Ian Doxsee

Advanced Writing in the Sciences

ENGW 3307
1/19/2015
ACS Style

Natural Product Synthesis Provides New Reactions For My Future Career

The growth of synthetic organic chemistry has provided continuous discoveries about the
formation of ever-more-complex molecules through new reaction techniques. These novel techniques
allow the synthesis of natural products, produced in nature by enzymes that were finely-tuned over
millions or billions of years, to proceed in a scientist's test tube. Unfortunately, many of these reactions
are very atom inefficient, meaning that to put A and B together, A must first be linked with X (in
order to increase its reactivity) and B must be linked with Y (again, to increase reactivity). After the
reaction between A and B is completed, X and Y simply fall off and are thrown away. Simple atom
inefficiency isn't the reason that this is so undesired, though. Oftentimes the synthesis of A-X and B-Y
is not possible or requires the protection and deprotection of other functional groups in the molecule,
adding many steps to the process and reducing yields and purity. Speaking of purity, once X and Y are
cleaved from the bond formation of A and B, there may be issues with separating them from the rest of
the reaction mixture. Purification challenges can sap enormous amounts of time from a project, so
again a simple methodology for connecting two (relatively) unprotected molecules together in an atomefficient way is desired. There are many reactions that connect molecules in an atom efficient way, but
all of them have such severe limitations as to be more academic curiosities than synthetically
applicable methodologies.
Professor Phil Baran's work on complex natural product synthesis has often dealt with the
previously mentioned problems of scaffold construction via inefficient bond formation. His work has
often focused on taxanes, a novel class of chemotherapy drugs with incredible potency but which are
nearly impossible to synthesize in any large quantities due to the lack of reactions in this area. In
reading his recent communication to the Journal of the American Chemical Society entitled A
Practical and Catalytic Reductive Olefin Coupling, I loved how his first major insight was in trying to
imitate nature, not by constructing elaborate enzymes and fine-tuning biosynthetic pathways, but by
focusing on the basic electron pushing of what nature does. He realized that the class of molecules he
was interested in synthesizing were made by simple carbon-carbon bond formations in nature, and this
inspired his initial bond disconnection between two carbons that most synthetic chemists would not
think to disconnect due to preconceived notions about reactivity. Cutting this bond led to his
hypothesized method of reactivity between these two carbons two alkenes, one connected to an

electron-withdrawing group so as to increase reactivity and selectivity. What impressed me most about
this train of thought is less the disconnection he made (a first-year organic chemistry student could
point to this bond), but more about the biosynthetic mimicry and intense intellectual curiosity that led
to the knowledge of similar alkene reactivities that provide precedent for this paper.
Professor Baran's argument in this paper is that alkenes can be converted to radical species,
allowing them to act as electrophiles for bond formation. This argument is well-supported by
mechanistic hypotheses, and was also tested ingeniously by deuterium labeling studies, which showed
the incorporation of a single deuterium atom at the expected position. The control reaction for this test
was also performed, as per good scientific process, showing that the simple exposure of the product
molecule to deuterated solvent did not lead to hydrogen-deuterium exchange. Baran's attention to detail
in this paper was, in my opinion, exceptional. He always does a good job of covering all his bases with
regards to potential questions about the viability of his science. I attended one of his talks at MIT and
he fielded some tough questions from a couple very famous professors (each of whom has a reaction
named after him), successfully communicating the work that his lab had done in order to establish that
the observed effects were in fact real. The ability to think critically about one's own research is not
something that can be easily learned, and I view Baran as an exceptional example of someone whose
ability to be self-critical and skeptical allows his research to shine.
When I first got introduced to chemistry during my senior year of high school, my professor
instilled in me the importance of asking testable yes/no hypotheses in order to guide my thinking and
figure out what's really going on in a complex system. My hypotheses should narrow down the
possibilities, rather than trying to reinforce my preconceived notions of how the science should be
working. Phil Baran's group has absolutely taken this motto to heart, even trying to see from the start
whether their newly discovered reaction was a fluke. The fact that so many check-up experiments
were performed and explained in this paper reinforces his commitment to this self-skepticism.
One thing that impresses me about this paper is its applicability to audiences of very different
experiences in chemistry. Anyone with a scientific background will be able to understand the
motivation behind Baran's research, while more advanced chemists will be drawn in by the detailed
experimental notes, including a couple invaluable tables showing yields of this reaction on a number of
varied substrates. Additionally, this paper isn't just a niche example of a reaction that's applicable to
five chemists in the world. This new reaction has the potential to change how every single natural
products synthesis research group conducts their research, insofar as the design of their synthetic
scheme. Natural products synthesis is driven by the rational design of a single synthetic route, often 20
steps or more, to the desired product. Many of these steps are often lengthy protections/deprotections

(masking all reactive groups except for the two you want to react) in order to allow other carboncarbon bond forming reactions to proceed. Baran's new reaction in this paper allows these groups to
design new syntheses around a novel carbon-carbon bond-forming reaction, in essence mimicing how
nature does this biosynthesis. That's exactly what Baran hopes to do mimicing the cyclase phase
(construction of the carbon skeleton), followed by the oxidase phase (selectively oxidizing various
positions in order to install all the required functionality). His previous papers have been split between
synthetic mimics of these two phases. His previous work on taxanes, the natural product chemotherapy
drugs, have yielded novel chemoselective oxidation reactions that allow a simple carbon scaffold to be
functionalized quickly and selectively. Combined with this new paper, natural product synthesis may be
seeing a revitalization.
Natural product synthesis has always been a split discipline, focusing both on obtaining the goal
compound and various analogs in order to probe biological activity, and also on the development and
application of new reactions to the task at hand. To me at least, the second half is significantly more
interesting and provides more opportunities for interdisciplinary work between these chemists and
others. After all, many of the desired compounds are intensely active in the human body, often as anticancer agents or antibacterials. Using the new reaction schemes of the natural products chemists can
provide an opportunity for drug discovery chemists in pharmaceutical industry to develop new analogs
of these complicated natural products for drug development. That's where I get really interested in this
area when new techniques and methodologies have a potential impact on my future career. My
current research in Graham Jones' laboratory on anti-psychotic compounds hasn't seen the use of
Baran's chemistry yet, but some of his other work on aromatic chlorinating reagents was considered
earlier in the project as an alternative route to the desired anti-psychotic drug. The new chemistry that
natural products chemists like Baran discover will not be immediately applicable to every project, but it
gives more options to consider when planning out the overall synthetic scheme of a project. I was lucky
to be invited to Baran's seminar at MIT during my second co-op while working at Novartis, since his
presentation made me think about how applicable his chemistry might be to my project at the time, and
to other projects I had previously worked on while working at Cubist or in Jones' lab. Professor
Baran's research on this topic and on other similar topics has the ability to change what types of
reactions I will be considering for a project's overall scheme and running in my future career as a drug
discovery chemist (once I graduate with my Masters), which is what makes me so interested in this
topic and in future papers to come from his laboratory.

Acknowledgements:
Prof. Musselman, Dan Chamberlain. For constructive criticism and recommendations regarding my
earlier draft of this paper.

References:
Lo, J.; Yabe, Y.; Baran, P. A Practical and Catalytic Reductive Olefin Coupling. J. Am. Chem. Soc.
2014.