M. Bonsignore et al. / Tetrahedron 68 (2012) 8251e8255
8255
column chromatography with a 97:3 CH2Cl2/MeOH mixture as el-
Supplementary data
uent. To a stirred solution of isolated product (1 equiv, 2.9 mmol) in
dry THF (15 mL) were added diphenylphosphinic chloride
(2.5 equiv, 7.5 mmol) and TEA (2.5 equiv, 7.5 mmol) at 0 ꢀC. After
the additions, the mixture was heated to reflux overnight. The re-
action mixture was cooled to room temperature and NaHCO3
(3 mL) was added. The CH2Cl2 layer was separated and the water
layer was washed with CH2Cl2 (3ꢂ10 mL). The combined organic
solution was dried over Na2SO4, filtered and the solvent was
evaporated. The product was purified by column chromatography
with a 9:1 CH2Cl2/CH3OH mixture as eluent (18 % yield).
Synthesis and characterization of catalysts 2e5, selected 1H
NMR and HPLC chromatograms of chiral aldol products. Supple-
mentary data associated with this article can be found in the online
References and notes
1. Okhuma, T.; Noyori, R. In Comprehensive Asymmetric Catalysis: Supplement 1;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, NY, 2004.
2. Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayakea, C. H. Adv. Synth. Catal.
2011, 353, 1825.
3. Anastas, P. T. Green Chemistry Textbook; Oxford University Press: New York, NY,
2004.
4. Asymmetric Organic Catalysis; Berkessel, A., Groger, H., Eds.; Wiley-VCH:
Weinheim, 2005.
4.3. Typical procedure of enantioselective direct aldol re-
actions between thioesters and aldehydes
5. For a review on Lewis base-catalyzed reactions see: Denmark, S. E.; Beutner, G.
L. Angew. Chem., Int. Ed. 2008, 47, 1560.
6. Rossi, S.; Benaglia, M.; Genoni, A.; Benincori, T.; Celentano, G. Tetrahedron 2011,
67, 158.
To
a
stirred solution
of
catalyst
(0.1e0.01 equiv,
0.03e0.003 mmol) in the chosen solvent (2 mL), thioester (2 equiv,
0.60 mmol) and diisopropylethylamine (10 equiv, 3 mmol) were
added. The mixture was then cooled to the chosen temperature and
freshly distilled tetrachlorosilane (1.5 equiv, 0.45 mmol) was added
dropwise via syringe. After 15 min, freshly distilled aldehyde
(1 equiv, 0.30 mmol) was added. The mixture was stirred for 5 h (if
the operating temperature is 0 ꢀC) or 12 h (if the operating tem-
perature is ꢁ25 ꢀC), then the same amount of tetrachlorosilane
(1.5 equiv, 0.45 mmol) was added.
After a proper time (see tables) the reaction was quenched by
the addition of a saturated aqueous solution of NaHCO3 (3 mL). The
mixture was allowed to warm up to room temperature and stirred
for 30 min, then water (5 ml) and ethyl acetate (15 mL) were added.
The two-layer mixture was separated and the aqueous layer was
extracted with ethyl acetate (15 mL). The combined organic layers
were washed with saturated NH4Cl (20 mL) and brine (20 mL),
dried over Na2SO4, filtered, and concentrated under vacuum at
room temperature. The crude product was purified by column
chromatography with different hexane/ethyl acetate mixtures as
eluent to afford the pure aldol adducts.
7. Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem. Soc. 2002, 124, 13405.
8. (a) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432; for more
recent contributions see Refs. 5 and 9, and: (b) Denmark, S. E.; Eklov, B. M.; Yao,
P. J.; Eastgate, M. D. J. J. Am. Chem. Soc. 2009, 131, 11170 and references cited; See
also: (c) Massa, A.; Roscigno, A.; De Caprariis, P.; Filosa, R.; Di Mola, A. Adv.
Synth. Catal. 2010, 352, 3348 and references cited.
9. For a review on hypervalent silicates-mediated reactions see: (a) Benaglia, M.;
Guizzetti, S.; Pignataro, L. Coord. Chem. Rev. 2008, 252, 492; (b) Benaglia, M.;
Guizzetti, S.; Rossi, S. Silicate-mediated Stereoselective Reactions Catalyzed by
Chiral Lewis bases In Catalytic Methods in Asymmetric Synthesis: Advanced
Materials, Techniques and Applications; Gruttadauria, M., Giacalone, F., Eds.; John
Wiley and Sons: Hoboken, NJ, 2011.
10. (a) Kotani, S.; Hashimoto, S.; Nakajima, M. Tetrahedron 2007, 63, 3122; (b)
Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem. Commun. 2008, 4309; (c)
Sugiura, M.; Kumahara, M.; Nakajima, M. Chem. Commun. 2009, 3585; (d)
Kotani, S.; Shimoda, Y.; Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2009, 50,
4602; (e) Sugiura, M.; Sato, N.; Sonoda, Y.; Kotani, S.; Nakajima, M. Chem. Asian
J. 2010, 5, 478.
11. For a recent review article dedicated to the use of chiral phosphine oxides in
organocatalysis see: Rossi, S.; Benaglia, M. Org. Biomol. Chem. 2010, 8, 3824.
12. Simonini, V.; Benaglia, M.; Benincori, T. Adv. Synth. Catal. 2008, 350, 561.
13. Rossi, S.; Benaglia, M.; Cozzi, F.; Genoni, A.; Benincori, T. Adv. Synth. Catal. 2011,
353, 848.
14. For a detailed description of the synthesis and characterization of these chiral
Lewis bases see the Experimental section and Supplementary data.
15. Compounds 3 and 4 had been previously synthesized and tested in the Lewis-
base catalyzed stereoselective reduction of ketoimines with trichlorosilane (for
a review see: Guizzetti, S.; Benaglia, M. Eur. J. Org. Chem. 2010, 5529 ) showing
Yield and ee for each reaction are indicated in the tables. The
syn/anti ratio was calculated by 1H NMR spectroscopy, the enan-
tiomeric excess was determined by HPLC.
to be particularly efficient in the reduction of b-iminoesters to b-aminoesters
that was performed in high yields and up to 85% enantioselectivity: Bonsignore,
M.; Benaglia, M.; Annunziata, R.; Celentano, G. Synlett 2011, 1085.
4.4. Location of transition structures
16. In ancillary experiments it was found that catalysts 3 and 4 promoted the direct
aldol reaction between cyclohexanone and benzaldehyde (DCM, 0 ꢀC, 24 h) in
25% yield, 76:24 anti/syn, 25% ee for anti isomer and 65% yield, 70:30 anti/syn,
12% ee for anti isomer, respectively. For a recent contribution in the field see:
Kotani, S.; Aoki, S.; Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2011, 52, 2834.
17. DFT studies are in progress to verify this hypothesis and to tailor the catalyst to
different reaction partners. The PM6 transition structures will be used as
starting point for DFT calculations
Preliminary conformational studies were performed on catalyst
3 with Molecular Mechanics techniques using the MMFFs force
field as implemented in the MacroModel/Batchmin package.18 The
lowest energy structure with the correct orientation of the phos-
phoroamide and phosphonate oxygens was then selected for the
input structure of the diastereoisomeric transition structures; these
were then fully minimized at the semiempirical PM6 level with
18. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.
02; Gaussian: Wallingford CT, 2009.
Gaussian09,19 and characterized with
analysis.
a
complete vibrational
Acknowledgements
ꢀ
Financial support by Ministero dell’ Istruzione, Universita e
ricerca (MIUR)d(Nuovi metodi catalitici stereoselettivi e sintesi
stereoselettiva di molecole funzionali) is gratefully acknowledged.
M.B. thanks the European COST Action CM0905-Organocatalysis.
€
19. MacroModel, Version 9.9; Schrodinger: New York, NY, 2011.