Stereocontrolled Synthesis of Some Novel Azaheterocyclic β-Amino Ester Stereoisomers with Multiple Stereogenic Centers

Abstract

The synthesis of some new functionalized azaheterocyclic β-amino esters with multiple stereocenters has been achieved from readily available unsaturated bicyclic β-amino acids by a stereocontrolled synthetic protocol involving N-allylation/propargylation, ring-opening metathesis, and selective ring closure with chemodifferentiation through ring-closing metathesis (RCM). The RCM transformation was investigated under various experimental conditions to analyze the scope of the catalyst, yield, conversion, and substrate effect. The structure of the starting (oxa)norbornene β-amino acids predetermined the structure of the new azaheterocyclic derivatives; the synthetic procedure proceeded with conservation of the configuration of the stereogenic centers.

Key words

amino esters - azaheterocycles - cyclization - ring-closing metathesis - stereocontrol - asymmetric synthesis

• References and Notes

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• 31 Ring-Rearrangement Metathesis Reaction; General Procedure Ethylene and the appropriate metathesis catalyst (G-1, G-2, HG-1, or HG-2; 3 mol%) were added to a solution of the appropriate N-allylated or N-propargylated N-tosyl-protected ester (100 mg) in anhyd CH₂Cl₂ (10 mL), and the mixture was stirred at RT for 4 h. To decompose the catalyst, a mixture of H₂O (12 mL), MeOH (2 mL), and NaHCO₃ (0.1 g) was added and the mixture was stirred for an additional 2 h. The phases were separated and the aqueous phase was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel). Ethyl (4aS,6R,7S,7aR)-1-Tosyl-6-vinyl-2,4a,5,6,7,7a-hexahydro-1H-cyclopenta[b]pyridine-7-carboxylate [(±)-13] Prepared from compound (±)-12 according to the general procedure and purified by column chromatography [silica gel, hexane–EtOAc (8:1)] as a pale-yellow oil; yield: 78% with G-1 catalyst, 71% with G-2, 69% with HG-1, and 74% with HG-2; R_f = 0.40 (hexane–EtOAc, 4:1).¹H NMR (500 MHz, CDCl₃): δ = 1.17 (t, J = 7.10 Hz, 3 H, CH₃), 1.87–1.96 (m, 1 H, H-5), 2.03–2.11 (m, 1 H, H-5), 2.39–2.42 (s, 3 H, Ar-CH₃), 2.65–2.71 (m, 1 H, 4aH), 2.76–2.87 (m, 1 H, H-6), 3.18 (t, J = 6.80 Hz, 1 H, H-7), 3.54–3.60 (m, 1 H, H-2), 3.85–3.96 (m, 2 H, O–CH₂– and H-2), 3.98–4.05 (m, 1 H, O–CH₂–), 4.55–4.64 (m, 1 H, 7aH), 4.98–5.09 (m, 2 H, =CH₂), 5.53–5.58 (m, 1 H, H-4), 5.64–5.69 (m, 1 H, H-3), 5.73–5.81 (m, 1 H, –CH=), 7.25–7.29 (d, J = 8.40 Hz, 2 H, CH-Ar), 7.66–7.69 (d, J = 8.40 Hz, 2 H, CH-Ar). ¹³C NMR (126 MHz, CDCl₃): δ = 14.13, 21.50, 34.01, 35.38, 41.07, 44.57, 52.75, 56.54, 60.32, 116.21, 119.79, 127.00, 128.16, 129.62, 136.75, 137.04, 143.11, 171.95. HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₀H₂₆NO₄S: 376.1575; found: 376.1577.