The research program in Professor Nguyen’s laboratory lies at the crossroads of cancer drug discovery, medicinal chemistry, chemical biology, organic chemistry, and catalysis. The broad goals of our group are (1) to design with the aid of computational insights and subsequently synthesize sulfated oligosaccharides, aminoglycosides, and glycopolymers as potent inhibitors of heparanase for studying multiple myeloma, pancreatic cancer, metastatic breast cancer, brain tumor, and diabetes; (2) to study saponin molecules as novel vaccine adjuvants for use in humans to combat a range of diseases; (3) to develop carbohydrate molecules to control of hyperphosphorylated tau-mediated cell dysfunction and death; (4) to develop catalytic stereoselective glycosylation mediated by organocatalysts for the synthesis of bioactive oligosaccharides and glycopeptides; and (5) to investigate metal-catalyzed asymmetric reactions for the synthesis of drug-like molecules and for potent use as the PET imaging agents. These efforts substantially expand the use of chemistry to discover new therapies for improving human health.

TUNING SULFATION PATTERNS AND HYDROPHOBIC PROPERTIES OF OLIGOSACCHARIDE AND GLYCOPOLYMER HS MIMETICS TO ATTENUATE HEPARANASE’S ACTIVITY (Collaborator: Professor Israel Vlodavsky at Technion – Israel Institute of Technology)

Heparanase is an endo-beta-D-glucuronidase that cleaves heparan sulfate (HS) polysaccharide chains in the extracellular matrix (ECM) and the cell surface basement membrane (BM). This enzyme is regarded as a regulator of aggressive tumor behavior as clinical studies have shown that raised heparanase levels correlated with increased tumor size, amplified tumor angiogenesis, enhanced metastasis, and poor patient prognosis. This enzyme hydrolyzes GlcAβ(1,4)GlcNS glycosidic bonds (see Figure 1) of the HS chains, releasing sequestered pools of HS oligosaccharide-binding growth factors for signaling activation, which promote tumor angiogenesis and growth. Cleavage of HS chains also degrades the structural integrity of the BM and the ECM, permitting migration of malignant cells into the bloodstream and promoting cancer metastasis. Upregulation of HPSE is ubiquitous amongst all types of cancers.

Figure 1.  Heparanase cleaves the internal GlcAβ(1,4)GlcNS glycosidic bonds of HS chains with Glu 225 and Glu 343 as key amino acid residues in the active site.

Several saccharide-based heparan sulfate (HS) mimetics have been developed as HPSE inhibitors and progressed into clinical trials. However, many were ultimately halted due to harmful off-target interactions with other HS-binding proteins (HSBPs). A promising alternative is to create glycopolymers with functionalized glycan residues integrated into their polymer backbones. This approach seeks to preserve the natural biological functions of endogenous HS while improving therapeutic efficacy and reducing unwanted side effects.

Our work focus on the design and synthesis of glycopolymers with a disaccharide component of GlcNS-α(1→4)GlcA, which exhibit remarkable HPSE inhibition with minimal off-target activities. These glycopolymers emulate the multivalent characteristics of HS, providing multiple interaction sites for effective binding to HPSE. Using computational modeling, we designed glycopolymer-based HS mimetics with a precisely controlled degree of polymerization and glycan residues carrying tailored sulfation patterns. This design enhances specificity for the target HSBP while ensuring the desired biological activity. The glycopolymers were synthesized via ring-opening metathesis polymerization using the third-generation Grubbs catalyst, which allows fine-tuning of polymer length and molecular weight by adjusting catalyst loading (Figure 2).

Among these compounds, sulfated glycopolymer GPM3C, containing 12 repeating disaccharide units on a polymeric backbone, emerged as the most potent HPSE inhibitor, demonstrating picomolar inhibitory concentrations. The lead glycopolymer, surpassed previously reported monovalent and polymeric HPSE inhibitors in potency and displayed much greater selectivity for HPSE over other off-target HSBPs. It also exhibited strong antimetastatic activity in both in vitro and in vivo models of mammary carcinoma and myeloma, and provided significant protection against HPSE-mediated damage to pancreatic β cells and human islets—highlighting potential applications in diabetes treatment (Figure 2).

Figure 2.  Screening, synthesis, and therapeutic applications of glycopolymers.

Overall, these findings emphasize the importance of multivalency and precise structural control in polymeric HS mimetics, enabling highly specific HSBP targeting and advancing their potential for precision therapeutics.

Our group also previously synthesized eleven trisaccharides (see Figure 3) that are highly tunable in structure and sulfation pattern, allowing us to determine how heparanase recognizes heparan sulfate (HS) substrate and selects a favorable cleavage site. Our study shows that (1) beta-linked reducing end activated heparanase and was hydrolyzed by heparanase; (2) alpha-linked reducing end inhibited heparanase and was resistant toward hydrolysis; (3) absence of 6-O-SO3– at +1 and at −2 of GlcN (glucosamine) decreased binding to heparanase; (4) N-acetyl groups instead of N-SO3– at the −2 and +1 reduced potency; (5) 3-O-SO3– at +1 and at −2 of GlcN decreased binding to heparanase; and (6) 2-O-SO3– at -1 of GlcA (glucuronic acid) decreased binding to heparanase. We are currently developing and synthesizing a library of HS trisaccharide mimetics with precisely defined sulfation patterns and tailored hydrophobic properties to modulate HPSE activity. We replaced the amino linker at the reducing end with a lipophilic linker and discovered that it significantly increased the potency of our compounds against HPSE. Additionally, installing hydrophobic groups on the trisaccharide backbone further enhances the activity and selectivity against HPSE.

Figure 3.  Sulfated trisaccharides for SAR studies against HPSE.

1)  Loka, R. S.; Yu, F.; Sletten, E. T.; Nguyen, H. M. “Design, Synthesis, and Evaluation of Heparan Sulfate Mimicking Glycopolymers for Inhibiting Heparanase Activity” Chem. Commun. 2017, 53, 9163-9166.

2) Sletten, E. T.; Loka, R. S.; Yu, F.; Nguyen, H. M. “Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers” Biomacromolecules 2017, 18, 3387-3399.

3) Loka, R. S..; Sletten, E. T.; Barash, U.; Vlodavsky, I.; Nguyen, H. M.  “Specific Inhibition of Heparanase by a Gylcopolymer with Well-Defined Sulfation Pattern Prevents Breast Cancer Metastasis in Mice” ACS Appl. Mater. Interfaces  2019, 11, 244-254.

4) Zhu, S.; Samala, G.; Sletten, E. T.; Stockdill, J. L.; Nguyen, H. M. “Facile Triflic-Acid-Catalyzed alpha-1,2-cis-Thiol Glycosylations: Scope and Application to the Synthesis of S-Linked Oligosaccharides, Glycolipids, Sublancin Glycopeptide, and Tn/Tf Antigens” Chem. Sci. 2019, 10, 10475-10480.  This paper was selected as part of the Chemical Science 2019 HOT Article Collection.

5) Loka, R. S.; Song, Z.; Sletten, E. T.; Kayla, Y.; Vlodavsky, I.; Zhang, K.; Nguyen, H. M. “Heparan Sulfate Mimicking Glycopolymer Prevents Pancreatic Beta Cell Destruction and Suppresses Inflammatory Cytokine Expression in Islets under the Challenge of Upregulated Heparanase. ” ACS Chemical Biology 2022, 17, 1387-1400.

6) Abdulsalam, H.; Li, J.; Loka, Ravi S.; Sletten, E. T.; Nguyen, H. M. Sulfated Glucosamine-Glucuronic Acid Disaccharide Functionalized Polymers Have a High Affinity for the SARS-CoV-2 Spike Protein.” ACS Med. Chem. Lett. 2023, 14, 1411-1418.

7) Singh, K.;  Tapayan, A. W.; Sletten, E. T.; Loka, R. S.; Barash, U.; Vlodavsky, I.; Nguyen, H. M.* “Heparanase-Inhibiting Polymeric Heparan Sulfate Mimetic Attenuates Myeloma Tumor Growth and Bone Metastasis” ACS Appl. Bio Mater. 2025 (ASAP).

AMINOGLYCOSIDES AS SULFATED AND HYDROPHOBIC GLYCANS TO TARGET HEPARANASE-DRIVEN TUMOR PROGRESSION, METASTASIS, INFLAMMATION, AND ER STRESS (Collaborators: Professor Israel Vlodavsky at Technion – Israel Institute of Technology and Professor Kezhong Zhang at Wayne State University College of Medicine)

Cancer remains one of the leading causes of death worldwide, with aggressive and metastatic forms having particularly poor survival rates. A key driver of cancer spread is heparanase (HPSE), the only enzyme capable of cleaving heparan sulfate (HS)—a structural glycosaminoglycan in the extracellular matrix (ECM) and basement membrane (BM). By degrading HS chains, HPSE releases growth and pro-angiogenic factors that stimulate tumor growth, angiogenesis, and invasion. HPSE is overexpressed in cancers such as multiple myeloma, pancreatic cancer, breast cancer, and glioblastoma, making it an attractive therapeutic target.

Several HS mimetics have been developed as HPSE inhibitors, but most carbohydrate-based candidates have failed in clinical trials due to:

  1. Severe off-target effects — strong binding to proteins such as platelet factor 4 (PF4) and antithrombin III, leading to complications like heparin-induced thrombocytopenia (HIT).
  2. Synthetic complexity — heparan sulfate analogs often require 30–40 synthetic steps with multiple protecting-group manipulations, making large-scale production challenging, time-intensive, and costly for drug development

The Nguyen Group addresses these challenges by repurposing aminoglycosides—antibiotics with pseudo-oligosaccharide structures—as scaffolds for HPSE inhibition. Compounds such as tobramycin and paromomycin possess multiple amine groups suitable for site-selective sulfation, enabling us to mimic HS sulfation patterns without lengthy total synthesis and allowing each inhibitor to be prepared in fewer than 10 steps. This streamlined approach not only improves scalability but also provides flexibility for structural modifications. Leveraging this advantage, we have incorporated strategic sulfation and hydrophobic motifs to explore structure–activity relationships (SAR) and tune selectivity toward HPSE while minimizing binding to off-target proteins. We have designed a library of aminoglycoside-based heparanase inhibitors with strategic sulfation and hydrophobic modifications, yielding high nanomolar potency and remarkable selectivity. In vitro, these inhibitors significantly reduce growth and viability in HPSE-overexpressing cancer cell lines, including both hematologic (multiple myeloma) and solid tumors (pancreatic, breast, glioblastoma).

Figure 1. Development of aminoglycoside-based heparanase inhibitors with nanomolar potency, high selectivity, and strong in vitro efficacy, demonstrating the ability to attenuate key hallmarks of cancer.

Current studies aim to:

  • Expand testing to a broader range of HPSE-driven cancers.
  • Investigate effects on invasion, migration, survival mechanisms, ECM remodeling, immune surveillance, and angiogenesis pathways.
  • Optimize scaffold modifications for potency, selectivity, and pharmacokinetics.
  • Advance candidates toward preclinical in vivo studies.
  • Study the mechanism of our compounds that exert their anti-tumor effects by (1) regulating HPSE-associated tumor-associated genes; (2) modulating ER-stress-related genes linked to pancreatic beta-cell dysfunction and diabetes, and (3) suppressing inflammation-related genes associated with HPSE

By combining the accessibility of aminoglycosides, strategic chemical modification, and targeted biological evaluation, our research seeks to deliver a new class of selective, scalable, and effective heparanase inhibitors—addressing long-standing challenges in cancer therapy.

1) Wakpal, J.; Pathiranage, P.; Walker, A. Nguyen, H. M. “Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies.” Angew. Chem. Int. Ed. 2023, 62, e202304325

2) Philip, L.; Abdulsalam, H.; Singh, K.; Nguyen, H. M.* “Investigation into the Binding Domains of Platelet Factor 4 Unlocks New Avenues for the Design and Synthesis of Selective Pseudo-Tetrasaccharide Heparanase-Inhibiting Heparan Sulfates.” Eur. J. Med. Chem. 2025, 295, 117792

3) Abdulsalam, H.; Philip, L.; Singh, K.; Farhoud, M.; Neta, I.; Vlodavsky, I.; Nguyen, H. M.* “Design of Paromomycin and Neomycin as Sulfated and Hydrophobic Glycans to Target Heparanase-Driven Tumor Progression and Metastasis” J. Med. Chem. 2025, 68, 12058-12084.

4) Hotor, M.; Wakpal, J.; Effah, S.; Walker, A.; Nguyen, H. M.* “Could Hydrophobicity of Sulfated Pseudo-Trisaccharides Derived from Repurposing Aminoglycoside Tobramycin Modulate the Enzymatic Activity of Heparanase?” J. Med. Chem. 2025, 68, 12708-12732.

SYNTHESIS AND EVALUATION OF CARBOHYDRATE VACCINE ADJUVANTS (Collaborator: Professor Steve Varga – St. Jude Children’s Research Hospital)

Successful vaccinations are characterized by strong robust immune responses against the inoculated antigens, providing long-term protective immunity against various diseases. Vaccine formulations often include a vaccine adjuvant that is co-administered with the antigen in order to boost the body’s immune response to the vaccine, extend the length of time between doses, and decrease the required dosage of antigens. Vaccine adjuvants help activate and modulate the immune response and the choice of adjuvant plays a critical role in ensuring an effective vaccine. Currently, however, there is only a few human vaccine adjuvants with an extensive safety record and minimal toxicity approved for clinical use. Therefore, there is a great demand for the development of novel adjuvants that not only significantly enhances the immune response to a co-administered antigen, but also must be minimally toxic for clinical use, cost-effective, and stable for long-term storage.

Figure 1. Graphical representation of lablaboside F derivative synthesis and biological testing

In the effort to discover novel vaccine adjuvants, an in vivo screening of 47 saponins from medicinal plants for their immunostimulatory and hemolytic activities has led to the discovery of new potential vaccine adjuvants. Among 47 saponin natural products evaluated, soyasaponins and lablabosides have emerged as the most potent adjuvants, exhibiting remarkable adjuvant activity with almost negligible toxicity. Synthetic preparation of these compounds is preferable over extraction as it allows for the modification of the parent compound and the generation of quantities necessary for biological activity.

Between the six natural lablaboside derivatives tested, lablaboside F showcased the highest level of adjuvant activity. Lablaboside F is composed of a triterpene oleanonic acid core that has two C2-branched trisaccharides on the western and eastern side of the core (Figure 1). Lablaboside F was synthesized utilizing protonated phenanthroline to catalyze the stereoselective glycosylation of the C2-branched trisaccharides to the oleanolic acid core. Similarly, eight lablaboside F derivatives were prepared to explore the structure-activity relationship (SAR) of lablaboside F. In vitro and in vivo testing of the compounds revealed truncated derivative S5 as the highest potential vaccine adjuvant showcasing an excellent safety profile and adjuvant activity in vivo. The SAR studies on the first generation of lablaboside F derivatives revealed the importance of the eastern trisaccharide and has informed the design of the second generation of lablaboside F derivatives.

Multiple soyasaponin compounds (A1, A2, I, and V) have been identified as potential vaccine adjuvants (Figure 2). Soyasaponins are structurally varied, characterized by a triterpene core (soyasapogenal A or B) with either one or two sugar chains. These saponins have been extracted and tested in vitro and in vivo showcasing excellent safety profiles and adjuvant activity. To explore the SAR of these soyasaponins, the triterpene cores, soyasapogenal A and B, are extracted in bulk and glycosylated with a variety of different sugar patterns to create a library of soyasaponin derivatives.

The overall goal of our project is to direct the chemical synthesis and preclinical evaluation for soyasaponins and lablabosides which hold promise as potent adjuvants with negligible toxicity for vaccine therapeutics.

Figure 2. Graphical representation of soyasaponin extraction and preparation

1)  Ghorai, J.; Santhin, A. B.; Almounajed, L.; Hartwig, S. M.; Varga, S. M.; Nguyen, H. M.* “Protonated Phenanthroline Catalyzed Stereoselective Glycosylation: Total Synthesis of Lablaboside F and Derivatives as Saponin Vaccine Adjuvants” 2025 (manuscript submitted).

UNDERSTANDING AND TARGETING HEPARAN SULFATE-TAU INTERACTION IN ALZHEIMER’S DISEASE THROUGH HS OLIGOSACCHARIDE MIMETICS (Collaborators: Professor Min-Hao Kuo at Michigan State University and Professor Kezhong Zhang at Wayne State University College of Medicine)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss, cognitive decline, and the presence of two key pathological hallmarks: extracellular amyloid-β plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (p-tau). Although early therapeutic efforts primarily targeted amyloid-β, mounting evidence and clinical outcomes have shifted the focus toward tau pathology as a more promising avenue for disease-modifying intervention.

Under physiological conditions, tau stabilizes neuronal microtubules. In AD, however, tau undergoes abnormal hyperphosphorylation, leading to microtubule destabilization, toxic aggregate formation, and propagation of pathology in a prion-like manner. This spread is thought to be facilitated by interactions between tau and cell-surface heparan sulfate proteoglycans (HSPGs) (Figure 1), with specific sulfation patterns of heparan sulfate (HS) playing a critical role in tau binding, uptake, and aggregation.

Figure 1. (A) Interactions of HSPG and tau protein. (B) Structure of HS polysaccharide.

Building on these insights, our research focuses on the rational design, synthesis, and evaluation of HS-mimetic oligosaccharides with precisely defined sulfation patterns and tailored lipophilic modifications. These compounds serve both as molecular probes to dissect tau–HS interactions and as potential therapeutic agents to block tau propagation and prevent downstream neuronal dysfunction. (Figure 2)

Figure 2. Graphical representation of the research focus for the Alzheimer’s disease project

This project highlights the utilization of PIMAX (protein interaction modules-assisted function X) p-tau model, which can aggregate without requiring an artificial inducer such as heparin, making it ideal for tau-induced AD research. In addition, the project aims to elucidate the role of heparanase overexpression in AD pathogenesis by examining its impact on p-tau-induced microglial activation, thereby providing insight into neuroinflammatory responses associated with AD progression.

1) Zhu, S.;** Song, Z.;** Tapayan, A. S.;** Singh, K.;** Wang, K.-W.; Hagar, H. T.; Zhang, J.; Kim, H.; Thepsuwan, P.; Kuo, M.-H.; Zhang, K.; Nguyen, H. M. “Effects of Heparan Sulfate Trisaccharide Containing Oleanolic Acid in Attenuating Hyperphosphorylated Tau-Induced Cell Dysfunction Associated with Alzheimer’s Disease” J. Med. Chem. 2025, 68, 3356-3372.

PHENANTHROLINE CATLYZED STEREOSELECTIVE GLYCOSYLATIONS

Carbohydrates are widespread in nature and have been considered as the frontier of medicinal chemistry. In general, the sugar based biomolecules are constructed from rudimentary glycosylation reactions, which take place between a glycosyl donor (electrophile) and glycosyl acceptor (nucleophile). These reactions allow for the establishment of two different α- and β- stereoisomers that differ in the configuration of the anomeric carbon and differ in their medicinal properties. Controlling the stereoselectivity of glycosylation reactions to exclusively generate the desired stereoisomer is challenging. Current efforts have been focused of developing small-molecule organic catalysts to control the stereoselectivity of the reaction through cooperative interactions, thus eliminating the need for substrate and reagent control.

α-1,2-cis linked glycosides are important components of bioactive oligosaccharides, however, stereoselective synthesis of α-1,2-cis glycosides has proven to be a hurdle when utilizing traditional modes of carbohydrate activation. Current synthetic methods often rely on the nature of the protecting groups bound to the electrophile to influence selectivity, thereby making them highly specific for each electrophilic coupling partner. Furthermore, catalytic approaches to α-1,2-cis glycosidic bond are relatively limited.

We discovered that phenanthroline, a rigid and planar compound with two fused pyridine rings, could be used as a nucleophilic catalyst to efficiently access high yielding and diastereoselective α-1,2-cis glycosides through the coupling of hydroxyl acceptors with α-glycosyl bromide donors (Figure 1A). We have conducted an extensive investigation into the reaction mechanism, wherein the two glycosyl phenanthrolinium ion intermediates, a 4C1 chair-liked beta-conformer and a B2,5 boat-like alpha-conformer, have been detected in a ratio of 2:1 (β:α) using variable temperature NMR experiments. Furthermore, NMR studies illustrate that a hydrogen bonding is formed between the second nitrogen atom of phenanthroline and the C1-anomeric hydrogen of sugar moiety to stabilize the phenanthrolinium ion intermediates. To obtain high α-1,2-cis stereoselectivity, a Curtin-Hammett scenario was proposed wherein interconversion of the 4C1 chair-like beta-conformer and B2,5 boat-like α-conformer is more rapid than nucleophilic addition. Hydroxyl attack takes place from the α-face of the more reactive 4C1 beta-phenanthrolinium intermediate to give an alpha-anomeric product. The phenanthroline catalyst is also effective at promoting stereoselective 1,2-cis furanosylations (Figure 1B). NMR experiments and density-functional theory calculations support an associative mechanism in which the rate-determining step occurs from an invertive displacement of the faster reacting phenanthrolinium ion intermediate with alcohol nucleophile. The phenanthroline catalysis system is applicable to a number of furanosyl bromide donors to provide the challenging 1,2-cis substitution products in good yield with high anomeric selectivities. While arabinofuranosyl bromide provides β-1,2-cis products, xylo- and ribofuranosyl bromides favor α-1,2-cis products.

Figure 1. Phenanthroline as a catalyst in stereoselective 1,2-cis glycosylations.

Another application of phenanthroline as a nucleophilic catalyst was explored to synthesize α-glycosylated carboxylic acids with high diastereoselectivity through bromide displacement from activated sugars (Figure 2A). Here, strong hydrogen bonding between the carboxylic acid-OH and the C2-oxygen of the sugar enhances nucleophilicity of the carbonyl oxygen, dictating α-selectivity. In another context, commercially available phenanthroline serves as an effective additive in the stereoselective formation of α-2-deoxy glycosides from 2-deoxy glycosyl chlorides, overcoming the inherent instability, low reactivity, and stereocontrol challenges of this sugar class (Figure 2B).

Phenanthroline has also been applied as a catalyst in stereoselectively producing 1,2-cis S-furanosides (Figure 2C). This method delivers excellent 1,2-cis selectivity for S-products, aided by the distinct hydrogen-bonding and reactivity profiles of thiols compared to alcohols. Computational and experimental investigations identified thiol nucleophiles to be less reactive and more selective than oxygen nucleophiles, where the displaced bromide forms a stronger hydrogen bond with alcohol nucleophiles compared to thiol, resulting in higher reactivity.

More recently, protonated phenanthroline has been utilized as a cooperative catalyst in the stereoselective synthesis of 1,2-trans glycosides (Figure 2D). C2-substituted sugars cannot utilize neighboring group participation as a mode of stereoselective control. As such, protonated phenanthroline has been kinetically, mechanistically, and computationally determined to interact with α-trichloroacetimidate donors and the acceptor in an SN2-like reaction where the protonated phenanthroline orients the nucleophile for top face attack, not requiring anchimeric assistance. Additionally the by-product trichloroacetamide has been determined to play a role in the transition state to ensure the rigid planer protonated phenanthroline can interact with both the donor and acceptor (Figure 2D). Protonated phenanthroline has been determined to catalyze alcohol, aniline, phenol, and carboxylic acid nucleophiles, showcasing its wide utility.

Figure 2. Phenanthroline as a catalyst.

1) Yu, F.; Li, J.; DeMent, P. M.; Tu, Y-J.; Schlegel, H. B.; Nguyen, H. M. “Phenanthroline-Catalyzed Stereoretentive Glycosylations” Angew. Chem. Int. Ed. 2019, 58, 6957-6961.

2)  Yu, F.; Dickson, J. L.; Loka, R. S.; Xu, H.; Schaugaard, R. N.; Schlegel, H. B.; Luo, L.; Nguyen, H. M. “Diastereoselective sp3 C–O Bond Formation via Visible Light-Induced, Copper-Catalyzed Cross-Couplings of Glycosyl Bromides with Aliphatic Alcohols” ACS Catalysis. 2020, 10, 5990-6001.

3) DeMent, P. M.; Wakpal, J.; Liu, C.; Schaugaard, R. N.; Schlegel, H. B.; Nguyen, H. M. “Phenanthroline-Catalyzed Stereoselective Formation of alpha-1,2-cis-2-Deoxy-2-Fluoro Glycosides” ACS Catalysis. 2021, 11, 2108-2120.

4) Li, J.; Nguyen, H. M. “A Mechanistic Probe into 1,2-cis Glycoside Formation Catalyzed by Phenanthroline and Further Expansion of Scope” Advanced Synthesis & Catalysis 2021, 363, 4054-4066.

5) Xu, H.; Schaugaard, R. N.; Li, J.; Schlegel, H. B.; Nguyen, H. M. “Stereoselective 1,2-cis Furanosylations Catalyzed by Phenanthroline.” J. Am. Chem. Soc. 2022, 144, 7441-7456.

6) Li, J.; Nguyen, H. M. “Phenanthroline Catalysis in Stereoselective 1,2-cis Glycosylations.” Acc. Chem. Res. 2022, 55, 3738-3751.

7) Alom, N. E.; Rani, N.; Schlegel, H. B.;* Nguyen, H. M. * “Highly Stereoselective a-1,2-cis Glycosylated Carboxylic Acids by Phenanthroline Catalysis.” Org. Chem. Front. 2024, 11, 5769-5783.

8) Ghorai, J.; Almounajed, L.; Noori, S.; Nguyen, H. M.* “Cooperative Catalysis in Stereoselective O– and N-Glycosylations with Glycosyl Trichloroacetimidates Mediated by Singly Protonated Phenanthrolinium Salt and Trichloroacetamide.” J. Am. Chem. Soc. 2024, 146, 34413-34426.

9) Boddu, R. K.; Rani, N.; Schlegel, H. B.;* Nguyen, H. M. * “Why Is Thiol Unexpectedly Less Reactive but More Selective Than Alcohol? Mechanistic Insight into Phenanthroline-Catalyzed Stereoselective O- vs. S-Furanosylations” Org. Biol. Chem. 2025, 23, 328-342.

10) Li, C.-X.; English, C. K.; Ahiadorme, D. A.; Nguyen, H. M. “Phenanthroline Assisted Stereoselective Synthesis of 2-Deoxy Glycosides.” ACS Omega, 2025, 10, 18700-18708

IRIDIUM/RHODIUM CATALYZED ASYMMETRIC ALLYLIC FLUORINATION AND REGIOSELECTIVE ALLYLIC RADIO-FLUORINATION.

The incorporation of fluorine atoms has far-reaching impacts in organic chemistry. Over the past decade, molecules containing carbon-fluorine bonds have become increasingly prevalent in pharmaceutical, agricultural, and materials chemistry. Currently, 20% of pharmaceutical targets and 30% of agrochemicals on the market contain at least one carbon-fluorine bond. The introduction of a fluorine atom into biologically active molecules has the potential to improve several factors, including absorption, metabolism, and potency of the drug candidate. A significant amount of research has been conducted on the selective incorporation of fluorine into a variety of functional groups. However, the formation of allylic fluorides has been significantly understudied, leading to a need for the creation of new methodologies. Transition metal catalysis has come to the forefront as a viable option to selectively produce these carbon-fluorine bonds.

Allylic fluorides are key scaffolds in a variety of biologically relevant molecules. Traditional methods to form allylic fluorides lack the ability to produce a single regio-isomer, and instead lead to a mixture of linear and branched products. The creation of one single enantiomer is of paramount importance as different enantiomers can have variable affects in vivo. We discovered racemic allylic trichloroacetimidates as competent electrophiles in a chiral bicyclo[3.3.0]octadiene-ligated iridium-catalyzed asymmetric fluorination with Et3N·3HF (Figure 1a). The methodology represents an effective route to prepare a wide variety of alpha-linear, alpha-branching, and beta-heteroatom substituted allylic fluorides in good yields, excellent branched-to-linear ratios, and high levels of enantioselectivity. Additionally, the catalytic system is amendable to the fluorination of optically active allylic trichloroacetimidate substrates to afford the fluorinated products in good yields with exclusively branched selectivity. Excellent levels of catalyst-controlled diastereoselectivities using either (R,R) or (S,S)-bicyclo[3.3.0]octadiene ligand are observed. The synthetic utility of the fluorination process is illustrated in the asymmetric synthesis of 15-fluorinated prostaglandin and neuroprotective agent P7C3-A20.

We further translated our methodology for the synthesis of allylic [18F]fluorides that could be used for positron emission tomography (PET) imaging. PET imaging has become a powerful tool for the qualitative and quantitative assessment of metabolically active diseases. Several substrates were isolated to determine the radiochemical yield and the molar activity (ratio of radiolabeled product to non-radiolabeled product). To show the practicality of the method, thiol-ene “click” chemistry was used to couple an amino acid to a radio-labeled substrate (Figure 1b). Our studies are significant as this methodology has the potential to lead to new radio-tracers for the labeling of peptides and amino acids for PET imaging.

Recently, we expanded our allylic fluorination approach to access the difficult-to-synthesize 1,2-disubstituted allylic fluorides using a chiral diene-ligated rhodium catalyst, Et3N ⋅ 3HF as a fluoride source, and Morita-Baylis-Hillman (MBH) trichloroacetimidates. The direct enantioselective fluorination of 1,2-disubstituted allylic trichloroacetimidates (Figure 1c) remains a synthetic challenge. Unlike monosubstituted π-allylmetal intermediates, where the syn complex (Scheme 1a) is strongly favored over the anti complex due to unfavorable A1,3 allylic strains in the anti-conformation, 1,2-disubstituted π-allyl intermediates tend to favor the anti complex because of destabilizing 1,2-steric interactions in the syn complex (Figure 1c). Depending on the size of the C2-substituents, either the syn or anti π-allyl complex may predominate. Additionally, the catalyst must overcome any background reaction involving nucleophilic fluoride addition followed by elimination of the trichloroacetimidate leaving group, which produces linear allylic fluoride products B and C (Scheme 1b). Therefore, developing catalytic methods that can effectively control the relative populations of these two π-allyl complex isomers and suppress background reactions is highly important.

Mechanistic, computational, and experimental studies were conducted in collaboration with the Gutierrez group (University of Maryland) for both the Ir-catalyzed allylic fluorination of the monosubstituted trichloroacetimidate, as well as the Rh-catalyzed fluorination of the 1,2-disubstituted trichloroacetimidate. Results revealed the critical role of the trichloroacetimidate acting as both a leaving group and a ligand.

The reaction proceeds by an initial ionization of the allylic trichloroacetimidate in the presence of the metal catalyst with an overall retention of configuration due to the pre-coordination of the central metal to the trichloroacetimidate substrate (Figure 1a). The ligated trichloroacetimidate-iridium complex can undergo equilibration between the two diastereomeric pi-allyl-iridium complexes through a dynamic kinetic asymmetric transformation (DYKAT)-like mechanism allowing for formation of an enantioenriched allylic fluoride in high regioselectivity and asymmetric induction.

Figure 1.

1) Topczewski, J. J.; Tewson, T. J.; Nguyen, H. M. “Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates.” J. Am. Chem. Soc. 2011, 133, 19318-19321.

2) Zhang, Q.; Mixdorf, J. C.; Reynders III, G. J.; Nguyen, H. M. “Rhodium-Catalyzed Benzylic Fluorination of Trichloroacetimidates with Triethylamine Trihydrofluoride.”Tetrahedron. 2015, 71, 5932-5938 (Special Issue for Professor Trost’s 2014 Tetrahedron Award).

3) Zhang, Q.; Stockdale, D. P.; Mixdorf, J. C.; Topczewski, J. J.; Nguyen, H. M. “Iridium-Catalyzed Enantioselective Fluorination of Racemic, Secondary Allylic Trichloroacetimidates.” J. Am. Chem. Soc. 2015, 137, 11912-11915.

5) Mixdorf, J. M.; Sorlin, A. M.; Zhang, Q.; Nguyen, H. M. “Asymmetric Synthesis of Allylic Fluorides via Fluorination of Racemic Allylic Trichloroacetimidates Catalyzed by a Chiral-Iridium Complex”ACS Catal. 2018, 8 (2), 790-801.

6) Mixdorf, J. M.; Sorlin, A. M.; Dick, D. W.; Nguyen, H. M. “Iridium-Catalyzed Radiosynthesis of Branched Allylic [18F]Fluorides” Org. Lett.  2019, 21, 60-64.

7) Sorlin, A. M.; Mixdorf, J. C.; Rotella, M.; Martin, R.; Gutierrez, O.; Nguyen, H. M. “The Role of Trichloroacetimidate To Enable Iridium-Catalyzed Regio- and Enantioselective Allylic Fluorination: A Combined Experimental and Computational Study” J. Am. Chem. Soc. 2019, 143, 14843-14852.

8) Sorlin, A. M.; Fuad, U. O.; English, C. K.; Nguyen, H. M. “Advances in Nucleophilic Allylic Fluorination” ACS Catalysis. 2020, 10, 11980-12010.

9) Usman, F.; Gogoi, A. R.; Gutierrez, O.; Nguyen, H. M. “Rhodium-Catalyzed Asymmetric Synthesis of 1,1-Disubstituted Allylic Fluorides” Angew. Chem. Int. Ed. 2023, 62, e202314843.

IRIDIUM/RHODIUM CATALYZED ASYMMETRIC ALLYLIC AMINATION OF TERTIARY TRICHLOROACETIMIDATES

Transition-metal-catalyzed allylic substitutions have become a useful tool for enantioselective construction of asymmetric carbon-carbon and carbon-heteroatom functionalities found in a wide variety of natural products, pharmaceuticals, and agrochemicals. Our group has reported on the development of the allylic substitution methodologies to access challenging chiral C-O, C-N, and C-S motifs. Reactive unactivated nucleophiles were employed; these nucleophiles include aromatic carboxylic acids, alkyl carboxylic acids, aromatic amines, and aromatic thiols. Reactions of these heteroatom nucleophiles lead to the highly branched-selective allylic substitution products in good yields and high levels of enantioselectivities. Early in this study, we focused on the development of chiral secondary amines using monosubstituted trichloroacetimidates (Figure 10a). However, due to the importance of chiral tertiary amines and the challenges associated with their asymmetric access, we proceeded to develop our strategy for their asymmetric synthesis.

Chiral amines are valuable building blocks in pharmaceuticals and naturally occurring alkaloids. It is estimated that at least 80% of small molecule pharmaceuticals feature an amine moiety, and 60% of those are tertiary amines.  The ubiquitous presence of amines in biologically relevant molecules is ascribed to their unique physicochemical properties. Our group has focused on the development of a method that ultimately resulted in the first reported dynamic kinetic asymmetric transformation (DYKAT) of acyclic tertiary allylic electrophiles with aniline and cyclic amine nucleophiles. Hayashi’s diphenyl bicyclo[2.2.2]octadiene was the most efficient ligand in the DYKAT reaction with highest yields and asymmetric induction. This methodology allows for the high-yielding, regio- and enantioselective synthesis of quaternary amine-containing centers. This operationally simple process is catalyzed by a chiral diene-ligated rhodium(I) complex and utilizes easily prepared branched trichloro-acetimidates and unactivated anilines. The synthetic utility of this method was then illustrated by application to the preparation of both enantioenriched amino acid derivatives and nitrogen-containing heterocycles.

The challenges with the access of aliphatic tertiary amines and their ability to inhibit catalysis have been well reported (Figure 10b). As a result, we revisited our previously established allylic amination to investigate its feasibility with aliphatic secondary amines. This also led to the first reported example for regio- and enantioselective synthesis of α-trisubstituted-α-tertiary amines based on chiral diene-ligated rhodium-catalyzed asymmetric allylic substitution of racemic tertiary allylic trichloroacetimidates with acyclic and cyclic aliphatic secondary amines (Figure 10c). We also conducted a combined experimental and computational investigation to gain insights into the key aspects of the mechanism. Computations revealed that both syn and anti π-allyl intermediates are formed upon ionization of racemic allylic substrates; however, syn π-allyl manifolds are more reactive than the anti forms. Isomerization of π-allyl intermediates via the π–σ–π mechanism is faster than the subsequent outersphere nucleophilic attack, favoring the formation of a single enantiomer of product. The thermodynamically more stable syn π-allyl complex was found to be kinetically more reactive, leading to the major (S)-branched allylic substituted product. Hydrogen bond interactions between amine-NH and β-oxygen of allylic substrates play a critical role in enabling the high levels of branched selectivity. The chiral diene-ligated rhodium catalyst effectively promotes an asymmetric environment around the syn π-allyl moiety, kinetically favoring one diastereomeric allyl complex to undergo nucleophilic substitution, leading to the α-trisubstituted-α-tertiary amine product with high levels of enantioselectivity.

Recently, we expanded the application of our tertiary trichloroacetimidate amination towards the development of pharmaceutical components for drug chemistry. The utilization of β-fluoroamines as pharmaceutical components for drug development has attracted a considerable amount of interest. However, direct access to tertiary β-fluoroamines is challenging. Our approach enables the asymmetric synthesis of challenging tertiary β-fluoroamines using a wide range of anilines and cyclic aliphatic amines. DFT calculations were employed to elucidate the observed difference in reactivity between the fluoromethyl-substituted trichloroacetimidates and their methyl-substituted counterparts. The computational analysis revealed that the ionization transition energy required to generate the reactive π-allyl was higher with the fluorinated trichloroacetimidate substrate. Furthermore, this developed protocol provides efficient direct asymmetric access to tertiary β-fluoroamines in synthetically useful yields and selectivities.

Figure 1. Challenges and amination methodology of tertiary trichloroacetimidate

1) Arnold, J. S.; Cizio, G.; Nguyen, H. M. “Rhodium-Catalyzed Regio- and Enantioselective Amination of Racemic Secondary Allylic Trichloroacetimidates with Acyclic N- Methyl Anilines.” Chem. Commun.2012, 48, 11531-11533.

2) Arnold, J. S.; Nguyen, H. M. “Rhodium-Catalyzed Asymmetric Amination of Allylic Trichloroacetimidates.” Synthesis, 2013, 45, 2101-2108.

3) Arnold, J. S.; Mwenda, E. T.; Nguyen, H. M. “Rhodium-Catalyzed Sequential Allylic Amination and Olefin Hydroacylation Reactions: Enantioselective Synthesis of Seven-Membered Nitrogen Heterocycles.” Angew. Chem. Int. Ed. 2014, 53, 3688-3692.  This article was selected as a “HOT PAPER.”

4) Mwenda, E. T.; Nguyen, H. M. “Enantioselective Synthesis of 1,2-Diamines Containing Tertiary and Quaternary Centers through Rhodium-Catalyzed DYKAT of Racemic Allylic Trichloroacetimidates” Org. Lett. 2017, 19, 4814-4817

5) Arachchi, M. K.; Nguyen, H. M. “Iridium-Catalyzed Enantioselective Allylic Substitutions of Racemic, Branched Trichloroacetimidates with Heteroatom Nucleophiles: Formation of Allylic C-O, C-N, and C-S Bonds” Advanced Synthesis & Catalysis 2021, 363, 4239-4246.

6) Arachchi, M. K.; Schaugaard, R. N.; Schlegel, H. B.; Nguyen, H. M. “Scope and Mechanistic Probe into Asymmetric Synthesis of alpha-Trisubstituted-Alpha-Tertiary Amines via Rhodium Catalysis” J. Am. Chem. Soc. 2023,145, 19642-19654.

7) Chukwu, F. O.; Arachchi, M. K.; Nguyen, H. M.* “Rhodium-Catalyzed Allylic Amination for the Enantioselective Synthesis of Tertiary β-Fluoroamines” Org. Lett. 2025, 27, 594-599.