About

Richmond Sarpong, born in 1974, is an Executive Associate Dean and Professor of Chemistry at the University of California, Berkeley. He holds a B.A. in Chemistry from Macalester College (1995) and a Ph.D. in Organic Chemistry from Princeton University (2001). He was a UNCF-Pfizer Postdoctoral Fellow at Caltech from 2000 to 2004. His research focuses on organic and organometallic chemistry, particularly the total synthesis of biologically active and architecturally complex natural products. His work aims to develop new synthetic methods and strategies, inspired by nature, to synthesize natural products that can serve as tools for studying biological systems or as starting points for therapeutics development. Sarpong's group addresses current limitations in synthetic organic chemistry by exploring new directions for carbon-carbon bond formation, including methods coupled with strain release and aromatization, as well as the generation of reactive intermediates such as metallo-carbenoids and radicals. His research includes natural products like teleocidin B, cyathane diterpenoids, and mycotoxins, with a focus on advancing synthetic methodology and understanding complex molecule synthesis.

Research topics

• Artificial Intelligence
• Computer Science
• Chemistry
• Programming language
• Data science
• Mathematics
• Nanotechnology
• Organic chemistry
• Combinatorial chemistry
• Engineering
• Materials science
• Software engineering
• Physics

Selected publications

• Higher-Level Strategies for Computer-Aided Retrosynthesis

  ACS Central Science · 2026-03-05 · 2 citations

  articleOpen access

  Retrosynthesis is a core technique in organic chemistry that simplifies target molecules into more readily available components. Computer-aided synthesis planning (CASP) automates this process by recursively proposing immediate precursors to identify multistep synthetic pathways. However, CASP typically struggles for complex molecules that require longer synthetic pathways and present a greater number of possible disconnections. Here, we introduce a new higher-level framework for computer-aided retrosynthesis. Our approach abstracts detailed substructures in pathway intermediates not appearing in the target product, allowing the algorithm to emphasize higher-level strategies while postponing the consideration of specific functional group choices, thus reducing the effective width and depth of the search space. This framework achieves higher top-k accuracy in single-step retrosynthesis and identifies multistep routes for more targets than the original approach. Through case studies on complex drugs and natural products, we demonstrate how routes proposed by our framework provide a powerful basis for developing full synthesis plans, particularly in challenging cases where the original approach fails, while enabling chemists to leverage their expertise to refine the synthesis design. Ultimately, focusing on higher-level strategies enables an effective and intuitive approach for challenging targets in computer-aided retrosynthesis.

  PublisherDOI

• An “Inside-Out” Strategy Enables a 14-Step Total Synthesis of Hispidospermidin

  JACS Au · 2026-01-06

  articleOpen accessSenior authorCorresponding

  Traditionally, a retrosynthesis aims to disconnect a molecular target into simpler precursors as quickly as possible, prioritizing the early deconstruction of primary contributors to the molecule’s overall structural complexity (i.e., primary complexity elements). The complementary approach, which rapidly constructs complexity early in the forward synthesis, is much less common. Herein, we report a 14-step protective group-free total synthesis of the polycyclic sesquiterpenoid alkaloid hispidospermidin, which exploits an early-stage complexity-generating bicycle formation to forge the carbon skeleton, followed by subsequent peripheral functionalizations. Specifically, a key Giese conjugate addition of a bridgehead radical established the quaternary center, and a novel isomerization was discovered, which enabled a one-pot protocol to establish the trans-hydrindane moiety, and application of a C–H desaturation/etherification sequence constructed the tetrahydrofuran moiety at a late stage. Uniquely, our strategy generates the primary complexity element, the bicyclo[3.3.1]nonane core, in the first step of the synthesis, whereas the three previous syntheses feature mid- to late-stage bicycle construction (total of 23–31 steps). Analysis of the structural complexity landscape of the four syntheses of hispidospermidin suggests that building a molecule from the “Inside-Out”, as described here, may be a broadly applicable strategy to expedite the total synthesis of topologically complex molecules.

  PublisherDOI

• Strategic Applications of Single-Atom Skeletal Editing in Natural Product Synthesis

  Journal of the American Chemical Society · 2026-05-22

  articleOpen accessCorresponding

  Skeletal editing is rapidly reshaping synthetic chemistry by enabling precise, atom-level modifications to complex molecular frameworks. Despite recent advances in methodology development, skeletal editing has yet to realize its full impact on complex molecule synthesis. In this Perspective, we highlight the power of single-atom skeletal editing transformations in enabling efficient syntheses of various complex natural products and advocate for the development of new methods and novel applications. We present guidelines rooted in historical precedent along with modern case studies that highlight when skeletal edits enable efficient synthesis, and where reactivity gaps still limit broader adoption. By analyzing the existing literature, we aim to inspire novel retrosynthetic disconnections, and steer new method development, which, collectively, will advance the fields of total synthesis and skeletal editing.

  PublisherOA PDFDOI

• Methylglyoxal-induced glycation stress promotes aortic stiffening: Putative mechanistic roles of oxidative stress and cellular senescence

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-06 · 2 citations

  preprintOpen access

  Background: Here, we assessed the role of the advanced glycation end-product (AGE) precursor methylglyoxal (MGO) and its non-crosslinking AGE MGO-derived hydroimidazolone (MGH)-1 in aortic stiffening and explored the potential of a glycation stress-lowering compound (Gly-Low) to mitigate these effects. Methods: Young (3-6 month) C57BL/6 mice were supplemented with MGO (in water) and Gly-Low (in chow). Aortic stiffness was assessed in vivo via pulse wave velocity (PWV) and ex vivo through elastic modulus. Putative mechanisms underlying MGO- and MGH-1-induced aortic stiffening were explored using complementary experimental approaches in aortic tissue and cultured human aortic endothelial cells (HAECs). Moreover, aortic stiffness was assessed in old (24 month) mice after consumption of Gly-Low-enriched chow. Results: MGO-induced glycation stress increased PWV in young mice by 21% (P<0.05 vs. control), which was prevented with Gly-Low (P=0.93 vs. control). Ex vivo, MGO increased aortic elastic modulus 2-fold (P<0.05), superoxide production by ∼40% (P<0.05), and MGH-1 expression by 50% (P<0.05), which were all mitigated by Gly-Low. Chronic MGO exposure elevated biomarkers of cellular senescence in HAECs, comparable to a known senescence inducer Doxorubicin, an effect partially blocked by Gly-Low. Moreover, elevated aortic elastic modulus induced by Doxorubicin (P<0.05 vs. control) was prevented with Gly-Low (P=0.71 vs. control). Aortic RNA sequencing implicated preservation of endogenous cellular detoxification pathways with Gly-Low following exposure to MGH-1. Old mice supplemented with Gly-Low had lower PWV (P<0.05) relative to old control mice. Conclusions: MGO-induced glycation stress contributes to aortic stiffening and glycation stress lowering compounds hold promise for mitigating these effects. What Is New?: experimental models, we establish that MGO-mediated glycation stress independently induces aortic stiffening. Furthermore, we demonstrate that the glycation-lowering compound, Gly-Low, mitigates MGO-induced aortic stiffening by mitigating excessive oxidative stress and cellular senescence, and can lower aortic stiffness in old mice. Mechanistically, activation of the detoxification enzyme, glyoxalase-1 (Glo-1), is a novel pathway by which Gly-Low mediates its therapeutic effects on aortic stiffening. Lastly, we show that Gly-Low holds promise for lowering aortic stiffness in old age. What Is Relevant?: Aortic stiffening is a major risk factor for cardiovascular diseases (CVD) and a significant predictor of CV-related morbidity and mortality. Yet, the underlying mechanisms driving this process remain incompletely understood. This study identifies MGO-derived glycation stress as a critical and modifiable factor contributing to aortic stiffening through pathways involving excessive oxidative stress and cellular senescence. By establishing the efficacy of Gly-Low in mitigating these effects, our findings underscore the importance of targeting glycation stress in the context of aging, and likely in other settings of glycation stress, to improve arterial health and reduce CVD risk. Clinical/Pathophysiological Implications: These findings have significant clinical implications, as they demonstrate that glycation stress is a viable and modifiable therapeutic target for the prevention and treatment of aortic stiffening. Gly-Low offers a promising therapeutic approach to ameliorate glycation stress- and age-related aortic stiffening, by directly targeting excess glycation stress, oxidative stress, and cellular senescence. Additionally, the involvement of the Glo-1 detoxification pathway suggests a specific molecular target for future interventions aimed at improving arterial health and mitigating the progression of CVD.

  PublisherOA PDFDOI

• Total synthesis and biological activity of “carbamorphine”: O-to-CH ₂ replacement in the E-ring of the morphine core structure

  Proceedings of the National Academy of Sciences · 2025-06-30 · 3 citations

  articleOpen accessSenior authorCorresponding

  Morphine is a µ-opioid receptor (MOR) agonist and potent analgesic. However, it displays several side effects including respiratory depression and addiction. Here, we show that a single heavy atom replacement in the morphine core structure (O to CH 2 exchange in the E-ring) prepared through a 15-step total synthesis displays a different pharmacological profile. The total synthesis features an intramolecular inverse electron-demand Diels−Alder cycloaddition and a stereoselective Giese radical addition to construct a quaternary carbon center. Unlike morphine, where the (–)-morphine enantiomer binds the MOR, both enantiomers of this “carba” variant, which we have named carbamorphine, possess activity as agonists of the MOR. Cell-based functional assays show that (+)-carbamorphine shows reduced G-protein as well as β-arrestin efficacy at the MOR. In mouse behavioral assays, (+)-carbamorphine exhibits MOR-selective antinociception while showing reduced respiratory depression and a lack of conditioned place preference at supratherapeutic doses. Overall, through a net “single-atom” change (i.e., O to CH 2 ) in the morphine framework, different pharmacological profiles have been realized. This work provides a basis for additional syntheses and the study of morphine analogs that incorporate atom changes in the core framework.

  PublisherDOI

• Two-Step Constitutional Isomerization of Saturated Cyclic Amines Using Borane Catalysis

  JACS Au · 2025-01-21 · 4 citations

  articleOpen accessSenior authorCorresponding

  The prevalence of saturated azacycles within pharmaceuticals, natural products, and agrochemicals has prompted the development of many methods that modify their periphery. In contrast, technologies that interconvert distinct saturated azacyclic frameworks, which would uniquely facilitate access to underexplored chemical space, are highly limited. Existing approaches for modifying the core of azacycles usually require either the installation of reactive functionality, which must later be removed in subsequent steps, or the use of tailored substrates, limiting applicability to drug discovery. Herein, we report a borane-catalyzed contraction of saturated N-hydroxy azacycles. This transformation is uniquely enabling, allowing reorganization of the connectivity of the substrate without altering the molecular formula and generating products without vestigial functionality derived from auxiliary groups. The outcome of the reductive Stieglitz-type contraction can be attributed to a key stereoelectronic interaction enforced by geometric constraints, the mechanism of which we investigate using density functional theory. The method developed here enables the rapid late-stage reorganization of bioactive molecules featuring cyclic and linear amines. Overall, a general platform for saturated amine constitutional isomerization has been achieved.

  PublisherDOI

• Skeletal Editing Strategies Driven by Total Synthesis

  Accounts of Chemical Research · 2025-05-15 · 33 citations

  articleSenior authorCorresponding

  ConspectusSingle-atom skeletal editing strategies that precisely modify the core frameworks of molecules have the potential to streamline and accelerate organic synthesis by enabling conceptually simple, but otherwise synthetically challenging, retrosynthetic disconnections. In contrast to broader skeletal remodeling and rearrangement strategies, these methodologies more specifically target single-atom changes with high selectivity, even within complex molecules such as natural products or pharmaceuticals. For the past several years, our laboratory has developed several skeletal editing methodologies, including single-atom ring contractions, expansions, and transpositions of both saturated and unsaturated heterocycles, as well as other carbon scaffolds. This Account details the evolution of “skeletal editing logic” within the context of our extensive work on natural product total synthesis.Early work in the Sarpong group leveraged metal-mediated C–C bond cleavage of in situ-generated strained intermediates to accomplish total syntheses of natural products, such as the icetexane diterpenoids and cyathane diterpenes. Continuing our focus on leveraging C–C bond cleavage through “break-it-to-make-it” strategies, we then developed carvone remodeling strategies to access a variety of terpenoids (including longiborneol sesquiterpenoids, phomactins, and xishacorenes) from hydroxylated pinene derivatives. In applying this skeletal remodeling and C–C cleavage framework to alkaloid natural products, such as the preparaherquimides and lycodine-type alkaloids, we recognized that single-atom changes to the saturated nitrogen-containing rings within these natural products would enable the direct conversion between distinct but structurally related natural product families. Thus, we began developing methods that selectively modify the core frameworks of N-heterocycles; this focus led to our work on the deconstructive fluorination and diversification of piperidines and ultimately to our recent body of work on direct, single-atom core framework modifications (single-atom skeletal editing). In the context of saturated heterocycles, we developed photomediated enantioselective ring contractions of α-acylated motifs and reductive ring contractions of cyclic hydroxylamines. For unsaturated heterocycles, we have developed ring contractions of azines (e.g., pyrimidine to pyrazole), 15N isotopic labeling of azines, and phototranspositions of indazoles to benzimidazoles. To direct our focus on reaction development, a cheminformatic analysis of heteroaromatic skeletal edits served to quantitatively inform which transformations would most significantly expand the accessible chemical space. Apart from heterocycles, we also reported single-nitrogen insertion through the reductive amination of carbonyl C–C bonds. Ultimately, the goal of this research is to develop mild and selective skeletal editing methodologies that can be applied to total synthesis and organic synthesis more generally. While recent total syntheses from our group have targeted simplified retrosyntheses through single-atom skeletal editing logic (e.g., daphenylline and harringtonolide), multiple steps were still required to achieve the formal desired “edit”. As such, the continued development of truly single-step, mild, and selective reactions that can edit the cores of highly complex molecules remains highly desirable.

  PublisherDOI

• Methylglyoxal-induced glycation stress promotes aortic stiffening: putative mechanistic roles of oxidative stress and cellular senescence

  Aging · 2025-11-14

  articleOpen access

  BACKGROUND: Here, we assessed the role of the advanced glycation end-product (AGE) precursor methylglyoxal (MGO) and its non-crosslinking AGE MGO-derived hydroimidazolone (MGH)-1 in aortic stiffening and explored the potential of a glycation stress-lowering compound (Gly-Low) to mitigate these effects. METHODS: through elastic modulus. Putative mechanisms underlying MGO- and MGH-1-induced aortic stiffening were explored using complementary experimental approaches in aortic tissue and cultured human aortic endothelial cells (HAECs). Moreover, aortic stiffness was assessed in old C57BL/6J (24 month) mice after consumption of Gly-Low-enriched chow. RESULTS: MGO-induced glycation stress increased PWV in young mice by 21% (P<0.05 vs. control), which was prevented with Gly-Low (P=0.93 vs. control). Ex vivo, MGO increased aortic elastic modulus ~100% (P<0.05), superoxide production by ~40% (P<0.05), and MGH-1 expression by 50% (P<0.05), which were all mitigated by Gly-Low. Chronic MGO exposure elevated biomarkers of cellular senescence in HAECs, comparable to a known senescence inducer Doxorubicin, an effect partially blocked by Gly-Low. Moreover, elevated aortic elastic modulus induced by Doxorubicin (P<0.05 vs. control) was prevented with Gly-Low (P=0.71 vs. control). Aortic RNA sequencing implicated preservation of endogenous cellular detoxification pathways with Gly-Low following exposure to MGH-1. Old mice supplemented with Gly-Low had lower PWV (P<0.05) relative to old control mice. CONCLUSIONS: MGO-induced glycation stress contributes to aortic stiffening and glycation stress lowering compounds hold promise for mitigating these effects.

  PublisherOA PDFDOI

• Interrogation of Enantioselectivity in the Photomediated Ring Contractions of Saturated Heterocycles

  Journal of the American Chemical Society · 2025-01-02 · 17 citations

  articleOpen accessSenior authorCorresponding

  ) bonds in the ring contracted products; however, the origins of enantioselectivity remain poorly understood. In this work, enantioselectivity of the ring contraction has been explored across an expanded structurally diverse substrate scope, revealing a wide range of enantioselectivities (0-99%) using two distinct CPA catalysts. Mechanistic investigations support rate-determining excitation that generates short-lived achiral intermediates that are intercepted by the CPA in an enantiodetermining ring closure. The effects of competitive uncatalyzed reactivity and light-driven reversibility of the enantiodetermining ring closure on enantioselectivity have been elucidated. Statistical models were built by regressing the range of enantioselectivities from the substrate scope against key structural features of the products for both CPA catalysts. The resultant models suggested distinct factors that influence the enantioselectivity response for each catalyst and enabled rational modification of a pharmaceutically relevant target molecule to improve enantioselectivity. Finally, density functional theory (DFT)-based transition state analysis identified distinct noncovalent interactions with each catalyst that correlated with the unique selectivity-relevant features uncovered through statistical modeling. Our findings not only offer comprehensive insight into the origins of enantioselectivity in this system but should also aid future development of related photomediated CPA-catalyzed reactions.

  PublisherOA PDFDOI

• Synthetic Studies toward the Aphidicolin Family of Diterpenoid Natural Products

  The Journal of Organic Chemistry · 2025-07-09

  articleSenior authorCorresponding

  Herein, we report an investigation of several synthetic strategies to access the aphidicolin family of natural products. Some unsuccessful approaches include strategies featuring Diels-Alder cycloadditions, Cope rearrangement, divinyl cyclopropane-Cope rearrangement, and C-C cleavage "cut-and-sew" reactions. Separating key bond-forming and bond-breaking steps into a two-step "sew-and-cut" strategy, a penta-carbocycle containing the embedded aphidicolin core was synthesized using an intramolecular [2 + 2]-photocycloaddition reaction─the "sew" step─to obtain a "linear" cycloadduct. Additionally, a constitutional "crossed" isomer of this [2 + 2]-adduct was obtained in a condition-dependent manner, providing insight into factors that can be leveraged to alter [2 + 2]-selectivity for complex substrates. Future application of contemporary C-C cleavage methodologies to facilitate the "cut" step should afford a suitable common intermediate for the synthesis of many members of the aphidicolin family.

  PublisherDOI

Recent grants

• Total Synthesis of Bioactive Natural Products

  NIH · $2.7M · 2009–2019

• Sequential Coupling/Pericyclic Reactions of a Dihalogenated Pyrone for Complex Molecule Synthesis

  NSF · $835k · 2019–2024

• Renewal: Strategies and Methods for Complex Molecule Synthesis

  NIH · $5.4M · 2019–2027

• Novel Strategies for Natural Products Synthesis

  NIH · $3.3M · 2008–2021

• Chemical Synthesis Using Carbon-Carbon Bond Activation/Cleavage of Carvone Derivatives

  NSF · $450k · 2016–2019

Frequent coauthors

• David E. Olson

  Multidisciplinary Association for Psychedelic Studies

  55 shared

• Jared T. Shaw

  55 shared

• Djamaladdin G. Musaev

  Atlanta University Center

  46 shared

• Terry P. Lebold

  Janssen (United States)

  41 shared

• Gary M. Gallego

  Pfizer (United States)

  33 shared

• Jose B. Roque

  31 shared

• Kanny K. Wan

  National Center for Advancing Translational Sciences

  30 shared

• Regan J. Thomson

  Northwestern University

  30 shared