Asymmetric Synthesis
FULL PAPER
d-Lactone 6c: 1H NMR(400 MHz, CDCl 3): d=1.03 (t, J=7.2 Hz, 3H),
1.06 (d, J=7.2 Hz, 3H), 1.27 (d, J=7.2 Hz, 3H), 1.61 (m, 2H), 1.80 (m,
2H), 1.90 (brs, 1H), 2.67 (dq, J=7.2, 3.6 Hz, 1H), 3.74 (t, J=3.6 Hz,
1H), 3.76 ppm (ddd, J=10.8, 8.2, 3.2 Hz, 1H); 13C NMR(100 MHz,
sembly of triketides see: f) A. L. Wilkinson, U. Hanefeld, B. Wilkin-
son, P. F. Leadlay, J. Staunton, Tetrahedron Lett. 1998, 39, 9827;
g) J. R. Gage, D. A. Evans, Org. Synth. 1990, 68, 83; h) B. C. Rai-
mundo, C. H. Heathcock, Synlett 1995, 1213; reviews of the catalytic
asymmetric aldol reaction see: i) D. A. Evans, J. V. Nelson, T. Taber,
Top. Stereochem, 1982, 13, 1; j) C. Palomo, M. Oiarbide, J. M.
García, Chem. Eur. J. 2002, 8, 36; for examples of direct metal or-
ganic catalytic aldol reactions see: k) Y. M. A. Yamada, N. Yoshika-
wa, H. Sasai, M. Shibasaki, Angew. Chem. 1997, 109, 1942; Angew.
Chem. Int. Ed. Engl. 1997, 36, 1871; l) N. Yoshikawa, N. Kumagai, S.
Matsunaga, G. Moll, T. Oshima, T. Suzuki, M. Shibasaki, J. Am.
Chem. Soc. 2001, 123, 2466; m) B. M. Trost, H. Ito, J. Am. Chem.
Soc. 2000, 122, 12003; n) B. M. Trost, E. R. Silcoff, H. Ito, Org. Lett.
2001, 3, 2497; o) D. A. Evans, J. S. Tedrow, J. T. Shaw, C. W.
Downey, J. Am. Chem. Soc. 2002, 124, 392.
CDCl3): d=9.3, 11.1, 15.9, 26.1, 38.9, 41.7, 75.5, 82.6, 174.5 ppm; [a]D25
=
À69.0 (c=1.5 in CHCl3); (CP-Chirasil-Dex CB);
Tinj =2508C, Tdet
=
2758C, flow=1.8 mLminÀ1, ti =1008C (35 min), tf =2008C (808CminÀ1):
major isomer: tR =36.28 min; minor isomer: tR =36.37 min.; MALDI-
TOF MS: m/z calcd for [M+Na]+: 195.0992; found: 195.0991.
Direct catalytic synthesis of acrylate 7: A mixture of a-benzyloxyacetalde-
hyde (1.5 mmol), aqueous formaldehyde (1 mmol, 36% aqueous solu-
tion), and l-proline (10 mol%) in DMF (2 mL) was vigorously stirred at
508C. After 8 h the reaction was cooled to room temperature. The reac-
tion was quenched by extraction with water, and the combined aqueous
layers were back-extracted with three portions of EtOAc. The organic
layers were then combined and dried over anhydrous Na2SO4, which was
subsequently removed by filtration. After purification of the crude prod-
uct mixture by silica-gel column chromatography (EtOAc/pentane mix-
[8] For synthesis of ketoses see: a) M. Majewski, P. Nowak, J. Org.
Chem. 2000, 65, 5152; b) M. Majewski, P. Nowak, Synlett 1999, 1447;
c) D. Enders, S. J. Ince, Synthesis 2002, 619; d) D. Enders, M. Voith,
S. J. Ince, Synthesis 1996, 1775; e) D. Enders, O. F. Prokopenko, G.
Raabe, J. Runsink, Synthesis 1996, 1095; for an excellent review on
the use of protected dihydroxy acetones in synthesis see: f) D.
Enders, M. Voith, A. Lenzen, Angew. Chem. 2005, 117, 1330;
Angew. Chem. Int. Ed. 2005, 44, 1330, and references therein.
[9] a) W. -D. Fessner, Stereosel. Biocatal. (Ed.: R. N Patel), Marcel
Dekker, New York 2000, p 239; b) T. D. Machajewski, C. -H. Wong,
Angew. Chem. 2000, 112, 1406; Angew. Chem. Int. Ed. 2000, 39,
1352; c) A. Heine, G. DeSantis, J. G. Luz, M. Mitchell, C. -H. Wong,
I. A. Wilson, Science 2001, 294, 369; d) H. J. M. Gijsen, C. -H. Wong,
J. Am. Chem. Soc. 1994, 116, 8422; e) H. J. M. Gijsen, C. -H. Wong,
J. Am. Chem. Soc. 1995, 117, 7585; f) H. J. M. Gijsen, C. -H. Wong,
J. Am. Chem. Soc. 1995, 117, 2947; g) J. Liu, C. -H. Wong, Angew.
Chem. 2002, 114, 1462; Angew. Chem. Int. Ed. 2002, 41, 1404;
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3840; Angew. Chem. Int. Ed. 2001, 40, 3726; b) B. List, Tetrahedron
2002, 58, 5573; c) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248; Angew. Chem. Int. Ed. 2004, 43, 5138; d) P. Merino, T. Tejero,
Angew. Chem. 2004, 116, 3055; Angew. Chem. Int. Ed. 2004, 43,
2995.
[11] For selected direct organocatalytic aldol reactions see: a) Z. G.
Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615; b) U. Eder, R.
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1
tures) the solvent was removed in vacuo to afford compound 7. H NMR
(400 MHz, CDCl3): d=4.93 (s, 2H), 5.14 (d, J=3.1 Hz, 3H), 5.24 (d, J=
3.1 Hz, 1H), 7.32–7.38 (m, 5H), 9.13 ppm (s, 1H); 13C NMR(100 MHz,
CDCl3): d=70.1, 103.7, 127.3, 128.1, 128.6, 135.5, 158.1, 188.0 ppm.
Direct catalytic synthesis of b-hydroxy aldehyde 8: Acrylate 7 (1 mmol)
was dissolved in DMF (1 mL), along with l-proline (10 mol%). Next, a
suspension of propionaldehyde (2 mmol) in DMF (2 mL) was added to
the reaction mixture at 48C over the course of 16 h. Once the addition
had been completed, the solution was allowed to warm to room tempera-
ture and was stirred for a further 24 h. The reaction was quenched by ex-
traction with water, and the combined aqueous layers were back-extract-
ed with three portions of EtOAc. The organic layers were then combined
and dried over anhydrous MgSO4, which was subsequently removed by
filtration. After purification of the crude product mixture by silica-gel
column chromatography (EtOAc/pentane mixtures) the solvent was re-
moved in vacuo to afford the desired cross-aldol adduct 8. 1H NMR
(400 MHz, CDCl3): d=1.12 (d, J=7.1 Hz, 3H), 2.77 (m, 1H), 4.25 (d, J=
2.7 Hz, 1H), 4.36 (d, J=2.7 Hz, 1H), 4.56 (m, 1H), 4.79 (s, 2H), 7.28–
7.41 (m, 5H), 9.77 ppm (s, 1H); 13C NMR(100 MHz, CDCl 3): d=7.8,
49.5, 69.7, 71.6, 83.7, 127.5, 128.0, 128.5, 128.5, 136.3, 160.7, 204.1 ppm.
[a]2D5 =À3.7 (c=1.0 in CHCl3).
Acknowledgements
Support by Prof. J.-E. Bäckvall and Stockholm University is gratefully ac-
knowledged. We thank Prof. H. Adolfsson for valuable discussions and
the Swedish National Research council, Lars Hierta Foundation and
Wenner-Gren Foundation for financial support.
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4783