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Synthesis and antimicrobial properties of cyclic fluorodiamines containing boronate esters
Heteroatom Chemistry ( IF 1.1 ) Pub Date : 2017-11-01 , DOI: 10.1002/hc.21405
Diya Zhu 1 , Carmanah D. Hunter 1 , Samuel R. Baird 1 , Bradley R. Davis 2 , Allyson Bos 2 , Stephen J. Geier 1 , Christopher M. Vogels 1 , Andreas Decken 3 , Christopher A. Gray 2, 3 , Stephen A. Westcott 1
Affiliation  

Eight new aminoboron compounds derived from primary diamines and the pinacol-protected product of 3-fluoro-2-formylphenylboronic acid have been prepared and characterized fully. Reactions proceed to give the corresponding cyclic products arising via initial aldimine formation followed by a secondary hydroamination step. One compound contains a pendant amine group which was used to make a novel boron-containing Schiff-base ligand along with the To be submitted to Heteroatom Chemistry 2 corresponding zinc(II) metal complex. All compounds were tested for their initial antimicrobial activities against a number of fungi and bacteria. 1 │ INTRODUCTION Interest in small molecule boron pharmaceutical chemistry has grown tremendously in recent years as researchers continue to discover new and remarkable applications for these interesting molecules. A number of excellent reviews have recently been published describing the history and current directions of bioactive boron chemistry.[1-7] α-Aminoboronic acids have been well-recognized as being a unique class of potent enzyme inhibitors for several decades. Only recently, however, has the boropeptide Velcade® (Fig. 1a) been approved by the FDA as the first ever boron-containing pharmaceutical molecule. Indeed, Velcade, or bortezomib, is used for the treatment of multiple myeloma (a cancer of the plasma cells) and mantle cell lymphoma (a cancer of the lymph nodes). Since this remarkable step forward in boron pharmaceutical chemistry, Tavaborole or Kerydin,® (Fig. 1b) a simple fluorine-containing boron compound, has been marketed as a topical antifungal medication for the treatment of onychomycosis, a fungal infection of the nail and nail bed.[8] FIGURE 1 Small molecule boron compounds (a) Velcade and (b) Tavaborole To be submitted to Heteroatom Chemistry 3 The bioactivity associated with small molecule boron compounds is believed to arise from the electrophilic nature of the three-coordinate boron atom, which contains an essentially empty formally p-derived orbital. The boron atom can readily form dative Lewis acid-base bonds with nucleophiles (i.e. the hydroxyl group in serine, etc) and transform from a neutral trigonal three-coordinate species into a four-coordinate tetrahedral adduct. Unlike covalent bonds generated when using organic ‘suicide inhibitors’, this dative bonding interaction can be reversible but also provide great stability, differentiating small molecule boron compounds from traditional pharmaceuticals. We have previously disclosed that addition of certain diamines to 2-formylphenylboronic acid, and the corresponding pinacol boronate ester, afforded a family of novel cyclic boron compounds that showed significant antimicrobial activities.[9] Inspired by the recent success of Tavaborole, where the fluorine substituent was essential for the compound’s efficacy, we have expanded on our initial findings and report herein on a series of cyclic diamines derived from pinacol-protected 3-fluoro-2formylphenylboronic acid. 2 │ RESULTS AND DISCUSSION The incorporation of fluorine into small molecules is a well-known strategy for increasing the bioactivity and efficacy of small molecule pharmaceuticals.[10-12] As such, we have extended our initial work in this area by examining the chemistry and bioactivities of diamines derived from commercially-available 3To be submitted to Heteroatom Chemistry 4 fluoro-2-formylphenylboronic acid (FBA). Protection of the boronic acid group via dehydration with pinacol afforded the corresponding boronate ester 1 in high yields (>90%). Unlike the boronic acid precursor, which is prone to further dehydration to afford the insoluble anhydride trimeric boroxine,[13] compound 1 is remarkably soluble in common organic solvents such as THF and diethyl ether. Reaction of 1 with one equivalent of ethylenediamine in diethyl ether at room temperature resulted in the heterocyclic diamine 2, which was isolated in 97% yield as a white precipitate (Scheme 1). Interestingly, the 11B NMR data for 2 shows a sharp singlet at 10.3 ppm, which is consistent with the boron atom being four-coordinate in solution.[9] By comparison, the three coordinate boron atom in the starting aldehyde 1 appears as a broad peak at 30 ppm. Two disparate sets of resonances are also observed in the 1H NMR data for 2 at 2.98 and 2.76 ppm for the ethylene hydrogens in the backbone of the five-membered diamine ring. A singlet at 5.28 ppm is observed for the methine hydrogen on the carbon bound to the arene ring and the two amine groups. As expected, no significant change is observed in the 19F NMR data for the fluorine atom upon complexation[14] and elemental analysis data is consistent with the proposed structure. Compound 2 presumably arises via initial aldimine formation followed by an intramolecular hydroamination of the activated aldimine C=N double bond using the pendant amine group.[9] The Lewis acid-mediated and metal-catalyzed intramolecular hydroamination of imines to give 5and 6membered heterocycles is an area of considerable recent interest.[15-19] To be submitted to Heteroatom Chemistry 5 SCHEME 1 Synthetic pathways to diamines 2-7 Similar reactivity was observed for reactions of 1 with 1,3-diaminopropane which afforded 3 in moderate isolated yields. However, attempts to add 1,4diaminobutane to 1 lead to the formation of the corresponding polycyclic compound, which contains a seven-membered diamine ring, along with a number of unidentified products and isolation was therefore not attempted. Reactions of 1,2-diamino-2-methylpropane were of singular interest as they gave selective formation of compound 4 in high yields as deduced by multinuclear NMR spectroscopy. Two possible regioisomeric mixtures could be envisioned from this reaction if there was little differentiation of the primary amine group that initially attacks the aldehyde electrophilic carbon atom and forms the To be submitted to Heteroatom Chemistry 6 intermediate aldimine. However, only one set of resonances was observed in the 1H and 13C NMR data suggesting one major racemic (chiral at the ipso carbon and the coordinated nitrogen atom) regioisomer mixture where the two methyl groups in the backbone play a significant role in the regiochemistry of the reaction. To confirm the structure of 4, we carried out an X-ray diffraction study and the molecular structure of which is shown in Fig. 2a and crystallographic data provided in Table 1. As expected the amine group bonded to the boron atom is the sterically-least congested one where the dimethyl groups avoid the steric bulk of the large pinacolato fragment. Bond distances and angles are similar to those reported previously for related systems.[9] (a) (b) FIGURE 2 The molecular structures of (a) rac-4 and (b) rac-5 with probability ellipsoids drawn at the 50% confidence level and hydrogen atoms and molecules of solvent for rac-5 omitted for clarity. Selected bond distances (Å) and angles (o) for rac-4: B(1)-O(1) 1.427(3), B(1)-O(2) 1.469(3), B(1)-C(13) 1.626(3), B(1)-N(1) 1.710(3); O(1)-B(1)-O(2) 107.23(15), O(1)-B(1)-C(13) 116.57(18), O(2)-B(1)-C(13) 116.16(17), O(1)-B(1)-N(1) 112.22(17), O(2)-B(1)-N(1) 106.14(15). Selected bond distances (Å) and angles (o) for one molecule of rac-5 in the asymmetric unit: B(1)-O(1) 1.437(3), B(1)-O(2) 1.460(3), B(1)-C(7) 1.603(4), B(1)-N(1) 1.707(3); O(1)-B(1)-O(2) 106.6(2), O(1)-B(1)-C(7) 116.8(2), O(2)-B(1)-C(7) 117.24(17), O(1)-B(1)-N(1) 112.97(16), O(2)-B(1)-N(1) 105.03(19). To be submitted to Heteroatom Chemistry 7 To examine the possibility of using N-substituted diamines we then investigated the reaction of N-phenylethylenediamine with 1 and found the reaction proceeded selectively at room temperature to give one regioisomeric mixture, 5, where the least sterically-hindered amine group is bound to the boron atom. Once again, spectroscopic data are consistent with this formula and an X-ray diffraction study confirmed the formation of this racemic isomer (Fig. 2b). Bond distances and angles are also consistent with those found in compound 4. Addition of a diethyl ether solution of 2-aminobenzylamine to 1 gave the corresponding cyclic product 6, where the least sterically-hindered amine group is presumably bound to the boron atom. To confirm the regioselectivity in this reaction, we carried out a single crystal X-ray diffraction study on this compound, the molecular structure of which is shown in Fig. 3. FIGURE 3 The molecular structure of rac-6 with ellipsoids drawn at the 50% probability level and hydrogen atoms and solvent molecules omitted for clarity. Selected bond distances (Å) and angles (o): B(1)-O(2) 1.435(3), B(1)-O(1) 1.438(3), B(1)-C(7) 1.620(3), B(1)-N(2) 1.706(3); O(2)-B(1)O(1) 108.19(16), O(2)-B(1)-C(7) 116.03(17), O(1)-B(1)-C(7) 117.14(17), O(2)-B(1)-N(2) 111.80(16), O(1)-B(1)-N(2) 108.13(15). To be submitted to Heteroatom Chemistry 8 We then turned our attention to reactions of 1 with diethylenetriamine to give the cyclic product 7, with contains a pendant primary amine linkage that allows for the potential functionalization into a wide array of possible groups. To demonstrate this point, reaction of 7 with salicylaldehyde in CH2Cl2 at reflux afforded the novel Schiff-base derivative 8, albeit in somewhat low isolated yields (20%). To investigate the potential use of this compound as a ligand for transition metals, we decided to examine its reactivity with diethylzinc as Zn(II) Schiff-base complexes are well-known to display potent antimicrobial activities.[20-25] We were delighted to find that addition of 8 at low temperatures to solutions of ZnEt2 afforded the corresponding Schiff-base complex 9 in moderate yields (Scheme 2). The observation that a peak is observed unchanged in the 11B NMR spectra at 10.4 ppm confirms that the boron group remains intact during this reaction. Spectroscopic data and elemental analysis are consistent with the proposed structure but, unfortunately, all attempts to grow

中文翻译:

含硼酸酯的环状氟二胺的合成及抗菌性能

8种伯二胺衍生的新型氨基硼化合物和频哪醇保护的3-氟-2-甲酰基苯基硼酸产物已得到充分制备和表征。反应进行得到相应的环状产物,通过最初的醛亚胺形成,然后是二次加氢胺化步骤。一种化合物含有侧链胺基团,该基团用于制备新型含硼席夫碱配体以及提交给杂原子化学 2 的相应锌 (II) 金属络合物。测试了所有化合物对多种真菌和细菌的初始抗菌活性。1 │ 简介 近年来,随着研究人员不断发现这些有趣分子的新的显着应用,人们对小分子硼药物化学的兴趣急剧增长。最近发表了许多优秀的评论,描述了生物活性硼化学的历史和当前方向。[1-7] 几十年来,α-氨基硼酸被公认为是一类独特的强效酶抑制剂。然而,直到最近,硼肽 Velcade®(图 1a)才被 FDA 批准为第一个含硼药物分子。事实上,万珂或硼替佐米用于治疗多发性骨髓瘤(浆细胞癌)和套细胞淋巴瘤(淋巴结癌)。自从硼药物化学取得这一显着进步以来,Tavaborole 或 Kerydin®(图 1b)是一种简单的含氟硼化合物,已作为局部抗真菌药物上市销售,用于治疗甲真菌病,一种指甲和指甲的真菌感染床。[8] 图 1 小分子硼化合物 (a) Velcade 和 (b) Tavaborole 将提交给杂原子化学 3 与小分子硼化合物相关的生物活性被认为是由三配位硼原子的亲电性质产生的,它包含一个基本上空的形式 p 导出轨道。硼原子可以很容易地与亲核试剂(即丝氨酸中的羟基等)形成配位路易斯酸碱键,并从中性的三配位三配位物质转变为四配位四面体加合物。与使用有机“自杀抑制剂”时产生的共价键不同,这种配价键相互作用是可逆的,但也提供了极大的稳定性,将小分子硼化合物与传统药物区分开来。我们之前已经披露,将某些二胺添加到 2-甲酰基苯基硼酸和相应的频哪醇硼酸酯中,提供了一系列具有显着抗菌活性的新型环状硼化合物。 [9] 受 Tavaborole 最近成功的启发,其中氟取代基对化合物的功效至关重要,我们扩展了我们的初步发现,并在此报告了一系列衍生自频哪醇保护的 3-氟-2甲酰基苯基硼酸的环状二胺。2 │ 结果与讨论 将氟掺入小分子是提高小分子药物生物活性和功效的众所周知的策略。[10-12] 因此,我们通过检查衍生自市售 3 的二胺的化学和生物活性来扩展我们在该领域的初步工作,以提交给杂原子化学 4 氟-2-甲酰基苯基硼酸 (FBA)。通过用频哪醇脱水保护硼酸基团以高产率(>90%)提供相应的硼酸酯1。与硼酸前体容易进一步脱水以提供不溶性酸酐三聚环硼氧烷不同,[13] 化合物 1 显着溶于常见有机溶剂,如四氢呋喃和乙醚。1 与一当量乙二胺在乙醚中在室温下反应生成杂环二胺 2,以 97% 的产率将其分离为白色沉淀(方案 1)。有趣的是,2 的 11B NMR 数据显示在 10.3 ppm 处有一个尖锐的单峰,这与硼原子在溶液中为四配位一致。 [9] 相比之下,起始醛 1 中的三配位硼原子在 30 ppm 处表现为一个宽峰。在 2 的 1H NMR 数据中也观察到两组不同的共振,在 2.98 和 2.76 ppm 处,对于五元二胺环主链中的亚乙基氢。对于与芳烃环和两个胺基团结合的碳上的次甲基氢,观察到 5.28 ppm 处的单峰。正如预期的那样,络合后氟原子的 19F NMR 数据没有观察到显着变化[14],元素分析数据与所提出的结构一致。化合物 2 大概是通过初始醛亚胺形成然后使用侧胺基团对活化的醛亚胺 C=N 双键进行分子内加氢胺化而产生的。[9] 路易斯酸介导和金属催化的亚胺分子内加氢胺化得到 5 和 6 元杂环是最近引起相当大兴趣的领域。 [15-19] 提交给杂原子化学 5 方案 1 二胺的合成途径 2-7对于 1 与 1,3-二氨基丙烷的反应,观察到类似的反应性,以中等分离产率得到 3。然而,尝试将 1,4-二氨基丁烷添加到 1 导致形成相应的多环化合物,其中包含一个七元二胺环,以及许多未知的产物,因此没有尝试分离。1,2-二氨基-2-甲基丙烷的反应具有独特的意义,因为它们以高产率选择性形成化合物 4,如多核 NMR 光谱推断。如果最初攻击醛亲电碳原子并形成待提交给杂原子化学 6 中间体醛亚胺的伯胺基团几乎没有差异,则可以从该反应中设想两种可能的区域异构混合物。然而,在 1H 和 13C NMR 数据中仅观察到一组共振,表明存在一种主要的外消旋(在同碳和配位的氮原子处手性)区域异构体混合物,其中骨架中的两个甲基在区域化学中起重要作用。反应。为了确认 4 的结构,我们进行了 X 射线衍射研究,其分子结构如图 2a 所示,晶体学数据见表 1。正如预期的那样,与硼原子键合的胺基是空间上最不拥挤的,其中二甲基避免了大频那可乐片段的空间体积。键距离和角度与之前报道的相关系统相似。 [9] (a) (b) 图 2 (a) rac-4 和 (b) rac-5 的分子结构,在 50% 置信水平绘制概率椭球,为清楚起见省略了 rac-5 的氢原子和溶剂分子。rac-4 的选定键距 (Å) 和角度 (o):B(1)-O(1) 1.427(3), B(1)-O(2) 1.469(3), B(1)-C (13) 1.626(3), B(1)-N(1) 1.710(3);O(1)-B(1)-O(2) 107.23(15),O(1)-B(1)-C(13) 116.57(18),O(2)-B(1)-C( 13) 116.16(17), O(1)-B(1)-N(1) 112.22(17), O(2)-B(1)-N(1) 106.14(15)。不对称单元中一个 rac-5 分子的选定键距 (Å) 和角度 (o):B(1)-O(1) 1.437(3),B(1)-O(2) 1.460(3)、B(1)-C(7) 1.603(4)、B(1)-N(1) 1.707(3);O(1)-B(1)-O(2) 106.6(2),O(1)-B(1)-C(7) 116.8(2),O(2)-B(1)-C( 7) 117.24(17),O(1)-B(1)-N(1) 112.97(16),O(2)-B(1)-N(1) 105.03(19)。提交给杂原子化学 7 为了检查使用 N-取代二胺的可能性,我们然后研究了 N-苯基乙二胺与 1 的反应,发现该反应在室温下选择性地进行,得到一种区域异构混合物 5,其中空间最小-受阻胺基团与硼原子结合。再一次,光谱数据与该公式一致,X 射线衍射研究证实了这种外消旋异构体的形成(图 2b)。键距和角度也与化合物 4 中发现的一致。将 2-氨基苄胺的乙醚溶液加成到 1 中得到相应的环状产物 6,其中空间位阻最小的胺基团可能与硼原子结合。为了证实该反应的区域选择性,我们对该化合物进行了单晶 X 射线衍射研究,其分子结构如图 3 所示。 图 3 rac-6 的分子结构在 50为清楚起见,省略了百分比概率水平和氢原子和溶剂分子。选定的键距 (Å) 和角度 (o):B(1)-O(2) 1.435(3), B(1)-O(1) 1.438(3), B(1)-C(7) 1.620 (3)、B(1)-N(2) 1.706(3);O(2)-B(1)O(1) 108.19(16), O(2)-B(1)-C(7) 116.03(17), O(1)-B(1)-C(7) ) 117.14(17), O(2)-B(1)-N(2) 111.80(16), O(1)-B(1)-N(2) 108.13(15)。提交给杂原子化学 8 然后我们将注意力转向 1 与二亚乙基三胺的反应,得到环状产物 7,其中包含一个侧链伯胺键,允许潜在的官能化成各种可能的基团。为了证明这一点,7 与水杨醛在 CH 2 Cl 2 中回流反应得到了新的席夫碱衍生物 8,尽管分离产率有点低(20%)。为了研究该化合物作为过渡金属配体的潜在用途,我们决定检查其与二乙基锌的反应性,因为众所周知,Zn(II) 席夫碱配合物显示出有效的抗菌活性。 [20-25] 我们很高兴发现在低温下将 8 添加到 ZnEt2 溶液中以中等产率提供相应的席夫碱络合物 9(方案 2)。在 11B NMR 光谱中观察到的峰在 10.4 ppm 处没有变化,这证实了在该反应期间硼基团保持完整。光谱数据和元素分析与提议的结构一致,但不幸的是,所有尝试都增加了
更新日期:2017-11-01
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