Synthesis of beta-hydroxy-beta-(fluoronitrophenyl)alanines: vital components in the assembly of biologically active cyclic peptides.

Article abstract of DOI:10.1021/ol9906054

[formula: see text] Numerous biologically active cyclic peptides, such as the antibiotic vancomycin, contain amino acid residues connected through side-chain biaryl or aryl-alkyl ether linkages. Nucleophilic aromatic substitution reactions have recently b

Full text of DOI:10.1021/ol9906054

ORGANIC
LETTERS
1999
Vol. 1, No. 2
295-297
Synthesis of
â-Hydroxy-â-(fluoronitrophenyl)alanines:
Vital Components in the Assembly of
Biologically Active Cyclic Peptides
Craig A. Hutton
School of Chemistry, The UniVersity of Sydney, NSW 2006, Australia
c.hutton@chem.usyd.edu.au
Received April 20, 1999
ABSTRACT
Numerous biologically active cyclic peptides, such as the antibiotic vancomycin, contain amino acid residues connected through side-chain
biaryl or aryl−alkyl ether linkages. Nucleophilic aromatic substitution reactions have recently been shown to provide a general method for the
formation of such ether linkages, and consequently the synthesis of functionalized fluoronitro-substituted aromatic amino acids is of great
interest. Herein, a method for the stereospecific synthesis of 3-fluoro-4-nitro- and 4-fluoro-3-nitro-threo-â-hydroxyphenylalanine is described.
Recent advances in nucleophilic aromatic substitution
(SNAr) reactions of fluoronitro-substituted aromatic amino
acids have shown the SNAr methodology to be exceptionally
useful for the synthesis of biologically active cyclic peptides
containing biaryl or alkyl-aryl ether linkages.1-5 In particu-
lar, 4-fluoro-3-nitro-â-hydroxyphenylalanine derivatives have
been used extensively in the synthesis of vancomycin and
its analogues.2 Additionally, SNAr reactions of 3-fluoro-4-
nitrophenylalanine derivatives have been employed in the
synthesis of cyclic peptides such as the cycloisodityrosine-
containing peptides,3 K-13,4 and the cyclopeptide alkaloids.5
(1) (a) Feng, Y.; Wang, Z.; Jin, S.; Burgess, K. J. Am. Chem. Soc. 1998,
120, 10768. (b) Raeppel, S.; Raeppel, F.; Suffert, J. Synlett 1998, 794. (c)
Zhu, J. Synlett 1997, 133.
Several syntheses of 4-fluoro-3-nitro-â-hydroxyphenyl-
alanine derivatives have been reported, all of which proceed
via aldol-type reactions of glycine anion equivalents with
4-fluoro-3-nitrobenzaldehyde, utilizing either Evans2a,6 or
Schollkopf3b chiral auxiliaries or enzyme-mediated reactions.7
Although synthesis of the (2S,3S)-isomer (erythro-isomer)
of 4-fluoro-3-nitro-â-hydroxyphenylalanine using Evans’
imide enolate methodology occurs with high diastereoselec-
tivity and in high yield,6a synthesis of the (2S,3R)-isomer
(2) (a) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.;
Barrow, J. C.; Katz, J. L. Angew. Chem., Int. Ed. Engl. 1998, 37, 2700. (b)
Boger, D. L.; Beresis, R. T.; Loiseleur, O.; Wu, J. H.; Castle, S. L. Bioorg.
Med. Chem. Lett. 1998, 8, 721. (c) Rama Rao, A. V. Pure Appl. Chem.
1998, 70, 391. (d) Boger, D. L.; Borzilleri, R. M.; Nukui, S.; Beresis, R. T.
J. Org. Chem. 1997, 62, 4721. (e) Rama Rao, A. V.; Gurjar, M. K.;
Lakshmipathi, P.; Reddy, M. M.; Nagarajan, M.; Pal, S.; Sarma, B. V. N.
B. S.; Tripathy, N. K. Tetrahedron Lett. 1997, 38, 7433. (f) Beugelmans,
R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J.; Zhu, J. J. Org. Chem.
1994, 59, 5535.
(3) (a) Bigot, A.; Beugelmans, R.; Zhu, J. Tetrahedron 1997, 53, 10753.
(b) Boger, D. L.; Zhou, J.; Borzilleri, R. M.; Nukui, S.; Castle, S. L. J.
Org. Chem. 1997, 62, 2054. (c) Boger, D. L.; Borzilleri, R. M. Bioorg.
Med. Chem. Lett. 1995, 5, 1187.
(6) (a) Evans, D. A.; Watson, P. S. Tetrahedron Lett. 1996, 37, 3251.
(b) Zhu, J.; Boullion, J.-P.; Singh, G. P.; Chastanet, J.; Beugelmans, R.
Tetrahedron Lett. 1995, 39, 7081.
(7) Kimura, T. K.; Vassilev, V. P.; Shen, G.-J.; Wong, C.-H. J. Am.
Chem. Soc. 1997, 119, 11734.
(4) Beugelmans, R.; Bigot, A.; Zhu, J. Tetrahedron Lett. 1994, 35, 7741.
(5) (a) East, S. P.; Shao, F.; Williams, L.; Joullie, M. M. Tetrahedron
1998, 54, 13371. (b) Laib, T.; Zhu, J. Tetrahedron Lett. 1998, 39, 283.
10.1021/ol9906054 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/27/1999

(threo-isomer) is often associated with low diastereoselec-
tivity and poor yields.3b,6b,8
treatment of 2 with NBS gave a 1.1:1 mixture of the threo-
and erythro-diastereomers, respectively, of the bromide 3,
in quantitative yield (Scheme 1).
To date, no synthesis of 3-fluoro-4-nitro-â-hydroxyphen-
ylalanine has been reported. Derivatives of 3-fluoro-4-nitro-
â-hydroxyphenylalanine may provide an entry to the syn-
thesis of 3′-bridged ethers of arylalanine derivatives, such
as those present in the phomopsins,9 thereby complementing
the present methods for the preparation of 4′-bridged ethers
such as those present in vancomycin.
Scheme 1
A high-yielding, stereospecific route to both the 3-fluoro-
4-nitro- and 4-fluoro-3-nitro-(2S,3R)-â-hydroxyphenyl-
alanines, 10a and 10b, achieved by elaboration of the
bromination-hydrolysis methodology developed by Easton
and Hutton10,11 is presented here.
Recent studies by the author10 have shown that the
hydrolysis of N-phthaloyl-â-bromoarylalanine methyl esters
provides the corresponding â-hydroxyarylalanine derivatives,
with the selectivity being controlled by facially selective
stabilization of the intermediate benzylic cation by the
neighboring ester moiety (Figure 1a). The introduction of
Treatment of the bromide 3 with silver nitrate in aqueous
acetone under standard conditions (20 °C, 24 h) resulted in
only 5% conversion of the bromide. Heating of the mixture
at 50 °C for 3 days was required to drive the reaction to
completion, with the reduced rate of reaction attributed to
destabilization of the intermediate carbocation by the electron-
withdrawing aryl substituents. Hydrolysis of the bromide 3
did indeed proceed with relatively high diastereoselectivity
(95:5 threo:erythro); however, alcohol 4 was isolated in only
moderate yield (35%). The (Z)-dehydroarylalanine derivative
5 was also isolated from the reaction mixture, in 50% yield,
indicating that elimination of hydrogen bromide becomes
competitive with production of the corresponding alcohol
as sufficiently electron withdrawing aromatic substituents
destabilize formation of the benzylic carbocation.
Figure 1. Facially selective stabilization of cationic intermediate
through a neighboring group effect: (a) R ) OMe; (b) R ) NHtBu.
electron-withdrawing substituents onto the aromatic ring was
shown to result in increased selectivity for the threo-isomer
of the â-hydroxyarylalanine derivative. Consequently, it was
anticipated that the presence of the electron-withdrawing
fluoro and nitro groups in bromide 3 would furnish a highly
diastereoselective conversion of 3 to the alcohol 4 under the
reported conditions. Initial efforts toward the synthesis of
â-hydroxy-â-(fluoronitrophenyl)alanine 10a were therefore
conducted following preparation of the protected fluoro-
nitrophenylalanine derivative 2 from (S)-4-fluoro-3-nitro-
phenylalanine 1a12 under standard conditions.10 Subsequent
Reactions of the corresponding 3-fluoro-4-nitrophenyl-
alanine derivatives were not attempted as the 3-fluoro and
4-nitro substituents are significantly more electron withdraw-
ing than the corresponding 4-fluoro and 3-nitro substituents,
suggesting that substitution at the benzylic center would be
further disfavored.
(8) Evans (ref 2a) reports that the stannous triflate mediated aldol reaction
of 6 with 4-fluoro-3-nitrobenzaldehyde proceeds to give the corresponding
threo-â-hydroxy amino acid derivative with 95:5 diastereoselectivity,
whereas Zhu et al. (ref 6b) report that the identical reaction gives only
moderate diastereoselectivity and chemical yield.
Due to the prevalence of the elimination reaction of the
bromoester 3, a different carboxyl protecting group was
employed. Amide groups have been shown to favor substitu-
tion reactions over elimination in similar systems, as well
as furnishing the substitution products with very high
stereoselectivity.13 This is attributed to an increased magni-
tude of the neighboring group effect by the amide moiety
(Figure 1b) compared to that for the corresponding ester
(9) Mackay, M. F.; Donkelaar, A. V.; Culvenor, C. C. V. J. Chem. Soc.,
Chem. Commun. 1986, 1219.
(10) Hutton, C. A. Tetrahedron Lett. 1997, 38, 5899.
(11) Easton, C. J.; Hutton, C. A.; Roselt, P. D.; Tiekink, E. R. T.
Tetrahedron 1994, 50, 7327.
(12) Vergne, C.; Bois-Choussy, M.; Ouazzani, J.; Beugelmans, R.; Zhu,
J. Tetrahedron: Asymmetry 1997, 8, 391.
296
Org. Lett., Vol. 1, No. 2, 1999

moiety (Figure 1a). The bromination-hydrolysis methodol-
ogy was therefore attempted following protection of the
carboxylic acid as its N-tert-butylamide derivative.
Introduction of the N-phthaloyl group was achieved by
treatment of (S)-4-fluoro-3-nitrophenylalanine 1a with N-
carbethoxyphthalimide (NCEP). Subsequent treatment with
ethyl chloroformate and triethylamine followed by tert-
butylamine afforded the NR-phthaloyl-N-tert-butylamide
derivative 7a in 78% yield (Scheme 2). Bromination of 7a
elimination of HBr was detected, in accord with literature
precedent.13
Subsequent deprotection of the â-hydroxyarylalanine
derivative 9a upon treatment with 5N HCl/acetic acid (2:1)
gave the free amino acid, 4-fluoro-3-nitro-â-hydroxyphenyl-
alanine 10a, in 82% yield. This procedure therefore repre-
sents a rapid, stereospecific, and high-yielding conversion
of the amino acid 1a to the threo-â-hydroxyamino acid 10a.
Similar conditions were employed in the preparation of
3-fluoro-4-nitro-â-hydroxyphenylalanine 10b. Protection of
(S)-3-fluoro-4-nitrophenylalanine 1b12 gave 7b in 74% yield,
and subsequent treatment with NBS gave the bromide 8b
(98%) as a 1:1 mixture of diastereomers (Scheme 2). More
vigorous conditions were required to convert the bromide
8b to the alcohol 9b than for the corresponding reaction of
the isomeric bromide 8a, due to the increased electron-
withdrawing nature of the 4-nitro and 3-fluoro substituents,
relative to the 3-nitro and 4-fluoro substituents. Treatment
of the bromide 8b with silver sulfate in aqueous acetone at
85 °C for 4 days in a sealed vessel gave the alcohol 9b in
59% yield, with recovery of the bromide 8b in 12% yield.
Longer reaction times and higher reaction temperatures did
not result in increased yields of the alcohol 9b, though lower
amounts of starting bromide 8b were recovered. Deprotection
of the â-hydroxyarylalanine derivative 9b gave 3-fluoro-4-
nitro-â-hydroxyphenylalanine 10b in 78% yield.
Scheme 2
These procedures therefore provide for the rapid, ste-
reospecific synthesis of â-hydroxy-â-(fluoronitrophenyl)-
alanines 10a and 10b which are suitable for incorporation
into syntheses of a variety of biologically active ether-bridged
cyclic peptides such as vancomycin.
Acknowledgment. The author acknowledges the support
of the Australian Research Council (award of an APD
Fellowship and ARCSG) and the School of Chemistry,
University of Melbourne, at which parts of this work were
conducted.
with NBS gave the bromide 8a as a 1:1 mixture of
diastereomers, in 99% yield. Treatment of the bromide 8a
with silver sulfate in aqueous acetone at 65 °C for 3 days
gave the alcohol 9a in 85% yield. Only the (2S,3R)-isomer
of the alcohol 9a was produced, and no product from
Supporting Information Available: Full experimental
details and characterization for compounds 2-5 and 7-10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Easton, C. J.; Hutton, C. A.; Merrett, M. C.; Tiekink, E. R. T.
Tetrahedron 1996, 52, 7025.
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