Amine-catalyzed direct asymmetric Mannich-type reactions

Article abstract of DOI:10.1016/S0040-4039(00)01908-0

Three chiral cyclic secondary amines are shown to be catalysts for the direct asymmetric Mannich-type reaction of acetone with a variety of preformed aldimines derived from o-anisidine. A simple one-pot three-component reaction procedure consisting of aldehyde, acetone, p-anisidine and an amine catalyst provides the corresponding β-amino ketones with 50-89% ee under very mild conditions.

Full text of DOI:10.1016/S0040-4039(00)01908-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 199–201
Amine-catalyzed direct asymmetric Mannich-type reactions
Wolfgang Notz, Kandasamy Sakthivel, Tommy Bui, Guofu Zhong 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, CA 92037, USA
Received 23 October 2000; accepted 27 October 2000
Abstract—Three chiral cyclic secondary amines are shown to be catalysts for the direct asymmetric Mannich-type reaction of
acetone with a variety of preformed aldimines derived from o-anisidine. A simple one-pot three-component reaction procedure
consisting of aldehyde, acetone, p-anisidine and an amine catalyst provides the corresponding b-amino ketones with 50–89% ee
under very mild conditions. © 2000 Published by Elsevier Science Ltd.
Optically active b-amino ketones, esters, and alcohols
are versatile synthons that may be employed in the
construction of a wide variety of nitrogen containing
natural products. One classic route to 1,3-amino ke-
tones and esters involves Mannich-type reactions.1
Asymmetric Mannich-type reactions have typically in-
volved addition of enolates to chiral aldimines2 or
hydrazones3 wherein the chiral controller of the reac-
tion is used in stoichiometric amounts. Recently, asym-
metric Mannich-type reactions that employ chiral Lewis
acids to catalyze the reaction of preformed enolate
equivalents (e.g. silyl enol ethers) with aldimines4 and
an example of a direct asymmetric Mannich-type
reaction5 have been reported.
dimethylthiazolidine-4-carboxylic acid 3 (DMTC) are
among the most promising (Table 1a).
In order to further test their utility in directing the
addition of acetone to imines, reactions of preformed
aldimine 4c in DMSO/acetone (4:1) at room tempera-
ture were studied in the presence of 20 mol% of cata-
lysts 1, 2 and 3, (entry 3, Table 1a). Within 48 h, all of
the chiral amines employed catalyzed the addition of
acetone to imine 4c resulting in the formation of b-
amino ketone 5c with comparable yield, albeit with
varying degrees of enantioselectivity. In particular, the
reaction using penicillamine derivative DMTC 3 pro-
vided the desired product in 80% ee.
For the past few years we have devoted considerable
effort to the development of catalytic asymmetric aldol
and related reactions that are facilitated by amine-
based mechanisms.6 These studies, originally founded in
the area of catalytic antibodies, have resulted in the
development of simple amine catalysts for these types
of reactions. We have reported amine-catalyzed direct
asymmetric aldol reactions7 and a Robinson annulation
reaction.8 Herein we explore catalysis of the aza-variant
of the aldol reaction and disclose the development of
chiral amine-based catalysis of direct asymmetric Man-
nich-type reactions.
In additional comparative studies of these catalysts,
aldimines derived from the reaction of o-anisidine with
benzaldehyde, p-acetamido benzaldehyde, and 1-naph-
thaldehyde (entries 1, 2, 4, Table 1a) were reacted in
DMSO/acetone (4:1) with 20 mol% catalyst at room
temperature Based on these results, we judged DMTC 3
to be the most promising catalyst for further investiga-
tions. In all reactions, the condensation product was
observed as a side-product and was the main product
when using preformed aldimines derived from o-
aminophenol. This side-product does not form by
deamination of the Mannich products since, upon
treatment of racemic 5a with DMTC 3 for 5 days under
the standard reaction conditions, neither the elimina-
tion product nor any resolution of the racemate was
detected.
During the course of screening studies for aldol and
Robinson annulation catalysts, various chiral amines
and thiazolidine carboxylic acids were identified as
promising Mannich catalysts8,9 and diamine salt 1,
L-
proline 2, and the penicillamine derivative
L-5,5-
Next, we attempted to extend our studies to the non-
aromatic aldimines derived from cyclohexanecarbox-
aldehyde and isobutyraldehyde. In these cases we were
* Corresponding author.
0040-4039/01/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01908-0

200
W. Notz et al. / Tetrahedron Letters 42 (2001) 199–201
Table 1.
unable to prepare the o-anisidine derived aldimines in
pure form. Alternatively, we have studied one-pot
three-component reactions (Table 1b) and found that
the reaction of a 1:1-mixture of aldehyde and p-ani-
sidine proceeded smoothly in DMSO/acetone (4:1) at
room temperature for 24 h in the presence of catalyst 3
to give the corresponding Mannich products 7a–f
(Table 1b). However, studies with aromatic aldehydes
in one-pot reactions with o-anisidine did not furnish the
desired Mannich products. Removal of the N-protec-
tive groups used here is readily achieved by treatment
with cerium ammonium nitrate (CAN).10
for the corresponding aldol reactions using these
catalysts.7,9
In summary, we have achieved direct catalytic enan-
tioselective Mannich-type reactions of both aliphatic
and aromatic aldimines with acetone by using simple
chiral amines 1–3 as catalysts providing the corre-
sponding b-amino ketones with high enantiomeric ex-
cesses. Further, chiral b-amino ketones 7a–f can be
synthesized in a one-pot three-component reaction con-
sisting of aldehyde, p-anisidine, acetone, and catalyst in
DMSO. Our best catalysts,
L
-proline 2 and penicil-
lamine derivative 3, are nontoxic, relatively inexpensive,
and readily available in both enantiomeric forms. This
methodology represents advantages in terms of reaction
conditions, catalyst stability, cost, and optical yield and
extends the scope of organocatalysis using chiral
amines. During the course of our studies, a report
regarding proline-catalyzed Mannich-type reactions
analogous to those described here was published.12
Like the analogous aldol reaction, these reactions are
assumed to proceed via an enamine mechanism. The
absolute stereochemistry of the new stereogenic center
formed by the catalysis of amines 2 and 3 has been
determined by comparison of the optical rotation and
chiral-phase HPLC data of derivative 8, which were
identical to those of 8 obtained after derivatization of 9
(Scheme 1) obtained via Kobayashi’s methodology.10
Catalysis mediated by diamine salt 1 yields products of
the opposite absolute configuration of those provided
by 2 and 3. The stereochemistry observed can be ration-
alized by transition state geometries I and II (Scheme
1).11 Note that the facial selectivity in these Mannich-
type reactions is opposite that which we have observed
Acknowledgements
This study was supported by the NIH (CA27489) and
the Skaggs Institute for Chemical Biology.

W. Notz et al. / Tetrahedron Letters 42 (2001) 199–201
201
OMe
NH
OMe
NH
OMe
NH
MeMgBr, THF
91%
MeMgBr, THF
88 %
EtSOC
ee > 98 %
O
HO
9
5d
ee = 88 %
8
see ref. 11
[α]D = + 87 (c=0.5, CHCl3)
O
R'
N
R
R'
N
O
S
N
N
R
H
N
H
H
H
II
I
si-attack
re-attack
Scheme 1. Determination of absolute configuration of Mannich-product 5d and potential transition states I and II.
References
1998, 63, 6090. (f) Kobayashi, S.; Ishitani, H.; Ueno, M.
J. Am. Chem. Soc. 1998, 120, 431. (g) Ishihara, K.;
Miyata, M.; Hattori, K.; Yamamoto, H. J. Am. Chem.
Soc. 1994, 116, 10520.
1. For reviews, see: (a) Kleinman, E. F. In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I.; Heathcock,
C. H., Eds.; Pergamon Press: New York, 1991; Vol. 2,
pp. 893–951. (b) Hart, D. J.; Ha, D.-C. Chem. Rev. 1989,
89, 1447. (c) Arend, M.; Westermann, B.; Risch, N.
Angew. Chem., Int. Ed. 1998, 37, 1044. (d) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069.
2. (a) Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12.
(b) Mu¨ller, R.; Goesmann, H.; Waldmann, H. Angew.
Chem., Int. Ed. 1999, 38, 184. (c) Enantioselective Synthe-
sis of i-Amino Acids; Juraisti, E., Ed.; Wiley-VCH: New
York, 1997. (d) Davis, F. A.; Szewczyk, J. M.; Reddy, R.
E. J. Org. Chem. 1996, 61, 2222. (e) Corey, E. J.; Decicco,
C. P.; Newbold, R. C. Tetrahedron Lett. 1991, 32, 5287.
(f) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520. (g)
Kambara, T.; Hussein, A.; Fujieda, H.; Iida, A.;
Tomioka, K. Tetrahedron Lett. 1998, 39, 9055.
5. (a) Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron
1999, 55, 8857. (b) Yamada, K.; Harwood, S. J.; Gro¨ger,
H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 3504.
6. (a) Wagner, J.; Lerner, R. A.; Barbas, III, C. F. Science
1995, 270, 1797. (b) Bjo¨rnestedt, R.; Zhong, G.; Lerner,
R. A.; Barbas, III, C. F. J. Am. Chem. Soc. 1996, 118,
11720. (c) Zhong, G.; Hoffmann, T.; Lerner, R. A.;
Danishefsky, S.; Barbas, III, C. F. J. Am. Chem. Soc.
1997, 119, 8131. (d) Hoffmann, T.; Zhong, G.; Last, B.;
Shabat, D.; Anderson, J.; Gramatikova, S.; Lerner, R.
A.; Barbas, III, C. F. J. Am. Chem. Soc. 1998, 120, 2768.
(e) Zhong, G.; Lerner, R. A.; Barbas, III, C. F. Angew.
Chem., Int. Ed. 1999, 38, 3738.
7. (a) List, B.; Lerner, R. A.; Barbas, III, C. F. J. Am.
Chem. Soc. 2000, 122, 2395; (b) Notz, W.; List, B. J. Am.
Chem. Soc. 2000, 122, 7386.
8. Bui, T.; Barbas, III, C.F. Tetrahedron Lett. 2000, 41,
6951.
9. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, III, C. F.,
submitted for publication.
10. Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
2000, 122, 8180.
3. Enders, D.; Ward, D.; Adam, J.; Raabe, G. Angew.
Chem., Int. Ed. 1996, 35, 981. See also: Risch, N.; Esser,
A. Liebigs Ann. Chem. 1992, 233.
4. (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.;
Tomioka, K. J. Am. Chem. Soc. 1997, 119, 2060. (b)
Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
1997, 119, 7153. (c) Hagiwara, E.; Fujii, A.; Sodeoka, M.
J. Am. Chem. Soc. 1998, 120, 2472. (d) Ferraris, D.;
Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc.
1998, 120, 4548. (e) Ferraris, D.; Young, B.; Cox, C.;
Drury III, W. J.; Dudding, T.; Lectka, T. J. Org. Chem.
11. A (Z)-imine has been proposed earlier for this type of
reaction. See: Corey, E. J.; Decicco, C. P.; Newbold, R.
C. Tetrahedron Lett. 1991, 39, 5287.
12. List, B. J. Am. Chem. Soc. 2000, 122, 9337.
.