Total Synthesis of Peramine, a Defensive Alkaloid Produced by Endophytic Fungi of Cool Season

52 Pages·2017·1.98 MB·English

by  Matthew Rolfe Nelli

College of William and Mary
W&M ScholarWorks
Undergraduate Honors Theses Theses, Dissertations, & Master Projects
5-2016
Total Synthesis of Peramine, a Defensive Alkaloid
Produced by Endophytic Fungi of Cool Season
Grasses Possessing Anti-Insect Properties
Matthew Rolfe Nelli
College of William and Mary
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Recommended Citation
Nelli, Matthew Rolfe, "Total Synthesis of Peramine, a Defensive Alkaloid Produced by Endophytic Fungi of Cool Season Grasses
Possessing Anti-Insect Properties" (2016).Undergraduate Honors Theses.Paper 955.
https://scholarworks.wm.edu/honorstheses/955
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Abstract

The total synthesis of peramine, a pyrrolopyrazine natural product containing a
guanidine functionality, is described. Peramine is an anti-insect defensive alkaloid
produced by fungi endophytic to cool season grasses. Peramine is one of four classes of
alkaloid produced by these endophytic fungi and production of this compound is
widespread across fungal-grass mutualisms. Unique to our synthesis of peramine is an
enolate alkylation of a pyrrole-fuse diketopiperazine and an amenable route to derivatives
of peramine. Our synthesis is comprised of seven steps and three chromatographic
separations, making it as efficient as the previous two syntheses and better with respect to
total yield.
Table of Contents

Acknowledgements ......................................................................................................... ii

Dedication ........................................................................................................................... iii

List of Tables ...................................................................................................................... iv

List of Figures ..................................................................................................................... v

List of Schemes ................................................................................................................. vi

Chapter 1. The Biological Background of Peramine ........................................... 1

Chapter 2. Synthesis of Peramine ........................................................................... 14

Appendix ........................................................................................................................... 33

i
Acknowledgements

First I would like to thank Professor Jonathan Scheerer, for giving me the
opportunity to work in his lab three years ago and mentoring me every step of the
way. Even though this project has had its moments where I thought it would never
be completed, I am grateful that he was always available to help and guide me.
Additionally, I give my thanks to Professor Robert Hinkle, Professor Lisa Landino,
and Professor Joshua Puzey for being a part of my honors committee. I would also
like to thank the rest of the William and Mary chemistry faculty for creating a stellar
educational environment and making my time here truly remarkable.
I would also like to thank my fellow honors students, Jacob Robins and Jill
Williamson, for sharing this journey with me in completing our theses. I know I
would not have been able to finish this without each of them. I would like to thank
the rest of my lab mates in the Scheerer group as well, for helping me towards me
successes and assisting me during my many failures. Thanks to Kyujin Kim and Nick
Angello who worked over the summer with me and helped give the lab spirit. Thank
you Margaret Olesen for being a good friend, I wish you the best of luck in your
future endeavors and thank you Jonathan Perkins for making Adv. Inorganic
Chemistry so much more enjoyable. Also, thanks to Jenna Landen, Ryan Perry,
Elizabeth Kelley, and Skylar Norman. I hope you all enjoy the rest of your time at
William and Mary and I wish you the best of success.

ii
To my parents, Lisa and Chris Nelli, for always believing in my abilities and pushing
me to continually strive for more. Without their love and support I would have
never accomplished this undertaking.

iii
List of Tables

2.1: Comparison between our synthesis and the previous syntheses of peramine .. 23

iv
List of Figures

1.1: Neotyphodium hyphae growing in between the cells of a rye grass host................. 1

1.2: Asexual and sexual life cycle of the epichloae fungi ......................................................... 2

1.3: The four classes of fungal alkaloids ........................................................................................ 3

1.4: Example of an insect choice feeding assay ........................................................................... 5

1.5:Localization of peramine in the host plant ........................................................................... 7

1.6: Peramine cascades up the food chain to higher trophic levels. ................................... 8

2.1: The neonicotinoids ..................................................................................................................... 24

v
List of Schemes

1.1: Proposed biosynthetic pathway of peramine .................................................................. 10

2.1 s of the pyrrolopyrazine core ................................................................ 16

2.2:: DInugm-Maas’n ssyknet Mheosdiification of the Gabriel Synthesis ........................................................ 16

2.3 and the diacetate derivative ........ 17

2.4: Completion of Dumas’ synthessis o off t pheer paymrrinoelopyrazine core ................................... 18

2.5:: BCorimmpblleet iaonnd o Rf oBwriamnb’sl es yanntdh esi ..................................... 19

2.6: Our retrosynthetic strategy R...o..w....a..n...’.s.. .s..y...n..t..h...e..s..i.s.. .o...f. .p...e..r..a...m....i.n...e....................................... 20

2.7: Synthesis of the pyrrole-fused diketopiperazine ........................................................... 20

2.8: Alkylation of acyl pyrrole with allyl bromide .................................................................. 21

2.9: Completion of our synthesis of peramine ......................................................................... 22

2.10: Synthesis of N-nitro peramine ............................................................................................ 24

vi
Chapter One

Grass-Endophyte Mutualisms

Several cool season grasses of the family Poaceae (e.g. perennial rye grasses or tall
fescue) contain fungal endophytes of the family Clavicipitaceae (Ascomycota). A group of
these fungal endophytes, called epichloae, form mutualistic symbioses with members of the
grass subfamily Poöideae and are comprised of the sexual genus Epichloë and the asexual
genus Neotyphodium. These symbioses are highly specific; one specie of epichloae is
typically only compatible with one genus of host plant as a result co-phylogenetic evolution
(Epichloë) or a complex process of interspecific hybridizations involving the combinations
of two or sometimes three ancestors (Neotyphodium).1 Both of these genera live all of their
lifecycle intercellularly in the host plant (Figure 1.1) and asymptomatically infect all
aboveground tissues excluding the roots. Transmission to the next generation is typically
done by vertical transmission, whereby the fungus colonizes the host seed. This
colonization, just like the infection of the mature host plant, is asymptomatic and causes
little to no damage to the host seed and future mature plant. The Epichloë, unlike the
Neotyphodium, can also propagate to a new host via horizontal transmission, where the
fungus suppresses host plant growth and produces spore-bearing stromata in order to
spread to neighboring plants via wind dispersal. However, very few species of Epichloë
exhibit this behavior as most spread via vertical transmission (Figure 1.2).1,2,3

Figure 1.1: Neotyphodium hyphae growing in between the cells of a rye grass host.

1