Proline-catalyzed highly enantioselective and anti-selective mannich reaction of unactivated ketones: Synthesis of chiral α-amino acids

Article abstract of DOI:10.1002/anie.200803515

(Chemical Equation Presented) Universal L-proline: The title reaction complements well-known syn-selective Mannich reactions. The Mannich products can be converted readily into the free amino acids by hydrogenolytic deprotection under mild conditions (see scheme). DMSO = dimethyl sulfoxide; R¹ = alkyl, OH; R² = alkyl.

Full text of DOI:10.1002/anie.200803515

Angewandte
Chemie
DOI: 10.1002/anie.200803515
Asymmetric Catalysis
Proline-Catalyzed Highly Enantioselective and anti-Selective
Mannich Reaction of Unactivated Ketones: Synthesis of Chiral
a-Amino Acids**
Bjꢀrn T. Hahn, Roland Frꢀhlich, Klaus Harms, and Frank Glorius*
Dedicated to Professor Manfred T. Reetz on the occasion of his 65th birthday
Mannich reactions have proved very useful for the synthesis
of enantiomerically pure amino alcohol, aminocarbonyl, and
amino acid derivatives, which are important structural motifs
of biologically active molecules. In this respect, the develop-
ment of enantioselective organocatalytic Mannich reactions,
particularly those catalyzed by proline, represents a major
advancement.[1,2] In contrast to metal-catalyzed methods that
require the use of enol ethers and other preformed nucleo-
philes, pyrrolidine-based catalysts enable the direct and atom-
economical coupling of aldehydes or ketones with imines by
in situ enamine formation. Furthermore, by using proline or
related amine organocatalysts, Mannich products can be
formed with two adjacent stereocenters, predominantly in the
syn configuration.[3] The use of iminoglyoxylates, such as 1, as
electrophiles is of particular interest, as valuable a-amino acid
derivatives, such as 2, are formed (Scheme 1).[3c–e] The
development of a direct anti-selective Mannich reaction has
been a longstanding challenge. Interestingly, the use of
3-pyrrolidinecarboxylic acid (b-proline) in place of 2-pyr-
rolidinecarboxylic acid (proline or a-proline) leads to an
inversion of the selectivity and, thus, the preferential for-
mation of anti products.[4] However, b-proline, although of
low structural complexity, requires a 5- to 10-step synthesis.[5]
We have developed a highly enantio- and anti-selective
Mannich reaction of unactivated ketones and readily avail-
able cyclic imines 3 with simple l-proline as the catalyst
(Scheme 1). The Mannich products are interesting a-amino
Scheme 1. Proline-catalyzed Mannich reactions with representative
selectivities. DMSO=dimethyl sulfoxide, PMP=p-methoxyphenyl.
acid derivatives that contain a new protecting group. Facile
hydrogenolytic one-step cleavage of the protecting group
under mild conditions provides free a-amino acids with
unchanged stereoisomeric purity, as indicated by NMR
spectroscopy.
Typically, acyclic imines are employed as substrates in
organocatalytic Mannich reactions. We reasoned that cyclic
iminoglyoxylates 3[6] would be useful alternative imine
substrates locked in a Z configuration.[7,8] The change in the
configuration of the imine double bond should result in the
formation of anti-configured amino acid derivatives. Imines 3
can be prepared readily from commercially available starting
materials (Scheme 2). The key step of the synthesis is the
SeO2-mediated rearrangement of the 4,4-disubstituted
2-methyl-1,3-oxazoline 5 to the desired 5,5-disubstituted
5,6-dihydro-1,4-oxazin-2-one 3.[8]
[*] B. T. Hahn, Dr. R. Frꢀhlich,[+] Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfꢁlische Wilhelms-Universitꢁt Mꢂnster
Corrensstrasse 40, 48149 Mꢂnster (Germany)
Fax: (+49) 251-8333202
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/en/
index.html
Dr. K. Harms[+]
Fachbereich Chemie, Philipps-Universitꢁt Marburg
Hans-Meerwein-Strasse, 35032 Marburg (Germany)
Scheme 2. Synthesis of the acceptors.
[+] X-ray crystal-structure analysis.
At the outset of our study, we compared the 5,5-dimethyl-
and 5,5-diphenyl-substituted imine substrates 3a and 3b.
Both imines reacted with cyclohexanone to give the corre-
sponding Mannich product with high diastereo- and enantio-
selectivity (Table 1, entries 1 and 2). Owing to the higher
levels of selectivity observed with dihydrooxazinone 3b, this
imine was selected for further l-proline-catalyzed reactions
[**] We thank the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft for generous financial support. The
research of F.G. was supported by the Alfried Krupp Prize for Young
University Teachers of the Alfried Krupp von Bohlen und Halbach
Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803515.
Angew. Chem. Int. Ed. 2008, 47, 9985 –9988
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9985

Communications
Table 1: Scope and selectivity of the anti-selective Mannich reaction.[a]
Entry
Product
Yield[b] [%]
d.r.[c]
ee [d] [%]
Entry
9
Product
Yield[b] [%]
d.r.[c]
ee[d] [%]
>99
1[e]
80
10:1
95
73
12:1
2[f]
91
78
>20:1
>99
10[f]
75
30
–
–
81
80
3[g]
20:1
99
11
4
60
>20:1
97
12[h]
59
>20:1
98
5[h]
30
70
>20:1
>20:1
99
13
14
15
91[i]
70[i]
84[k]
>20:1
>20:1
10:1
>99
>99[j]
98
6
>99
7
90[i]
>20:1
94
8[h]
40
10:1
>99
[a] Reaction conditions: 3b (1 mmol), l-proline (0.3 mmol), ketone (3 mmol), anhydrous DMSO (10 mL), 24 h. [b] Yield of the isolated product.
[c] The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of the crude product. [d] The ee value was determined by HPLC or GC
on a chiral stationary phase. [e] Imine 3a was used. [f] Proline: 0.2 equivalents. [g] (S)-5-Pyrrolidin-2-yl-1H-tetrazole and the solvent CH2Cl2 were used
instead of l-proline and DMSO. [h] Ketone: 5 equivalents. [i] A mixture of regioisomers was obtained. [j] The ee value after crystallization is given. [k] A
mixture of diastereomers was obtained.
with a series of different ketones in dry DMSO. Clean product
formation was observed, as well as high levels of stereoselec-
tivity. The use of cyclic ketones with different ring sizes led to
the desired products with very high selectivities (Table 1,
entries 2–5). When the more lipophilic catalyst 5-pyrrolidin-2-
yl-1H-tetrazole was used in CH2Cl2,[9a] cyclohexanone reacted
smoothly with the same levels of stereoselectivity as observed
with proline (Table 1, entry 3). When cyclopentanone, which
is known for its relatively low reactivity in related studies,[9]
was used, the product was formed in low yield, but the high
selectivity was maintained (Table 1, entry 5). Acyclic aliphatic
ketones reacted highly selectively to form the desired amino
acid derivatives (Table 1, entries 6–9). Typically, small
amounts of regioisomers were also formed. Interestingly,
with the methyl ketones acetone and mesityl oxide, which
give rise to products with one stereocenter, lower levels of
enantioselectivity were observed (Table 1, entries 10 and 11).
Finally, very high levels of selectivity were observed with a
number of functionalized ketones (Table 1, entries 12–15).
Especially noteworthy is the high enantioselectivity of the
reaction with hydroxyacetone to form 4m (98% ee; (Table 1,
entry 15).
The absolute and relative configurations of some repre-
sentative products (Table 1, entries 1, 2, 6, and 15) were
9986 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 9985 –9988

Angewandte
Chemie
established by X-ray crystallography (Figure 1).[10] The
expected a(R),b(S) configuration was found in all cases.
The absolute configuration of the other Mannich products
was assigned by analogy and through comparison of their sign
para-methoxyphenyl group.[2] Oxidative conditions are
required to deprotect the nitrogen atom.[3d] A complementary
and readily cleavable protecting group would greatly expand
the usefulness of organocatalytic Mannich reactions in com-
plex multistep syntheses. The diphenylethylene group in our
Mannich products acts as a protecting group for both the N
and the O terminus of an a-amino acid.[13]
Deprotection of the chiral 1,4-morpholin-2-one products
is possible under mild conditions by simple hydrogenolysis.
This simultaneous deprotection of the N and the O terminus
provided the free amino acids without any epimerization, as
indicated by NMR spectroscopy (Scheme 4). The lipophilic
by-product 2,2-diphenylethanol (8) can be removed easily
with organic solvents; protonated amino acids 7 were
obtained as white solids after lyophilization.
Figure 1. Crystal structure of the morpholinone 4d.
of optical rotation.[11] This stereoselectivity is in agreement
with the predicted attack of the enamine at the Re face of the
imine to provide the anti-configured products (Scheme 3).
Scheme 4. Hydrogenative cleavage of the diphenylethylene protecting
group. General procedure: The 5,5-diphenyl-1,4-morpholin-2-one was
stirred with concentrated aqueous HBF4 (1 equiv) and 20% (w/w)
Pd(OH)2/C in EtOH/H2O (2:1) at 408C under H2 (40 bar). Without
HBF4, the reaction is slower.
Scheme 3. Houk model of the transition state of the proline-catalyzed
Mannich reaction (TS1) applied to the cyclic imine 3b.[12]
In summary, we have developed a highly enantio- and
anti-selective proline-catalyzed Mannich reaction of unacti-
vated ketones. We demonstrated that the use of cyclic
acceptors enables the highly stereoselective synthesis of
chiral 3-substituted 1,4-morpholin-2-ones. These products
correspond to a-d-amino acids that are protected at the N
and O terminus by the diphenylethylene group. This protect-
ing group for a-amino acids can be cleaved readily by
hydrogenolysis in aqueous ethanol to furnish the free amino
acid. In combination with asymmetric catalysis, these cyclic
iminoglyoxylates should become versatile building blocks for
the synthesis of chiral a-amino acids.
The application of the generally accepted model for the
transition state of the proline-catalyzed Mannich reaction of
acyclic imines (TS1)[12] to the corresponding reaction of the
cyclic imine 3b is informative (Scheme 3). For 3b, a reason-
able chairlike transition state (TS2) and a boatlike transition
state (TS3) can be envisaged. Comparison of TS1 and TS2
shows that products with opposite (syn versus anti) config-
urations result. We were surprised to find that the bulky
geminal diphenyl group does not negatively affect the
selectivity, although it comes into close proximity with the
proline ring. However, the geminal diphenyl group might
increase the energy of undesired transition states, such as TS3,
and thus favor the desired transition state TS2. In T3, there is
an unfavorable steric interaction between the geminal
diphenyl group and R3. The absence of this interaction
might explain the low levels of selectivity observed for the
reactions of acetone and mesityl oxide (R3 = H; Table 1,
entries 9 and 10).
Received: July 19, 2008
Published online: November 12, 2008
Keywords: amino acids · asymmetric catalysis ·
.
Mannich reaction · organocatalysis · proline
Not only does the diphenylethylene group have a
stereodirecting effect, but it also functions as a new protecting
group that can be cleaved readily to give the free a-amino
acids. For reasons of substrate and product stability and
activity, N-aryl imines are often used as electrophiles in
known organocatalytic Mannich reactions, generally with the
[1] For a leading reference on (proline) organocatalysis, see: a) B.
List, Chem. Commun. 2006, 819; for further excellent reviews,
see: b) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248;
Angew. Chem. Int. Ed. 2004, 43, 5138; c) A. Berkessel, H.
Grꢀger, Asymmetric Organocatalysis: From Biomimetic Con-
cepts to Applications in Asymmetric Synthesis, Wiley-VCH,
Angew. Chem. Int. Ed. 2008, 47, 9985 –9988
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9987

Communications
Weinheim, 2005; d) J. Seayad, B. List, Org. Biomol. Chem. 2005,
3, 719.
[6] For other examples with cyclic imines, see: a) W. Zhuang, S.
Saaby, K. A. Jørgensen, Angew. Chem. 2004, 116, 4576; Angew.
Chem. Int. Ed. 2004, 43, 4476; b) B. Jiang, J. J. Dong, Y. G. Si,
X. L. Zhao, Z. G. Huang, M. Xu, Adv. Synth. Catal. 2008, 350,
1360; for the use of cyclic imines as chiral templates, see: c) X.
Chen, J. Chen, J. Zhu, Synthesis 2006, 4081; d) K. Mori, K.
Rikimaru, T. Kan, T. Fukuyama, Org. Lett. 2004, 6, 3095; e) S.
Tohma, K. Rikimaru, A. Endo, K. Shimamoto, T. Kan, T.
Fukuyama, Synthesis 2004, 909; f) M. Ueda, H. Miyabe, M.
Teramachi, O. Miyata, T. Naito, Chem. Commun. 2003, 426;
g) Y.-J. Chen, F. Lei, L. Liu, D. Wang, Tetrahedron 2003, 59, 7609.
[7] K. Watanabe, T. Hirasawa, K. Hiroi, Chem. Pharm. Bull. 2002,
50, 372.
[2] For reviews on organocatalytic Mannich reactions, see: a) A.
Ting, S. E. Schaus, Eur. J. Org. Chem. 2007, 5797; b) J. M. M.
Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg, F. P. J. T.
Rutjes, Chem. Soc. Rev. 2008, 37, 29; for a general review on the
use of chiral auxiliaries, also in Mannich reactions, see: c) Y.
Gnas, F. Glorius, Synthesis 2006, 1899.
[3] For selected examples of proline-catalyzed Mannich reactions,
see: a) B. List, J. Am. Chem. Soc. 2000, 122, 9336; b) B. List, P.
Pojarliev, W. T. Biller, H. J. Martin, J. Am. Chem. Soc. 2002, 124,
827; c) A. Cꢁrdova, W. Notz, G. Zhong, J. M. Betancort, C. F.
Barbas III, J. Am. Chem. Soc. 2002, 124, 1842; d) W. Notz, S.
Watanabe, N. S. Chowdari, G. Zhong, J. Betancort, F. Tanaka,
C. F. Barbas III, Adv. Synth. Catal. 2004, 346, 1131; e) N. S.
Chowdari, J. T. Suri, C. F. Barbas III, Org. Lett. 2004, 6, 2507;
f) D. Enders, C. Grondal, M. Vrettou, G. Raabe, Angew. Chem.
2005, 117, 4147; Angew. Chem. Int. Ed. 2005, 44, 4079; g) D.
Seebach, A. K. Beck, D. M. Badine, M. Limbach, A. Eschen-
moser, A. M. Treasurywala, R. Hobi, W. Prikoszovich, B. Linder,
Helv. Chim. Acta 2007, 90, 425.
[4] a) H. Zhang, S. Mitsumori, N. Utsumi, M. Imai, N. Garcia-
Delgado, M. Mifsud, K. Albertshofer, P. H.-Y. Cheong, K. N.
Houk, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2008, 130,
875; b) H. Zhang, M. Mifsud, F. Tanaka, C. F. Barbas III, J. Am.
Chem. Soc. 2006, 128, 9630; for other selected examples of
organocatalytic anti-selective Mannich reactions, see: c) Q.-X.
Guo, H. Liu, C. Guo, S.-W. Luo, Y. Gu, L.-Z. Gong, J. Am. Chem.
Soc. 2007, 129, 3790; d) T. Kano, Y. Yamaguchi, O. Tokuda, K.
Maruoka, J. Am. Chem. Soc. 2005, 127, 16408; e) I. Ibrahem, A.
Cordova, Chem. Commun. 2006, 1760, f) J. Franzꢂn, M. Marigo,
D. Fielenbach, T. C. Wabnitz, A. Kjærsgaard, K. A. Jørgensen, J.
Am. Chem. Soc. 2005, 127, 18296; g) T. Kano, Y. Yamaguchi, O.
Tokuda, K. Maruoka, J. Am. Chem. Soc. 2005, 127, 16408. In
general, high selectivities were observed with cyclic and acyclic
ketones; however, low levels of selectivity were observed with
acyclic a-unfunctionalized ketones.
[8] C. M. Shafer, D. I. Morse, T. F. Molinski, Tetrahedron 1996, 52,
14475.
[9] a) A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold,
S. V. Ley, Org. Biomol. Chem. 2005, 3, 84; b) V. Aureggi, V.
Franckvicius, M. O. Kitching, S. V. Ley, D. A. Longbottom, A. J.
Oelke, G. Sedelmeier, Org. Synth. 2008, 85, 72; c) A. Hartikka,
P. I. Arvidsson, Tetrahedron: Asymmetry 2004, 15, 1831; d) H.
Torii, M. Nakadai, K. Ishihara, S. Saito, H. Yamamoto, Angew.
Chem. 2004, 116, 2017; Angew. Chem. Int. Ed. 2004, 43, 1983.
[10] CCDC 694197 (4d), 694198 (4m), 694199 (4a), and 694982 (6)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[11] The sign of optical rotation is positive for products 4a–m
(Table 1, entries 2–15).
[12] a) S. Bahmanyar, K. N. Houk, Org. Lett. 2003, 5, 1249; b) L.
Hoang, S. Bahmanyar, K. N. Houk, B. List, J. Am. Chem. Soc.
2003, 125, 16; c) S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc.
2001, 123, 12911; d) S. Bahmanyar, K. N. Houk, H. J. Martin, B.
List, J. Am. Chem. Soc. 2003, 125, 2475. TS2 and TS3 are rather
simple applications of the Houk model and are not backed by
any further calculations; see also Ref. [3g].
[13] The related diphenylmethyl group has been used previously as a
protecting group for amines: a) K. M. Czerwinski, L. Deng, J. M.
Cook, Tetrahedron Lett. 1992, 33, 4721; b) E. Bacquꢂ, J.-M. Paris,
S. Le Bitoux, Synth. Commun. 1995, 25, 803.
[5] J. Blanchet, M. Pouliquen, M.-C. Lasne, J. Rouden, Tetrahedron
Lett. 2007, 48, 5727, and references therein. The authors state the
price of b-proline to be 265 euros per gram.
9988 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 9985 –9988