Chamberland, Stephen
Title:
Associate Professor - Organic Chemistry
Office:
PS 229
Phone:
(801) 863-6017
Fax:
(801) 863-8064
Mail Code:
179

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Natural product total synthesis and development of natural-product based medicines

INTRODUCTION

For millennia, humans have been learning about and taking advantage of the earth’s bountiful flora and fauna.  Parts and extracts of plants, animals, and minerals have been used to treat pain and cure diseases, but only within the last two centuries have scientists been able to identify the specific chemical(s) responsible for the observed effect of a natural medicine.  Our research is centered in the preparation and study of these naturally occurring chemical compounds, which are called natural products.  Specifically, we focus on developing convergent, efficient, robust, and, most importantly, repeatable syntheses of biologically active and architecturally intriguing natural products and natural-product based derivatives.

DEPLOYMENT OF A DIRECT, EARLY STAGE GUANIDINYLATION APPROACH FOR ORGANIC SYNTHESIS

Thus far, we have capitalized on an early stage, direct guanidinylation reaction to prepare aminoguanidine-containing natural products, such as clavatadine A and phidianidines A and B.  Though a direct approach is atypical, our success illuminates that early introduction of a protected guanidine functional group can lead to rapid assembly of aminoguanidine-containing natural products.  Further, direct guanidinylation streamlines the preparation of these compounds by obviating the unnecessary amine protecting group steps that are typically employed.  We hope to capitalize on insights gleaned from these successful forays and extend the utility of our approach by preparing newly discovered aminoguanidine-containing natural products.

TOWARD THE DEVELOPMENT OF NATURAL-PRODUCT BASED MEDICINES

Even if the biological target(s) of a natural product is/are known, our ability to prepare quantities of the chemical may foster further work to elucidate the specific mechanism of action that occurs when the compound associates with the target.  As a result, our research in this area is critical to enhance understanding of the key protein-substrate interactions that lead to catalysis.  This knowledge may lead to the potential development a novel, natural-product based synthetic pharmaceutical compound to treat or prevent disease.

Student Development Plan

Research in the Chamberland group will give students a firm foundation in experimental organic chemistry and medicinal chemistry.  For example, through their research, students will gain hands-on experience collecting and interpreting spectroscopic data for product determination, troubleshooting chemical reactions, and will gain proficiency searching databases and the primary literature.  Projects will be chosen based on established expertise and interests, such as the application of our direct guanidinylation reaction, but should also intrigue students and attract external funding.  A primary goal of research published by the Chamberland group is to provide substantial pedagogical opportunities for undergraduate students and for the scientific community.  Furthermore, to allow students the opportunity to obtain results quickly, projects will be chosen such that the synthesis targets are relatively simple and easy to construct using a convergent synthetic approach.  Once medicinally interesting compounds are synthesized, we will work with collaborators or within our lab to determine the activity of these compounds against their biological target(s).

 

PEER-REVIEWED PUBLICATIONS (*indicates undergraduate student coauthor, indicates PI, indicates external collaborator)

Independent Research:

1. Malmberg, C. E.; †Chamberland, S. A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products. J. Vis. Exp., 2016, 115, e53593, DOI:  10.3791/53593

https://www.jove.com/embed/player?id=53593&access=k3mp2ptq&t=1&a=1&i=1&s=1

2.  *Conn, S. J.; *Vreeland, S. M.; *Wexler, A. N.; Pouwer, R. H.; Quinn, R. J.; Chamberland, S. Total Synthesis of Clavatadine A.  J. Nat. Prod. 2015, 78, 120-124.  DOI: 10.1021/np500772u

Clavatadine A

3.  *Buchanan, J. C.; *Petersen, B. P.; Chamberland, S.  Concise Total Synthesis of Phidianidine A and B. Tetrahedron Lett. 2013, 54, 6002-6004.  DOI: 10.1016/j.tetlet.2013.08.063

Phidianidine A and B

Undergraduate, Graduate, and Postdoctoral Research:

4.  Chamberland, S.; Grüschow, S.; Sherman, D. H.; Williams, R. M.  Synthesis of Potential Early-Stage Intermediates in the Biosynthesis of FR900482 and Mitomycin C. Org. Lett. 2009, 11, 791–794. DOI: 10.1021/ol802631c

2009 Abstract

5.  Namiki, H. N.; Chamberland, S.; Gubler, D. A.; Williams, R. M.  Synthetic and Biosynthetic Studies of FR900482 and Mitomycin C:  An Efficient and Stereoselective Hydroxymethylation of an Advanced Benzazocane Intermediate.  Org. Lett. 2007, 9, 5341–5344. DOI:  10.1021/ol701960v

2007 Abstract

6.  Chamberland, S.; §Ziller, J. W.; Woerpel, K. A.  Structural Evidence that Alkoxy Substituents Adopt Electronically Preferred Pseudoaxial Orientations in Six-Membered Ring Dioxocarbenium Ions.  J. Am. Chem. Soc. 2005, 127, 5322–5323.  § indicates X-ray crystallographer. DOI:  10.1021/ja050830i

abstractpicture27.  Chamberland, S.; Woerpel, K. A.  Using Nucleophilic Substitution Reactions to Understand How a Remote Alkyl or Alkoxy Substituent Influences the Conformation of Eight-Membered Ring Oxocarbenium Ions.  Org. Lett2004, 6, 4739–4741. DOI:  10.1021/ol047998d

2004 Abstract

8.  Kelly, T. R.; *Chamberland, S.; Silva, R. A. Total Synthesis of Luotonin A.  Tetrahedron Lett1999, 40, 2723–2724.  DOI:  10.1016/S0040-4039(99)00349-4

1999 TL