Organic molecules containing chiral ?-substituted amines and ethers can be applied to the synthesis of countless medicinally relevant molecules. These valuable compounds have been prepared by routes wherein the carbon-based stereogenic center is introduced using ?indirect? diastereo- or enantioselective methods that require the preparation of intermediates that contain ?-substituted leaving groups (e.g., ZnI, halides, triflate, trichloroacetimidates, phosphates); such approaches lead to lengthy and somewhat inefficient pathways that increase the time required to secure the desired molecules, substantially increasing the cost of preparing compounds that are important to human healthcare. There are also the issues of selectivity and substrate scope: not only must high enantioselectivity and diastereoselectivity be achieved through the use of readily accessible and cost-effective catalysts, expansion in the scope of compatible substrate is imperative. Particularly challenging are schemes that lead to chiral ?-substituted amines and ethers through enantio-, diastereo- and regioselective activation of otherwise unreactive ?- amino or ?-ethereal C?H bonds. We will develop catalytic processes that combine an assortment of nucleophiles (enolates, Breslow intermediates, enamines, (hetero)arenes, and allyl silanes, amines and alcohols), and amines or ethers to generate - in a single operation - a diastereomically pure and highly enantiomerically enriched product. The resulting compounds will contain one or two stereogenic centers. Some will carry ?- or ?-amino carbonyl units as well as ?-(hetero)aryl, ?-allyl amino units that are indispensable building blocks in biologically active molecules. Others will carry ?-acyl, ?-carbonyl, ?-(hetero)aryl, ?-amino, ?-alkoxy ether moieties. Various chiral ?-substituted amine and ether compounds will thus become readily accessible; preparation of these entities would otherwise require several operations that can at times proceed with moderate selectivity. Chiral organoborane catalysts and Lewis acid co-catalysts will be used to promote the proposed transformations. We will utilize the above strategies to design pathways that are significantly more efficient than those previously disclosed. We will develop catalytic processes that can be applied for the late stage functionalization of biologically important amine and ether molecules. Among the medicinally relevant molecules that will be subjected to the late stage functionalization are Cymbalta, Sensipar, Methylphenidate, Metoprolol, Vyvanse and OxyContin, as well as various deoxy sugar molecules.

Public Health Relevance

Development of methods to prepare various medicinally active agents in a cost-effective, efficient, reliable and selective manner is vital to advances in human health care. The proposed research will produce unique, inexpensive and highly potent catalysts that promote efficient formation of some of the most ubiquitous units found in a large number of biologically significant molecules, but which cannot be accessed easily by other methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM128695-01
Application #
9574521
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Lees, Robert G
Project Start
2018-07-15
Project End
2023-06-30
Budget Start
2018-07-15
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code