Ti-catalyzed regio- and enantioselective synthesis of unsaturated α- amino nitriles, amides, and acids. Catalyst identification through screening of parallel libraries [7]

Full text of DOI:10.1021/ja994121e

J. Am. Chem. Soc. 2000, 122, 2657-2658
2657
Scheme 1
Ti-Catalyzed Regio- and Enantioselective Synthesis of
Unsaturated r-Amino Nitriles, Amides, and Acids.
Catalyst Identification through Screening of Parallel
Libraries
James R. Porter, Wolfgang G. Wirschun, Kevin W. Kuntz,
Marc L. Snapper,* and Amir H. Hoveyda*
Table 1. Ti-Catalyzed Enantioselective Addition of Cyanide to
R,â-Unsaturated Aryliminesa
Department of Chemistry, Merkert Chemistry Center
Boston College, Chestnut Hill, Massachusetts 02467
ReceiVed NoVember 29, 1999
Due to the significance of R-amino acids in chemistry and
biology, the search for efficient methods that lead to the formation
of these important compounds in the optically pure form
continues.1 Several procedures have been devised that afford
R-amino acids in high selectivity, but many of these protocols
rely on the use of chiral auxiliaries.2 Other approaches depend
on catalytic enantioselective reduction of dehydroamino acids,
and several chiral hydrogenation catalysts have been disclosed
that deliver optically pure R-amino acids in high yield and
selectivity.3,4 Recently, we reported a Ti-catalyzed process for
the asymmetric cyanide addition to aryl imines, which affords
the derived aryl amino nitriles efficiently and with exceptional
enantiocontrol;5,6 the identity of the optimal catalyst was deter-
mined through synthesis and screening of parallel ligand libraries.7
Subsequent hydrolysis of the nitrile and simultaneous deprotection
of the amine unit afford the desired optically pure aryl R-amino
acids. These protocols thus allow access to R-amino acids that
are not available by the catalytic asymmetric hydrogenation
reaction.
a Conditions: 10 mol % Ti(i-OPr)4, 10 mol % chiral ligand, 2 equiv
TMSCN, toluene, 24 h; hexanes workup (see Supporting Information).
Entries 1-2 at +4 °C, entries 3-4 at -20 °C. 1.5 equiv of i-PrOH
added over 20 (entries 1-2) or 10 h (entries 3-4). b Determined by
analysis of the 1H NMR (400 MHz) of the upurified reaction mixture.
c Determined by chiral HPLC analysis in comparison with authentic
materials (Chiralcel OD, entries 1-3; Chiralpak AD, entry 4). d Purified
by recrystallization.
After these studies we began to examine the catalytic asym-
metric cyanide addition to R,â-unsaturated imines (Scheme 1).
We reasoned that if these reactions proceed regioselectively (1,2-
vs 1,4-addition) and enantioselectively, an efficient route to
various unsaturated R-amino acids would be at hand and the
generality of the catalytic asymmetric Strecker process would be
significantly enhanced. The following considerations provided us
with additional impetus: (1) â,γ-Unsaturated R-amino acids have
biologically significant properties (e.g., antibiotic8 and enzyme
inhibitory9 properties). (2) â,γ-Unsaturated amino acids are not
easily accessed by catalytic hydrogenation.10 (3) The resident
alkene unit in the intermediate amino nitrile may in principle be
stereoselectively functionalized en route to more complex R-amino
acids.
Due to the results of our studies regarding the addition of
cyanide to aryl- and alkylimines,5 we selected Ti(Oi-Pr)4 as the
metal salt of choice and diphenylmethylene as the amine
protecting group. Tripeptide ligand libraries were then prepared
and the reaction of unsaturated imine 1 with TMSCN was
screened in the presence of Ti(Oi-Pr)4 (10 mol % ligand and metal
complex). Screening of a total of approximately 60 peptidic
ligands11 indicates that the most selective ligand (3) is the one
(1) (a) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergamon: Oxford, 1989. (b) O’Donnell, M. J., Ed. Tetrahedron Symposia
in Print; Tetrahedron: Oxford, 1988; Vol. 44, 5253-5614. (c) Duthaler, R.
O. Tetrahedron 1994, 50, 1539-1650.
(2) For representative recent examples, see: (a) Davis, F. A.; Portonovo,
P. S.; Ready, R. E.; Chiu, Y. J. Org. Chem. 1996, 61, 440-441. (b) Zhu, J.;
Deur, C.; Hegedus, L. S. J. Org. Chem. 1997, 62, 7704-7710. (c) Myers, A.
G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1997, 119,
656-673.
(3) Burk, M. J.; Kalberg, C. S.; Pizzano, S. J. Am. Chem. Soc. 1998, 120,
4345-4353 and references therein.
(4) For representative recent non-hydrogenation catalytic asymmetric
methods to R-amino acids, see: (a) O’Donnell, M. J.; Delgado, F.; Hostettler,
C.; Scwesinger, R. Tetrahedron Lett. 1998, 39, 8775-8778. (b) Ferraris, D.;
Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548-
4549. (c) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347-
5350. (d) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40,
8671-8674. (e) Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.; Hazel, R.
G.; Jorgensen, K. A. J. Org. Chem. 1999, 64, 4844-4849.
(5) 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, 4284-4285.
(6) For related studies on catalytic asymmetric CN addition to imines,
see: (a) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem.
Soc. 1996, 118, 4910-4911. (b) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 1998, 120, 4901-4902. (c) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 1998, 120, 5315-5316. (d) Ishitani, H.; Komiyama, S.; Kobayashi, S.
Angew. Chem., Int. Ed. Engl. 1998, 37, 3186-3188. (e) Corey, E. J.; Grogan,
M. J. Org. Lett. 1999, 1, 157-160.
(7) For initial reports on screening of parallel peptide-based libraries, see:
(a) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P.; Snapper, M.
L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1668-1671. (b)
Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.; Snapper, M. L.;
Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1704-1707. (c)
Shimizu, K. D.; Snapper, M. L.; Hoveyda, A. H. Chem. Eur. J. 1998, 4, 1885-
1889.
(8) For example, see: Huroda, Y.; Okuhara, M.; Goto, T.; Kohaska, M.;
Aoki, H.; Imanaka, H. J. Antibiotics 1980, 33, 132-136.
(9) For example, see: Girodeau, J. M.; Agouridas, C.; Masson, M.; Pineau,
R.; Le Goffic, F. J. Med. Chem. 1986, 29, 1023-1030.
(10) For Rh-catalyzed hydrogenation of R,â,γ,δ-unsaturated acetamide
esters to obtain allylglycines, see: Burk, M. J.; Bedingfield, K. M.; Kiesman,
W. F.; Allen, J. G. Tetrahedron Lett. 1999, 40, 3093-3096 and references
therein. Presumably, the site-selective hydrogenation is due to the coordination
between the Rh-based catalyst and the acetamide directing group.
(11) See the Supporting Information for details on the identity of the ligands
screened. Since the screening for entries 1 of Tables 1 and 2, in addition to
those reported in ref 5, indicated that t-Leu and Thr(t-Bu) are optimal AA1
and AA2 units, respectively, only the Schiff base libraries were screened for
the remaining substrates.
10.1021/ja994121e CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/07/2000

2658 J. Am. Chem. Soc., Vol. 122, No. 11, 2000
Communications to the Editor
Table 2. Ti-Catalyzed Enantioselective Addition of Cyanide to
R,â-Unsaturated Alkenyliminesa
Treatment of optically enriched aminonitriles to acidic condi-
tions leads to the formation of the derived primary amides. The
example shown in Scheme 2 is illustrative (17 (94% ee) f 20
(94% ee)). Several conditions were examined for the conversion
of the amide to the derived unsaturated R-amino acid. After
extensive experimentation, we established that sequential exposure
of the amide to TFA and Et3SiH (amine deprotection) and
methanolic acid (amide hydrolysis) leads to the formation of the
optically pure amino acid (>99% ee);13 subsequent catalytic
hydrogenation of 21 (H2, 10% Pd(C)) affords (S)-valine in 94%
isolated yield and >99% ee. Several issues regarding the
hydrolysis/deprotection of optically enriched amino nitriles
deserve comment: (1) Hydrolysis of conjugated aminonitriles is
significantly more difficult than those of the saturated aryl or alkyl
derivatives. Accordingly, the conditions presented here for cyanide
hydrolysis are less severe than those reported previously.5 A
change of conditions is required, since the originally reported
protocols result in substantial loss of HCN and reformation of
the imine (aldehyde) substrate. (2) In the case of Boc-protected
amino acid 21 (Scheme 2), no detectable loss of enantiopurity is
observed. However, it is possible that under these conditions some
loss of enantiopurity occurs; for example, the amide formed from
amino nitrile 2 (97% ee) is obtained in 84% ee (77% yield).
a Conditions: 15 mol % Ti(i-OPr)4, 15 mol % chiral ligand, 2 equiv
TMSCN, toluene, -20 °C. 1.5 equiv of n-BuOH added over 10 h.
b Determined by analysis of the 1H NMR (400 MHz) of the unpurified
reaction mixture. c Determined by chiral HPLC analysis in comparison
with authentic materials (Chiralcel OD, entries 1 and 3; Chiralcel OJ,
entry 2). d Yield after silica gel chromatography.
with 2-hydroxy-1-naphthaldehyde Schiff base and t-Leu at the
AA1 and Thr(t-Bu) at the AA2 position (84% ee).12 As depicted
in entry 1 of Table 1, when the reaction is repeated with the
optimal ligand (+4 °C) on larger scale with the addition of i-PrOH
(to improve efficiency),5 the unpurified aminonitrile 2 can be
obtained in 84% ee (>98% conversion). Recrystallization of the
resulting white solid affords 2 in 80% purified yield and 97% ee.
Careful analysis of the reaction mixture indicated <2% of the
1,4-addition product. It is important to note that the corresponding
saturated imine (derived from 3-phenylpropanal) undergoes
catalytic cyanide addition under identical conditions with notably
lower levels of enantiocontrol (15-25% yield, 24% ee).
As illustrated in entries 2-3 of Table 1, the more electron rich
unsaturated imines 4 and 6 undergo Ti-catalyzed addition, albeit
with lower enantioselectivity (78% and 76% ee, respectively).
Whereas catalyst screening indicates that 3 is also the ligand of
choice for 4, tripeptide Schiff base 8 proves to be the more
effective ligand for the asymmetric synthesis of 7. In contrast to
amino nitrile 7, recrystallization of 5 leads to improvement of its
enantiopurity (61% yield, 97% ee). It merits mention that reaction
of 6 at 4 °C leads to only 51% ee; accordingly, the asymmetric
cyanide addition shown in entry 3 was performed at -20 °C to
improve stereochemical control. As shown in entry 4 of Table 1,
the electron-deficient unsaturated imine undergoes cyanide ad-
dition to afford aminonitrile 10 with the highest selectivity (90%
ee); recrystallization of 10 delivers the amino nitrile in 87% yield
and 97% ee (see the Supporting Information for details).
As the data in Table 2 indicate, the Ti-catalyzed cyanide
addition may also be performed with aliphatic unsaturated imines;
in these cases product recrystallization does not lead to the
improvement of product ee. Several additional points regarding
these asymmetric reactions are the following: (1) Comparison
of the data in entries 1-3 indicates that the presence of a
substituent R to the CdN leads to higher levels of enantioselec-
tivity (compare entry 1 to entries 2-3). (2) Higher catalyst
loadings are required in comparison to the aromatic substrates in
Table 1, otherwise the more effective uncatalyzed background
reaction leads to diminution of stereoselectivity. (3) As before,
in the absence of the unsaturation, significantly lower levels of
asymmetric induction are attained: Ti-catalyzed cyanide addition
to the imine derived from isobutyraldehyde proceeds in 94% yield
and 57% ee (vs 95% ee in entry 3, Table 2).
Scheme 2
In summary, we disclose Ti-catalyzed regio- and enantio-
selective addition of cyanide to unsaturated imines. Both aromatic
and aliphatic substrates may be used to obtain unsaturated amino
nitriles in good yield and enantiomeric excesses. Cyanide hy-
drolysis and amine deprotection can be carried out to afford
optically enriched R-amino amides and acids; in certain cases,
these conversions lead to slight lowering of enantiopurity.
Research toward establishing more general conditions for the
conversion of nitriles to acids is in progress. Future studies also
include stereoselective functionalization of the unsaturated amino
nitriles and the development of additional asymmetric C-C bond
forming processes through screening of parallel catalyst libraries.
Acknowledgment. This research was supported by the NIH (GM-
57212). Additional funds were provided by ArQule and DuPont (to
A.H.H.). W.G.W. was a Deutsche Forschungsgemeinschaft postdoctoral
fellow. M.L.S. is a Sloan Research Fellow and a DuPont and a Glaxo-
Wellcome Young Investigator. A.H.H. and M.L.S. are Dreyfus Teacher-
Scholars. This work is dedicated to the memory of the late Professor
Joseph T. Vanderslice.
Supporting Information Available: Experimental procedures and
spectral and analytical data for all recovered starting materials and reaction
products (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
Ti-catalyzed asymmetric additions to doubly unsaturated imines
proceed with appreciable levels of enantioselectivity as well. The
example depicted in eq 1 is illustrative (18 f 19). Similar to the
trend observed for substrates in Table 2, the ee is <90% in the
absence of the R-alkyl substituent.
JA994121E
(12) The corresponding n-Bu amide may be used equally effectively instead
of the Gly derivative within the chiral ligand.
(13) Loss of the minor enantiomer (∼3%) is presumably achieved in the
crystallization of the amino acid.