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Synlett 2004(5): 0791-0794  
DOI: 10.1055/s-2004-817782
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Philip C. Andrewsa, Vijaya Bhaskara, Karen M. Bromfieldb, Aileen M. Dodda, Peter J. Duggan*a, Sandhya A. M. Duggana, Tom D. McCarthyc
a School of Chemistry, Monash University, Clayton, Melbourne, Victoria, 3800, Australia
b Centre for Green Chemistry, Monash University, Clayton, Melbourne, Victoria, 3800, Australia
c Biomolecular Research Institute, Private Bag 10, Melbourne, Victoria, 3169, Australia
Fax: +61(3)99054597; e-Mail: peter.duggan@sci.monash.edu.au;
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Publication History

Received 14 November 2003
Publication Date:
17 February 2004 (online)

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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.

Key words

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

    References

  • 4a Welch JT. Tetrahedron  1987,  43:  3123 
    CrossrefGoogle Scholar
  • 4b Welch JT. Eswarakrischnan S. Fluorine in Bioorganic Chemistry   Wiley; New York: 1991. 
    CrossrefGoogle Scholar
  • 4c Biomedical Frontiers of Fluorine Chemistry   Ojima I. McCarthy JR. Welch JT. ACS Books, American Chemical Society; Washington: 1996. 
    CrossrefGoogle Scholar
  • 5 Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedicinal Targets   Soloshonok VA. Wiley; Chichester UK: 1999. 
    Google Scholar
  • 6 Frey PA. Magnusson OT. Chem. Rev.  2003,  103:  2129 
    CrossrefGoogle Scholar
  • 7 Walker B. Lynas JF. Cell Mol. Life Sci.  2001,  58:  596 
    Google Scholar
  • 8 Sorochinsky A. Voloshin N. Markovsky A. Belik M. Yasuda N. Uekusa H. Ono T. Berbasov DO. Soloshonok VA. J. Org. Chem.  2003,  68:  7448 
    CrossrefPubMedGoogle Scholar
  • 9 Somekh L. Shanzer A. J. Am. Chem. Soc.  1982,  104:  5836 
    CrossrefGoogle Scholar
  • 10 Charvillon FB. Amouroux R. Tetrahedron Lett.  1996,  37:  5103 
    CrossrefGoogle Scholar
  • For solid state structures of 2 and related amides, see:
  • 11a Andrews PC. Duggan PJ. Fallon GD. McCarthy TD. Peatt AC. J. Chem. Soc., Dalton Trans.  2000,  1937 
    Google Scholar
  • 11b Andrews PC. Duggan PJ. Fallon GD. McCarthy TD. Peatt AC. J. Chem. Soc., Dalton Trans.  2000,  2505 
    Google Scholar
  • 11c Andrews PC. Duggan PJ. Maguire M. Nichols PJ. J. Chem. Soc., Chem. Commun.  2001,  53 
    Google Scholar
  • 12a Davies SG. Ichihara O. Tetrahedron: Asymmetry  1991,  2:  183 
    CrossrefGoogle Scholar
  • 12b Davies SG. Garrido NM. Ichihara O. Walters IAS. J. Chem. Soc., Chem. Commun.  1993,  1153 
    CrossrefGoogle Scholar
  • 13a Bunnage ME. Chernega AN. Davies SG. Goodwin CJ. J. Chem. Soc., Perkin Trans. 1  1994,  2373 
    CrossrefGoogle Scholar
  • 13b Brackenridge I. Davies SG. Fenwick DR. Ichihara O. Polywka MEC. Tetrahedron  1999,  55:  533 
    CrossrefGoogle Scholar
  • 14 Davies SG. Walters IAS. J. Chem. Soc., Perkin Trans. 1  1994,  1129 
    CrossrefGoogle Scholar
  • 15a Davies SG. Fenwick DR. Chem. Commun.  1997,  565 
    CrossrefGoogle Scholar
  • 15b Davies SG. Smethurst CAP. Smith AD. Smyth GD. Tetrahedron: Asymmetry  2000,  11:  2437 
    CrossrefGoogle Scholar
  • 16 Lal GS. Pez GP. Syvret RG. Chem. Rev.  1996,  96:  1737 
    CrossrefPubMedGoogle Scholar
  • 19 Davies SG. Ichihara O. Walters IAS. J. Chem. Soc., Perkin Trans. 1  1994,  1141 
    CrossrefGoogle Scholar
  • 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 MoKα 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: +44 (1223)336033 or e-mail: ]

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

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).

18

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).

21

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).