8698
R. Rios et al. / Tetrahedron Letters 48 (2007) 8695–8699
Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975; (d)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
The organocatalytic reaction was readily scaled up
and gave access to a variety of proline derivatives. For
example, optically active 3-substituted proline deriva-
tives such as 9a were accessible using the chiral amine
7-catalyzed reaction (Scheme 2).
5138; (e) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew.
¨
Chem., Int. Ed. 2007, 46, 1570.
3. Moroder, L.; Renner, C.; Lopez, J. J.; Mutter, M.;
Tuchscherer, G. In Cis–Trans Isomerization in Biochemis-
try; Dugave, Christophe, Ed.; Wiley-VCH: Weinheim,
Germany, 2006, Chapter 11.
Thus, reductive deoxygenation of 5-hydroxypyrrolidine
3a gave the corresponding N-protected 3-phenylpyrrol-
idine 9a in 94% yield.14 Moreover, a highly diastereo-
selective decarboxylation/epimerization/ester hydrolysis
sequence on 9a gave proline 10a in 62% yield as a single
diastereoisomer (>25:1 dr). It should be mentioned that
the cis-proline derivative of 10a was also readily avail-
able by decarboxylation of 9a.5d Thus, both diastereo-
isomers of the 3-substituted proline derivatives are
available. Changing the protective group from an acetyl
group to a Boc group gave the known proline 11a
in 94% yield ready to be used in peptide synthesis.
Comparison with the literature revealed that the abso-
lute configuration of 11a at C3 was S and C2 was R
4. For reviews see: (a) Pandey, G.; Banerjee, P.; Gadre, S. R.
Chem. Rev. 2006, 106, 4484; (b) Najera, C.; Sansano, J. M.
Angew. Chem., Int. Ed. 2005, 44, 6272; (c) Husinec, S.;
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6. Emerson, K. M.; Ho, G.-J. Synthesis of Substituted
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7. Selected examples see: (a) Halland, N.; Aburell, P. S.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272;
(b) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 15051; (c) Yang, J.
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25
25
(½aꢁD ꢀ34.7 (c 0.5, CHCl3)), lit. (½aꢁD ꢀ35.9 (c 1.0,
CHCl3)15).16 Thus, efficient shielding of the Re-face of
the chiral iminium intermediate by the bulky aryl groups
of 7 leads to stereoselective Si-facial nucleophilic conju-
gate attack on the b-carbon of 1 (Scheme 1). This is
in accordance with other amine-catalyzed reactions
between malonates and enals.9 Next, the released N-pro-
tected aminoaldehyde intermediate undergoes favored
hemiaminal formation to give 5-hydroxypyrrolidine 3.
´
Franen, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 15710; (e) Yamamoto, Y.; Momiyama, N.; Yamam-
oto, H. J. Am. Chem. Soc. 2004, 126, 5962; (f) Ramachary,
D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem.,
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Int. Ed. 2003, 42, 4233; (g) Sunden, H.; Ibrahem, I.;
In summary, we have reported a highly enantioselective
organocatalytic synthesis of 5-hydroxypyrrolidines,
which are formed in high yields with 90–99% ee. More-
over, the organocatalytic tandem reaction represents a
versatile asymmetric entry to different proline deriva-
tives. Mechanistic studies, synthetic applications of
this transformation, and the development of other
enantioselective tandem reactions are ongoing in our
laboratory.
´
Eriksson, L.; Cordova, A. Angew. Chem., Int. Ed. 2005,
44, 4877; (h) Enders, D.; Huttl, M. R. M.; Grondal, C.;
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´
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L.; Cordova, A. Tetrahedron Lett. 2006, 47, 8547; (m)
Govender, T.; Hojabri, L.; Moghaddam, F. M.; Arvids-
son, P. I. Tetrahedron: Asymmetry 2006, 17, 1763; (n)
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Sunden, H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.;
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Acknowledgments
Cordova, A. Chem. Eur. J. 2007, 13, 574; (o) Carlone,
A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew.
We gratefully acknowledge the Swedish National
Research Council and Carl-Trygger Foundation for
financial support.
Chem., Int. Ed. 2007, 46, 1101; (p) Enders, D.; Huttl, M.
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R. M.; Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem.,
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