Application of Olefin Metathesis for the Synthesis of Constrained β-Amino Esters from Norbornenes

Abstract

Synthesis of a number of novel, conformationally rigid β-amino esters has been achieved via a tandem olefin metathesis ­reaction. The starting materials are readily accessible from the ­Diels-Alder adduct between cyclopentadiene and maleic anhydride.

metathesis - amino acids - Diels-Alder reactions

References and Notes

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9b

Conditions for the conversion warranted exposure of the material to high catalyst loading (20 mol%) and ethene gas (3 atm) for three cycles to obtain good conversion (88%).

10

The most diagnostic peaks for the epimerization are: cis-amino ester H_eq δ = 3.3 ppm and trans-amino ester H_ax δ = 2.6 ppm.

11

General Procedure for Olefin Metathesis Reactions - Synthesis of 5.
A flask was charged with alkyne 4 (51 mg, 0.14 mmol) and freshly distilled CH₂Cl₂ (50 mL). Ethene gas was then bubbled through the solution for 20 s. Grubbs I catalyst (11 mg, 0.014 mmol) was then added and a balloon filled with ethene gas was fitted to the flask. The reaction was allowed to stir at r.t. overnight. The reaction mixture was concen-trated in vacuo and subjected to column chromatography eluting with PE-EtOAc (19:1 to 4:1) to furnish 5 as a white solid in 96% yield (52 mg). Mp 144-146 °C. ¹H NMR (250 MHz, CDCl₃): δ = 1.16-1.27 (m, 1 H, CH₂CHCHN), 2.20-2.28 (m, 1 H, CH₂CHCHN), 2.39 (s, 3 H, CH₃), 2.56-2.66 (br s, 1 H, CHCO₂), 2.60 (br s, 1 H, CHCHN), 2.71-2.86 (m, 1 H, CHCHCO₂), 3.68 (s, 3 H, CO₂CH₃), 3.76 (dt, 1 H, NCH₂, J = 18.0, 2.0 Hz), 4.45-4.92 (m, 1 H, NCH₂), 4.45-4.92 (m, 1 H, CHN), 4.92-5.17 (m, 4 H, 2 × CH=CH₂) 5.42 (br s, 1 H, HC=C*), 5.58 (ddd, 1 H, HC=CH₂, J = 17.5, 10.0, 7.5 Hz), 6.16 (dd, 1 H, HC=CH₂, J = 18.0, 11.0 Hz), 7.28 (m, 2 H, 2 × ArH), 7.79 (m, 2 H, 2 × ArH). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.9 (CH₃), 34.7 (CHCHCO₂), 36.2 (CH₂CHCHN), 39.2 (NCH₂), 44.2 (CHCHN), 51.1 (CHCO₂), 52.5 (CO₂CH₃), 59.5 (CHN), 112.8 (CH=CH₂), 115.8 (CH=CH₂), 127.4 (2 × ArC), 129.9 (2 × ArC), 130.6 (HC=C*), 131.6 (HC=C*), 136.7 (CH=CH₂) 137.8 (1 × ArC), 139.6 (CH=CH₂), 143.6 (1 × ArC), 173.4 (C=O). IR (thin film): ν_max = 1163, 1345 (SO₂), 1735 (C=O), 2952 (sat. C-H) cm^-1. MS (CI, NH₃): m/z calcd for C₂₁H₂₅NO₄S: 387.1504; found: 387.1497 [M⁺].

12

Analytical data for 10: ¹H NMR (250 MHz, CDCl₃): δ = 1.23 (ddd, 1 H, CH₂CHCH=CH, J = 13.0, 8.5, 4.5 Hz), 2.24 (m, 1 H, CH₂CHCH=CH), 2.40 (s, 3 H, CH₃), 2.48-2.50 (br m, 1 H, CHCH=CH), 2.66-2.74 (m, 1 H, CHCO₂CH₃), 2.78-2.87 (m 1 H, CHCH=CH₂), 3.66 (s, 3 H, CO₂CH₃), 3.68-3.78 (m, 1 H, CH₂N), 4.14-4.22 (m, 1 H, CH₂N), 4.55 (dd, CHN, 1 H, J = 10.5, 8.0 Hz), 4.91-5.01 (m, 2 H, CH=CH₂), 5.45-5.71 (m, 2 H, CH=CH), 5.45-5.71 (m, 1 H, CH=CH₂), 7.25 (m, 2 H, 2 × ArH), 7.66 (m, 2 H, 2 × ArH). ¹³C NMR (62 5 MHz, CDCl₃): δ = 21.9 (CH₃), 34.2 (CHCH=CH), 35.8 (CH₂CHCH=CH), 39.8 (CH₂N), 44.1 (CHCH=CH₂), 50.9 (CHCO₂CH₃), 52.4 (CO₂CH₃), 59.6 (CHN), 115.6 (CH=CH₂), 121.4 (HC=CH), 127.4 (2 × ArC), 129.9 (2 × ArC), 130.8 (HC=CH), 138.0 (1 × ArC), 140.0 (CH=CH₂), 143.5 (1 × ArC), 173.6 (C=O). IR (thin film): ν_max = 1164, 1345 (SO₂), 1734 (C=O), 2952 (sat. C-H) cm^-1. MS (CI, NH₃): m/z calcd for C₁₉H₂₃NO₄S: 361.1348; found: 361.1355 [M⁺].