Stereoselective Synthesis of β-Amino-α-Fluoro Esters via Diastereoselective Fluorination of Enantiopure β-Amino Enolates

Abstract

β-Amino-α-fluoro esters have been prepared stereoselectively from t-butyl cinnamate and ethyl crotonate via tandem conjugate addition of lithium (S)-(-)-N-benzyl-N-α-methylbenzylamide, followed by fluorination with N-fluorobenzenesulfonimide. The ­absolute stereochemistry of the major diastereomers formed in each reaction was confirmed by X-ray crystallography. Complete deprotection to give (2S,3S)-α-fluoro-β-phenylalanine followed by Fmoc protection was achieved.

β-amino acids - diastereoselectivity - lithium amides - conjugate additions - fluorination

References

1

Current Address: Kinacia Pty Ltd, Level 5, Clive Ward Centre, 16 Arnold St, Box Hill, Victoria, 3128, Australia.

2

Current Address: Mayne Pharma Pty Ltd, 551 Blackburn Road, Mt Waverley, Victoria, 3149, Australia.

3

Current Address: Starpharma Ltd, Level 6, Baker Heart Research Building, Commercial Road, Prahran, Victoria, 3181, Australia.

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For solid state structures of 2 and related amides, see:

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17

Experimental Procedure for Tandem Conjugate Addition/Fluorination of t -Butyl Cinnamate ( 1a): (S)-(-)-N-Benzyl-N-α-methylbenzyl amine(2) (1.22g, 5.77 mmol, 1.1 equiv) in dry THF (20 mL) was cooled to -10 °C and treated dropwise with n-BuLi (3.61 mL, 1.6 M in hexane, 5.77 mmol, 1.1 equiv). The resultant deep red/purple lithium amide solution was cooled to -78 °C and t-butyl cinnamate (1.07 g, 5.24 mmol) in THF (15 mL) was added. This resulted in the immediate dissipation of the purple colour to leave a yellow solution, which was stirred for a further 30 min at -78 °C. N-Fluorobenzenesulfonimide(3) (1.82 g, 5.77 mmol, 1.1 equiv) in THF (15 mL) was then added and the reaction was stirred for a further 5 h at -78 °C. While the reaction mixture was still at -78 °C, an aliquot (10 mL) was removed and quenched with sat. NH₄Cl. The resulting mixture was extracted with Et₂O, and the organic extracts washed with brine, dried and concentrated to give a yellow oil. The remaining reaction mixture was allowed to warm to r.t. overnight, then worked up in a similar manner. The two separate samples were shown to be identical by ¹H and ¹⁹F NMR spectroscopy, possessing a diastereomeric ratio of 82:18. These samples were combined and purified by flash chromatography (SiO₂, 10% Et₂O/petroleum ether) to yield a colourless oil (2.3 g, quant.) which partially crystallised on standing at r.t. A sample of the crystalline solid was recrystallised from 95% aq EtOH to give colourless acicular crystals which were composed exclusively of t-butyl (2S,3S,αS)-3-[N-benzyl-N-(α-methylbenzyl)amino]-2-fluoro-3-phenylpropanoate (4a). Representative data: Major diastereoisomer 4a: mp 48-52 °C (95% aq EtOH). IR (nujol): 1718 (s), 1494 (m), 1153 (br s) cm^-1. HRMS (ESI): m/z [MH⁺, C₂₈H₃₃FNO₂] calcd 434.2495; found: 434.2465; m/z [MNa⁺, C₂₈H₃₂FNNaO₂] calcd 456.2315; found: 456.2278. ¹H NMR (300 MHz, CDCl₃): δ = 1.16 (s, 9 H), 1.19 (d, J = 7 Hz, 3 H), 3.84 and 3.96 (AB system, J _AB = 14 Hz, 2 H), 4.18 (q, J = 6 Hz, 1 H), 4.34 (dd, J = 33 and 3 Hz, 1 H), 5.05 (dd, J = 50 and 3 Hz, 1 H), 7.18-7.48 (m, 15 H). ¹³C NMR (50 MHz, CDCl₃): δ = 15.9, 27.6, 52.0, 57.8, 63.4 (d, J = 17 Hz), 82.3, 90.8 (d, J = 196 Hz), 126.7, 127.0, 127.8, 128.1, 128.2, 129.9, 130.6, 137.1, 141.3, 143.8, 167.5 (d, J = 33 Hz). ¹⁹F NMR (282.4 MHz, CDCl₃): δ = -199.4 (dd, J = 33 and 50 Hz). [α]_D ²⁴ +28.3 (c 0.2, CDCl₃). Characteristic data of minor diastereoisomer: ¹H NMR (300 MHz, CDCl₃): δ = 5.10 (dd, J = 50 and 8 Hz). ¹⁹F NMR (282.4 MHz, CDCl₃): δ = -187.7 (dd, J = 20 and 50 Hz).

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Tandem Conjugate Addition/Fluorination of Ethyl Crotonate ( 1b): Followed similar procedure to reaction of compound 1a. Representative data: Major diastereoisomer 4b: mp 34-35 °C (95% aq EtOH). IR (nujol): 1734 (s), 1496 (m), 1452 (m), 1368 (m), 1284 (s), 1032 (br. s) cm^-1. HRMS (ESI): m/z [MH⁺, C₂₁H₂₇FNO₂] calcd 344.2026; found: 344.2018; m/z [MNa⁺, C₂₁H₂₆FNNaO₂] calcd 366.1845; found: 366.1833. ¹H NMR (300 MHz, CDCl₃): δ = 1.03-1.25 (m, 6 H), 1.34 (d, J = 6 Hz, 3 H), 3.30-3.53 (m, 1 H), 3.57-4.17 (m, 5 H), 4.71 (dd, J = 50 and 5 Hz, 1 H), 7.15-7.50 (m, 10 H). ¹³C NMR (50 MHz, CDCl₃): δ = 12.7, 13.9, 16.4, 50.7, 53.3 (d, J = 20 Hz), 57.7, 61.2, 92.1 (d, J = 197 Hz), 126.8, 126.9, 127.8, 128.1, 128.2, 128.4, 141.4, 143.3, 169.0 (d, J = 24 Hz). ¹⁹F NMR (282.4 MHz, CDCl₃): δ = -202.1 (dd, J = 26 and 50 Hz). [α]_D ²⁴ +12.4 (c 0.2, CDCl₃). Characteristic data of minor diastereoisomer: ¹H NMR (300 MHz, CDCl₃): δ = 4.67 (dd, J = 49 and 4 Hz). ¹⁹F NMR (282.4 MHz, CDCl₃): δ = -201.1 (dd, J = 28 and 49 Hz).

19 Davies SG. Ichihara O. Walters IAS. J. Chem. Soc., Perkin Trans. 1  1994,  1141 

20a

X-ray Crystallography: Single crystals of 4a and 4b of suitable quality for X-ray diffraction studies were obtained from 95% aq EtOH solutions at 4 °C. Crystals were coated in oil, mounted on a fibre and data collected on an Enraf Nonius KappaCCD at 123 K with MoK_α radiation (λ = 0.71073 Å). Structures were solved using direct methods [20b] and refined by full matrix least-squares on F ^² . All H atoms were placed in calculated positions (C-H 0.95 Å) and included in the final least-squares refinement. All other atoms were located and refined anisotropically. Flack parameters were indeterminate since no heavy atoms are present and absolute stereochemistry was based on the stereochemistry of the starting amine (see text). Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 175705 for 4a and 175706 for 4b. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: [phone] or e-mail: ]

20b Sheldrick GM. SHELXS 97, Program for the Solution of Crystal Structures   University of Göttingen; Germany: 1997. 

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Representative data: Compound 5: IR (neat): 3387 (m), 1754 (s), 1370 (s), 1160 (s) cm^-1. HRMS (ESI): m/z [MH⁺, C₁₃H₁₉FNO₂] calcd 240.1400; found: 240.1402. ¹H NMR (300 MHz, CDCl₃): δ = 1.32 (s, 9 H), 1.66 (br. s, NH₂), 4.39 (dd, J = 4 and 21 Hz, 1 H), 5.00 (dd, J = 4 and 49 Hz, 1 H), 7.29-7.39 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 28.2, 57.7 (d, J = 20 Hz), 83.2, 92.5 (d, J = 189 Hz), 127.8 (d, J = 1 Hz), 128.3, 128.8, 140.1 (d, J = 2 Hz), 167.1 (d, J = 24 Hz). ¹⁹F NMR (282.4 MHz, CDCl₃): δ = -198.1 (dd, J = 21 and 49 Hz); [α]_D ²⁷ +11.95 (c 1.9, CHCl₃). Compound 6: mp 180-182 °C. IR (KBr): 3100-2500 (br. s), 1627 (s),1591 (s), 1408 (s), 699 (s). HRMS (ESI): m/z [MNa⁺, C₉H₁₀FNNaO₂] calcd 206.0594; found: 206.0593. Microanalysis: calcd for C₉H₁₀FNO₂: C, 59.01%; H, 5.50%; N, 7.65%. Found: C, 59.05%; H, 5.53%; N, 7.57%. ¹H NMR (300 MHz, CD₃OD): δ = 4.69 (d, J = 23 Hz, 1 H), 5.06 (d, J = 51 Hz, 1 H), 7.32-7.49 (m, 5 H). ¹³C NMR (75 MHz, CD₃OD): δ = 57.7 (d, J = 21 Hz), 91.5 (d, J = 190 Hz), 129.6, 129.8, 130.1, 135.3, 172.6. ¹⁹F NMR (282.4 MHz, CD₃OD): δ = -192.8 (dd, J = 25 and 51 Hz). [α]_D ²² -40 (c 0.4, CH₃OH). Compound 7: mp 204-208 °C. IR (KBr): 3424 (br. s), 1694 (s), 1617 (s), 1522 (s), 1239 (m), 736 (m s) cm^-1. HRMS (ESI): m/z [MNa⁺, C₂₄H₂₀FNNaO₄] calcd 428.1274; found: 428.1276. ¹H NMR (300 MHz, d ₆-DMSO): δ = 4.16-4.28 (m, 3 H), 4.67 (br. d, J = 52 Hz, 1 H), 5.07 (ddd, J = 23, 8 and 4 Hz, 1 H), 7.21-7.41 (m, 9 H), 7.66-7.87 (m, 4 H), 8.30 (d, J = 7 Hz, 1 H). ¹³C NMR (75 MHz, d ₆-DMSO): δ = 46.3, 56.5 (d, J = 22 Hz), 65.6, 92.7 (d, J = 190 Hz), 119.9, 125.2, 126.7, 127.0, 127.5, 127.6, 127.7, 128.9, 140.6, 143.7, 155.5, 169.1 (d, J = 19 Hz). ¹⁹F NMR (282.4 MHz, d ₆-DMSO): δ = -186.4 (br. s). [α]_D ²¹ +2.5 (c 0.16, CH₃OH).