Asymmetric Synthesis of b-Halo-aryl b-Amino Acid Derivatives

Steven D. Bull, Stephen G. Davies,*Santiago Delgado-Ballester, Peter M. Kelly, Luke. J. Kotchie, Massimo Gianotti, Mario Laderas and Andrew D. Smith

The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QY,UK.

E.Mail:steve.davies@chemistry.ox.ac.uk

LithiumN-benzyl-N-a-methyl-4-methoxybenzylamide may be employed as a homochiral ammonia equivalent for the synthesis of homochiralb-haloaryl-b-amino acid derivativesviaa strategy involving its conjugate addition toa,b-unsaturatedb-haloaryl acceptors and subsequent oxidative deprotection with ceric ammonium nitrate.

Preparation of (E)-tert-butyl 3-(3-fluorophenyl)-prop-2-enoate(2)

Preparation of (E)-tert-butyl 3-(3-fluorophenyl)-prop-2-enoate2

Structure:

Following general procedure 1,tert-butyl diethylphosphonoacetate (2.73g, 10.83mmol),n-BuLi (2.5M 4.2ml, 10.3mmol) in THF (10ml) and 3-fluorobenzaldehyde (1.22g, 9.85mmol) in THF (10ml) gave, after purification by column chromatography on silica gel (hexane:Et2O 40:1),2(2.01g, 92perc) as a colourless oil

IR: (film) ()

2980 CH
1712 C=O

HNMR: 400 MHz (CDCl3)

delta delta1 H shape J annot
1.56 9 s
6.38 1 d 16.0 C(2) H
7.07 1 m
7.18 7.38 3 m
7.52 1 d 16.0 C(3) H

CNMR: 100 MHz (CDCl3)

delta annot
28.6
81.2
114.6
117.2
122.1
124.3
130.8
137.4
142.5
163.3
166.5;

MS: CI+ ()()

Found:

Formula:

method:

Required:

overall:

Preparation of (E)-tert-butyl 3-(2-iodophenyl)prop-2-enoate(3)

Preparation of (E)-tert-butyl 3-(2-iodophenyl)prop-2-enoate3

Structure:

Following general procedure 1,tert-butyl diethylphosphonoacetate (5.0g, 19.8mmol),n-BuLi (1.6M 11.85ml, 19.0mmol) in THF (20ml) and 2-iodobenzaldehye (4.0g, 17.2mmol) in THF (10ml) gave, after purification by column chromatography on silica gel (hexane:Et2O 40:1),3(5.39g, 93perc) as a yellow oil

IR: (film) ()

2977 CH
1708 C=O
1637 C=C

HNMR: 400 MHz (CDCl3)

delta delta1 H shape J annot
1.55 9 s
6.25 1 d 15.7 C(2) H
7.04 1 t 7.6 Ph(4) HC 6H 4I
7.34 1 t 7.6 Ph(5) HC 6H 4I
7.56 1 d 7.6 Ph(6) HC 6H 4I
7.83 1 d 15.7 C(3) H
7.90 1 d 7.6 Ph(3) HC 6H 4I

CNMR: 100 MHz (CDCl3)

delta annot
28.6
81.2
101.7
123.4
127.7
128.9
130.7
135.9
140.4
147.1
166.0;

MS: CI+ ()()

Found:

Formula:

method:

Required:

overall:

Acknowledgements

The authors wish to thank the EPSRC and RhCHAR:244ne Poulenc Rorer for providing a CASE award (A. D. S), New College, Oxford for a Junior Research Fellowship (A. D. S), the FundaciCHAR:243n SCHAR:232neca for providing a studentship (S. D-B) and the University of Bologna for funding (M. G).

References

1 M. A. Patane, M. G. Bock and H. G. Selnick, PCT int. Appl. WO 9857641 A119981223, 1998, CA: 1998, 130, 81520; S. P. Adams, K. C. Lin, W. C. Lee, A. C. Castro, C. N. Zimmerman, C. E. Hammond, Y. S. Liao, J. H. Cuervo and J. Singh, PCT Int. Appl. WO 9622966 A1 960801, 1996.
2 S. J. Faulconbridge, K. E. Holt, L. G. Sevillano, C. J. Lock, P. D. Tiffin, N. Tremayne and S. Winter, Tetrahedron Lett. 2000 41 2679.
3 J. D. Bourzat and A. Commercon, Tetrahedron Lett. 1993 34 6049.
4 M. K. Mokhallalati, M-J. Wu and L. N. Pridgen, Tetrahedron Lett. 1993 34 47.
5 For an approach toward the asymmetric synthesis ofb-haloaryl-b-amino esters on solid phase see Y. Lee and R. B. Silverman, Org. Lett. 2000 303.
6 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry 1991 183; M. E. Bunnage, A. J. Burke, S. G. Davies and C. J. Goodwin, Tetrahedron: Asymmetry, 1995, 165; S. G. Davies and D. J. Dixon, J. Chem. Soc., Perkin 1, 1998, 2629; S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1996, 1919; S. G. Davies and O. Ichihara, Tetrahedron Lett., 1999, 40, 9313.
7 S. D. Bull, S. G. Davies, P. M. Kelly, M. Gianotti and A. D. Smith, J. Chem. Soc. Perkin Trans. 1, in press; ( S)- N-a-methyl-4-methoxybenzylamine is commercially available from Lancaster Synthesis Ltd, Morecambe, UK.
8 S. D. Bull, S. Delgado-Ballester, S. G. Davies, G. Fenton, P. M. Kelly and A. D. Smith, Synlett 2000 9 1257.
9 All reaction diastereoselectivities were calculated by 1H 400MHz NMR spectroscopic analysis of the crude reaction mixture.
10 J. F. Costello, S. G. Davies and O. Ichihara, Tetrahedron : Asymmetry 1994 5 1999.
11 G. Cristalli, E. Camaioni, S. Vittori, R. Volpini, P. A. Borea, A. Conti, S. Dionisotti, E. Ongini and A. Monopoli, J. Med. Chem., 1995 3 8, 1462.