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Synlett 2017; 28(07): 815-818
DOI: 10.1055/s-0036-1589935
DOI: 10.1055/s-0036-1589935
letter
Synthesis of Orthogonally N-Protected, C-4 Functionalized Cyclic Guanidines from l-Serine
Further Information
Publication History
Received: 18 December 2016
Accepted after revision: 27 December 2016
Publication Date:
17 January 2017 (online)
![](https://www.thieme-connect.de/media/synlett/201707/lookinside/thumbnails/st-2016-d0700-l_10-1055_s-0036-1589935-1.jpg)
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.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1589935.
- Supporting Information
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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): νmax = 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): νmax = 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): νmax = 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): νmax = 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.
For other leading references dealing with the synthesis of cyclic guanidine amino acids, see: