CC BY ND NC 4.0 · Synlett 2019; 30(04): 508-510
DOI: 10.1055/s-0037-1611672
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Synthesis of 4-(Arylmethyl)proline Derivatives

Simon Loosli
,
Carlotta Foletti
,
Marcus Papmeyer
,
ETH Zürich, Laboratory for Organic Chemistry, D-CHAB, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland   Email: Helma.Wennemers@org.chem.ethz.ch
› Author Affiliations
The authors gratefully acknowledge financial support by the Swiss National Science Foundation (grant 200020_178805).
Further Information

Publication History

Received: 20 December 2018

Accepted after revision: 16 January 2019

Publication Date:
25 January 2019 (eFirst)

 

These authors contributed equally.

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

A synthesis of 4-(arylmethyl)proline by using Suzuki cross-couplings was developed. The route permits access to a variety of 4-substituted proline derivatives bearing various aryl moieties that expand the toolbox of proline analogues for studies in chemistry and ­biology.

Supporting Information

 
  • References and Notes

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  • 15 tert-Butyl (4S/4R)-N-(tert-Butoxycarbonyl)-4-(2-naphthylmethyl)-l-prolinate (7a); Typical Procedure An oven-dried Schlenk flask was charged with methylene derivative 5 (4.0 g, 14.1 mmol, 1 equiv) under N2. A 0.5 M soln of 9-BBN in THF (31.0 mL, 15.5 mmol, 1.1 equiv) was added in one portion, and the solution was stirred vigorously at 60 °C for 6 h. The mixture was then allowed to cool to r.t. and 5 M aq. KOH (5.6 mL, 5 M, 28.0 mmol, 2 equiv) was added. The mixture was stirred for 20 min, then 2-bromonaphthalene (7a; 3.8 g, 18.36 mmol, 1.3 equiv) was added together with PEPPSI (287.7 mg, 423 μmol, 0.03 equiv). The mixture was stirred for a further 16 h at r.t., then H2O (120 mL) and EtOAc (120 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (3 × 120 mL), and the organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The resulting yellow–brown oil (9.9 g) was purified by column chromatography (silica gel, 0–25% EtOAc–hexane) to give a colorless oil; yield: 4.8 g (83%). 1H NMR (500 MHz, C2Cl4D2, 60 °C): δ = 7.82–7.71 (m, 3 H), 7.59–7.52 (m, 1 H), 7.48–7.37 (m, 2 H), 7.27 (dd, J = 8.4, 1.7 Hz, 1 H), 4.26–4.02 (m, 1 H), 3.75–3.55 (m, 1 H), 3.14 (dd, J = 10.6, 9.0 Hz, 1 H), 2.89–2.76 (m, 2 H), 2.72–2.44 (m, 1 H), 2.42–1.88 (m, 1 H), 1.63 (ddd, J = 12.8, 9.5, 7.9 Hz, 1 H), 1.51–1.33 (m, 18 H). 13C NMR (126 MHz, C2Cl4D2, 60 °C): δ = 172.2, 172.0, 153.6, 137.6, 137.4, 133.5, 133.5, 132.1, 128.1, 128.1, 127.6, 127.5, 127.4, 127.2, 127.1, 126.8, 126.8, 126.1, 125.4, 80.9, 80.8, 79.6, 79.5, 59.8, 59.7, 52.1, 51.6, 39.3, 39.2, 37.7, 36.7, 36.4, 28.4, 28.0, 28.0. HRMS (ESI+): m/z [M + H]+ calcd C25H34NO4: 412.2482; found: 412.2485. (4S)- and (4R)-1-[(9H-Fluoren-9-ylmethoxy)carbonyl]-4-(2-naphthylmethyl)-l-proline (8a); Typical Procedure Prolinate 7a (4.8 g, 11.7 mmol, 1 equiv) was dissolved in a 6 M soln of HCl in 1,4-dioxane (110 mL), and the mixture was stirred for 3 h at r.t. The pH was adjusted to 8–9 with sat. aq NaHCO3, then a soln of FmocCl (3.6 g, 14.0 mmol, 1.2 equiv) in 1,4-dioxane (50 mL) was added, and the mixture was stirred at r.t. for 2 h. Low-boiling volatiles were removed under reduced pressure, and EtOAc (50 mL) was added. The solution was acidified to pH 2–3 with 1 M HCl, and the organic phase was separated and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried (MgSO4), and filtered. All volatiles were removed under reduced pressure, and the product was purified by column chromatography (silica gel, 0–5% MeOH in CH2Cl2 with 0.1% HCO2H) to give a white powder: yield: 4.7 g (84%). The diastereoisomers were subsequently separated by reverse-phase semipreparative HPLC [Reprosil-Gold 120 C18, 10 μm; 250 × 30 mm column, MeCN and H2O–MeCN–TFA (100:1:0.1)]. (4S)-Diastereomer [α]D –40.7 ± 0.5 (c 0.2, MeOH). TLC (silica gel, 2% MeOH in CH2Cl2): Rf  = 0.56. FTIR (neat): 3051, 2923, 1701, 1421, 1352, 1247, 1176, 1122, 1006, 972, 843, 739 cm–1. 1H NMR (500 MHz, C2Cl4D2, 60 °C): δ = 7.92–7.79 (m, 3 H; Ar), 7.77–7.60 (m, 3 H; Ar), 7.59–7.44 (m, 4 H; Ar), 7.43–7.21 (m, 5 H; Ar), 4.55–4.41 (m, 2 H; CH2–Fmoc), 4.41–4.28 (m, 1 H; Hα), 4.28–4.18 (m, 1 H; CH–Fmoc), 3.77–3.52 (m, 1 H; Hδ), 3.25–3.16 (m, 1 H; Hδ), 3.01–2.79 (m, 2 H; CH2-Naph), 2.57 (hept, J = 7.7 Hz, 1 H; Hγ), 2.50–2.36 (m, 1 H; Hβ), 2.12–1.93 (m, 1 H; Hβ). 13C NMR (500 MHz, C2Cl4D2, 60 °C): δ = 173.2 (CO2H), 156.4 (C=OFmoc), 143.5 (Ar), 141.1 (Ar), 137.0 (Ar), 133.4 (Ar), 132.1 (Ar), 128.2 (Ar), 127.6 (Ar), 127.5 (Ar), 127.4 (Ar), 127.0 (Ar), 126.9 (Ar), 126.7 (Ar), 126.1 (Ar), 125.5 (Ar), 124.8 (Ar), 119.8 (Ar), 67.9 (CH2–Fmoc), 59.4 (Cα), 52.2 (Cδ), 47.1 (CH–Fmoc), 39.7 (Cγ), 38.8 (CH2–Naph), 34.4 (Cβ). HRMS (ESI+): m/z [M + H]+ calcd for C31H28NO4: 478.2013; found: 478.2003. (4R)-Diastereomer [α]D –10.8 ± 0.3 (c 0.2, MeOH). TLC (silica gel, 2% MeOH in CH2Cl2): Rf  = 0.56. FTIR (neat): 3045, 2966, 1700, 1661, 1417, 1351, 1241, 1282, 1122, 1002, 947, 887, 737 cm–1.1H NMR (500 MHz, C2Cl4D2, 60 °C): δ = 7.91–7.80 (m, 3 H; Ar), 7.73 (dd, J = 7.6, 2.9 Hz, 2 H; Ar), 7.62 (s, 1 H; Ar), 7.59–7.48 (m, 4 H; Ar), 7.39 (tt, J = 7.6, 1.4 Hz, 2 H; Ar), 7.35–7.27 (m, 3 H; Ar), 4.56–4.36 (m, 3 H; Hα, CH2–Fmoc), 4.32–4.19 (m, 1 H; CH–Fmoc), 3.74–3.49 (m, 1 H; Hδ), 3.31–3.10 (m, 1 H; Hδ), 2.97–2.80 (m, 2 H; CH2–Naph), 2.80–2.65 (m, 1 H; Hγ), 2.47–1.88 (m, 2 H; Hβ). 13C NMR (500 MHz, C2Cl4D2, 60 °C): δ = 173.8 (CO2H), 156.1 (C=OFmoc), 143.5 (Ar), 141.1 (Ar), 136.8 (Ar), 133.4 (Ar), 132.1 (Ar), 128.2 (Ar), 127.6 (Ar), 127.5 (Ar), 127.4 (Ar), 127.0 (Ar), 127.0 (Ar), 126.8 (Ar), 126.1 (Ar), 125.5 (Ar), 124.8 (Ar), 119.82 (Ar), 67.9 (CH2–Fmoc), 59.2 (Cα), 51.7 (Cδ), 47.1 (CH–Fmoc), 38.9 (CH2–Naph, Cγ), 34.3 (Cβ). HRMS (ESI+): m/z [M + H]+ calcd C31H28NO4: 478.2013; found: 478.2003.
  • 16 Note that the Suzuki reaction is not compatible with the use of Fmoc-protected amines. The stereochemistry at the stereogenic centers was retained during the synthesis.