Practical and highly enantioselective synthesis of β-alkynyl-β- amino esters through Ag-catalyzed asymmetric Mannich reactions of silylketene acetals and alkynyl imines

Article abstract of DOI:10.1021/ol050910r

(Chemical Equation Presented) A readily available iso-leucine-based phosphine ligand is used to promote Ag-catalyzed Mannich reactions between silylketene acetals and various alkynyl imines. Reactions can be effected in the presence of 5 mol % catalyst, w

Full text of DOI:10.1021/ol050910r

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2711-2713
Practical and Highly Enantioselective
Synthesis of -Alkynyl- -amino Esters
â
â
through Ag-Catalyzed Asymmetric
Mannich Reactions of Silylketene
Acetals and Alkynyl Imines
Nathan S. Josephsohn, Emma L. Carswell, Marc L. Snapper,* and
Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
amir.hoVeyda@bc.edu
Received April 25, 2005
ABSTRACT
A readily available iso-leucine-based phosphine ligand is used to promote Ag-catalyzed Mannich reactions between silylketene acetals and
various alkynyl imines. Reactions can be effected in the presence of 5 mol % catalyst, without the need for rigorous exclusion of air, and with
commercially available solvents (without purification) to afford the desired
â-alkynyl-â-amino esters in 84−94% ee and 61−91% isolated yield.
â-Amino acids and derivatives constitute an important class
of organic molecules critical to the preparation of a variety
of biologically significant molecules.1 Accordingly, in recent
years a number of efforts have focused on the development
of efficient and stereoselective methods that allow access to
such compounds.1 In terms of related catalytic asymmetric
methods, enantioselective hydrogenations of â-amino acry-
lates2 and conjugate additions of N-based nucleophiles to
unsaturated carbonyls3 have been introduced. Moreover,
several investigations have been concerned with catalytic
asymmetric additions of different enolate equivalents to
imines (Mannich reactions).4
Although significant advances in the development of
methods for the synthesis of â-amino esters have occurred,
a number of challenges in connection with substrate general-
(2) For recent examples, see: (a) Tang, W.; Zhang, X. Org. Lett. 2002,
4, 4159-4161. (b) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang,
X. J. Am. Chem. Soc. 2002, 124, 4952-4953. (c) Tang, W.; Wang, W.;
Chi, Y.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 3509-3511. (d) Hsiao,
Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.;
Armstrong, J. D.; Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan,
C. J. Am. Chem. Soc. 2004, 126, 9918-9919.
(3) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959-
8960. (b) Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem., Int.
Ed. 2000, 39, 3635-3638. (c) Sibi, M. P.; Asano, Y. J. Am. Chem. Soc.
2001, 123, 9708-9709. (d) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc.
2002, 124, 2134-2136. (e) Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.;
Jasperse, C. P. J. Am. Chem. Soc. 2003, 125, 11796-11797.
(1) For related reviews, see: (a) EnantioselectiVe Synthesis of â-Amino
Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997. (b) Ma, J.-A. Angew.
Chem., Int. Ed. 2003, 42, 4290-4299. (c) Kleinmann, F. F. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: New York, 1991; Vol. 2, Chapter 4.1. (d) Cardillo, G.; Tomasini,
C. Chem. Soc. ReV. 1996, 117-128. (e) Juaristi, E.; Lopez-Ruiz, H. Curr.
Med. Chem. 1999, 6, 983-1004. (f) Beddow, J. E.; Davies, S. G.; Smith,
A. D.; Russell, A. J. Chem. Commun. 2004, 2778-2779 and references
therein.
(4) For examples of catalytic asymmetric Mannich reactions with ester-
derived nucleophiles and nonactivated imines, see: (a) Isgitani, H.; Ueno,
M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119, 7153-7154. (b) Xue, S.;
Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2001, 40, 2271-
2274. (c) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
12964-12965. (d) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jorgensen,
K. A. J. Org. Chem. 2003, 68, 2583-2591. (e) Akiyama, T.; Itoh, J.; Yokota,
K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566-1568. (f) Cozzi,
P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, ASAP.
10.1021/ol050910r CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/26/2005

ity persist. Regarding catalytic asymmetric Mannich reac-
tions, one critical issue arises from the fact that nearly all
the investigations to date have focused on transformations
that deliver â-amino esters that bear a â-ester5,6 or a â-aryl
group4 (reactions of imines derived from aromatic aldehydes).
There are only a few cases where R,â-unsaturated imines
are used, and methods that yield â-alkyl amino esters are
relatively scarce, particularly those that deliver high enan-
tioselectivities (>90% ee).6,7 Finally, to the best of our
knowledge, none of the catalytic asymmetric methods
disclosed so far deliver â-alkynyl-â-amino esters.8
to 94% ee; optically enriched amino esters are readily
converted to a number of synthetically useful derivatives
(e.g., â-alkyl-â-amino esters). The Ag-catalyzed transforma-
tion requires a chiral phosphine ligand (1) that can be easily
prepared from commercially available materials, including
an inexpensive amino acid (iso-Leu). Moreover, the enan-
tioselective processes can be carried out in air without the
need for purified solvent.
As summarized in Scheme 1, we recently disclosed an
Scheme 1. Ag-Catalyzed Enantioselective Synthesis of
â-Amino Ketones
As the data summarized in Table 1 indicate, Ag-catalyzed
addition of silylketene acetal 3 to a wide range of alkynyl
imines (2a-h) proceeds smoothly at -60 °C to afford
â-amino esters 4a-h in 61-91% isolated yield and 84-
94% ee (>98% conversion in all cases). It is noteworthy
that the Ag-catalyzed protocol is equally efficient and
enantioselective with alkynyl imines that bear silyl (entry
1), aryl (entries 2-4), alkyl (entries 5, 6, and 8) and alkenyl
(entry 7) substituents.
efficient Ag-catalyzed method for enantioselective addition
of silyl enol ethers to a variety of imines to afford the desired
â-amino ketones in high enantioselectivity (typically >90%
ee).9 One notable attribute of the above protocol is that it is
not limited to reactions of aryl imines; alkyl, alkenyl, and
alkynyl imines can be used as well.
Table 1. Ag-Catalyzed Enantioselective Mannich Reaction of
Silylketene Acetal 3 to Alkynyl Imines 2a-h
On the basis of such recent advances, and considering the
above-mentioned methodological deficiencies, we set out to
establish whether the catalytic system depicted in Scheme 1
can be used to effect catalytic asymmetric Mannich reactions
between nonaryl imines and silylketene acetals.
Herein, we report a highly efficient Ag-catalyzed enantio-
selective method for the addition of silylketene acetals to a
variety of alkynyl imines (eq 1). The catalytic asymmetric
protocol delivers the desired â-alkynyl-â-amino esters in up
(5) For representative examples of metal-catalyzed asymmetric Mannich
reactions involving glyoxylate-derived imines, see: (a) Ferraris, D.; Young,
B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548-4549. (b)
Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450-
5458. (c) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338-
339. (d) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura,
M. J. Am. Chem. Soc. 2003, 125, 2507-2515. (e) Uraguchi, D.; Terada,
M. J. Am. Chem. Soc. 2004, 126, 5356-5357. (f) Ooi, T.; Kameda, M.;
Fujii, J.; Maruoka, K. Org. Lett. 2004, 6, 2397-2399.
(6) For examples of Mannich reactions promoted by chiral organic
catalysts, see: (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am.
Chem. Soc. 2002, 124, 827-833. (b) Notz, W.; Tanaka, F.; Barba, C. F.
Acc. Chem. Res. 2004, 37, 580-591. (c) Cordova, A. Chem. Eur. J. 2004,
10, 1987-1997.
(7) (a) Kobayashi, S.; Kobayashi, J.; Ishiani, H.; Ueno, M. Chem. Eur.
J. 2002, 8, 4185-4190. (b) Matsunaga, S.; Yoshida, T.; Morimoto, H.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8777-8785.
(8) For an example of a noncatalytic enantioselective synthesis of a
â-alkynyl-â-amino ester, see: Saito, S.; Hatanaka, K.; Yamamoto, H. Org.
Lett. 2000, 2, 1891-1894.
a Isolated yields after silica gel chromatography; all reactions proceeded
to >98% conversion, based on 400 MHz 1H NMR analysis. b Determined
by chiral HPLC analysis; see Supporting Information for details. c Reaction
times are 36 h.
(9) For other Ag-catalyzed asymmetric reactions promoted in the presence
of phosphine 1, see: (a) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2003, 125, 4018-4019. (b) Josephsohn, N. S.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734-
3735.
Our investigation focused on transformations with phenyl
ester 3 for several reasons: (a) Initial studies indicated that
other ester derivatives (e.g., tert-butyl esters) undergo
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Org. Lett., Vol. 7, No. 13, 2005

efficient addition but in lower enantioselectivity (see Scheme
2 for an example). (b) Preparation of silylketene acetal 3 is
removal of the N-activating group is effected oxidatively
through a procedure developed in these laboratories,10
concomitant with installment of an amide unit. In a similar
fashion, as also depicted in Scheme 2, oxidative removal of
the anisidyl unit of 4b (94% ee) in the presence of activated
optically pure amino acid 7 leads to the formation of 8 in
73% yield and >98% ee after silica gel chromatography.
Synthesis of tert-butyl ester 10, which proceeds in 61%
isolated yield to afford the desired product in >98% ee, is
noteworthy for two reasons. (a) It provides an illustration of
the lower enantioselectivity of Ag-catalyzed reactions in-
volving silylketene acetals of alkyl esters (72 vs 94% ee
obtained with ketene acetal 3). (b) The oxidative conditions
used for the removal of the anisidyl unit are compatible with
an acid-sensitive group such as a tert-butyl ester. Optically
enriched â-amino esters that contain a â-alkyne group can
serve as versatile building blocks in the synthesis of
biologically active molecules.11
Scheme 2. One-Pot Removal of N-Activating Group and
Subsequent Functionalization
In summary, we have developed an efficient Ag-catalyzed
method for enantioselective synthesis of â-alkynyl-â-amino
acids, a class of compounds that cannot be accessed by other
catalytic enantioselective Mannich protocols. The optically
enriched (84-94% ee) products obtained can be function-
alized in a number of ways to afford a range of useful
â-amino esters. Hydrogenation of the alkyne group delivers
difficult-to-access â-alkyl-â-amino esters. Removal of the
N-activating group can be effected en route to optically
enriched unprotected â-amino esters or, alternatively, after
in situ coupling with activated esters, to a variety of amides.
Future studies will focus on the development of other
catalytic asymmetric Mannich reactions and related applica-
tions to the synthesis of biologically significant molecules.
typically more convenient and efficient than ketene acetals
derived from alkyl esters (vs phenyl ester). (c) Phenyl esters
can be more readily converted to a variety of other esters.
(d) Preliminary screening indicated that catalytic asymmetric
additions with tert-butyl(dimethyl)silylketene acetals afford
significantly lower enantioselectivities (<50% ee).
Acknowledgment. This paper is dedicated to Professor
Richard R. Schrock on the occasion of his 60th birthday.
Financial support was generously provided by the NIH (GM-
57212). N.S.J. is grateful to Schering-Plough Research
Institute for a graduate fellowship.
Next, we examined several key functionalizations that may
be carried out with optically enriched â-alkynyl amino esters.
Thus, as illustrated by the example in eq 2, Pd-catalyzed
hydrogenation of 4d (obtained in 92% ee) leads to the
formation of â-amino ester 5 in 84% isolated yield after silica
gel chromatography. It is important to note that, under the
conditions outlined in Table 1, imines derived from aliphatic
aldehydes do not provide the desired product in the presence
Supporting Information Available: Experimental and
analytical data for substrates and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050910R
1
of silylketene acetal 3 (<2% conversion by 400 MHz H
(10) (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 10409-10410. (b) Akullian, L. C.; Snapper,
M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4244-4247. (c)
Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Org. Lett. 2003, 5, 3273-
3275.
NMR analysis).
(11) For example, see: (a) Zablocki, J. A.; Rico, J. G.; Garland, R. B.;
Rogers, T. E.; Williams, K.; Schretzman, L. A.; Rao, S. A.; Bovy, P. R.;
Tjoeng, F. S.; Lindmark, R. J.; Toth, M. V.; Zupec, M. E.; McMakins, D.
E.; Adams, S. P.; Miyano, M.; Markos, C. S.; Milton, M. N.; Paulson, S.;
Herin, M.; Jacmin, P.; Nicholson, N. S.; Panzer-Knodle, S. G.; Haas, N.
F.; Page, J. D.; Szalony, J. A.; Taite, B. B.; Salyers, A. K.; King, L. W.;
Campion, J. G.; Feigen, L. J. Med. Chem. 1995, 38, 2378-2394. (b) Cossy,
J.; Schmitt, A.; Cinquin, C.; Buisson, D.; Belotti, D. J. Med. Chem. Lett.
1997, 7, 1699-1700.
As demonstrated by preparation of Boc-protected â-amino
ester 6 from 4b (68% isolated yield), shown in Scheme 2,
Org. Lett., Vol. 7, No. 13, 2005
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