Library · Materials, chemistry & fabrication
What Asymmetric & Chiral Synthesis got wrong, from 45 theses
Summary written by a model from the records below: Chiral and asymmetric synthesis investigations often encounter severe difficulties achieving satisfactory enantioselectivity and chemical yield across diverse reaction classes. Many approaches are hindered by catalyst deactivation, adverse reaction media, steric and electronic substrate mismatches, and competition from simpler baseline methodologies. These records come from graduate theses, 2021 to 2026, each labeled with its degree where the repository states it, and 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.
Plus 9 problems the authors left open, listed at the end.
Failure modes, by theses reporting them
Select a mode to jump to its records.
Chiral catalysts and ligands fail to establish adequate stereochemical control
Screening of diverse chiral metal complexes, organocatalysts, and phosphine or bisoxazoline ligands repeatedly gave racemic products or low enantiomeric excess. Peripheral structural modifications and alternative catalyst backbones also failed to improve transition state organization or stereoinduction.
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 · PhD
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
Stereoselective palladium-catalysed c(sp3)–h functionalisation of saturated heterocycles at unactivated c3 positions · Imperial · PhD
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 · PhD
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.
Total syntheses of (±)-melicolones A and B, design, synthesis and evaluation of novel carbazole based photocages · UT Austin · PhD
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 · University of Marburg · PhD
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 · UT Southwestern
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.
Regio- and enantioselective C-C and C-N bond formations catalyzed by amphiphilic [pi]-allyliridium C,O-benzoate complexes · UT Austin · PhD
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 · PhD
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 · PhD
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 · PhD
Considered and rejected
Considered and rejected: Rejected modifying only ortho/para substituents on the salicylaldehyde moiety to improve enantioselectivity for electron-poor alkenes, focusing instead on chiral diamine backbone modification.
New Radical Approaches to C–C Bond Formation in Small Molecules · Cornell · PhD
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.
Reaction media, thermal conditions, and additive interactions disrupt chiral catalysts or trigger racemization
Polar solvents, basic reagents, and non-coordinating counterions disrupted vital chiral ion-pairing assemblies or promoted unwanted racemization of substrates. High reaction temperatures, acidic protonation, and hydrogen-bonding solvents further degraded catalyst stability and stereocontrol.
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 · Tübingen · PhD
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 · PhD
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)
Asymmetric Catalysis of Ionic 1,2-Rearrangements · Harvard · PhD
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 · UT Southwestern · PhD
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 · PhD
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 · PhD
Proposed chiral catalytic systems perform worse than established baseline methods
Evaluated asymmetric transformations frequently delivered lower yields and enantioselectivities than previously reported catalysts or alternative reagents. Simpler approaches including biological synthesis, altered additives, and alternative coupling methods proved superior to the tested chiral protocols.
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 · PhD
Lost to a baseline
Synthesis of chiral thiazolium salt 61e gave 36% yield with P2S5-Py2 versus 69% with P4S10.
A Facile Method for the Synthesis of Thiazolium Salts Using P2S5-Py2 Complex and Their Application in Intermolecular Stetter Reactions · Saskatchewan · Master's
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 · BUAP · PhD
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 · PhD
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 · University of Marburg · PhD
Competing side reactions and poor conversions diminish the yield of desired chiral products
Asymmetric reaction pathways were often hindered by low substrate conversions, homocoupling, and catalyst coordination that shut down productive reactivity. Several reactions diverted into undesired side products such as homoallylic ethers or ketones instead of generating the targeted stereodefined compounds.
Tried and failed
Auxiliary-controlled asymmetric Baylis-Hillman reaction applied to benzyloxyacetaldehyde and sultam acrylamide. Reason: Failed to form the desired stereodefined lactone product
A Trioxacarcin Prodrug with Accelerated Reversion and an Enterobacteriaceae-Selective Antibiotic with Low Induction of Resistance · Harvard · PhD
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 · PhD
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 · TU Wien · PhD
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 · PhD
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 · PhD
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 · PhD
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 · PhD
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 · PhD
Kinetic resolutions and multi-step asymmetric routes are abandoned due to operational complexity or poor selectivity
Enzymatic and chemical kinetic resolutions frequently exhibited low selectivity factors or unfavorable trade-offs between activity and enantioselectivity. High reagent expenses, multiple complex synthetic steps, and isolation difficulties prompted researchers to abandon chiral routes in favor of achiral synthesis or classical resolution.
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 · PhD
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 · Nottingham · PhD
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 · PhD
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 · Nottingham · Doctorate
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.
Trioxacarcin-based Antibody-Drug Conjugates: Optimization of payload structure and a triazene linker system design · Harvard · PhD
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 · PhD
Substrate steric congestion and lacking directing features suppress asymmetric induction
Substrates bearing alpha or beta branching, bulky substituents, or unsaturated and basic groups suffered poor enantioselectivity and sluggish conversion. In addition, the absence of necessary hydrogen-bond donors or distal catalyst coordination failed to provide the preorganization required for chiral induction.
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 · PhD
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 · PhD
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
Asymmetric Catalysis of Ionic 1,2-Rearrangements · Harvard · PhD
Considered and rejected
Considered and rejected: Abandoned asymmetric intramolecular coupling on achiral propyl-tethered phenols due to distal catalyst coordination yielding 0-13% ee.
Metal-Catalyzed And Photocatalytic Systems For Oxidative Inter- And Intramolecular Phenol Coupling · Penn · PhD
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
Bypassing premetalated reagents in carbon-carbon bond forming reactions : leveraging stereogenic-at-metal complexes and/or nonmetallic reductants · UT Austin · PhD
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
Enantioselective Synthesis of Stereogenic-at-Phosphorus(V) Compounds via Hydrogen-Bond-Donor Catalysis · Harvard · PhD
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 · PhD
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 · PhD
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.
Total syntheses of (±)-melicolones A and B, design, synthesis and evaluation of novel carbazole based photocages · UT Austin · PhD
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.
Bypassing premetalated reagents in carbon-carbon bond forming reactions : leveraging stereogenic-at-metal complexes and/or nonmetallic reductants · UT Austin · PhD
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 · PhD
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 · PhD
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 · PhD
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 · PhD
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 · PhD
Who has worked on this
Authors of the public theses cited on this page, most-cited first.
- Marcus H Sak · Harvard · PhD · 2026
Enzymatic Principles in Selective Small-Molecule Catalysis - Pierre Gérard Joseph Palamini · EPFL · PhD · 2025
Radical-Mediated Azidation of Benzylic C-H Bonds and Azidofunctionalization of Alkenes - Elisabetta Ronchi · Harvard · PhD · 2022
Development and Study of Novel Catalytic Reactions to Efficiently Address Synthetic Challenges: Enantioselective Multicomponent Synthesis of Homoallylic Amines and Site-Selective Debenzylation of Mono - Hayden Sharma · Harvard · PhD · 2022
Asymmetric Catalysis of Ionic 1,2-Rearrangements - Agata A Bikovtseva · Harvard · PhD · 2026
Catalytic control over selectivity in the synthesis of glycosides and quaternary centers - Wojciech Gruchot · Harvard · PhD · 2026
Trioxacarcin-based Antibody-Drug Conjugates: Optimization of payload structure and a triazene linker system design - Jake Matthew Aquilina · UT Southwestern · PhD · 2026
Chemical Investigations in Complex Alkaloid Synthesis - Simon Stammwitz · Leibniz Universität Hannover · PhD · 2026
Die 1,2-Boronat-Umlagerung in den Fragmentsynthesen von Disorazol C1 und Tedanolid C, sowie die Synthesen von Antroalbocin A und Illihenin A - Lucas Valdes · Harvard · PhD · 2025
A Trioxacarcin Prodrug with Accelerated Reversion and an Enterobacteriaceae-Selective Antibiotic with Low Induction of Resistance - Anton Dieckmann · Leibniz Universität Hannover · PhD · 2025
Studien zur Derivatisierung der [11]-Cytochalasine - Feng Han · University of Marburg · PhD · 2025
Design and Synthesis of Cyclometalated Chiral-at- Ruthenium Complexes for Asymmetric Catalysis Design und Synthese von cyclometallierten chiral-at-Ruthenium Komplexen für asymmetrische Katalyse - Sharanappa Maduraya Bagale · Imperial · PhD · 2024
Development of ‘green’ catalysis: a chiral phase-transfer catalyst for michael reactions, and peracetic acid as an atom-economical reagent for acetoxylation reactions
Checking a claim in this area?
We can run the same search on any method or claim. If nothing turns up, we will say so, and that proves nothing on its own.