Organocatalysed asymmetric Mannich reactions

(Cooperation Northern Netherlands) and EFRO (European
Fund for Regional Development).
Scheme 44
With 4-Cl or 4-F-substituents, the reaction of acyclic ketones
with aromatic aldehydes in the presence of (substituted) aniline
also proceeded with high enantioselectivities (up to 86% ee).
No diastereoselective examples were reported.
5 Conclusions
This survey of organocatalytic methods for the synthesis of
asymmetric Mannich bases leads us to conclude that this is a
promising field for which many new applications in the
synthesis of biologically active compounds will emerge. It also
becomes evident that the use of proline as the catalyst gives
easy access to syn-products in high yields with high regio-,
chemo-, diastereo- and enantioselectivity. Since proline is
commercially available in L- and D-form, the products can also
be obtained in both enantiomeric forms. Both one-pot threecomponent
reactions and reactions with preformed imines
have extensively been studied using unmodified ketones and
aldehydes as Mannich-donors. It must be noted that a
relatively high catalyst loading generally has to be used
(typically 10–30 mol%). This is mainly due to the low solubility
of proline in (a)polar organic solvents. Some research groups
have therefore developed new, more soluble catalysts to
overcome this problem. However, this led to more expensive
catalysts of which the scope still needs to be fully investigated.
Moreover, since proline catalysis only gives access to synadducts,
anti-directing catalysts were also desired. Nowadays,
a series of enamine forming amines are available that give rise
to the anti-products in good selectivity.
Besides catalysis by proline and derivatives, chiral bases
have also been successfully employed in combination with
electron-poor imines and active methylene compounds.
Success in this particular reaction is often facilitated by
introducing thiourea moieties, that interact with the system
through cooperative hydrogen bonding.
Finally, chiral Brønsted acids (mostly phosphoric acids)
have been employed to include the iminium ion in a chiral ion
pair, which also results in enantioselective addition onto the
iminium species.
Acknowledgements
anti-Selective Brønsted acid-catalysed reactions.
This work forms part of the Ultimate Chiral Technology
project supported in part with funds provided by SNN
References
1 A. Berkessel and H. Gröger, Asymmetric Organocatalysis, Wiley-
VCH, Weinheim, 2005; P. I. Dalko, Enantioselective
Organocatalysis, Wiley-VCH, Weinheim, 2007.
2 M. Arend, B. Westermann and N. Risch, Angew. Chem., Int. Ed.,
1998, 37, 1044–1070.
3 For a short survey of highlights in this field, see: M. M. B. Marques,
Angew. Chem., Int. Ed., 2006, 45, 348.
4 For a recent review in this area, see: A. Ting and Scott E. Schaus,
Eur. J. Org. Chem., 2007, DOI: 10.1002/ejoc.200700409.
5 B. List, J. Am. Chem. Soc., 2000, 122, 9336.
6 B. List, P. Pojarliev, W. T. Biller and H. J. Martin, J. Am. Chem.
Soc., 2002, 124, 827–833, and references therein.
7 W. Notz, S. Watanabe, N. S. Chowdari, G. Zhong, J. M.
Betancort, F. Tanaka and C. F. Barbas III, Adv. Synth. Catal.,
2004, 346, 1131–1140, and references therein.
8 W. Notz, F. Tanaka and C. F. Barbas III, Acc. Chem. Res., 2004,
37, 580–591, and references therein.
9 A. Córdova, Chem.–Eur. J., 2004, 10, 1987–1997.
10 Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima,
M. Shoji and K. Sakai, Angew. Chem., Int. Ed., 2003, 42,
3677–2680.
11 Y. Hayashi, T. Urushima, M. Shin and M. Shoji, Tetrahedron,
2005, 61, 11393–11404.
12 I. Ibrahem, W. Zou, Y. Xu and A. Córdova, Adv. Synth. Catal.,
2006, 348, 211–222, and references therein.
13 S. Fustero, D. Jiménez, J. F. Sanz-Cervera, M. Sánchez-Roselió,
E. Esteban and A. Simón-Fuentes, Org. Lett., 2005, 7, 3433, and
references therein.
14 B. Westermann and C. Neuhaus, Angew. Chem., Int. Ed., 2005, 44,
4077–4079.
15 D. Enders, C. Grondal, M. Vrettou and G. Raabe, Angew. Chem.,
Int. Ed., 2005, 44, 4079–4083.
16 I. Ibrahem, W. Zou, M. Enqvist, Y. Xu and A. Córdova, Chem.–
Eur. J., 2005, 11, 7024–7029.
17 A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold and
S. V. Ley, Org. Biomol. Chem., 2005, 3, 84–96.
18 N. S. Chowdari, M. Ahmad, K. Albertshofer, F. Tanaka and
C. F. Barbas, III., Org. Lett., 2006, 8, 2839–2842.
19 W. Wang, J. Wang and H. Li, Tetrahedron Lett., 2004, 45,
7243–7246.
20 Y. Hayashi, J. Yamaguchi, K. Hibino, T. Sumiya, T. Urushima,
M. Shoji, D. Hashizume and H. Koshino, Adv. Synth. Catal., 2004,
346, 1435–1439.
21 P. G. M. Wuts and T. W. Greene, Greene’s Protective
Groups in Organic Synthesis, Wiley-VCH, Weinheim, 4th edn,
2007.
22 S. De Lamo Marin, T. Martens, C. Mioskowski and J. Royer,
J. Org. Chem., 2005, 70, 10592–10595.
23 J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg,
P. L. Alsters, F. L. van Delft and F. P. J. T. Rutjes, Tetrahedron
Lett., 2006, 47, 8109–8113.
24 J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg,
H. E. Schoemaker, M. Schürmann, F. L. van Delft and
F. P. J. T. Rutjes, Adv. Synth. Catal., 2006, 349, 1332–1336.
25 D. Enders, C. Grondal and M. Vrettou, Synthesis, 2006, 21,
3597–3604.
26 J. Vesely, R. Rios, I. Ibrahem and A. Córdova, Tetrahedron Lett.,
2007, 48, 421–425.
27 J. W. Wang, M. Stadtler and B. List, Angew. Chem., Int. Ed., 2007,
46, 609–611.
28 A. Córdova and C. F. Barbas, III., Tetrahedron Lett., 2002, 43,
7749–7752.
29 W. Notz, F. Tanaka, S.-I. Watanabe, N. S. Chowdari, J. M.
Turner, R. Thayumanavan and C. F. Barbas, J. Org. Chem., 2003,
68, 9624–9634.
30 J. Franzén, M. Marigo, D. Fielenbach, T. C. Wabnitz,
A. Kjærsgaerd and K. A. Jørgensen, J. Am. Chem. Soc., 2005,
127, 18296–18304.
40 | Chem. Soc. Rev., 2008, 37, 29–41 This journal is ß The Royal Society of Chemistry 2008