Enantioselective catalytic addition of HCN to ketoimines. Catalytic synthesis of quaternary amino acids.

Article abstract of DOI:10.1021/ol005636+

[formula: see text] Highly enantioselective addition of HCN to ketoimines has been achieved for the first time using readily accessible and recyclable Schiff base catalysts. Essentially quantitative isolated yield and enantioselectivity of up to 95% ee wa

Full text of DOI:10.1021/ol005636+

ORGANIC
LETTERS
2000
Vol. 2, No. 6
867-870
Enantioselective Catalytic Addition of
HCN to Ketoimines. Catalytic Synthesis
of Quaternary Amino Acids
Petr Vachal and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
jacobsen@chemistry.harVard.edu
Received February 8, 2000
ABSTRACT
Highly enantioselective addition of HCN to ketoimines has been achieved for the first time using readily accessible and recyclable Schiff base
catalysts. Essentially quantitative isolated yield and enantioselectivity of up to 95% ee was obtained. Furthermore, some of the Strecker
adducts could be recrystallized in high recovery, yielding optically pure materials. Conversion of the r-aminonitrile adducts to the corresponding
r-quaternary r-amino acids was effected in high yield by a formylation/hydrolysis sequence.
Compounds bearing R-quaternary R-amino acid units as
structural components display a wide assortment of interest-
ing biological properties.1 For example, derivatives of
R-methyl phenylglycine and its analogues have shown
promising inhibitory activity toward metabotropic glutamate
receptors,2 platelet aggregation,3 and proteases including
trypsin and matrix metalloproteinases.4 Interest in quaternary
amino acids is fueled further by the fact that derivatives of
these compounds exhibit unusual conformational constraints.5
As a result, significant effort has been directed toward
uncovering general and practical protocols for the preparation
of optically pure quaternary amino acids. Most of the
methods identified thus far rely on optically active starting
materials or the use of stoichiometric chiral auxiliaries,6
although successful catalytic approaches have been reported
very recently.7 In principle, a most attractive and versatile
solution would be provided through a catalytic enantio-
selective addition of HCN across the CdN bond of ke-
toimines (eq 1). While considerable progress has been made
(1) Enzyme-inhibitors, see, for example: (a) Saari, W. S.; Halczenko,
W.; Cochran, D. W.; Dobrinska, M. R.; Vincek, W. C.; Titus, D. C.; Gaul,
S. L.; Sweet, C. S. J. Med. Chem. 1984, 27, 713. (b) Fenteany, G.; Standeart,
R. F.; Lane W. S.; Choi, S.; Corey, E. J.; Schreiber, S. L. Science 1995,
268, 726. Antibiotic structures, see, for example: (c) Hanessian S.; Haskell
T. H. Tetrahedron Lett. 1964, 2451. Peptidomimetics, see, for example:
(d) Jung, G.; Beck-Sickinger, A. G. Angew. Chem., Int. Ed. Engl. 1992,
31, 367. (e) Veber, D. F.; Freidinger R. M. Trends Neuorosci. 1995, 8,
392.
(2) (a) Ma, D.; Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120. (b)
Sekiyama, N.; Hayashi, Y. Nakanishi, S.; Jane, D. E.; Tse, H.-W.; Birse,
E. F.; Watkins, J. C. Br. J. Pharmacol. 1996, 117, 1493. (c) Ma, D.; Tian,
H. Tetrahedron: Asymmetry 1996, 6, 1567.
recently in the development of effective catalysts for the
asymmetric hydrocyanation of aldimines,8 there are no
(5) Miyashita, K.; Miyabe, H.; Tai, K.; Kurozumi, C.; Iwaki, H.; Imanishi,
T. Tetrahedron 1999, 55, 12109 and references therein.
(6) (a) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; John Wiley & Sons: New York, 1995. (b) Seebach, D.; Sting,
A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708. (c)
Seebach, D.; Hoffmann, M. Eur. J. Org. Chem. 1998, 1337. (d) Moody, C.
J.; Gallagher, P. T.; Lightfoot, A. P.; Slawin, A. M. Z. J. Org. Chem. 1999,
64, 4419.
(3) Stilz, H. U.; Jablonka, B.; Just, M.; Knolle, J.; Paulus, E. F.; Zoller,
G. J. Med. Chem. 1996, 39, 2118.
(4) Hirayama, R.; Yamamoto, M.; Tsukida, T.; Matsuo, K.; Obata, Y.;
Sakamoto, F.; Ikeda, S. Bioorg. Med. Chem. 1997, 5, 765.
10.1021/ol005636+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/24/2000

reported examples of enantioselective catalytic Strecker
reactions involving ketoimines. We report here the first
success in this area, and outline a new and practical method
for the preparation of R-substituted amino acids and their
derivatives. The approach is illustrated in the gram-scale
synthesis of optically pure (>99.9% ee) R-methyl phenyl-
glycine.
Resin-bound catalyst 1a was discovered and optimized for
the Strecker reaction of aldimines using a combinatorial
parallel library approach.8b,g This catalyst displays remarkable
substrate scope in the asymmetric hydrocyanation of
aldimines,8g and we used it as a starting point for the
evaluation of ketoimines using acetophenone-derived 2a9 as
a model substrate. With 4 mol % of 1a and 1.25 equiv of
HCN10 at -75 °C, complete conversion of imine 2a occurred
within 180 h and the Strecker adduct 3a was obtained in
high yield and 85% ee (Table 1, entry 1). The reactivity of
used with catalyst 1a, urea 1b catalyzed the formation of
Strecker adduct 3a within less than half the time yet with
similar enantioselectivity (entry 2). The soluble analogue 1c
displayed higher reactivity yet, allowing complete reaction
within 30 h using only 2 mol % catalyst (entry 3).
A series of ketoimines were evaluated using catalyst 1c,
and moderate-to-high enantioselectivity was obtained in the
formation of the corresponding Strecker adducts (Table 1,
entries 3-6). The products (3a-d) were found to be stable
under neutral conditions, but they underwent rapid decom-
position under either acidic or basic conditions via a retro-
Strecker reaction. Attempts to protect the amino group to
prevent the decomposition pathway were only partially
successful. Even highly reactive electrophiles such as tri-
fluoroacetic anhydride provided only moderate yields (40-
50%) of the corresponding amide.
Replacement of the N-allyl protective group with an
N-benzyl group in the imine substrates led to more stable
Strecker adducts and slightly increased enantioselectivity as
well. Under identical reaction conditions to those described
above (2 mol % 1c, 1.25 equiv of HCN, -75 °C) good
reactivity and 90% ee was achieved with acetophenone-
derived imine 2e (Table 2, entry 1). Since our goal was a
Table 1
Table 2
3
2
yielda
(%)
eeb
yielda
(%)
eec
entry
product
catalyst
t (h)
(%)
entry
product
R
t (h)
(%)
1
2
3
4
5
6
3a
3a
3a
3b
3c
3d
1a (4 mol %)
1b (4 mol %)
1c (2 mol %)
1c (2 mol %)
1c (2 mol %)
1c (2 mol %)
180
80
30
17
65
17
98
99
97
96
97
98
85
82
85
69
89
41
1
2
3
3e
3f
3g
C6H5
p-CH3C6H4
p-BrC6H4
24
80
80
97
90
91
93
98b
quant
(76)
quant
(79)
98
quant
(75)
97b
(>99.9)
93
4
3h
p-NO2C6H4
80
(>99.9)
88
95
a
Isolated yield of product determined to be >99% pure by HPLC
5
6
3i
3j
p-CH3OC6H4
p-CF3C6H4
60
65
b
analysis. All ee’s were determined by GC or HPLC chromatography using
commercial chiral columns. See Supporting Information.
(>99.9)
91
42
7
8
9
3k
3l
3m
m-BrC6H4
o-BrC6H4
(CH3)3C
60
90
15
45
98
the catalyst was improved measurably by replacing the
thiourea with a urea linkage. Under the same conditions as
70
a
Isolated yield, >99% pure by HPLC analysis unless noted otherwise;
yields in parentheses were obtained after recrystallization from hexanes.
(7) (a) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727. (b)
Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532. (c) Belokon,
Y. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.; Vyskocil, S.;
Kagan, H. B. Tetrahedron: Asymmetry 1999, 10, 1723. (d) Kuwano, R.;
Ito, Y. J. Am. Chem. Soc. 1999, 121, 3236.
b >97% pure by HPLC analysis. All ee’s were determined by GC or
c
HPLC chromatography using commercial chiral columns (see Supporting
Information); ee’s in parentheses were obtained after recrystallization from
hexanes.
(8) (a) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am.
Chem. Soc. 1996, 118, 4910. (b) Sigman, M. S.: Jacobsen, E. N. J. Am.
Chem. Soc. 1998, 120, 4901. (c) Sigman, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 1998, 120, 5315. (d) Ishitani, H.; Komiyama, S.; Kobayashi,
S. Angew Chem. Int. Ed. Eng. 1998, 37, 3186. (e) Krueger, C. A.; Kuntz,
K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284. (f) Corey, E. J.; Grogan,
M. J. Org. Lett. 1999, 1, 157. (g) Sigman, M. S.; Vachal, P.; Jacobsen, E.
N. Angew. Chem., Int. Ed., in press. (h) Takamura, M.; Hamashima, Y.;
Usuda, H.; Kanai, M.; Shibasaki, M. Submitted for publication.
practical protocol for preparation of R-alkyl amino acids, it
was critical to demonstrate that the N-benzyl group could
be removed while still preserving the quaternary center,
which is also a benzylic amine. Indeed, selective debenzy-
(9) All ketoimines were prepared by reaction of the appropriate ketone
and amine in dichloromethane in the presence of 3 Å sieves. Full
experimental details are provided as Supporting Information.
(10) Solutions of hydrogen cyanide were generated prior to the Strecker
reaction by combination of equimolar amounts of TMSCN and methanol
in toluene at 5 °C for 2 h.
868
Org. Lett., Vol. 2, No. 6, 2000

lation11 of N-benzyl R-methyl phenylglycine (5e) could be
effected under mild conditions (10% Pd-C and 1 atm H2,
1.7 N HCl in MeOH/H2O) to yield R-methyl phenylglycine
(6) in quantitative yield as its hydrochloride salt (Scheme
1).
tions (Scheme 1).12 The quaternary center in 4e was stable
toward strongly acidic conditions, and sequential hydrolysis
of the nitrile and formamide groups could be effected using
concentrated hydrochloric acid to yield amino acid 5e in
nearly quantitative yield. Debenzylation of 5e was achieved
as described above to afford R-methyl phenylglycine (6) in
90-91% ee. Unfortunately, it was not possible to enhance
the optical purity of 6 nor of any of its precursors by
recrystallization.
Scheme 1
Examination of a series of benzyl derivatives as N-
protective groups for the Strecker reaction revealed generally
little influence of substituents on enantioselectivity (Table
3), and in the case of p-bromobenzyl derivative 3q, the
Table 3
yielda
(%)
eec
entry
product
R
t (h)
(%)
1
2
3
4
3n
3o
3p
3q
OCH3
CF3
(CH3)3C
Br
36
50
30
40
97
95
95
93
92
89
Catalyst 1c proved effective for the asymmetric hydro-
cyanation of a variety of N-benzyl ketoimines (Table 2).
Strecker adducts 3e-k were isolated in essentially quantita-
tive yield by filtration of the crude product mixtures through
a short silica gel column. High enantioselectivity was
obtained with imines bearing both electron-withdrawing (e.g.,
2h and 2j) and electron-donating aromatic substituents (e.g.,
2f and 2i). While the m-bromo-subustituted derivative 2k
underwent hydrocyanation in excellent yield and 91% ee,
the ortho-substituted analogue 2l proved to be a problematic
substrate. The Strecker adduct 3l was found to undergo
complete decomposition within several hours at room tem-
perature and could only be isolated in marginal yield and
enantioselectivity (entry 8). In contrast, the aliphatic keto-
imine substrate 2m (R ) tBu) underwent clean reaction, and
adduct 3m was isolated in 70% ee. Some of the Strecker
adducts (3g, 3h, and 3j) were isolated as crystalline
compounds, and recrystallization from hexanes afforded
optically pure (>99.9% ee) materials in high recovery (75-
79% overall isolated yield). Furthermore, since catalyst 1c
is soluble in hexanes, no chromatographic purification was
necessary as the catalyst remained dissolved in the mother
liquors.
95
92
(75)
(>99.9)
adduct was isolable as a crystalline compound. Recrystalli-
zation of the crude product from hexanes yielded optically
pure (>99.9% ee) material in 75% overall recovery. Optically
pure 3q was converted to R-methyl phenylglycine (6) in 93%
overall yield and >99.9% ee (70% overall yield from imine
2q) following the protocol in Scheme 1.13
The asymmetric hydrocyanation of 2q can be carried out
successfully under a variety of experimental conditions. For
example, elevation of the temperature from -75 °C to +5
°C led to a decrease in the requisite reaction time from 40 h
to 8 min, and the adduct 3q was still obtained in essentially
quantitative yield and in 87% ee (Table 4, entries 1 and 2).
This material could be recrystallized to optical purity in 72%
overall yield. Furthermore, catalyst 1c was easily recovered
by chromatography in 97% yield, and reused in the Strecker
reaction with results identical to those obtained with freshly
prepared catalyst (entry 3). As noted above, the resin-bound
catalyst (1b) is substantially less reactive but it offers
distinctive operational advantages because it is more easily
separated and recycled. With 10 mol % 1b at -40 °C, the
hydrocyanation of 2q required 6 h to reach completion, and
the Strecker adduct was isolated in quantitative yield and
90% ee simply by catalyst removal by filtration followed
Even though N-benzyl-protected Strecker adducts 3e-m
are more stable than their N-allyl analogues, efforts to effect
the direct hydrolysis of the nitrile functionality under acidic
or basic conditions were still unsuccessful as a result of a
competing retro-Strecker pathway. It was, however, possible
to protect 3e as its formamide derivative 4e using in situ
generated acetic formic anhydride under solvent free condi-
(12) Edwards, R. J. Am. Chem. Soc. 1942, 64, 1583.
(13) The absolute stereochemistry of 6 was assigned by comparison of
its optical rotation with literature values: (a) Terashima, S.; Yamada, S. I.
Chem. Pharm. Bull. 1968, 15, 1953. (b) Obrecht, D.; Bohdal, U.; Broger,
C.; Bur, D.; Lehmann, C.; Ruffieux, R.; Schoenholzer, P.; Spiegler, C.;
Mueller, K. HelV. Chim. Acta 1995, 78, 563.
(11) Hassan, N. A.; Bayer, E.; Jochims, J. C. J. Chem. Soc., Perkin Trans.
1 1998, 22, 3748.
Org. Lett., Vol. 2, No. 6, 2000
869

Table 4
entry
catalyst
1c (2 mol %)
1c (2 mol %)
1c (recycled, 2 mol %)
1c (0.1 mol %)
1b (6 mol %)
1b (10 mol %)
1b (1st recyle, 10 mol %)
1b (2nd recyle, 10 mol %)
[2q]initial (M)
T (°C)
t
yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
0.1
0.5
0.5
0.5
0.1
0.3
0.3
0.3
-75
+5
+5
40 h
8 min
8 min
2.5 h
120 h
6 h
97 (75)
95 (72)
96 (73)
96 (70, 53c)
quant. (76)
quant. (77)
quant. (76)
quant. (77)
92 (>99.9)
87 (>99.9)
88 (>99.9)
69 (91, >99.9c)
91 (>99.9)
90 (>99.9)
90 (>99.9)
91 (>99.9)
+5
-70
-40
-40
-40
6 h
6 h
a,b See Table 3. c Overall yield and ee obtained after second recrystallization from hexanes.
by solvent evaporation. Recrystallization from hexanes
provided 3q in 77% overall yield and >99.9% ee (entry 6).
Recycling of 1b had no deleterious effect on reactivity or
enantioselectivity (entries 7 and 8).
a variety of useful R-quaternary amine derivatives in
enantiopure form. We hope that this finding may enable even
broader application of quaternary amino acids and related
building blocks in both drug discovery and fundamental
research.
Given that Schiff bases 1a-c were selected from parallel
libraries for the enantioselective Strecker reaction of one
specific imine substrate (N-benzylpivalaldimine),8g it is
striking that these catalysts in fact promote the hydrocya-
nation of an extraordinary range of imines with high
enantioselectivity. Despite their relatively small size (FW
of 1c ) 621) and the broad substrate scope they display,
these Strecker catalysts have interesting features reminiscent
of enzymes. For instance, they operate in the absence of a
metal; they appear to “fold” into well-defined, rigid struc-
tures; and their reactions obey clean Michaelis-Menten
kinetics.14 The addition of ketoimines to the list of useful
substrates is significant, as it allows a practical approach to
Acknowledgment. This work was supported by the NIH
(GM-43214). Predoctoral fellowships to P.V. sponsored by
Alfred Bader and by Bristol Myers Squibb are gratefully
acknowledged. We thank Dr. Matthew Sigman, Miss Chris-
tine Espino, and Dr. Albert Delmonte for critical background
experiments.
Supporting Information Available: Complete experi-
mental procedures, analytical data, and chiral chromato-
graphic analyses of hydrocyanation products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) Zondlo, N. J.; Sigman, M. S.; Jacobsen, E. N. Manuscript in
preparation.
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Org. Lett., Vol. 2, No. 6, 2000