Synthesis of Ocotillol-Type Ginsenosides

Shen, Renzeng; Cao, Xin; Laval, S.; Sun, Jiansong; Yu, Biao

doi:10.1021/acs.joc.6b01265

Cited by 25 publications

(11 citation statements)

References 66 publications

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“…同样, 在以 TMSOTf 为促进剂的反应中, 反应温度的提高和溶剂极性的增加, 均使反应副产物增多(Entries 10～11). 再次, 我们探讨了 Au(I)催化的糖基邻炔基苯甲酸酯型给体法 [15] , 以 Ph 3 PAuNTf 2 为催化剂, 转化率达到了 92%, 然而几乎无目标产物 5a 获得(Entry 13), 说明本反应条件对 C-3 位糖苷化没有选择性, 文献亦有类似报道 [7] . 最后, 我们探讨了全乙酰基保护的糖基供体(donor)对 C-3 位糖苷化选择性反应的影响, 对比全苯甲酰基保护糖基供体的糖苷化反应(Entry 6), C-3 位糖苷化产物 5b 的产率明显降低(Entry 14), 文献亦有类似无选择性的报道 [10e] .…”

Section: 结果与讨论unclassified

“…因此, 有课题组研究了 PHQ 的合成方法 , 主要包括 : (1) 俞飙课题组 [7] 报道了以 20(S)-PPD 为原料, 先差异化保护 C-12 位和 C-3 位的羟基, 再氧化环化, 并通过 C-3 位羟基脱保护分离出 C-24 位差向异构体, 然后再依次 C-3 位和 C-25 位羟基差异化保护后, C-3 位羟基选择性脱保护, 用 Ph 3 PAuNTf 2 促进剂与邻炔基苯甲酸酯型糖基供体糖苷化, 最后脱保护所有羟基合成 PHQ 的线路, 总收率仅有 28.2%, 且促进剂 Ph 3 PAuNTf 2 的成本较高, 以及邻炔基苯甲酸酯型糖基供体的制备较为复杂(Scheme 1, 线路 A); (2)李平亚课题组 [6] 和 Yang 等 [5] 分别报道了以原人参二醇组皂苷和 Rh2 为原料, 经氧化环化合成 PHQ 的线路, 由 Rh2 合成 PHQ 的已知最高产率为 54.6% [4] , 但 Rh2 本身也是难得的天然产物资源, 其化学合成从原料 20(S)-PPD 开始, 需要 C-12 位羟基先保护再糖苷化, 然后脱保护制得 [8] , 产率约在 47.4% [9] , 因此本线路的总产率也仅有 25.9% (Scheme 1, 线路 B). 图式 1 已报道的拟人参皂苷 HQ 合成方法 Scheme 1 Reported approaches for the synthesis of pseudoginsenoside HQ 和 C-25 位的羟基后才能有效地 C-3 位糖苷化 [7,8] , 增加了反应步骤, 合成效率也因此低下. 且在奥克梯隆型皂苷元上直接糖苷化探索研究中, 目前的糖苷化条件对 C-3 位糖苷化无选择性 [7,10] .…”

unclassified

“…图式 1 已报道的拟人参皂苷 HQ 合成方法 Scheme 1 Reported approaches for the synthesis of pseudoginsenoside HQ 和 C-25 位的羟基后才能有效地 C-3 位糖苷化 [7,8] , 增加了反应步骤, 合成效率也因此低下. 且在奥克梯隆型皂苷元上直接糖苷化探索研究中, 目前的糖苷化条件对 C-3 位糖苷化无选择性 [7,10] .…”

unclassified

“…其中, 糖端基质子的耦合常数J 1', 2' 为 7.8 Hz 可以判断所合成化合物 1 的糖苷键为 β 构型; 糖苷化前后 C-3 位的化学位移向低场移动, 由 δ C 78.8 移至 δ C 90.6, C-12 位与 C-25 位的化学位移无变化, 可以判断所合成化合物 1 的糖苷键连接在 C-3 位上. 且化合物 1 与文献报道 PHQ 在氘代吡啶中的图谱数据基本一致[4,5,7] . 结论本文以商品易得的 20(S)-PPD 为原料, 经 3 步反应简明、高效地合成具有高活性的稀有人参皂苷 Rh2 在体内的主要代谢产物 PHQ, 总收率 32%(回收产率 45%).…”

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Simple and Efficient Synthesis of Pseudoginsenoside HQ

Yang¹,

Li²,

Yang³

et al. 2017

Chin. J. Org. Chem.

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Pseudoginsenoside HQ [PHQ, 3β-O-β-D-glucopyranosyl-(20S,24S)-epoxydammarane-12β,25-diol] is the main in vivo metabolite of 20(S)-ginsenoside Rh2 which has high biological activities, with potential medicinal value. The reported chemical synthesis of PHQ suffered complex synthetic route and low overall yield because the rational protecting group strategies were required for the key glycosylation on C-3 position of sapogenins. In this paper, the glycosylation conditions on C-3 position of ocotillol type sapogenins were investigated, and it was found that it could realize the selective glycosylation on C-3-position of sapogenins to prepare PHQ under the Ag 2 CO 3 promoter without the protecting group strategy. A new synthesis of PHQ was achieved in three steps via epoxidation, selective glycosylation and debenzoylation reaction of glycon using commercially available 20(S)-protopanoxadiol as the starting material. This method provides a simple and efficient way for the preparation of PHQ and its derivatives. Keywords pseudoginsenoside HQ; glycosylation; ocotillol type ginsenoside; chemical synthesis 20(S)-人参皂苷 Rh2 属于红参中的极微量组分, 为原人参二醇组皂苷. 药理学研究证实 Rh2 具有良好的肿瘤细胞生长抑制作用 [1] , 已进入临床研究阶段. 其主要作用机制是调节机体免疫功能 [1a] , 诱导肿瘤细胞凋亡 [1c] , 对化学抗癌药物具有增效减毒作用 [2]. 此外, 在抗过敏、抗炎、耐缺氧等方面均有作用. 近年来, 体内、外的代谢研究表明 20,24-环氧的奥克梯隆型代谢产物可能是 C-20 位不含糖基的人参皂苷(如人参皂苷 Rg3、 Rh2、Rg2 和 Rh1)及其苷元(如原人参二醇(PPD)和原人参三醇(PPT))在体内发挥作用的真正有效成分 [3]. 拟人参皂苷 HQ (PHQ, 1)是 Rh2 在体内的主要代谢产物和潜在的真正有效成分 [4] , 化学名称为 3β-O-β-D-吡喃葡萄糖基-(20S,24S)-环氧达玛-12β,25-二醇, 属于四环三萜类奥克梯隆(Ocotillol)型人参皂苷(图 1). 活性研究表明, PHQ 具有较好的肿瘤细胞生长抑制作用 [5]. 目前, PHQ 主要通过天然来源极其稀少的 Rh2 氧化环化制

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Section: 结果与讨论unclassified

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Simple and Efficient Synthesis of Pseudoginsenoside HQ

Yang¹,

Li²,

Yang³

et al. 2017

Chin. J. Org. Chem.

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“…The discovery of this type showed that the natural ones were mainly existed in American ginseng, Vietnam ginseng, or Panax japonicas [ 10 , 11 , 12 ]. Recently, the semisynthesis has been receiving more and more attention aiming to increase the yields or obtain the novel ocotillol-type saponin [ 13 , 14 , 15 , 16 ]. In our study, a novel ocotillol-type ginsenoside, named 12-riboside-pseudoginsengenin DQ (RPDQ), was semi-synthesized successfully by glycosylation reaction of pseudoginsengenin DQ.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and Metabolism Studies of 12-Riboside-Pseudoginsengenin DQ by UPLC-MS/MS and UPLC-QTOF-MSE

et al. 2018

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Pharmacokinetic and metabolism studies of 12-riboside-pseudoginsengenin DQ (RPDQ), a novel ginsenoside with an anti-cancer effect, were carried out, aiming at discussing the characteristics of the ginsenoside with glycosylation site at C-12. In the pharmacokinetic analysis, we developed and validated a method by UPLC-MS to quantify RPDQ in rat plasma. In the range of 5–1000 ng/mL, the assay was linear (R2 > 0.9966), with the LLOQ (lower limit of quantification) being 5 ng/mL. The LOD (limit of detection) was 1.5 ng/mL. The deviations of intra-day and inter-day, expressed as relative standard deviation (RSD), were ≤ 3.51% and ≤ 5.41% respectively. The accuracy, expressed as relative error (RE), was in the range –8.82~3.47% and –5.61~2.87%, respectively. The recoveries were in the range 85.66~92.90%. The method was then applied to a pharmacokinetic study in rats intragastrically administrated with 6, 12, and 24 mg/kg RPDQ. The results showed that RPDQ exhibited slow oral absorption (Tmax = 7.0 h, 7.5 h, and 7.0 h, respectively), low elimination (t1/2 = 12.59 h, 12.83 h, and 13.74 h, respectively) and poor absolute bioavailability (5.55, 5.15, and 6.08%, respectively). Moreover, the investigation of metabolites were carried out by UPLC-QTOF-MS. Thirteen metabolites of RPDQ were characterized from plasma, bile, urine, and feces of rats. Some metabolic pathways, including oxidation, acetylation, hydration, reduction, hydroxylation, glycine conjugation, sulfation, phosphorylation, glucuronidation, glutathione conjugation, and deglycosylation, were profiled. In general, both the rapid quantitative method and a good understanding of the characteristics of RPDQ in vivo were provided in this study.

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Triterpenoid Glycosides

2024

Carbohydrate Chemistry in the Total Synthesis of Naturally Occurring Glycosides

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Synthesis of Ocotillol-Type Ginsenosides

Cited by 25 publications

References 66 publications

Simple and Efficient Synthesis of Pseudoginsenoside HQ

Simple and Efficient Synthesis of Pseudoginsenoside HQ

Pharmacokinetic and Metabolism Studies of 12-Riboside-Pseudoginsengenin DQ by UPLC-MS/MS and UPLC-QTOF-MSE

Triterpenoid Glycosides

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