1924
M. Morcillo et al.
PAPER
Chem. Soc. 1985, 107, 4252. (b) North, M.; Zagotto, G.
Synlett 1995, 639. (c) Albers, T.; Biagini, S. C. G.; Hibbs, D.
E.; Hursthouse, M. B.; Malik, K. M. A.; North, M.; Uriarte,
E.; Zagotto, G. Synthesis 1996, 393.
Aldol Reactions of Cyclohexanone with Aromatic Aldehydes
Catalysed by Phenylalanine (8) or Tryptophan (14); General
Procedure
To a mixture of S-amino acid 8 or 14 (10 mol%) and aldehyde (1
mmol) was added propylene or ethylene carbonate (5 or 6; 1 mL),
cyclohexanone (22c; 196 mg, 2 mmol), and H2O (0–5 mmol) under
an inert atmosphere. The resulting mixture was stirred at r.t. for 24–
144 h. The reaction mixture was then poured into H2O (10 mL) and
extracted with Et2O (10 mL). The organic phase was washed with
H2O (7 × 10 mL), dried (Na2SO4), and the solvent removed in vac-
uo. The residue at this stage was analysed by 1H NMR spectroscopy
and chiral HPLC to obtain the diastereoselectivity and enantioselec-
tivities. The residue was then purified by column chromatography
(gradient from hexane–EtOAc, 9:1 to 4:1) to give the aldol prod-
ucts. Racemic HPLC standards were prepared by a literature proce-
dure.24 All of the aldol products are known compounds and the
absolute configuration of the major enantiomer of the aldol products
was determined by comparison of the chiral HPLC retention times
with literature data.11
(4) The current UK Aldrich catalogue price for (S)-proline is
£ 0.31/g whilst the cost of (R)-proline is £ 13.32/g (prices
based on the largest available quantities). In contrast, the
S-enantiomers of phenylalanine and tryptophan are available
for £ 0.28/g and £ 0.54/g, respectively and the R-enantiomers
are available for £ 2.53/g and £ 2.11/g, respectively. Thus,
(R)-proline is 43 times more expensive than (S)-proline,
whereas (R)-phenylalanine is only 9 times as expensive as
(S)-phenylalanine and (R)-tryptophan is only 4 times as
expensive as (S)-tryptophan.
(5) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G.
R.; Leazer, J. L. Jr.; Linderman, R. J.; Lorenz, K.; Manley,
J.; Pearlman, B. A.; Wells, A.; Zaksh, A.; Zhang, T. Y.
Green Chem. 2007, 9, 411.
(6) (a) Rodríguez, B.; Rantanen, T.; Bolm, C. Angew. Chem. Int.
Ed. 2006, 46, 6924. (b) Rodríguez, B.; Bruckmann, A.;
Bolm, C. Chem. Eur. J. 2007, 13, 4710.
(7) (a) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew.
Chem. Int. Ed. 2006, 45, 8100. (b) Gruttadauria, M.;
Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33.
(8) Toma, Š.; Mečiarova, M.; Šebesta, R. Eur. J. Org. Chem.
2009, 321.
(9) (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. Eur. J. 2009, 15, 1804.
(10) Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D. G.
J. Am. Chem. Soc. 2007, 129, 15100.
(11) (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 2010,
21, 1262. (c) North, M.; Villuendas, P. Org. Lett. 2010, 12,
2378.
(12) Schäffner, B.; Schäffner, F.; Verevkin, S. P.; Börner, A.
Chem. Rev. 2010, 110, 4554.
(13) (a) North, M.; Omedes-Pujol, M. Tetrahedron Lett. 2009,
50, 4452. (b) North, M.; Omedes-Pujol, M. Belstein J. Org.
Chem. 2010, 6, 1043.
Aldol Reactions of 4-Nitrobenzaldehyde with Ketones Cataly-
sed by Phenylalanine (8) or Tryptophan (14); General Proce-
dure
To a mixture of S-amino acid 8 or 14 (10 mol%) and ketone 22 (2
mmol for acetone and cyclopentanone, 5 mmol for pyranone, and 8
mmol for acetone) was added propylene or ethylene carbonate (1
mL), 4-nitrobenzaldehyde (151 mg, 1 mmol), and H2O (1 mmol ex-
cept for reactions involving acetone as substrate when no H2O was
added) under an inert atmosphere. The resulting mixture was stirred
at r.t. for 72 h. The reaction mixture was then poured into H2O (10
mL) and extracted with Et2O (10 mL). The organic phase was
washed with H2O (7 × 10 mL), dried (Na2SO4), and the solvent re-
moved in vacuo. The residue at this stage was analysed by 1H NMR
spectroscopy and chiral HPLC to obtain the diasteroselectivity and
enantioselectivities. The residue was then purified by column chro-
matography (gradient from hexane–EtOAc, 9:1 to 1:1) to give the
aldol products. Racemic HPLC standards were prepared by a liter-
ature procedure.24 All of the aldol products are known compounds
and the absolute configuration of the major enantiomer of the aldol
products was determined by comparison of the chiral HPLC reten-
tion times with literature data.11
(14) Clements, J. H. Ind. Eng. Chem. Res. 2003, 42, 663.
(15) Silva, L. B.; Freitas, L. C. G. J. Mol. Struct.: THEOCHEM
2007, 806, 23.
Supporting Information for this article is available online at
(16) (a) Yoshida, M.; Ihara, M. Chem. Eur. J. 2004, 10, 2886.
(b) Dai, W.-L.; Luo, S.-L.; Yin, S.-F.; Au, C.-T. Appl. Catal.,
A 2009, 366, 2. (c) Sakakura, T.; Kohno, K. Chem.
Commun. 2009, 1312. (d) North, M.; Pasquale, R.; Young,
C. Green Chem. 2010, 12, 1514. (e) Ballivet-Tkatchenko,
D.; Dibenedetto, A. Synthesis of Linear and Cyclic
Carbonates, In Carbon Dioxide as Chemical Feedstock;
Aresta, M., Ed.; Wiley-VCH: Weinheim, 2010, 169–212.
(17) (a) Meléndez, J.; North, M.; Pasquale, R. Eur. J. Inorg.
Chem. 2007, 3323. (b) Meléndez, J.; North, M.; Pasquale, R.
Angew. Chem. Int. Ed. 2009, 48, 2946. (c) Meléndez, J.;
North, M.; Villuendas, P. Chem. Commun. 2009, 2577.
(d) Clegg, W.; Harrington, R. W.; North, M.; Pasquale, R.
Chem. Eur. J. 2010, 16, 6828.
References
(1) (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. (e) Pellissier, H. Recent Developments in
Asymmetric Organocatalysis; RSC Publishing: Cambridge,
2010.
(2) (a) List, B. Synlett 2001, 1675. (b) Gröger, H.; Wilken, J.
Angew. Chem. Int. Ed. 2001, 40, 529. (c) List, B.
Tetrahedron 2002, 58, 5573. (d) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481. (e) List, B. Acc. Chem. Res.
2004, 37, 548. (f) Kazmaier, U. Angew. Chem. Int. Ed. 2005,
44, 2186.
(18) North, M.; Villuendas, P.; Young, C. Chem. Eur. J. 2009,
11454.
(19) Meléndez, J.; North, M.; Villuendas, P.; Young, C. Dalton
Trans. 2011, 40, 3885.
(20) Metcalfe, I. S.; North, M.; Pasquale, R.; Thursfield, A.
(3) Proline is also widely used as a chiral reagent and chiral
auxiliary. For examples, see: (a) Belokon, Y. N.; Bulychev,
A. G.; Vitt, S. V.; Struchkov, Y. T.; Batsanov, A. S.;
Timofeeva, T. V.; Tsyryapkin, V. A.; Ryzhov, M. G.;
Lysova, L. A.; Bakhmutov, V. I.; Belikov, V. M. J. Am.
Energy Environ. Sci. 2010, 3, 212.
(21) (a) Bassan, A.; Zou, W.; Reyes, E.; Himo, F.; Córdova, A.
Angew. Chem. Int. Ed. 2005, 44, 7028. (b) Córdova, A.;
Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W.
Synthesis 2011, No. 12, 1918–1925 © Thieme Stuttgart · New York