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Synlett 2010(20): 3011-3014  
DOI: 10.1055/s-0030-1259050
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Willam J. Nodes, Kenneth Shankland, Sundaram Rajkumar, Alexander J. A. Cobb*
School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK
Fax: +44(118)3784638; e-Mail: a.j.a.cobb@reading.ac.uk;
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Publication History

Received 4 October 2010
Publication Date:
17 November 2010 (online)

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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

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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).

13

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.

14

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