- Email: [email protected]
Synthesis of homochiral hydroxy-α-amino acid derivatives
Tetrahe&,n
Letters, Vo1.31. No.489 pi 7059-7(k% 1990
oo4o4039/90 53.00 + .oo Pcrgmon Press plc
Priited in Great Britain
SYNTHESIS
OF HOMOCHIRAL
HYDROXY-a-AMINO
ACID
DERIVATIVES
Christopher J. Easton*, Craig A. Hutton, Eng Wui Tan and Edward Ft. T. Tiekink
Departments of Chemistry, University of Adelaide, G.P.O. Box 498, Adelaide, South Australia 5001
Summary:
Treatment of N-phthaloyl-a-amino
acid methyl esters with N-bromosuccinimide,
reaction with silver nitrate in aqueous acetone, affords homochiral hydroxy-a-amino stereochemistry of which is predetermined by that of the starting amino acids.
Hydroxy-substituted
a-amino
acids have attracted
considerable
physiological activity, either in the free form or as components of peptides’. enzyme inhibitors* the stereocontrolled
attention
the
due mainly to their
They have also been used as
and in synthesis 3. Although a number of elegant methods have been developed for most suffer the disadvantage
synthesis of these compounds4,
and many are only enantioselective the homochiral hydroxy-a-amino the cases of (Id) and (2d).
rather than enantiospecific.
acid derivatives
the direct substitution
of derivatives
in
of proteinogenic
of the products is defined by that of the starting materials.
There has been one other report5 of the direct hydroxylation
of a tyrosine derivative,
was not generally applicable, even to the reaction of the corresponding The amino acid derivative
that they are indirect,
In this report we describe a synthesis of
(Id), (2d), (4~) and (5c), which is diastereoselective
The method involves
amino acids and the absolute stereochemistry
anhydride6,
followed by
acid derivatives,
(la) was prepared
by treatment
followed by esterification with acidified methanol.
phenylalanine
but that procedure derivative.
of (S)-phenylalanine
with phthalic
Reaction of (la) with N-bromosuccinimide
in refluxing carbon tetrachloride under nitrogen, with reaction initiated by irradiation with a 250-W mercury lamp, gave a 1:l mixture the diastereomeric
bromides (lb) and (lc) in quantitative
the mixture with silver nitrate (1.5 equiv.) in water/acetone yield of a 5:1 mixture of the diastereomers were
separated
either
dichloromethane/hexane.
(2:3) at room temperature
of the P-hydroxyphenylalanine
by reverse-phase
chromatography
The major diastereomer
yield7.
derivative
or by fractional
(Id) had m.p. 185186oC.
Treatment of
for 24 h gave a 93% (Id) and (le), which crystallization
from
[a]D16 -67.0° (~0.006,
ethanol), ‘i-i NMR (CDCl3) 63.86 (s, 3H), 5.13 (d, J 10.4 Hz, lH), 5.51 (d, J 4.6 Hz, lH), 5.71 (dd, J 4.6, 10.4 Hz, lH), 7.24 (m. 5H), 7.70 (m, 2H) and 7.79 (m, 2H)8.
The minor diastereomer
(le)
had m.p.
110-i 11 OC, ‘H NMR (CDC5) 6 3.79 (s, 3H), 4.34 (d, J 2.3 Hz, lH), 5.02 (d, J 8.4 Hz, lH), 5.52 (dd, J 2.3, 8.4 Hz, lH), 7.26 (m, 5H), 7.68 (m, 2H) and 7.75 (m, 2H). The relative and absolute stereochemistry (Id) was determined by X-ray crystallographic
analysis (Figure 1)s. The absolute
stereochemistry
of
of (Id)
7060
PhthACO H 2 Me
(1)
a)R’=R2=H b) R1=H;R2=Br c)R’=Sr;R2=H d)R1=H;R2=OH e) R’=OH;R2=H
Me (Me),CRR .R
I
(Me)& Phth AH’
CH2
Phth A i
C02Me
(4)
C02Me
0
(5)
(6)
a)R=H b) R = Br c)R=OH
is predetermined
by that of (S)-phenylalanine,
and the diastereoselectivity
observed in the production of
(Id) can be attributed to nucleophilic attack from the less hindered face of the intermediate
carbocation
(Figure 2). The procedure hydroxy-a-amino corresponding
used in the preparation
acid derivatives.
of (Id)
is suitable
The amino acid derivatives
for the preparation
(2a), (4a) and (sa) were prepared from the
(S)-amino acids, as described above for the preparation
of (la).
acetic anhydride gave the acetate @a), which reacted with N-bromosuccinimide diastereomeric
of a range of
Treatment of (2a) with
to give a 1:l mixture of the
bromides (3b) and (3~). Reaction of the mixture with silver nitrate in aqueous acetone,
followed by hydrolysis with aqueous methanol in the presence of gtoluenesulphonic mixture of the diastereomers
of the P-hydroxytyrosine
derivative
acid, gave a 6:l
(2d) [m.p. 200-202 OC, [aID 6 -70.7O
(GO.004, ethanol), lH NMR (CDC13) 6 3.85 (s, 3H), 4.76 (s, lH), 5.02 (d, J 10.3 Hz, lH), 5.44 (d, J 4.8 Hz, lH), 5.64 (dd, J 4.8, 10.3 Hz, lH), 6.71 (d. 8.6 Hz, 2H), 7.19 (d, 8.6 Hz, 2H), 7.72 (m, 2H) and 7.80 (m, 2H)] and (se) [‘H NMR (CDC13) 6 3.78 (s, 3H), 4.27 (d, J 2.1 Hz, lH), 4.84 (s, lH), 4.97 (d, J 8.6 Hz, lH), 5.49 (dd, J 2.1.8.6 Hz, lH), 6.65 (d, 8.6 Hz, 2H), 7.20 (d, 8.6 Hz, 2H), 7.69 (m, 2H) and 7.76 (m, 2H)]. Similar reactions of the derivatives of valine (4a) and leucine (5a) with N-bromosuccinimide corresponding
gave the
bromides (4b) and (Sb), which reacted with silver nitrate in aqueous acetone to give the
P-hydroxyvaline
derivative (4~) [m.p. 79-80 OC, [CX]D16-49.3O (90.005, ethanol),
‘H NMR (CDCl3) 6 1.31
(s, 3H), 1.53 (s, 3H), 3.77 (s, 3H), 4.41 (br. s, lH), 4.91 (s, lH), 7.80 (m, 2H) and 7.91 (m, 2H)] and the derivative (5~) [m.p. 71-72 oC, [aID
y-hydroxyleucine
-25.90 (90.005, ethanol),
‘H NMR (CDC13) 6 1.24
(s, 3H), 1.31 (s, 3H), 1.70 (br. s, lH), 2.38 (dd, J 8.8, 15.1 Hz, lH), 2.50 (dd, J 4.0, 15.1 Hz, lH), 3.73 (s, 3H), 5.15 (dd, J 4.0, 8.8 Hz, IH), 7.74 (m, 2H) and 7.86 (m, 2H)], respectively. (5C) occurred
without
racemization.
Only one enantiomer
detected when analysed by 1H NMR spectroscopy under conditions (R,S)-valine.
which resolved
the enantiomers
Treatment of the y-hydroxyleucine
The production of (4~) and
of the hydroxyvaline
derivative
(4~) was
in the presence of the chiral shift reagent Eu(hfbc)glO, of a corresponding
derivative
racemic sample prepared
(5~) with 2,2,2-trifluoroethanol
from
gave the known
(S)-lactone (6)’ l. The synthesis stereocontrolled stereochemistry hydroxylation
of (id),
(2d), (4~) and (5~) illustrates
synthesis of homochiral
hydroxy-a-amino
of the starting amino acids is retained is determined by that of the bromination
turn reflects the stability of the corresponding
a complementary
acid derivatives. in the products.
of the N-phthaloylamino
intermediate
radicals.
method45
Using this procedure The regioselectivity acid derivatives,
The procedure
H20:
the
of the which in
is suitable for the
7 Ph
COaMe
Figure 1. Molecular structure of (1 d)
for the
Figure 2. Diastereoselective reaction to give (Id)
7062
preparation of free hydroxy amino acids, as illustrated by the deprotection
of (Id) on treatment with a 2:l
mixture
5 h, to give
of 6N hydrochloric
acid
and
acetic
acid,
at reflux
for
the
known’
2
(2S,3R)-3-phenylserine.
Acknowledgement:
References 1.
and
This work was supported by a grant from the Australian Research Council.
Notes
For examples see: D. H. Williams, Act. Chem. Res., 1984, 77, 364; C. M. Harris, H. Kopecka and T. M. Harris, J. Am. Chem. Sot., 1983, 705, 6915; S. D. Jolad, J. J. Hoffmann, S. J. Torrance, R. M. Wiedhopf, J. R. Cole, S. K. Arora, Ft. B. Bates, R. L. Gargiulo and G. R. Kriek, J. Am. Chem. Sot., 1977, 99, 8040; and references cited therein.
2.
I. Cenci di Belle, P. Dorling, L. Fellows and B. Winchester, FEBS Lett., 1984, 776, 61.
3.
M. J. Miller, Act. Chem. Res., 1986, 79, 49; D. M. Floyd, A. W. Fritz, J. Pluscec, E. R. Weaver and C. M. Cimarusti, J. Org. Chem., 1982, 47, 5160.
4.
For selected references see: G. Guanti, L. Banfi, E. Narisano and C. Scolastico,
Tetrahedron, 1988,
44, 3671; D. Seebach, E. Juaristi, D. D. Miller, C. Schickli and T. Weber, He/v. Chim. Acta, 1987, 70, 237; A. V. Rama Rao, T. G. Murali Dhar, D. Subhas Bose, T. K. Chakraborty Tetrahedron, 1989,45, Tetrahedron
7361; A.V. Rama Rao, J. S. Yadav, S. Chandrasekhar
Lett., 1989, 30, 6769; M. E. Jung and Y. H. Jung, Tetrahedron
and M. K. Gurjar,
and C. Srinivas Rao, Lett., 1989, 30, 6637;
D. A. Evans, E. B. Sjogren, A. E. Weber and R. E. Conn, Tetrahedron Lett., 1987, 28, 39; C.-Q. Sun and D. H. Rich, Tetrahedron Left., 1988, 29, 5205; N. Kurokawa and Y. Ohfune, J. Am. Chem. Sot., 1986,
708, 6041; D. A. Evans and A. E. Weber, J. Am. Chem. Sot., 1987,
Roemmele
709, 7151; R. C.
and H. Rapoport, J. Org. Chem., 1989, 54,1866; and references quoted therein. Lett., 1988, 29, 5177.
5.
K. Shimamoto
6.
J. C. Sheehan, D. W. Chapman and R. W. Roth, J. Am. Chem. Sot., 1952, 74,3822.
7.
C. J. Easton, E. W. Tan and M. P. Hay, J. Chem. Sot., Chem. Commun., 1989,385.
8.
All new compounds gave satisfactory 1 H NMR, IR, high resolution mass spectral and microanalytical
and Y. Ohfune, Tetrahedron
data. 9.
Molecular structure of (Id); trigonal space group, p3221, a = 11.810(7), c = 19.556(7) AO, R =0.053 for 1077 reflections.
10. H. L. Goering, J. N. Eikenberrry, G. S. Koermer and C. J. Lattimer, J. Am. Chem. SOC., 1974, 96, 1493. 11. S. Clarke, R. C. Hider and D. I. John, J. Chem. Sot., Perkin Trans. 7,1973, 230. 12. K. Vogler, Helv. Chim. Acta, 1950, 33, 2111.
(Received in UK 13 September 1990)
Letters, Vo1.31. No.489 pi 7059-7(k% 1990
oo4o4039/90 53.00 + .oo Pcrgmon Press plc
Priited in Great Britain
SYNTHESIS
OF HOMOCHIRAL
HYDROXY-a-AMINO
ACID
DERIVATIVES
Christopher J. Easton*, Craig A. Hutton, Eng Wui Tan and Edward Ft. T. Tiekink
Departments of Chemistry, University of Adelaide, G.P.O. Box 498, Adelaide, South Australia 5001
Summary:
Treatment of N-phthaloyl-a-amino
acid methyl esters with N-bromosuccinimide,
reaction with silver nitrate in aqueous acetone, affords homochiral hydroxy-a-amino stereochemistry of which is predetermined by that of the starting amino acids.
Hydroxy-substituted
a-amino
acids have attracted
considerable
physiological activity, either in the free form or as components of peptides’. enzyme inhibitors* the stereocontrolled
attention
the
due mainly to their
They have also been used as
and in synthesis 3. Although a number of elegant methods have been developed for most suffer the disadvantage
synthesis of these compounds4,
and many are only enantioselective the homochiral hydroxy-a-amino the cases of (Id) and (2d).
rather than enantiospecific.
acid derivatives
the direct substitution
of derivatives
in
of proteinogenic
of the products is defined by that of the starting materials.
There has been one other report5 of the direct hydroxylation
of a tyrosine derivative,
was not generally applicable, even to the reaction of the corresponding The amino acid derivative
that they are indirect,
In this report we describe a synthesis of
(Id), (2d), (4~) and (5c), which is diastereoselective
The method involves
amino acids and the absolute stereochemistry
anhydride6,
followed by
acid derivatives,
(la) was prepared
by treatment
followed by esterification with acidified methanol.
phenylalanine
but that procedure derivative.
of (S)-phenylalanine
with phthalic
Reaction of (la) with N-bromosuccinimide
in refluxing carbon tetrachloride under nitrogen, with reaction initiated by irradiation with a 250-W mercury lamp, gave a 1:l mixture the diastereomeric
bromides (lb) and (lc) in quantitative
the mixture with silver nitrate (1.5 equiv.) in water/acetone yield of a 5:1 mixture of the diastereomers were
separated
either
dichloromethane/hexane.
(2:3) at room temperature
of the P-hydroxyphenylalanine
by reverse-phase
chromatography
The major diastereomer
yield7.
derivative
or by fractional
(Id) had m.p. 185186oC.
Treatment of
for 24 h gave a 93% (Id) and (le), which crystallization
from
[a]D16 -67.0° (~0.006,
ethanol), ‘i-i NMR (CDCl3) 63.86 (s, 3H), 5.13 (d, J 10.4 Hz, lH), 5.51 (d, J 4.6 Hz, lH), 5.71 (dd, J 4.6, 10.4 Hz, lH), 7.24 (m. 5H), 7.70 (m, 2H) and 7.79 (m, 2H)8.
The minor diastereomer
(le)
had m.p.
110-i 11 OC, ‘H NMR (CDC5) 6 3.79 (s, 3H), 4.34 (d, J 2.3 Hz, lH), 5.02 (d, J 8.4 Hz, lH), 5.52 (dd, J 2.3, 8.4 Hz, lH), 7.26 (m, 5H), 7.68 (m, 2H) and 7.75 (m, 2H). The relative and absolute stereochemistry (Id) was determined by X-ray crystallographic
analysis (Figure 1)s. The absolute
stereochemistry
of
of (Id)
7060
PhthACO H 2 Me
(1)
a)R’=R2=H b) R1=H;R2=Br c)R’=Sr;R2=H d)R1=H;R2=OH e) R’=OH;R2=H
Me (Me),CRR .R
I
(Me)& Phth AH’
CH2
Phth A i
C02Me
(4)
C02Me
0
(5)
(6)
a)R=H b) R = Br c)R=OH
is predetermined
by that of (S)-phenylalanine,
and the diastereoselectivity
observed in the production of
(Id) can be attributed to nucleophilic attack from the less hindered face of the intermediate
carbocation
(Figure 2). The procedure hydroxy-a-amino corresponding
used in the preparation
acid derivatives.
of (Id)
is suitable
The amino acid derivatives
for the preparation
(2a), (4a) and (sa) were prepared from the
(S)-amino acids, as described above for the preparation
of (la).
acetic anhydride gave the acetate @a), which reacted with N-bromosuccinimide diastereomeric
of a range of
Treatment of (2a) with
to give a 1:l mixture of the
bromides (3b) and (3~). Reaction of the mixture with silver nitrate in aqueous acetone,
followed by hydrolysis with aqueous methanol in the presence of gtoluenesulphonic mixture of the diastereomers
of the P-hydroxytyrosine
derivative
acid, gave a 6:l
(2d) [m.p. 200-202 OC, [aID 6 -70.7O
(GO.004, ethanol), lH NMR (CDC13) 6 3.85 (s, 3H), 4.76 (s, lH), 5.02 (d, J 10.3 Hz, lH), 5.44 (d, J 4.8 Hz, lH), 5.64 (dd, J 4.8, 10.3 Hz, lH), 6.71 (d. 8.6 Hz, 2H), 7.19 (d, 8.6 Hz, 2H), 7.72 (m, 2H) and 7.80 (m, 2H)] and (se) [‘H NMR (CDC13) 6 3.78 (s, 3H), 4.27 (d, J 2.1 Hz, lH), 4.84 (s, lH), 4.97 (d, J 8.6 Hz, lH), 5.49 (dd, J 2.1.8.6 Hz, lH), 6.65 (d, 8.6 Hz, 2H), 7.20 (d, 8.6 Hz, 2H), 7.69 (m, 2H) and 7.76 (m, 2H)]. Similar reactions of the derivatives of valine (4a) and leucine (5a) with N-bromosuccinimide corresponding
gave the
bromides (4b) and (Sb), which reacted with silver nitrate in aqueous acetone to give the
P-hydroxyvaline
derivative (4~) [m.p. 79-80 OC, [CX]D16-49.3O (90.005, ethanol),
‘H NMR (CDCl3) 6 1.31
(s, 3H), 1.53 (s, 3H), 3.77 (s, 3H), 4.41 (br. s, lH), 4.91 (s, lH), 7.80 (m, 2H) and 7.91 (m, 2H)] and the derivative (5~) [m.p. 71-72 oC, [aID
y-hydroxyleucine
-25.90 (90.005, ethanol),
‘H NMR (CDC13) 6 1.24
(s, 3H), 1.31 (s, 3H), 1.70 (br. s, lH), 2.38 (dd, J 8.8, 15.1 Hz, lH), 2.50 (dd, J 4.0, 15.1 Hz, lH), 3.73 (s, 3H), 5.15 (dd, J 4.0, 8.8 Hz, IH), 7.74 (m, 2H) and 7.86 (m, 2H)], respectively. (5C) occurred
without
racemization.
Only one enantiomer
detected when analysed by 1H NMR spectroscopy under conditions (R,S)-valine.
which resolved
the enantiomers
Treatment of the y-hydroxyleucine
The production of (4~) and
of the hydroxyvaline
derivative
(4~) was
in the presence of the chiral shift reagent Eu(hfbc)glO, of a corresponding
derivative
racemic sample prepared
(5~) with 2,2,2-trifluoroethanol
from
gave the known
(S)-lactone (6)’ l. The synthesis stereocontrolled stereochemistry hydroxylation
of (id),
(2d), (4~) and (5~) illustrates
synthesis of homochiral
hydroxy-a-amino
of the starting amino acids is retained is determined by that of the bromination
turn reflects the stability of the corresponding
a complementary
acid derivatives. in the products.
of the N-phthaloylamino
intermediate
radicals.
method45
Using this procedure The regioselectivity acid derivatives,
The procedure
H20:
the
of the which in
is suitable for the
7 Ph
COaMe
Figure 1. Molecular structure of (1 d)
for the
Figure 2. Diastereoselective reaction to give (Id)
7062
preparation of free hydroxy amino acids, as illustrated by the deprotection
of (Id) on treatment with a 2:l
mixture
5 h, to give
of 6N hydrochloric
acid
and
acetic
acid,
at reflux
for
the
known’
2
(2S,3R)-3-phenylserine.
Acknowledgement:
References 1.
and
This work was supported by a grant from the Australian Research Council.
Notes
For examples see: D. H. Williams, Act. Chem. Res., 1984, 77, 364; C. M. Harris, H. Kopecka and T. M. Harris, J. Am. Chem. Sot., 1983, 705, 6915; S. D. Jolad, J. J. Hoffmann, S. J. Torrance, R. M. Wiedhopf, J. R. Cole, S. K. Arora, Ft. B. Bates, R. L. Gargiulo and G. R. Kriek, J. Am. Chem. Sot., 1977, 99, 8040; and references cited therein.
2.
I. Cenci di Belle, P. Dorling, L. Fellows and B. Winchester, FEBS Lett., 1984, 776, 61.
3.
M. J. Miller, Act. Chem. Res., 1986, 79, 49; D. M. Floyd, A. W. Fritz, J. Pluscec, E. R. Weaver and C. M. Cimarusti, J. Org. Chem., 1982, 47, 5160.
4.
For selected references see: G. Guanti, L. Banfi, E. Narisano and C. Scolastico,
Tetrahedron, 1988,
44, 3671; D. Seebach, E. Juaristi, D. D. Miller, C. Schickli and T. Weber, He/v. Chim. Acta, 1987, 70, 237; A. V. Rama Rao, T. G. Murali Dhar, D. Subhas Bose, T. K. Chakraborty Tetrahedron, 1989,45, Tetrahedron
7361; A.V. Rama Rao, J. S. Yadav, S. Chandrasekhar
Lett., 1989, 30, 6769; M. E. Jung and Y. H. Jung, Tetrahedron
and M. K. Gurjar,
and C. Srinivas Rao, Lett., 1989, 30, 6637;
D. A. Evans, E. B. Sjogren, A. E. Weber and R. E. Conn, Tetrahedron Lett., 1987, 28, 39; C.-Q. Sun and D. H. Rich, Tetrahedron Left., 1988, 29, 5205; N. Kurokawa and Y. Ohfune, J. Am. Chem. Sot., 1986,
708, 6041; D. A. Evans and A. E. Weber, J. Am. Chem. Sot., 1987,
Roemmele
709, 7151; R. C.
and H. Rapoport, J. Org. Chem., 1989, 54,1866; and references quoted therein. Lett., 1988, 29, 5177.
5.
K. Shimamoto
6.
J. C. Sheehan, D. W. Chapman and R. W. Roth, J. Am. Chem. Sot., 1952, 74,3822.
7.
C. J. Easton, E. W. Tan and M. P. Hay, J. Chem. Sot., Chem. Commun., 1989,385.
8.
All new compounds gave satisfactory 1 H NMR, IR, high resolution mass spectral and microanalytical
and Y. Ohfune, Tetrahedron
data. 9.
Molecular structure of (Id); trigonal space group, p3221, a = 11.810(7), c = 19.556(7) AO, R =0.053 for 1077 reflections.
10. H. L. Goering, J. N. Eikenberrry, G. S. Koermer and C. J. Lattimer, J. Am. Chem. SOC., 1974, 96, 1493. 11. S. Clarke, R. C. Hider and D. I. John, J. Chem. Sot., Perkin Trans. 7,1973, 230. 12. K. Vogler, Helv. Chim. Acta, 1950, 33, 2111.
(Received in UK 13 September 1990)