Overman Rearrangement of Fluorinated Allylic Alcohols as a Key Step for the Synthesis of Glycyldecylamide (GDA) Mimics

Abstract

Overman rearrangements based on secondary 2-fluoroallylic alcohols were performed to synthesize fluorinated primary allylic amines for the first time. The vinylic fluorine atom dramatically slows down the reaction rate. Long alkyl chain fluorinated allylic amine, which is a mimic of a drug against schizophrenia, was further coupled with Boc-protected phenyl glycine, forming a Gly-Phe peptide mimic.

Key words

allylic amines - fluorinated building blocks - alcohols - Overman rearrangement - peptide mimics

• References and Notes

• 1a Hagmann WK. J. Med. Chem. 2008; 15: 4359
• 1b Van der Veken P, Senten K, Kertész I, De Meester I, Lambeir AM, Maes MB, Scharpé S, Haemers A, Augustyns K. J. Med. Chem. 2005; 48: 1768
• 2a Fischer MD, Campbell MM. Chem. Rev. 1998; 98: 763
• 2b Giannis A, Kolter T. Angew. Chem., Int. Ed. Engl. 1993; 32: 1244 ; Angew. Chem. 1993, 105, 1303

For peptide mimics, see for example:
• 3a Allmendinger T, Furet P, Hungerbühler E. Tetrahedron Lett. 1990; 31: 7297
• 3b Urban JJ, Tillman BG, Cronin WA. J. Phys. Chem. A 2006; 110: 11120
• 3c Abraham RJ, Ellison SL. R, Schonholzer P, Thomas WA. Tetrahedron 1986; 42: 2101
• 3d Welch JT, Liu J, Boros GL, DeCorte B, Bergmann K, Gimi R. Biomedical Frontiers of Fluorine Chemistry . In ACS Symposium Series 639 . Ojima I, McCarthy JR, Welch JT. ACS; Washington: 1996: 129
• 4a Overman L. J. Am. Chem. Soc. 1974; 96: 597
• 4b Overman L. J. Am. Chem. Soc. 1976; 98: 2901
• 5 Allmendinger T, Felder E, Hungerbühler E. Tetrahedron Lett. 1990; 31: 7301
• 6a Watanabe D, Koura M, Saito A, Yanai H, Nakamura Y, Okada M, Sato A, Taguchi T. J. Fluorine Chem. 2011; 132: 327
• 6b Percy JM, Prime ME. J. Fluorine Chem. 1999; 100: 147
• 7 Javitt DC, Frusciante M. Psychopharmacology 1997; 129: 96
• 8a Alvernhe G, Laurent A, Haufe G. Synthesis 1987; 561
• 8b Haufe G, Alvernhe G, Laurent E, Ernet T, Goj O, Kröger S, Sattler A. Org. Synth. 1999; 76: 159
• 8c Ernet T, Haufe G. Synthesis 1997; 953
• 8d Tranel F, Haufe G. J. Fluorine Chem. 2004; 125: 1593
• 9 Zhou C, Li J, Fu C, Ma S. Org. Lett. 2008; 10: 581
• 10 Synthesis of 4c: Under an argon atmosphere, DBU (60 μL, 0.40 mmol, 0.2 equiv) was added to a solution of allylic alcohol 1c (521 mg 2.00 mmol, 1.0 equiv) in trichloroacetonitrile (2 mL) at 0 °C and the mixture was stirred for 1 h at this temperature. The resulting brownish mixture was evaporated in vacuo and the resulting crude product was filtered through a silica gel column (EtOAc–cyclohexane, 1:10) to afford the trichloroacetimidate as a colorless oil. Yield: 775 mg (1.96 mmol, 98%). ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (t, ³ J = 6.7 Hz, 3 H, 16-CH₃), 1.21–1.47 (m, 22 H, 5- to 15-CH₂), 1.84–1.94 (m, 2 H, 4-CH₂), 4.66 (dd, ² J = 3.3 Hz, ³ J = 48.7 Hz, 1 H, 1-CH), 4.76 (dd, ² J = 3.3 Hz, ³ J = 17.0 Hz, 1 H, 1-CH_B), 5.41 (dt, ³ J = 6.7 Hz, ³ J = 13.2 Hz, 1 H, 3-CH_A), 8.43 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.5 (C-16), 23.0 (C-15), 25.1 (C-5), 29.5, 29.7, 29.7, 29.8, 29.9, 30.0, 30.0, 31.7, 32.3, 34.5 (C-4 and C-6 to C-14), 75.7 (d, ² J = 33.6 Hz, C-3), 91.3 (s, C-18), 92.2 (d, ² J _C–F = 16.8 Hz, C-1), 161.6 (C17-NH), 162.5 (d, ¹ J _C–F = 260.4 Hz, C-2). ¹⁹F NMR (282 MHz, CDCl₃): δ = –110.2 to 110.5 (ddd, ³ J = 13.0, 17.1, 48.6 Hz). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₃₁Cl₃FNNaO: 424.1347; found: 424.1351.
• 11 Overman rearrangement to 7c; Typical Procedure: Trichloroacetamide 4c was transferred into a Jung-tube and heated at reflux in p-xylene for 28 h. The reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was purified by column chromatography (EtOAc–cyclohexane, 1:10) to give trichloroacetamide 7c. Yield: 461 mg (1.41 mmol, 60%); mp 55 °C. ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (t, ³ J = 6.7 Hz, 3 H, 16-CH₃), 1.21–1.43 (m, 22 H, 5- to 15-CH₂), 2.06–2.13 (m, 2 H, 4-CH₂), 4.05 (dd, ² J = 5.8 Hz, ³ J = 15.9 Hz, 2 H, 1-CH₂), 4.88 (dt, ³ J = 7.6 Hz, ³ J = 36.7 Hz, 1 H, 3-CH), 6.93 (br s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.5 (C-16), 22.7 (C-15), 23.8 (C-5), 29.3–34.5 (t, C-4 and C-6 to C-14), 42.2 (dd, ² J = 31.8 Hz, C-1), 92.3 (s, C-18), 110.4 (dd, ² J = 13.9 Hz, C-3), 153.4 (dd, ¹ J = 252.6 Hz, C-2), 162.2 (C-17). ¹⁹F NMR (282 MHz, CDCl₃): δ = –118.4 to –118.6 (dt, ³ J = 15.9 Hz, ³ J = 37.4 Hz). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₃₁Cl₃FNNaO: 424.1347; found: 424.1351
• 12 Yanai H, Okada H, Sato A, Okada M, Taguchi T. Tetrahedron Lett. 2011; 52: 2997
• 13 Hydrolysis of Amides; Typical Procedure: Trichloroacetamide 7c (74 mg, 0.24 mmol) was heated at reflux in a mixture of ethanol (15 mL) and 3 M sodium hydroxide solution (1.5 mL) for 4 h. After cooling to room temperature, CH₂Cl₂ (15 mL) was added and the phases were separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 15 mL) and the organic layers were combined, washed with brine (30 mL), and dried over magnesium sulfate. The solvent was evaporated and the crude product was dissolved in a little CH₂Cl₂. Adding a few drops of HCl gave the corresponding primary amine as the hydrochloride 10c. Yield: 46 mg (0.16 mmol, 81%). ¹H NMR (400 MHz CD₃OD): δ = 0.89 (t, ³ J = 6.4 Hz, 3 H, 16-CH₃), 1.25–1.44 (m, 22 H, 5- to 15-CH₂), 2.11–2.19 (m, 2 H, 4-CH₂), 3.71 (d, ³ J = 17.8 Hz, 2 H), 5.19 (dt, ³ J = 7.6 Hz, ³ J = 36.6 Hz, 1 H). ¹³C NMR (101 MHz, CD₃OD): δ = 13.5 (C-16), 22.0 (C-15), 22.7 (C-5), 28.5, 28.7, 29.9, 30.0 (C-6 to C-14), 31.7 (C-4), 42.4 (d, ² J = 31.7 Hz, C-1), 104.8 (d, ² J = 15.1 Hz, C-3), 158.9 (d, ¹ J = 252.8 Hz, C-2). ¹⁹F NMR (282 MHz, CD₃OD): δ = –118.8 to –119.0 (m). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₃₃FN: 258.2603; found: 258.2609.
• 14a Jiang XY, Chu L, Wang RW, Qing FL. Tetrahedron Lett. 2012; 53: 6853
• 14b Christie SD. R, Warrington AD, Lunnis CJ. Synthesis 2009; 148
• 15 Carpina LA. J. Am. Chem. Soc. 1993; 115: 4397
• 16 Synthesis of 2-Fluorohexadec-2-en-N-Phe-Boc (13): Hydrochloride 10c (17 mg, 0.055 mmol), Boc-Phe-OH (14.7 mg, 0.055 mmol) and DIPEA (37.6 μL, 0.22 mmol) were dissolved in DMF (2 mL). Subsequently, EDC (12.7 mg, 0.066 mmol) and HOBT (9.00 mg, 0.066 mmol) were added and the solution was stirred overnight at room temperature. After adding EtOAc (5 mL), the mixture was washed with an aqueous solution of citric acid (5 wt%, 2 mL) and an aqueous NaHCO₃ solution (5 wt%, 2 mL). The organic layer was dried over MgSO₄ and the solvent was evaporated. Purification of the crude product by column chromatography (EtOAc–cyclohexane, 3:1) gave 13 as a white solid. Yield: 25 mg (0.049 mmol, 93%); mp 78 °C. ¹H NMR (400 MHz CDCl₃): δ = 0.83 (t, ³ J = 6.7 Hz, 3 H, 16-CH₃), 1.19–1.29 (m, 22 H, 5- to 15-CH₂), 1.37 (s, 9 H, Boc-CH₃), 1.99 (m, 2 H, 4-CH₂), 3.05 (m, 2 H), 3.85 (dd, ³ J = 5.6 Hz, ³ J = 15.2 Hz, 2 H), 4.01 (m, 1 H, CH), 4.65 (dt, ³ J = 7.6 Hz, ³ J = 37.1 Hz, 1 H), 5.09 (br s, 1 H, NH), 6.20 (t, ³ J = 5.7 Hz, 1 H, NH), 7.17–7.31 (m, 5 H, ArH). ¹³C NMR (101 MHz, CDCl₃): δ = 14.1 (C-16), 22.7 (C-15), 23.4 (d, ³ J = 5.1 Hz, C-4), 28.3–29.7 (C-5 to C14), 29.4 (C-28 to C-30), 37.4 (C-19), 38.5 (C-3), 40.1 (d, ³ J = 32.4 Hz, C-1), 54.9 (C-18), 80.3 (C-27), 108.3 (C-3), 126.9 (d, C-23), 128.6 (d, C-24/22), 129.3 (d, C-25/21), 136.6 (d, C-20), 153.3 (d, ¹ J = 253.1 Hz, C-2), 155.5 (s, C-28), 171.1 (s, C-17). ¹⁹F NMR (282 MHz, CDCl₃): δ = –118.0 (³ J = 15.1, ³ J = 37.1 Hz). HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₅₀FN₂O₃: 505.3800; found: 505.3802; m/z [M + Na]⁺ calcd for C₃₀H₄₉FNNaO₃: 527.3619; found: 527.3620.
• 17 All commercial available reagents were used without further purification. Air-sensitive reactions were conducted in flame-dried flasks under an argon atmosphere. Melting points are uncorrected. Peptide synthesis grade DMF was used for peptide coupling. NMR spectra were recorded at 300 (¹H), 75 (¹³C) and at 282 MHz (¹⁹F) and are reported in ppm downfield from TMS (¹H and ¹³C, CDCl₃ as internal standard) and CFCl₃ (¹⁹F). Signals were assigned with the help of ¹H NMR (GCOSY), (¹H and ¹³C) with GHSQC and GHMBC. Mass spectra were recorded with a Finnigan MAT 4200S under ESI conditions. Column chromatography (silica gel Merck 60, 0.040–0.063 mm) was used for purification. Fluorinated allylic alcohols were prepared according to reported protocols (see ref. 8).