Ring-to-Thread Chirality Transfer in [2]Rotaxanes for the Synthesis of Enantioenriched Lactams

Abstract

The synthesis of chiral mechanically interlocked molecules has attracted a lot of attention in the last few years, with applications in different fields, such as asymmetric catalysis or sensing. Herein we describe the synthesis of orientational mechanostereoisomers, which include a benzylic amide macrocycle with a stereogenic center, and nonsymmetric N-(arylmethyl)fumaramides as the axis. The base-promoted cyclization of the initial fumaramide thread allows enantioenriched value-added compounds, such as lactams of different ring sizes and amino acids, to be obtained. The chiral information is effectively transmitted across the mechanical bond from the encircling ring to the interlocked lactam. High levels of enantioselectivity and full control of the regioselectivity of the final cyclic compounds are attained.

Keywords: Base-Promoted Cyclization; Chirality Transfer Process; Enantioselective; Hydrogen-Bonded Rotaxanes; Mechanostereoisomers.

Figure 1

Schematic representations of: A) a pair of mechanically planar rotaxanes (enantiomers) and one example of a mechanically planar ligand used in Au^I catalysis; B) two orientational mechanostereoisomers and an example of a α‐CD‐based orientational isomer having multiple stereocenters at the ring; C) orientational mechanostereoisomers with a single stereogenic center, and a general representation of an isomer having just one stereogenic center at the ring (this work).

Scheme 1

Diastereoselective functionalization of a [2]rotaxane where the chiral macrocycle induces: A) a marginally diastereoselective end‐capping reaction of the thread in pseudorotaxane 1; B) a selective oxidation to afford a diastereomeric mixture of rotaxanes 4. R=3,5‐^tBu₂C₆H₃

Scheme 2

Base‐promoted cyclization of: A) N‐benzylfumaramide‐based [2]pseudorotaxanes 5 in a diastereoselective manner; B) enantiopure N‐α‐(methylbenzyl)fumaramide‐based [2]pseudorotaxanes 7; C) an orientational mechanostereoisomer 9 in an enantioselective fashion (this work).

Scheme 3

Synthesis of the enantiopure “U”‐shaped precursor (R)‐10. Reagents and conditions: 1) (i) Ti(OEt)₄, 75 °C, 15 h; (ii) NaBH₄, −50 °C to 25 °C, 15 h; 2) (i) n‐BuLi, THF, −78 °C, 10 min, then DMF, 25 °C, 1 h; (ii) NaBH₄, 2 h, 25 °C; 3) phthalimide, PPh₃, diethyl azodicarboxylate, THF, 25 °C, 24 h; 4) hydrazine hydrate, THF:EtOH (9 : 1), reflux, 18 h; 5) EDCI, DMAP, CH₂Cl₂, 25 °C, 48 h; 6) (i) HCl 6 M in dioxane, MeOH, 25 °C, 3 h; (ii) Amberlyst A21®, CH₂Cl₂:MeOH (4 : 1), 25 °C, 3 h.

Scheme 4

Synthesis of the mechanically planar chiral rotaxanes 9 a as a mixture of diastereoisomers (57 : 43 dr). Reagents and conditions: 1) isophthaloyl dichloride, Et₃N, CHCl₃, 25 °C, 4 h. Diastereomeric ratio determined by ¹H NMR spectroscopy and HPLC. Insets: A) HPLC chromatogram of the mixture of rotaxanes 9 a (Chiralpak IC‐3 column, 95 : 5 CH₂Cl₂:iPrOH, 0.5 mL min⁻¹, 254 nm); B) Partial ¹H NMR spectra of the mixture of rotaxanes 9 a (400 MHz, CDCl₃, 273 K).Signals related to the fumaramide double bond are highlighted in red. Signals related to the macrocycle are highlighted in light blue.

Figure 2

X‐ray structure of rotaxane (R,S_mp )‐9 a (minor diastereoisomer). A) inclined view; B) side view. Intramolecular hydrogen‐bond lengths [Å] (and angles [°]): N1−H01−O6 2.41 (171.3); N2−H02−O6 2.16 (167.9); N3−H03−O5 2.24 (159.5); N4−H04−O5 2.21 (164.8).

Scheme 5

Synthesis of the mechanically planar chiral rotaxanes 9 as mixtures of diastereoisomers through a 3‐component clipping reaction. Reagents and conditions: isophthaloyl chloride, Et₃N, CHCl₃, 25 °C, 4 h. Diastereomeric ratio determined by HPLC.

Scheme 6

CsOH‐promoted cyclization of rotaxanes 9 a followed by a thermal dethreading. The base‐promoted cyclization of both mechanical epimers 9 a can yield the four possible diastereoisomers of the interlocked trans‐β‐lactams 20 a. After dethreading, the enantioenriched trans‐β‐lactam 6 a is obtained. Reagents and conditions: 1) CsOH (8 equiv), DMF, 0 °C, 4 days; 2) DMF, 80 °C, 12 h. ^a Absolute configuration determined by derivatization of 6 a (see Supporting Information). ^b Enantiomeric ratio determined by chiral HPLC.

Scheme 7

One‐pot synthesis of the enantioenriched trans‐β‐lactams 6. A) Substrate scope; B) X‐ray structure of macrocycle (R)‐21. Reagents and conditions: 1) CsOH (8 equiv), DMF, 0 °C, 4 days; 2) (i) HCl (1 M), pH=7; (ii) 100 °C, 8 h. Enantiomeric ratio determined by chiral HPLC. ^a Reaction performed at 25 °C for 2 days.

Scheme 8

Synthesis of the enantioenriched β‐amino acid 22 e and the γ‐lactam 23 e. Reagents and conditions: 1) (i) CsOH (8 equiv), DMF, 0 °C, 4 days, then extraction with AcOEt; 2) HCl (1 M), MeOH, 65 °C, 24 h. Enantiomeric ratio taken from the methylated γ‐lactam 23 e.

Scheme 9

Synthesis of the enantioenriched cis‐γ‐lactams 23 a and 24 a. Reagents and conditions: 1) HCl 1 M, DMSO:MeOH (1 : 1), 100 °C, 24 h; 2) (i) CsOH, DMF, 0 °C, 4 days; (ii) HCl (1 M), pH=1, DMF:MeOH (1 : 1), 100 °C, 24 h. Enantiomeric ratio determined by chiral HPLC.

Figure 3

Computed transition structures of: A) Chemical diagrams of the four possible transition states TS (same orientation of the thread) for the cyclization step; B) (3S,4R)‐ TS _R,Rmp and (3R,4S)‐ TS _R,Rmp for the cyclization step (same orientation of the macrocycle) and decomposition of the energy difference between (3R,4S)‐ TS _R,Rmp and (3S,4R)‐ TS_R,Rmp (ΔΔE ^≠) into contributions from the energy difference of the macrocycles (ΔΔE _mac) and threads (ΔΔE _thread) and also between the interaction energies of the thread with the macrocycle (ΔΔE _int); C) (3S,4R)‐ TS _R,Smp and (3R,4S)‐ TS _R,Smp (same orientation of the macrocycle) and analogous decomposition of the difference in energies between (3R,4S)‐ TS _R,Smp and (3S,4R)‐ TS _R,Smp . Energies are shown in kJ mol⁻¹ and distances in angstroms.