Synlett 2018; 29(08): 1102-1106
DOI: 10.1055/s-0036-1591551
letter
© Georg Thieme Verlag Stuttgart · New York

Identification of 1,5,7-Triazabicyclododecene and Polystyrene-Supported Superbases as Efficient Hydroxylaminolysis Agents of Sterically Hindered and Epimerizable Esters

Romain Pierre
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France   Email: [email protected]   Email: [email protected]
,
Frédéric Gaigne
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France   Email: [email protected]   Email: [email protected]
,
Ghizlane El-Bazbouz
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France   Email: [email protected]   Email: [email protected]
,
Grégoire Mouis
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France   Email: [email protected]   Email: [email protected]
,
Gilles Ouvry
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France   Email: [email protected]   Email: [email protected]
,
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France   Email: [email protected]   Email: [email protected]
,
Craig S. Harris*
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France   Email: [email protected]   Email: [email protected]
› Author Affiliations
The work communicated in this letter was part of a short laboratory project carried out by Romain Pierre in support of obtaining the qualification of Diplome d’Ingenieur from the CNAM (Conservatoire National des Arts et Métiers), Paris.
Further Information

Publication History

Received: 07 December 2017

Accepted after revision: 18 February 2018

Publication Date:
13 April 2018 (online)


Abstract

In modern pharmaceutical research, the need for reliable protocols for the preparation of chemical libraries in a controlled manner is quintessential to driving the Design-Make-Test cycle in drug discovery programs. In this letter, we communicate the identification of 1,5,7-triazabicyclododecene and polystyrene-supported superbases as efficient hydroxylaminolysis agents of sterically hindered and epimerizable esters and, to some extent, amides, using iChem Explorer® as the conditions scouting tool.

Supporting Information

 
  • References and Notes

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    • 7b Typical procedure: To a stirred solution of the methyl ester (1 equiv) in MeOH (4 vol), was added DBU (3 equiv) and 50% v/v aqueous solution NH2OH (aq) (10 equiv) at room temperature. The reaction mixture was stirred for 48 h or until full conversion. The crude product was then purified directly using a mass-triggered preparative LCMS Waters X-Terra reverse-phase column (C-18, 5μ silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/min) and decreasing polar mixtures of water (containing 0.1% formic acid) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford the final compounds, usually as crystalline solids.
  • 8 The iChem Explorer® is compatible with Agilent 1100 and 1200 HPLC systems. This heating/cooling stirring module allows the progress of reactions in up to 57 vials to be closely monitored during a single run (http://www.ichemexplorer.com/Articles/ iChemExplorerFeatures.html).
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  • 10 Chiral HPLC conditions: PIC Solutions Chiral SFC; Column ID, 5 μm ×4.6×250 mm; scCO2 / 25% i-PrOH; flow rate: 4 mL/min; wavelength: 210 nm; t R = 3.4 (R), 4.5 (S) min.
  • 11 The authors recognize that a catalytic amount of base could be employed for this reaction, which is in accordance with the proposed mechanism. In the interest of our medicinal chemistry projects, whereby we were looking for high throughput process to prepare diverse libraries, we preferred to use an excess of superbase to assure rapid and complete hydroxylaminolysis.
  • 12 Hydroxylaminolysis of methyl (S)-2-benzamido-2-phenylacetate (6); General Procedure To a stirred solution of 50 wt. % NH2OH (aq) (216 μL, 3.53 mmol, 10 equiv) and the base (0.5–3 equiv) was added methyl benzoyl-d/l-phenylalaninate (100 mg, 0.35 mmol, 1 equiv) and the reaction mixture was stirred at r.t. until completion (<10 min to 12 h) and purified directly by mass-triggered preparative LCMS to afford N-(2-(hydroxyamino)-2-oxo-1-phenylethyl)benzamide (7; 90 mg, 90%) as a beige solid. LCMS (t R = 1.01 min) purity: 100%; MS (ES+): m/z = 285.04 [M+H]+; 1H NMR (400 MHz, DMSO-d 6): δ = 11.02 (s, 1 H), 9.01 (s, 1 H), 8.85 (d, J = 8.1 Hz, 1 H), 8.06–7.79 (m, 2 H), 7.62–7.20 (m, 9 H), 5.62 (d, J = 8.2 Hz, 1 H); 13C NMR (101 MHz, DMSO): δ = 166.74, 166.27, 138.50, 133.91, 131.47, 128.30, 128.21, 127.79, 127.66, 127.45, 54.68.
  • 13 Evaluation of TBD as an acylation catalyst with other nucleophiles; General Procedure To a stirred solution of nucleophile (10 equiv) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (3 equiv) (supported or in solution) in MeOH (4 vols) at r.t., was added methyl benzoyl-l-phenylalaninate (4; 50 mg, 0.18 mmol, 1 equiv) and the crude reaction mixture was stirred for 1–24 h and purified directly by mass-trigger Prep LCMS to obtain 9. (S)-N-(1-Hydrazineyl-1-oxo-3-phenylpropan-2-yl)benzamide: Yield: 40 mg (78%); LCMS (t R = 0.87 min) purity: 100%; MS (ES+): m/z = 284.02 [M+H]+; 1H NMR (400 MHz, DMSO-d 6): δ = 9.30 (s, 1 H), 8.56 (d, J = 8.5 Hz, 1 H), 7.85–7.72 (m, 2 H), 7.56–7.47 (m, 1 H), 7.47–7.39 (m, 2 H), 7.39–7.30 (m, 2 H), 7.26 (dd, J = 8.3, 6.7 Hz, 2 H), 7.20–7.11 (m, 1 H), 4.67 (td, J = 8.7, 6.0 Hz, 1 H), 3.07–2.98 (m, 2 H). (S)-N-(1-Oxo-3-phenyl-1-(piperidin-1-yl)propan-2-yl)benzamide: Yield: 21 mg (35%); LCMS (t R = 1.16 min) purity: 100%; MS (ES+): m/z = 337.12 [M+H]+; 1H NMR (400 MHz, DMSO-d 6): δ = 8.75 (d, J = 8.2 Hz, 1 H), 7.78–7.87 (m, 2 H), 7.47–7.58 (m, 1 H), 7.21–7.34 (m, 4 H), 7.13–7.21 (m, 1 H), 5.12 (td, J = 8.3, 6.4 Hz, 1 H), 3.43 (dd, J = 6.8, 4.4 Hz, 4 H), 2.89–3.13 (m, 2 H), 1.13–1.63 (m, 6 H). (S)-N-(1-((Benzyloxy)amino)-1-oxo-3-phenylpropan-2-yl)benzamide: Yield: 15 mg (23%); LCMS (t R = 1.13 min) purity: 100%; MS (ES+): m/z = 375.10 [M+H]+; 1H NMR (400 MHz, DMSO-d 6): δ = 11.41 (s, 1 H), 8.68 (d, J = 8.2 Hz, 1 H), 7.73–7.96 (m, 2 H), 7.07–7.62 (m, 14 H), 4.67–4.83 (m, 2 H), 4.56 (td, J = 8.7, 6.2 Hz, 1 H), 2.93–3.09 (m, 2 H). (S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)benzamide: Yield: 15 mg (31%); LCMS (t R = 0.91 min) purity: 100%; MS (ES+): m/z = 269.05 [M+H]+; 1H NMR (400 MHz, DMSO-d 6): δ = 8.49 (d, J = 8.5 Hz, 1 H), 7.74–7.83 (m, 2 H), 7.48–7.61 (m, 2 H), 7.40–7.47 (m, 2 H), 7.34 (d, J = 7.2 Hz, 2 H), 7.25 (t, J = 8.5 Hz, 1 H), 7.13–7.20 (m, 1 H), 7.11 (s, 1 H), 4.64 (dd, J = 8.5, 4.1 Hz, 1 H), 2.90–3.20 (m, 2 H).
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