Chapter Four · failure evidence
What Asymmetric & Chiral Synthesis got wrong, from 67 dissertations
Attempts to achieve asymmetric induction and chiral resolution frequently encounter substantial chemical and physical hurdles across diverse synthetic transformations. Researchers consistently face challenges including inadequate stereocontrol by chiral catalysts, disruptive reaction media, competitive side pathways, and technical or financial limitations in chiral separation. These records come from PhD theses at 21 institutions, 2021 to 2026. Each links to its thesis. They were extracted by language models reading the full text, so treat each as a lead to read, not a verdict.
Chiral catalysts and ligands fail to establish stereocontrol resulting in racemic or low enantiomeric excess products
Screening of chiral ligands, hydrogen-bond donors, and metal catalysts frequently resulted in racemic mixtures or poor stereochemical induction during functionalization reactions. These failures occurred because catalysts lacked sufficient facial discrimination, failed to preorganize transition states, or allowed reactive intermediates to escape the chiral sphere.
Tried and failed
chiral metal-catalyzed radical C-H functionalization applied to asymmetric benzylic C-H azidation. Reason: radical intermediate escaped catalyst sphere or lacked chiral induction, giving completely racemic product
Radical-Mediated Azidation of Benzylic C-H Bonds and Azidofunctionalization of Alkenes · EPFL
Tried and failed
chiral gold-catalyzed intramolecular alkyne hydroarylation applied to enantioselective synthesis of inherently chiral scaffolds. Reason: catalytic system afforded poor enantioselectivity despite high chemical yield
Recent progress towards catalytic asymmetric construction of inherently chiral scaffolds. · Cambridge
Tried and failed
chiral phosphoric acid ligands in Pd-catalysed functionalisation applied to enantioselective C(sp3)-H arylation of heterocycles. Outcome: no signal. Reason: chiral phosphoric acids failed to induce enantioselectivity, yielding racemic products
Tried and failed
single-point structural modifications to chiral catalyst applied to enantioselective asymmetric catalytic reactions. Outcome: worse than baseline. Reason: individual peripheral steric and electronic substitutions failed to improve ground-state preorganization or stereodetermining transition-state selectivity
Enzymatic Principles in Selective Small-Molecule Catalysis · Harvard
Considered and rejected
Considered and rejected: Decided against pursuing asymmetric total synthesis of individual enantiomers after chiral Rh catalysts (Rh2(S-TCPTTL)4) yielded maximum 15–16% ee, continuing with racemic route.
Considered and rejected
Considered and rejected: Abandonment of the chiral Lewis-acid / oxazolidinone approach (156 with Sc(OTf)3 / Ir(dFppy)3) for enantioselective dihydrophenalene synthesis due to failure to establish stereocontrol.
Photoannulierungen zu Dihydrophenalenonen und 1-Tetralonen · open_UMR Marburg DSpace 10.0
Considered and rejected
Considered and rejected: Rejected using acyclic monodentate aryl imines (3.91) for asymmetric induction due to inability to induce enantioselectivity (0% ee across all chiral ligands tested)
Development of Metal-Catalyzed and Photochemical Approaches to Carbon-Carbon Bond Forming Reactions · DSpace at UTSWMED
Tried and failed
substoichiometric chiral amino alcohol catalyzed organozinc addition applied to enantioselective aldehyde vinylation. Outcome: worse than baseline. Reason: substoichiometric chiral ligand catalyst loading resulted in severe loss of enantioselectivity
Synthesis of C4-Modified Tetracyclines with Anticancer Activity · Harvard
Tried and failed
chiral ligand-directed transition metal catalytic asymmetric amination applied to linear allylic substrates. Outcome: no signal. Reason: Chiral ligands failed to induce enantioselectivity during substitution on linear allylic substrates.
Tried and failed
chiral bisoxazoline ligand for enantioselective radical functionalization applied to copper-catalyzed cyclopropyl amide diazidation. Outcome: no signal. Reason: The chiral ligand failed to induce enantioselectivity, yielding racemic product (49.8:50.2 er)
Diamine Synthesis via the Nitrogen-Directed Azidation of sigma- and pi-C-C Bonds · EPFL
Considered and rejected
Considered and rejected: Chiral primary amine organocatalysts were abandoned in favor of chiral metal catalysis due to low enantioselectivity (<10% to 30% ee).
Dearomative reductive functionalisation reactions of azaarenes · Oxford
Tried and failed
Copper-catalyzed asymmetric hydroamination using chiral phosphine ligands applied to 1-alkylcyclopropenes. Reason: Facile alkene insertion lacking facial discrimination gave poor enantioselectivity
Development of Copper(I) Hydride-Catalyzed Asymmetric Olefin Hydrofunctionalization Reactions · MIT
Tried and failed
dual catalytic asymmetric gamma-allylation applied to alpha,beta-unsaturated aldehydes. Reason: catalyst, ligand, and allyl source combinations failed to achieve direct asymmetric functionalisation
Application of new methodologies using principles of green chemistry in organic synthesis · Texas Tech
Tried and failed
catalytic asymmetric nucleophilic epoxidation and dihydroxylation applied to conjugated cyclic dienes. Reason: dihydroxylation was completely unsuccessful and nucleophilic epoxidation yielded unsatisfactory enantioselectivities
Enantioselective total synthesis of the pentacyclic type II polyketide antibiotic formicamycin H · UT Austin
Considered and rejected
Considered and rejected: Rejected using chiral bidentate phosphine ligands (such as (R)-BINAP, (R)-JosiPhos, (R)-DM-SEGPHOS, iPr-PHOX) for propargylic amine cyclization due to complete lack of reactivity or enantioselectivity.
Chiral resolutions and chromatographic separations suffer from poor selectivity, matrix incompatibility, or excessive costs
Techniques for chiral separation and kinetic resolution often failed due to low selectivity factors, inadequate chromatographic resolution, and peak tailing from polar analytes. Additionally, preparative chiral columns, specialized selectors, and derivatizing agents were frequently rejected due to severe operational complexity and prohibitive financial expense.
Tried and failed
enzymatic hydrolysis of racemic branched nitriles applied to enantioselective synthesis of chiral nitriles. Reason: enzymes exhibited an inverse trade-off between catalytic activity and enantioselectivity
Enzymatic cascades for stereoselective and regioselective amide bond assembly · Imperial
Considered and rejected
Considered and rejected: Rejected kinetic resolution of racemic carbonimidothioate reagents with chiral amine nucleophiles due to low selectivity factors (s ≤ 5.8), prompting the shift to a chiral auxiliary approach.
Enantioselective Alkali Metal Catalysis · Harvard
Considered and rejected
Considered and rejected: Rejected chiral HPLC for resolution of 2-cyclohexyl-2-phenylacetic acid due to failure/inefficiency, choosing fractional recrystallization of diastereomeric amine salts instead.
Design, Synthesis, and Development of Novel Fluorescently Labelled Allosteric Probes for the Human Beta2-Adrenoceptor · University of Nottingham Repository
Tried and failed
chiral derivatization with reversed-phase liquid chromatography applied to separation of alanine isomers. Reason: beta-alanine could not be chromatographically resolved from D- or L-alanine enantiomers
Investigating the role of the gut metabolome in appetite regulation and obesity · Imperial
Tried and failed
crystallization on colloidal magnetic nanoparticles applied to chiral separation from racemic solution. Outcome: no signal. Reason: colloidal magnetic particles lacked the well-defined flat surface orientation required for spin-dependent enantioselectivity
A New Spin on the Origin of Biological Homochirality · Harvard
Considered and rejected
Considered and rejected: Rejected chiral HPLC stereospecificity analysis due to high method complexity and sample preparation cost.
Etablierung eines mikrobiellen Kultivierungsprozesses für die Duft- und Aromastoffproduktion zur digital unterstützten Prozessoptimierung · Leibniz Universität Hannover Repository
Considered and rejected
Considered and rejected: Chiral derivatization on GC-MS rejected in favor of vancomycin chiral columns due to harmful nature and high cost of derivatizing agents.
Development and Validation of Toxicological Methods for Cognitive Stimulants in Traditional and Alternative Matrices · DSpace at SHSU
Considered and rejected
Considered and rejected: Coated chiral stationary phases were rejected for crude high-throughput reaction screening in favor of immobilized chiral stationary phases to tolerate unpurified reaction mixtures.
Computational and Experimental Studies in Selective Organocatalysis · Harvard
Considered and rejected
Considered and rejected: Rejected chiral columns (CHIRALPAK AD-H, CHIRALCEL OD-H) for E/Z separation due to poor peak separation/tailing caused by analyte polarity; selected reverse-phase C18 chromatography instead.
Total Synthesis of Marine Macrolide Mangrolide D · DSpace at UTSWMED
Considered and rejected
Considered and rejected: Preparative chiral chromatography with an amylose-1 column for gram-scale purification of Phth-F-Phe enantiomers was rejected due to excessive cost (~$10,000).
MOLECULAR DESIGN STRATEGIES AND IMAGING OF ELECTRONIC PEPTIDE NANOMATERIAL SCAFFOLDS · JScholarship
Considered and rejected
Considered and rejected: Decided against separating enantiomers of 2.26 because its 228 µM IC50 did not justify chiral HPLC costs.
Altes Target, Neue Hits - Entwicklung von Inhibitoren für die PIM1-Kinase New Hits for an old Target - Development of novel Inhibitors of PIM1-Kinase · open_UMR Marburg DSpace 10.0
Considered and rejected
Considered and rejected: Use of gamma-cyclodextrin as chiral selector rejected due to prohibitively high cost for routine laboratory analyses, opting for beta-cyclodextrin.
Analytical Method Development and Mission Design Studies to Inform the Search for Biosignatures on Ocean Worlds · Georgia Tech
Complex asymmetric catalytic methodologies underperform compared to simpler baselines or alternative reagents
Several asymmetric reaction designs delivered lower chemical yields, poorer diastereoselectivity, or diminished enantioselectivity relative to established simpler baselines. Consequently, researchers abandoned intricate chiral catalyst routes in favor of simpler achiral transformations, alternative metal catalysts, or biological synthesis.
Lost to a baseline
Butadiene-mediated crotylations of chiral primary alcohols exhibited lower diastereoselectivity compared to identical reactions mediated by methyl allene.
Lost to a baseline
DDQ/chiral phosphoric acid catalyst method by Reddy group surpassed vanadium-catalyzed asymmetric coupling using simpler starting materials
Aerobic Oxidation Of Phenols And Other Arenes By Transition Metal Catalysis · Penn
Lost to a baseline
Synthesis of chiral thiazolium salt 61e gave 36% yield with P2S5-Py2 versus 69% with P4S10.
Lost to a baseline
Asymmetric reduction of heteroaromatic ferrocenyl ketones via CBS/Ru-BINAP previously gave moderate enantioselectivity (41-68% ee) compared to 96-98% ee via (Fc)ZnEt addition
Catalytic Asymmetric Additions of in situ Generated Functionalized Zinc Reagents to Aldehydes · Penn
Lost to a baseline
Chemical asymmetric synthesis produced DEHP with moderate yields in the esterification step compared to the biological synthesis by B. thuringiensis
Identificación de productos naturales de Bacillus thuringiensis con actividad · Repositorio Institucional BUAP
Lost to a baseline
4CzIPN exhibited lower yield in the asymmetric dicarbofunctionalization of enamides compared to Ru(phen)3PF6.
Lost to a baseline
Previously developed chiral-at-metal catalyst -Ru8 gave 32% yield and 38% e.e. (S) on diazoketone 129a compared to 99% yield and 93% e.e. (R) with -Ru6*
Design and Synthesis of Cyclometalated Chiral-at- Ruthenium Complexes for Asymmetric Catalysis Design und Synthese von cyclometallierten chiral-at-Ruthenium Komplexen für asymmetrische Katalyse · open_UMR Marburg DSpace 10.0
Considered and rejected
Considered and rejected: Rejected developing custom chemical methodology for asymmetric cyclisation of diene 181, choosing instead chiral HPLC resolution of racemic tricycle 117.
Evolved P450 mutants as general oxidation catalysts for target synthesis via C–H activation · Oxford
Tried and failed
standard chiral bisphosphine ligands for transition-metal catalysis applied to enantioselective reductive carbonyl allene coupling. Outcome: worse than baseline. Reason: standard bidentate diphosphines gave poor conversion and low chemical yield
Enantioselective iridium and ruthenium-catalyzed carbonyl reductive coupling via hydrogen transfer · UT Austin
Considered and rejected
Considered and rejected: Rejected 2nd-generation BIMP catalysts with cis-tert-butyl chiral backbones (e.g. 98) for direct aldol additions due to lack of enantioselectivity improvement over 1st-generation benzhydryl designs.
Catalytic enantioselective methods for challenging polar addition reactions · Oxford
Considered and rejected
Considered and rejected: Rejected the top CASP-suggested chiral amine catalyst (8S,9S)-6'-methoxycinchonan-9-amine for (S)-warfarin synthesis due to high cost (> $500/g), substituting (1S,2S)-(+)-1,2-diphenylethylenediamine ((S,S)-DPEN) instead.
Flow Chemistry Guided by Computer-Aided Synthesis Planning · MIT
Considered and rejected
Considered and rejected: Abandoned asymmetric Shi epoxidation / diastereomer separation route in favor of achiral epoxidation due to operational simplicity.
N-HETEROCYCLIC CARBENES: FROM DESIGN TO SYNTHESIS AND THEIR APPLICATION AS NUCLEOPHILIC CATALYSTS · Penn
Unwanted side reactions and competing pathways undermine stereospecificity and conversion
Asymmetric transformations were often disrupted by chemoselectivity shifts, catalyst inhibition, homocoupling, or dual electrophilic centers that eroded stereospecificity. Substrate chelation and scaling issues also led to severe drops in chemical conversion or the generation of undesired byproducts.
Tried and failed
Auxiliary-controlled asymmetric Baylis-Hillman reaction applied to benzyloxyacetaldehyde and sultam acrylamide. Reason: Failed to form the desired stereodefined lactone product
Tried and failed
combinatorial module swapping at domain boundaries applied to modular polyketide synthases. Reason: incomplete reduction by the downstream catalytic domain produced an undesired ketone byproduct rather than the target chiral intermediate
Bioinformatics analysis and engineering of polyketide synthases · UT Austin
Considered and rejected
Considered and rejected: Abandoned synthesis of (Rs,Sc)-1,2,2,3,3-pentadeuterio-3-phenylpropyl p-tolyl sulfoxide due to failed chiral reduction and inseparable sulfinic ester diastereomers, replacing it with the neopentyl derivative.
Considered and rejected
Considered and rejected: Abandoned Lewis acid-catalyzed asymmetric ATRA after extensive screening due to poor stereocontrol and Lewis acid inhibition of radical addition.
Synthesis and functionalization of α-Chiral Bicyclo[1.1.1]pentanes · Oxford
Considered and rejected
Considered and rejected: Pure enantiomer epichlorohydrin was rejected for chiral synthesis due to dual electrophilic centers causing loss of stereospecificity (glycidyl nosylate used instead).
Synthesis and biological evaluation of novel PqsR antagonists to combat Pseudomonas aeruginosa infections · University of Nottingham Repository
Tried and failed
multicomponent allylation using chiral hydrogen-bond donors applied to weakly nucleophilic amides. Reason: weak nucleophiles shifted chemoselectivity toward competing oxocarbenium ion trap forming homoallylic ethers
Considered and rejected
Considered and rejected: Abandoned asymmetric Mo-catalyzed RCM of acryl ester 156 due to irreproducible and poor conversion (<=27%) caused by ester oxygen chelation.
Efforts towards the total synthesis of elisabethin A · DSpace-CRIS at TU Wien
Considered and rejected
Considered and rejected: Desymmetrization route of triol 3.19 to chiral epoxide 3.22 abandoned due to non-commercial reagents, high step count, and volatility/mass losses of low-MW intermediates.
Considered and rejected
Considered and rejected: Abandoned chiral lithium organyl / Cu-mediated cross-coupling (Knochel method) for enone 167 due to severe drop in yields upon scale-up (down to 7-29%).
Die 1,2-Boronat-Umlagerung in den Fragmentsynthesen von Disorazol C1 und Tedanolid C, sowie die Synthesen von Antroalbocin A und Illihenin A · Leibniz Universität Hannover Repository
Considered and rejected
Considered and rejected: Cu/TMEDA-catalyzed SN2 substitution on chiral tosylate 137/140 abandoned due to <20% conversion.
TOTAL SYNTHESIS OF THE REPORTED STRUCTURE OF NEAUMYCIN B · Penn
Considered and rejected
Considered and rejected: Rejected asymmetric ethyl N-diphenylmethylene glycine as a cross-coupling substrate because it predominantly underwent Cu-catalysed homocoupling instead
Catalytic and mechanistic studies towards understanding copper-catalysed C-C cross-coupling · Imperial
Harsh or incompatible reaction environments induce racemization or catalyst decomposition
Basic or harsh reaction environments frequently induced product racemization, forcing the abandonment of enantiopure precursors. Additionally, polar solvents, high temperatures, acidic protonation, or non-coordinating counterions disrupted vital chiral ion pairs and hydrogen-bonding networks, degrading catalyst activity and stereocontrol.
Tried and failed
using excess basic amine reagent applied to chiral amide bond formation. Reason: basic reaction conditions induced substrate racemization
Considered and rejected
Considered and rejected: Rejected using an enantiomerically pure precursor for [18F]talazoparib synthesis due to risk of racemization under harsh conditions; synthesized racemic mixture and resolved via chiral 2D-HPLC instead.
Expanding the Toolbox for Positron Emission Tomography – Radiotracer Development from PARP to Reporter Genes · Publikationssystem UB Tuebingen
Tried and failed
polar solvents in chiral phase-transfer catalysis applied to asymmetric Michael additions. Outcome: worse than baseline. Reason: polar solvents disrupt chiral ion-pairing interactions, causing near-complete loss of enantioselectivity and poor diastereoselectivity
Tried and failed
chiral squaramide hydrogen-bond donor catalysis applied to enantioselective Matteson rearrangement. Reason: catalyst deprotonation led to catalyst decomposition and poor enantioselectivity (5% ee)
Tried and failed
chiral Lewis base organocatalysis under acidic conditions applied to acid-promoted carbohydrate debenzylation. Outcome: worse than baseline. Reason: catalyst basic sites undergo protonation by the acid promoter, suppressing reaction reactivity
Considered and rejected
Considered and rejected: Abandoned chiral Brønsted/Lewis acid catalysis for desymmetrization due to high temperature requirements (>80 °C) causing low enantioselectivity (<=10% ee)
Chemical Investigations in Complex Alkaloid Synthesis · DSpace at UTSWMED
Considered and rejected
Considered and rejected: Avoided reliance on HFIP for asymmetric reaction development because strong H-bond donation disrupts substrate-chiral catalyst interactions.
The stereoselective synthesis of heterocycles through cation-triggered annulation · Oxford
Tried and failed
non-coordinating counterion in dual hydrogen-bond catalysis applied to enantioselective propargylic substitution. Outcome: no signal. Reason: the bulky non-coordinating counterion failed to bind the chiral hydrogen-bond donor catalyst, causing complete loss of stereocontrol
New Strategies for Stereocontrol of Highly Electrophilic Intermediates in Asymmetric Catalysis · Harvard
Substrate steric and electronic mismatches impede chiral induction and reaction progress
Substrates bearing steric hindrance, olefinic substitution, or lacking essential directing groups consistently degraded enantioselectivity. Electronic mismatches and competitive Lewis base coordination further compromised transition-state preorganization and inhibited reaction advancement.
Tried and failed
chiral hydrogen-bond-donor catalysis applied to enantioselective phosphonium dealkylation. Outcome: did not generalise. Reason: ortho-aryl steric clash and aliphatic substituents failed to induce sufficient stereocontrol in transition-state preorganization
Enzymatic Principles in Selective Small-Molecule Catalysis · Harvard
Tried and failed
chiral hydrogen-bond-donor catalyzed asymmetric electrocyclization applied to highly substituted divinyl ketones. Outcome: did not generalise. Reason: more substituted alkenes yielded poor enantioselectivity in Nazarov cyclization
Studies on the Structure and Function of Dual Hydrogen-Bond-Donor Catalysts · Harvard
Tried and failed
enantioselective 1,2-rearrangement via chiral lithium Lewis acid applied to sterically hindered, unsaturated, or basic boronates. Outcome: did not generalise. Reason: electronic mismatches, steric hindrance, and competitive Lewis base coordination degraded enantioselectivity
Lost to a baseline
Handled chiral Diels-Alder cycloaddition between dienophile 122 and diene 128 produced predominantly the undesired constitutional isomer 161 (34-47% yield) due to poor diene polarization.
Studien zur Derivatisierung der [11]-Cytochalasine · Leibniz Universität Hannover Repository
Tried and failed
catalytic asymmetric nucleophilic aromatic substitution without directing group applied to macrocyclic substrate lacking hydrogen-bond donor. Outcome: worse than baseline. Reason: absence of the N-H binding site in the bridging position reduced yield and enantioselectivity
Recent progress towards catalytic asymmetric construction of inherently chiral scaffolds. · Cambridge
Tried and failed
transition-metal-catalyzed asymmetric allylic alkylation applied to sterically hindered branched alkyl pronucleophiles. Outcome: did not generalise. Reason: steric hindrance from alpha- or beta-branching impeded reaction progress
Tried and failed
hydrogen-bond-donor asymmetric desymmetrization catalysis applied to alkyl phosphonic dichlorides. Outcome: did not generalise. Reason: alkyl substituents lack the steric/electronic interactions needed for high chiral induction compared to aryl groups
Left open by the authors
Problems the authors named and did not get to.
Left open
Develop an asymmetric catalytic system for the enantioselective alkylazidation of dehydroamino esters with high enantioselectivity. Blocker: Requires a wet-lab chemistry environment, specialized reagents, and experimental optimization.
Radical-Mediated Azidation of Benzylic C-H Bonds and Azidofunctionalization of Alkenes · EPFL
Left open
Develop reaction conditions for Diels-Alder and vinylcyclopropane-cyclopentene rearrangements that preserve enantioselectivity without racemizing the chiral oxazolidine auxiliary. Blocker: Requires a synthetic chemistry wet lab and specialized reagents
Chemodivergent Asymmetric Synthesis via Catalytically Formed Chiral Auxiliary · EPFL
Left open
Screen chiral catalysts to improve the enantiomeric excess of the enantioselective 1,3-dipolar cycloaddition for synthesizing melicolones A and B. Blocker: Requires a synthetic chemistry wet lab and specialized reagents/catalysts.
Left open
Develop catalytic enantioselective diazidation and functionalization of cyclopropyl or cyclobutyl amides using chiral ligands. Blocker: Requires a wet chemistry lab to screen chiral ligands and perform asymmetric synthesis experiments.
Diamine Synthesis via the Nitrogen-Directed Azidation of sigma- and pi-C-C Bonds · EPFL
Left open
Improve diastereoselectivity in iridium-catalyzed asymmetric allylic alkylation of non-symmetric nitroalkanes such as nitroethane and (1-nitroethyl)benzene. Blocker: Requires wet lab synthetic organic chemistry experimentation and specialized chemical reagents.
Left open
Investigate mechanisms of racemisation in NCO2Me-protected sulfinamide salts and sulfonimidoyl fluorides with varying steric and electronic groups. Blocker: Requires wet lab chemical synthesis and analytical equipment (e.g., chiral HPLC/NMR) to determine reaction mechanisms and racemisation pathways.
Enantiospecific SuFEx reactions of sulfonimidoyl fluorides towards sulfonimidamides and sulfoximines · Imperial
Left open
Synthesize asymmetric dienones and syn/anti asymmetric spiroaminals via sequential mono-HWE olefination using two distinct aldehydes. Blocker: Requires a wet chemistry laboratory and chemical reagents
Synthesis of spiroaminal 2,8-disubstituted-1,7-diazaspiro[5,5]undecane derivatives · Imperial
Left open
Develop asymmetric versions of copper-catalyzed carboamination reactions using chiral ligands or catalysts. Blocker: Requires a synthetic chemistry wet laboratory, specialized reagents, and experimental optimization.
Diversification of π-systems as reaction partners for copper catalyzed carboamination · UT Austin
Left open
Synthesize bedaquiline using chiral amine bases to refine diastereoselectivity and enantioselectivity. Blocker: Requires a wet chemistry laboratory and reagents to perform organic synthesis.
Robust Processes for Polymer Modification and Pharmaceutical Synthesis · MIT
Left open
Develop and screen polar-solvent-compatible Lewis acidic chiral catalysts for enantioselective Matteson homologations. Blocker: Requires wet-lab chemical synthesis and experimental reaction screening
Catalytic control over selectivity in the synthesis of glycosides and quaternary centers · Harvard
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