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

在过去的十年里，为了“逃离平原”，药物化学家们开始追求小而紧凑的富含sp3的结构，这些结构既能保持构象控制，又能提高溶解度和选择性。用饱和生物同位异构体取代苯环已成为获得具有更高生物活性和物理化学特征的新型无专利分子的重要策略。双环己烷（BCHs）是一类用于药物发现的新兴生物异构体，然而，与更知名的双环戊烷（BCP）生物异构体相比，这些双环结构的合成途径仍然有限。邻位二取代苯是药物中常见的基序，邻位二取代苯是首批出现的生物异构体之一。虽然已经报道了以a模式连接取代基的BCH生物异构体，但以b模式连接取代基的BCH生物异构体很少受到关注-我们的初步研究表明该结构代表了邻二取代苯的更好的生物异构体。在当前自由基化学的复兴中，单电子转移（SET）被用于生成自由基，众所周知的试剂，钐（II）二碘化（SmI2），仍然是最重要的SET试剂之一，其商业可用性和广泛使用证明了这一点。尽管有成千上万的出版物描述了它的使用，但一个众所周知的缺点掩盖了SmI2；该试剂几乎总是在化学计量过量的情况下使用。以前的一些关于SmI2催化的研究总是需要超化学计量量的共还原剂，并且是不切实际的，然而宝洁集团最近描述了由SmI2催化的第一个C-C偶联；这是克服与该试剂使用相关的主要限制的关键一步。现在，我们建议通过探索易获得的双环丁烷（BCB）酮与烯烃伴侣的催化偶联以产生双环[2.2.1]己烷（BCH）酮来扩展这种自由基接力催化的合成范围；烯烃（或炔）在碳-碳键上的正式插入。在未发表的初步结果中，仅使用7.5 mol%的SmI2， BCB酮就与丙烯腈、二乙烯基砜和丙烯酸酯进行了化学选择性催化偶联，得到了高分离收率的BCHs。值得注意的是，酮的烷基（R1）取代基上的支化似乎是耐受良好的。此外，初步实验表明，BCH支架产品可以很容易地操纵；能以接近定量的产量转化为酯和酰胺。我们还将评估BCB羧酸衍生物作为合作伙伴，包括酯类和酰胺类。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，烷基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调查后，我们将利用这些催化自由基偶联，并通过制备饱和版本的沙利度胺类似物，进一步验证BCHs是邻二取代苯和融合双环体系的富含sp3的生物同位体。虽然IMiDs本身就是重磅疗法，例如来那度胺，但由于它们在临床评估的化学降解剂（PROTACs）中作为CRBN连接酶结合剂的效用，它们目前受到特别高的关注。能与Sm两点结合的BCB酮与丙烯酸甲酯对映选择性催化偶联；随后的Baeyer-Villiger氧化，更容易接近的酯的选择性还原和溴化将产生富集对映体的溴。已知胺与BCH溴酯的烷基化反应可得到来那度胺类似物。在起始BCB酮上的额外取代将提供饱和类似物，具有额外的出口载体，可用于构建药物偶联物。

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.