Synthesis of Orthogonally N-Protected, C-4 Functionalized Cyclic Guanidines from l-Serine

Abstract

A straightforward and efficient preparation of five-membered cyclic guanidines bearing an ester, a hydroxymethyl or a Weinreb amide functional group at C-4 is described from l-serine. The novel synthetic route provides cyclic guanidines in which the three nitrogen atoms are orthogonally protected making them highly suitable for further transformations into natural products or their analogues via the introduced functional groups.

Key words

cyclic guanidine - amino acid - azide - orthogonal protection - Weinreb amide

• References and Notes

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• 20 Methyl (2S)-3-[2,3-Bis(benzyloxycarbonyl)guanidino]-2-(p-methoxybenzylamino)propanoate (14) To a solution of amine 12 (669 mg, 2.8 mmol) in CH₂Cl₂ (15 mL) were successively added at r.t. 1,3-bis(benzyloxycarbonyl)-2-methylisothiourea (13, 1.22 g, 3.4 mmol) and Et₃N (0.93 mL, 6.7 mmol). The reaction mixture was stirred overnight, the solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (EtOAc–heptane, 40:60), providing compound 14 as a yellow oil (1.47 g, 95% yield from 11); [α]_D ²⁰ +5.5 (c 0.97, CHCl₃). IR (neat): ν_max = 3330, 1733, 1638, 1561, 1513, 1246, 1204, 1054, 698 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 11.7 (s, 1 H, NH), 8.82 (br s, 1 H, NH), 7.37 (m, 6 H, CH, Cbz), 7.30 (d, J = 7.5 Hz, 4 H, Cbz), 7.26 (d, J = 8.6 Hz, 2 H, CH, PMB), 6.80 (d, J = 8.6 Hz, 2 H, CH PMB), 5.19 (d, J = 1.7 Hz, 2 H, CH₂, Cbz), 5.09 (s, 2 H, CH₂), 3.90–3.79 (m, 1 H), 3.80 (d, J = 12.8 Hz, 1 H, CH₂, PMB), 3.76 (s, 3 H, MeO), 3.70 (s, 3 H, MeO), 3.64 (d, J = 12.8 Hz, 1 H, CH₂, PMB), 3.64–3.37 (m, 2 H), 1.85 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 173.4 (C), 163.8 (C), 159.0 (C), 156.2 (C), 153.7 (C), 136.9 (C), 134.9 (C), 131.4 (C), 129.8 (2 CH, PMB), 129.0 (CH, Cbz), 128.9 (CH, Cbz), 128.8 (CH, Cbz), 128.6 (CH, Cbz), 128.4 (CH, Cbz), 128.1 (CH, Cbz), 114.0 (2 CH, PMB), 68.4 (CH₂, Cbz), 67.3 (CH₂, Cbz), 58.8 (CH-N), 55.5 (CH₃, MeO), 52.5 (CH₃, MeO), 51.4 (CH₂), 42.8 (CH₂). HRMS: m/z calcd for C₂₉H₃₃N₄O₇ [M + H]⁺: 549.2344; found: 549.2329. N-Methoxy-N-methyl (2S)-3-[2,3-Bis(benzyloxycarbonyl)-guanidino]-2-(p-methoxybenzylamino)propanamide (27) Treatment of amine 26 (0.7 mmol) as described above provided, after flash chromatography of the crude product on silica gel (EtOAc–heptane, 6:4), compound 27 as a yellow oil (87% yield from 25); [α]_D ²⁰ –15.3 (c 1.12, CHCl₃). IR (neat): ν_max = 3330, 2931, 1732, 1638, 1563, 1512, 1245, 1204, 1052, 803, 746, 697 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 11.6 (br s, 1 H, NH), 8.85 (br s, 1 H, NH), 7.40–7.24 (m, 10 H, CH, Cbz) 7.28 (d, J = 8.6 Hz, 2 H, CH, PMB), 6.78 (d, J = 8.6 Hz, 2 H, CH, PMB), 5.24 (d, J = 12.2 Hz, 1 H, CH₂, Cbz), 5.18 (d, J = 12.2 Hz, 1 H, CH₂, Cbz), 5.10 (d, J = 12.4 Hz, 1 H, CH₂), 5.05 (d, J = 12.4 Hz, 1 H, CH₂), 3.89–3.81 (m, 1 H, CH₂), 3.79 (d, J = 13.0 Hz, 1 H, CH₂, PMB), 3.75 (s, 3 H, MeO), 3.74–3.70 (m, 1 H, CH), 3.54 (s, 3 H, MeO), 3.51 (d, J = 12.8 Hz, 1H, CH₂, PMB), 3.15 (s, 3 H, MeN), 3.20–3.10 (m, 1 H, CH₂), 1.96 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 163.8 (C), 158.9 (C), 156.1 (C), 153.7 (C), 137.0 (C), 135.0 (C), 131.8 (C), 130.4 (2 CH, PMB), 128.9 (CH, Cbz), 128.9 (CH, Cbz), 128.8 (CH, Cbz), 128.6 (CH, Cbz), 128.3 (CH Cbz), 128.1 (CH Cbz), 113.9 (2 CH PMB), 68.3 (CH₂, Cbz), 67.2 (CH₂, Cbz), 61.8 (CH₃ MeO), 55.7 (CHN), 55.5 (CH₃, MeO), 51.4 (CH₂), 43.3 (CH₂), 32.5 (CH₃, MeN). HRMS: m/z calcd for C₃₀H₃₆N₅O₇ [M + H]⁺: 578.2609; found: 578.2618.
• 21 Methyl (4S)-2-(benzyloxycarbonylimino)-3-(p-methoxybenzyl)imidazolidine-4-carboxylate (15) A solution of compound 14 (2.56 g, 4.6 mmol) in MeCN (25 mL) was heated at 70 °C for 2 d. The reaction mixture was then cooled to r.t., the solvent was removed under vacuum, and the residue was purified by flash column chromatography on silica gel (EtOAc–heptane, 1:1) to provide the cyclic guanidine 15 as a colorless oil (1.39 g, 75%); [α]_D ²⁰ +25.7 (c 0.9, CHCl₃). IR (neat): ν_max = 3374, 2926, 1646, 1587, 1513, 1248, 1128, 1095, 799 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.95 (br s, 1 H, NH), 7.37 (d, J = 6.8 Hz, 2 H, Cbz), 7.31–7.21 (m, 3 H, Cbz), 7.10 (d, J = 8.6 Hz, 2 H, CH, PMB), 6.78 (d, J = 8.6 Hz, 2 H, CH PMB), 5.16–5.05 (m, 3 H), 4.10–4.03 (m, 2 H,), 3.99 (dd, J = 10.0, 6.0 Hz, 1 H, CH₂), 3.73 (s, 3 H, MeO), 3.67 (s, 3 H, MeO), 3.63 (dd, J = 10.0, 6.0 Hz, 1 H, CH₂). ¹³C NMR (75 MHz, CDCl₃): δ = 170.4 (C), 164.4 (C), 163.5 (C), 159.3 (C), 137.3 (C), 130.0 (2 CH, PMB), 128.3 (2 CH, Cbz), 128.2 (2 CH, Cbz), 127.7 (CH, Cbz), 114.1 (2 CH, PMB), 67.0 (CH₂, Cbz), 56.4 (CHN), 55.3 (CH₃, MeO), 52.7 (CH₃, MeO), 46.2 (CH₂), 44.5 (CH₂). HRMS: m/z calcd for C₂₁H₂₄N₃O₅ [M + H]⁺: 398.1710; found: 398.1711. N-Methoxy-N-methyl (4S)-2-(benzyloxycarbonylimino)-3-(p-methoxybenzyl)imidazolidine-4-carboxamide (28) Treatment of compound 27 (0.6 mmol) as described above provided, after flash column chromatography of the crude product on silica gel (EtOAc–heptane, 8:2), compound 28 as a colorless oil (74%); [α]_D ²⁰ +27.4 (c = 0.92, CHCl₃). IR (neat): ν_max = 3374, 2926, 1646, 1587, 1513, 1248, 1128, 1095, 799 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.94, (br s, 1 H, NH), 7.43–7.24 (m, 5 H, CH, Cbz), 7.26 (d, J = 8.5 Hz, 2 H, CH, PMB), 6.81 (d, J = 8.5 Hz, 2 H, CH, PMB), 5.23 (d, J = 14.7 Hz, 1 H, CH₂), 5.16 (d, J = 12.4, 2 H, CH₂), 5.10 (d, J = 12.4, 2 H, CH₂), 4.27 (dd, J = 10.6 Hz, 6.5 Hz, 1 H, CH), 3.98 (d, J = 14.7, 1 H, CH₂), 3.81–3.73 (m, 1 H, CH₂), 3.76 (s, 3 H, MeO), 3.46 (dd, J = 9.6 Hz, 6.6 Hz, 1 H, CH₂), 3.35 (s, 3 H, MeO), 3.14 (s, 3 H, MeN). ¹³C NMR (75 MHz, CDCl₃): δ = 169.9 (C), 164.6 (C), 164.2 (C), 159.4 (C), 137.6 (C), 130.4 (2 CH, PMB), 128.5 (CH, Cbz), 128.3 (CH, Cbz), 127.8 (CH, Cbz), 114.2 (2 CH, PMB), 67.1 (CH₂, Cbz), 61.4 (CH₃, MeO), 55.5 (CH₃, MeO), 55.0 (CH-N), 45.9 (CH₂), 44.6 (CH₂), 29.9 (CH₃, MeN). HRMS: m/z calcd for C₂₂H₂₇N₄O₅ [M + H]⁺: 427.1976; found: 427.1984.