Asymmetric strecker synthesis of α-amino acids via a crystallization-induced asymmetric transformation using (R)-phenylglycine amide as chiral auxiliary

Article abstract of DOI:10.1021/ol007042c

Matrix presented Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and can be isolated in 76-93% yield and dr > 99/1. The diastereomerically pure α-amino nitrile obtained from pivaldehyde (R₁ = t-Bu, R₂ = H) was converted in three steps to (S)-tert-leucine in 73% yield and >98% ee.

Full text of DOI:10.1021/ol007042c

ORGANIC
LETTERS
2001
Vol. 3, No. 8
1121-1124
Asymmetric Strecker Synthesis of
r-Amino Acids via a
Crystallization-Induced Asymmetric
Transformation Using (R)-Phenylglycine
Amide as Chiral Auxiliary
,†
Wilhelmus H. J. Boesten,† Jean-Paul G. Seerden,‡ Ben de Lange,*
Hubertus J. A. Dielemans,† Henk L. M. Elsenberg,† Bernard Kaptein,†
Harold M. Moody,† Richard M. Kellogg,‡ and Quirinus B. Broxterman*
,†
DSM Research Life Sciences-Organic Chemistry and Biocatalysis, P.O. Box 18,
6160 MD Geleen, and Syncom B.V., Kadijk 3, 9747 AT Groningen, The Netherlands
rinus.broxterman@dsm-group.com
Received December 22, 2000 (Revised Manuscript Received March 15, 2001)
ABSTRACT
Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied
by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and can be isolated in
76−93% yield and dr > 99/1. The diastereomerically pure r-amino nitrile obtained from pivaldehyde (R ) t-Bu, R ) H) was converted in three
1
2
steps to (S)-tert-leucine in 73% yield and >98% ee.
The asymmetric synthesis of R-amino acids and derivatives
is an important topic as a result of their extensive use in
pharmaceuticals and agrochemicals and as chiral ligands.
Many highly enantioselective approaches have been re-
ported.1 Industrial production of R-amino acids via the
Strecker reaction is historically one of the most versatile
methods to obtain these compounds in a cost-effective
manner, making use of inexpensive and easily accessible
starting materials.2 The Strecker reaction is usually followed
by resolution of the racemic amino acid or amino acid amide
obtained after hydrolysis of the amino nitrile.3 Either process
leads to a maximum yield of 50% if the unwanted enantiomer
is not racemized. In principle, asymmetric synthesis ap-
(2) (a) Kunz, H. In Houben-Weyl: StereoselectiVe Synthesis; Helmchen,
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme Verlag:
Stuttgart, 1995, 1931; Vol. E 21, D.1.4.4. (b) Shafran, Y. M.; Bakulev, V.
A.; Mokrushin, V. S. Russ. Chem. ReV. 1989, 58, 148 (c) Strecker, A. Ann.
Chem. Pharm. 1850, 75, 27.
(3) For reviews, see: resolution by aminoamidases. (a) Sonke, T.;
Kaptein, B.; Boesten, W. H. J.; Broxterman, Q. B.; Schoemaker, H. E.;
Kamphuis, J.; Formaggio, F.; Toniolo, C.; Rutjes, F. P. J. T. In Stereo-
selectiVe Biocatalysis; Patel, R., Ed.; Dekker: New York, 2000; Chapter
2. (b) Resolution by acylases. Drauz, K.; Waldmann, H. In Enzyme Catalysis
in Organic Synthesis; VCH: Weinheim, 1995; Vol. 1, p 393.
† DSM Research Life Sciences-Organic Chemistry & Biocatalysis. E-mail
for Ben de Lange: Ben-B.Lange-de@dsm-group.com.
‡ Syncom B.V.
(1) (a) Calmes, M.; Daunis, J. Amino Acids 1999, 16, 215. (b) Cativiela,
C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517 (c)
Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids; Pergamon:
Oxford, 1989.
10.1021/ol007042c CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/30/2001

Table 1. Asymmetric Strecker Reactions of (R)-Phenylglycine Amide 1 and Pivaldehyde 2
entry
sovent
temp (°C)
time (h)
yield (%)a
dr (R,S)-3/(R,R)-3b
1
2
3
4
5
6
7
8
9
MeOH
rt
rt
rt
rt
20
22
22
20
20
24
24
24
24
80
51
84
65
69
81
84
84
93
65/35
99/1
88/12
96/4
81/19
85/15
96/4
MeOH/2-PrOH, 1/9c
2-PrOH
2-PrOH/t-BuOH, 4/1c
MeOH/H2O, 35/1c
rt
H2O
H2O
H2O
H2O
55
60
65
70
98/2
>99/1
a Isolated yield after: evaporation of the solvent (entry 1) or filtration of precipitated amino nitrile 3 (entries 2-9). b The dr was determined by 1H NMR
spectroscopy. c Ratio in volume/volume.
proaches that lead to a maximum yield of 100% of a single
enantiomer are more advantageous.
have been used as starting materials, which lead, respectively,
to enantiomerically enriched tert-leucine and R-methyl-dopa,
two important nonproteogenic R-amino acids for pharma-
ceutical applications. In addition, tert-leucine has consider-
able utility as a chiral building block.14
The asymmetric Strecker reaction of (R)-phenylglycine
amide 1, pivaldehyde 2 and HCN generated in situ from
NaCN and AcOH was studied (Table 1). Amino nitriles
(R,S)-3 and (R,R)-3 were obtained in 80% yield in a ratio of
65:35 by stirring an equimolar mixture of 1 (as AcOH salt)
Recently several catalytic asymmetric Strecker reactions
leading to N-protected amino nitriles in high ee’s and high
yields have been published.4 Alternatively, diastereoselective
Strecker syntheses using a broad variety of chiral inducing
agents, like R-arylethylamines,5 â-amino alcohols and de-
rivatives,6 amino diols,7 sugar derivatives,8 and sulfinates9
have been reported to provide the R-amino nitriles with
varying diastereoselectivities. A major drawback of these
chiral auxiliaries can be cost and/or availability, because they
are used in stoichiometric amounts and in principle lost
during the conversion. Furthermore, in many cases the
R-amino nitriles need to be purified in a separate step to
obtain diastereomerically pure compounds. Purification
requires, for example, crystallization or chromatography,
which may lead to losses. An interesting solution to these
problems would be a crystallization-induced asymmetric
transformation,10,11 in which one diastereomer precipitates
and the other epimerizes in solution via the corresponding
imine. This would lead both to high yield and high
diastereoselectivity in a practical one-pot procedure.
Recently, optically pure (R)-phenylglycine amide 1 became
readily accessible as a result of application on an industrial
scale as key intermediate in the enzymatic synthesis of
â-lactam antibiotics.12 Either aminopeptidase-catalyzed hy-
drolysis of racemic phenylglycine amide3 or asymmetric
transformation of racemic phenylglycine amide with (S)-
mandelic acid as resolving agent13 can be used to prepare 1.
Because of its ready availability on a large scale and its
anticipated easy removal via catalytic hydrogenolysis, we
decided to investigate the application of (R)-phenylglycine
amide 1 as chiral auxiliary in asymmetric synthesis.
(4) (a) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int.
Ed. Engl. 2000, 39, 1279. (b) Porter, J. R.; Wirschun, W. G.; Kuntz, K.
W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657.
(c) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2000, 122, 762. (d) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2,
867. (e) Corey, E. J.; Grogan, M. Org. Lett. 1999, 1, 157.
(5) (a) Vincent, S. P.; Schleyer, A.; Wong, C.-H. J. Org. Chem. 2000,
65, 4440. (b) Wede, J.; Volk, F.-J.; Frahm, A. W. Tetrahedron: Asymmetry
2000, 11, 3231. (c) Juaristi, E.; Leon-Romo, J. L.; Reyes, A.; Escalante, J.
Tetrahedron: Asymmetry 1999, 10, 2441. (d) Speelman, J. C.; Talma, A.
G.; Kellogg, R. M.; Meetsma, A.; de Boer, A.; Beurskens, P. T.; Bosman,
W. P. J. Org. Chem. 1989, 54, 1055. (e) Stout, D. M.; Black, L. A.; Matier,
W. L. J. Org. Chem. 1983, 48, 5369.
(6) (a) Dave, R. H.; Hosangadi, B. D. Tetrahedron 1999, 55, 11295. (b)
Ma, D.; Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120. (c) Chakraborty,
T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995, 51, 9179.
(7) Weinges, K.; Brachmann, H.; Stahnecker, P.; Rodewald, H.; Nixdorf,
M.; Irngarter H. Liebigs Ann. Chem. 1985, 566.
(8) Kunz, H.; Sager, W.; Schanzenbach D.; Decker, M. Liebigs Ann.
Chem. 1991, 649.
(9) Davis, F. A.; Fanelli, D. L. J. Org. Chem. 1998, 63, 1981.
(10) Only very few examples of crystallization-induced asymmetric
transformations in Strecker reactions have been reported based on arylalkyl-
methyl ketones: (a) Weinges, K.; Gries, K.; Stemmle, B.; Schrank, W.
Chem. Ber. 1977, 110, 2098. (b) Weinges, K.; Klotz, K.-P.; Droste, H.
Chem. Ber. 1980, 113, 710.
(11) For a broad discussion of crystallization-induced asymmetric
transformation, see: Vedejs, E.; Chapman, R. W.; Lin, S.; Muller, M.;
Powell, D. R. J. Am. Chem. Soc. 2000, 122, 3047 and references therein.
(12) Bruggink, A.; Roos, E. S.; de Vroom, E. Org. Process Res. DeV.
1998, 2, 128.
(13) (a) Boesten, W. H. J. European Patent Appl. EP 442584, 1991
(Chem. Abstr. 1992, 116, 42062r). (b) Boesten, W. H. J. European Patent
Appl. EP 442585, 1991 (Chem Abstr. 1992, 116: 42063s).
(14) Bommarius, A. S.; Schwarm, M.; Stingl, K.; Kottenhahn, M.;
Huthmacher, K.; Drauz, K. Tetrahedron: Asymmetry 1995, 6, 2851.
In this paper, the first two examples of the use of (R)-
phenylglycine amide in asymmetric Strecker reactions are
presented. Pivaldehyde and 3,4-dimethoxyphenylacetone
1122
Org. Lett., Vol. 3, No. 8, 2001

with 2 and NaCN in MeOH overnight at room temperature,
followed by evaporation of the solvent (entry 1). The
diastereomeric ratio of (R,S)-3 and (R,R)-3 was determined
by 1H NMR on the basis of the relative integration between
the t-Bu signals at 1.05 ppm for (R,S)-3 and 1.15 ppm for
(R,R)-3. The assignments have been made on the basis of
the absolute configuration as established by X-ray analysis
and conversion to (S)-tert-leucine (vide infra).
Because in methanol crystallization of amino nitrile 3 did
not take place, first the solvent was varied in order to attempt
to find conditions for a crystallization-induced asymmetric
transformation. At a MeOH/2-PrOH ratio of 1/9 amino nitrile
(R,S)-3 was isolated in 51% yield and dr 99/1 (entry 2). Other
combinations of alcoholic solvents failed to lead to a higher
yield of precipitated (R,S)-3 in high dr (entries 3 and 4). On
further screening of solvents it was observed that upon
addition of H2O to the methanol solution selective precipita-
tion of amino nitrile (R,S)-3 occurred giving (R,S)-3 and
(R,R)-3 in a ratio of 81:19 and 69% yield (entry 5). The
asymmetric Strecker reaction was further studied in H2O
alone using temperature as a variable. The results of these
experiments are given in Table 1 (entries 6-9). After
addition of NaCN/AcOH at 23-28 °C to (R)-phenylglycine
amide 1 and pivaldehyde 2 in H2O, the mixture was heated
to the indicated temperatures.
Figure 2. Crystallization-induced asymmetric transformation of
amino nitrile 3.
mation can be explained as shown in Figure 2. Apparently,
the re-face addition of CN- to the intermediate imine 4 is
preferred at room temperature in methanol and results in a
dr 65/35. At elevated temperatures in water the diastereo-
meric outcome and yield of the process is controlled by the
reversible reaction of the amino nitriles 3 to the intermediate
imine and by the difference in solubilities of both dia-
stereomers under the applied conditions.16,17
After approximately 24 h of stirring, the mixture was
cooled to 30 °C and the precipitated amino nitrile filtered
The absolute configuration of amino nitrile (R,S)-3 was
confirmed by X-ray analysis as shown in Figure 318 and by
conversion to (S)-tert-leucine.
1
and analyzed by H NMR to determine the dr. The results
in Table 1 show that optimal results were achieved after 24
h of stirring in water at 70 °C. The amino nitrile (R,S)-3
was obtained in 93% yield and a dr > 99/1 via a crystal-
lization-induced asymmetric transformation (entry 6). At
lower temperatures the epimerization reaction is slower.15
The crystallization-induced asymmetric transformation in
water at 70 °C is verified further by the observed increase
of the dr of (R,S)-3 as a function of the reaction time (Figure
1). After 30 h the precipitated (R,S)-3 was obtained with a
dr > 99/1.
Figure 3. X-ray structure of amino nitrile (R,S)-3.
Conversion of the amino nitrile (R,S)-3 to (S)-tert-leucine
7 was accomplished via the reaction sequence shown in
Scheme 1. Hydrolysis of (R,S)-3 to the diamide (R,S)-5
Figure 1. Crystallization-induced asymmetric transformation of
amino nitrile 3 in water at 70 °C.
(16) For example, in the case of phenylacetone (not illustrated) it was
found that in solution the initially formed minor isomer preferentially
precipitated under crystallization conditions.
(17) For a discussion of asymmetric transformation of R-amino nitriles
with mandelic acid, see: Hassan, N. A.; Bayer, E.; Jochims, J. C. J. Chem.
Soc., Perkin Trans. 1 1998, 3747.
The observed diastereoselectivity in the asymmetric Streck-
er step via the crystallization-induced asymmetric transfor-
(18) The crystal structure of (R,S)-3 has been deposited at the Cambridge
Crystallographic Data Center and allocated the deposition number CCDC
154034.
(15) At higher temperatures, lower yields of product were found, probably
by degradation of amino nitrile.
Org. Lett., Vol. 3, No. 8, 2001
1123

Scheme 1
Scheme 2
1H NMR analysis. It was found that in solution at room
temperature an equilibrium of 55:45 exists between the two
diastereomers (R,S)-9 and (R,R)-9. Clearly, again a crystal-
lization-induced asymmetric transformation has occurred.
In summary, (R)-phenylglycine amide 1 is an excellent
chiral auxiliary in the asymmetric Strecker reaction with
pivaldehyde or 3,4-dimethoxyphenylacetone. Nearly dia-
stereomerically pure amino nitriles can be obtained via a
crystallization-induced asymmetric transformation in water
or water/methanol. This practical one-pot asymmetric Streck-
er synthesis of (R,S)-3 in water leads to the straightforward
synthesis of (S)-tert-leucine 7. Since (S)-phenylglycine amide
is also available, this can be used if the other enantiomer of
a target molecule is required. More examples are currently
under investigation to extend the scope of this procedure.19
proceeded smoothly in concentrated H2SO4 in high yield and
without racemization.
Removal of the phenylacetamide group under 2 atm of
H2 with catalytic Pd/C afforded (S)-tert-leucine amide 6 in
90% yield. Finally, hydrolysis of the amide was ac-
complished by heating in 6 N HCl at 100 °C to give (S)-
tert-leucine 7 in 86% yield and >98% ee. The absolute
configuration assignment, (S), was made by comparison with
an authentic sample.3 Obviously, other routes to convert the
amino nitrile derivatives to the amino acid can be envisaged
and are under investigation.
The crystallization-induced asymmetric transformation,
using (R)-phenylglycine amide 1 as chiral auxiliary in
diastereoselective Strecker reactions, was further explored
with 3,4-dimethoxyphenylacetone 8 (Scheme 2).
The optimized asymmetric Strecker reaction of (R)-
phenylglycine amide 1 (used as HCl salt) and an equimolar
amount of 3,4-dimethoxyphenylacetone 8 in MeOH/H2O (6/1
v/v) gave, after addition of NaCN (30% aqueous solution)
and stirring for 96 h at room temperature, the nearly
diastereomerically pure (dr > 99/1) amino nitrile 9 as a solid
in 76% isolated yield. The dr could easily be determined by
Acknowledgment. Mr. A. Meetsma of the department
of crystallography of the University of Groningen is ac-
knowledged for the X-ray structure of (R,S)-3.
Supporting Information Available: Procedures and
characterization data of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL007042C
(19) Several other amino nitriles could be obtained as crystalline materials
from H2O/MeOH mixtures, e.g., R1 ) iPr, R2 ) H; R1 ) Ph, R2 ) Me; R1
) iPr, R2 ) Me. Conditions are being sought to obtain also a crystallization-
induced asymmetric transformation in these cases.
1124
Org. Lett., Vol. 3, No. 8, 2001