(S,S)-(+)-pseudoephedrine α-iminoglyoxylamide as a chiral glycine cation equivalent: A modular and flexible approach to enantioenriched α-amino ketones

Article abstract of DOI:10.1021/ol800934r

(Chemical Equation Presented) We have studied the ability of an α-imino glyoxylamide derived from (S,S)-(+)-pseudoephedrine as a valuable chiral electrophile for the preparation of α-amino carbonyl compounds. In this context, the addition of Grignard reagents to the azomethine moiety of this chiral electrophile afforded the expected α-amino amide adducts in good yields and diastereoselectivities. Moreover, these adducts have been transformed into enantioenriched α-amino ketones by exploiting the ability of pseudoephedrine amides to undergo selective monoaddition to the carbamoyl group with organolithium reagents.

Full text of DOI:10.1021/ol800934r

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2613-2616
(S,S)-(+)-Pseudoephedrine
r-Iminoglyoxylamide as a Chiral Glycine
Cation Equivalent: A Modular and
Flexible Approach to Enantioenriched
r-Amino Ketones
Nerea Ruiz, Jose L. Vicario, Dolores Bad´ıa,* Luisa Carrillo, and Beatriz Alonso
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa, UniVersidad del
Pa´ıs Vasco/Euskal Herriko Unibertsitatea, P.O. Box 644, 48080 Bilbao, Spain
dolores.badia@ehu.es
Received April 23, 2008
ABSTRACT
We have studied the ability of an r-imino glyoxylamide derived from (S,S)-(+)-pseudoephedrine as a valuable chiral electrophile for the
preparation of r-amino carbonyl compounds. In this context, the addition of Grignard reagents to the azomethine moiety of this chiral electrophile
afforded the expected r-amino amide adducts in good yields and diastereoselectivities. Moreover, these adducts have been transformed into
enantioenriched r-amino ketones by exploiting the ability of pseudoephedrine amides to undergo selective monoaddition to the carbamoyl
group with organolithium reagents.
The stereoselective addition of carbon nucleophiles to the
CdN double bond of R-imino carbonyl compounds is an
important reaction in organic synthesis.1 This transformation
enables the preparation of optically active R-amino carbonyl
compounds such as R-amino acids among others, which are
valuable synthetic intermediates and chiral building blocks
in organic synthesis.2 In this context, several catalytic1b,3 and
chiral auxiliary-mediated4 methods have been reported in the
literature for the asymmetric addition reaction of organo-
metallic reagents to R-imino esters or related derivatives.
However, despite the presence of a highly electrophilic
azomethine functionality, the conjugation of the CdN double
bond to a carbonyl group leads to a lack of regiochemical
(3) For some recent examples, see: (a) Aydin, J.; Kumar, K. S.; Sayah,
M. J.; Wallner, O. A.; Szabo, K. J. J. Org. Chem. 2007, 72, 4689. (b)
Colombo, F.; Annunziata, R.; Benaglia, M. Tetrahedron Lett. 2007, 48,
2687. (c) Fuchibe, K.; Hatemata, R.; Akiyama, R. Tetrahedron 2006, 62,
11304. (d) Kiyohara, H.; Nakamura, Y.; Matsubara, R.; Kobayashi, S.
Angew. Chem., Int. Ed. 2006, 45, 1615. (e) Basra, S.; Fennie, M. W.;
Kozlowski, M. C. Org. Lett. 2006, 8, 2659. (f) Kong, J.-R.; Cho, C.-W.;
Krische, M. J. J. Am. Chem. Soc. 2005, 127, 11269. (g) Ji, J.-X.; Au-Yeung,
T. T.-L.; Wu, J.; Yip, C. W.; Chan, A. S. C. AdV. Synth. Catal. 2004, 346,
42. (h) Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem., Int. Ed.
2003, 42, 3927. (i) Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.;
Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1999, 64, 4844. (j) Hanessian,
S.; Yang, R.-Y. Tetrahedron Lett. 1996, 37, 8997.
(1) For some reviews see: (a) Meester, W. J. N.; van Maarseveen, J. H.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Eur. J. Org. Chem.
2003, 2519. (b) Taggi, A. E.; Hafez, A. M.; Letcka, T. Acc. Chem. Res.
2003, 36, 10.
(2) For some reviews on the asymmetric synthesis of R-amino acids,
see: (a) Najera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584. (b) Groger,
H. Chem. ReV. 2003, 103, 2795.
10.1021/ol800934r CCC: $40.75
Published on Web 05/20/2008
2008 American Chemical Society

control in the addition reaction, as competitive conjugate
addition leads to N-alkylated products.5
Scheme 1
The commercially available, inexpensive reagent (S,S)-
(+)-pseudoephedrine has provided excellent results as chiral
auxiliary in several C-C and C-X bond-forming reactions
in which, in most cases reported, amides derived from this
amino alcohol have been employed as nucleophiles via their
corresponding enolates.6 We have recently shown that
pseudoephedrine can also play the role of an efficient chiral
auxiliary linked to the electrophile reagent in conjugate
addition reactions.7 Additional advantages of the use of this
auxiliary are related to the unique reactivity pattern displayed
by amide function present at the obtained adducts, which
allows the preparation of a wide range of other interesting
chiral building blocks. In particular, we became interested
in the formation of ketones by 1,2-addition of organolithium
reagents to the carbamoyl functional group in which the
pseudoephedrine amino alcohol moiety has shown to play a
crucial role by stabilizing the tetrahedral intermediate formed
after the 1,2-addition step and therefore avoids the competi-
tive overaddition reaction. In this context, pseudoephedrine
amides have shown to operate with similar efficiency as
morpholine or Weinreb amides.8
pated that the obtained adducts could be suitable substrates
for the preparation of enantioenriched R-amino ketones by
means of a subsequent selective addition of organolithium
reagents to the pseudoephedrine amide moiety.9
We started our work with the synthesis of the starting
N-benzyl-R-imino amide derived from pseudoephedrine
(Scheme 2), which was carried out by esterification of
Scheme 2
With these precedents in mind, we decided to explore the
possibility of carrying out stereocontrolled additions to the
azomethine function of an R-imino amide derived from (S,S)-
(+)-pseudoephedrine glyoxylamide in which the amino
alcohol plays the role of an efficient chiral auxiliary linked
to the electrophile (Scheme 1). In addition, we also antici-
(4) For some selected recent examples, see: (a) Kulkarni, N. A.; Yao,
C.-F.; Chen, K. Tetrahedron 2007, 63, 7816. (b) Beenen, M. A.; Weix,
D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304. (c) Viso, A.;
Fernandez de la Pradilla, R.; Flores, A.; Garcia, A.; Tortosa, M.; Lopez-
Rodriguez, M. L. J. Org. Chem. 2006, 71, 1442. (d) Neelesh, A. K. Chen,
K. Tetrahedron Lett. 2006, 47, 611. (e) Berree, F.; Debache, A.; Marsac,
Y.; Collet, B.; Bleiz, P. G.; Carboni, B. Tetrahedron 2006, 62, 4027. (f)
Ueda, M.; Miyabe, H.; Sugino, H.; Naito, T. Org. Biomol. Chem. 2005, 3,
1124. (g) Singh, N.; Anand, R. D.; Trehan, S. Tetrahedron Lett. 2004, 45,
2911. (h) Bull, S. D.; Davies, S. G.; Garner, A. C.; Savory, E. D.; Snow,
E. J.; Smith, A. D. Tetrahedron: Asymmetry 2004, 15, 3989. (i) Wipf, P.;
Stephenson, C. R. J. Org. Lett. 2003, 5, 2449. (j) Chiev, K. P.; Roland, S.;
Mangeney, P. Tetrahedron: Asymmetry 2002, 13, 2205. (k) Di Fabio, R.;
Alvaro, G.; Bertani, B.; Donati, D.; Giacobbe, S.; Marchioro, C.; Palma,
C.; Lynn, S. M. J. Org. Chem. 2002, 67, 7319. (l) Bertrand, M. P.; Coantic,
S.; Feray, L.; Nouguier, R.; Perfetti, P. Tetrahedron 2000, 56, 3951. (m)
Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396.
commercially available glyoxylic acid monohydrate with
MeOH followed by treatment with (S,S)-(+)-pseudoephe-
drine, yielding the corresponding glyoxylamide in its cyclic
form (1). Next, 1 was reacted with benzylamine in the
presence of anhydrous Na2SO4, furnishing 2-benzylamino-
4,5-dimethyl-6-phenyl-morpholin-3-one (2), which is also the
cyclic form of the required R-imino glyoxylamide derived
from (S,S)-pseudoephedrine. This compound was obtained
1
pure by H NMR and as a 3:1 mixture of diastereoisomers
(5) Fiaud, J.-C.; Kagan, H. B. Tetrahedron Lett. 1971, 12, 1019.
(6) For the first use of pseudoephedrine as chiral auxiliary, see: (a)
Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc.
1994, 116, 9361. (b) Myers, A. G.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496. For a review, see:
(c) Myers, A. G.; Charest, M. G. Handbook of Reagents for Organic
Synthesis: Chiral Reagents for Asymmetric Synthesis; Paquette, L. A., Ed.;
Wiley Interscience: New York, 2003; p 485. For other examples, see: (d)
Iza, A.; Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2006, 4065. (e)
Vicario, J. L.; Rodriguez, M.; Badia, D.; Carrillo, L.; Reyes, E. Org. Lett.
2004, 6, 3171. (f) Smitrovich, J. H.; Boice, G. N.; Qu, C.; Dimichelle, L.;
Nelson, T. D.; Huffman, M. A.; Murry, J.; McNamara, J.; Reider, P. J.
Org. Lett. 2002, 4, 1. (g) Hutchison, P. C.; Heightman, T. D.; Procter, D. J.
Org. Lett. 2002, 4, 4583. (h) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. J. Org.
Chem. 2001, 66, 5801. (i) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. J. Org.
Chem. 2001, 66, 9030. (j) Anakabe, E.; Vicario, J. L; Bad´ıa, D.; Carrillo,
L.; Yoldi, V. Eur. J. Org. Chem. 2001, 4343. (k) Myers, A. G.; Barbay,
J. K.; Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207. (l) Vicario, J. L.;
Bad´ıa, D.; Dom´ınguez, E.; Rodr´ıguez, M.; Carrillo, L. J. Org. Chem. 2000,
65, 3754. (m) Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.
(7) (a) Reyes, E.; Vicario, J. L.; Carrillo, L.; Badia, D.; Uria, U.; Iza,
A. J. Org. Chem. 2006, 71, 7763. (b) Etxebarria, J.; Vicario, J. L.; Badia,
D.; Carrillo, L.; Ruiz, N. J. Org. Chem. 2005, 70, 8790.
2 and 2′, which could not be separated and therefore had to
be employed in the next step without further purification.
We next proceeded to carry out the reaction of organo-
metallic reagents to the mixture of 2 and 2′ (Table 1). When
we performed the reaction using 2.2 equiv of MeMgCl in
THF at -78 °C (entry 1) we observed the clean formation
(8) For a detailed study see ref 6a. For other related examples, see: (a)
Zhou, X.-T.; Lu, L.; Furkert, D. P.; Wells, C. E.; Carter, R. G. Angew.
Chem., Int. Ed. 2006, 45, 7622. (b) Robertson, J.; Dallimore, J. W. P.; Meo,
P. Org. Lett. 2004, 6, 3857. (c) White, J. D.; Xu, Q.; Lee, C.-S.; Valeriote,
F. A. Org. Biomol. Chem. 2004, 2, 2092. (d) Vicario, J. L.; Bad´ıa,
D.; Carrillo, L. Tetrahedron: Asymmetry 2003, 14, 489. (e) Vicario,
J. L.; Bad´ıa, D.; Carrillo, L. Tetrahedron: Asymmetry 2002, 13, 745. (f)
Smith, A. B., III; Adams, C. M.; Kozmin, S. A.; Paone, D. V. J. Am. Chem.
Soc. 2001, 123, 5925. See also refs 6d and 6k.
(9) Myers has reported the 1,2-addition of Grignard reagents to N-Boc
R-amino amides derived from pseudoephedrine. Myers, A. G.; Yoon, T.
Tetrahedron Lett. 1995, 36, 9429.
2614
Org. Lett., Vol. 10, No. 12, 2008

Scheme 3
Table 1. Diastereoselective Addition of Organometallic
Reagents to the Mixture of Morpholin-3-ones 2 and 2′
propose an S configuration for the newly created stereogenic
center for amide 3b and, by analogy, to all amides 3a-d
prepared.
Finally, we proceeded with the synthesis of enantioen-
riched R-amino ketones by monoaddition of organolithium
reagents to the amide moiety of adducts 3a-f (Table 2).11
Table 2. Synthesis of Enantioenriched R-Amino Ketones
a Yield of pure product after flash column chromatography purification.
b Determined by 1H NMR analysis of crude reaction mixture. c Reaction
was carried out using 4.4. equiv of Grignard reagent. d Global yield for
both regioisomers (eluted together during flash column chromatography
purification).
yield
ee
entry substrate
R1
R2
product (%)a (%)b
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3b
3c
3d
3e + 4e
3e + 4e
Me
Me
Me
Me
n-Bu
i-Pr
t-Bu
Ph
6a
6b
6c
6d
6e
7c
6f
6g
6h
83
55
29
54
42
24
27
54d
80d
84
84
>99
82
of the expected addition product to the azomethine moiety
in good yield and diastereoselectivity. Surprisingly, lowering
the temperature had a remarkable negative effect on both
yield and diastereoselectivity (entries 2 and 3). We tried to
increase the yield of the reaction by using the more reactive
MeLi as nucleophile (entries 4 and 5) but with no success,
observing a sluggish reaction with poorer yield and dr. We
could significantly improve the yield by using excess
MeMgCl without affecting the diastereoselectivity of the
reaction (entry 6). In all of these experiments we did not
observe the formation of any regioisomeric N-alkylation
byproduct. However, when we proceeded to extend these
optimized conditions to other different Grignard reagents
(entries 7-11), we found that the nature of the organome-
tallic reagent had a striking influence in the regioselectivity
of the reaction, observing that, while methyl, allyl, aryl, and
vinyl Grignard reagents reacted cleanly to furnish exclusively
the desired product 3 derived from the addition to the CdN
double bond (entries 6-9), the use of primary and secondary
alkyl magnesium halides resulted in mixtures of regioisomers
3/4 in a variable ratio (entries 10-12).
CH2dCHCH2 Et
CH2dCH2
Ph
n-Bu
n-Bu
78
Me
Ph
Me
Ph
94
80
90
a Yield of pure product after flash column chromatography purification.
b Determined by chiral HPLC analysis of crude reaction mixture (see
Supporting Information for details). c The addition reaction took place as
expected but together with a rearrangement process, furnishing a dehydro-
R-amino ketone product (7) in which no stereogenic centers were present
(see Supporting Information). d Calculated yield by considering that a 65/
35 mixture of 3e and 4e was employed as starting material.
As can be observed in Table 2, the addition took place as
anticipated, affording R-amino ketones 5a-i in moderate
yields and allowing the use of different organolithium
reagents. An excess of nucleophile had to be employed in
order to quantitatively deprotonate the two acidic NH and
OH groups before the 1,2-addition step occurs. It is
noteworthy that the adducts 6a-h were obtained with optical
purities comparable to those of the corresponding precursors
3a-e, which indicates that the addition reaction to the
pseudoephedrine amide moiety took place with none or very
little epimerization at the highly acidic R-protons of the
substrates 3a-e, which might have been expected under
these basic conditions.
The determination of the absolute configuration of the
newly created stereogenic center during the addition step was
carried out by chemical correlation. Acid hydrolysis of amide
3b followed by esterification with MeOH furnished known10
methyl (S)-2-benzylamino-pent-4-enoate 5 (Scheme 3). The
obtained [R]20 value matched with that reported in the
D
literature for the same (S)-enantiomer, which allowed us to
(11) We also tested the addition of Grignard reagents to N-benzylgly-
cinamide 3a as reported by Myers for N-Boc-glycinamides (see ref 9), but
the reaction proceeded sluggisly and we could not observe the formation
of any R-amino ketone product.
(10) Del Valle, J. R.; Goodman, M. J. Org. Chem. 2004, 69, 8946.
Org. Lett., Vol. 10, No. 12, 2008
2615

In conclusion, we have explored the ability of (S,S)-(+)-
pseudoephedrine R-iminoglyoxylamide as a useful chiral
glycine cation equivalent for the preparation of R-amino
carbonyl compounds. This substrate can be easily prepared
from cheap and readily available starting materials and reacts
eficiently with Grignard reagents, affording the corresponding
R-amino amide adducts in good yields and diastereoselec-
tivities, although the regioselectivity strongly depends upon
the nature of the Grignard reagent. In addition, the intrinsic
reactivity of the pseudoephedrine amide moiety allows the
preparation of enantioenriched R-amino ketones by carrying
out a selective monoaddition reaction across the amide
functional group, leading to the target compounds without
signifficant epimerization in the previously created stereo-
genic center. This results in a very practical and modular
synthetic protocol for the construction of a range of R-amino
ketones in which the two substituents can be assembled
provided that the adequate Grignard and organolithium
reagent are chosen.
Acknowledgment. The authors thank the University of
the Basque Country (Subvencio´n General a Grupos de
Investigacio´n, 9/UPV00041.310-15835/2004) and the Min-
isterio de Educacio´n y Ciencia (project CTQ2005-02131/
BQU and a fellowship to N.R.) for financial support. The
authors also acknowledge PETRONOR, S.A. for the gener-
ous gift of solvents.
Supporting Information Available: Characterization of
1
all new compounds and copies of their H and 13C NMR
spectra. This information is available free of charge via the
Internet at http://pubs.acs.org.
OL800934R
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Org. Lett., Vol. 10, No. 12, 2008