Phil S. Baran


Phil S. Baran is a synthetic organic chemist and Professor in the Department of Chemistry at the Scripps Research Institute. His work is focused on synthesizing complex natural products, the development of new reaction methodologies within synthetic organic electrochemistry, and the development of new reagents. He holds several patents and has authored over 300 research articles.

Early life and education

Phil S. Baran was born in Denville, New Jersey, on August 10, 1977, and grew up in Coral Springs, Florida. He remembers being a poor student at high school, preferring to play role-playing games, write computer programs and build with Lego.
Encouraged by his chemistry teacher to experiment after school, Baran quickly channeled his creativity into crafting molecules. In 1995 he began a chemistry degree at New York University, and enthusiastically accepted Schuster's offer to work in his lab, synthesizing compounds that linked C60 with porphyrins to make artificial photosynthetic systems. He received his BS in chemistry from New York University in 1997.
He went on to earn his PhD from The Scripps Research Institute in 2001, under the supervision of K. C. Nicolaou, an experience he recalls was 'like hardcore Navy Seal training' and where he co-authored 30 papers in less than four years.
He then pursued a postdoctoral fellowship in the laboratory of Nobel Laureate Elias James Corey at Harvard University who reflected on Baran's time in his lab, saying, "He had a phenomenal grasp of synthetic chemistry," and "felt that he could be a leader in his generation."

Independent academic career

Phil Baran began his independent career at the Scripps Research Institute in the summer of 2003, at only 26 years old, and received tenure just three years later. In the 20 years since then, he has supervised over 300 graduate students, post-doctoral scholars, visiting scholars and interns. He is currently the Dr. Richard A. Lerner Endowed Chair at Scripps Research
His work is focused on practicality and simplicity in the total synthesis of organic molecules, eschewing protecting groups, functional group manipulations, and non-essential redox manipulations. Several of his total syntheses are now being adopted for commercial production. His contributions in methodology center around practical C-H functionalization reactions and have had a remarkable impact based on actual drug candidates brought into the clinic using these methods and the sales of numerous reagents he has commercialized for use in the pharmaceutical industry. Additionally, since the mid 2010's, Baran's lab has focused on developing electrochemical methodologies for use in total synthesis and medicinal chemistry as it allows for more atom economical and environmentally-conscious protocols.
Phil Baran has given hundreds of talks all over the world and is the recipient of dozens of distinguished awards. Among many honors, he has notably earned the Amgen Young Investigator Award, ACS Award in Pure Chemistry, the MacArthur Fellowship, the Mukaiyama Award, the ACS Elias J. Corey Award, the Danisco Science Excellence Medal Award, and the Edison Patent Award.

Industry career and collaborations

In addition to his numerous achievements in academia, Baran also holds many accolades in industry as a scientific entrepreneur, company co-founder, consultant and scientific advisor. He co-founded his first company Sirenas Marine Discovery in 2012 alongside Eduardo Esquenazi and Jake Beverage —a company that is dedicated to marine-inspired molecular discoveries and pre-clinical leads for cancer, HIV, and infectious diseases. In 2016, he joined forces with fellow Scripps colleagues, Benjamin F. Cravatt and Jin-Quan Yu to co-found Vividion Therapeutics with the goal of identifying small molecules that bind currently undrugged targets via a covalent-first chemoproteomics approach. Vividion was sold to Bayer in 2021 for $2 billion. In the same year, Baran founded Elsie Biotechnologies, an antisense oligonucleotide -based company with the goal of discovering therapeutic agents that can achieve desirable medicinal effects not attainable with existing drugs by modulating gene expression of DNA or RNA. Elsie Biotechnologies was sold to GlaxoSmithKline in 2024 for $50 million. Baran also co-founded and is on the scientific advisory team of Galileo Biosystems, a preclinical stage biopharmaceutical company focused on developing therapeutic agents for inflammatory and autoimmune diseases. He also serves on the scientific advisory board for seven additional companies and has consulted for over twenty more, including presently at Bristol-Meyers-Squibb, Gilead, and BASF Corporation.
In 2014, Baran began a partnership with , well-known laboratory equipment manufacturer, to bring to market a revolutionary piece of equipment that promised to standardize electrochemical protocols and make electrochemistry accessible to the average organic chemist. Three years after the partnership began, the ElectraSyn was at the American Chemical Society annual meeting, drawing a large crowd of eager chemists. In the seven years since, the ElectraSyn and subsequent ElectraSyn 2.0 have been widely adopted into the synthetic community and utilized towards hundreds of research articles and patents. The publicity surrounding Baran's partnership with IKA was highlighted with a memorable promotional video .

Strategies for synthesis

1. Ideality

In June 2010, Baran authored a paper describing the "Ideal Synthesis" in which he  presents a simple and informative definition of "ideality" when comparing molecular syntheses. Building off of ideas discussed by James B. Hendrickson in 1975, "ideality" refers to the concept of making molecules in a way that minimizes concession steps and maximizes construction steps. Importantly, this conversation of synthetic ideality is limited to comparisons of syntheses of the same molecule.

https://www.nature.com/articles/nature05569 Considerations for the ideal synthesis:

  1. Minimize non-C-C or C-heteroatom bond forming reactions
  2. Maximize the percentage of C−C bond-forming and strategic C−C bond-breaking events relative to the total number of steps
  3. Choose disconnections that maximize convergency
  4. Redox-Economical: the oxidation state of intermediates should fluctuate as little as possible during the synthesis
  5. Maximize structural changes per step
  6. Protecting Group-free synthesis: reduce or eliminate protecting group concession steps
  7. Invention-oriented discoveries: effort should be spent on the invention of new methodology to facilitate the aforementioned criteria and to uncover new aspects of chemical reactivity
  8. Minimize known biosynthetic pathways

    2. Two-Phase Synthesis

A unique approach to the synthesis of terpenes was put forth and executed in the context of numerous natural products that loosely mimics the way Nature crafts such molecules. By rapidly building up a carbon skeleton followed by oxygenation dramatically shorter routes are made possible as exemplified with the syntheses listed below:
  • 14-Step Synthesis of -Ingenolfrom -3-Carene
  • C-H Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation
  • Development of a Concise Synthesis of -Ingenol
  • Nineteen-step total synthesis of -phorbol
  • Scalable Synthesis of -Thapsigargin
  • Divergent synthesis of thapsigargin analogs
  • Two-Phase Synthesis of -Taxuyunnanine D
  • Two-Phase Synthesis of Taxol
  • Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

    3. Radical Retrosynthesis

Radical retrosynthesis adds to the toolbox of synthetic planning by additionally considering intuitive radical disconnections and cross-coupling molecular partners. As methods develop towards more 1e- thinking, this strategic and tactical approach to synthesis will continue to aid in the construction of interesting and valuable natural products and medicinally important compounds. Radical retrosynthesis maximizes convergency by making disconnections that are not wedded to traditional polar bond analysis. The most useful methods from a tactical standpoint in this regard use radical cross coupling..

4. Practical & Scalable Syntheses

Implicit in aiming for the ideal synthesis is being able to access useful quantities of a molecule by simple, scalable routes.

Total syntheses

Methods towards synthesis

C-H Functionalization

Olefin Functionalization

Radical Chemistry

Decarboxylative Coupling

Simplifying Oligonucleotide Synthesis

Simplifying Peptide Synthesis

  • CITU—reagent for peptide synthesis and decarboxylative cross-coupling
  • Thermodynamic peptide macrocyclization
  • General method for chemoselective, and modular functionalization of serine residues

    Halogenation

  • Direct difluoromethylation via Zn2
  • N–X Anomeric Amides as Electrophilic Halogenation Reagents
  • Guanidine-based chlorinating reagent, CBMG or "Palau'chlor"
  • Regioselective bromination of N-oxides

    Strain Release

  • Strain-release amination
  • Stereospecific strain-release cyclopentylation of amines, alcohols, thiols, carboxylic acids, and other heteroatoms
  • Enantiocontrolled Azetidine Library Synthesis via Strain Release Functionalization of 1-Azabicyclobutanes

    Electrochemical methods

Misc

Reagents developed

  • -PI Reagent
  • -PSI Reagent
  • CBMG or "Palau'chlor"
  • CITU
  • * Zinc trifluoromethanesulphinate, zinc difluoromethanesulphinate, zinc trifluoroethanesulphinate, zinc monofluoromethanesulphinate, zinc isopropylsulphinate, zinc triethyleneglycolsulphinate
  • Among others, listed at

    Publications

Phil S. Baran has authored and co-authored nearly and has an h-index of 133 with over 60,000 citations across his group's publications. Articles authored by Baran and his group can be found in numerous prestigious journals including Science, Nature, Journal of American Chemical Society, Angewandte Chemie, Journal of Organic Chemistry, among several others.
Baran co-wrote the digital interactive reference text The Portable Chemist's Consultant: A Survival Guide for Discovery, Process, and Radiolabeling as well as several book chapters and forewords.