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.

Peptides play an important role in the discovery of new drugs due to their high chemical activity in virtually every biological process.[1] However, major drawbacks that lower their potential as therapeutic agents are fast degradation by peptidases and low transmembrane permeability.[2] Based on quantum chemical calculations, Abraham and Allmendinger suggested that the fluoroolefin moiety was a good isostere for the amide bond with respect to electron-density distribution, orientation of dipole moment, steric features (similar bond length and angles), and conformation fixing.[3] Formally, the carbon–fluorine bond replaces the carbonyl group and the double bond equates to the NH function. Introduction of the fluorovinyl moiety results in higher stability towards hydrolysis and configurational stability. Allmendinger introduced this moiety into a dipeptide isostere to mimic Gly-Gly and Phe-Gly. In later investigations they choose to use the Overman rearrangement[4] to introduce a nitrogen function into the fluorinated template to replace the Phe-Gly peptide bond of a neurotransmitter. Biological tests proved the properties were similar to those anticipated by calculation: the fluorolefin moiety can therefore serve as a peptide isostere.[5] Later, other authors used this rearrangement so synthesize fluorinated allylic amines.[6] To the best of our knowledge, the Overman rearrangement has not been applied to fluorinated secondary allylic alcohols with the double bond in the terminal position. Here we report the use of the Overman rearrangement as the key step in the synthesis of a mimic of the amide bond in glycyldecylamide (GDA). GDA was shown to be a very potent therapeutic agent against phencyclidine-induced psychotic symptoms in rodents, which are similar to schizophrenia.[7]

In this work, we present the synthesis of primary fluorinated allylic amines by using the pathway discussed above. Thus, 2-fluoroallylic alcohols 1b and 1c, the starting materials for the Overman rearrangement, were prepared from terminal olefins according to our well-established three-step procedure of bromofluorination, HBr elimination, and allylic oxidation in 25–38% overall yield (Scheme [1]).[8] In the case of 2-fluoroallylic alcohol 1a, N -iodosuccinimde was used as halogen source leading to the iodofluorinated product, which undergoes clean HI elimination in the following step, whereas in the case of the vicinal bromofluoride, HF elimination was a competing reaction.

2-Fluoro-3-phenylpropen-3-ol (2) could not be synthesized in this way due to unsuccessful allylic oxidation, but was available in low yield under the conditions illustrated in Scheme [2].[9] Changing reaction conditions such as solvent, amount of Selectfluor or reaction time did not improve the yield but increased the number of fluorinated side products.

To study the influence of the 2-fluorine atom on the Overman rearrangement, we also prepared the fluorine-free allylic alcohol 3 by allylic oxidation. The precursors of the Overman rearrangement, trichloroacetimidates 4–6, were obtained from allylic alcohols 1–3 by treatment with trichloroacetonitrile and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The fluorine atom had no significant influence on this reaction (Scheme [3] and Table [1]).[10] The trichloroacetimidates were heated to reflux in p-xylene, leading to the corresponding trichloroacetamides, which were purified by column chromatography.[11]

The mechanism of the thermally induced Overman rearrangement is similar to that of the Claisen rearrangement. The typical six-membered transition state leads exclusively to rearranged products in the trans-configuration (Scheme [4]). The stereochemistry was established by the trans-coupling constant (³ J _H–F = 36.7 Hz). Due to the similar steric features of the fluorine and hydrogen atoms, the fluorine has no significant effect on the steric demand of the transition state.

However, placing a fluorine atom at the terminal double bond slowed down the reaction rate dramatically. Compared to substrates bearing the fluorinated double bond in an internal position,[12] substrates with the fluorinated double bond in the terminal position require much longer reaction time at high temperature. In addition, the rearrangement of 2-fluoroallylic trichloroacetimidates 4a–c needed five times longer compared with the rearrangement of fluorine-free compound 6. In contrast, fluorinated aromatic trichloroacetimidate 5 rearranged much faster due to the formed conjugated system involving the phenyl ring and the double bond.

Hydrolysis to the corresponding fluorinated primary amines 10–12 was accomplished with high yields by heating 7–9 to reflux in 3 M ethanolic sodium hydroxide solution (Scheme [5] and Table [2]).[13] Changing the solvent to toluene and lowering the temperature did not lead to complete rearrangement, even after 120 h reaction time but, instead, led to an increased number of fluorinated side products. Use of the more polar solvent DMF also resulted in an increased number of fluorinated side products and decreased yields of the target products. Microwave-supported reactions with p-xylene never showed complete conversion and led to a number of fluorinated side products. Attempts to catalyze the reaction with Pd(OAc)₂, PdCl₂, PdCl₂(MeCN)₂ or PtCl₂ were not successful. No reaction occurred by stirring the catalysts with the 2-fluoroallylic trichloroacetimidates at room temperature in CH₂Cl₂ or toluene. Heating the mixtures never led to the desired product but led to the formation of a complex mixture of fluorinated products (analyzed by ¹⁹F NMR spectroscopy). The reasons are still unclear and further investigations of the transition-metal-catalyzed Overman rearrangement of 2-fluoroallylic alcohol derivatives are in progress. In contrast, fluorine-free allylic trichloroacet­imidate 6 rearranged to the corresponding trichloracetamide under PdCl₂(MeCN)₂ catalysis.[14]

Subsequently, fluorinated allylic amine 10c was coupled to Boc-protected phenylalanine to form compound 13, containing a fluoroolefin moiety as an amide bond mimic and a peptide bond.[15] [16] (Scheme [6]).

In summary, we have reported a convenient way to synthesize fluorinated primary allylic amines in 69–75% overall yields from 2-fluoroallylic alcohols by Overman rearrangement.[10] [11] [13] [16] [17] The fluorinated long chain aliphatic allylic amine 10c is a bioisostere of a potential schizophrenia therapeutic agent GDA. Compound 10c can be considered as an isostere for N-terminal glycine. We also established the utility of the fluorinated primary allylic amines for coupling with amino acids, forming compound 13, which might be applied as a pro-drug. Currently, we are studying the applicability of fluorinated allylic amines as building blocks for more complex fluorinated nitrogen compounds.

Acknowledgment

Support by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 424) is gratefully acknowledged.

• References and Notes

• 1a Hagmann WK. J. Med. Chem. 2008; 15: 4359
  Search in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 2a Fischer MD, Campbell MM. Chem. Rev. 1998; 98: 763
  CrossrefSearch in Google Scholar
• 2b Giannis A, Kolter T. Angew. Chem., Int. Ed. Engl. 1993; 32: 1244 ; Angew. Chem. 1993, 105, 1303
  CrossrefSearch in Google Scholar

For peptide mimics, see for example:
• 3a Allmendinger T, Furet P, Hungerbühler E. Tetrahedron Lett. 1990; 31: 7297
  CrossrefSearch in Google Scholar
• 3b Urban JJ, Tillman BG, Cronin WA. J. Phys. Chem. A 2006; 110: 11120
  CrossrefSearch in Google Scholar
• 3c Abraham RJ, Ellison SL. R, Schonholzer P, Thomas WA. Tetrahedron 1986; 42: 2101
  CrossrefSearch in Google Scholar
• 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
  Search in Google Scholar
• 4a Overman L. J. Am. Chem. Soc. 1974; 96: 597
  Search in Google Scholar
• 4b Overman L. J. Am. Chem. Soc. 1976; 98: 2901
  Search in Google Scholar
• 5 Allmendinger T, Felder E, Hungerbühler E. Tetrahedron Lett. 1990; 31: 7301
  CrossrefSearch in Google Scholar
• 6a Watanabe D, Koura M, Saito A, Yanai H, Nakamura Y, Okada M, Sato A, Taguchi T. J. Fluorine Chem. 2011; 132: 327
  CrossrefSearch in Google Scholar
• 6b Percy JM, Prime ME. J. Fluorine Chem. 1999; 100: 147
  CrossrefSearch in Google Scholar
• 7 Javitt DC, Frusciante M. Psychopharmacology 1997; 129: 96
  CrossrefSearch in Google Scholar
• 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
  Search in Google Scholar
• 8c Ernet T, Haufe G. Synthesis 1997; 953
  Thieme Connect
• 8d Tranel F, Haufe G. J. Fluorine Chem. 2004; 125: 1593
  CrossrefSearch in Google Scholar
• 9 Zhou C, Li J, Fu C, Ma S. Org. Lett. 2008; 10: 581
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 14b Christie SD. R, Warrington AD, Lunnis CJ. Synthesis 2009; 148
  Thieme Connect
• 15 Carpina LA. J. Am. Chem. Soc. 1993; 115: 4397
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• 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).

• References and Notes

• 1a Hagmann WK. J. Med. Chem. 2008; 15: 4359
  Search in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 2a Fischer MD, Campbell MM. Chem. Rev. 1998; 98: 763
  CrossrefSearch in Google Scholar
• 2b Giannis A, Kolter T. Angew. Chem., Int. Ed. Engl. 1993; 32: 1244 ; Angew. Chem. 1993, 105, 1303
  CrossrefSearch in Google Scholar

For peptide mimics, see for example:
• 3a Allmendinger T, Furet P, Hungerbühler E. Tetrahedron Lett. 1990; 31: 7297
  CrossrefSearch in Google Scholar
• 3b Urban JJ, Tillman BG, Cronin WA. J. Phys. Chem. A 2006; 110: 11120
  CrossrefSearch in Google Scholar
• 3c Abraham RJ, Ellison SL. R, Schonholzer P, Thomas WA. Tetrahedron 1986; 42: 2101
  CrossrefSearch in Google Scholar
• 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
  Search in Google Scholar
• 4a Overman L. J. Am. Chem. Soc. 1974; 96: 597
  Search in Google Scholar
• 4b Overman L. J. Am. Chem. Soc. 1976; 98: 2901
  Search in Google Scholar
• 5 Allmendinger T, Felder E, Hungerbühler E. Tetrahedron Lett. 1990; 31: 7301
  CrossrefSearch in Google Scholar
• 6a Watanabe D, Koura M, Saito A, Yanai H, Nakamura Y, Okada M, Sato A, Taguchi T. J. Fluorine Chem. 2011; 132: 327
  CrossrefSearch in Google Scholar
• 6b Percy JM, Prime ME. J. Fluorine Chem. 1999; 100: 147
  CrossrefSearch in Google Scholar
• 7 Javitt DC, Frusciante M. Psychopharmacology 1997; 129: 96
  CrossrefSearch in Google Scholar
• 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
  Search in Google Scholar
• 8c Ernet T, Haufe G. Synthesis 1997; 953
  Thieme Connect
• 8d Tranel F, Haufe G. J. Fluorine Chem. 2004; 125: 1593
  CrossrefSearch in Google Scholar
• 9 Zhou C, Li J, Fu C, Ma S. Org. Lett. 2008; 10: 581
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 14b Christie SD. R, Warrington AD, Lunnis CJ. Synthesis 2009; 148
  Thieme Connect
• 15 Carpina LA. J. Am. Chem. Soc. 1993; 115: 4397
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• 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).

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