Enhancing the selectivity of prolinamide organocatalysts using the mechanical bond in [2]rotaxanes

Abstract

The synthesis of a pair of switchable interlocked prolinamides and their use as organocatalysts in three different enamine-activated processes are reported. A diacylaminopyridine moiety was incorporated into the thread for directing [2]rotaxane formation further allowing the association of complementary small molecules. The rotaxane-based systems were tested as organocatalysts in asymmetric enamine-mediated processes, revealing a significantly improved catalytic ability if compared with the non-interlocked thread. The presence of an electron-withdrawing nitro group at the macrocycle helps to achieve high conversions and enantioselectivities. These systems are able to interact with N-hexylthymine as a cofactor to form supramolecular catalysts displaying a divergent catalytic behaviour. The presence or absence of the cofactor controls the chemoselectivity in competitive reactions.

Fig. 1. Design of (a) an interlocked DAP-based organocatalyst and (b) the formation of its hydrogen-bonding supramolecular complex.

Scheme 1. Synthesis of DAP-based non-interlocked and interlocked catalysts 4 and 6a-b. Reaction conditions: (i) ethyl chloroformate, Et₃N, THF, 0 °C; then addition of N-(6-aminopyridin-2-yl)-3,3-diphenylpropanamide S1; 25 °C, overnight; then reflux for 3 h; (ii) 3,3-diphenylpropanoyl chloride, Et₃N, CH₂Cl₂, 25 °C, overnight; (iii) p-xylylenediamine, isophthaloyl dichloride, Et₃N, CHCl₃, 25 °C, 4 h; (iv) TFA, CHCl₃, overnight. Experimental procedures can be found in the ESI.

Fig. 2. Computed minimum-energy co-conformer of the supramolecular complex 6a·T′ (with T′ = N¹-methylthymine) at the M06/cc-pVDZ theoretical level.

Scheme 2. Formation of the imidazolidone derivative of (a) thread 4 and (b) rotaxane 6a. Reaction conditions: (i) acetone (20 equiv.), CDCl₃ (0.025 M), 25 °C, 2 days. The full experimental procedures can be found in the ESI.

Fig. 3. Selected enamine-type processes studied in this work.

Scheme 3. Michael versus aldol addition of acetone using rotaxane 6b as the catalyst in the presence or absence of N-hexylthymine (T). Reaction conditions: p-nitrobenzaldehyde (1 equiv.), trans-β-nitrostyrene (1 equiv.), acetone (1.5 equiv.), catalyst 6b (10 mol%), N-hexylthymine (5 equiv., if required), CH₂Cl₂ (0.25 M), 25 °C, 5 days.^a Determined by ¹H NMR from the crude reaction. ^b e. r. determined by HPLC using a Daicel ChiralPak AS-H column.