Enantioselective intramolecular Michael addition of nitronates onto conjugated esters: Access to cyclic γ-amino acids with up to three stereocenters

Article abstract of DOI:10.1021/ja9070915

(Chemical Equation Presented) A highly stereoselective synthesis of conformationally constrained cyclic γ-amino acids has been devised. The key step involves an intramolecular cyclization of a nitronate onto a conjugated ester, promoted by a bifunctional

Full text of DOI:10.1021/ja9070915

Published on Web 10/14/2009
Enantioselective Intramolecular Michael Addition of Nitronates onto Conjugated
Esters: Access to Cyclic γ-Amino Acids with up to Three Stereocenters
William J. Nodes,† David R. Nutt,‡ Ann M. Chippindale,‡,§ and Alexander J. A. Cobb*,†
School of Pharmacy and Department of Chemistry, UniVersity of Reading, Whiteknights, Reading, Berks RG6 6AD, U.K.
Received August 25, 2009; E-mail: a.j.a.cobb@reading.ac.uk
Table 1. Development of Bifunctional Organocatalytic
Intramolecular Michael Addition
The asymmetric Michael reaction is one of the most powerful
carbon-carbon bond-forming reactions available to the organic chemist
and remains an important challenge within organic synthesis.1 Since
the start of the new millenium, much work has focused on asymmetric
organocatalytic processes.2 In most cases, the Michael acceptor is
almost always a conjugated enone, enal, or nitroalkene variant.3 Very
few examples of other Michael acceptors exist,4 in particular the
conjugated ester, which is surprising given its synthetic utility. Within
our laboratory, we were particularly drawn to the use of nitronates in
the intramolecular Michael addition to conjugated esters as an entry
to cyclically constrained γ-amino acids (Scheme 1).
Scheme 1. Catalytic Synthesis of γ-Amino Acids: Concept
dra
ee (%)b c
,
entry
solvent
catalyst (mol %)
yield (%)
1
2
3
4
5
6
7
8
9
DCE
DCE
DCE
DCE
THF
C6H6
CH2Cl2
H2O
MeCN
MeCN
MeCN
A (10)
B (10)
C (10)
D (10)
C (10)
C (10)
C (10)
C (10)
C (10)
C (20)e
C (30)e
78
11
79
77
67
71
83
51
87
81
81
4:1
1:1
4:1
4:1
>19:1
2:1
>19:1
9:1
>19:1
9:1
90
4
92
94d
95
96
95
95
95
96
96
Unnatural peptides (foldamers) incorporating such unusual amino
acids have recently received much attention because of their interesting
folding properties.5 Furthermore, these compounds represent analogues
of γ-aminobutyric acid (GABA) and are therefore of biological
significance.6 However, neither the enantiomerically pure synthesis
of γ-amino acids7 nor the synthesis of cyclically constrained variants
has been widely reported. We envisioned that our route would address
this by utilizing the intramolecular Michael addition of a nitronate to
a conjugated ester. Importantly, with this procedure, up to three
contiguous stereocenters can be constructed in one step. Furthermore,
the presence of a nitro group can allow it to act as a masked amine
during subsequent peptide synthesis.7 However, to the best of our
knowledge, to date no asymmetric methods, organocatalytic or
otherwise, exist for closing a nitronate onto a conjugated ester.8
On the basis of previous studies using nitronates as nucleophiles,9
we decided to investigate the potential of chiral bifunctional organo-
catalysts in this process and thus screened a range of thiourea catalysts
(Table 1). Using catalyst A, we were delighted to obtain cyclized
product 2 in an acceptable yield and with excellent enantioselectivity.
A subsequent catalyst screen showed that under these conditions,
bifunctional cinchona catalysts C and D gave superior enantioselec-
tivities (Table 1, entries 3 and 4). Interestingly, the use of hydroqui-
nidine-derived catalyst D gives the oppositely configured product to
hydroquinine-derived catalyst C in almost identical yield, diastereo-
selectivity, and enantioselectivity.
10
11
9:1
a Determined by 1H NMR spectroscopy. b Determined by HPLC
analysis on the corresponding benzyl ester. c Absolute stereochemistry
was determined by Nef Reaction on the product and comparison of the
optical rotation with literature values (see the Supporting Information).
d The opposite enantiomer was observed. e Reaction was complete after
2 days.
lower dr. It is thought that longer reaction times allow the system to
equilibrate to the thermodynamically more stable trans system. We
tested this hypothesis by re-exposing compound (+)-2 with an initial
dr of 5.7:1 to catalyst C in CDCl3 at room temperature. After 3 days,
the dr was 6.1:1, and after 6 days, the dr had improved to 6.4:1.
However, increases in temperature, use of additives, and increased
concentration deteriorated either the diastereoselectivity or enantiose-
lectivity of the process.
A variety of substrates were screened using the optimized conditions
(Table 1, entry 9). Pleasingly, the enantioselectivities of the reaction
process remained very good, as did the diastereoselectivities (Table
2). Of particular interest were the systems leading to three asymmetric
centers (entries 4-6 and 9), which gave excellent enantioselectivities
and impressive diastereoselectivities. The relative configurations were
determined by 1H NMR analysis of the corresponding lactams and, in
the case of 5, X-ray crystallography (see the Supporting Information).
Interestingly, in the racemic reaction, whereby the precursor to
compound 5 was simply exposed to cesium fluoride, the C1′ epimer
was obtained in a 6:1 diastereomeric ratio.
Ultimately, reaction in acetonitrile was shown to give the best
balance among yield, diastereoselectivity, and enantioselectivity (Table
1, entry 9). Although increased catalyst loading did improve the results
in terms of reaction time, it gave a lower yield and, interestingly, a
In all cases except entry 8, reactions were stopped after 7 days to
allow for completion and equilibration to the trans product. However,
compounds 5, 6, and 10 were produced more slowly and had not
† School of Pharmacy.
‡ Department of Chemistry.
§ X-ray crystallographer.
9
16016 J. AM. CHEM. SOC. 2009, 131, 16016–16017
10.1021/ja9070915 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope for Intramolecular Michael Additiona
Figure 1. Optimized structure of a simplified thiourea interacting with the
deprotonated precursor of 5, as obtained at the B3LYP/3-21G level of theory
with the GAMESS-UK program.10
Scheme 3. N- and C-Terminal Derivatizations
In conclusion, we have shown the first use of bifunctional organo-
catalysis in the intramolecular Michael addition of nitronates to
conjugated esters. We have also demonstrated its utility in peptide
chemistry, and further mechanistic investigations of the reaction are
underway in our laboratories.
a Determined by 1H NMR spectroscopy. b Determined by HPLC
analysis. c Absolute configuration was assigned by analogy to
compounds 2 and 5. d Reaction was complete after 2 days.
Acknowledgment. Financial support was provided by the EPSRC
(to W.J.N.).
reached completion, accounting for the moderate yields, but the
enantioselectivity of each remained excellent.
Finally, Z esters were also utilized within this methodology.
Interestingly, these reactions did not proceed efficiently, and only the
simple Z substrate of 1 partially worked to produce compound 2 with
the opposite absolute configuration and decreased diastereoselectivity
and enantioselectivity (Table 2, entry 10).
We propose that the thiourea needs to coordinate to both the
nitronate and the ester in order to activate the system and allow the
reaction to proceed. This can only occur effectively with the E ester,
as the geometry of the Z ester prevents such an interaction from
occurring (Scheme 2). This may also account for the lower diastereo-
selectivity and enantioselectivity with the Z ester.
Supporting Information Available: Experimental procedures, char-
acterization data, and CIF and PDB files. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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Scheme 2. Proposed Explanation for Z Ester Nonreactivity
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Ab initio electronic structure calculations indicate that the E/Z
configuration of the double bond indeed facilitates or prevents the
thiourea moiety from interacting simultaneously with the nitro and
ester groups (Figure 1).
In order to demonstrate the utility of these compounds in the
synthesis of peptides, we performed N- and C-terminal derivatizations.
Reduction of the nitro group of compound 2 and subsequent DCC
coupling to N-Boc-L-valine gave dipeptide precursor 11 with no loss
of enantiopurity nor any observable lactam formation (Scheme 3a).
The acid of product 5 was coupled with MeO-L-valine at the
C-terminus, also with no loss of enantiopurity (Scheme 3b), giving
dipeptide precursor 12.
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Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 5608.
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D.; Desmae¨le, D. Tetrahedron Lett. 1998, 39, 1349. (b) Marsh, G. P.;
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J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929. (b) Okino, T.;
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