Enantioselective Organocatalytic Michael Addition of Aldehydes to Nitroethylene: Efficient Access to γ²-Amino Acids

The development of asymmetric conjugate addition reactions for C–C bond formation remains an important challenge in organic synthesis.^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 generated.⁴ β-Aryl nitroalkenes have been the most common Michael acceptors for reactions developed by other research groups.^3–5 These Michael reactions provide α,β-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 challenging, 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 aminoethylation 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.

Scheme 1.

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.

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 that the role of the acidic component may be to facilitate catalyst turnover and/or to prevent catalyst deactivation pathways.

Table 1.

Organocatalyzed Michael Reaction

entry	catalyst	co-catalyst	yieldb (%)	eec
1	20 mol %	none	95	>95%
2	5 mol %	none	<10	n.d.d
3a	5 mol %	HOAc (200 mol %)	95	>95%
4	2 mol %	HOAc (20 mol %)	30	n.d.d
5	2 mol %	TFA (20 mol %)	8	n.d.d
6a	2 mol %	HOAc (200 mol %)	55	n.d.d
7	2 mol %	B (5 mol %)	96	>95%

^aHOAc used as solvent.

^bFrom ¹H NMR of the crude reaction mixture.

^cDetermined by a ¹H NMR ee assay.¹⁶

^dNot determined.

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 particularly 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. Enantioselectivity was determined in most cases after reduction of the initial aldehyde product to the corresponding β-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 β-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 functional 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.

Table 2.

Highly Efficient and Enantioselective Michael Reaction of Aldehydes with Nitroethylene

entry	product	R	t (h)	yielda (%)	eeb (%)
1	2a	Me	48	95	98
2	2b	Et	48	96	98
3	2cc,d	i-Pr	32	94	97
4	2d	n-Bu	48	95	99
5	2e	i-Bu	54	94	>99
6	2f	Bn	32	93	99
7	2gc	CH2-c-Hex	48	93	>99
8	2hc	CH2COOMe	54	92	96
9	2i	(CH2)2COOtBu	54	94	97
10	2j	4-OtBuC6H4CH2	32	94	98
11	2k	(CH2)4N(Boc)2	48	92	98

^aIsoated yield.

^bDetermined by chiral HPLC analysis.

^cDetermined by chiral HPLC analysis on the corresponding aldehyde.

^dAt 23 °C.

We used compound 2b, prepared on a 10 mmol scale reaction, to show that the β-substituted-δ-nitrobutanol derivatives generated via 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-α-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 β-substituted-δ-nitrobutanol configurations were assigned by analogy. The enantiomeric excess of 3 and 4 was measured by ¹H NMR after coupling of these acids to L- and D-phenylalanine methyl ester. The short synthetic route in Scheme 2 provides a high overall yield (62% from nitroethylene) and is operationally simple.

Scheme 2.

Scheme 3.

Incorporation of γ-amino acid residues into a growing peptide chain can be difficult because of cyclization side reactions. For example, carbodiimide-mediated coupling of Boc-protected γ²-amino acid 4 (30 mM) to L-phenylalanine methyl ester provides only 13% yield of the desired amide; the major product under these conditions is the N-Boc γ-lactam derived from 4 (69%; Scheme 3). However, the analogous reaction with γ-nitro acid 3, under identical conditions, gives the desired amide in 88% yield. The nitro group can be subsequently reduced via hydrogenation and protected. Thus, γ-nitro acids such as 3, intermediates in our synthetic route, are valuable building blocks for γ-peptide synthesis, with the nitro group serving as a protected amino group.

The highly enantioselective Michael additions reported here constitute a method for formal aminoethylation of aldehydes. The reaction is catalyzed by a chiral pyrrolidine, and relatively low catalyst loading is possible if a carboxylic acid co-catalyst is used. When coupled with subsequent aldehyde reduction, this process provides β-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