ORGANIC LETTERS
A Chiral Solvent Effect in Asymmetric Organocatalysis
2010 Vol. 12, No. 10 2378-2381
Michael North* and Pedro Villuendas School of Chemistry and UniVersity Research Centre in Catalysis and Intensified Processing, Bedson Building, Newcastle UniVersity, Newcastle upon Tyne, NE1 7RU, U.K.
[email protected] Received March 29, 2010
ABSTRACT
Proline-catalyzed aldol reactions between enolizable ketones and aromatic aldehydes can be carried out in propylene carbonate. When enantiomerically pure propylene carbonate is used, the combination of (R)-proline and (R)-propylene carbonate constitutes a matched pair, while (S)-proline and (R)-propylene carbonate constitutes a mismatched pair.
Over the last 10 years, asymmetric organocatalysis has developed from a minor curiosity into an extensively used tool in synthesis.1 The first widely used catalyst was the amino acid proline,2 building on its use in the Hajos-ParrishEder-Sauer-Wiechert reaction,3 which had been reported over 30 years ago. While many other organocatalysts have since been designed and utilized, proline retains its place as the most sustainable of the organocatalysts as it is directly available from biological sources without any need for chemical transformations. Organocatalyzed reactions are commonly carried out in traditional solvents such as DMSO, DMF, and chlorinated solvents.1,2,4 Although both water5 and ionic liquids6 have also been used as solvents for organocatalyzed reactions, the (1) For recent reviews of asymmetric organocatalysis, see: (a) Pellissier, H. Tetrahedron 2007, 63, 9267. (b) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery Today 2007, 12, 8. (c) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (d) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (2) For reviews of proline-catalyzed reactions, see: (a) List, B. Synlett 2001, 1675. (b) Gro¨ger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529. (c) List, B. Tetrahedron 2002, 58, 5573. (d) List, B. Acc. Chem. Res. 2004, 37, 548. (e) Kazmaier, U. Angew. Chem., Int. Ed. 2005, 44, 2186. (3) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. 10.1021/ol1007313 2010 American Chemical Society Published on Web 04/16/2010
green credentials of both of these solvents have been questioned.7 In some cases, organocatalyzed reactions can also be carried out solvent-free.8 Recently, we reported9 the use of ethylene and propylene carbonate 1 and 2 (Figure 1) as sustainable10,11 solvents for (S)-proline 3 catalyzed crossaldol reactions between an enolizable ketone and an aromatic aldehyde. For reactions involving cyclohexanone, there was a significant difference in the chemical yield, diastereoselectivity, and enantioselectivity observed in the two solvents (4) (a) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481. (b) Kacprzak, K.; Gawron˜ski, J. Synthesis 2001, 961. (5) (a) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45, 8100. (b) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103. (c) Gruttadauria, M.; Giacalone, F.; Noto, R. AdV. Synth. Catal. 2009, 351, 33. (6) Toma, S.; Mecˇiarova, M.; Sˇebesta, R. Eur. J. Org. Chem. 2009, 321. (7) (a) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798. (b) Wu, B.; Liu, W.; Zhang, Y.; Wang, H. Chem.sEur. J. 2009, 15, 1804. (8) (a) Rodrı´guez, B.; Rantanen, T.; Bolm, C. Angew. Chem., Int. Ed. 2006, 46, 6924. (b) Rodrı´guez, B.; Bruckmann, A.; Bolm, C. Chem.sEur. J. 2007, 13, 4710. (9) (a) North, M.; Pizzato, F.; Villuendas, P. ChemSusChem 2009, 2, 862. (b) Clegg, W.; Harrington, R. W.; North, M.; Pizzato, F.; Villuendas, P. Tetrahedron: Asymmetry in press. (10) Cyclic carbonates are manufactured commercially by the reaction of epoxides with CO2: Clements, J. H. Ind. Eng. Chem. Res. 2003, 42, 663.
Table 1. Synthesis of Aldol Products 5a-f and 6a-e in Chiral and Achiral Propylene Carbonate entry aldehyde solvent proline
Figure 1. Structures of cyclic carbonates and proline.
with ethylene carbonate being the more effective solvent. In contrast, for reactions involving acetone as the enamine precursor, there was no consistent difference between the two solvents. This solvent effect was explained on the basis of the large difference in dielectric constant between the two solvents (90 and 65 for 1 and 2, respectively).12 In this letter, we show that propylene carbonate 2 also displays a pronounced chiral solvent effect in these reactions and that, by use of the appropriate combination of solvent enantiomer and proline enantiomer, the enantio- and diastereoselectivity of organocatalyzed aldol reactions can in some cases be significantly enhanced.
Scheme 1. Synthesis of Aldol Products from Cyclohexanonea
a Structures 5 and 6 show the relative configuration of the products. The absolute configuration of the major enantiomer depends on which enantiomer of proline is used as the catalyst.
As a test reaction, the aldol reaction between cyclohexanone and 4-trifluoromethylbenzaldehyde 4a was selected (Scheme 1), with reactions being carried out under the optimized conditions we have previously reported9 using 2 equiv of cyclohexanone, 10 mol % of proline, and 1 equiv of water (relative to the amount of aldehyde). The results of reactions carried out in both racemic and (R)-propylene carbonate are presented in Table 1. Entry 1 of Table 1 shows the standard result obtained using racemic propylene carbonate 2 as solvent. Replacing racemic (11) Recent catalyst developments allow the synthesis of cyclic carbonates to be carried out under very mild conditions using waste CO2: (a) Mele´ndez, J.; North, M.; Pasquale, R. Eur. J. Inorg. Chem. 2007, 3323. (b) Mele´ndez, J.; North, M.; Pasquale, R. Angew. Chem., Int. Ed. 2009, 48, 2946. (c) Mele´ndez, J.; North, M.; Villuendas, P. Chem. Commun. 2009, 2577. (d) North, M.; Villuendas, P.; Young, C. Chem.sEur. J. 2009, 11454. (e) Metcalfe, I. S.; North, M.; Pasquale, R.; Thursfield, A. Energy EnViron. Sci. 2010, 3, 212. (12) Silva, L. B.; Freitas, L. C. G. J. Mol. Struct. (THEOCHEM) 2007, 806, 23. (13) (a) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417. (b) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.; Meo, P. L.; Riela, S.; Noto, R. Eur. J. Org. Chem. 2007, 4688. (14) Billimoria, J. D. J. Chem. Soc. 1955, 1126. Org. Lett., Vol. 12, No. 10, 2010
1 2 3 4 5g 6g 7g 8 9 10 11 12 13 14 15 16 17 18 19
14a 4a 4a 4a 4b 4b 4b 4c 4c 4c 4d 4d 4d 4e 4e 4e 4f 4f 4f
(RS)-2 (R)-2 (R)-2 (R)-2 (RS)-2 (R)-2 (R)-2 (RS)-2 (R)-2 (R)-2 (RS)-2 (R)-2 (R)-2 (RS)-2 (R)-2 (R)-2 (RS)-2 (R)-2 (R)-2
(S) (S) (R) (RS) (S) (S) (R) (S) (S) (R) (S) (S) (R) (S) (S) (R) (S) (S) (R)
yield ee 5 ee 6 (%)h de (5:6)a (%)b (%)b 49 26 63 43 47 65 75 21 22 36 83 89 94 22 67 72 98 89 98
4.7:1 3.3:1 6.3:1 6.1:1 4.5:1 6:1 7:1 4.8:1 3:1 4.5:1 7.9:1 3.6:1 5.9:1 7.4:1 7.6:1 9.2:1 100:0 100:0 100:0
93c 52c 96d 1 93c 85c 96d 95c 60c 97d 91c 85c 91d 92c 95c 96d 98c 98c 98d
68e 44e 66f 0 77e 55e 75f 73e 51e 82f 86e 68e 79f 91e 79e 86f
a Determined by 1H NMR spectroscopy. b Determined by chiral HPLC analysis on a Chiralpak AD-H column and comparison of retention times with literature data13 and racemic standards.14 The low intensity of the HPLC peaks corresponding to compound 6 means that differences in ee of
