Asymmetric Phase-Transfer-Catalyzed Synthesis of Five-Membered Cyclic γ-Amino Acid Precursors

Abstract

The first example of an intramolecular enantioselective Michael addition of nitronates onto conjugated systems utilizing a chiral phase-transfer catalyst is described. A range of five-membered γ-nitro esters with up to three stereocentres have been prepared and the relative and absolute configurations proven by chemical and crystallographic methods. The products are rapidly obtained and are precursors to five-membered cyclic γ-amino acids.

Key words

organocatalysis - phase transfer - intramolecular - ­nitronate - Michael addition

References and Notes

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• 12 This was determined by Nef reaction of the product to form the α-substituted ketone (Scheme 2) and the resulting optical rotation compared to the literature values, see: Kerr MS. Read de Alaniz J. Rovis T. J. Am. Chem. Soc.  2002,  124:  10298 

11

Assigned both by comparison to the ^¹H NMR of a related compound (see ref. 10a) and by analogous assignment of
the proton signal from the exclusively trans crystals of compound 22 (as shown by X-ray crystallography).

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Typical Procedure for Organocatalytic Cyclization
Ethyl 2-[(1 S ,2 R )-2-nitrocyclopentyl]acetate (2)
To a solution of (E)-ethyl-7-nitrohept-2-enoate (1, 50.3 mg, 0.25 mmol) in toluene (3 mL) was added phase-transfer catalyst 11 (10 mol%) and K₂CO₃ (7 mg, 0.05 mmol). The resulting solution was stirred for 18 h at 23 ˚C. After this time, the solvent was removed under reduced pressure to give a pale yellow oil that was subjected to flash column chromatography (SiO₂; Et₂O-hexane, 1:4). The resulting colourless oil (50.3 mg, 0.25 mmol, quant.) was analyzed by chiral HPLC analysis [Chiralcel OD; 0.46 cm ø × 25 cm; hexane-propan-2-ol (96:4); 1 mL min^-¹; t _R (major diastereo-mer) = 7.06 min, 7.63 min; t _R (minor diastereomer) = 8.03 min, 8.69 min]. [α]_D -3.1 (c 1, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): 1.24-1.28 (3 H, J = 7.2 Hz, CH ₃), 1.35-2.37 (6 H, cyclopent-H), 2.42 (2 H, m, CH ₂CO₂Et), 2.91 (1 H, hex, J = 8.8 Hz, CHCH₂CO₂Et), 4.14 (2 H, q, J = 7.2 Hz, CH₂CH₃), 4.81 (1 H, m, CHNO₂) [NB: the 1S,2S signal appears as a multiplet at δ = 5.01]. IR: 2979, 1732, 1547, 1373, 1269, 1187, 1028, 913, 734, 648 cm^-¹. HRMS: m/z calcd for C₉H₁₅NO₄Na⁺: 224.0893; found: 224.0894.

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X-ray crystal structural information (CCDC 789178) available from the Cambridge Crystallographic Data Centre (CCDC) at http://www.ccdc.cam.ac.uk.