Stereospecific Synthesis of Conformationally Constrained γ-Amino Acids: New Foldamer Building Blocks That Support Helical Secondary Structure

Abstract

A highly stereoselective synthesis of novel cyclically constrained γ-amino acid residues is presented. The key step involves organocatalytic Michael addition of an aldehyde to 1-nitrocyclohexene. After aldehyde reduction, this approach provides optically active β-substituted-δ-nitro alcohols (96-99% e.e.), which can be converted to γ-amino acid amino acid residues with a variety of substituents at the α-position. We have used these new building blocks to prepare α/γ-peptide foldamers that adopt a specific helical conformation in solution and in the solid state.Oligomers constructed from β-amino acid residues ("β-peptides") or from combinations of α-and β-amino acid residues ("α/β-peptides") can adopt protein-like folding patterns. 1, 2 These conformational properties provide a basis for ongoing development of β-and α/β-peptides that display interesting functional properties. β-Amino acid residues can be endowed with higher intrinsic folding propensities than those of α residues by use of cyclic constraints to limit backbone torsional mobility, and this capacity for residue-based rigidification has proven to be important for both structure and function of β-and α/β-peptide foldamers.3 -6 Analogous benefits should result from the use of constrained γ-amino acid residues in foldamers, but it is difficult to explore this hypothesis because only a few types of ring-containing γ-amino acids are known. 7,8 The few cyclic γ residues examined to date have been found to promote sheet secondary structure,8b,c which contrasts with the helix-favoring effects of the most common cyclic β residues. 1,2,5,6 Here we report a new synthetic approach that provides γ-amino acids containing a cyclohexyl constraint on the C β -C γ bond and a variable side chain at C α . All three stereocenters of the γ-amino acid skeleton are generated from achiral precursors in a single process with high diastereo-and enantioselectivity. We show that the new type of γ-amino acid residue supports helix formation by an α/γ-peptide backbone. Figure 1 shows our synthetic approach, the key step of which is the pyrrolidine-catalyzed Michael addition of an aldehyde to 1-nitrocyclohexene. Chiral pyrrolidines have been shown to catalyze the Michael addition of aldehydes to nitroalkenes with high stereoselectivity. 9,10 Most precedents involve β-aryl nitroalkenes, such as β-nitrostyrene, which lead to γ 2,3 -amino acids.10a-d We have reported that Michael addition of aldehydes to nitroethylene provides access to γ 2 -amino acids. Our attention was drawn to 1-nitrocyclohexene as a Michael acceptor because the adducts could be easily converted to novel cyclically constrained γ-amino acid residues. Reaction of n-butanal and 1-nitrocyclohexene (2:1 molar ratio) in the presence of 20 mol % A in toluene provided only 25% of the Michael adduct after 24 hr, and the two major diastereomers (2a and 3a) were produced in a ~1:1 ratio (Table 1). When 10 mol % B was employed as a co-catalyst, the Michael adduct yield rose to 44% yield, and 2a was favored (6:1 dr)...

α-Helix Mimicry with α/β-Peptides

“…Unfortunately, few β 2 -amino acid building blocks are commercially available at present. (3) Incorporation of γ-amino acid residues (Guo et al, 2009). This prospect is attractive because an αβααγα hexad contains the same number of backbone atoms as an ααααααα heptad, and we recently found that use of properly preorganized β and γ residues leads to formation of a helix very similar to the α-helix (Sawada & Gellman, 2011).…”

Adapting to Substrate Challenges: Peptides as Catalysts for Conjugate Addition Reactions of Aldehydes to α,β‐Disubstituted Nitroolefins

“…[3][4][5][6][7] However, examples of addition reactions of carbonyl compounds to nitroolefins, which bear not only a substituent in the b-but also in the a-position, are rare. [8][9][10][11][12] The development of conjugate addition reactions of aldehydes to such a,b-disubstituted nitroolefins is highly desirable, as the resulting g-nitroaldehydes bear three consecutive stereogenic centers and are therefore valuable intermediates for the synthesis of, for example, chiral pyrrolidines and fully substituted g-amino acids or g-butyrolactams (Scheme 1). Progress has likely been hampered by the lower reactivity of a,b-disubstituted nitroolefins compared to their b-monosubstituted counterparts as well as difficulties in controlling the absolute configuration at the carbon atom bearing the nitro group.…”

“…Progress has likely been hampered by the lower reactivity of a,b-disubstituted nitroolefins compared to their b-monosubstituted counterparts as well as difficulties in controlling the absolute configuration at the carbon atom bearing the nitro group. In fact, the only a,b-disubstituted nitroolefins that have been explored in organocatalytic conjugate addition reactions with aldehydes are either cyclic [8,9] or profit from activation of the nitro group by an intramolecular hydrogen-bond donor. [10] A single example of the addition of an aldehyde to an acyclic non-activated disubstituted nitroolefin in the course of a total synthesis provided the product in low diastereoselectivity due to poor control of the stereogenic center at the carbon atom bearing the nitro group.…”

Asymmetric Synthesis with Silicon‐Based Bulky Amino Organocatalysts

“…[23] The direct Michael additions of cyclohexanone to nitroolefins catalyzed by prolinol tert-butyldiphenylsilyl ether (14e, Scheme 13) via enamine catalysis were conducted successfully in good yields (up to 99%) and high stereoselectivities (up to 98:2 diastereomeric ratio and 95% enantiomeric excess). [24] Later, the authors found that the 4-trifluoromethanesulfonamidylprolinol tert-butyldiphenylsilyl ether bifunctional organocatalyst 14a is a highly efficient catalyst for the asymmetric Michael addition reactions of ketones and aldehydes to nitrostyrenes, leading to excellent yields (> 99%), high diastereoselectivities (up to 99:1 dr) and excellent enantioselectivities in the most cases (up to 99% ee).…”