A highly enantioselective route to either enantiomer of both α- and β-amino acid derivatives

Article abstract of DOI:10.1021/ja017833p

This report describes the unprecedented use of unmodified aldehydes as donors in a catalytic asymmetric Mannich-type reaction. The proline-catalyzed reaction of N-PMP-protected α-imino ethyl glyoxylate with unmodified aliphatic aldehydes provided a genera

Full text of DOI:10.1021/ja017833p

Published on Web 02/08/2002
A Highly Enantioselective Route to Either Enantiomer of Both r- and â-Amino
Acid Derivatives
Armando Co´rdova, Shin-ichi Watanabe, Fujie Tanaka, Wolfgang Notz, and Carlos F. Barbas, III*
The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received December 20, 2001
Scheme 1. Synthesis of â-Amino Carbonyl Compounds and
The Mannich reaction is a classic method for the preparation of
â-amino ketones and aldehydes and therefore a very important
carbon-carbon bond-forming reaction in organic synthesis. The
versatility and potential to create both functional and structural
diversity using this reaction have long stimulated the creativity of
chemists. For example, it has been employed numerous times
successfully as a key step in natural product synthesis as well as
medicinal chemistry.1
Derivatives Based on Mannich Reactions of Aldehydes with Imines
Scheme 2. Further Modifications of 3-Formyl-R-L-amino Acid 1a
The intense demand for stereoselective transformations encom-
passed in modern drug development has led to a number of
asymmetric versions of this type of transformation. The first
diastereoselective methods reported employed the addition of
preformed enolates to preformed imines using stoichiometric
amounts of chiral auxiliaries.2 Only recently, the first examples of
catalytic asymmetric additions of enolates to imines were reported.3
One disadvantage of these reactions is the preparation and stability
of the preformed enolates used. A significant advance was achieved
when unmodified ketones were used in these catalytic asymmetric
versions rather than preformed enolates to provide chiral â-amino
ketones.4 To date, however, no other unmodified donor has been
used in a direct catalytic enantioselective Mannich-type reaction.
In this context, the extension to aldehyde donors would be of
particular interest,5 since, in combination with amino acid catalysis,
it would provide facile access to either enantiomer of â-amino acids,
â-lactams, as well as â-amino alcohol derivatives (Scheme 1).1b
On the basis of our previous research,4a,6 we became interested
in whether enamine intermediates formed from aliphatic aldehydes
might serve as nucleophiles in a stereoselective, amino acid-
catalyzed Mannich-type addition to imines.7 Herein, we disclose
the successful, unprecedented use of unmodified aldehydes in direct
catalytic asymmetric Mannich-type reactions with R-imino ethyl
glyoxylate as an acceptor to form aldehyde-substituted R-amino
acids with excellent diastereo- and enantioselectivities.
a Reagents and Conditions: (a) i: NaClO2, KH2PO4, 2-methyl-2-butene,
t-BuOH/H2O; ii: CH2N2, Et2O, 89% two steps; (b) LHMDS, THF, -20
°C, 96%; (c) i: LiOH, Dioxane/H2O; ii: CH2N2, Et2O, 92% two steps.
To broaden the scope of this transformation, a number of aliphatic
aldehydes were reacted with N-PMP-protected R-imino ethyl
glyoxylate10 under these reaction conditions to afford â-formyl
functionalized amino acids 1-7 (Table 1). In all cases, the reaction
proceeded smoothly with excellent enantioselectivities. Higher
diastereoselectivities were achieved with increased bulkiness of the
substituents on the aldehyde donor in the order of R ) Me < Et <
i-Pr < n-Pent. Significantly, in the case of aldehydes with a chain
length longer than five carbon atoms (entries 4-7, Table 1), one
diastereomer was formed predominantly (dr > 19:1) as determined
by 1H NMR.11 This result constitutes an excellent entry into
sterically demanding amino acid derivatives. For example, R-amino
acid 6 was obtained as a single product with complete stereocontrol
in 89% yield. It is noteworthy that these reactions proceed efficiently
with only 1.5 equiv of aldehyde donor. For example, 1 could be
obtained in gram quantities from a single reaction. Furthermore,
the catalyst loading could be reduced to as low as 5% without
diminishing the efficiency of the catalytic process. This is a
significant improvement over our previous reports of ketones as
donors in Mannich reactions4a and aldehydes as donors in Michael-
type reactions.7a
In an initial experiment, isovaleraldehyde (0.2 M), N-PMP-
protected R-imino ethyl glyoxylate8 (0.1 M), and L-proline (10 mol
%) were stirred in DMSO at room temperature. After 8 h the imine
was consumed and the only detectable product was the â-formyl
functionalized leucine derivative 1, which could be isolated in 80%
yield, with dr > 10:1 and 87% ee (eq 1).
These Mannich products are versatile synthons for other syntheti-
cally valuable building blocks. For example, the aldehyde group
of the Mannich product 1 can be readily oxidized (NaClO2) and
subsequently esterified (CH2N2) to afford the aspartic acid derivative
8 without loss of the ee and dr (Scheme 2).
Base-promoted cyclization12 of amino acid 8 by means of
LHMDS provided the carbapenem antibiotic PS-6 precursor 913 in
excellent yield. 1H NMR analysis of 9 and 10 revealed a cis
relationship of the vicinal methine protons at C-3 and C-4 based
Next, we performed a solvent screen under the same reaction
conditions and were pleased to find that the yields, diastereoselec-
tivities, and enantioselectivities of 1 were comparable in all the
solvents investigated, with dioxane providing the highest ee of 1
(ee ) 93%).9
3
on their vicinal coupling constant J3,4 ≈ 5.9 Hz.13 The absolute
stereochemistry of 9 was determined to be (3S,4S) based on
synthesis and comparison to the known R-alkyl-â-lactam 1014 via
an efficient hydrolysis/esterification protocol. Thus, L-proline
9
1866 VOL. 124, NO. 9, 2002 J. AM. CHEM. SOC.
10.1021/ja017833p CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Products from the Proline-Catalyzed Mannich Reaction
of Unmodified Aldehydes with N-PMP-Protected R-Imino Ethyl
Glyoxylate
Supporting Information Available: Complete analytical data for
all new compounds (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For review, see: (a) Kleinmann, E. F. In ComprehensiVe Organic
Synthesis; Trost, B. M.; Flemming, I., Eds.; Pergamon Press: New York,
1991; Vol. 2, Chapter 4.1. (b) Arend, M.; Westermann, B.; Risch, N.
Angew. Chem., Int. Ed. 1998, 37, 1044. (c) Kobayashi, S.; Ishitani, H.;
Chem. ReV. 1999, 99, 1069. (d) Denmark, S.; Nicaise, O. J.-C. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamomoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, 93. (d) For examples,
see: EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.;
Weinheim, 1997.
(2) See: (a) Palomo, C.; Oiarbide, M.; Gonzales-Rego, M. C.; Sharma, A.
K.; Garcia, J. M.; Landa, C.; Linden, A. Angew. Chem., Int. Ed. 2000,
39, 1063. (b) Enders, D.; Ward, D.; Adam, J.; Raabe G. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 981. (d) Corey, E. J.; Decicco, C. P.; Newbold,
R. C. Tetrahedron Lett. 1991, 39, 5287. (e) Seebach, D.; Betschart, C.;
Schiess, M. HelV. Chim. Acta 1984, 67, 1593. Evans, D. A.; Urpi, F.;
Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am. Chem. Soc. 1990,
112, 8215. (f) Arend, M.; Risch, N. Angew. Chem., Int. Ed. Engl. 1995,
34, 2639. (g) Kober, R.; Papadopoulos, K.; Miltz, W.; Enders, D.; Steglich,
W.; Reuter, H.; Puff, H. Tetrahedron 1985, 42, 1693.
(3) (a) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121,
5450. (b) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000,
122, 8180. (c) Ishihara, K.; Miyata, M.; Hattori, K.; Yamamoto, H. J.
Am. Chem. Soc. 1994, 116, 10520. (d) Ishitani, H.; Ueno, M.; Kobayashi,
S. J. Am. Chem. Soc. 1997, 119, 2060. (e) Ferraris, D.; Yong, B.; Dudding,
T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548. (f) Ferraris, D.; Young,
B.; Cox, C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi, A. E.;
Lectka, T. J. Am. Chem. Soc. 2002, 124, 67. (g) Kobayashi, S.; Matsubara,
R.; Kitagawa, H. Org. Lett. 2002, 4, 143.
(4) (a) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III
Tetrahedron Lett. 2001, 42, 199. (b) Juhl, K.; Gathergood, N.; Jorgensen,
K. A. Angew Chem., Int. Ed. 2001, 40, 2995. (c) Yamasaki, S.; Iida, T.;
Shibasaki, M. Tetrahedron 1999, 55, 8857. (d) List, B. J. Am. Chem.
Soc. 2000, 122, 9336. (e) Co´rdova, A.; Notz, W.; Zhong, G.; Betancort,
J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, ASAP.
(5) There have been reports of noncatalytic diastereoselective Mannich-type
reactions of enamines derived from aldehydes with ternary iminium salts.
See: (a) ref 1b. (b) Risch, N. Arend, M. Angew. Chem., Int. Ed. Engl.
1994, 33, 2422.
(6) (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000,
122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am.
Chem. Soc. 2001, 123, 5260. (c) Bui, T.; Barbas, C. F., III Tetrahedron
Lett. 2000, 41, 6951. (d) Betancort, J. M.; Sakthivel, K.; Thayumanavan,
R.; Barbas, C. F., III Tetrahedron Lett. 2001, 42, 4441.
(7) Such enamines were used successfully in Michael reactions and the self-
aldolization of acetaldehyde. See: (a) Betancort, J. M.; Barbas, C. F., III
Org. Lett. 2001, 3, 3737. (b) Co´rdova, A.; Notz, W.; Barbas, C. F., III J.
Org. Chem. 2002, 67, 301.
a PMP ) p-methoxyphenyl. b Yields of isolated pure product after column
chromatography. In a typical experiment, N-PMP-protected R-imino ethyl
glyoxylate (0.5 mmol) was dissolved in anhydrous dioxane (Vtot ) 5 mL),
the corresponding aldehyde donor (0.75 mmol) was added followed by
L-proline (5 mol %) and the mixture was stirred for 2-24 h at room
temperature. Following aqueous workup with half-saturated ammonium
chloride solution and extraction with ethyl acetate, the organic layer was
dried (MgSO4), filtered, and concentrated and the residue purified by column
chromatography (silica, hexanes/ethyl acetate mixtures) to afford the
corresponding Mannich addition product. c dr ) syn/anti as determined by
NMR after column chromatography. d The ee values of products 1-7 were
determined by chiral-phase HPLC analysis. e dr ) syn/anti as determined
by NMR of the crude product after extraction.
(8) The imine was prepared according to Juhl et al. See ref 4b.
(9) EtOAc: 75% yield, dr > 10:1, 88% ee; Dioxane: 81% yield, dr > 10:1,
93% ee; CHCl3: 62% yield, dr > 10:1, 74% ee; THF: 79% yield, dr >
10:1, 88% ee; Ether: 70% yield, dr > 10:1, 80% ee. The reactions were
also performed at 4 °C in THF (75% yield, dr > 10:1 dr, 92% ee) and
dioxane (82% yield, dr > 10:1, 96% ee).
catalyzes a si-facial attack to the imine by an aldehyde enamine
intermediate and provides L-amino acids with syn stereochemistry.
This result is in accordance with the previously proposed transition
states for proline-catalyzed Mannich reactions with ketones.4a,d
In conclusion, for the first time unmodified aldehydes were
successfully used as donors in catalytic asymmetric Mannich-type
reactions. We showed that the proline-catalyzed reaction of N-PMP-
protected R-imino ethyl glyoxylate with aldehydes provides a highly
enantioselective entry to functional amino acids, â-lactam anti-
biotics,15 and serine protease inhibitors16 and the corresponding
products 1-7 were obtained in high yields and excellent diastereo-
selectivities. In addition, the number of different functionalities
present in the products allows for a large variety of further chemical
modifications. As demonstrated for derivatives 8-10, our products
can be efficiently converted into pharmaceutically valuable syn-
thons. Moreover, our methodology is atom-economic, starts with
achiral, readily available and inexpensive materials, and provides
a facile route to either enantiomer of both R-amino acid and â-amino
acid derivatives with high stereocontrol. Further research addressing
the scope and applicability of this methodology is currently under
investigation.
(10) n-PMP aldimines preformed from benzaldehyde or p-nitrobenzaldehyde
did not afford the Mannich products under these conditions.
(11) 1H NMR of the crude reaction mixture showed a diastereomeric ratio of
>19:1 and complete conversion of the imine. We observed that the
Mannich products are unstable if stored at room temperature and prone
to epimerization during silica gel column chromatography, which decreases
the diastereomeric ratio and provides the other diastereoisomer in excellent
ee (>98%). The Mannich products can be stored in solution (EtOAc) at
-25 °C without decomposition, epimerization and loss of ee.
(12) (a) Guanti, G.; Narisano, E.; Banfi, L. Tetrahedron Lett. 1987, 28, 4331.
(b) Gennari, C.; Venturini, I.; Gislon, G.; Schimperna, G. Tetrahedron
Lett. 1987, 28, 227.
(13) (a) Manhas, M. S.; Ghosh, M.; Bose, A. K. J. Org. Chem. 1990, 55, 575.
(b) Greff, Z.; Horvath, Z.; Nyitrai, J.; Kajtar-Peredy, M.; Brlik, J. J. Chem.
Research 1990, S, 170. (c) Greff, Z.; Horvath, Z.; Nyitrai, J.; Kajtar-
Peredy, M.; Brlik, J. J. Chem. Research 1990, M, 1201.
(14) Palomo, C.; Aizpurua, J. M.; Gracenea, J. J.; Garcia-Granada, S.; Pertierra,
P. Eur. J. Org. Chem. 1998, 2201, 1. [R]D ) -95 (c ) 0.5, CH2Cl2); lit.
[R]D ) -108.7 (c ) 1.0, CH2Cl2).
(15) (a) Palomo, C. In Recent Progress in the Chemical Synthesis of Antibiotics
and Related Microbial Products; Lukacs, G., Ohno, M., Eds.; Springer:
Berlin, 1990; Vol. 1, p 565. (b) Kant, J.; Walker, D. G. In The Organic
Chemistry of â-Lactams; Page, M. I., Ed.; VCH: New York, 1993; p 121.
(16) (a) Firestone, R. A.; Barker, P. L.; Pisano, J. M.; Ashe, B. M.; Dahlgren,
M. E. Tetrahedron 1990, 46, 2255. (b) Magriotis, P. A. Angew. Chem.,
Int. Ed. 2001, 40, 4377. (c) Edwards, P. D.; Bernstein, P. R. Med. Res.
ReV. 1994, 14, 127. (d) Mascaretti, O. A.; Boschetti, C. E.; Danelon, G.
O.; Mata, E. G.; Roveri, O. A. Current Med. Chem. 1995, 1, 441.
Acknowledgment. This study was supported in part by the NIH
(CA27489) and the Skaggs Institute for Chemical Biology. We
thank Dr. J. M. Betancort for helpful discussions.
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