The imine (+)-pseudoephedrine glycinamide: A useful reagent for the asymmetric synthesis of (R)-α-amino acids

Article abstract of DOI:10.1016/S0957-4166(01)00027-1

The new imine derived from Myers (+)-pseudoephedrine glycinamide can be diastereoselectively alkylated with alkyl halides at room temperature using NaOEt or LiO-tert-Bu as bases under phase transfer conditions. Hydrolysis to the corresponding alkylated products was easily achieved under mild conditions to afford (R)-α-amino acids.

Full text of DOI:10.1016/S0957-4166(01)00027-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 181–183
The imine (+)-pseudoephedrine glycinamide: a useful reagent for
the asymmetric synthesis of (R)-a-amino acids
Gabriela Guillena and Carmen Na´jera*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 21 December 2000; accepted 15 January 2001
Abstract—The new imine derived from Myers (+)-pseudoephedrine glycinamide can be diastereoselectively alkylated with alkyl
halides at room temperature using NaOEt or LiO-tert-Bu as bases under phase transfer conditions. Hydrolysis to the
corresponding alkylated products was easily achieved under mild conditions to afford (R)-a-amino acids. © 2001 Elsevier Science
Ltd. All rights reserved.
The diastereoselective electrophilic alkylation of chiral
glycine-derived enolates is one of the most powerful
methods for the asymmetric synthesis of a-amino acids.1
Based on this concept, (+)- or (−)-pseudoephedrine
glycinamide 1 or 2 have been alkylated with high
diastereoselectivity and the alkylated products
hydrolyzed to give enantiomerically enriched (R)- or
(S)-a-amino acids, respectively.2 The alkylation process
requires the use of strong anionic bases such as n-BuLi
or LDA at 0°C. Glycine or alanine imine templates are
useful reagents for the synthesis of a-amino acids because
they are easily enolizable and can be alkylated under very
mild reaction conditions for example by phase transfer
catalysis, or with organic bases.3 Recently we reported
the successful use of chiral glycinate imine 34 derived
from (+)- and (−)-ephedrine imidazolidinones and cyclic
alaninates 45 for the asymmetric synthesis of mono-alky-
lated a-amino acids and a-methyl a-amino acids, respec-
tively. Those reagents can be alkylated under phase
transfer conditions by using weak bases such as LiOH
or K2CO3. Particularly, (+)- and (−)-1,5-dimethyl-4-
phenylimidazolidin-2-one derived glycinates 3 present a
labile imide bond and are prepared by acylation of the
imidazolidinone with chloroacetyl chloride followed by
amination and final imine formation. Additionally, these
compounds are easily hydrolyzed under basic conditions
to give the chiral auxiliary and the glycine moiety, for
this reason the alkylation under phase transfer condi-
tions must be carried out at −20°C.4 In connection with
the previous work we thought it would be of interest to
prepare pseudoephedrine glycinamide imine 5 as a chiral
template for the asymmetric synthesis of a-amino acids.
This reagent should be more stable than the imidazolidi-
none derivatives 3 and could be prepared by a more di-
rect way, furthermore it should be more easily enolizable
than the N-unsubstituted pseudoephedrine reagent 1.
* Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00027-1

182
G. Guillena, C. Na´jera / Tetrahedron: Asymmetry 12 (2001) 181–183
Scheme 1.
The preparation of compound 5 was carried out in 71%
yield by direct condensation of N-[bis(methylthio)-
methylene]glycine methyl ester with (+)-pseudo-
ephedrine after deprotonation with n-butyllithium in
the presence of lithium chloride at 0°C, conditions
which have been described for compound 1.2a The
alkylation process of compound 5 was initially studied
with allyl iodide under different reaction conditions
(Scheme 1 and Table 1). Under solid–liquid PTC condi-
tions the alkylation process in the presence of K2CO3,
KOH or CsOH as bases and 10 mol% of tetra-n-butyl-
ammonium bromide (TBAB) in THF as solvent gave
1:1 mixtures of enolate and OH alkylation products.
The alkylated compound 6a was obtained in 39–45%
yield with almost negligible asymmetric induction. The
reaction conditions used in the case of imidazolidinone
derived glycinimide 3 failed (LiOH, LiCl, TBAB or
DBU, LiCl) after 24 h at rt.4 When stronger bases such
as NaH, LiOBut, KOBut or NaOEt were used in THF
as solvent, the alkylation reaction took place mainly at
the C-center with high diastereoselectivity for these
alkoxide bases (Table 1, entries 1–4). In the case of
NaOEt, O-alkylation was avoided when a 10 mol% of
TBAB was added increasing simultaneously the yield
and the diastereoselectivity of the C-alkylated products
in shorter reaction times (Table 1, entry 5).
Several alkyl halides were tested using the best reaction
conditions of either LiOtBu or NaOEt/TBAB in THF
at rt, affording compounds 6 with good d.r.6 The
hydrolysis of the imine group by means of aqueous 1 M
HCl in THF at rt gave the corresponding glycinamides
7 in 75–80% isolated yields, which have the same
spectroscopic properties as those previously reported by
Table 1. Diastereoselective alkylation of imine pseudoephedrine glycinamide 5a
Entry
Base (equiv.)
RHal
Reaction time (h)
C:O alkylation ratiob
Product
Yieldc
No.
drb
1
2
3
4
5
6
7
8
NaH (1.5)
CH2ꢀCHCH2I
CH2ꢀCHCH2I
CH2ꢀCHCH2I
CH2ꢀCHCH2I
CH2ꢀCHCH2I
CH2ꢀCHCH2I
PhCH2Br
PhCH2Br
CH3I
CH3I
CH3CH2I
4
1.5d
24
0.75
3
0.75
0.5
3.5
5
2
3
3
15
99:1
99:1
99:1
99:1
90:10
99:1
99:1
92:8
99:1
90:10
99:1
80:20
75:25
6a
6a
6a
6a
6a
6a
6b
6b
6c
6c
6d
6d
6e
75
36
50
50
64
72
60
62
57
38
49
16
40
63:37
93:7
95:5
93:7
88:12
95:5
95:5
91:9
97:3
90:10
98:2
KOBut (1.0)
LiOBut (1.0)e
LiOBut (1.0)
NaOEt (3.0)
NaOEt (3.0)f
LiOBut (1.0)
NaOEt (3.0)f
LiOBut (1.0)
NaOEt (3.0)f
LiOBut (1.0)
NaOEt (3.0)f
LiOBut (1.0)
9
10
11
12
13
CH3CH2I
EtO2CCH2I
90:10
82:18
a The reactions were carried out in THF at rt.
b Determined by GLC.
c Yield of isolated product after column chromatography, based on compound 5.
d At 0°C.
e LiCl (6 equiv.) was added.
f TBAB (10 mol%) was added.

G. Guillena, C. Na´jera / Tetrahedron: Asymmetry 12 (2001) 181–183
183
Myers’ group. Glycinamides 7 were hydrolyzed to (R)-
a-amino acids 8a (R=allyl) and 8b (R=benzyl) in
70–89% yield, respectively, by simple heating under
reflux in water.2a (+)-Pseudoephedrine was recovered
from this process in ca. 75% yield. The diastereoselec-
tivity of the alkylation process was determined by
transformation of glycinamides 7 into their acylated
derivatives 9 by treatment with acetic anhydride in
pyridine and 4-(dimethylamino)pyridine (DMAP) and
analyzing the products by chiral GLC (Chirasil-Val).
As in the case of reagent 1, the alkylation of compound
5 took place at the same face as the methyl group of the
(+)-pseudoephedrine.
Clayson, J.; Boa, A. N. Contemp. Org. Synth. 1995, 173–
187; (f) North, M. Contemp. Org. Synth. 1996, 323–343;
(g) Studer, A. Synthesis 1996, 793–815; (h) Seebach, D.;
Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 2709–2748; (i) Cativiela, C.; D´ıaz-de-Villegas, M.
D. Tetrahedron: Asymmetry 1998, 9, 3517–3599; (j) Amino
Acids, Peptides and Proteins, Specialist Periodical Reports
Chem. Soc. London, 1968–1995 Vols. 1–28.
2. (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J.
Am. Chem. Soc. 1994, 116, 9361–9362; (b) Myers, A. G.;
Yoon, T.; Gleason, J. L. Tetrahedron Lett. 1995, 36,
4555–4558; (c) Myers, A. G.; Gleason, J. L.; Yoon, T. J.
Am. Chem. Soc. 1995, 117, 8488–8489; (d) Myers, A. G.;
Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc.
1997, 119, 656–673; (e) Smith, III, A. B.; Benowitz, A. B.;
Favor, D. A.; Sprengeler, P. A.; Hirsmann, R. Tetrahedron
Lett. 1997, 38, 3809–3812; (f) Myers, A. G.; Gleason, J.
Org. Synth. 1998, 76, 57–76.
3. For a review on this topic, see: Abella´n, T.; Chinchilla, R.;
Galindo, N.; Guillena, G.; Na´jera, C.; Sansano, J. M. Eur.
J. Org. Chem. 2000, 2689–2697.
4. (a) Guillena, G.; Na´jera, C. Tetrahedron: Asymmetry 1998,
9, 1125–1129; (b) Guillena, G.; Na´jera, C. Tetrahedron:
Asymmetry 1998, 9, 3935–3938; (c) Guillena, G.; Na´jera,
C. J. Org. Chem. 2000, 65, 7310–7322.
5. (a) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Na´jera, C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 995–997; (b) Abel-
la´n, T.; Na´jera, C.; Sansano, J. M. Tetrahedron: Asymme-
try 1998, 9, 2211–2214; (c) Chinchilla, R.; Galindo, N.;
Na´jera, C. Tetrahedron: Asymmetry 1998, 9, 2769–2772;
(d) Chinchilla, R.; Galindo, N.; Na´jera, C. Synthesis 1999,
704–717; (e) Abella´n, T.; Na´jera, C.; Sansano, J. M. Eur.
J. Org. Chem. 2000, 2809–2820.
6. Typical procedure: To a solution of glycinamide 5 (0.3
mmol, 100 mg) and LiO-tert-Bu (0.3 mmol, 24 mg) or
NaOEt (0.9 mmol, 61 mg) and TBAB (0.09 mmol, 31 mg)
in THF (3 mL) was added the corresponding alkyl halide
(1.5 mmol). After the reaction was completed (TLC moni-
toring) water was added and the reaction was extracted
with CH2Cl2 (10 mL). The organic layer was washed with
water (3×10 mL), dried (Na2SO4), evaporated in vacuo (15
torr) and the residue purified by flash chromatography on
silica gel (Hex/EtOAc mixtures) affording compounds 6.
The corresponding benzophenone derivative could be
also prepared from the reaction between the chlorohyd-
rate of Myers’ reagent 2 and benzophenone imine.
However, this product was very sensitive during the
alkylation process, during purification and even on
standing at 0°C. As such, it could only be isolated in
less than 20% yield. Pseudoephedrine was exclusively
isolated in all these attempts.
In conclusion, the pseudoephedrine–glycinamide
derived imine 5 is a good derivative of Myers’ reagent
1 because it can be prepared in one step from (+)-pseu-
doephedrine and can be alkylated diastereoselectively at
rt and under less basic conditions than 1.
Acknowledgements
We thank the Spanish Ministerio de Educacio´n y Cul-
tura (M.E.C.) (PB97-0123) for financial support.
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