Stereocontrolled mannich reaction with enolizable imines using (S,S)-(+)-pseudoephedrine as chiral auxiliary. Asymmetric synthesis of α,β-disubstituted β-aminoesters and β-lactams

Full text of DOI:10.1021/jo010697m

9030
J . Org. Chem. 2001, 66, 9030-9032
tested. Now, we report herein the extension of this
Ster eocon tr olled Ma n n ich Rea ction w ith
methodology to the use of enolizable imines only by
manipulating the enolate counterion and therefore with-
out the need to convert either the initial carbonyl
substrate or the azomethine reagent into a more reactive
derivative. This procedure represents a very straightfor-
ward and general access to chiral nonracemic R,â-
disubstituted â-aminoester derivatives with any kind of
substitution pattern at the alkyl chain.
En oliza ble Im in es Usin g
(S,S)-(+)-P seu d oep h ed r in e a s Ch ir a l
Au xilia r y. Asym m etr ic Syn th esis of
r,â-Disu bstitu ted â-Am in oester s a n d
â-La cta m s
J ose L. Vicario, Dolores Bad´ıa,* and Luisa Carrillo
Departamento de Quı´mica Orga´nica II, Facultad de
Ciencias, Universidad del Paı´s Vasco/ Euskal Herriko
Unibertsitatea, P.O. Box 644, E-48080 Bilbao, Spain
Resu lts a n d Discu ssion
When the lithium enolate of propionamide 1 was
reacted with the p-anisidine-based (E)-imine 2a 5 in the
presence of 4 equiv of LiCl (Scheme 1), as previously
reported,4a no addition product was obtained and the
starting propionamide was recovered unchanged together
with a complex mixture of products probably derived from
polymerization of the imine reagent (entry 1, Table 1).
The same results were obtained when the reaction was
performed with prior activation of the imine with a Lewis
acid like BF3‚OEt2 (entries 2-4, Table 1). Only in the
case of imine 2c, which is slightly less prone to racem-
ization, was obtained a small amount of the desired
addition product. However, when we submitted the
lithium enolate derived from propionamide 1 to a trans-
metalation step with 2 equiv of ZnCl2 prior to the addition
of the imine, the desired â-aminoamide adducts were
obtained in good yields after flash column chromatogra-
phy purification (entries 5-8, Table 1).6 The yield of the
addition reaction was significantly improved when an
excess of azomethine reagent was used, in the conditions
previously reported for nonenolizable imines.4a It should
be pointed out that the use of nonenolizable imine 2d (R
) Ph) yielded the desired adduct in comparable yield and
in the same absolute configuration in both newly created
chiral centers to that found when the lithium enolate of
1 was employed (entries 8 and 9, Table 1).4a
qopbaurm@lg.ehu.es
Received J uly 10, 2001
In tr od u ction
The Mannich reaction involving enolizable azomethine
compounds in most cases fails to give good results due
to the preference of the azomethine substrate to undergo
enolization rather than the desired nucleophilic addition.1
There are only a few procedures that overcome these
limitations, and in this context, modified derivatives of
either the enolate2 or the azomethyne reagent3 have been
employed.
On the other hand, the strategies employed to exert
stereocontrol in the newly created chiral centers involve
the introduction of the chiral information by incorporat-
ing chiral ligands present in the reaction medium in
either a stoichiometric or a catalytic way or by using
chiral imines or enolates.4 In regard to this last topic,
there are only a few known methods for diastereoselective
Mannich reactions employing chiral auxiliaries attached
to the enolate. This is in contrast with the parent aldol
reactions that have been extensively developed. We have
recently4a reported a very effective procedure for per-
forming stereocontrolled Mannich reactions using a chiral
enolate derived from (S,S)-(+)-pseudoephedrine propi-
onamide, in which several nonenolizable imines were
In all cases, the reaction proceeded with extremely high
simple (anti/syn ratio 3/3′ > 99:1) and facial (3/4 ratio >
99:1) diastereoselection, and amides 3a -d were obtained
as one diastereoisomer out of the four possible ones,
(1) Risch, N.; Arend, M. Stereoselective Synthesis (Houben-Weyl), Vol.
E21/ 3; Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E.,
Eds.; Thieme: Stuttgart, 1996; p 1833.
(2) (a) Schneider, C.; Reese, O. Angew. Chem., Int. Ed. 2000, 39,
2948. (b) List, B. J . Am. Chem. Soc. 2000, 122, 9336. (c) Glasson, S.
R.; Canet, J .-L.; Troin, Y. Tetrahedron Lett. 2000, 41, 9797. (d) Cozzi,
P. G.; di Simone, B.; Umani-Ronchi, A. Tetrahedron Lett. 1996, 37,
1691. (e) Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; J ayasinghe, L. R.
J . Org. Chem. 1991, 56, 1681. (f) Liebeskind, L. S.; Welker, M. E.;
Goedken, V. J . Am. Chem. Soc. 1984, 106, 441. (g) Dubois, J .-E.;
Axiotis, G. Tetrahedron Lett. 1984, 25, 2143.
(3) (a) Cooke, J . W. B.; Berry, M. B.; Caine, D. M.; Cardwell, K. S.;
Cook, J . S.; Hodgson, A. J . Org. Chem. 2001, 66, 334. (b) 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. (c) Saito, S.; Hatanaka, K.; Yamamoto, H. Org. Lett. 2000, 2,
1891. (d) D’Oca, M. G. M.; Pilli, R. A.; Vencato, I. Tetrahedron Lett.
2000, 41, 9709. (e) Kise, N.; Ueda, N. J . Org. Chem. 1999, 64, 7511. (f)
Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J . A. J . Org.
Chem. 1999, 64, 1278. (g) Kawakami, T.; Ohtake, H.; Arakawa, H.;
Okachi, T.; Imada, Y.; Murahashi, S.-I. Org. Lett. 1999, 1, 107. (h)
Higashiyama, K.; Kyo, H.; Takahashi, H. Synlett 1998, 489. (i) Cainelli,
G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G. Tetrahedron
1996, 52, 1685. (j) Davis, F. A.; Reddy, R. T.; Teddy, R. E. J . Org. Chem.
1992, 57, 6387. (k) Andre´s, C.; Gonza´lez, A.; Pedrosa, R.; Pe´rez-Encabo,
A. Tetrahedron Lett. 1992, 33, 2895. (l) Brown, M. J .; Overman, L. E.
J . Org. Chem. 1991, 56, 1933. (m) Uyehara, T.; Suzuki, I.; Yamamoto,
Y. Tetrahedron Lett. 1989, 30, 4275. (n) Nagao, Y.; Dai, W.-M.; Ochiai,
M. Tetrahedron Lett. 1988, 29, 6133.
(4) (a) Vicario, J . L.; Bad´ıa, D.; Carrillo, L. Org. Lett. 2001, 3, 773
and references therein. See also: (b) Notz, W.; Sakthivel, K.; Bui, T.;
Zhong, G.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 199. (c) Saito,
S.; Hatanaka, K.; Yamamoto, H. Tetrahedron 2001, 57, 875. (d)
McLaren, A. B.; Sweeney, J . B. Synlett 2000, 1625. (e) Ahn, J .-B.; Yun,
C.-S.; Kim, K. H.; Ha, D.-C. J . Org. Chem. 2000, 65, 9249. (f) Ishitani,
H.; Ueno, M.; Kobayashi, S. J . Am. Chem. Soc. 2000, 122, 8180. (g)
Enders, D.; Oberbo¨rsch, J .; Adam, J . Synlett 2000, 644. (h) Allef, P.;
Kunz, H. Tetrahedron: Asymmetry 2000, 11, 375. (i) Palomo, C.;
Aizpurua, J . M.; Gracenea, J . J . J . Org. Chem. 1999, 64, 1693. (j) Fujii,
A.; Hagiwara, E.; Sodeoka, M. J . Am. Chem. Soc. 1999, 121, 5450. (k)
Viso, A.; De la Pradilla, R.; Garc´ıa, A.; Alonso, M.; Guerrero-Strachan,
L.; Fonseca, I. Synlett 1999, 1543.
(5) 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; see: Hine, J .; Yeh, C. Y. J . Am. Chem. Soc. 1967, 89,
2669.
(6) For some examples of Mannich-type reactions using zinc(II)
enolates, see: (a) Comins, D. L.; Kuethe, J . T.; Hong, H.; Lakner, F.
J .; Concolino, T. E.; Rheingold, A. L. J . Am. Chem. Soc. 1999, 121,
2651. (b) van Maanen, H. L.; Kleijn, H.; J astrzebski, J . T. B. H.;
Verweij, J .; Kieboom, A. P. G.; van Koten, G. J . Org. Chem. 1995, 60,
4331. (c) van Maanen, H. L.; Kleijn, H.; J astrzebski, J . T. B. H.; van
Koten, G. Bull. Soc. Chim. Fr. 1995, 132, 86. (d) van der Steen, H. H.;
Kleijn, H.; Britovsek, G. J . P.; J astrzebski, J . T. B. H.; van Koten, G.
J . Org. Chem. 1992, 57, 3906.
10.1021/jo010697m CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/29/2001

Notes
J . Org. Chem., Vol. 66, No. 26, 2001 9031
Sch em e 1
Sch em e 2
Ta ble 2. Hyd r olysis/Ester ifica tion of Am id es 3a -e a n d
Su bsequ en t Ba se-P r om oted Cycliza tion
R
product
yielda (%)
product
yieldb (%)
Me
Et
i-Pr
Ph
5a
5b
5c
5d
88
89
88
83
6a
6b
6c
6d
93
88
90
91
Ta ble 1. Ster eocon tr olled Rea ction of En ola tes of Am id e
1 w ith Sever a l Im in es 2a -d
entry product
R
procedurea yieldb (%)
3/4c
3/3′c
a
Yield of product after flash column chromatography purifica-
1
2
3
4
5
6
7
8
9
3a
3a
3b
3c
3a
3b
3c
3d
3d
3a
Me
Me
Et
i-Pr
Me
Et
i-Pr
Ph
Ph
A
0
0
0
15
79
81
85
83
86
0
tion with ee >99% calculated by HPLC (Chiralcel OD column, UV
detector, n-hexane/2-propanol 90:10, 1.00 mL/min). Yield of
product after flash column chromatography purification with ee
>99% calculated by HPLC (Chiralcel OD column, UV detector,
n-hexane/2-propanol 98:2, 0.80 mL/min).
Ad
Ad
Ad
B
b
>99:1 >99:1
>99:1 >99:1
>99:1 >99:1
>99:1 >99:1
>99:1 >99:1
>99:1 >99:1
B
B
B
and found to be almost enantiomerically pure as proven
by HPLC analysis in a chiral stationary phase, under
conditions previously optimized for a racemic mixture
(Scheme 2, Table 2). Finally, â-aminoesters 5a -d were
subjected to a already reported base-promoted cycliza-
tion8 affording, after flash column chromatography pu-
rification, the target â-lactams 6a -d in good yields and
as only one detectable stereoisomer (Scheme 2, Table 2).
Thus, the observed value for J 3,4 coupling constants in
the 1H NMR spectrum in comparison with those reported
in the literature allowed us to confirm an anti configu-
ration for the â-lactams 6.9 Besides, a comparison of the
A
10
Me
Ae
a
Procedure A: Reaction using the lithium enolate of 1 (see ref
b
4a). Procedure B: Reaction using the Zn (II) enolate of 1. Yield
of product after flash column chromatography purification. c Cal-
culated by HPLC (Chiralcel OD column, UV detector, n-hexane/
d
2-propanol 70:30, 1.00 mL/min). Reaction using the imine pre-
viously activated with BF3‚OEt2. e Reaction using the imine
previously activated with ZnCl2.
attending to the configuration of the two newly created
chiral centers. This fact was checked by HPLC analysis
of the crude reaction mixtures under conditions previ-
ously optimized for a mixture of the four possible
isomers.7
obtained [R]20 value for 6d with that reported in the
D
literature9a allowed us to establish the absolute config-
uration of the newly created chiral centers in the Man-
nich reaction. This is also indicating that all conversions
performed on the amides 3a -d (hydrolysis, esterification,
and base-promoted cyclization) proceeded without race-
mization in any of the chiral centers.
To ensure that a zinc(II) enolate-like species was
formed during the reaction and that ZnCl2 was not acting
simply as a Lewis acid that activates the azomethine
bond toward the nucleophilic addition (like in the case
of the lithium enolate of 1 and imine 2c activated with
BF3‚OEt2, entry 4, Table 1), we subjected the lithium
enolate of 1 to reaction with a solution containing 4 equiv
of the imine 2a and 4 equiv of ZnCl2. Under these
conditions, no addition product was obtained (entry 10,
Table 1), a result that confirms our hypothesis that the
formation of an intermediate zinc(II) enolate was respon-
sible for the good results obtained in the reaction with
enolizable imines. Relying on the fact that the configu-
ration of the newly chiral centers (entries 8 and 9, Table
1) is independent of the metallic enolate counterion, the
high stereocontrol observed is in accordance with a
previously proposed mechanism for Mannich reaction
with nonenolizable imines employing enolates derived
from pseudoephedrine amide derivatives.4a This mecha-
nism consistent with an absolute configuration (2R,3R)
for the newly chiral centers created at the adducts 3a -
c.
In summary, a very easy and efficient procedure for
performing stereocontrolled Mannich reactions that al-
lows the use of either nonenolizable and enolizable imines
as azomethine electrophilic reagents has been developed
using (S,S)-(+)-pseudoephedrine as chiral auxiliary. The
methodology involves the addition of a pseudoephedrine
propionamide Zn(II) enolate to the imine CdN double
bond. The obtained â-aminoamide adducts have shown
to be adequate synthons for the synthesis of R-methyl-
â-alkyl-â-aminoesters and 3-methyl-4-alkyl-â-lactams in
an enantiopure form. In view of the large number of
amides and imines susceptible to be employed, the broad
application of this method should be anticipated, thus
opening the access to a full range of chiral nonracemic
â-amino acid derivatives with different substitution
patterns at the alkyl chain. The fact that pseudoephe-
drine is cheap and commercially available in both enan-
tiomeric forms makes the reported procedure even more
interesting from a synthetic and economic point of view.
The so-obtained amides 3a -d were subjected to a
hydrolysis/esterification procedure, affording the corre-
sponding R-methyl-â-amino acid derivatives as their
corresponding methyl esters 5a -d . These derivatives
were recovered in good yields after flash chromatography
(8) (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.
(9) (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J .
Am. Chem. Soc. 1997, 119, 2060. (b) Barbaro, G.; Battaglia, A.;
Giorgianni, P. J . Org. Chem. 1994, 59, 906. (c) Palomo, C.; Aizpurua,
J . M.; Galarza, R.; Iturburu, M.; Legido, M. Bioorg. Med. Chem. Lett.
1993, 3, 2461.
(7) A sample containing the four possible diastereoisomers, to used
as a standard mixture for chiral HPLC, was obtained as previously
reported (ref 4a)

9032 J . Org. Chem., Vol. 66, No. 26, 2001
Notes
Exp er im en ta l Section 10
trated HCl, and the volatile residues were removed under
vacuum. MeOH (15 mL) and concentrated H2SO4 (1 mL) were
then added to the resulting sluggish solid, following by heating
at reflux the mixture for 6 h. Water (10 mL) was added, 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
5a after flash column chromatography purification (hexanes/
AcOEt 1:1). Yield: 88%. [R]20D: -15.6 (c ) 0.1, CH2Cl2). 1H NMR
(δ, ppm): 1.12 (d, 3H, J ) 6.4 Hz); 1.15 (d, 3H, J ) 6.7 Hz); 2.73
(m, 1H); 3.68 (s, 3H); 3.73 (s, 3H); 3.78 (m, 1H); 6.58 (d, 2H, J )
7.9 Hz); 6.77 (d, 2H, J ) 7.9 Hz). 13C NMR (δ, ppm): 11.9; 17.4;
43.5; 51.6; 52.6; 55.7; 114.8, 115.4; 141.0; 152.0; 175.8. IR
(CHCl3): 3375 (NH); 1728 (CdO). MS (EI) m/z (rel int): 237
(M+, 18), 150 (100). Anal. Calcd for C13H19NO3: C, 65.80; H, 8.07;
N, 5.90. Found: C, 65.75; H, 8.02; N, 5.81.
Gen er a l P r oced u r e for th e Ba se-P r om oted Cycliza tion
of Am in oester s 5a -d . Syn th esis of (3R,4R)-(-)-1-(4-Meth -
oxyp h en yl)-3,4-d im eth yla zetid in -2-on e (6a ). A solution of
LHMDS (1 mmol) in THF was slowly added over a cooled (-20
°C) solution of the starting â-aminoester 5a (1 mmol) in dry THF
(15 mL). The mixture was stirred for 5 min at this temperature
and quenched with a 4 M HCl solution (15 mL). The mixture
was extracted with CH2Cl2 (3 × 10 mL), the collected organic
fractions were dried over Na2SO4 and filtered, and the solvent
was removed in vacuo yielding pyrrolidin-2-one 6a after flash
column chromatography purification (hexanes/EtOAc 8:2).
Yield: 93%. Mp: 77-79 °C (EtOH). [R]20D: -17.6 (c ) 0.2, CH2-
Cl2). IR (KBr): 1760 (CdO). 1H NMR (δ, ppm): 1.34 (d, 3H, J )
7.5 Hz); 1.47 (d, 3H, J ) 6.0 Hz); 2.84 (dq, 1H, J ) 2.2, 7.5 Hz);
3.71 (dq, 1H, J ) 2.2, 6.0 Hz); 3.76 (s, 3H); 6.86 (d, 2H, J ) 7.8
Hz); 7.30 (d, 2H, J ) 7.8 Hz). 13C NMR (δ, ppm): 12.9; 17.8;
46.5; 51.3; 55.5; 114.4, 118.3; 131.1; 155.8; 167.4. MS (EI) m/z
(rel int): 205 (M+, 40), 149 (100). Anal. Calcd for C12H15NO2:
C, 70.22; H, 7.37; N, 6.82. Found: C, 70.20; H, 7.32; N, 6.88.
Gen er a l P r oced u r e for Ster eocon tr olled Ma n n ich Re-
action s with En olizable Im in es. Syn th esis of (2R,3R,1′S,2′S)-
(+)-3-(4-Meth oxyp h en yla m in o)-N,2-d im eth yl-N-(2′-p h en yl-
2′-h yd r oxy-1′-m eth yleth yl)bu ta n a m id e (3a ). A solution of
propionamide 1 (1 mmol) in THF (10 mL) was slowly added to
a solution of LDA (2 mmol) in THF (20 mL) at -78 °C. After
being stirred for 1 h at this temperature, the mixture was
allowed to reach to room temperature and stirred for another
15 min. The reaction was then cooled to -78 °C, and a solution
of ZnCl2 (2 mmol) in THF (10 mL) was added. The reaction was
stirred for 1 h at -78 °C and then allowed to warm to 0 °C, at
which time a solution of the imine 2a (4 mmol) was slowly added.
The mixture was stirred until TLC analysis indicated full
conversion, and water (2 mmol) was then added. The resulting
ZnO precipitate was filtered off and washed with CH2Cl2, and a
saturated solution of Na2CO3 (40 mL) was added to the filtrate.
The crude reaction mixture was extracted with CH2Cl2, the
combined organic fractions were collected, dried over Na2SO4,
and filtered, and the solvent rwas removed in vacuo affording
3a after flash column chromatography purification (hexanes/
AcOEt 2:8). Yield: 79%. Mp: 86-89 °C (Et2O). [R]20D: +58.6 (c
1
) 0.2, CH2Cl2). H NMR (δ, ppm) (2:1 rotamer ratio; *indicates
minor rotamer resonances): 0.96-1.38 (m, 9H); 2.27 (m, 1H);
2.78 (s, 3H); 2.88* (s, 3H); 3.21* (m, 1H); 3.53 (m, 1H); 3.70 (s,
3H); 3.72* (s, 3H); 3.98 (m, 1H); 4.51 (m, 1H); 6.58 (m, 2H); 6.78
(m, 2H); 7.26-7.33 (m, 5H). 13C NMR (δ, ppm) (2:1 rotamer ratio;
*indicates minor rotamer resonances): 9.1; 9.5*; 14.2*; 14.3;
17.9*; 18.0; 32.3; 32.9*; 41.2*; 41.4; 52.8; 53.6*; 55.6; 57.7*; 58.2;
75.8; 76.3*; 114.6, 114.7*, 114.9, 115.1*, 126.4*, 126.8, 127.6,
127.8*, 128.3, 128.6*; 141.2, 141.7*, 142.0, 142.3*; 151.8*, 152.1;
176.6*, 177.6. IR (KBr): 3338 (NH); 1619 (CdO). MS (EI) m/z
(rel int): 370 (M+, 1), 204 (100). Anal. Calcd for C22H30N2O3: C,
71.32; H, 8.16; N, 7.56. Found: C, 71.39; H, 8.11; N, 7.57.
Gen er a l P r oced u r e for th e Hyd r olysis/Ester ifica tion of
Am id es 2a -d . Syn th esis of (2R,3R)-(-)-Meth yl 3-(4-Meth -
oxyp h en yla m in o)-2-m eth ylbu ta n oa te (5a ). A solution of the
starting amide 3a (1 mmol) in dioxane (10 mL) was added to a
4 M H2SO4 solution (10 mL) and heated at reflux for 6 h. The
reaction was carefully quenched with a 4 M NaOH solution until
pH ) 12 and extracted with CH2Cl2 (3 × 10 mL). (S,S)-(+)-
Pseudoephedrine was recovered from the organic extracts in ca.
83% yield. The aqueous phase was then acidified with concen-
Ack n ow led gm en t . Financial support from the
Basque Government (a fellowship to J .L.V. and Project
No. GV00170.30-7307/19) is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for compounds 3b-d , 5b-d , and 6b-d are provided.
Chiral HPLC chromatograms for compounds 3a , 5a , and 6a
and retention times for all isomers of compounds compounds
3b-d , 5b-d , and 6b-d are included. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(10) For general experimental procedures, see: Vicario, J . L.; Bad´ıa,
D.; Dom´ınguez, E.; Carrillo, L. J . Org. Chem. 1999, 64, 4610.
J O010697M