Enantioselective organocatalytic Michael addition of aldehydes to nitroethylene: Efficient access to γ2-amino acids

Article abstract of DOI:10.1021/ja800345r

Enantioselective organocatalytic Michael addition of aldehydes to nitroethylene catalyzed by (S)-diphenylprolinol silyl ether provides β-substituted-δ-nitroalcohols in nearly optically pure form (96-99% ee). The Michael adducts bear a single substituent adjacent to the carbonyl and can be efficiently converted to protected γ²-amino acids, which are essential for the systematic conformational studies of γ-peptide foldamers. Copyright

Full text of DOI:10.1021/ja800345r

Published on Web 04/04/2008
Enantioselective Organocatalytic Michael Addition of Aldehydes
to Nitroethylene: Efficient Access to γ2-Amino Acids
Yonggui Chi, Li Guo, Nathan A. Kopf, and Samuel H. Gellman*
Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706
Received January 15, 2008; E-mail: gellman@chem.wisc.edu
Scheme 1
The development of asymmetric conjugate addition reactions for
C-C bond formation remains an important challenge in organic syn-
thesis.1,2 Much recent work has focused on organocatalytic Michael
addition of carbonyl compounds to nitroalkenes.3–5 Among these
reactions, Michael addition of aldehydes to nitroalkenes is of particular
interest because of the valuable synthetic intermediates that are gener-
ated.4 ꢀ-Aryl nitroalkenes have been the most common Michael accep-
tors for reactions developed by other research groups.3–5 These
Michael reactions provide R,ꢀ-disubstituted-γ-nitrobutanals. Our
attention was drawn to nitroethylene as a Michael acceptor because the
adducts would bear a single substituent adjacent to the carbonyl and
could be readily converted to γ2-amino acids. γ2-Amino acids represent
potential building blocks for γ-peptide6 and heterogeneous backbone
foldamers.7 In addition, derivatives of the neurotransmitter γ-amino
butyric acid (GABA)8 are of potential biomedical utility, as illustrated
by the use of Pregabalin and Baclofen to treat neurological disorders.9
The preparation of enantiomerically pure γ-amino acids is challeng-
ing, and this synthetic burden has limited the study of γ-peptide
foldamers to date. A variety of routes to enantioenriched γ2-amino
acids have been described,10 but these approaches often involve
specialized chiral auxiliaries and may not be ideal for preparing
multigram quantities of protected γ2-amino acids bearing diverse
side chain functionality, which is necessary for foldamer research.6,7
Here we report an asymmetric organocatalytic method for aminoethyl-
ation of aldehydes, which leads to a new and efficient synthesis of
γ2-amino acids (Scheme 1). Our approach pairs a chiral pyrrolidine
catalyst with a carefully chosen acidic co-catalyst to promote Michael
addition of aldehydes to nitroethylene with high enantioselectivity.
We initially evaluated two widely used chiral pyrrolidines, L-proline
and (S)-diphenylprolinol silyl ether (A),11 for the ability to promote
the Michael reaction between n-pentanal and nitroethylene (2:1 molar
ratio). We assumed that such reactions would proceed via enamine
intermediates. L-Proline (20 mol %) provided very little of the Michael
adduct; instead the major product in a variety of solvents resulted from
aldol condensation of n-pentanal, a process that is known to be
catalyzed by proline.12 In contrast, when 20 mol % of A was employed
in toluene, the desired Michael adduct was generated in 95% yield
with >95% ee, and little or no aldol product was formed.
Table 1. Organocatalyzed Michael Reaction
entry
catalyst
co-catalyst
yieldb (%)
eec
1
2
3
4
5
6
7
20 mol %
5 mol %
5 mol %
2 mol %
2 mol %
2 mol %
2 mol %
none
none
95
<10
95
>95%
d
n.d.
a
HOAc (200 mol %)
HOAc (20 mol %)
TFA (20 mol %)
HOAc (200 mol %)
B (5 mol %)
>95%
d
n.d.
d
30
8
n.d.
d
a
55
n.d.
96
>95%
a HOAc used as solvent. b From 1H NMR of the crude reaction
mixture. c Determined by a 1H NMR ee assay.16 d Not determined.
that the role of the acidic component may be to facilitate catalyst
turnover and/or to prevent catalyst deactivation pathways.
Many pyrrolidine-catalyzed processes require relatively high levels
of catalyst (10-20 mol %). Use of 2 mol % of A with 20 mol % of
acetic acid led to a substantial decline in efficiency (30% Michael
adduct; Table 1). Switching to a more acidic co-catalyst, trifluoroacetic
acid (20 mol %), caused a decrease in yield (8% Michael adduct).
Increasing the amount of acetic acid to 200 mol % led to only a modest
improvement (55% Michael adduct). Evaluation of a number of other
potential acidic co-catalysts identified 3-nitrobenzoic acid (B) as partic-
ularly effective: combining 2 mol % of pyrrolidine A with 5 mol %
of B provided the Michael adduct in 96% yield with >95% ee.
Having established A + B as an effective catalyst/co-catalyst pair for
enantioselective Michael reaction of n-pentanal, we next investigated
the scope for the aldehyde substrate (Table 2). These reactions were
carried out with 2 mol % of A and 20 mol % of B at 3 °C. Enantio-
selectivity was determined in most cases after reduction of the initial alde-
hyde product to the corresponding ꢀ-substituted-δ-nitrobutanol derivative.
This approach enabled ee determination via HPLC because aldehyde
reduction eliminates the possibility of epimerization. As initially observed
for n-pentanal, a variety of aldehydes with hydrocarbon appendages
give excellent yields and enantioselectivities. Even a ꢀ-branched substrate,
3-methylbutanal, can be employed, although elevated temperature (23 °C)
is required to achieve full conversion (Table 2, entry 3). Our long-term
interest in using γ-amino acids to construct biologically active foldamers17
will require access to examples that bear appropriately protected function-
al groups in the side chain. Entries 9-11 of Table 2 show that our
catalytic Michael addition method enables incorporation of side chains
corresponding to those of glutamic acid, tyrosine, and lysine into γ2-
amino acid precursors, with excellent yields and enantioselectivities.
We used compound 2b, prepared on a 10 mmol scale reaction, to
show that the ꢀ-substituted-δ-nitrobutanol derivatives generated via
Previous work has shown that carefully chosen acidic co-
catalysts can enhance pyrrolidine- or imidazolidinone-catalyzed
Michael addition of aldehydes to enones,13 and we therefore
examined co-catalyst effects14 on the Michael addition of n-pentanal
to nitroethylene. When 5 mol % of A was employed as catalyst,
without any co-catalyst, <10% Michael adduct was generated after
1 h, and little further adduct was generated after 24 h (Table 1).
However, use of 5 mol % of A along with 200 mol % of acetic
acid gave a 95% yield of the Michael adduct after 24 h with
excellent stereoselectivity (>95% ee).15 These observations suggest
9
5608 J. AM. CHEM. SOC. 2008, 130, 5608–5609
10.1021/ja800345r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Highly Efficient and Enantioselective Michael Reaction of
subsequent aldehyde reduction, this process provides ꢀ-substituted-
δ-nitrobutanol derivatives, which are potentially valuable chiral
intermediates. We have shown that such intermediates can be
converted expeditiously to protected γ2-amino acids, which are
interesting as foldamer building blocks. Relatively few methods
have been previously described for γ2-amino acid synthesis,10 and these
approaches might be challenging to apply to examples featuring diverse
side chain functionality. Mechanistic studies regarding the role of acid
co-catalyst and the catalytic pathway are in progress.18
Aldehydes with Nitroethylene
entry
product
R
t (h)
yielda (%)
eeb (%)
1
2a
Me
Et
48
48
32
48
54
32
48
54
54
32
48
95
96
94
95
94
93
93
92
94
94
92
98
98
2
2b
c,d
2c
3
i-Pr
n-Bu
i-Bu
Bn
97
4
2d
2e
99
Acknowledgment. This research was supported by NSF (CHE-
055190). Y.C. was supported in part by a fellowship from Abbott
Laboratories. NMR spectrometers were purchased with partial
support from NIH and NSF, and X-ray equipment by NSF. We
thank Dr. Ilia Guzei for X-ray structure analysis, and Prof. H.
Wennemers for sharing unpublished results.
5
>99
99
6
2f
c
7
CH2-c-Hex
>99
2g
c
8
CH2COOMe
96
2h
9
2i
(CH2)2COOtBu
4-OtBuC6H4CH2
(CH2)4N(Boc)2
97
10
11
2j
2k
98
98
a Isoated yield. b Determined by chiral HPLC analysis. c Determined
by chiral HPLC analysis on the corresponding aldehyde. d At 23 °C.
Supporting Information Available: Experimental procedures and
compound characterizations. This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 2
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Scheme 3
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the Michael addition/reduction sequence could be converted in a
straightforward manner to appropriately protected, enantioenriched γ2-
amino acids (Scheme 2). Jones oxidation of 2b provided the γ-nitro-
R-alkylbutyric acid 3, which was then transformed to protected γ2-
amino acid 4 in an efficient one-pot operation involving nitro group
reduction followed by Boc protection. The absolute configuration of
2b was determined as (R) by the X-ray structure analysis of the
L-phenylalanine derivative 5 (Scheme 3), and other ꢀ-substituted-δ-
nitrobutanol configurations were assigned by analogy. The enantio-
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these acids to L- and D-phenylalanine methyl ester. The short synthetic
route in Scheme 2 provides a high overall yield (62% from nitro-
ethylene) and is operationally simple.
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carbodiimide-mediated coupling of Boc-protected γ2-amino acid 4 (30
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desired amide; the major product under these conditions is the N-Boc
γ-lactam derived from 4 (69%; Scheme 3). However, the analogous
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hydrogenation and protected. Thus, γ-nitro acids such as 3, intermedi-
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synthesis, with the nitro group serving as a protected amino group.
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