Yu Han

This thesis focuses on the development of synthetic strategies toward chiral sulfur(VI)-based sequence-defined oligomers, sequence-controlled polymers, and small molecules. Chapter 1 introduces the key concepts involved in this thesis and reviews recent developments related to these fields. It provides an overview of the general synthetic strategies to access different types of sequence-defined oligomers and introduces the SuFEx and SuPhenEx reactions, which were mainly employed throughout this thesis. The background of the design of chiral sulfur(VI)-based Brønsted acids is also briefly introduced.

Compared with other click reactions, SuFEx and its derived reaction SuPhenEx, possess several advantages, including mild reaction conditions, no requirement for metal catalysts, and broader structural diversity. More importantly, they enable precise control of chirality at the S(VI) reactive sites. In recent years, chiral SuFEx reactions have been widely explored in both small molecules and polymers. However, their application in sequence-defined oligomers and sequence-controlled polymers remains underdeveloped. In Chapter 2, chiral SuFEx chemistry is introduced into the synthesis of sequence-defined oligomers and sequence-controlled polymers. By combining SuFEx and SuPhenEx reactions, the configuration of each sulfur center can be independently controlled along the oligomer chain. With a switchable cap, these oligomers can be further transformed into sequence-controlled polymers via tail-to-head-type SuPhenEx polymerization, enabling the transfer of chirality from the oligomer level to the polymer level. Compared with previously reported polymers introduced in chapter 1, these sequence-controlled polymers achieve a higher level of control in both sequence and chirality.

During practical investigations, it was found that in iterative stepwise growth-based on SuFEx reactions, the “click” characteristics of the reaction are significantly reduced as the length of polymer chain increases. To address this issue, in Chapter 3 an iterative exponential growth strategy based on oxidation/SuPhenEx reactions was developed, enabling a more efficient chain extension. Using this strategy, sequence-defined oligomers up to a 20-mer were obtained while maintaining high reactivity. This approach effectively replaces SuFEx in the chain extension process and avoids problems associated with the hydrolysis of S-F reactive sites and decreased reactivity in long chain extension, which would otherwise lead to reduced yields.

After establishing the construction of S(VI)-O linked sequence-defined oligomers, the focus was shifted toward the synthesis of small molecules utilizing the acidity at the α-position. In Chapter 4, a series of diverse chiral-at-sulfur(VI) Brønsted acids were synthesized, including compounds with a single S(VI) stereocenter, two symmetric chiral S(VI) centers, and a BINOL-derived chiral architecture. In these structures, the NH acidic sites are directly connected to the sulfur(VI) center, which may make these chiral-at-sulfur(VI) Brønsted acids applicable in asymmetric catalysis.

At the end of the thesis, Chapter 5 provides a general discussion of the synthetic strategies developed in this work, along with an analysis of the limitations of current methods and the issues encountered in early solid-phase approaches. Feasible improvement strategies and future perspectives are proposed accordingly.