Addition of allylmagnesium bromide to ROPHy/SOPHy aldoximes: Asymmetric synthesis of protected β-amino acids

Article abstract of DOI:10.1055/s-1998-1767

A new asymmetric synthesis of protected β-amino acids is described in which the key step is the diastereoselective addition of allylmagnesium bromide to O-(1-phenylbutyl) aldoximes.

Full text of DOI:10.1055/s-1998-1767

July 1998
SYNLETT
733
Addition of Allylmagnesium Bromide to ROPHy/SOPHy Aldoximes: Asymmetric Synthesis
of Protected β-Amino Acids
Christopher J. Moody and James C. A. Hunt
Department of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, U.K.
Received 9 April 1998
Abstract: A new asymmetric synthesis of protected β-amino acids is
described in which the key step is the diastereoselective addition of
allylmagnesium bromide to O-(1-phenylbutyl) aldoximes.
spectra of 2, and with the exception of the isobutyraldoxime 1d was
greater than 92%. The configuration of the new asymmetric centre in
hydroxylamines 2 was assumed to be the same as the auxiliary on the
basis of our previous results, and in the case of 2a was confirmed by
conversion into the N-protected (R) β-amino ester 4a. The conversion
was achieved by cleavage of the N-O bond using the zinc/acetic acid/
The occurrence of β-amino acids as constituents of a range of
biologically active natural products, together with their role as
precursors to β-lactams, and their incorporation into β-peptides with
11
ultrasound method; the resulting amines were not isolated but were
immediately converted into the benzyl carbamates 3 by reaction with
1
defined secondary structure, has focused attention on these
12,13
benzyl chloroformate (Scheme, Table).
At this stage the
2
homologues of α-amino acids. The development of new methods for
enantiomeric purity of the amine derivatives 3 was established by HPLC
on a chiral stationary phase (Table). Finally the double bond was
the asymmetric synthesis of β-amino acids is therefore of current
2
interest, and several methods have been reported. Among these are: the
cleaved by ozonolysis in methanolic sodium hydroxide to give the N-
3
homologation of α-amino acids using the Arndt-Eistert procedure, the
13-15
Cbz amino esters 4 in moderate yield (Scheme, Table).
The
asymmetric conjugate addition of amines and amides to α,β-unsaturated
configuration of the β-phenyl-β-alanine derivative 4a was confirmed as
4
carboxylic acid derivatives, and the diastereoselective addition of ester
16
(R) by comparison of its optical rotation with a literature value.
enolate equivalents or allyl organometallic reagents to the C=N double
5,6
bond of imines or hydrazones. In the last context we have recently
reported the highly diastereoselective addition of organometallic
In summary, we have established a simple method for the asymmetric
reagents to the C=N bond of (R)- and (S)-O-(1-phenylbutyl) oximes
synthesis of both homoallylamines and protected β-amino acids.
7
(ROPHy and SOPHy oximes), and their application in the asymmetric
8
9
synthesis of the piperidine alkaloid coniine, and of α-amino acids. We
now report an extension of this methodology in a new asymmetric
synthesis of β-amino acids based on the addition of allylmagnesium
bromide to a range of ROPHy/SOPHy aldoximes.
Acknowledgements
This work was supported by the EPSRC. We thank Dr. Andrew
Lightfoot for helpful discussions.
References and Notes
The E-oxime ethers 1, precursors of the β-amino acids, were readily
prepared by reaction of the appropriate aldehyde with (R)- or (S)-O-(1-
phenylbutyl) hydroxylamine (ROPHy or SOPHy); in the case of
(1) For an account of Seebach’s work on β-peptides, see: Seebach, D.;
Matthews, J. L. Chem. Commun. 1997, 2015.
7
(2) For reviews on the asymmetric synthesis of β-amino acids, see:
Cole, D. C. Tetrahedron 1994, 50, 9517; Cardillo, G.; Tomasini,
C. Chem. Soc. Rev. 1996, 25, 117; Enantioselective Synthesis of β-
Amino Acids, ed. Juaristi, E. Wiley-VCH, New York, 1997.
isobutyraldehyde, the Z-oxime was also formed (16%) but this was
readily separated by chromatography. The oxime ethers 1 underwent
addition of allylmagnesium bromide in the presence of boron trifluoride
10
etherate to give the hydroxylamines 2 in excellent yield (Table). The
1
diastereoselectivity of the addition was determined from the H NMR

734
LETTERS
SYNLETT
(3) For recent examples of the Arndt-Eistert homologation of α-
amino acids, see: Seebach, D.; Overhand, M.; Kuhnle, F. N. M.;
Martinoni, B.; Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim.
Acta 1996, 79, 913; Guibourdenche, C.; Seebach, D.; Natt, F.
Helv. Chim. Acta 1997, 80, 1; Leggio, A.; Liguori, A.; Procopio,
A.; Sindona, G. J. Chem. Soc. Perkin Trans. 1 1997, 1969; Marti,
R. E.; Bleicher, K. H.; Bair, K. W. Tetrahedron Lett. 1997, 38,
6145.
consumed (typically 2-12 hours). The reaction mixture was
quenched at -78 °C with water, allowed to warm to room
temperature, and extracted with ether (3 x 15 mL). The extracts
were combined, dried (K
CO ), filtered and evaporated. The
2
3
residue was purified by flash chromatography on silica gel using
dichloromethane-light petroleum (1:2) as eluent to give the
hydroxylamine 2.
(11) Enders, D.; Kempen, H. Synlett 1994, 969.
(4) Davies, S. G.; Fenwick, D. R. Chem. Commun. 1995, 1109;
Enders, D.; Wahl, H.; Bettray, W. Angew. Chem. Int. Ed. Engl.
1995, 34, 455; Enders, D.; Wiedemann, J.; Bettray, W. Synlett
1995, 369; Falborg, L.; Jorgensen, K. A. J. Chem. Soc., Perkin
Trans. 1 1996, 2823; Davies, S. G.; Fenwick, D. R.; Ichihara, O.
Tetrahedron-Asymmetry 1997, 8, 3387.
(12) The N-O bond cleavage and N-protection steps were carried out
exactly as described in ref. 9.
(13) Selected data
22
Carbamate 3a, mp 68-69 °C (light petroleum), [α]
+43.6 (c
D
0.55, CH Cl ).
Carbamate 3b, mp 67-68 °C (light petroleum), [α]
2
2
22
-36.6 (c 0.7,
-16.0 (c 0.5,
D
(5) Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883; Mokhallalati,
M. K.; Wu, M.; Pridgeon, L. N. Tetrahedron Lett. 1993, 34, 47;
Davis, F. A.; Szewczyk, J. M.; Reddy, R. E. J. Org. Chem. 1996,
61, 2222; Cozzi, P. G.; Simone, B. D.; Umani-Ronchi, A.
Tetrahedron Lett. 1996, 37, 1691; Kunz, H.; Burgard, A.;
Schanzenbach, D. Angew. Chem. Int. Ed. Engl. 1997, 36, 386;
Enders, D.; Schankat, J.; Klatt, M. Synlett 1994, 795.
CH Cl ).
2
2
22
arbamate 3c, mp 70-71 °C (light petroleum), [α]
D
CH Cl ).
Carbamate 3d, oil, [α]
Carbamate 3e, oil, [α]
2
2
22
-30.0 (c 2.0, CH Cl ).
2 2
D
22
-29.7 (c 0.97, CH Cl ).
2 2
D
16
22
Amino ester 4a, mp 65-66 °C (hexane), (lit., 65 °C), [α]
D
16
21
+17.1 (c 1, CHCl ) (lit., [α]
-15.8 (c 0.55, CHCl ) for (S)-
3
D
3
(6) For other recent approaches, see ref. 2, and the following: Seki,
M.; Matsumoto, K. Tetrahedron Lett. 1996, 37, 3165; Righi, G.;
Dachille, R.; Bonini, C. Tetrahedron Lett. 1996, 37, 6893; Juaristi,
E.; Quintana, D.; Balderas, M.; Garciaperez, E. Tetrahedron-
Asymmetry 1996, 7, 2233; Soloshonok, V. A.; Ono, T.;
Soloshonok, I. V. J. Org. Chem. 1997, 62, 7538; Park, Y. S.; Beak,
P. J. Org. Chem. 1997, 62, 1574; Bower, J. F.; Jumnah, R.;
Williams, A. C.; Williams, J. M. J. J. Chem. Soc., Perkin Trans. 1
1997, 1411; Davis, F. A.; Reddy, G. V.; Liang, C. H. Tetrahedron
Lett. 1997, 38, 5139.
enantiomer).
Amino ester 4b, mp 76-77 °C (hexane), [α]
24
-26.0 (c 0.5,
-14.0 (c 0.7,
D
D
CHCl ).
3
25
Amino ester 4c, mp 71-72 °C (hexane), [α]
CHCl ).
3
24
Amino ester 4d, oil, [α]
Amino ester 4e, oil, [α]
-24.6 (c 1.4, CHCl ).
3
-18.0 (c 0.4, CHCl ).
3
D
D
25
(14) Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675.
(15) Ozone was passed through a solution of the Cbz-protected amine
(7) Gallagher, P. T.; Hunt, J. C. A.; Lightfoot, A. P.; Moody, C. J. J.
Chem. Soc., Perkin Trans. 1 1997, 2633.
3 (1.64 mmol) in CH Cl (13 mL) and methanolic sodium
2
2
hydroxide (2.5 M; 3.3 mL) at -78 °C. After 2 h a yellow
precipitate had formed. Ether (5 mL) and water (5 mL) were
added and the mixture was allowed to warm to room temperature,
and extracted with ether (5 x 5 mL). The extracts were combined,
(8) Moody, C. J.; Lightfoot, A. P.; Gallagher, P. T. J. Org. Chem.
1997, 62, 746.
(9) Moody, C. J.; Lightfoot, A. P.; Gallagher, P. T. Synlett 1997, 659.
dried (Na SO ), filtered and evaporated. Column chromatography
on silica gel eluting with ether-light petroleum (1:1) gave the
amino ester 4.
2
4
(10) The oxime ether 1 (3.9 mmol) was dissolved in toluene (10 mL)
under nitrogen and cooled to -78 °C. Boron trifluoride etherate
(11.8 mmol) was added and the mixture was stirred for 15 min.
Allylmagnesium bromide (11.8 mmol) was added dropwise over
15 min. and the mixture was stirred until all starting material was
(16) Crombie, L.; Haigh, D.; Jones, R. C. F.; Mat-Zin, A. R. J. Chem.
Soc., Perkin Trans. 1 1993, 2047.