LETTER
Stereoselective Synthesis of b-Amino-a-Fluoro Esters
793
(3) Current Address: Starpharma Ltd, Level 6, Baker Heart
Research Building, Commercial Road, Prahran, Victoria,
3181, Australia.
(4) (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Welch, J.
T.; Eswarakrischnan, S. Fluorine in Bioorganic Chemistry;
Wiley: New York, 1991. (c) Biomedical Frontiers of
Fluorine Chemistry; Ojima, I.; McCarthy, J. R.; Welch, J. T.,
Eds.; ACS Books, American Chemical Society:
recrystallised from 95% aq EtOH to give colourless acicular
crystals which were composed exclusively of t-butyl
(2S,3S,aS)-3-[N-benzyl-N-(a-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): d = 1.16 (s, 9 H),
1.19 (d, J = 7 Hz, 3 H), 3.84 and 3.96 (AB system, JAB = 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): d = 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): d = –199.4
(dd, J = 33 and 50 Hz). [a]D24 +28.3 (c 0.2, CDCl3).
Washington, 1996.
(5) Enantiocontrolled Synthesis of Fluoro-Organic
Compounds: Stereochemical Challenges and Biomedicinal
Targets; Soloshonok, V. A., Ed.; Wiley: Chichester UK,
1999.
(6) Frey, P. A.; Magnusson, O. T. Chem. Rev. 2003, 103, 2129.
(7) Walker, B.; Lynas, J. F. Cell Mol. Life Sci. 2001, 58, 596.
(8) Sorochinsky, A.; Voloshin, N.; Markovsky, A.; Belik, M.;
Yasuda, N.; Uekusa, H.; Ono, T.; Berbasov, D. O.;
Soloshonok, V. A. J. Org. Chem. 2003, 68, 7448.
(9) Somekh, L.; Shanzer, A. J. Am. Chem. Soc. 1982, 104, 5836.
(10) Charvillon, F. B.; Amouroux, R. Tetrahedron Lett. 1996, 37,
5103.
(11) For solid state structures of 2 and related amides, see:
(a) Andrews, P. C.; Duggan, P. J.; Fallon, G. D.; McCarthy,
T. D.; Peatt, A. C. J. Chem. Soc., Dalton Trans. 2000, 1937.
(b) Andrews, P. C.; Duggan, P. J.; Fallon, G. D.; McCarthy,
T. D.; Peatt, A. C. J. Chem. Soc., Dalton Trans. 2000, 2505.
(c) Andrews, P. C.; Duggan, P. J.; Maguire, M.; Nichols, P.
J. J. Chem. Soc., Chem. Commun. 2001, 53.
(12) (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry
1991, 2, 183. (b) Davies, S. G.; Garrido, N. M.; Ichihara, O.;
Walters, I. A. S. J. Chem. Soc., Chem. Commun. 1993, 1153.
(13) (a) Bunnage, M. E.; Chernega, A. N.; Davies, S. G.;
Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1994, 2373.
(b) Brackenridge, I.; Davies, S. G.; Fenwick, D. R.; Ichihara,
O.; Polywka, M. E. C. Tetrahedron 1999, 55, 533.
(14) Davies, S. G.; Walters, I. A. S. J. Chem. Soc., Perkin Trans.
1 1994, 1129.
Characteristic data of minor diastereoisomer: 1H NMR (300
MHz, CDCl3): d = 5.10 (dd, J = 50 and 8 Hz). 19F NMR
(282.4 MHz, CDCl3): d = –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): d = 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): d = 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): d =
–202.1 (dd, J = 26 and 50 Hz). [a]D24 +12.4 (c 0.2, CDCl3).
Characteristic data of minor diastereoisomer: 1H NMR (300
MHz, CDCl3): d = 4.67 (dd, J = 49 and 4 Hz). 19F NMR
(282.4 MHz, CDCl3): d = –201.1 (dd, J = 28 and 49 Hz).
(19) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc.,
Perkin Trans. 1 1994, 1141.
(15) (a) Davies, S. G.; Fenwick, D. R. Chem. Commun. 1997,
565. (b) Davies, S. G.; Smethurst, C. A. P.; Smith, A. D.;
Smyth, G. D. Tetrahedron: Asymmetry 2000, 11, 2437.
(16) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96,
1737.
(20) (a) 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 MoKa radiation
(17) Experimental Procedure for Tandem Conjugate
Addition/Fluorination of t-Butyl Cinnamate (1a): (S)-(–)-
N-Benzyl-N-a-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
(l = 0.71073 Å). Structures were solved using direct
methods20b and refined by full matrix least-squares on F2. 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: ] (b)Sheldrick,
G. M. SHELXS 97, Program for the Solution of Crystal
Structures; University of Göttingen: Germany, 1997.
(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): d = 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),
separate samples were shown to be identical by 1H and 19
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
F
Synlett 2004, No. 5, 791–794 © Thieme Stuttgart · New York