About

Noah Burns is an Associate Professor of Chemistry at Stanford University. His research explores the boundaries of modern organic synthesis to more rapidly create species of the highest molecular complexity. His projects in the Burns Lab are inspired by natural products, focusing on their importance as synthetic targets and their potential to address important scientific questions. The lab's major efforts include the development of methods for the selective halogenation of organic molecules, such as dihalogenation and halofunctionalization, which are fundamental transformations in the field. Breakthroughs in this area aim to enable the controlled evaluation of the therapeutic potential of numerous chiral organohalogens. Additionally, the group works on the practical total synthesis of natural products, especially those with unanswered chemical, medicinal, biological, or biophysical questions, including the construction of unusual lipids with intriguing physical properties. Noah Burns was born in Oakland, California, and grew up in south central Maine. He studied chemistry at Columbia University, graduating summa cum laude in 2004 under Professor James Leighton. He completed his Ph.D. at The Scripps Research Institute in 2009 with Professor Phil Baran, focusing on the synthesis of haouamine A, a marine alkaloid. As an NIH postdoctoral fellow at Harvard University with Professor Eric Jacobsen, he developed a catalytic enantioselective [5+2] cycloaddition. He joined Stanford's faculty in 2012 and was named a Terman Fellow in 2013.

Research topics

• Chemistry
• Organic chemistry
• Nanotechnology
• Combinatorial chemistry
• Materials science
• Medicinal chemistry
• Chemical engineering
• Computational chemistry
• Classical mechanics
• Photochemistry
• Chemical physics
• Physics

Selected publications

• Biosynthesis of GMGT lipids by a radical SAM enzyme associated with anaerobic archaea and oxygen-deficient environments

  Nature Communications · 2024-06-19 · 19 citations

  articleOpen access

  Abstract Archaea possess characteristic membrane-spanning lipids that are thought to contribute to the adaptation to extreme environments. However, the biosynthesis of these lipids is poorly understood. Here, we identify a radical S -adenosyl-L-methionine (SAM) enzyme that synthesizes glycerol monoalkyl glycerol tetraethers (GMGTs). The enzyme, which we name GMGT synthase (Gms), catalyzes the formation of a C(sp 3 )–C(sp 3 ) linkage between the two isoprenoid chains of glycerol dialkyl glycerol tetraethers (GDGTs). This conclusion is supported by heterologous expression of gene gms from a GMGT-producing species in a methanogen, as well as demonstration of in vitro activity using purified Gms enzyme. Additionally, we show that genes encoding putative Gms homologs are present in obligate anaerobic archaea and in metagenomes obtained from oxygen-deficient environments, and appear to be absent in metagenomes from oxic settings.

  PublisherOA PDFDOI

• Fluorination Affects the Force Sensitivity and Nonequilibrium Dynamics of the Mechanochemical Unzipping of Ladderanes

  Journal of the American Chemical Society · 2024-11-13 · 7 citations

  article

  When multiple reaction steps occur before thermal equilibration, kinetic energy from one reaction step can influence overall product distributions in ways that are not well predicted by transition state theory. An understanding of how the structural features of mechanophores, such as substitutions, affect reactivity, product distribution, and the extent of dynamic effects in the mechanochemical manifolds is necessary for designing chemical reactions and responsive materials. We synthesized two tetrafluorinated [4]-ladderanes with fluorination on different rungs and found that the fluorination pattern influenced the force sensitivity and stereochemical distribution of products in the mechanochemistry of these fluorinated ladderanes. The threshold forces for mechanochemical unzipping of ladderane were decreased by α-fluorination and increased by γ-fluorination; these changes correlated to the different stabilizing or destabilizing effects of fluorination patterns on the first transition state. Using ab initio steered molecular dynamics (AISMD), we compared the product distributions of synthesized and hypothetical ladderanes with different substitution patterns. These calculations suggest that fluorination on the first two bonds of ladderane gives rise to a larger fraction of dynamic trajectories and a larger fraction of E-alkene product through a mechanism resulting from larger momentum because of the greater atomic mass of fluorine. Fluorination on the third and fourth rungs instead gives a larger fraction of E-alkene product primarily due to electronic effects. These combined experimental and computational studies of the mechanochemical unzipping of fluorinated ladderanes provide an example of how relatively simple substituents can affect the extent of nonstatistical dynamics and, thus, mechanochemical outcomes.

  PublisherDOI

• Author response for "Structure-Function Relationships in Pure Archaeal Bipolar Tetraether Lipids"

  2024-07-31

  peer-review
  PublisherDOI

• Structure–function relationships in pure archaeal bipolar tetraether lipids

  Chemical Science · 2024-01-01 · 12 citations

  articleOpen accessCorresponding

  small-angle X-ray scattering (SAXS) and cryogenic electron microscopy (cryo-EM). SAXS studies on bulk aqueous dispersions of GDGT lipids over 10-90 °C revealed lamellar and non-lamellar phases and their transitions. Next we asked whether vesicles overwhelmingly composed of a single GDGT species can undergo fusion as it is difficult to conceptualize such behavior with the assumption that such membranes have a monolayer structure. Interestingly, we observed that GDGT vesicles undergo fusion with influenza virus with lipid mixing kinetics comparable to that with vesicles composed of monopolar phospholipids. Our results suggest that GDGT membranes may consist of regions with a bilayer structure or form bilayer structures transiently which facilitate fusion and thus offer insight into how archaea may perform important physiological functions that require dynamical membrane behavior.

  PublisherOA PDFDOI

• Total Synthesis of (+)‐Discorhabdin V**

  Angewandte Chemie · 2023-11-13

  articleOpen accessSenior authorCorresponding

  Abstract The discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, particularly those featuring a bridging carbon‐nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Herein we report the first total synthesis and full stereochemical assignment of (+)‐discorhabdin V. To access the pyrroloiminoquinone we developed a convergent N‐ alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon‐nitrogen bridge, and a reductive N,O ‐acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative configuration of (+)‐discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined by circular dichroism and the use of an amino acid derived chiral starting material. Our work represents one of only two reports of a total synthesis of a nitrogen‐bridged discorhabdin and paves the way for future biological evaluation of such compounds.

  PublisherOA PDFDOI

• Structure-Function Relationships in Pure Archaeal Bipolar Tetraether Lipids

  ChemRxiv · 2023-12-07

  preprintOpen access

  Archaea, the third fundamental domain of life are distinguished from bacteria and eukaryotes due to the presence of unique lipids in their cell membranes. Archaeal bipolar lipids are among the most unusual lipids occurring in nature because of their presumed ability to span the entire membrane. They are challenging to extract in pure form from natural sources or synthesize chemically, and as a result, prior studies on pure lipids have been limited. Here we have utilized synthesis to enable in-depth biophysical investigations on a series of archaeal glycerol dialkyl glycerol tetraether (GDGT) lipids having symmetric or unsymmetric combinations of polar head groups. We showed that these lipids self-assemble to form membrane-bound vesicles in aqueous media, encapsulate polar molecules, and reconstitute a functional integral membrane protein. Membrane thicknesses and electron density profiles were investigated by performing small-angle X-ray scattering (SAXS) studies and cryogenic electron microscopy (cryo-EM) imaging on unilamellar vesicles of GDGT lipids. SAXS studies on bulk aqueous dispersions of GDGT lipids over a large temperature range (10-90 °C) allowed us to identify lamellar and non-lamellar phases and their interconversions under various buffer conditions. We also studied how the propensity to form various mesophases is reflected in the functional behavior of the GDGT membranes. Specifically, we asked whether vesicles overwhelmingly composed of GDGTs can undergo fusion as it is difficult to conceptualize such behavior with the assumption that such membranes have a monolayer structure. Interestingly, we observed that GDGT vesicles undergo fusion with influenza virus with lipid mixing kinetics comparable to that with vesicles composed of typical monopolar phospholipids. Our results suggest that GDGT membranes may consist of regions with a bilayer structure which facilitates fusion and thus offer insight into how archaea may perform important physiological functions that require dynamical membrane behavior.

  PublisherOA PDFDOI

• Biosynthesis of H-GDGTs linked to ocean oxygen deficiency

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-10-20 · 5 citations

  preprintOpen access

  Abstract Archaeal membrane lipids GDGTs (glycerol dialkyl glycerol tetraethers) are biomarkers used for tracking Earth’s historical environmental changes. Among these GDGTs, the H-shaped GDGTs (H-GDGTs, or GMGTs) represent a less-explored and often overlooked subset, with its biosynthetic pathway and geological significance remaining elusive. Here, we identified the gene responsible for biosynthesizing H-GDGTs, which encodes to a radical S -adenosyl-L-methionine (SAM) enzyme, named as H-GDGTs bridge synthase (Hbs). Heterologous expression of the gene hbs in a methanogen, as well as in vitro activity assay using the purified Hbs enzyme were performed. Additionally, we found that the genes encoding Hbs are exclusively present in obligate anaerobic archaea genomes and the metagenomes obtained from oxygen-deficient environments, but not in oxic settings. The H-GDGTs lipids were also consistently enriched in the modern oxygen-deficient environments, and remarkably accumulated in ancient sediments during oceanic anoxic event-2 (OAE-2, ∼94 million years ago) period. Our findings indicate H-GDGTs holds significant promise as a novel biomarker for studying historical ocean oxygen deficiency supported by a well-established biological basis.

  PublisherOA PDFDOI

• Total Synthesis of (+)-Discorhabdin V

  ChemRxiv · 2023-06-20 · 6 citations

  preprintOpen accessSenior author

  The discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, with none featuring a bridging carbon–nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Here we report the first total synthesis and full stereochemical assignment of (+)-discorhabdin V in 13 linear steps. To access the pyrroloiminoquinone we developed a convergent N-alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon–nitrogen bridge, and a reductive N,O-acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative stereochemistry of (+)-discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined via circular dichroism and the use of an amino acid-derived chiral starting material. Our work represents the first report of a total synthesis of a nitrogen-bridged discorhabdin and paves the way for future biological evaluation of such compounds.

  PublisherOA PDFDOI

• A Metal-Free Cyclobutadiene Reagent for Intermolecular [4+2] Cycloadditions

  ChemRxiv · 2023-02-13

  preprintOpen accessSenior author

  Cyclobutadiene is a highly reactive antiaromatic hydrocarbon that has fascinated chemists for over sixty years. However, its preparation and uses in chemical synthesis are sparing, in part due to its lengthy synthesis that generates hazardous byproducts including excess heavy metals. Herein, we report a scalable, metal-free cyclobutadiene reagent, diethyldiazabicyclohexene dicarboxylate, and explore its intermolecular [4+2] cycloadditions with various electron-deficient alkenes. We also demonstrate its utility in a three-step total synthesis of dipiperamide G, and a diverse array of derivatizations including bromocyclobutadiene.

  PublisherOA PDFDOI

• CCDC 2167762: Experimental Crystal Structure Determination

  The Cambridge Structural Database · 2023-02-15

  datasetOpen access1st authorCorresponding

  An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

  PublisherDOI

Recent grants

• Selective Halogenation Reactions for the Synthesis of Chiral Bioactive Small Molecules

  NIH · $1.5M · 2015–2021

• NIH Grant F32GM089036

  NIH · $133k · 2012

Frequent coauthors

• Eric N. Jacobsen

  Harvard University Press

  42 shared

• Matthew L. Landry

  19 shared

• David E. Olson

  Multidisciplinary Association for Psychedelic Studies

  19 shared

• Jared T. Shaw

  19 shared

• Steven G. Boxer

  Stanford University

  17 shared

• Dennis X. Hu

  16 shared

• Frederick J. Seidl

  16 shared

• Grace M. McKenna

  Stanford University

  15 shared

Awards & honors

• Terman Fellow (2013)