康 · 学术 | Pharmaron Launches the 68th Pharmaron Virtual Lecture

康龙化成举办第六十八期“合成与药物化学前沿”名师线上讲座

2026 年 8 月 27 日，北京 —— 英国巴斯大学的亚历克斯?克雷斯韦尔（Alex Cresswell）教授受邀做客康龙化成第六十八期“合成与药物化学前沿”名师线上讲座主讲，以“重新编程烷基胺反应性”为主题，系统呈现了其团队围绕未保护烷基胺α位C-H官能团化发展的光氧化还原催化平台化学及其在药物合成与规模放大中的应用。报告主要介绍了克雷斯韦尔教授课题组五个方面的研究：1. 叠氮自由基介导的伯胺α位C-H官能团化；2. 连续流成环化学：氮杂环丁烷、螺环与稠环体系；3. 烷基胺α位C-H乙烯基化与同系化反应；4. 二级胺的位点选择性α官能团化；5. AESOP（氨基亚砜）试剂平台实现吡咯烷的模块化合成及机理研究。

克雷斯韦尔教授首先阐述了该领域的核心挑战：伯脂肪胺是商业可得性最高的合成砌块，但其固有反应性集中于C-N键形成和发生在氨基上的化学；在不对胺基进行保护的前提下直接对α位C-H键进行C-C键构建，曾被2019年制药工业联合展望文章列为合成化学的关键未解难题。为解决这一问题，克雷斯韦尔教授团队做了以下研究：

1、叠氮自由基介导的伯胺α位C-H官能团化：克雷斯韦尔教授团队发现光氧化还原催化可由叠氮阴离子原位产生叠氮自由基——是一种高效的氢原子转移试剂，可选择性攫取未保护胺α位C-H的氢原子生成α氨基自由基，进而被苯乙烯、杂芳环、乙烯基硼及活化吲哚等受体捕获，直接构筑C-C键。反应采用廉价有机光催化剂，420 nm蓝光照射，停留时间仅10-20分钟，并全部在商用连续流光反应装置中开发验证，确保了毫克级到公斤级的可放大性。

2、连续流成环化学：氮杂环丁烷、螺环与稠环体系：以丙烯酸酯为受体对α氨基自由基加成再进行α-内酰胺化可构筑δ-内酰胺及δ-内酯，广泛适用于螺环体系构建。采用乙烯基硫鎓盐为受体时，反应中的强亲电性受体与底物胺发生快速的背景副反应N-烷基化，团队借助连续流分泵进料与-20℃低温彻底逆转C-/N-选择性，实现氮杂环丁烷的直接合成；再通过对硝基苯磺酰基活化策略将困难底物收率由约10%提升至近60%。该方法已在康龙化成英国的实验室实现硫鎓盐公斤级制备与氮杂环丁烷 200 克级连续流放大，并通过全部工艺安全测试。

3、烷基胺α位C-H乙烯基化与同系化：对γ-氨基锍中间体以强碱 NaHMDS 处理，消除硫鎓基团直接得到α-乙烯基胺——这是首个在胺α位直接安装简单乙烯基的转化，产物可经 Johnson-Lemieux 氧化等衍生为系列α三级胺；结合重氮转移与Winstein [2,3]-σ迁移重排，还实现了伯胺的碳链同系化，并发展了磺内酰胺、磺酰氟等新化学空间的构建路线。

4、二级胺的位点选择性α官能团化：未保护的二级胺因竞争性N-烷基化长期被认为难以适用，团队借助连续流低温分泵策略以几乎相同的催化剂体系实现突破。该反应选择性官能团化取代较多的一侧，实现α季碳/叔碳胺的高非对映选择性构建；利用该选择性进行双α烷基化，可直接在胺骨架上“缝上”螺环；由环状二级胺可构筑 5,5-稠合双环内酰胺，其团队正将其应用于天然产物苦参碱的全合成。

5、AESOP 试剂平台与机理研究：针对药物设计中重要却合成困难的α芳基吡咯烷类，克雷斯韦尔团队利用自研的α氨基官能团化反应策略制备“氨基亚砜试剂（AESOP）”：该试剂与醛缩合后，经 NaHMDS 介导的环化与亚砜消除一锅串联得到吡咯啉，还原后即得吡咯烷或螺环吡咯烷。底物覆盖各类苯甲醛、吡啶等杂芳醛；评估表明以原文条件将试剂放大至 60 克并高效构建螺环二胺化合物库。通过更换试剂可覆盖三元至六元全部螺环尺寸，并提出 “螺环扫描” 概念。机理方面，与德州农工大学合作利用快速进样核磁阐明了非对映体演化、硫差向异构化及决速步苄位C-H断裂（KIE ≈ 8.6）等关键过程。

克雷斯韦尔教授总结，这套光催化胺重编程技术可通用、选择性高且支持工业化，解决药用胺杂环合成步骤繁琐、选择性差、放大困难的行业痛点。后续团队将重点开发手性试剂、发展定点骨架修饰手段，拓展高难度杂环底物，持续推动药物合成化学发展。

讲座尾声，克雷斯韦尔教授和康龙化成线上参会人员围绕反应机理、底物开发、工艺放大、工业落地等内容开展充分问答交流。

Frontiers in Synthetic and Medicinal Chemistry

--The 68th Pharmaron Virtual Lecture

Beijing, China, Aug. 27, 2026 - Professor Alex Cresswell from the University of Bath, UK, delivered a lecture at the 68th session of Pharmaron’s Frontiers in Synthetic and Medicinal Chemistry virtual lecture series, titled "Reprogramming Alkyl Amine Reactivity". He presented his team's photoredox-catalysed platform for α-C–H functionalization of unprotected alkyl amines and its applications in pharmaceutical synthesis and scale-up. The lecture covered five directions: 1. azidyl-radical-mediated α-C–H functionalization of primary amines; 2. flow-enabled annulation chemistry (azetidines, spirocycles and fused bicycles); 3. α-C–H vinylation and homologation; 4. site-selective α-functionalization of secondary amines; 5. AESOP (amino sulfoxide protocol) reagents for modular pyrrolidine synthesis and mechanistic studies.

Professor Cresswell first outlined the central challenge: primary aliphatic amines are among the most abundant commercial building blocks, yet their innate reactivity centers on C–N bond formation and chemistry on the amino group, and direct C–C bond construction at α-C–H bonds of unprotected amines was flagged by a 2019 pharmaceutical-industry perspective as a key unsolved problem in synthetic chemistry. His team's research includes:

1. Azidyl radical HAT chemistry. Photoredox catalysis generates an azidyl radical in situ from azide anion a highly efficient hydrogen atom transfer agent that selectively abstracts from C–H bond α to unprotected amine; the resulting α-amino radical is trapped by styrene, heteroarene, vinyl boron reagent and activated indole to forge C–C bond. Using cheap organic photocatalysts under 420 nm irradiation with 10–20 min residence times, all reactions are developed in commercial continuous-flow photoreactors, guaranteeing scalability from milligrams to kilograms.

2. Flow-enabled annulations. Acrylate addition followed by lactamization delivers δ-lactams and δ-lactones and broadly enables spirocycle construction. With vinyl sulfonium salt traps — which undergo rapid background N-alkylation in batch — separate pumping in flow at ?20 °C inverts the C/N selectivity, achieving direct azetidine synthesis; nosyl activation lifts yields of difficult substrates from ~10% to nearly 60%. Pharmaron UK scaled the sulfonium salt to over 1 kg and the azetidine to 200 g in flow, passing all safety tests.

3. α-Vinylation and homologation. NaHMDS treatment of γ-amino sulfonium intermediates eliminates the sulfonium group to give α-vinylated amines — reportedly the first direct installation of a simple vinyl group at a C–H bond adjacent to an amine, which elaborate to α-tertiary amines; diazo transfer and Winstein [2,3]-sigmatropic rearrangement enable amine homologation, with route to sultam and sulfonyl fluoride expanding accessible chemical space.

4. Site-selective secondary amine chemistry. Low-temperature (?25 °C) flow operation overcame competitive N-alkylation. Unlike literature precedent, the reaction selectively functionalizes the more substituted side (ca. 7:3), enabling highly diastereoselective α-quaternary/tertiary amines; double α-alkylation "stitches" spirocycles onto amine scaffolds, and cyclic secondary amines furnish 5,5-fused bicyclic lactams, now applied to a total synthesis of matrine. 

5. AESOP reagents and mechanism. For α-aryl pyrrolidines — prevalent in drug design yet difficult to access — the group's "amino sulfoxide protocol (AESOP)" reagents, prepared via their own photochemistry, condense with aldehydes and undergo NaHMDS-mediated cyclization and sulfoxide elimination in one pot to deliver pyrrolines, reducible to pyrrolidines and spiro-pyrrolidines. The scope covers benzaldehydes of all classes and heteroaryl aldehydes. All spiro-ring sizes from three- to six-membered are accessible, underpinning the "spiro-scanning" concept. Rapid-injection NMR studies with Texas A&M elucidated diastereomer evolution, sulfur epimerization and rate-determining benzylic C–H cleavage (KIE ≈ 8.6).

Professor Cresswell concluded that this photoredox amine?reprogramming platform offers universal, selective and industrially viable C?H functionalization, solving major pain points of tedious workflows, poor selectivity and difficult scale?up for medicinal heterocycle synthesis. Future efforts will focus on chiral?reagent development, site?specific skeleton modification and difficult?substrate expansion to advance synthetic medicinal chemistry.

After the lecture, Professor Cresswell engaged in a lively discussion with Pharmaron’s audience on mechanism, substrate scope and industrial translation during the Q&A session.