Towards the automation of small molecule synthesis: The development of an impact-prioritized list couplings and blocks for building block assembly of most linear natural products

General synthetic methods that broadly enable the preparation of functionally important organic small molecules can be exceptionally impactful. Identification of such methods has traditionally been done on an ad hoc basis and largely driven by the goal of enabling a customized approach to each target structure. Here we report an en masse analysis of most linear natural products which has revealed an impact-prioritized list building blocks that would provide a Lego kit for the iterative synthesis-based access to greater than 75% of the chemical space occupied by these 100k linear natural products. We also identified an impact prioritized list of the heavy hitting coupling reactions needed to access this chemical space and completed an in-depth analysis of the top 20 reactions. This investigation of the corresponding local chemical environments for each coupling revealed a specific impact-prioritized substrate scope and functional group compatibility required to access this class of compounds. Because this analysis was not restricted to known chemistry, many of the identified couplings represent an actionable list of methodological problems that currently lack such a generalized solution compatible with iterative synthesis. To show the utility of this method, we selected one of the identified top coupling problems that lacked a general solution, the stereoretentive cross-coupling of primary Csp3 boronic acids to vinyl halides, and rationally developed a new phosphine ligand that enables high yield and diastereospecificity for much of computationally pre-determined substrate scope. This coupling methodology can then be integrated into the synthesis of natural products. As more coupling reactions are solved, the amount of natural product functional space that can be accessed is increased allowing for the understanding and optimization of function. The completion of this platform and all of the corresponding coupling represents and exciting and achievable roadmap towards the broad access to linear natural products and their functions using an automated synthesis platform. We hope to bringing the power of synthesis to non-specialists to drive the understanding and optimization of molecular function.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2020

Author dc:creator

• Palazzolo Ray, Andrea Marie Elizabeth

Contributors dc:contributor

• Burke, Martin D
• Hergenrother, Paul J
• Peng, Jian
• Sarlah, David

• Natural Products
• synthesis
• building blocks
• retrosynthsis
• substrate scope
• chemical space coverage
• stereochemically defined
• automated synthesis

Statement dc:rights

• Copyright 2019 Andrea Palazzolo Ray

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/106413

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/106413