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Efficient Extraction of Highly Polar Solvents From Reaction Mixtures
Efficient Extraction of Highly Polar Solvents From Reaction Mixtures
DOI: 10.1002/anie.200502630
Asymmetric Catalysis
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Chemie
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349
Highlights
Scheme 4. Possible different reaction pathways that might occur during the reaction between
two different unmodified aldehydes.
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4 8C). Thus, proline was found to activate aldimines preferentially to aldehydes. The best results were reported
when aromatic and heteroaromatic acceptors were used instead of the aliphatic ones. The desired cross-Mannich
adducts were isolated after reduction to
the corresponding b-amino alcohol 15 to
avoid decomposition during purification.
Scheme 5. One-pot, direct cross-Mannich reaction of two different aldehydes with high
syn diastereo- and enantioselectivity by proline catalysis.
Angewandte
Chemie
the Mannich reaction affords the syn adduct whereas the aldol reaction gives
the anti adduct (Scheme 7). List et al.
and C@rdova explored certain mechanistic features and found that a single
proline molecule is involved in the
transition state as well as in the mechanism. Since proline is a bifunctional
acid/base catalyst that acts like a Lewis
base type catalyst, and allows enamine
formation, and also like a general acid
(because of its increased pKa value relative to primary amino acids) it is
regarded as an artificial enzyme.
A plausible explanation was proposed for the observed diastereoselectivity in the (S)-proline-catalyzed direct
asymmetric Mannich reactions. They
were proposed to occur by the attack
of the si face of the enamine on the
si face of an imine with an E configuration, rather than the proposed re-face
attack in the cross-aldol reaction. Similar to the cross-aldol reaction, the
trasition statea six-membered metal-
free
ZimmermannTraxler
systemis stabilized by hydrogen bonding between the
nitrogen atom (imine) and the
carboxylic acid (proline). The
attack of the imine at the
re face was considered disfavored because of steric congestion between the PMP
group and the pyrrolidine unit.
One of the drawbacks of
using proline as the catalyst is
the limited choice of solvent,
since only polar solvents such
as DMSO, DMF, N-methylScheme 8.
pyrrolidine (NMP), and N,Ndimethylacetamide (DMA)
can be used. More recently,
Ley and co-workers screened new catalysts and solvents for the catalytic asymmetric Mannich reaction.[16] Among the
catalysts tested, a new catalysttetrazole 21 (Scheme 8)was found to catalyze the asymmetric Mannich reactions
of ketone 19 and N-PMP-protected a-
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Highlights
and permits access to a wide variety of
optically active compounds as well as
active compounds such as amino acid
derivatives. Remarkable advancements
have been reported over the last five
years, including one-pot, three-component procedures with absolute stereocontrol and high yields, and the competition between cross-aldol and crossMannich reactions could be overcome
by controlling the reaction conditions.
The success of this reaction will unquestionably prompt chemists to develop
new catalysts that will overcome the
limitations presented in this Highlight.
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