Asymmetric synthesis of beta-substituted alpha-methyl-beta-amino esters by Mannich reaction of (S,S)-(+)-pseudoephedrine acetamide derived enolate with imines.

Article abstract of DOI:10.1021/ol0155384

[reaction: see text]. The reaction of an (S,S)-(+)-pseudoephedrine acetamide based enolate with several imines afforded smoothly and with full stereochemical control a series of beta-substituted alpha-methyl-beta-aminoamides that upon hydrolysis/esterific

Full text of DOI:10.1021/ol0155384

ORGANIC
LETTERS
2001
Vol. 3, No. 5
773-776
Asymmetric Synthesis of â-Substituted
r-Methyl-â-amino Esters by Mannich
Reaction of (S,S)-(+)-Pseudoephedrine
Acetamide Derived Enolate with Imines
Jose L. Vicario, Dolores Bad´ıa,* and Luisa Carrillo
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencias, UniVersidad del Pa´ıs
Vasco-Euskal Herriko Unibertsitatea, P.O. Box E-644, 48080 Bilbao, Spain
qopbaurm@lg.ehu.es
Received January 9, 2001
ABSTRACT
The reaction of an (S,S)-(+)-pseudoephedrine acetamide based enolate with several imines afforded smoothly and with full stereochemical
control a series of â-substituted r-methyl-â-aminoamides that upon hydrolysis/esterification afforded the corresponding â-aminoester derivatives
in good yields and in almost enantiomerically pure form.
Chiral â-amino acids, although less abundant than their
R-counterparts, are important components of numerous
natural products and therapeutic agents1 (e.g., taxol side
chain), and they are also key precursors in the synthesis of
â-lactam antibiotics.2 Furthermore, the substitution of R-ami-
no acids for â-amino acids in biologically active peptides
has also been used very recently as a promising tactic to
prepare peptide analogues with increased potency and
enzymatic stability. For these reasons, the asymmetric
synthesis of â-amino acid derivatives with different substitu-
tion patterns at the carbon chain has become a field of
increasing interest in synthetic organic chemistry during the
past few years.3 Among the different methodologies found
in the literature for this purpose, one of the most widely used
is the nucleophilic addition of an enolate across a CdN bond
of an imine or related species.4 In this context, the strategies
employed to exert stereocontrol in the newly created chiral
centers involve the introduction of the chiral information at
the imine5 the enolate6 or by incorporating chiral ligands in
the reaction medium either in a stoichiometric7 or catalytic8
way.
If we assume that an enolate with one substituent at the
R-possition and with a determined geometry (E or Z)
undergoes a Mannich reaction with an imine, four possible
estereoisomers can be formed (Figure 1). Under kinetic
conditions, the stereochemistry of the first chiral center would
be controlled by the approach of the imine from one of the
two diastereotopic faces of the enolate (the so-called enan-
(1) See, for example: (a) Drey, C. N. C. In Chemistry and Biochemistry
of Amino Acids; Barret, G. C., Ed.; Chapman and Hall: London, New York,
1985. (b) Spatola, A. F. In Chemistry and Biochemistry of Amino Acids,
Peptides and Proteins; Weinstein, B., Ed.; Wiley & Sons: New York, 1983.
(2) For reviews, see: (a) van der Steen, F. H.; van Koten, G. Tetrahedron
1991, 47, 7503. (b) Brown, M. J. Heterocycles 1989, 29, 2225. (c) Hart, D.
J.; Ha, D.-C. Chem. ReV. 1989, 89, 1447.
(3) For some reviews, see: (a) Cardillo, G.; Tomasini, C. Chem. Soc.
ReV. 1996, 117. (b) Cole, D. C. Tetrahedron 1994, 50, 9517. See also: (c)
EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997.
Figure 1.
10.1021/ol0155384 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/06/2001

tiofacial differenciation or diastereofacial selectivity) and
therefore by the presence of the chiral information attached
to the enolate.9 The stereochemistry of the second chiral
center would be controlled by the approach of the imine from
one of its two enantiotopic faces (named as simple diaste-
reoselection) and therefore by the steric requirements derived
from a cyclic transition state such as a Zimmermann-
Traxler-like or related mechanism.10 The main target when
planning a Mannich reaction is to achieve complete stereo-
control in both of the aforementioned aspects, thus allowing
the preparation of a single isomer from the four possible
ones.
which (S,S)-(+)-pseudoephedrine acetamide based enolates
smoothly reacted with several aldehydes, yielding the cor-
responding R,â-disubstituted â-hydroxy acid derivatives in
an almost enantiomerically pure form. A further advantage
of this methodology is that the amide aldol adducts can be
derivatized to a wide range of other synthetically useful chiral
synthons and that the auxiliary can be easily removed and
recovered.12 With these results in mind and in connection
with our research in the field of asymmetric synthesis,13 we
report herein the further extension of the aforementioned
methodology to the reaction of enolates with imines, which
has provided access to chiral nonracemic R,â-disubstituted
â-amino acid derivatives.
In a previous paper11 we have reported a very efficient
procedure for performing asymmetric aldol reactions in
Propionamide 1 was deprotonated with 2 equiv of LDA,
and the dianion formed was reacted with several p-anisidine-
based imines, leading to the desired â-aminoamides in good
yields after flash column chromatography purification (Scheme
1).14
(4) Recent reviews: Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99,
1069 (b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Enders, D.; Reinhold,
U. Tetrahedron: Asymmetry 1997, 8, 1895.
(5) (a) Mu¨ller, R.; Ro¨ttele, H.; Henke, H.; Waldmann, H. Chem. Eur. J.
2000, 6, 2032. (b) Kawecki, R. J. Org. Chem. 1999, 64, 8724. (c) Liu, G.;
Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem.
1999, 64, 1278. (d) Higashiyama, K.; Kyo, H.; Takahashi, H. Synlett 1998,
489. (e) Guenoun, F.; Zair, T.; Lamaty, F.; Pierrot, M.; Lazaro, R.;
Viallefont, P. Tetrahedron Lett. 1997, 38, 1563. (f) Kunz, H.; Burgard, A.;
Schanzenbach, D. Angew. Chem., Int. Ed. Engl. 1997, 36, 386. (g) Cainelli,
G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G. Tetrahedron 1996,
52, 1685. (h) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett.
1996, 37, 3881. (i) Cozzi, P. G.; di Simone, B.; Umani-Ronchi, A.
Tetrahedron Lett. 1996, 37, 1691. (j) van Maanen, H. L.; Kleijn, H.;
Jastrzebski, J. T. B. H.; Verweij, J.; Kieboom, A. P. G.; van Koten, G. J.
Org. Chem. 1995, 60, 4331. (k) Matsumura, Y.; Tomita, T. Tetrahedron
Lett. 1994, 35, 3737. (l) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi,
F.; Raimondi, L. Tetrahedron Lett. 1993, 34, 6921. (m) Davis, F. A.; Reddy,
R. T.; Teddy, R. E. J. Org. Chem. 1992, 57, 6387. (n) Andre´s, C.; Gonza´lez,
A.; Pedrosa, R.; Pe´rez-Encabo, A. Tetrahedron Lett. 1992, 33, 2895. (o)
Brown, M. J.; Overman, L. E. J. Org. Chem. 1991, 56, 1933.
Scheme 1a
a (i) 1. LDA, LiCl, THF, -78 °C; 2. RCHdNPMP, THF, 0 °C.
(6) (a) Palomo, C.; Oiarbide, M.; Gonza´lez-Rego, C.; Sharma, A. K.;
Garc´ıa, J. M.; Gonza´lez, A.; Landa, C.; Linden, A. Angew. Chem., Int. Ed.
2000, 39, 1063. (b) Kawakami, T.; Ohtake, H.; Arakawa, H.; Okachi, T.;
Imada, Y.; Murahashi, S.-I. Org. Lett. 1999, 1, 107. (c) Bravo, P.; Fustero,
S.; Guidetti, M.; Volonterio, A.; Zanda, M. J. Org. Chem. 1999, 64, 8731.
(d) Barbaro, G.; Battaglia, A.; Guerrini, A.; Bertucci, C. J. Org. Chem.
1999, 64, 4643. (e) Enders, D.; Ward, D.; Adam, J.; Raabe, G. Angew.
Chem., Int. Ed. Engl. 1996, 35, 981. (f) Shimizu, M.; Teramoto, Y.;
Fujisawa, T. Tetrahedron Lett. 1995, 36, 729. (g) Braun, M.; Sacha, H.;
Galle, D.; El-Alali, A. Tetrahedron Lett. 1995, 36, 4213. (h) Oppolzer, W.;
Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 5603. (i) Nagao, Y.;
Dai, W.-M.; Ochiai, M. Tetrahedron Lett. 1988, 29, 6133. (j) Gennari, C.;
Venturini, I.; Gislon, G.; Schimperna, G. Tetrahedron Lett. 1987, 28, 227.
(k) Liebeskind, L. S.; Welker, M. E.; Goedken, V. J. Am. Chem. Soc. 1984,
106, 441. (l) Gluchowski, C.; Cooper, L.; Bergbreiter, D. E.; Newcomb,
M. J. Org. Chem. 1980, 45, 3413.
(7) (a) Fujieda, H.; Janai, M.; Kambara, T.; Iida, A.; Tomioka, K. J.
Am. Chem. Soc. 1997, 119, 2060. (b) Soloshonok, V. A.; Avilov, D. V.;
Kukhar, V. P.; van Meervelt, L. Mischenko, N. Tetrahedron Lett. 1997,
38, 4671. (c) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Molteni,
V.; Raimondi, L. Tetrahedron 1995, 51, 8941. (d) Ishihara, K.; Miyata,
M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
10520. (e) Corey, E. J.; Decicco, C. P.; Newbold, R. C. Tetrahedron Lett.
1991, 32, 5287.
(8) For a review, see: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999,
99, 1069. See also: (b) Arend, M. Angew. Chem., Int. Ed. 1999, 38, 2873
and references therein. (c) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am.
Chem. Soc. 1999, 121, 5450. (d) Yamada, K.; Harwood, S. J.; Gro¨ger, H.;
Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 3504. (e) Martin, S. F.;
Lopez, O. D. Tetrahedron Lett. 1999, 40, 8949. (f) Ferraris, D.; Young,
B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548. (g)
Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431.
(9) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 3, Part B, Chapter 2.
(10) (a) Bernardi, A.; Gennari, C.; Raimondi, L.; Villa, M. B. Tetrahderon
1997, 53, 7705. (b) Ha, D.-C.; Hart, D. J.; Yang, T.-K. J. Am. Chem. Soc.
1984, 106, 4819. (c) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc.
1957, 79, 1920.
In all cases, the reaction proceeded with extremely high
simple (anti/syn ratio >99:1, Table 1) and facial (2/3 ratio
>99:1, Table 1) diastereoselection, and amides 2a-e were
obtained as one diastereoisomer out of the four possible ones,
attending to the configuration of the two newly created chiral
centers, which was verified by HPLC analysis of the crude
reaction mixtures under conditions previously optimized for
(12) For the use of (S,S)-(+)-pseudoephedrine as chiral auxiliary, see:
(a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496. (b) Myers, A. G.;
Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1997, 119, 656.
(c) Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.
(13) (a) Vicario, J. L.; Bad´ıa, D.; Dom´ınguez, E.; Carrillo, L. Tetrahe-
dron: Asymmetry 2000, 11, 3779. (b) Carrillo, L.; Bad´ıa, D.; Dom´ınguez,
E.; Anakabe, E.; Osante, I.; Tellitu, I.; Vicario, J. L. J. Org. Chem. 1999,
64, 1115. (c) Vicario, J. L.; Bad´ıa, D.; Dom´ınguez, E.; Carrillo, L. J. Org.
Chem. 1999, 64, 4610. (d) Vicario, J. L.; Bad´ıa, D.; Dom´ınguez, E.; Crespo,
A.; Carrillo, L.; Anakabe, E. Tetrahedron Lett. 1999, 40, 7123. (e) Vicario,
J. L.; Bad´ıa, D.; Dom´ınguez, E.; Crespo, A.; Carrillo, L. Tetrahedron:
Asymmetry 1999, 10, 1947. (f) Carrillo, L.; Bad´ıa, D.; Dom´ınguez, E.;
Vicario, J. L.; Tellitu, I. J. Org. Chem. 1997, 62, 6716.
(14) In a general experimental procedure, 1 mmol of amide 1 was slowly
added to a suspension of LDA (2 mmol) and LiCl (5 mmol) in THF at
-78 °C. After 1 h of stirring at this temperature, the mixture was allowed
to reach room temperature and stirred for another 15 min. The reaction
was then cooled to 0 °C, and a solution of the corresponding imine (4 mmol)
was slowly added. The mixture was stirred until TLC analysis of aliquots
indicated full conversion (typically 4-6 h). The reaction was quenched
with water and extracted with CH2Cl2, the combined organic fractions were
collected, dried over Na2SO4, and filtered, and the solvent was removed in
vacuo, affording the wanted amides after flash column chromatography
purification (hexanes:AcOEt 2:8). All amides gave physical and spectro-
scopic data consistent with the proposed structures.
(11) Vicario, J. L.; Bad´ıa, D.; Dom´ınguez, E.; Rodr´ıguez, M.; Carrillo,
L. J. Org. Chem. 2000, 65, 3754.
774
Org. Lett., Vol. 3, No. 5, 2001

would lie in an axial possition in order to allow the only
available electron couple at the imine nitrogen to coordinate
with the lithium atom. Assuming an E configuration for the
CdN azomethyne bond,16 this would place the imine R
substituent in an axial possition in the cyclic transition state
and therefore afford the diastereoisomer of relative anti
configuration.
The resulting amides 2a-e were subjected to a hydrolysis/
esterification procedure, affording the target R-methyl-â-
amino acid derivatives as their corresponding methyl esters
(Scheme 2).17
Table 1. Stereocontrolled Reaction of Amide 1 with Several
Imines
prod.
R
yield (%)a
2/3b
anti/synb
2a
2b
2c
2d
2e
Ph
86
77
80
83
69
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
3,4-(MeO)2C6H3
2-furyl
2-thienyl
(CH3)3C
a Yield of product after flash column chromatography purification.
b Calculated by HPLC (Chiralcel OD column, UV detector, n-hexane/2-
propanol 70:30, 1.00 mL/min).
Scheme 2a
a mixture of the four possible isomers (see Supporting
Information).
It should also to be pointed out that the presence of LiCl
is necessary in the reaction medium, as in its absence only
starting materials were recovered. This contrasts with the
parent reaction of the same enolate with aldehydes, in which
the presence of LiCl was not necessary.11 We believe that
since imines have a much less electrophilic character than
aldehydes, a reactivity enhancement on the enolate species
is necessary which is provided by the presence of lithium
salts as has previously been reported.15 Also, the fact that
an excess of imine (4 equiv) is needed for the reaction to
complete in a reasonable time should be interpreted in the
same terms.
The results relating to the high diastereofacial control are
in accordance with a previously proposed mechanism12a,13c
in which the adduct of the pseudoephedrine amide Mannich
reaction should arise from the attack to the preformed Z
enolate from the less hyndered Si face of an intermediate in
an opened staggered conformation, which remains rigid by
the help of bridging solvent or iPrNH (from LDA) molecules
(Figure 2). With respect to the high simple diastereoselection,
a (i) 1. 4 M H2SO4/dioxane, reflux; 2. MeOH, H2SO4, reflux.
The aminoesters 4a-e were obtained in good yields after
flash chromatography purification and were almost enantio-
merically pure as proven by HPLC analysis in a chiral
stationary phase under conditions previously optimized for
a racemic mixture (see Supporting Information). This also
indicates that both conversions performed on the amides
2a-e (hydrolysis and esterification) proceeded without
racemization in any of the chiral centers (Table 2).
Table 2. Hydrolysis/Esterification of Amides 2a-e
prod.
R
yield (%)a
ee (%)b
4a
4b
4c
4d
4e
Ph
83
78
68
72
86
>99
>99
>99
>99
>99
3,4-(MeO)2C6H3
2-furyl
2-thienyl
(CH3)3C
a Yield of product after flash column chromatography purification.
b Calculated by HPLC (Chiralcel OD column, UV detector, n-hexane/2-
propanol 90:10, 1.00 mL/min).
To unambiguously assign the absolute configuration of
both chiral centers created in the first reaction, â-aminoester
Figure 2. Proposed mechanism for the Mannich reaction. (X)
denotes THF or Pr2NH molecules.
(16) All starting imines showed one 13C NMR resonance for the CdN
group indicating that only one of the two possible E/Z isomers of the
azomethyne bond was present. The preference for the E configuration in
imines in which the CdN bond is conjugated with one or more aromatic
rings has already been described. Hine, J.; Yeh, C. Y. J. Am. Chem. Soc.
1967, 89, 2669.
(17) In a typical procedure, a solution of the starting amide (1 mmol) in
dioxane (10 mL) was added to a 4 M H2SO4 solution (10 mL) and refluxed
for 6 h. The volatiles were removed in vacuo and MeOH (15 mL) was
added. The mixture was then heated to reflux temperature for an additional
6 h. Water (10 mL) was added, and the mixture was carefully basified with
NaOH and extracted with CH2Cl2. The collected organic fractions were
dried over Na2SO4 and filtered, and the solvent was removed in vacuo,
affording the desired â-aminoesters after flash column chromatography
purification (hexanes:AcOEt 1:1). All products gave physical and spectro-
scopic data consistent with the proposed structures.
i
it is in agreement with a pseudo-chair conformation for the
transition state10 in which the PMP substituent on the imine
(15) For the effect of LiCl in the reaction of pseudoephedrine amide
enolates, see: (a) Ru¨ck, K. Angew. Chem., Int. Ed. Engl. 1995, 34, 433.
See also: (b) Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard, P.
G.; Schleyer, P. R.; Bernstein, P. R. J. Am. Chem. Soc. 1996, 118, 1339
and references therein. (c) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.;
Mukhopadhyay, T.; Simson, M.; Seebach, D. Synthesis 1993, 1271 and
references therein.
Org. Lett., Vol. 3, No. 5, 2001
775

uration of 5a as (3R,4S) which should be extended to the
rest of the b-aminoesters 4a-e and amides 2a-e.
Scheme 3a
In summary, a very easy and efficient synthetic protocol
for the preparation of chiral R,â-disubstituted-â-aminoesters
in almost enantiomerically pure form has been developed
using (S,S)-(+)-pseudoephedrine as a chiral auxiliary. The
methodology involves the addition of a pseudoephedrine
acetamide enolate to a CdN imine bond followed by
hydrolysis/esterification of the resulting adducts. In view of
the large number of amides and imines amenable to this
process, broad application of this method should be antici-
pated, thus opening up access to a full range of chiral
nonracemic â-amino acid derivatives with different substitu-
tion patterns at the alkyl chain. In addition, the fact that
pseudoephedrine is inexpensive and commercially available
in both enantiomeric forms makes the reported procedure
even more attractive from both a synthetic and economic
point of view.
a (i) LiN(TMS)2, THF, -20 °C.
4a was transformed under a previously reported base-
promoted cyclization18 into the known â-lactam 5a (Scheme
3).19 Comparison of the observed J3,4 coupling constants in
the 1H NMR spectrum with those reported in the literature20
(J3,4 ) 5.8 Hz for the syn isomer and J3,4 ) 2.2 Hz for the
anti isomer) allowed us to propose an anti relative config-
uration between the two adjacent chiral centers. A compari-
son of the obtained [R]20D value for 5a with that reported in
the literature20 allowed us to establish the absolute config-
Acknowledgment. Financial support from the Basque
Government (a fellowship to J.L.V. and Project GV00170.30-
7307/19) is gratefully acknowledged.
(18) Guanti, G.; Narisano, E.; Banfi, L. Tetrahedron Lett. 1987, 28, 4331.
(19) The H NMR spectrum of the reaction crude showed the presence
1
Supporting Information Available: Experimental details
for the determination of anti/syn and 2/3 ratios and ee values
of aminoesters 4 by HPLC. This information is available
free of charge via the Internet at http://pubs.acs.org.
of only one diastereoisomer with respect to the relative configuration
between both chiral centers. HPLC analysis under conditions optimized
for racemic (()-5a (ChiralcelOD, UV detector, n-hexane/2-propanol 95:5,
0.80 mL/min) indicated the presence of only one of the two possible ones.
(20) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 2060.
OL0155384
776
Org. Lett., Vol. 3, No. 5, 2001