Asymmetric catalysis of the Strecker amino acid synthesis by a cyclic dipeptide

Full text of DOI:10.1021/ja952686e

4910
J. Am. Chem. Soc. 1996, 118, 4910-4911
Asymmetric Catalysis of the Strecker Amino Acid
Synthesis by a Cyclic Dipeptide
Mani S. Iyer, Kenneth M. Gigstad, Nivedita D. Namdev, and
Mark Lipton*
Department of Chemistry, Purdue UniVersity
West Lafayette, Indiana 47907
ReceiVed August 8, 1995
The condensation of aldehydes with ammonia and hydrogen
cyanide to form R-amino nitriles followed by hydrolysis of the
nitrile groups (the Strecker synthesis) is the oldest known
method for the de noVo synthesis of R-amino acids.1 The ever-
increasing interest in nonproteinogenic R-amino acids in a
variety of scientific disciplines has prompted the development
of numerous methods for the asymmetric synthesis of R-amino
acids.2 Among the methods developed, several enantioselective
versions of the Strecker synthesis in which optically active
amines replace ammonia to serve as chiral auxiliaries, with
moderate to good levels of asymmetric induction, have been
reported.3-5 To avoid the problems inherent to the use of chiral
auxiliaries (e.g., cost) one must instead use a chiral catalyst. In
this communication we report a version of the Strecker synthesis
employing such a chiral catalyst, permitting the conversion of
aldehydes to (S)-amino acids in high yield and, in some cases,
exceptionally high enantiomeric excess.
failure of the imidazole side chain of 2 to accelerate proton
transfer in the reaction of HCN with the putative aldimine
intermediate in the Strecker synthesis. Replacement of the
imidazole of 2 with a more basic guanidine side chain was
predicted to afford a catalyst capable of accelerating proton
transfer in the Strecker synthesis.
The synthesis of 1 begins with benzyloxycarbonyl-(S)-
glutamic acid, which upon protection as the oxazolidinone and
subsequent Curtius rearrangement8 is converted to the carbamate
3 in 81% yield. Hydrolysis of the oxazolidinone using KOH/
MeOH and coupling with (S)-phenylalanine methyl ester9 using
1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide/1-hydroxy-
benztriazole afford the dipeptide 4 (79% yield). The diketo-
piperazine 5 was formed in quantitative yield by catalytic
The catalyst employed in our studies (1) is a cyclic dipeptide
composed of (S)-phenylalanine and the lower homologue of (S)-
arginine, (S)-R-amino-γ-guanidinobutyric acid. The design of
1 proceeded from cyclo[(S)-His-(S)-Phe] (2), a cyclic dipeptide
that has previously been shown to catalyze the enantioselective
formation of cyanohydrins from aldehydes.6 While 2 fails to
afford any asymmetric induction in the mechanistically similar
Strecker synthesis,7 it was our belief that this resulted from the
(1) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.
(2) For recent reviews on this subject, see: (a) Williams, R. M. Synthesis
of Optically ActiVe R-Amino Acids; Pergamon: Oxford, 1989. (b) Williams,
R. M.; Hendrix, J. A. Chem. ReV. 1992, 92, 889-917. (c) Duthaler, R. O.
Tetrahedron 1994, 50, 1539-1650.
(3) (a) Harada, K. Nature 1963, 200, 1201. (b) Harada, K.; Fox, S.
Naturwissenschaften 1964, 51, 106. (c) Harada, K.; Okawara, T. J. Org.
Chem. 1973, 38, 707-710. (d) Patel, M. S.; Worsely, M. Can. J. Chem.
1970, 48, 1881-1884. (e) Weinges, K.; Gries, K.; Stemmle, B.; Schrank,
W. Chem. Ber. 1977, 110, 2098-2113. (f) Stout, D. M.; Black, L. A.;
Matier, W. L. J. Org. Chem. 1983, 48, 5369-5373. (g) Phadtare, S. K.;
Kamat, S. K.; Panse, G. T. Ind. J. Chem. 1985, 24B, 811-814. (h)
Subramanian, P. K.; Woodard, R. W. Synth. Commun. 1986, 16, 337-
342. (i) Saito, K.; Harada, K. Tetrahedron Lett. 1989, 30, 4535-4538. (j)
Speelman, J. C.; Talma, A. G.; Kellogg, R. M. J. Org. Chem. 1989, 54,
1055-1062. (k) Herranz, R.; Sua´rez-Gea, M. L.; Vinuesa, S.; Garc´ıa-Lo´pez,
M. T.; Mart´ınez, A. Tetrahedron Lett. 1991, 32, 7579-7582. (l) Inaba, T.;
Fujita, M.; Ogura, K. J. Org. Chem. 1991, 56, 1274-1279. (m) Chakraborty,
T. K.; Reddy, G. V.; Hussain, K. A. Tetrahedron Lett. 1991, 32, 7597-
7600. (n) Inaba, T.; Kozono, I.; Fujita, M.; Ogura, K. Bull. Chem. Soc.
Jpn. 1992, 65, 2359-2365. (o) Andre´s, C.; Maestro, A.; Pedrosa, R.; Pe´rez-
Encabo, A.; Vicente, M. Synlett 1992, 45-47. (p) Davis, F. A.; Reddy, R.
E.; Portonovo, P. S. Tetrahedron Lett. 1994, 35, 9351-9354. (q) Chakraborty,
T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995, 51, 9179-9190.
(4) (a) Weinges, K.; Graab, G.; Nagel, D.; Stemmle, B.; Chem. Ber. 1971,
104, 3594-3606 (b) Weinges, K.; Stemmle, B. Chem. Ber. 1973, 106,
2291-2297. (c) Weinges, K.; Klotz, K.-P.; Droste, H. Chem. Ber. 1980,
113, 710-721. (d) Weinges, K.; Blacholm, H. Chem. Ber. 1980, 113, 3098-
3102. (e) Weinges, K.; Brune, G.; Droste, H. Liebigs Ann. Chem. 1980,
212-218. (f) Weinges, K.; Brachmann, H.; Stahnecker, P.; Rodewald, H.;
Nixdorf, M.; Irngartinger, H. Liebigs Ann. Chem. 1985, 566-578.
(5) (a) Kunz, H.; Sager, W. Angew. Chem., Int. Ed. Engl. 1987, 26, 557-
559. (b) Kunz, H.; Pfrengle, W. J. Am. Chem. Soc. 1988, 110, 651-652.
(c) Kunz, H.; Sager, W.; Pfrengle, W.; Schanzenbach, D. Tetrahedron Lett.
1988, 29, 4397-4400. (d) Kunz, H.; Pfrengle, W. Tetrahedron 1988, 44,
5487-5494. (e) Kunz, H.; Sager, W.; Schanzenbach, D.; Decker, M. Liebigs
Ann. Chem. 1991, 649-654.
hydrogenolysis of the benzyloxycarbonyl group of 4 followed
by cyclization in refluxing methanol. Deprotection of 5 using
HCl in ethyl acetate was followed by guanidylation with 3,5-
dimethylpyrazole-1-carboxamidine nitrate10 to afford the catalyst
1. Reverse phase HPLC purification of 1 produces the catalyst
in 45% yield from 5.
Initial experiments involved treatment of benzaldehyde with
ammonia and hydrogen cyanide in the presence of 2 mol % of
catalyst 1 under a variety of reaction conditions. The enantio-
meric purity of the resultant R-amino nitrile was determined
by derivatization with (+)-MTPA chloride11 and comparison
(8) Scholtz, J. M.; Bartlett, P. A. Synthesis 1989, 542-544.
(9) The possibilty of epimerization during basic hydrolysis of the
oxazolidinone was excluded by coupling the resultant acid to both (S)- and
(R)-phenylalanine methyl ester. The diastereomers thus obtained were
1
(6) (a) Oku, J.; Inoue, S. J. Chem. Soc., Chem. Commun. 1981, 229-
230. (b) Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181-
185. (c) Danda, H. Synlett 1991, 263-264. (d) Danda, H.; Nishikawa, H.;
Otaka, K. J. Org. Chem. 1991, 56, 6740-6741.
distinguishable by H-NMR and free of diastereomeric impurities.
(10) Scott, F. L.; O'Donovan, D. G.; Reilly, J. J. Am. Chem. Soc. 1953,
75, 4053.
(11) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543-2549.
(7) Iyer, M. S.; Lipton, M. A. Unpublished results.
S0002-7863(95)02686-2 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 20, 1996 4911
Table 1. Conversion of Substituted Imines to R-Amino Nitriles
Table 2. Conversion of N-Benzhydryl Imines to R-Amino Nitriles
yield,a %
ee,b %
R
solvent
yield,a %
ee,b %
entry
R
temp, °C
4-OMePhCH2
3,4,5-(OMe)3PhCH2
Ph2CH
CH3OH
CH3OH
CH3OH
i-PrOH
97
98
95
88
>99
>98
>99
75
1
2
3
4
5
6
7
8
9
Ph (6-7a)
-25
-25
-75
-25
-75
-75
-75
-75
-75
-75
-75
-75
97
97
94
96
90
80
82
71
86
94
81
80
>99
83
>99
64
96
>99
80
<10
<10
32
<10
17
4-ClPh (6-7b)
4-ClPh (6-7b)
4-OMePh (6-7c)
4-OMePh (6-7c)
3-ClPh (6-7d)
3-OMePh (6-7e)
3-NO2 (6-7f)
3-pyridyl (6-7g)
2-furyl (6-7h)
i-Pr (6-7i)
t-BuOCO
1
a Based on H-NMR of crude product. b Determined by 19F-NMR
of (+)-MTPA derivatives.
of the 19F-NMR spectrum of the crude product with that of an
authentic racemate derivatized in identical fashion. The con-
figuration of the products was established by conversion of
underivatized R-amino nitriles to phenylglycine and determi-
nation of the sign of its optical rotation.12 These experiments
proved unsatisfactory due to the unexpected configurational
instability of the initial product, 2-aminophenylacetonitrile. As
a consequence, the reactions of N-substituted imines were
studied instead (Table 1).
10
11
12
t-Bu (6-7j)
a Based on 1H-NMR of crude product. b Determined by chiral HPLC
chromatography using a Daicel ChiralPak AD column.
derivatives afforded essentially racemic products. In light of
this striking contrast and the configurational instability of
2-aminophenylacetonitrile (Vide supra), the question arose as
to whether the low enantioselectivities of entries 8 and 9 resulted
from racemization of the product R-amino nitriles 7f,g. Al-
though no deuterium exchange was observed when the 1H-NMR
spectra of 7f,g were examined, racemization via rapid revers-
ibility of HCN addition cannot be discounted at this point. In
contrast to the previous examples, the 2-furyl derivative (entry
10) and the aliphatic examples (entries 11 and 12) afforded low
selectivity. In all cases, the enantioselectivity could be improved
by lowering the reaction temperature, but preliminary studies
indicate that increasing the amount of catalyst did not improve
the outcome of any of the problematic reactions. In all cases
examined, the (S)-isomer was the major product.
Despite the structural resemblance between 1 and 2 and the
mechanistic similarities between the reactions they catalyze,
several important differences exist which belie the apparent
similarity. First, whereas 2 operates as a heterogeneous catalyst,
1 is fully soluble under the conditions of the Strecker synthesis.
Second, although both 1 and 2 are composed of (S)-amino acids,
they catalyze formation of enantiomeric products. Additionally,
studies conducted on 2 have demonstrated a dependence of the
enantioselectivity on the method of crystallization of the
catalyst,6b solvent viscosity,6c and enantioselective autocatalysis
by the product itself.6d Studies are ongoing in our laboratories
to investigate the effects of these and other factors on the
enantioselectivity of the Strecker synthesis using catalyst 1.
In this version of the reaction, a solution of a preformed imine
and 1 (2 mol %) in methanol was treated at -25 °C with
hydrogen cyanide (2 equiv). Intriguingly, the presence of alkyl
groups on the imine nitrogen resulted in the formation of (S)-
R-amino nitriles in high yield and exceptionally high enantio-
meric excess. Moreover, all the N-substituted R-amino nitriles
appear to be configurationally stable at room temperature, in
marked contrast to the parent 2-aminophenylacetonitrile and in
accord with literature precedent.
The various N-alkyl R-amino nitriles were hydrolyzed ac-
cording to literature conditions12 (6 N HCl, 60 °C, 6 h) to
attempt simultaneous hydrolysis of the nitrile and deprotection
of the nitrogen. Of the derivatives examined, only the benz-
hydryl-protected R-amino nitrile proved satisfactory in this
regard. When the optically active N-benzhydryl-R-amino nitrile
was subjected to these conditions, (S)-phenylglycine was
obtained without loss of optical activity as determined by optical
rotation.13 Benzaldehyde can thus be converted to (S)-phen-
ylglycine in three steps, in 92% yield and >99% ee.
The generality of this methodology was explored by subject-
ing various N-benzhydryl imines derived from aromatic and
aliphatic aldehydes to the reaction conditions described above
(Table 2). Enantiomeric purity of the product R-amino nitriles
was determined by chiral HPLC chromatography using a Daicel
ChiralPak AD column. Absolute configuration was assigned
by hydrolysis of the R-amino nitriles and comparison of the
optical rotations of the R-amino acids to literature values.14-18
The products derived from aromatic aldehydes (entries 1-7)
were obtained generally in high enantiomeric excess, although
the electron-deficient 3-nitro (entry 8) and 3-pyridyl (entry 9)
Acknowledgment. We thank the National Institutes of Health (GM
53091) for support of this research. In addition, we thank the Purdue
Research Foundation for supporting K.M.G. with a predoctoral fel-
lowship.
(12) Marvell, C. S.; Noyes, W. A. J. Am. Chem. Soc. 1920, 42, 2266-
2267.
Supporting Information Available: Experimental procedures for
the synthesis of 1, the products listed in Table 2, and characterization
of the amino acid products (6 pages). Ordering information is given
on any current masthead page.
(13) [R]25 ) +153° (c 2.8, 1 N HCl); lit. [R]25 ) +155° (c 2.8, 1 N
D
D
HCl).12
(14) Vernier, J. M.; Hegedus, L. S.; Miller, D. B. J. Org. Chem. 1992,
57, 6914-6920.
(15) Williams, R. M.; Hendrix, J. A. J. Org. Chem. 1990, 55, 3723-
3732.
JA952686E
(16) Weinges, K.; Reinel, U.; Maurer, W.; Ga¨ssler, N. Liebigs Ann. Chem.
1987, 833-838.
(18) Yokozeki, K.; Mitsugi, K.; Eguschi, C.; Iwagami, H. Ger. Offen.
DE 285 245, Dec. 14, 1978; Ajinomoto Inc., Tokyo.
(17) Schutt, H.; Schmidt, G. Ger. Offen. DE 3134 932, March 17, 1983.