4, 25.5, 26.9, 28.9, 40.1, 43.6, 47.7, 52.7, 171.3. HRMS: m/z calcd for C₁₀H₁₈NO₂ [M + H]: 184.1332; found: 184.1313.
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