An enantiomeric synthesis of allo-threonines and β-hydroxyvalines

Full text of DOI:10.1021/jo960141c

2582
J . Org. Chem. 1996, 61, 2582-2583
Communications
An En a n tiom er ic Syn th esis of
Sch em e 1
a llo-Th r eon in es a n d â-Hyd r oxyva lin es
Hui Shao and Murray Goodman*
Department of Chemistry and Biochemistry, University of
California, San Diego, La J olla, California 92093-0343
Received J anuary 22, 1996 (Revised Manuscript Received
February 28, 1996)
In conjunction with current efforts to design and
synthesize enantioselectively peptidomimetic building
blocks on a large scale, we require an efficient route to
â-hydroxy R-amino acids, such as allo-threonines and
â-hydroxyvalines. The allo-threonines, the diastereomers
of threonine, represent one of the most common families
of nonproteinogenic amino acid building blocks. In recent
years, L- and D-allo-threonines (aThr) have been found
as important constituents in an increasing family of
bioactive peptides, such as antibiotic hormaomycin,1
antitumor astins,2 antiviral viscosin,3 and phytotoxic
syringopeptins.4 More interestingly, allo-threonines are
the key building blocks in glycopeptides which are
associated with biological recognition and selectivity.5
The glycopeptidolipids present on the cell wall surface
of C-mycosides are characterized by a variable oligosac-
charide chain attached directly to the â-hydroxy group
of the D-allo-threonine.6 It has also been shown that
substitution of threonines by allo-threonines in peptide
sequences can render the molecules more resistant to
proteolysis under physiological conditions.7 Similarly,
chiral â-hydroxyvalines are important components in
biologically active molecules, such as potent anti-HIV
luzopeptins8 and the antibiotics aureobasidin A and
tigemonam.9,10
amino acids are based on the alkylation of enolates from
bis-lactims, oxazinones, or imidazolidinones or other
procedures,11,12 which involve multistep stoichiometric
preparation and careful purification of each correspond-
ing chiral auxiliary. We wish to describe an effective
method for the catalytic asymmetric synthesis of these
building blocks in high enantiomeric purity.
In order to prepare D-allo-threonine starting with
benzyl crotonate (Scheme 1), the Sharpless AD reaction
was carried out on this trans-disubstituted alkene with
AD-mix-â in the presence of methanesulfonamide. The
reaction proceeds smoothly to give diol 1 with excellent
optical purity.13-15 The diol 1 is converted to its 2,3-cyclic
sulfite with SOCl2 and oxidized to cyclic sulfate 2 in a
one-pot synthesis. It is reported that the cyclic sulfate
acts as an excellent leaving group with good regioselec-
In spite of their biological significance, the use of these
building blocks has been hampered by cost and scale up
problems. Most synthetic routes to these important
* To whom correspondence should be addressed.
(1) (a) Andres, N.; Wolf, H.; Za¨hner, H.; Ro¨ssner, E.; Zeeck, A.; Ko¨nig,
W. A.; Sinnwell, V. Helv. Chim. Acta 1989, 72, 426-437. (b) Ro¨ssner,
E.; Zeeck, A.; Ko¨nig, W. A. Angew. Chem., Int. Ed. Engl. 1990, 29,
64-65. (c) Ro¨ssner, E.; Zeeck, A.; Ko¨nig, W. A. Ibid. 1990, 29, 64-65.
(d) Zindel, J .; Meijere, A. J . Org. Chem. 1995, 60, 2968-2973.
(2) Morita, H.; Nagashima, S.; Takeya, K.; Itokawa, H. J . Chem.
Soc., Perkin Trans. 1995, 2327-2331 and references cited therein.
(3) Burke, T. R.; Knight, M.; Chandrasekhar, B. Tetrahedron Lett.
1989, 30, 519-522.
(11) Leading references of â-hydroxy R-amino acids: (a) Duthaler,
B. G.; Riediker, M. Angew. Chem., Int. Ed. Engl. 1989, 28, 497-498.
(b) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron
Lett. 1987, 28, 39-42. (c) Roemmele, R. C.; Rapoport, J . J . Org. Chem.
1989, 54, 1866-1875 and references cited therein. (d) Wipf, P. Miller,
C. P. J . Org. Chem. 1993, 58, 1575-1578 and references cited therein.
(e) Okonya, J . F.; Kolasa, T.; Miller, M. J . Ibid. 1995, 60, 1932-1935.
(f) Reno, D. S.; Lotz, B. T.; Miller, M. J . Tetrahedron Lett. 1990, 31,
827-830. (g) Scho¨llkopf, U. Tetrahedron 1983, 39, 2085. (h) Seebach,
D.; J uaristi, E.; Miller, D. D.; Schickli, C. Weber, T. Helv. Chim. Acta
1987, 70, 237-261. (i) Evans, D. A.; Weber, A. E. J . Am. Chem. Soc.
1986, 108, 6757-6761.
(12) For the synthesis of derivatives of â-hydroxyvaline, see: (a)
Ciufolini, M. A.; Swaminathan, S. Tetrahedron Lett. 1989, 30, 3027-
3028. (b) Scho¨llkopf, U.; Nozulak, J .; Groth, U. Synthesis 1982, 868-
870. (c) Hanson, R. L.; Singh, J .; Kissick, T. P.; Patel, R. N.; Szarka,
L. J .; Mueller, R. H. Bioorg. Chem. 1990, 18, 116-130.
(13) For reviews of the AD reactions, see: (a) Kolb, H. C.; VanNieu-
wenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 2483-2547. (b)
Berrisford, D. J .; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1059-1070. (c) J ohnson, R. A.; Sharpless, K. B. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New
York, 1993; pp 227-272.
(14) The enantiomeric excesses of all compounds were determined
by the HPLC method using a Chiralcel OD column with hexane and
2-propanol as the eluents.
(4) Ballio, A.; Barra, D.; Bossa, F.; Collina, A.; Grgurina, I.; Marino,
G.; Moneti, G.; Paci, M.; Segre, A.; Simmaco, M. FEBS Lett. 1991, 291,
109-112.
(5) Garg, H.; J eanloz, R. W. Adv. Carbohydr. Chem. Biochem. 1985,
43, 135-201.
(6) (a) Brenna, P. J .; Goren, M. B. J . Biol. Chem. 1979, 254, 4205-
4207. (b) Camphausen, R. T.; J ones, R. L.; Brenna, P. J . Am. Vet. Res.
1988, 49, 1307. (c) Gurjar, M. K.; Saha, U. K. Tetrahedron Lett. 1991,
32, 6621-6624. (d) Riviere, M.; Puzo, G. Biochemistry 1992, 31, 3575-
3580.
(7) Allen, M. C.; Wade, R. Int. J . Peptide Protein Res. 1988, 32,
89-97.
(8) (a) Konish, M.; Ohkuma, H.; Sakai, F.; Tsuno, T.; Koshiyama,
H.; Naito, T.; kawaguchi, H. J . Am. Chem. Soc. 1981, 103, 1241-1243.
(b) Arnold, E.; Clardy, J . ibid. 1981, 103, 1243-1244. (c) Hughes, P.;
Clardy, J . J . Org. Chem. 1989, 54, 3260-3264. (d) Boger, D.; Chen, J .
H. Ibid. 1995, 60, 7369-7371.
(9) Fujikawa, A.; In, Y.; Inoue, M.; Ishida, T. ibid. 1994, 59, 570-
578 and references cited therein.
(10) (a) Gordon, E. M.; Ondetti, M. A.; Pluscec, J .; Cimarusti, C.
M.; Bonner, D. P.; Sykes, R. B. J . Am. Chem. Soc. 1982, 104, 6053-
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Tetrahedron Lett. 1986, 27, 2789-2792.
(15) (a) Fleming, P. R.; Sharpless, K. B. J . Org. Chem. 1991, 56,
2869-2875. (b) Denis, J .; Correa, A.; Greene, A. E. Ibid. 1990, 55,
1957-1959. (c) Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G. J .;
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0022-3263/96/1961-2582$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 8, 1996 2583
Sch em e 2
chromatographic purification is necessary to purify 3
before hydrogenation to provide the final product in an
overall 68% yield. By changing the Sharpless chiral
catalytic ligand, the (2S,3S)-allo-threonine was also
obtained by a similar manner in a 60% yield and 98%
enantiomeric excess.
For the synthesis of â-hydroxyvaline, conventional
benzylation of 3,3-dimethylacrylic acid provided ben-
zyl 3,3-dimethylacrylate 5 which was subjected to
the Sharpless AD reaction. Using a very similar strat-
egy, optically pure (2R)-3-hydroxyvaline 9 can be ob-
tained on a large scale and in 98% enantiomeric excess
(Scheme 2).
In summary, we present an efficient route to prepare
allo-threonines and â-hydroxyvalines on a large scale and
in high enantiomeric excess. Most reagents involved are
inorganic salts and easily removed by simple aqueous
workup, and the crude form of intermediates can be used
for the next step without further purification. Purifica-
tion of the azido alcohol intermediate before hydrogena-
tion is recommended, however, to obtain highly pure
building blocks. Currently, we are extending this method
to synthesize other â-hydroxy R-amino acids using ap-
propriate R,â-unsaturated esters. This will allow us
access to a variety of new building blocks for peptidomi-
metic drug design.
tivity.16 Nucleophilic displacement by NaN3 at the R-C
of cyclic sulfate 2 occurs with clean inversion of chirality,
and acidic hydrolysis provides the desired R-azido ester
3.16 Compound 3 readily undergoes catalytic hydrogena-
tion to generate the optically pure (2R,3R)-allo-threonine.
The X-ray diffraction analysis of (2R,3R)-Boc-allo-threo-
nine 4 proves the correct structure of the final product.
In the large scale synthesis starting from the Sharpless
AD reaction (60 mmol and up), only one silica gel
Ack n ow led gm en t. We wish to thank Dr. Peter
Gantzel for X-ray diffraction studies. We also thank
Drs. Darin Kent, Qin Zhu, and J oseph Taulane for
helpful discussions. This work was supported by
NIHDK-15410.
(16) (a) Review: Lohray, B. B. Synthesis 1992, 1035-1052. (b) Gao,
Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538-7539. (c)
Lohray, B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett. 1989, 30,
2623-2626. (d) Berridge, M. S.; Franceschini, M. P.; Rosenfield, E.;
Tewson, T. J . J . Org. Chem. 1990, 55, 1211-1217. (e) Yokomatsu, T.;
Yoshida, Y.; Shibuya, S. Ibid. 1994, 59, 7930-7933.
Su p p or tin g In for m a tion Ava ila ble: The experimental
procedures and copies of 1H NMR spectra for compounds 7-9
(7 pages).
J O960141C