Enantioselective organocatalytic aminomethylation of aldehydes: A role for ionic interactions and efficient access to β2-amino acids

Article abstract of DOI:10.1021/ja061731n

Organocatalytic Mannich addition of aldehydes to a formaldehyde-derived iminium species catalyzed by proline-derived chiral pyrrolidines provides β-amino aldehydes with ≥90% ee. Mechanistic analysis of the proline-catalyzed reactions suggests that non-hyd

Full text of DOI:10.1021/ja061731n

Published on Web 05/09/2006
Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for
Ionic Interactions and Efficient Access to â2-Amino Acids
Yonggui Chi and Samuel H. Gellman*
Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706
Received March 13, 2006; E-mail: gellman@chem.wisc.edu
The Mannich reaction,1 in which an enol or enolate attacks an
imine or an iminium ion, is a powerful tool for introducing
aminoalkyl fragments into organic molecules. Imines derived from
aryl aldehydes have been common substrates in recent efforts to
develop asymmetric organocatalytic versions of this reaction; these
substrates necessarily provide Mannich adducts containing aryl
substituents adjacent to nitrogen.2 Our attention was drawn to
formaldehyde-derived substrates because â-amino aldehydes from
such substrates can be used to generate â2-amino acids, which are
valuable building blocks for â-peptide foldamers and other targets.3
Many routes to enantioenriched â2-amino acids have been described;
most involve chiral auxiliaries, and few are amenable to large-scale
synthesis.4 Here we report an enantioselective organocatalytic
method for aminomethylation of aldehydes, which leads to a new
and efficient synthesis of â2-amino acids (Scheme 1). Our observa-
tion. We follow precedent in invoking steric repulsion to rationalize
the results with 2-alkylpyrrolidines (E).
Our hypothesis is consistent with computational results of Houk
et al. for Mannich reaction of imines, in which an ionic attraction
between protonated imine and carboxylate was proposed.9 We tested
our hypothesis by conducting the L-proline-catalyzed reaction in
the presence of LiCl. If the putative iminium/carboxylate attraction
determines the direction of iminium approach to the enamine, then
the ionic additive should diminish enantioselectivity because the
lithium cation will compete with the iminium for ion pairing, and
chloride will compete with the carboxylate. Indeed, the L-proline-
catalyzed Mannich reaction showed little or no enantioselectivity
in the presence of 1 M LiCl (Table 1), which supports transition
Scheme 1. Aminomethylation of Aldehydes and Its Application in
â2-Amino Acid Synthesis
Table 1. Salt Effect
tions provide evidence that non-H-bonded ionic interactions at the
Mannich reaction transition state can influence stereochemical
outcome.
Formaldehyde does not form stable imines,5 so we examined
formaldehyde derivatives, such as A, that can generate a methylene
iminium species in situ.6 We examined L-proline and chiral
pyrrolidines as catalysts for nucleophilic activation of aldehyde
reactants. The Mannich reaction products, R-substituted â-amino
aldehydes, were immediately reduced to the corresponding â-sub-
stituted γ-amino alcohols to avoid epimerization. Initial studies
involving pentanal revealed modest enantioselectivity when the
reaction was carried out with 20 mol % catalyst in DMF at -25
°C for 24 h. The enantiomeric preference observed with L-proline
was opposite that observed with 2-alkylpyrrolidines derived from
L-proline, such as B or C7 (used with equimolar acetic acid). A
comparable switch in product configuration for organocatalytic
Mannich reactions involving aryl imines and for R-amination of
aldehydes has been observed by Barbas, Jørgensen, List, Cordova,
and others.2,11c The commonly accepted rationale for this stereo-
chemical preference switch involves hydrogen bonding:8 the
carboxylic acid group of the L-proline-derived enamine is thought
to H-bond to the electrophile at the transition state, while the
substituent of a 2-alkylpyrrolidine sterically repels the electrophile,
forcing it to approach the enamine from the opposite face. This
hypothesis is reasonable but cannot explain our results with
L-proline since our electrophile, an iminium ion, cannot accept a
hydrogen bond. We propose instead that approach of the electrophile
to the proline-derived enamine is controlled by an electrostatic
attraction of iminium to carboxylate (D); the carboxylate is
presumably generated by methoxide liberated upon iminium forma-
favored
entrya
catalyst
salt
time
eeb
enantiomerc
1
2
3
4
L-proline
L-proline
C-HOAc
C-HOAc
24 h
24 h
2 h
49
<5
67
S
LiCl
LiCl
R
R
2 h
80
a Yield of all reactions was >80% as measured by 1H NMR of the crude
reaction mixture before reduction; the reduction is quantitative. b Determined
by chiral phase HPLC. c See Supporting Information for stereochemistry
determination.
state model D. However, 1 M LiCl leads to a moderate but
reproducible enantioselectivity enhancement for the reaction cata-
lyzed by 2-alkylpyrrolidine C; a similar result was observed for
B.10 The origin of this enhancement is unclear.
In our initial studies, the reaction catalyzed by C gave better
enantioselectivity than did B. We attribute the improved enanti-
oselectivity of catalyst C relative to B to the increased steric bulk
of the 2-substituent in C. Jørgensen et al., Hayashi et al., and
Cordova et al. have recently reported nucleophilic activation of
aldehydes by F,11 in which the trimethylsilyl group provides a
further increase in steric bulk relative to the methyl group in C.
We found that F leads to an improvement in enantioselectivity
relative to C.10 Table 2 shows that Mannich reactions of five
aldehydes proceeded with g90% ee when catalyzed by 20 mol %
of F (with 20 mol % of acetic acid) in DMF containing 1 M LiCl.
9
6804
J. AM. CHEM. SOC. 2006, 128, 6804-6805
10.1021/ja061731n CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Aminomethylation of Aldehydes
commercially available, and such building blocks are readily
prepared from the analogous R-amino acids.16 Our catalytic route
offers large-scale access to â2-amino acids, as well as to other chiral
molecules (R-substituted â-amino aldehydes, â-substituted γ-amino
alcohols) of potential value.
Acknowledgment. This research was supported by NIH Grant
GM56414 and NSF Grant CHE-0551920. NMR equipment pur-
chase was supported in part by grants from NIH and NSF, and
X-ray equipment by NSF. We thank Dr. Ilia Guzei for X-ray
structure analysis.
isolated
entry
R
yield (%)a
ee (%)b
1
2
3
4
5
Et
Pr
i-Pr
Bn
84
87
86
81
65
90
92
91
92
90
Supporting Information Available: Experimental procedures and
compound characterizations. This material is available free of charge
via the Internet at http://pubs.acs.org.
MeO2CCH2
a After column chromatography on silica gel. b Determined by chiral
phase HPLC.
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