Resolution and Determination of the Absolute Configuration of a Twisted Bis-Lactam Analogue of Tröger’s Base: A Comparative Spectroscopic and Computational Study

Abstract

The first reported twisted bis-lactam, a racemic Tröger's base (TB) analogue (2), was resolved into its enantiomers on a chiral stationary phase HPLC column. The absolute configuration of (+)-2 was determined to be (R,R)-2 by comparing experimental and calculated vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectra. The absolute configuration of (-)-2 was determined by comparing experimental and calculated electronic circular dichroism (ECD) spectra. The corresponding theoretical spectra were calculated using the lowest energy conformation of (R,R)-2 and (S,S)-2 at the B3LYP/6-31G(d,p) level of theory. The absolute configuration of (+)-2 was also determined to (R,R)-2 by anomalous X-ray diffraction (AXRD) in a chiral space group P212121 using Cu-irradiation resulting in a very low Flack parameter of -0.06(3), despite the heaviest element being an oxygen atom, thus unambiguously confirming the results from the spectroscopic studies. We conclude that, for the Tröger's base (TB) analogue (2), we may rank the reliability of the individual methods for AC determination as AXRD ≫ VCD > ECD, while the synergy of all three methods provides very strong confidence in the assigned ACs of (+)-(R,R)-2 and (-)-(S,S)-2.

Tröger’s Base Twisted Amides: High Amide Bond Twist and N-/O-Protonation Aptitude

“…Benzofused 1-azabicyclo[3.3.1]­nonan-2-one derivative ( 2 ) has been used by us to demonstrate N-alkylation and the subsequent σ N–C bond cleavage of bridged lactams . Methyl-truncated Tröger’s base twisted amides 3 and 4 are analogues of the amides reported by Wärnmark and Cvengroš, respectively. , Amides 5 and 6 are Tröger’s base analogous of 3 and 4 lacking benzene rings, while twisted urea 7 was selected on the basis of the potential bridgehead oxidation in the course of synthesis of 3 . Note that related bridgehead iminium ions are well-known .…”

“…Stimulated by our interest in the properties of nonplanar cyclic and acyclic amides, we were attracted by the recently reported examples of Tröger’s base twisted amides , as models for a substantial twist of the amide bond. In 2012, Wärnmark and co-workers demonstrated that direct oxidation of the venerable Tröger’s base scaffold can be used to afford a twisted bis-amide with a remarkable twist of the amide bond (Figure B, τ = 41.0°, χ N = 57.9°, N–C­(O) = 1.430 Å, CO = 1.210 Å). In 2017, Cvengroš and co-workers reported the synthesis of an extended Tröger’s base twisted amide using one-step oxidation of the ethano-Tröger’s base (Figure B, τ = 29.8°, χ N = 45.5°, N–C­(O) = 1.401 Å, CO = 1.215 Å).…”

“…In 2017, Cvengroš and co-workers reported the synthesis of an extended Tröger’s base twisted amide using one-step oxidation of the ethano-Tröger’s base (Figure B, τ = 29.8°, χ N = 45.5°, N–C­(O) = 1.401 Å, CO = 1.215 Å). Since the Tröger’s base twisted amides reported by Wärnmark and Cvengroš (1) represent rare examples of significantly twisted amides with the additive Winkler–Dunitz parameter approaching 100° ((τ + χ N ) = 98.9° and 75.3°, respectively) and, in addition, (2) are prepared by a more facile and faster approach , that related twisted amides, ,, a better understanding of the structures and energetics could facilitate the design of novel twisted amides of both theoretical and practical synthetic interest. − ,− In this manuscript, we report a computational investigation into the structures and proton affinities of a diverse set of Tröger’s base twisted amides and compare them with related nonplanar bridged lactams.…”

Twisted Amides: From Obscurity to Broadly Useful Transition‐Metal‐Catalyzed Reactions by N−C Amide Bond Activation

“…This methodology elegantly exploits the high electrophilicity of the carbonyl group in twisted amides, providing direct access to stereochemically defined Tröger's base derivatives after hydrogenation. The authors showcased the utility of the thus‐obtained products in the synthesis of macrocyclic crown ether analogues of Tröger's base …”

Enantiomeric resolution, stereochemical assignment and toxicity evaluation of TPA enantiomers

“…The absolute configuration of the isolated TPA enantiomers was determined using ECD spectroscopy. The absolute configuration assignment is significant for understanding the stereoselective bioactivity (Rúnarsson et al, ), and the sign of the optical rotation is subject to error in the stereochemical assignment (Zhang et al, ). Therefore, ECD experiments were carried out to confirm the absolute configuration of the chiral TPA enantiomers.…”