A new and practical synthesis of α-amino acids from alkenyl boronic acids

Full text of DOI:10.1021/ja963178n

J. Am. Chem. Soc. 1997, 119, 445-446
445
A New and Practical Synthesis of r-Amino Acids
from Alkenyl Boronic Acids
the condensation of an organoboronic acid or boronate (1) with
an amine (2) and an R-keto acid (3).
Nicos A. Petasis* and Ilia A. Zavialov
Department of Chemistry and
Loker Hydrocarbon Research Institute
UniVersity of Southern California
Los Angeles, California 90089-1661
ReceiVed September 10, 1996
This method extends our recently discovered process for the
synthesis of geometrically pure allylamines via the condensation
In recent years there has been an increasing interest for new
practical methods to prepare novel non-natural R-amino acid
derivatives to serve as building blocks in combinatorial chem-
istry and drug discovery. Although many routes to amino acids
of amines with formaldehyde and alkenyl boronic acids.8
A
remarkable feature of this reaction is that it is triply convergent
and gives products with multiple sites for introducing molecular
diversity. The favorable experimental features of alkenyl
1
have been developed, there is still a need for concise and
convergent approaches that allow structure variability and facile
incorporation of functional groups and ring systems.
9
boronic acids, which are readily available and easy to handle
crystalline compounds, have prompted us to develop new
2
Herein we report a new, general, and practical method for
8,10
methods for their utilization in organic synthesis.
Their facile
the synthesis of â,γ-unsaturated R-amino acids. The parent
preparation from alkynes in geometrically pure form, combined
with their configurational stability and their tolerance of air and
water, makes these compounds highly desirable intermediates.
As shown in Table 1, alkenyl boronic acids react with amines
and R-keto acids, such as glyoxylic (entries 1-10) or pyruvic
acid (entry 11), to give directly the corresponding amino acids
in good yields and in geometrically pure form. This reaction
is practical and experimentally convenient and proceeds by the
simple stirring of the three components at 25-50 °C over 12-
1
6
compound in this class, vinyl glycine (4, R -R ) H), is
3
naturally occurring and has been studied extensively. Some
amino acids of this type are mechanism based irreversible
4
inhibitors of various pyridoxal phosphate dependent enzymes,
including amino acid aminotransferases and decarboxylases.
5
Such compounds have previously been prepared by multistep
routes or by specialized methods and can serve as precursors
to many other types of molecules upon further manipulation.
The novel approach described herein relies on the use of
4
8 h in a variety of solvents, including ethanol, toluene, and
6
organoboron compounds as the source of the side chain. It is
dichloromethane. Moreover, the reaction does not require
anhydrous or oxygen-free conditions, and it does not utilize
strong acids, strong bases, heavy metals, or other undesirable
chemicals. Furthermore, since the products are usually insoluble
they are easily isolated by filtration and washings with cold
acetone or dichloromethane to remove unreacted starting
materials and the boric acid byproduct. A simple recrystalli-
zation or ion exchange chromatography usually gives the product
with high purity.
7
a three-component variant of the Mannich reaction involving
(
1) (a) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergamon Press: Oxford, 1989. (b) Williams, R. M. Aldrichim. Acta 1992,
2
5, 11. (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
(
2) Petasis, N. A.; Zavialov, I. A., patent pending.
(
3) Dardenne, G.; Casimir, J.; Marlier, M.; Larsen, P. O. Phytochemistry
1
974, 13, 1897.
(4) For reviews, see: (a) Walsh, C. Tetrahedron 1982, 38, 871. (b)
Silverman, R. B. Mechanism-Based Enzyme InactiVation: Chemistry and
Enzymology; CRC Press: Boca Raton, FL, 1988. (c) Nangia, A.; Chan-
drakala, P. S. Current Science 1995, 68, 699. For some examples, see: (d)
Rando, R. R.; Relyea, N.; Cheng, L. J. Biol. Chem. 1976, 251, 3306. (e)
Danzin, C.; Casara, P.; Claverie, N.; Metcalf, B. W. J. Med. Chem. 1981,
Several types of amines can participate in this process giving
a variety of amino acid derivatives. These include primary
amines (entries 1-9 and 11), secondary amines (entry 10),
aromatic amines (entry 6), and even sterically hindered amines
2
4, 16. (f) Cooper, A. J. L.; Fitzpatrick, S. M.; Kaufman, C.; Dowd, P. J.
Am. Chem. Soc. 1982, 104, 332. (g) Hopkins, M. H.; Silverman, R. B.
Bioorg. Med. Chem. Lett. 1992, 2, 1371. (h) Berkowitz, D. B.; Jahng, W.-
J.; Pedersen, M. L. Bioorg. Med. Chem. Lett. 1996, 6, 2151 and references
therein.
(
entries 3 and 7). In addition to boronic acids with various
substitution patterns the reaction also works with boronate
derivatives (entry 9). Of special interest is the participation of
bromo-substituted derivatives (1b and 1c ) to form bromoalk-
(5) For a review, see: (a) Havlicek, L.; Hanus, J. Collect. Czech. Chem.
11
Commun. 1991, 56, 1365. For some additional examples, see: (b) Sibi, M.
P.; Renhowe, P. A. Tetrahedron Lett. 1990, 31, 7407. (c) Beaulieu, P. L.;
Duceppe, J. S.; Johnson, C. J. Org. Chem. 1991, 56, 4196. (d) Crisp, G.
T.; Glink, P. T. Tetrahedron 1992, 48, 3541. (e) Colson, P. J.; Hegedus, L.
S. J. Org. Chem. 1993, 58, 5918. (f) Pedersen, M. L.; Berkowitz, D. B. J.
Org. Chem. 1993, 58, 6966. (g) Heckendorn, R.; Allgeier, H.; Baud, J.;
Gunzenhauser, W.; Angst, C. J. Med. Chem. 1993, 36, 3721. (h) O’Donnell,
M. J.; Li, M.; Bennett, W. D.; Grote, T. Tetrahedron Lett. 1994, 35, 9383.
enyl amino acids (entries 8 and 9). Compounds of this type
4c,5m
were postulated to be “Trojan horse” inhibitors
by generat-
ing highly reactive allenic intermediates upon their exposure
to the appropriate enzymes.
By using readily cleavable amines it is possible to prepare
free amino acids. For example, trityl amine gives trityl-protected
(
i) Ibuka, T.; Suzuki, K.; Habashita, H.; Otaka, A.; Tamamura, H.; Mimura,
N.; Miwa, Y.; Taga, T.; Fujii, N. J. Chem. Soc., Chem. Commun. 1994,
151. (j) Hallinan, K. O.; Crout, D. H. G.; Errington, W. J. Chem. Soc.,
Perkin Trans. 1 1994, 3537. (k) Itaya, T.; Shimizu, S. Chem. Pharm. Bull.
995, 43, 398. (l) Berkowitz, D. B.; Smith, M. K. Synthesis 1996, 39. (m)
Berkowitz, D. B.; Pedersen, M. L.; Jahng, W.-J. Tetrahedron Lett. 1996,
7, 4309.
6) For other boron-mediated amino acid syntheses, see: (a) O’Donnell,
1
2
amino acids (entry 3), which are readily deprotected under
acidic conditions. Another amine that works even more
efficiently for this purpose is bis(4-methoxyphenyl)methyl-
2
1
1
3
amine (entry 5). The resulting derivative (4e) can be readily
converted to the unsubstituted amino acid (4f) by facile acid
hydrolysis.
3
(
M. J.; Falmagne, J.-B. J. Chem. Soc., Chem. Commun. 1985, 1168. (b)
Matteson, D. S.; Beedle, E. C. Tetrahedron Lett. 1987, 28, 4499. (c)
Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44, 5415.
Asymmetric versions of this process with good to excellent
stereoselectivities were observed when certain chiral amines
(
7) Tramontini, M.; Angiolini, L. Mannich bases: Chemistry and Uses;
CRC Press: Boca Raton, 1994.
(11) (a) Hyuga, S.; Chiba, Y.; Yamashina, N.; Hara, S.; Suzuki, A. Chem.
Lett. 1987, 1757. (b) Yamashina, N.; Hyuga, S.; Hara, S.; Suzuki, A.
Tetrahedron Lett. 1989, 30, 6555.
(
8) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583.
9) Reviews: (a) Negishi, E. Compreh. Organomet. Chem. 1983, 7, 303.
(
(
b) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic Press:
London, 1988. (c) Vaultier, M.; Carboni, B. Compreh. Organomet. Chem.
II 1996, 11, 191.
(12) (a) Zervas, L.; Theodoropoulos, D. M. J. Am. Chem. Soc. 1956,
78, 1359. (b) Alsina, J.; Giralt, E.; Albericio, F. Tetrahedron Lett. 1996,
37, 4195.
(
10) Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 567.
(13) Greenlee, W. J. J. Org. Chem. 1984, 49, 2632
S0002-7863(96)03178-2 CCC: $14.00 © 1997 American Chemical Society

446 J. Am. Chem. Soc., Vol. 119, No. 2, 1997
Communications to the Editor
Table 1. Synthesis of Amino Acids (4) by the Reaction of
Alkenyl Boronic Acids (1) with Amines (2) and R-Keto Acids (3)
Similarly, the use of (R)-2-phenylglycinol gave (S)-homophe-
nylalanine with equal selectivity.
Although other multicomponent routes to amino acids are
1
8
19
known, such as the Strecker and Ugi syntheses, these
methods rely on the use of undesirable cyanide or isocyanide
reagents and require more stringent experimental conditions as
well as additional hydrolysis steps. The method introduced
herein is more convenient and versatile in a number of ways
than other reported routes. Also, while several procedures using
glyoxylic acid derivatives to form electrophilic glycine equiva-
2
0
lents have been reported, the present method is shorter and
milder while it provides unique ways to control the geometry
and stereochemistry of the amino acid products.
Overall, this new boron-mediated reaction allows the practical,
stereoselective one-pot synthesis of R-amino acids and their
N-substituted derivatives. Further studies of the mechanism and
2
1
scope of this process are currently underway.
Acknowledgment. We gratefully acknowledge the Loker Hydro-
carbon Research Institute and the donors of The Petroleum Research
Fund, administered by the ACS, for partial support of this research.
I.A.Z. is also grateful for a University of Southern California Merit
Fellowship.
Supporting Information Available: Spectroscopic data of new
compounds (8 pages). See any current masthead page for ordering
and Internet access instructions.
JA963178N
(
15) Experimental procedure: To a stirred solution of glyoxylic acid
monohydrate (291 mg, 3.163 mmol) in CH2Cl2 (14 mL) was added 7 (434
mg, 3.163 mmol) in one portion, followed by 1a (469 mg, 3.169 mmol).
The reaction mixture was stirred vigorously at room temperature for 12 h.
The precipitate was isolated by filtration and washed with cold CH2Cl2 (15
1
mL). The crude material gave good spectroscopic data, while H-NMR
indicated >99% de. Recrystallization from H2O-tBuOH gave analytically
pure 8 (733 mg, 78%, >99% de).
(
16) Weller, H. N.; Gordon, E. M. J. Org. Chem. 1982, 47, 4160.
a
19
A: CHOCOOH‚H
Cl , 25 °C; D: 3a, EtOH, 50 °C; E: MeCOCOOH (3b),
, 25 °C. All products were geometrically pure. c Isolated yields
2
O (3a), EtOH, 25 °C; B: 3a, PhMe, 25 °C; C:
(17) The % ee was established by optical rotation and by F-NMR of
the Mosher amide of 9.
3
a, CH
2
2
b
(18) For some recent modifications, see: (a) Chakraborty, T. K.; Hussain,
K. A.; Reddy, G. V. Tetrahedron 1995, 51, 9179. (b) Davis, F. A.;
Portonovo, P. S.; Reddy, R. E.; Chiu, Y.-H. J. Org. Chem. 1996, 61, 440.
c) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem.
Soc. 1996, 118, 4910 and references therein.
CH Cl
2
2
after ion exchange chromatography (Dowex 50W-X8) or recrystalli-
zation from water/tert-butyl alcohol.
(
were used. While (S)-R-methylbenzylamine (5) gave 6 with
(19) (a) Ugi, I.; D o¨ mling, W.; H o¨ rl, W. EndeaVour 1994, 18, 115. (b)
Kunz, H.; Pfrengle, W. Tetrahedron 1988, 44, 5487. (c) Keating, T. A.;
Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
6
6% de, the use of (S)-2-phenylglycinol (7)14 was much more
effective, forming 8 in good yield and as a single diastereomer
(20) For some examples, see: (a) Ben-Ishai, D.; Moshenberg, R.; Altman,
(
>99% de).15 This high degree of diastereoselectivity is quite
J. Tetrahedron 1977, 33, 1533. (b) M u¨ nster, P.; Steglich, W. Synthesis 1987,
223. (c) O’Donnell, M. J.; Bennett, W. D. Tetrahedron 1988, 44, 5389. (d)
Roos, E. C.; Lopez, M. C.; Brook, M. A.; Hiemstra, H.; Speckamp, W. N.
J. Org. Chem. 1993, 58, 3259 and references therein.
remarkable considering that this C-C bond forming reaction
was performed at room temperature! Subsequent hydrogenation
of the hydrochloride salt of 8 gave (R)-homophenylalanine
hydrochloride (9)16 in enantiomerically pure form (>99% ee).
(21) We have already found that unprotected amino acids and peptides
17
can also participate in this reaction, while asymmetric induction can also
take place with chiral boronate derivatives. The reaction also works with
aryl boronic acids to afford arylglycine derivatives. These results will be
reported in due course.
(
14) For a review, see: Ager, D. J.; Prakash, I.; Schaad, D. R. Chem.
ReV. 1996, 96, 835.