Radical-relay SmI2 catalysis: Expedient access to new bioisosteres for medicinal chemistry

在过去的十年中，试图“逃离平原”导致药物化学家追求小而紧凑的富含sp3的结构，这些结构保留构象控制，同时提高溶解度和选择性。用饱和生物电子等排体取代苯环已成为获得具有改善的生物活性和物理化学特征的新的无专利分子的重要策略。双环己烷（BCH）是用于药物发现的一类新兴的生物电子等排体，然而，与更好地已知的双环戊烷（BCP）生物电子等排体相比，合成这些双环结构的途径仍然有限。BCH是最早出现的邻位二取代苯的生物电子等排体之一，邻位二取代苯是药物中的常见基序。虽然以模式a连接的取代基的BCH生物电子等排体已被报道，但以模式B连接的取代基的BCH生物电子等排体很少受到关注-我们的初步研究表明该结构代表了邻位二取代苯的更好的生物电子等排体。仍然是最重要的SET试剂之一，正如其商业可用性和广泛使用所证明的那样。尽管有1000多篇出版物描述了它的用途，但众所周知的缺点是SmI 2;该试剂几乎总是以化学计量过量使用。以前对SmI 2催化作用的一些研究总是需要超化学计量的共还原剂，这是不切实际的，然而Procter小组最近描述了SmI 2催化的第一个C-C偶联;这代表了克服与试剂使用相关的主要限制的关键一步。我们现在建议通过探索以下物质的催化偶联来扩展这种自由基中继催化的合成范围：容易获得的双环丁烷（BCB）酮与烯烃配对以产生双环[2.2.1]己烷（BCH）酮;将烯烃（或炔）正式插入C-C键。在未发表的初步结果中，使用低至7.5mol%的SmI 2，BCB酮与丙烯腈、二乙烯基砜和丙烯酸酯进行化学选择性催化偶联，以高分离收率得到BCH。此外，初步实验已经显示产物BCH支架可以如何容易地操纵;可以以接近定量的产率转化为酯和酰胺。我们还将评估BCB羧酸衍生物作为合作伙伴，包括酯和酰胺。一系列新的烯烃和炔烃伙伴也将在催化偶联中进行评估，包括具有a和b-取代的烯烃、炔酸酯和提供有趣的季a-氨基酸的烯烃。在对反应范围进行初步研究之后，我们将利用这些催化自由基偶联，并通过制备饱和形式的沙利度胺类似物，进一步验证BCH作为邻位二取代苯和稠合双环系统的富含sp3的生物电子等排体。由于它们在临床评价的化学降解剂（PROTAC）中作为CRBN连接酶结合剂的用途，它们目前受到特别高的关注。对映选择性催化偶联的BCB酮，能够两点结合到Sm，与丙烯酸甲酯将得到;随后的Baeyer-Villiger氧化，选择性还原的更容易的酯，溴化将提供enantioreficient溴。已知胺与BCH溴酯的烷基化将提供来那度胺类似物。起始BCB酮上的额外取代将递送带有额外出口载体的饱和类似物，用于可能用于药物缀合物的构建。

During the last decade, attempts to 'escape from flatland have led medicinal chemists to pursue small, compact sp3-rich structures that retain conformational control whilst improving solubility and selectivity. The replacement of benzene rings with saturated bioisosteres has become an important strategy to obtain new, patent-free molecules with improved biological activity and physicochemical profiles. Bicyclohexanes (BCHs) are an emerging class of bioisostere for use in drug discovery, however, synthetic access to these bicyclic architectures remains limited when compared to better-known bicyclopentane (BCP) bioisosteres. BCHs are amongst the first emerging bioisosteres for ortho-disubstituted benzenes, a common motif in drugs. While BCH bioisosteres with substituents attached in mode a have been reported, BCH bioisosteres with substituents attached in mode b have received little attention - our preliminary studies suggest the structure represents a better bioisostere for ortho-disubstituted benzenes.Amidst the current renaissance in radical chemistry, single electron transfer (SET) is used to generate radicals and the well-known reagent, samarium(II) diiodide (SmI2), remains one of the most important SET reagents, as evidenced by its commercial availability and widespread use. Despite 1000s of publications describing its use, a well-known disadvantage shadows SmI2; the reagent must almost always be used in stoichiometric excess. The handful of previous studies on catalysis with SmI2 invariably require super stoichiometric amounts of co-reductant and are impractical, however the Procter group have recently described the first C-C couplings catalyzed by SmI2; which represents a key step towards overcoming the major limitation associated with the reagent's use.We now propose to extend the synthetic reach of this radical relay catalysis by exploring the catalytic couplings of readily-accessible bicyclobutane (BCB) ketones with alkene partners to deliver bicyclo[2.2.1]hexane (BCH) ketones; a formal insertion of an alkene (or alkyne) into a C-C bond. In unpublished preliminary results, using as little as 7.5 mol% of SmI2, BCB ketones underwent chemoselective, catalytic coupling with acrylonitrile, divinyl sulfone, and acrylates to give BCHs in high isolated yield.Of note, branching in the alkyl (R1) substituent of the ketone appears to be well-tolerated. Furthermore, preliminary experiments have shown how the product BCH scaffold can be readily maniplulated; can be converted to ester and amide in near quantitative yield. We will also evaluate BCB carboxylic acid derivatives as partners, including esters and amides. A range of new alkene and alkyne partners will also be assessed in the catalytic couplings, including alkenes bearing a and b-substitution, alkynoates, and alkenes that deliver interesting quaternary a-aminoacids. Following an initial investigation of reaction scope, we will utilise these catalytic radical couplings, and further validate BCHs as sp3-rich bioisosteres for ortho-disubstituted benzenes and fused-bicyclic systems, by preparing saturated versions of thalidomide analogues.While IMiDs are blockbuster therapies in their own right, for example lenalidomide, they are currently of especially high interest due to their utility as CRBN ligase binders in clinically-evaluated chemical degraders (PROTACs). Enantioselective catalytic coupling of BCB ketone, capable of two-point binding to Sm, with methyl acrylate will give; subsequent Baeyer-Villiger oxidation, selective reduction of the more accessible ester, and bromination will deliver enantioenriched bromide. Alkylation of known amine with BCH bromo ester will provide Lenalidomide analogue. Additional substitution on the starting BCB ketones will deliver saturated analogues bearing an additional exit vector for possible use in the construction of drug conjugates.