Structural Studies and Anticancer Activity of a Novel Class of β‐Peptides

Functionalized oligomeric organic compounds with well‐defined β‐proline scaffold have been synthesized by a cycloadditive oligomerization approach in racemic and enantiopure forms. The structure of the novel β‐peptides was investigated by NMR spectroscopic and X‐ray methods determining the conformational shapes of the β‐proline oligomers in solution and solid states. The main structural elements subject to conformational switches are β‐peptide bonds between 5‐arylpyrrolidine‐2‐carboxylic acid units existing in Z/E configurations. The whole library of short β‐peptides and intermediate acrylamides has been tested on antiproliferative activity towards the hormone‐refractory prostate cancer cell line PC‐3 revealing several oligomeric compounds with low micromolar and submicromolar activities. Bromine‐substituted dimeric and trimeric acrylamides induced caspase‐dependent apoptosis of PC‐3 cells through cell‐cycle arrest and mitochondrial damage.     

Diphenylprolinol Silyl Ether Catalyzed Asymmetric Michael Reaction of Nitroalkanes and β,β‐Disubstituted α,β‐Unsaturated Aldehydes for the Construction of All‐Carbon Quaternary Stereogenic Centers

The asymmetric Michael reaction of nitroalkanes and β,β‐disubstituted α,β‐unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4‐addition products with an all‐carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for β‐substituents such as β‐aryl and β‐alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)‐ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,β‐unsaturated aldehydes, the retro‐Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.     

Catalytic Asymmetric Mannich‐Type Reaction Enabled by Efficient Dienolization of α,β‐Unsaturated Pyrazoleamides†

(E)‐α,β‐Unsaturated pyrazoleamides undergo facile dienolization to furnish copper(I)‐(1Z,3Z)‐dienolates as the major in the presence of a copper(I)‐(R)‐DTBM‐SEGPHOS catalyst and Et₃N, which react with aldimines to afford syn‐vinylogous products as the major diastereoisomers in high regio‐ and enantioselectivities. In some cases, the diastereoselectivity is low, possibly due to the low ratio of copper(I)‐(1Z,3Z)‐dienolates to copper(I)‐(1Z,3E)‐dienolates. (Z)‐Allylcopper(I) species is proposed as effective intermediates, which may form an equilibrium with copper(I)‐(1Z,3Z)‐dienolates. Interestingly, the present methodology is a nice complement to our previous report, in which (E)‐β,γ‐unsaturated pyrazoleamides were employed as the prenucleophiles in the copper(I)‐catalyzed asymmetric vinylogous Mannich‐Type reaction and anti‐vinylogous products were obtained. In the previous reaction, copper(I)‐ (1Z,3E)‐dienolates were generated through α‐deprotonation, which might form an equilibrium with (E)‐allylcopper(I) species. Therefore, it is realized in the presence of a copper(I) catalyst that (E)‐α,β‐unsaturated pyrazoleamides lead to syn‐products and (E)‐β,γ‐unsaturated pyrazoleamides lead to anti‐products. Finally, by use of (E)‐β,γ‐unsaturated pyrazoleamide, (E)‐α,β‐unsaturated pyrazoleamide, (R)‐DTBM‐SEGPHOS, and (S)‐DTBM‐SEGPHOS, the stereodivergent synthesis of all four stereoisomers is successfully carried out. Then by following a three‐step reaction sequence, all four stereoisomers of N‐Boc‐2‐Ph‐3‐Me‐piperidine are synthesized in good yields, which potentially serve as common structure units in pharmaceutically active compounds.     

Antiparallel Self‐Association of a γ,α‐Hybrid Peptide: More Relevance of Weak Interactions

To learn how a preorganized peptide‐based molecular template, together with diverse weak non‐covalent interactions, leads to an effective self‐association, we investigated the conformational characteristics of a simple γ,α‐hybrid model peptide, Boc‐γ‐Abz‐Gly‐OMe. The single‐crystal X‐ray diffraction analysis revealed the existence of a fully extended β‐strand‐like structure stabilized by two non‐conventional C?H???O=C intramolecular H‐bonds. The 2D ¹H NMR ROESY experiment led us to propose that the flat topology of the urethane‐γ‐Abz‐amide moiety is predominantly preserved in a non‐polar environment. The self‐association of the energetically more favorable antiparallel β‐strand‐mimic in solid‐state engenders an unusual ‘flight of stairs’ fabricated through face‐to‐face and edge‐to‐edge Ar???Ar interactions. In conjunction with FT‐IR spectroscopic analysis in chloroform, we highlight that conformationally semi‐rigid γ‐Abz foldamer in appositely designed peptides may encourage unusual β‐strand or β‐sheet‐like self‐association and supramolecular organization stabilized via weak attractive forces.     

(E)‐,(Z)‐Parallel Preparative Methods for Stereodefined β,β‐Diaryl‐ and α,β‐Diaryl‐α,β‐unsaturated Esters: Application to the Stereocomplementary Concise Synthesis of Zimelidine

Parallel and practical methods for the preparation of both (E)‐ and (Z)‐β‐aryl¹‐β‐aryl²‐α,β‐unsaturated esters 1 and (E)‐ and (Z)‐α‐aryl¹‐β‐aryl²‐α,β‐unsaturated esters 2 are described. These methods involve accessible, robust, stereocomplementary N‐methylimidazole (NMI)‐mediated enol tosylations (14 examples, 70–99 % yield), as well as stereoretentive Suzuki–Miyaura cross‐couplings (36 examples, 64–99 % yield). The highlighted feature of the present protocol is the use of parallel and stereocomplementary approaches to obtain highly (E)‐ and (Z)‐pure products 1 and 2 by utilizing sequential enol tosylations and cross‐coupling reactions. An expeditious and parallel synthesis of (E)‐ and (Z)‐zimelidine ( 3 ), which is a highly representative selective serotonin reuptake inhibitor (SSRI), was performed by utilizing the present methods.     

The E and Z isomers of 3‐(benzoxazol‐2‐yl)­prop‐2‐enoic acid

The carboxyl­ic acid group and the double bond are coplanar in (E)‐3‐(benzoxazol‐2‐yl)­prop‐2‐enoic acid, C₁₀H₇NO₃, whereas in isomeric (Z)‐3‐(benzoxazol‐2‐yl)­prop‐2‐enoic acid, also C₁₀H₇NO₃, they are almost orthogonal. In both isomers, a strong O—H⋯N hydrogen bond, with the carboxyl­ic acid group as a donor and the pyridine‐like N atom as an acceptor, and weak C—H⋯O interactions contribute to the observed supramolecular structures, which are completed by π–π stacking interactions between oxazole and benzenoid rings.     

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.     

Self‐Association of an Enantiopure β‐Pentapeptide in Nematic Liquid Crystals

Herein, we report for the first time that nematic liquid‐crystalline environments drive the reversible self‐aggregation of an enantiopure β‐pentapeptide into oligomers with a well‐defined structure. The peptide contains four (1S,2S)‐2‐aminocyclopentane carboxylic acid (ACPC) residues and the paramagnetic β‐amino acid (3R,4R)‐4‐amino‐1‐oxyl‐2,2,5,5‐tetramethylpyrrolidine‐3‐carboxylic acid (POAC). The structure of the oligomers was investigated by electron paramagnetic resonance (EPR) spectroscopy, which allowed us to obtain the intermonomer distance distribution in the aggregates as a function of peptide concentration in two nematic liquid crystals, E7 and ZLI‐4792. The aggregates were modeled on the basis of the EPR data, and their orientation and order in the nematic phase were studied by the surface tensor method.     

Nucleophilic Cyclopropanation Reaction with Bis(iodozincio)methane by 1,4‐Addition to α,β‐Unsaturated Carbonyl Compounds

Treatment of α,β‐unsaturated ketones with an electrophilic site at the γ‐position in the presence of trimethylsilyl cyanide with bis(iodozincio)methane afforded the (Z)‐silyl enol ether of the β‐cyclopropyl substituted ketone in good yields. The reaction proceeds by 1,4‐addition to form an enolate, and its sequential intramolecular nucleophilic attack to an adjacent electrophilic site. The reaction of γ‐ethoxycarbonyl‐α,β‐unsaturated ketone and bis(iodozincio)methane in the presence of trimethylsilyl cyanide afforded 1‐ethoxy‐1‐trimethylsiloxycyclopropane derivatives, which can be regarded as the homoenolate equivalent. Additionally, reaction of the obtained homoenolate equivalents with imines give 1‐(E)‐alkenyl‐2‐(1‐aminoalkyl)alkanols diastereoselectively.     

Induced Folding of Protein‐Sized Foldameric β‐Sandwich Models with Core β‐Amino Acid Residues

The mimicry of protein‐sized β‐sheet structures with unnatural peptidic sequences (foldamers) is a considerable challenge. In this work, the de novo designed betabellin‐14 β‐sheet has been used as a template, and α→β residue mutations were carried out in the hydrophobic core (positions 12 and 19). β‐Residues with diverse structural properties were utilized: Homologous β³‐amino acids, (1R,2S)‐2‐aminocyclopentanecarboxylic acid (ACPC), (1R,2S)‐2‐aminocyclohexanecarboxylic acid (ACHC), (1R,2S)‐2‐aminocyclohex‐3‐enecarboxylic acid (ACEC), and (1S,2S,3R,5S)‐2‐amino‐6,6‐dimethylbicyclo[3.1.1]heptane‐3‐carboxylic acid (ABHC). Six α/β‐peptidic chains were constructed in both monomeric and disulfide‐linked dimeric forms. Structural studies based on circular dichroism spectroscopy, the analysis of NMR chemical shifts, and molecular dynamics simulations revealed that dimerization induced β‐sheet formation in the 64‐residue foldameric systems. Core replacement with (1R,2S)‐ACHC was found to be unique among the β‐amino acid building blocks studied because it was simultaneously able to maintain the interstrand hydrogen‐bonding network and to fit sterically into the hydrophobic interior of the β‐sandwich. The novel β‐sandwich model containing 25 % unnatural building blocks afforded protein‐like thermal denaturation behavior.     

Practical Stereo‐ and Regioselective,Copper(I)‐Promoted Strecker Synthesis of Sugar‐Modified α,β‐Unsaturated Imines

The regio‐ and stereoselective, Lewis acid catalyzed Strecker reaction between Me₃SiCN and different aldimines incorporating a 2,3,4,6‐tetrakis‐O‐pivaloyl‐D ‐glucopyranosyl (Piv₄Glc) chiral auxiliary has been worked out. Depending on the conditions used, high yields (up to 95%) and good diastereoselectivities (de > 86%) were achieved under mild conditions (Table 1), especially with CuBr ? Me₂S as catalyst. Our protocol allows the ready preparation of asymmetric β,γ‐unsaturated α‐amino acids such as (R)‐2‐amino‐4‐phenylbut‐3‐enoic acid ( 13 ; Scheme 2) and congeners thereof.     

Phosphoryl group differentiating α‐amino acids from β‐ and γ‐amino acids in prebiotic peptide formation

In recent years β‐amino acids have increased their importance enormously in defining secondary structures of β‐peptides. Interest in β‐amino acids raises the question: Why and how did nature choose α‐amino acids for the central role in life? In this article we present experimental results of MS and ³¹P NMR methods on the chemical behavior of N‐phosphorylated α‐alanine, β‐alanine, and γ‐amino butyric acid in different solvents. N‐Phosphoryl α‐alanine can self‐assemble to N‐phosphopeptides either in water or in organic solvents, while no assembly was observed for β‐ or γ‐amino acids. An intramolecular carboxylic–phosphoric mixed anhydride (IMCPA) is the key structure responsible for their chemical behaviors. Relative energies and solvent effects of three isomers of IMCPA derived from α‐alanine (2a–c), with five‐membered ring, and five isomers of IMCPA derived from β‐alanine (4a–e), with six‐membered ring, were calculated with density functional theory at the B3LYP/6‐31G** level. The lower relative energy (3.2 kcal/mol in water) of 2b and lower energy barrier for its formation (16.7 kcal/mol in water) are responsible for the peptide formation from N‐phosphoryl α‐alanine. Both experimental and theoretical studies indicate that the structural difference among α‐, β‐, and γ‐amino acids can be recognized by formation of IMCPA after N‐phosphorylation. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem 94: 232–241, 2003     

The Development of a Stereoselective Method for the Synthesis of Tetrasubstituted Derivatives of α,β‐Unsaturated Carboxylic Acids

Alkenes possessing four different carbon‐linked substituents are the main structural motif of many biologically active compounds. The derivatives of (2E)‐3‐(3‐methoxyphenyl)‐2‐methylpent‐2‐enoic acid ((E)‐ 2c ) are suitable precursors for the synthesis of Tapentadol, a novel centrally acting analgesic. It was found that the Ni‐carbometallation reaction of disubstituted alkyne 8 with CO₂ and an Et₂Zn allows for efficient and practical preparation of (E)‐ 2c as a single (E)‐regioisomer in 89% of isolated yield. The influence of the size of the aliphatic substituent of alkyne and the steric hindrance of the organozinc reagent on stereochemical course of the carbometallation reaction was evaluated. Finally, air‐stable Ni(dme)Cl₂ was proposed as an alternative to widely used Ni(cod)₂ catalyst.     

Efficient Access to Enantiopure γ4‐Amino Acids with Proteinogenic Side‐Chains and Structural Investigation of γ4‐Asn and γ4‐Ser in Hybrid Peptide Helices

Hybrid peptides composed of α‐ and β‐amino acids have recently emerged as new class of peptide foldamers. Comparatively, γ‐ and hybrid γ‐peptides composed of γ⁴‐amino acids are less studied than their β‐counterparts. However, recent investigations reveal that γ⁴‐amino acids have a higher propensity to fold into ordered helical structures. As amino acid side‐chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ⁴‐residues with functional proteinogenic side‐chains and their structural analysis in hybrid‐peptide sequences. Here, the efficient and enantiopure synthesis of various N‐ and C‐terminal free‐γ⁴‐residues, starting from the benzyl esters (COOBzl) of N‐Cbz‐protected (E)‐α,β‐unsaturated γ‐amino acids through multiple hydrogenolysis and double‐bond reduction in a single‐pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected γ⁴‐amino acids (γ⁴‐Val, γ⁴‐Leu, γ⁴‐Ile, γ⁴‐Thr(OtBu), γ⁴‐Tyr, γ⁴‐Asp(OtBu), γ⁴‐Glu(OtBu), and γ‐Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central C^γ? C^β bond. To study the behavior of γ⁴‐residues with functional side chains in peptide sequences, two short hybrid γ‐peptides P1 (Ac‐Aib‐γ⁴‐Asn‐Aib‐γ⁴‐Leu‐Aib‐γ⁴‐Leu‐CONH₂) and P2 (Ac‐Aib‐γ⁴‐Ser‐Aib‐γ⁴‐Val‐Aib‐γ⁴‐Val‐CONH₂) were designed, synthesized on solid phase, and their 12‐helical conformation in single crystals were studied. Remarkably, the γ⁴‐Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side‐chain amide groups. Furthermore, the hydroxyl side‐chain of γ⁴‐Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ⁴‐residues in peptide single‐crystals reveal that the γ⁴‐residues in 12‐helices are more ordered as compared with the 10/12‐ and 12/14‐helices.     

Methyl 4‐O‐β‐D‐mannopyranosyl β‐D‐xylopyranoside

Methyl β‐D‐mannopyranosyl‐(1→4)‐β‐D‐xylopyranoside, C₁₂H₂₂O₁₀, (I), crystallizes as colorless needles from water, with two crystallographically independent molecules, (IA) and (IB), comprising the asymmetric unit. The internal glycosidic linkage conformation in molecule (IA) is characterized by a ϕ′ torsion angle (O5′_Man—C1′_Man—O1′_Man—C4_Xyl; Man is mannose and Xyl is xylose) of −88.38 (17)° and a ψ′ torsion angle (C1′_Man—O1′_Man—C4_Xyl—C5_Xyl) of −149.22 (15)°, whereas the corresponding torsion angles in molecule (IB) are −89.82 (17) and −159.98 (14)°, respectively. Ring atom numbering conforms to the convention in which C1 denotes the anomeric C atom, and C5 and C6 denote the hydroxymethyl (–CH₂OH) C atom in the β‐Xylp and β‐Manp residues, respectively. By comparison, the internal glycosidic linkage in the major disorder component of the structurally related disaccharide, methyl β‐D‐galactopyranosyl‐(1→4)‐β‐D‐xylopyranoside), (II) [Zhang, Oliver & Serriani (2012). Acta Cryst. C 68 , o7–o11], is characterized by ϕ′ = −85.7 (6)° and ψ′ = −141.6 (8)°. Inter‐residue hydrogen bonding is observed between atoms O3_Xyl and O5′_Man in both (IA) and (IB) [O3_Xyl...O5′_Man internuclear distances = 2.7268 (16) and 2.6920 (17) Å, respectively], analogous to the inter‐residue hydrogen bond detected between atoms O3_Xyl and O5′_Gal in (II). Exocyclic hydroxymethyl group conformation in the β‐Manp residue of (IA) is gauche–gauche, whereas that in the β‐Manp residue of (IB) is gauche–trans.     

Asymmetric Conjugate Reduction of α,β‐Unsaturated Ketones and Esters with Chiral Rhodium(2,6‐bisoxazolinylphenyl) Catalysts

New asymmetric conjugate reduction of β,β‐disubstituted α,β‐unsaturated ketones and esters was accomplished with alkoxylhydrosilanes in the presence of chiral rhodium(2,6‐bisoxazolinylphenyl) complexes in high yields and high enantioselectivity. (E)‐4‐Phenyl‐3‐penten‐2‐one and (E)‐4‐phenyl‐4‐isopropyl‐3‐penten‐2‐one were readily reduced at 60 °C in 95 % ee and 98 % ee, respectively, by 1 mol % of catalyst loading. (EtO)₂MeSiH proved to be the best hydrogen donor of choice. tert‐Butyl (E)‐β‐methylcinnamate and β‐isopropylcinnamate could also be reduced to the corresponding dihydrocinnamate derivatives up to 98 % ee.     

N‐[tert‐Butoxy­carbonyl­glycyl‐(Z)‐α,β‐dehydro­phenyl­alanylglycyl‐(E)‐α,β‐dehydro­phenyl­alanylphenyl­alanyl]‐4‐nitro­aniline ethanol solvate

The α,β‐dehydro­phenyl­alanine residues influence the conformation of the title penta­peptide Boc⁰–Gly¹–Δ^ZPhe²–Gly³–Δ^EPhe⁴–l ‐Phe⁵–p‐NA ethanol solvate, C₄₂H₄₃N₇O₉·C₂H₅OH. The first unsaturated phenyl­alanyl (Δ^ZPhe²) and the third glycyl (Gly³) residues form a type I β turn, while the second unsaturated phenyl­alanyl (Δ^EPhe⁴) and the last phenyl­alanyl (l ‐Phe⁵) residues are part of a type II β turn. All the amino acids in the peptide are linked trans to one another. The crystal structure is stabilized by intra‐ and inter­molecular hydrogen bonds.     

A Designed Three‐Stranded β‐Sheet in an α/β Hybrid Peptide

The incorporation of β‐amino acid residues into the antiparallel β‐strand segments of a multi‐stranded β‐sheet peptide is demonstrated for a 19‐residue peptide, Boc‐LV^βFV^DPGL^βFVVL^DPGLVL^βFVV‐OMe (BBH19). Two centrally positioned ^DPro–Gly segments facilitate formation of a stable three‐stranded β‐sheet, in which β‐phenylalanine (^βPhe) residues occur at facing positions 3, 8 and 17. Structure determination in methanol solution is accomplished by using NMR‐derived restraints obtained from NOEs, temperature dependence of amide NH chemical shifts, rates of H/D exchange of amide protons and vicinal coupling constants. The data are consistent with a conformationally well‐defined three‐stranded β‐sheet structure in solution. Cross‐strand interactions between ^βPhe3/^βPhe17 and ^βPhe3/Val15 residues define orientations of these side‐chains. The observation of close contact distances between the side‐chains on the N‐ and C‐terminal strands of the three‐stranded β‐sheet provides strong support for the designed structure. Evidence is presented for multiple side‐chain conformations from an analysis of NOE data. An unusual observation of the disappearance of the Gly NH resonances upon prolonged storage in methanol is rationalised on the basis of a slow aggregation step, resulting in stacking of three‐stranded β‐sheet structures, which in turn influences the conformational interconversion between type I′ and type II′ β‐turns at the two ^DPro–Gly segments. Experimental evidence for these processes is presented. The decapeptide fragment Boc‐LV^βFV^DPGL^βFVV‐OMe (BBH10), which has been previously characterized as a type I′ β‐turn nucleated hairpin, is shown to favour a type II′ β‐turn conformation in solution, supporting the occurrence of conformational interconversion at the turn segments in these hairpin and sheet structures.     

The Design of α/β‐Peptides: Study on Three‐Residue Turn Motifs and the Influence of Achiral Glycine on Helix and Turn

Novel three‐residue helix‐turn secondary structures, nucleated by a helix at the N terminus, were generated in peptides that have ‘β‐Caa‐L ‐Ala‐L ‐Ala,’ ‘β‐Caa‐L ‐Ala‐γ‐Caa,’ and ‘β‐Caa‐L ‐Ala‐δ‐Caa’ (in which β‐Caa is C‐linked carbo‐β‐amino acid, γ‐Caa is C‐linked carbo‐γ‐amino acid, and δ‐Caa is C‐linked carbo‐δ‐amino acid) at the C terminus. These turn structures are stabilized by 12‐, 14‐, and 15‐membered (mr) hydrogen bonding between NH(i)/CO(i+2) (i+2 is the last residue in the peptide) along with a 7‐mr hydrogen bond between CO(i)/NH(i+2). In addition, a series of α/β‐peptides were designed and synthesized with alternating glycine (Gly) and (S)‐β‐Caa to study the influence of an achiral α‐residue on the helix and helix‐turn structures. In contrast to previous results, the three ‘β–α–β’ residues at the C terminus (α‐residue being Gly) are stabilized by only a 13‐mr forward hydrogen bond, which resembles an α‐turn. Extensive NMR spectroscopic and molecular dynamics (MD) studies were performed to support these observations. The influence of chirality and side chain is also discussed.     

Stereochemical Models for Discussing Additions to α,β‐Unsaturated Aldehydes Organocatalyzed by Diarylprolinol or Imidazolidinone Derivatives – Is There an ‘(E)/(Z)‐Dilemma’?

The structures of iminium salts formed from diarylprolinol or imidazolidinone derivatives and α,β‐unsaturated aldehydes have been studied by X‐ray powder diffraction (Fig. 1), single‐crystal X‐ray analyses (Table 1), NMR spectroscopy (Tables 2 and 3, Figs. 2–7), and DFT calculations (Helv. Chim. Acta 2009 , 92, 1, 1225, 2010 , 93, 1; Angew. Chem., Int. Ed. 2009 , 48, 3065). Almost all iminium salts of this type exist in solution as diastereoisomeric mixtures with (E)‐ and (Z)‐configured ⁺NC bond geometries. In this study, (E)/(Z) ratios ranging from 88 : 12 up to 98 : 2 (Tables 2 and 3) and (E)/(Z) interconversions (Figs. 2–7) were observed. Furthermore, the relative rates, at which the (E)‐ and (Z)‐isomers are formed from ammonium salts and α,β‐unsaturated aldehydes, were found to differ from the (E)/(Z) equilibrium ratio in at least two cases (Figs. 4 and 5, a, and Fig. 6, a); more (Z)‐isomer is formed kinetically than corresponding to its equilibrium fraction. Given that the enantiomeric product ratios observed in reactions mediated by organocatalysts of this type are often ≥99 : 1, the (E)‐iminium‐ion intermediates are proposed to react with nucleophiles faster than the (Z)‐isomers (Scheme 5 and Fig. 8). Possible reasons for the higher reactivity of (E)‐iminium ions (Figs. 8 and 9) and for the kinetic preference of (Z)‐iminium‐ion formation are discussed (Scheme 4). The results of related density functional theory (DFT) calculations are also reported (Figs. 10–13 and Table 4).