CN115260256A - 一种甘露糖磷酸化衍生物及其制备方法和应用 - Google Patents
一种甘露糖磷酸化衍生物及其制备方法和应用 Download PDFInfo
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- CN115260256A CN115260256A CN202210867602.1A CN202210867602A CN115260256A CN 115260256 A CN115260256 A CN 115260256A CN 202210867602 A CN202210867602 A CN 202210867602A CN 115260256 A CN115260256 A CN 115260256A
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Abstract
本发明属于磷酸化甘露糖技术领域，尤其涉及一种甘露糖磷酸化衍生物及其制备方法和应用，改衍生物通过磷酸化反应和催化氢化程序获得，磷酸化甘露糖衍生物对胰腺癌细胞具有显著抑制作用，在制备新型抗肿瘤药物中具有良好的应用前景。
Description
技术领域
本发明属于磷酸化甘露糖技术领域，尤其涉及一种甘露糖磷酸化衍生物及其制备方法和应用。
背景技术
胰腺癌(PC)是消化系统高度致命的癌症，是癌症死亡的第4位主要原因。最近的基于人群的癌症发生资料显示，PC的发病率和死亡率在全球范围内呈明显上升趋势，其发病机制尚未完全了解。与其他常见肺癌和胃癌相比，PC的5年总体生存率不足8％，预后较差。手术切除是PC患者唯一的治疗方法，但在确诊时只有15％左右是合适的，化疗和放疗被广泛用于治疗不能手术的PC患者，但大多数患者对其耐药。多年来，5-氟尿嘧啶(5-FU)被认为是胰腺癌的最佳化疗药物。1997年，吉西他滨(GEM)已成为PC病例的首选药物，与5-FU相比显示出一定的生存获益和更好的疾病相关症状改善。然而，由于这些常规治疗效果有限，毒性大，治疗效果在过去几年没有显著提高。因此，迫切需要新的抗胰腺癌治疗方案和药物。
糖生物学研究表明，糖类与蛋白受体之间的可逆相互作用参与了从细胞通讯到肿瘤转移的许多生理和病理过程。基于这个原因，从糖类化合物中发现新型抗癌药物一直是寻找治疗胰腺癌新药的宝贵途径。Gonzalez等人证实甘露糖可被己糖激酶(HKs)转化为甘露糖-6-磷酸(M6P)，积累的M6P通过抑制HKs、磷酸葡糖异构酶(PGI)和葡萄糖-6-磷酸脱氢酶(G-6-PD)去影响细胞的葡萄糖糖酵解过程而发挥抗肿瘤作用(Mannose impairs tumourgrowth and enhances chemotherapy[J].Nature,2018.563(7733):719-723.)。这种抑制效果在PMI水平低的细胞系如结直肠肿瘤、人骨肉瘤以及人肺腺肿瘤中，表现的尤为明显。此外，其他报道已证明，在肿瘤微环境中，甘露糖受体可通过诱导细胞摄取甘露糖而参与肿瘤相关巨噬细胞(TAM)的活化，调控和激活T细胞的活动，从而提高免疫系统识别并杀死肿瘤细胞的能力(IL13-Mediated Dectin-1 and Mannose Receptor OverexpressionPromotes Macrophage Antitumor Activities through Recognition of SialylatedTumor Cells[J].Cancer Immunol Res,2019.7(2):321-334.)。最后，甘露糖影响Bcl-2蛋白家族，可使促凋亡蛋白NOXA水平升高，抗细胞凋亡蛋白Bcl-XL和Mcl-1水平降低，同时防止P53降解，导致线粒体外膜通透性增高，最终促进肿瘤细胞的凋亡，同时这种凋亡性在甘露糖与顺铂或阿霉素联合使用时明显增强(Conjugating doxorubicin to polymannose:anew strategy for target specific delivery to lung cancer cells,Journal ofBiomaterials Science,Polymer Edition,30:16,1471-1488)。
以上研究证据表明甘露糖与癌症相关，是预防和治疗癌症的潜在候选结构。但进一步的文献调研发现，当甘露糖浓度为25mM时，对3种肿瘤细胞Saos-2、U2OS-E1和KP-4产生较好的增殖抑制作用；在低糖(葡萄糖2.5mM)环境下，甘露糖浓度达到25mM时，对四种胰腺癌细胞AsPC-1、BxPC-3、PANC-1和SW1990的生长抑制作用较为理想(低糖与甘露糖协同抑制胰腺肿瘤生长.肿瘤防治研究[J].2020.47(05):319-323.)；对于肺癌细胞A549和肝癌细胞HCC827，甘露糖的抑制效果显示出时间和剂量依赖性，60mM处理48h时，抑制率达到70％(Mannose Suppresses the Proliferation and Metastasis of Lung Cancer byTargeting the ERK/GSK-3beta/beta-Catenin/SNAIL Axis[J].Onco Targets Ther,2020.13:2771-2781)。以上研究证明，甘露糖虽对多种肿瘤细胞有生长抑制作用，但所需剂量较大，成药性不佳，因此，在开发成糖类创新药物之前需要对甘露糖进行结构修饰，以提高其抗肿瘤活性。
发明内容
本发明的目的是提供一种甘露糖磷酸化衍生物及其制备方法和应用。
为达到上述目的，本发明采用的技术方案是：
一种甘露糖磷酸化衍生物，磷酸化甘露糖具有通式I或通式II所示化学结构或/和其可药用衍生物：
进一步的，X1+R1组合和X2+R2组合其中一个为H时，另一个组合为磷酸酯、膦酸酯、硫代磷(膦)酸酯、硼磷(膦)酸酯、焦磷酸酯及其盐中的一种；X3+R7组合和X4+R8组合其中一个为H时，另一个为磷酸酯、膦酸酯、硫代磷(膦)酸酯、硼磷(膦)酸酯、焦磷酸酯及其盐中的一种；R3、R4、R5、R6、R9、R10、R11、R12为氢原子，羟基、磷酸酯、膦酸酯、硫代磷(膦)酸酯、硼磷(膦)酸酯、焦磷酸酯及其盐中的一种。
进一步的，所述磷酸化甘露糖为α-构型或β-构型或D-甘露糖骨架或L-甘露糖骨架。
进一步的，所述通式I、通式II表示的化合物的药学上可接受的盐为无机酸盐、有机酸盐、烷基磺酸盐、芳基磺酸盐中的一种；无机酸盐为钠离子盐、钾离子盐、镁离子盐中的一种；有机酸盐为三乙胺盐、甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐中的一种；烷基磺酸盐为甲基磺酸盐、乙基磺酸盐中的一种；芳基磺酸盐为苯磺酸盐、对甲苯磺酸盐中的一种。
进一步的，所述通式I、通式II表示的化合物的药学上可接受的溶剂合物为通式I、通式II表示的化合物与水、乙醇、异丙醇、乙醚、丙酮的溶剂合物。
进一步的，本发明的所述通式I表示的磷酸化甘露糖衍生物选自如下具体化合物，
一种甘露糖磷酸化衍生物的制备方法，包括以下步骤：
(1)磷酸化反应：在氮气保护下，将底物糖溶解于超干二氯甲烷中，在搅拌下加入1H-四氮唑，然后加入二苄基-N,N-二异丙基亚磷酰胺，在室温下剧烈搅拌24小时后将反应混合物冷却至-45℃，滴加85％间氯过氧苯甲酸的二氯甲烷溶液，逐渐升温到室温，反应12小时，TLC检测原料反应完全后，将反应液真空旋干，残余物使用乙酸乙酯萃取，用10％的亚硫酸钠溶液洗涤三次，收集有机层，无水硫酸镁干燥，过滤后使用旋转蒸发仪减压浓缩，粗产物使用硅胶柱色谱分离纯化，N,N-二甲基甲酰胺作溶剂用于甲苷和D-甘露糖作底物；
(2)催化氢化：将底物苄基磷酸酯溶于无水甲醇中，配成0.02mmoL/mL的溶液，后加入超纯水使白色浊液返回到反应体系，在搅拌下加入碳酸氢钠粉末，并加入催化剂10％氢氧化钯/碳，在一个大气压的氢气气氛下室温搅拌2天，用聚四氟乙烯滤头滤掉钯催化剂，旋蒸浓缩，粗品使用C18柱纯化，超纯水洗脱，苯酚-硫酸法检测，收集产物冻干，得到白色固体钠盐的甘露糖磷酸化衍生物。
一种药物组合物，包括如上所述的通式I、通式II表示的磷酸化甘露糖衍生物、其药学上可接受的盐或药学上可接受的溶剂合物，和药学上可接受的赋形剂。
一种药物组合物的应用，所述药物组合物用于制备治疗乳腺癌、前列腺癌、肾细胞癌、脑癌、卵巢癌、结肠癌、膀胱癌、胰腺癌、胃癌、食道癌、皮肤黑素瘤、肝癌、肺癌、直肠癌、小肠癌、甲状腺癌、霍奇金淋巴瘤、唇腔癌、皮肤癌、白血病或多发性骨髓瘤药物中的应用。
发明机理：磷酸化修饰是糖类化合物重要的修饰方法之一，磷酸化糖在生物学中作为组织结构成分和信号转导剂，发挥着多种作用，在体内，磷酸化糖具有与靶蛋白相互作用强，半衰期长，可产生易受调控的细胞内信号的优点，因此，它们越来越多地用作生物研究的探针，以及抗肿瘤靶向药物和疫苗开发的先导化合物，磷酸化修饰是提高单糖生物活性，发现优良靶向药物的一种良好的方式，通过磷酸化甘露糖抗肿瘤生物实验可以清楚的看到增强的生物效应所需的全部磷酸基团修饰位置和个数。因此对甘露糖环特定位置羟基进行磷酸化修饰合成有重要意义。
本发明具有的优点是：本发明提供的制备方法与已有方法相比，是能明显缩短这一系列磷酸化甘露糖衍生物合成路线，实验证明本发明所述的式(I)化合物或其水合物、药学上可接受的盐或药学上可接受的溶剂合物或所述的药物组合物对胰腺癌细胞具有显著的抑制作用，在制备抗肿瘤药物上有着广阔的应用空间。
附图说明
图1是16个化合物对四种胰腺癌细胞SW1990、AsPC-1、BxPC-3和PANC-1以及人正常胰腺导管上皮细胞HPDE6-C7的生长抑制图，相比于对照组P≤0.0001。
图2是I-f抗胰腺癌活性与细胞毒性测试关系图。
具体实施方式
实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。化合物的结构用Bruker-500MHz型核磁共振仪测定，氘代二氯甲烷(CDCl2)、氧化氘(D2O)为溶剂，四甲基硅烷(TMS)为内标。层析柱一般使用200～300目硅胶为载体。
实施例1：I类化合物单磷酸酯I-a、I-b的制备
实施例1描述了甘露糖单磷酸酯I-a、I-b的合成，以商品化的D-甘露糖为原料合成而成，所使用的的试剂和条件包括:(a)MeOH,AcCl reflux；(b)DMF,DMP,p-TsOH,60℃；(c)DMF,NaH,BnBr,0℃to r.t；(d)80％AcOH,60℃；(e)MeCN,Fe(dipm)3,K2CO3,NapBr,80℃；(f)DMF,NaH,BnBr,0℃–r.t；(g)DCM:H2O 9:1,DDQ；(h)MeCN,Fe(dipm)3,K2CO3,BnBr,80℃；(i)1)DCM,tetrazole,(BnO)2PN(iPr)2,2)mCPBA,-45℃to r.t.；(j)MeOH:H2O(10:1v/v),NaHCO3,cat.Pd(OH)2/C,H2.注：DBP＝PO(OBn)2
固体盐I-a、I-b被制备从D-甘露糖为原料开始，在甲醇溶液中，乙酰氯(AcCl)提供的酸性条件下回流反应，乙醇多次重结晶得到甲基α-D-吡喃甘露糖苷1。在对甲基苯磺酸(p-TsOH)作用下，利用2,2-二甲氧基丙烷(DMP)对C2、C3位进行丙叉基保护得到化合物2。随后在强碱NaH作用下，用过量的BnBr对C-4，C-6羟基苄基化得到化合物3。在80％的AcOH作用下，将化合物3脱除丙叉基保护，得到二醇4。随后利用立体选择性催化剂Fe(dipm)3，对二醇4的C3-OH选择性萘亚甲基化，得到伯醇5。在强碱NaH作用下，用过量的BnBr对化合物5的C2-OH萘亚甲基化。最后用2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)脱除C2-Nap，得到化合物7。再次利用Fe(dipm)3，在相同的催化条件下，使用BnBr替换NapBr，对二醇4的C3-OH选择性苄基化，得到化合物9；利用亚磷酰胺法对化合物7和9进行磷酸化，得到化合物8和11，产率分别为90％和89％；最后苄基酯8和11在催化氢化条件下全脱保得到固体钠盐I-a、I-b，并在C18柱下纯化，产率均达到97％以上。
实施例2：I类化合物单磷酸酯I-c、I-d的制备
实施例2描述了甘露糖单磷酸酯I-c、I-d的合成，它们是以甘露糖甲苷1为原料合成而成，所使用的试剂和条件包括:(a)DMF,PhCH(OCH3)2,p-TsOH；(b)DMF,NaH,BnBr,0℃tor.t；(c)DCM,Et3SiH,TFA,0℃；(d)DCM,BH3·THF,Cu(OTf)2,r.t.；(e)DCM,tetrazole,(BnO)2PN(iPr)2,2)mCPBA,-45℃to r.t.；(f)DMF,NaH,BnBr,0℃to r.t；(g)MeOH:H2O(10:1v/v),NaHCO3,Pd(OH)2/C,H2.
固体盐I-a、I-b被制备从甘露糖甲苷1开始，在苯甲醛二甲缩醛(PhCH(OCH3)2)和对甲基苯磺酸p-TsOH的作用下对甲苷1的C4、C6羟基进行亚苄基保护得到二醇12。在氢化钠提供的碱性条件下，对C2、C3位羟基苄基化，得到化合物13。在乙腈溶液中，使用三乙基硅烷(Et3SiH)做氢源，碘单质催化，0℃对13的亚苄基进行选择性O4开环，得到化合物14；化合物13的选择性O6开环是在以二氯甲烷做溶剂，硼烷四氢呋喃络合物(BH3·THF)做氢源，三氟甲烷磺酸铜(Cu(OTf)2)催化下，室温反应完成的，生到化合物15。使用亚磷酰胺法对化合物14和15磷酸化，得到化合物16和17，产率分别为87％和80％；最后催化氢化全脱保得到固体钠盐I-c、I-d，并在C18柱下纯化，产率均达到97％以上。
实施例3：I类化合物二磷酸酯I-f、I-g、I-h、I-i的制备
实施例3描述了甘露糖二磷酸酯I-f、I-g、I-h、I-i的合成，它们是以甘露糖甲苷1为原料合成而成，所使用的试剂和条件包括:(a)MeCN,Fe(dipm)3,K2CO3,BnBr,80℃；(b)DCM,Et3SiH,TFA,0℃；(c)DCM,BH3·THF,Cu(OTf)2,0℃；(d)DCM,tetrazole,(BnO)2PN(iPr)2,2)mCPBA,-45℃to r.t.；(e)MeOH:H2O(10:1v/v),NaHCO3,Pd(OH)2/C,H2；(f)DMF,PhCH(OCH3)2,p-TsOH；(g)PhMe,DIBAL-H,AlCl3,0℃.
固体盐I-f、I-g、I-h、I-i被制备从甲苷1和二醇12开始，在区域选择性催化剂Fe(dipm)3的作用下对12的C3位苄基化得到化合物18。随后利用Et3SiH-TFA组合与BH3·THF-Cu(OTf)2组合，对亚苄基进行O4、O6开环，分别得到化合物19和20。后进行磷酸化反应，最后脱除苄基保护得到钠盐I-f、I-g。另一方面，用3倍量的PhCH(OCH3)2处理化合物1，得到全保护的手性混合物23，无需分离，在氢源二异丁基氢化铝(DIBAL-H)作用下，选择性O3开环，得到化合物24。之后利用与18相同的开环条件选择性O4、O6开环，分别得到化合物25和26；后进行磷酸化反应，最后脱除苄基保护得到钠盐I-h、I-i。
实施例4：I类化合物二磷酸酯I-e、I-j的制备
实施例4描述了甘露糖二磷酸酯I-e、I-j的合成，它们分别是以化合物4和13为原料合成而成，所使用的试剂和条件包括:(a)DCM,tetrazole,(BnO)2PN(iPr)2,2)mCPBA,-45℃to r.t.；(b)MeOH:H2O(10:1v/v),NaHCO3,Pd(OH)2/C,H2；(c)1M HCl,H2O,reflux.
固体盐I-e、I-j被制备分别从二醇4和化合物13开始，对4进行磷酸化反应，得到化合物29。后在催化氢化条件下脱除苄基保护，成功制备钠盐I-e。利用1M HCl溶液，回流反应，脱除化合物13的亚苄基保护，得到化合物30。后进行磷酸化，催化氢化全脱保，成功制备钠盐I-e和I-j.
实施例5：I类化合物三磷酸酯I-i、I-k的制备
实施例5描述了甘露糖三磷酸酯I-i、I-k的合成，它们是以化合物12为原料合成而成，所使用的试剂和条件包括:(a)DCM,Et3SiH,TFA,0℃；(b)DCM,BH3·THF,AlCl3,Et2O,0℃to r.t.；(c)DCM,tetrazole,(BnO)2PN(iPr)2,2)mCPBA,-45℃to r.t.；(d)MeOH:H2O(10:1v/v),NaHCO3,Pd(OH)2/C,H2.
固体盐I-i、I-k被制备从化合物12开始，使用Et3SiH-TFA组合，对化合物12的亚苄基进行选择性O4开环，得到化合物32，此外，利用BH3·THF做氢源，三氯化铝(AlCl3)作为催化剂，选择性O6开环，得到化合物33，亚磷酰胺法分别磷酸化32和33，并催化氢化脱除苄基保护，成功得到钠盐I-i和I-k。
实施例6：I类化合物三磷酸酯I-m、I-n的制备
实施例6描述了甘露糖三磷酸酯I-m、I-n的合成，它们分别是以化合物18和24为原料合成而成，所使用的试剂和条件包括:(a)1M HCl,H2O,reflux；(b)DCM,tetrazole,(BnO)2PN(iPr)2,2)mCPBA,-45℃to r.t.；(c)MeOH:H2O(10:1v/v),NaHCO3,Pd(OH)2/C,H2.
固体盐I-m和I-n被制备分别从化合物18和24开始，使用1M HCl溶液，回流反应，脱除亚苄基保护，得到化合物36和38。随后进行磷酸化，催化氢化脱保护得到钠盐I-m和I-n。
固体钠盐I-o与I-p是直接由甘露糖甲苷1和D-甘露糖为原料，先进行磷酸化反应，后催化氢化得到。
标准磷酸化程序为：
在氮气保护下，将底物糖(1mmoL)溶解于超干二氯甲烷(20mL)中，在搅拌下加入1H-四氮唑(每个OH基团2.25倍量)，然后加入二苄基-N,N-二异丙基亚磷酰胺(每个OH基团1.5equiv)，在室温下剧烈搅拌24小时，后将反应混合物放冷到-45℃，滴加85％间氯过氧苯甲酸(每个OH基团1.75倍量)的二氯甲烷(每mmoL间氯过氧苯甲酸1.5mL)溶液，逐渐升温到室温，反应12小时，TLC检测原料反应完全后，将反应液真空旋干，残余物使用乙酸乙酯萃取，用10％的亚硫酸钠溶液洗涤三次，收集有机层，无水硫酸镁干燥，过滤后使用旋转蒸发仪减压浓缩，粗产物使用硅胶柱色谱分离纯化，另外N,N-二甲基甲酰胺作溶剂用于甲苷和D-甘露糖作底物。
磷酸化前体的合成和表征：
化合物8：无色玻璃胶状；收率:90％.Rf＝0.63(PE:EA＝1:1).[α]20 D＝23.5(c1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.42–7.08(m,25H,Ar),5.04–4.92(m,4H,CH2Ph×2),4.78(ddd,J＝11.1,7.7,3.9Hz,2H,1-H,CHPh),4.74–4.69(m,2H,3-H,CHPh),4.66(t,J＝11.4Hz,2H,CH2Ph),4.50(dd,J＝21.9,11.5Hz,2H,CH2Ph),4.07–4.00(m,2H,2-H,4-H),3.80–3.69(m,3H,5-H,6-H,6'-H),3.32(s,3H,OCH3).31P NMR(162MHz,CDCl3)δ-1.73.13CNMR(101MHz,CDCl3)δ138.39,138.31,138.20,136.00,128.62,128.60,128.49,128.45,128.44,128.41,128.39,127.94,127.93,127.89,127.89,127.81,127.69,127.65,99.10,78.92,78.85,77.36,77.03,74.88,74.23,74.16,73.57,73.35,71.61,69.45,69.39,69.31,69.26,69.12,54.99.HRMS(ESI)m/z calcd for C42H45O9P[M+Na]+:747.2693,found:747.2645.
化合物11：无色玻璃胶状；收率:89％.Rf＝0.53(PE:EA＝2:1).[α]20 D＝3.4(c1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.41–7.11(m,25H,Ar),5.09–4.97(m,4H,CH2Ph×2),4.90–4.82(m,3H,CH2Ph,1-H),4.80(d,J＝4.0Hz,1H,2-H),4.63(d,J＝12.1Hz,1H,CHPh),4.55(t,J＝11.1Hz,2H,CH2Ph),4.46(d,J＝10.8Hz,1H,CHPh),3.95(dt,J＝9.0,2.7Hz,1H,3-H),3.84–3.68(m,4H,4-H,5-H,6-H,6'-H),3.33(d,J＝8.3Hz,3H,OCH3).31P NMR(162MHz,CDCl3)δ-1.65.13C NMR(101MHz,CDCl3)δ138.40,138.36,138.05,136.09,136.01,136.00,135.92,128.63,128.53,128.45,128.44,128.35,128.24,128.09,128.07,127.80,127.79,127.66,99.22,99.19,78.43,78.38,77.36,75.27,74.15,73.51,73.49,73.43,71.89,71.65,69.53,69.47,69.13.HRMS(ESI)m/z calcd for C42H45O9P[M+Na]+:747.2693,found:747.2675.
化合物16：无色玻璃胶状；收率:87％.Rf＝0.50(PE:EA＝2:1).[α]20 D＝20.2(c1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.38–7.26(m,10H,Ar),7.26–7.12(m,15H,Ar),4.95–4.80(m,5H,CHPh×5),4.78(d,J＝1.8Hz,1H,1-H),4.66(t,J＝8.3Hz,2H,CH2Ph),4.60–4.52(m,3H,CHPh×3),4.49(d,J＝12.0Hz,1H,CHPh),3.91(dd,J＝9.3,3.0Hz,1H,3-H),3.89–3.83(m,2H,5-H,6'-H),3.82–3.78(m,1H,2-H),3.75(dd,J＝11.3,6.6Hz,1H,6'-H),3.36(s,3H,OCH3).31P NMR(162MHz,CDCl3)δ-2.16.13C NMR(101MHz,CDCl3)δ138.61,138.30,138.21,136.20,136.16,136.12,136.08,128.54,128.49,128.43,128.40,128.38,128.31,127.95,127.84,127.83,127.79,127.69,127.65,127.60,127.41,99.11,78.31,78.28,77.36,74.55,74.43,74.37,73.40,72.87,72.06,71.31,71.26,69.51,69.42,69.37,69.33,69.28.HRMS(ESI)m/z calcd for C42H45O9P[M+Na]+:747.2693,found:747.2680.
化合物17：无色玻璃胶状；收率:80％.Rf＝0.80(PE:EA＝1:1).[α]20 D＝19.7(c1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.36–7.25(m,25H,Ar),5.15–4.97(m,4H,CHPh×4),4.90(d,J＝10.8Hz,1H,CHPh),4.75–4.52(m,6H,CHPh×3),4.40–4.22(m,2H,6-H,6'-H),3.95(t,J＝9.5Hz,1H,4-H),3.88(dd,J＝9.3,3.0Hz,1H,3-H),3.77(dd,J＝2.8,1.9Hz,1H,2-H),3.72(dd,J＝9.6,4.2Hz,1H,5-H),3.27(s,3H,OCH3).31P NMR(162MHz,CDCl3)δ-1.02.13C NMR(101MHz,CDCl3)δ156.82,138.49,138.40,138.31,128.62,128.60,128.50,128.47,128.46,128.09,128.05,128.00,127.90,127.79,127.72,99.11,80.21,77.36,75.25,74.69,74.30,72.90,72.22,70.95,70.88,69.41,69.36,69.33,69.27,66.95,66.89,54.96.HRMS(ESI)m/z calcd for C42H45O9P[M+Na]+:747.2693,found:747.2692.
化合物21：无色玻璃胶状；收率:91％.Rf＝0.55(PE:EA＝1:1).[α]20 D＝-1.5(c1.0,CHCl3).1H NMR(400MHz,CHCl3)δ7.44–7.04(m,30H,Ar),5.04–4.73(m,12H,CHPh×9,1-H,3-H,4-H),4.51(dt,J＝23.9,9.5Hz,3H,CHPh×3),3.96(dt,J＝9.4,2.8Hz,1H,2-H),3.86(ddd,J＝12.6,10.3,2.8Hz,2H,5-H,6-H),3.75(dd,J＝10.9,5.7Hz,1H,6'-H),3.37(s,3H,OCH3).31P NMR(162MHz,CHCl3)δ-1.93.13C NMR(101MHz,CHCl3)δ138.46,137.43,136.04,136.00,135.97,135.93,135.83,135.75,128.63,128.58,128.56,128.53,128.51,128.45,128.37,128.36,128.32,128.11,127.93,127.88,127.79,127.60,127.52,99.04,99.01,77.36,76.13,73.52,73.45,73.42,72.91,72.85,71.69,71.05,71.00,69.72,69.66,69.64,69.58,69.46,69.41,69.35,69.09,55.36.HRMS(ESI)m/z calcd forC49H52O12P2[M+Na]+:917.2826,found:917.2748.
化合物22:无色玻璃胶状；收率:91％.Rf＝0.625(PE:EA＝1:1).[α]20 D＝5.1(c1.0,CHCl3).1H NMR(400MHz,CHCl3)δ7.48–7.04(m,30H,Ar),5.08–4.89(m,8H,CHPh×8),4.82(ddd,J＝12.4,7.6,1.8Hz,3H,CHPh×2,2-H),4.72(d,J＝1.7Hz,1H,1-H),4.51(dd,J＝18.2,10.9Hz,2H,CHPh×2),4.30–4.20(m,2H,6-H,6'-H),3.93–3.88(m,1H,),3.73(d,J＝6.0Hz,2H),3.24(d,J＝8.1Hz,3H).31P NMR(162MHz,CHCl3)δ-0.87,-1.32.13C NMR(101MHz,CHCl3)δ138.10,137.85,136.00,135.97,135.94,135.92,135.90,135.87,135.80,128.67,128.65,128.64,128.61,128.57,128.56,128.52,128.47,128.41,128.26,128.10,128.07,128.06,127.98,127.90,127.86,127.77,99.17,99.14,78.26,78.21,77.36,75.28,73.44,73.26,73.21,71.85,70.69,70.62,69.57,69.52,69.51,69.47,69.44,69.39,69.36,69.31,66.66,66.61,55.17.HRMS(ESI)m/z calcd for C49H52O12P2[M+Na]+:917.2826,found:917.2766.
化合物27:无色玻璃胶状；收率:99％.Rf＝0.604(PE:EA＝1:1).[α]20 D＝5.4(c1.0,CHCl3).1H NMR(400MHz,CHCl3)δ7.33–7.17(m,30H,Ar),5.04–4.88(m,9H,CHPh×8,4-H),4.80–4.75(m,1H,3-H),4.70–4.60(m,3H,CHPh×2,1-H),4.55–4.46(m,2H,CHPh×2),4.13–4.09(m,1H,2-H),3.87(d,J＝10.4Hz,1H,6-H),3.84(d,J＝9.9Hz,1H,5-H),3.78(dd,J＝10.2,5.4Hz,1H,6'-H),3.34(s,3H,OCH3).31P NMR(162MHz,CHCl3)δ-1.89,-2.15.13CNMR(101MHz,CDCl3)δ138.55,138.10,136.04,135.98,135.96,135.94,135.92,135.90,135.87,135.85,128.61,128.59,128.54,128.52,128.49,128.49,128.41,128.32,128.10,128.08,128.06,128.04,127.70,127.68,127.58,127.44,98.73,77.36,76.73,76.66,76.62,76.57,73.36,73.04,72.98,72.95,72.89,70.98,70.94,69.73,69.72,69.67,69.66,69.59,69.57,69.54,69.51,69.17,55.17.HRMS(ESI)m/z calcd for C49H52O12P2[M+Na]+:917.2826,found:917.2759.
化合物28:无色玻璃胶状；收率:97％.Rf＝0.55(PE:EA＝2:3).[α]20 D＝17.3(c1.0,CHCl3).1H NMR(400MHz,CHCl3)δ7.52–7.02(m,30H,Ar),5.11–4.92(m,8H,CHPh×8),4.79–4.74(m,2H,CHPh,3-H),4.67(d,J＝11.9Hz,1H,CHPh),4.59(d,J＝1.6Hz,1H,1-H),4.54(dd,J＝16.4,11.4Hz,2H,CH2Ph),4.33–4.28(m,1H,CHPh),4.26–4.20(m,1H,CHPh),4.01–3.94(m,2H,2-H,4-H),3.71(dd,J＝6.8,4.9Hz,1H,5-H),3.25(s,3H,OCH3).31P NMR(162MHz,CHCl3)δ-1.07,-1.73.13C NMR(101MHz,CDCl3)δ135.38,135.17,133.36,133.31,133.28,133.24,133.20,133.17,133.13,133.10,125.94,125.92,125.90,125.84,125.82,125.80,125.77,125.73,125.34,125.28,125.27,125.21,125.13,125.06,96.36,76.03,75.97,74.65,74.28,72.29,70.83,70.76,67.91,67.84,66.82,66.77,66.75,66.70,66.67,66.65,66.62,66.60,63.84,63.79,52.36.HRMS(ESI)m/z calcd for C49H52O12P2[M+Na]+:917.2826,found:917.2762.
化合物29:无色玻璃胶状；收率:99％.Rf＝0.33(PE:EA＝1:1).[α]20 D＝5.9(c1.0,CHCl3).1H NMR(400MHz,CHCl3)δ7.32–7.16(m,30H,Ar),5.03(dt,J＝14.1,6.8Hz,7H,CHPh×7,),4.95–4.90(m,2H,CHPh,1-H),4.88–4.79(m,2H,2-H,3-H),4.75(d,J＝10.9Hz,1H,CHPh),4.58(t,J＝10.3Hz,1H,CHPh),4.51(s,1H,CHPh),4.43(d,J＝10.9Hz,1H,CHPh),3.95(t,J＝9.5Hz,1H,4-H),3.75(dt,J＝12.1,4.4Hz,2H,5-H,6-H),3.67(d,J＝9.2Hz,1H,6'-H),3.32(s,3H,OCH3).31P NMR(162MHz,CHCl3)δ-1.27,-2.11.13C NMR(101MHz,CHCl3)δ138.23,137.98,135.91,128.62,128.59,128.58,128.55,128.47,128.44,128.42,128.40,128.11,128.03,128.02,127.99,127.95,127.81,127.76,127.73,98.80,77.36,75.35,75.31,75.05,73.61,73.57,71.60,69.74,69.69,69.65,69.60,69.55,69.47,69.41,68.77,55.23.HRMS(ESI)m/z calcd for C49H52O12P2[M+Na]+:917.2826,found:917.2772.
化合物31:无色玻璃胶状；收率:77％.Rf＝0.75(PE:EA＝1:1).[α]20 D＝24.7(c1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.38–7.12(m,30H,Ar),5.07–4.83(m,8H,CHPh×8),4.78(q,J＝9.5Hz,1H,4-H),4.67–4.52(m,5H,CHPh×4,1-H),4.49(ddd,J＝11.1,7.3,1.6Hz,1H,6-H),4.26(ddd,J＝11.4,7.5,6.1Hz,1H,6'-H),3.88(dd,J＝9.3,3.0Hz,1H,3-H),3.82(dd,J＝9.5,5.5Hz,1H,5-H),3.77–3.72(m,1H,2-H),3.27(s,3H,OCH3).31P NMR(162MHz,CDCl3)δ-1.31,-2.04.13C NMR(101MHz,CDCl3)δ138.12,138.07,136.01,128.58,128.56,128.54,128.47,128.44,128.43,128.40,128.36,128.02,127.98,127.85,127.84,127.80,127.73,99.12,78.06,77.36,74.55,73.66,73.59,73.05,72.16,69.62,69.57,69.47,69.41,69.36,69.30,69.26,66.75,55.22.HRMS(ESI)m/z calcd for C49H52O12P2[M+Na]+:917.2826,found:917.2776.
化合物34：无色玻璃胶状；收率:68％.Rf＝0.54(PE:EA＝1:1).[α]20 D＝5.0(c1.0,CHCl3).1H NMR(400MHz,CDCl3)δ8.07–7.00(m,35H,Ar),5.05(dd,J＝15.9,8.5Hz,16H,CHPh×12,1-H,2-H,3-H,4-H),4.61–4.55(m,1H,CHPh),4.51–4.45(m,1H,CHPh),3.96–3.86(m,2H,5-H,6-H),3.86–3.78(m,1H,6'-H),3.42(s,3H,OCH3).31P NMR(202MHz,CDCl3)δ-1.49,-1.74,-2.42.13C NMR(101MHz,CDCl3)δ138.40,135.86,135.77,128.60,128.57,128.56,128.54,128.51,128.46,128.44,128.35,128.18,128.11,128.09,128.08,128.06,128.05,127.59,127.52,98.57,77.36,74.89,73.38,72.18,70.98,69.87,69.83,69.77,69.72,69.65,69.59,68.74,55.44.HRMS(ESI)m/z calcd for C56H59O15P3[M+Na]+:1087.2959,found:1087.2999.
化合物35：无色玻璃胶状；收率:49％.Rf＝0.56(PE:EA＝1:1).[α]20 D＝9.7(c1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.32–7.26(m,19H,Ar),7.26–7.15(m,16H,Ar),4.99(dddd,J＝23.3,18.9,10.9,5.6Hz,12H,CHPh×12),4.92–4.78(m,3H,1-H,2-H,3-H),4.74(d,J＝10.7Hz,1H,CHPh),4.45(d,J＝10.7Hz,1H,CHPh),4.37–4.17(m,2H,6-H,6'-H),3.84(t,J＝9.6Hz,1H,4-H),3.78–3.69(m,1H,5-H),3.26(d,J＝7.9Hz,3H,OCH3).31P NMR(202MHz,CDCl3)δ-0.84,-1.24,-1.79.13C NMR(101MHz,CDCl3)δ137.50,135.77,135.69,135.63,128.52,128.49,128.46,128.44,128.40,128.36,128.34,127.97,127.91,127.90,127.88,127.84,127.75,98.63,77.22,76.40,75.00,72.88,70.45,70.38,69.64,69.58,69.54,69.49,69.40,69.35,69.29,69.27,69.22,66.12,55.17.HRMS(ESI)m/z calcd forC56H59O15P3[M+Na]+:1087.2959,found:1087.2975.
化合物37：无色玻璃胶状；收率:57％.Rf＝0.45(PE:EA＝1:1).[α]20 D＝1.8(c1.0,CHCl3).1H NMR(500MHz,CDCl3)δ7.41–7.26(m,12H,Ar),7.26–7.09(m,23H,Ar),5.05–4.92(m,9H,CHPh×9),4.86(ddd,J＝21.0,11.7,3.2Hz,4H,CHPh×3,2-H),4.78(d,J＝11.1Hz,1H,CHPh),4.73(d,J＝1.3Hz,1H,1-H),4.67(q,J＝9.7Hz,1H,4-H),4.55–4.45(m,2H,6'-H,CHPh),4.32–4.20(m,1H,6-H),3.94(dt,J＝9.4,2.7Hz,1H,3-H),3.87(dd,J＝9.7,5.6Hz,1H,5-H),3.27(s,3H).31P NMR(202MHz,CDCl3)δ-1.08,-1.52,-1.77.13C NMR(101MHz,CDCl3)δ137.17,135.78,128.53,128.50,128.47,128.42,128.39,128.35,128.30,128.26,128.24,128.19,127.98,127.91,127.87,127.81,127.79,127.70,127.68,98.81,77.23,75.72,72.59,71.60,70.12,69.60,69.53,69.47,69.39,69.33,69.27,69.23,69.17,66.31,55.28.HRMS(ESI)m/z calcd for C56H59O15P3[M+Na]+:1087.2959,found:1087.2991.
化合物39：无色玻璃胶状；收率:91％.Rf＝0.55(PE:EA＝1:1).[α]20 D＝12.0(c1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.59–6.89(m,35H,Ar),5.11–4.91(m,12H,CHPh×12),4.86–4.79(m,1H,4-H),4.76–4.69(m,1H,3-H),4.63(d,J＝11.9Hz,1H,CHPh),4.53(dd,J＝13.6,6.8Hz,3H,CHPh,1-H,6'-H),4.32–4.25(m,1H,6-H),4.08–4.04(m,1H,2-H),3.83–3.77(m,1H,5-H),3.24(s,3H,OCH3).31P NMR(162MHz,CDCl3)δ-1.28,-1.68,-2.09.13C NMR(101MHz,CDCl3)δ137.75,135.98,135.91,135.83,135.78,135.77,135.71,135.70,135.67,135.64,135.60,128.50,128.49,128.45,128.43,128.40,128.31,128.11,127.99,127.96,127.91,127.89,127.88,127.66,127.61,98.69,77.34,77.22,76.49,76.23,76.20,76.15,73.47,72.12,72.06,72.03,71.97,70.11,70.07,70.00,69.69,69.64,69.59,69.50,69.45,69.24,69.19,69.14,66.35,66.30,55.12.HRMS(ESI)m/z calcd forC56H59O15P3[M+Na]+:1087.2959,found:1087.2995.
催化氢化程序为：
将底物苄基磷酸酯溶于无水甲醇中，配成0.02mmoL/mL的溶液，后加入超纯水(甲醇体积的十分之一)使白色浊液返回到反应体系，在搅拌下加入碳酸氢钠粉末(每个磷酸基团2倍量)，并加入催化剂10％氢氧化钯/碳(与底物质量相等)，在一个大气压的氢气气氛下室温搅拌2天。用聚四氟乙烯(PETF)滤头滤掉钯催化剂，旋蒸浓缩，粗品使用C18柱纯化，超纯水洗脱，苯酚-硫酸法检测，收集产物冻干，得到白色固体钠盐。
I类化合物的合成和表征：
化合物I-a:白色固体；收率:99％,[α]20 D＝26.5(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.87(s,1H,1-H),4.30(d,J＝8.6Hz,1H,2-H),3.87(dd,J＝12.3,2.2Hz,1H,6-H),3.77(dd,J＝12.3,5.9Hz,1H,6'-H),3.73–3.65(m,2H,3-H,4-H),3.63–3.54(m,1H,5-H),3.40(s,3H,OCH3).31P NMR(162MHz,D2O)δ4.12.13C NMR(101MHz,D2O)δ100.20,100.15,72.66,72.40,72.35,70.76,70.73,67.32,60.73,54.64.HRMS(ESI)m/z calcd for C7H14O9PNa[M-Na+]-:273.0381,found:273.0383.
化合物I-b:白色固体；收率:99％,[α]20 D＝62.0(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.76(d,J＝1.1Hz,1H,1-H),4.15(td,J＝8.8,3.4Hz,1H,3-H),4.05(dd,J＝3.3,1.7Hz,1H,2-H),3.87(dd,J＝12.2,2.1Hz,1H,6-H),3.74(dt,J＝12.2,7.0Hz,2H,4-H,6'-H),3.67–3.60(m,1H,5-H),3.40(s,3H,OCH3).31P NMR(162MHz,D2O)δ4.28.13C NMR(101MHz,D2O)δ100.53,73.54,72.36,69.50,66.92,60.94,54.60.HRMS(ESI)m/z calcd forC7H14O9PNa2[M-Na+]-:273.0381,found:273.0381.
化合物I-c:白色固体；收率:99％,[α]20 D＝73.0(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.73(s,1H,1-H),4.05(dd,J＝18.2,9.3Hz,1H,4-H),3.91(dd,J＝3.2,1.4Hz,1H,2-H),3.86(dd,J＝9.3,3.4Hz,1H,3-H),3.81(d,J＝3.7Hz,2H,6-H,6'-H),3.61(dt,J＝7.7,3.6Hz,1H,5-H),3.37(s,3H,OCH3).31P NMR(162MHz,D2O)δ1.92.13C NMR(101MHz,D2O)δ98.27,69.49,69.42,68.59,67.35,67.30,67.21,58.54,52.49.HRMS(ESI)m/z calcd forC7H14O9PNa[M-Na+]-:273.0381,found:273.0381.
化合物I-d:白色固体；收率：98％,[α]20 D＝33.5(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.75(s,1H,1-H),4.03(dd,J＝6.8,4.0Hz,1H,6-H),3.98–3.89(m,2H,2-H,6-H),3.85(t,J＝9.8Hz,1H,4-H),3.76(dd,J＝9.9,3.4Hz,1H,3-H),3.64(d,J＝9.5Hz,1H,5-H),3.39(s,3H,OCH3).31P NMR(162MHz,D2O)δ4.38.13C NMR(101MHz,D2O)δ100.97,71.97,71.90,70.09,69.88,65.87,62.46,62.41,54.70.HRMS(ESI)m/z calcd for C7H14O9PNa[M-Na+]-:273.0381,found:273.0382.
化合物I-e:白色固体；收率:99％,[α]20 D＝29.5(c 0.2,H2O).1H NMR(400MHz,d2o)δ5.00(s,1H,1-H),4.29(ddd,J＝8.5,3.4,1.6Hz,1H,2-H),4.25–4.18(m,1H,3-H),3.84(dt,J＝19.3,6.0Hz,2H,4-H,6-H),3.76(dd,J＝12.3,5.7Hz,1H,6'-H),3.66–3.57(m,1H,5-H),3.40(s,3H,OCH3).31P NMR(162MHz,D2O)δ4.86,3.46.13C NMR(101MHz,D2O)δ99.99,72.62,72.43,72.14,66.84,60.73,54.71.HRMS(ESI)m/z calcd for C7H14O12P2Na2[M-Na+]-:374.9864,found:374.9863.
化合物I-f:白色固体；收率:99％,[α]20 D＝29.0(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.98(d,J＝1.3Hz,1H,1-H),4.25(ddd,J＝8.2,3.3,1.7Hz,1H,2-H),4.15(dd,J＝18.8,9.5Hz,1H,4-H),3.92(dd,J＝12.9,4.2Hz,1H,6-H),3.85(ddd,J＝9.6,3.3,1.6Hz,1H,3-H),3.75(dd,J＝12.9,2.0Hz,1H,6-H),3.61–3.56(m,1H,5-H),3.38(s,3H,OCH3).31P NMR(162MHz,D2O)δ4.36,3.80.13C NMR(101MHz,D2O)δ99.99,72.33,72.08,72.03,70.40,69.72,60.51,54.68.HRMS(ESI)m/z calcd for C7H14O12P2Na2[M-Na+]-:374.9864,found:374.9863.
化合物I-g:白色固体；收率:97％,[α]20 D＝16.5(c 0.2,H2O).1H NMR(400MHz,d2o)δ4.87(d,J＝1.3Hz,1H,1-H),4.31(ddd,J＝8.9,3.2,1.7Hz,1H,2-H),4.06–3.92(m,2H,6-H,6'-H),3.84(t,J＝9.8Hz,1H,4-H),3.72(dd,J＝9.9,3.2Hz,1H,3-H),3.67–3.60(m,1H,5-H),3.40(s,3H,OCH3).31P NMR(162MHz,D2O)δ4.48,4.33.13C NMR(101MHz,D2O)δ100.40,100.35,72.39,72.35,72.17,72.10,70.40,70.38,67.00,62.79,62.75,54.73.HRMS(ESI)m/z calcd for C7H14O12P2Na2[M-Na+]-:374.9864,found:374.9861.
化合物I-h:白色固体；收率:98％,[α]20 D＝44.5(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.76(d,J＝3.2Hz,1H,1-H),4.32–4.16(m,2H,3-H,4-H),4.11(t,J＝3.0Hz,1H,2-H),3.97(dd,J＝13.5,5.5Hz,1H,6-H),3.78–3.69(m,2H,5-H,6'-H),3.41(s,3H,OCH3).31P NMR(162MHz,D2O)δ3.58,3.12.13C NMR(101MHz,D2O)δ100.18,74.15,73.51,69.50,60.45,54.96.HRMS(ESI)m/z calcd for C7H14O12P2Na2[M-Na+]-:374.9864,found:374.9862.
化合物I-i:白色固体；收率:99％,[α]20 D＝49.0(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.75(d,J＝1.0Hz,1H,1-H),4.16(td,J＝9.3,3.3Hz,1H,3-H),4.08(dd,J＝3.1,1.6Hz,1H,2-H),4.04–3.96(m,1H,6-H),3.95–3.86(m,1H,6'-H),3.83(t,J＝9.6Hz,1H,4-H),3.76–3.68(m,1H,5-H),3.41(s,3H,OCH3).31P NMR(162MHz,D2O)δ4.10,4.08.13C NMR(101MHz,D2O)δ100.58,73.47,71.92,71.84,69.46,66.53,62.89,54.78.HRMS(ESI)m/zcalcd for C7H14O12P2Na2[M-Na+]-:374.9864,found:374.9861.
化合物I-j:白色固体；收率:98％,[α]20 D＝44.0(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.75(s,1H,1-H),4.12(dd,J＝10.2,5.2Hz,1H,3-H),3.99(dd,J＝17.0,8.2Hz,1H,2-H),3.93–3.85(m,2H,4-H,6-H),3.84–3.73(m,2H,5-H,6'-H),3.41(d,J＝8.4Hz,3H,OCH3).31PNMR(162MHz,D2O)δ1.44,1.30.13C NMR(101MHz,d2o)δ98.86,73.51,71.43,71.38,70.67,62.41,60.22,54.93,48.75.HRMS(ESI)m/z calcd for C7H14O12P2Na2[M-Na+]-:374.9864,found:374.9862.
化合物I-l:白色固体；收率:99％,[α]20 D＝20.5(c 0.2,H2O).1H NMR(500MHz,D2O)δ5.00(d,J＝7.9Hz,1H,1-H),4.35(d,J＝7.1Hz,1H,2-H),4.24(t,J＝8.3Hz,1H,3-H),4.07–4.00(m,1H,6-H),3.91(ddd,J＝26.8,15.1,7.4Hz,2H,4-H,5-H),3.74(dd,J＝8.8,4.8Hz,1H,6'-H),3.43(s,3H,OCH3).31P NMR(162MHz,D2O)δ3.12,2.73,2.11.13C NMR(101MHz,D2O)δ99.04,74.73,73.02,71.03,70.95,64.74,64.67,62.38,54.97,48.74.HRMS(ESI)m/z calcd for C7H14O15P3Na3[M-Na+]-:476.9341,found:476.9342.
化合物I-m:白色固体；收率:97％,[α]20 D＝33.5(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.97(s,1H,1-H),4.23(d,J＝6.7Hz,1H,2-H),4.13(dd,J＝10.3,5.7Hz,1H,4-H),4.01(dd,J＝17.6,9.0Hz,1H,6-H),3.91–3.80(m,2H,6-H,3-H),3.79–3.71(m,1H,5-H),3.39(d,J＝9.8Hz,3H,OCH3).31P NMR(162MHz,D2O)δ4.01,3.75,3.59.13C NMR(101MHz,D2O)δ98.86,73.51,71.43,71.38,70.67,62.41,60.22,54.93,48.75.HRMS(ESI)m/z calcd forC7H14O15P3Na3[M-Na+]-:476.9341,found:476.9341.
化合物I-n:白色固体；收率:98％,[α]20 D＝39.0(c 0.2,H2O).1H NMR(400MHz,D2O)δ4.75(s,1H,1-H),4.24(d,J＝26.5Hz,2H,3-H,4-H),4.08(d,J＝8.1Hz,1H,6-H),4.02(s,1H,2-H),3.88(d,J＝23.5Hz,2H,5-H,6'-H),3.41(s,3H,OCH3).31P NMR(162MHz,D2O)δ4.01,3.26.13C NMR(101MHz,D2O)δ100.05,73.89,71.94,70.72,69.73,63.38,54.96.HRMS(ESI)m/z calcd for C7H14O15P3Na3[M-Na+]-:476.9341,found:476.9341.
体外抗肿瘤抑制活性测试部分
实验例1：式I类化合物对4株胰腺癌细胞的抑制作用
对合成的16个磷酸化甘露糖衍生物，选择4株不同的人胰腺癌细胞SW1990、AsPC-1、BxPC-3和PANC-1，并同时选择人正常胰腺导管上皮细胞HPDE6-C7进行活性筛选和毒性评估试验。
活性筛选方法：具体而言，SW1990、AsPC-1、BxPC-3和PANC-1细胞选择含10％胎牛血清、100U/mL青霉素和100μmg·mL-1链霉素的DMEM培养基，并在含5％CO2的37℃恒温培养箱中培养，待细胞生长状态良好对其进行计数，并以每孔5*104的密度铺于96孔板，每组4个复孔。待细胞贴壁(约24h)后，使用PBS溶解化合物，配置成浓度为1mg·mL-1溶液处理细胞，对照组用载体溶液处理。继续在37℃恒温培养箱作用72h后，每孔加入10μL MTT(5mg·mL-1)，，轻轻拍打均匀，置于培养箱中继续孵育4h。随后，吸出培养基和MTT，每孔分别加入150μL DMSO。将培养板放置于摇床上震荡15-30min，至甲臜完全溶解。随后用酶标仪，在490nm波长处检测每孔的吸光度(Optical Density,OD)。此外，实验中要设置调零孔(培养基、MTT、二甲基亚砜)。细胞活力＝(OD处理组-OD调零孔)/(OD对照组-OD调零孔)×100％。
通过实验结果通过对4株胰腺癌细胞和人正常胰腺导管上皮细胞系HPDE6-C7细胞筛选，最终确定甲基-α-d-吡喃葡萄糖苷-2,4-二磷酸钠离子盐I-f对胰腺癌细胞均具有较好的生长抑制作用。
实验例2：化合物I-f的毒性测试
具体而言，SW1990、AsPC-1、BxPC-3和PANC-1和人正常肝脏细胞LO2细胞选择含10％胎牛血清、100U/mL青霉素和100μmg·mL-1链霉素的DMEM培养基，并在含5％CO2的37℃恒温培养箱中培养，待细胞生长状态良好对其进行计数，并以每孔5*104的密度铺于96孔板，每组4个复孔。待细胞贴壁(约24h)后，使用PBS将I-f稀释成浓度梯度为0.0125mg·mL-1、0.025mg·mL-1、0.05mg·mL-1、0.1mg·mL-1、0.2mg·mL-1、0.4mg·mL-1、0.8mg·mL-1、1.6mg·mL-1、3.2mg·mL-1的溶液处理细胞，对照组用载体溶液处理。继续在37℃恒温培养箱作用72h后，每孔加入10μl MTT(5mg·mL-1)，轻轻拍打均匀，置于培养箱中继续孵育4h。随后，吸出培养基和MTT，每孔分别加入150μL DMSO。将培养板放置于摇床上震荡15-30min，至甲臜完全溶解。随后用酶标仪，在490nm波长处检测每孔的吸光度(Optical Density,OD)。72h后用酶标仪在490nm波长下测定OD值，并使用GraphPad Prism 8.0软件拟合浓度(mg·mL-1)-细胞活力(Cell/Viability％)曲线。
甘露糖经磷酸化修饰后，其抗胰腺癌活性有所提高。甘露糖C2、C4位修饰磷酸基团得到的衍生物I-f，对四种胰腺癌细胞(PANC-1，BxPC-3，SW1990，AsPC-1)的生长均有较强的抑制作用，抑制率分别为67.01％，66.12％，67.71％和42.18％。I-f对正常胰腺导管上皮细胞HPDE6-C7也有一定抑制作用，但抑制率低于胰腺癌细胞PANC-1，BxPC-3，SW1990，为61.21％(原因可能是由于长期培养条件下，HPDE6-C7细胞某些基因突变可无限增殖，使其具有肿瘤细胞特性)。此外，除对AsPC-1细胞以外，I-f的抗癌细胞生长作用呈浓度依赖性。值得一提的是，当I-f浓度高于0.8mg·mL-1之后，对胰腺癌细胞BxPC-3的生长抑制作用减弱较为明显，这揭示I-f发挥抗BxPC-3的作用机制不同于AsPC-1和PANC-1，导致细胞表现出较强的应激反应。最后，I-f在浓度0.0125mg·mL-1～3.2mg·mL-1范围内，对人正常肝脏细胞LO2无明显肝毒性，这一优点可能会克服目前吉西他滨用药产生的肝肾功能异常的缺点。
本发明的优点一，探索并优化了甘露糖羟基选择性保护策略，合成了16种糖砌块。策略中包含的方法有：DIBAL-H作用下甘露糖2,3-亚苄基选择性O3开环，BH3·THF和Et3SiH作用下的甘露糖4,6-亚苄基选择性O6，O3开环以及Fe(dipm)3介导的甘露糖区域选择性C3苄基化。最后采用亚磷酰胺法合成了16个磷酸酯化甘露糖及其钠盐。
根据文献调研与总结，发现近十年以来，对单糖不同位置进行磷酸化修饰的研究已有报道。如Joseph课题组探索一种简单地一锅两步程序，由TMSOTF催化1,1,1,3,3,3-六甲基二硅氮烷(HMDS)硅烷化，后在体系中直接添加吡啶和二苯基氯磷酸盐，继续反应36小时，以最少的保护步骤制备了带保护的C6-磷酸化糖衍生物(Simple one-potregioselective 6-O-phosphorylation of carbohydrates and trehalosedesymmetrization[J].Chem Commun(Camb),2013.49(98):11497-9.)。Shipton课题组对葡萄糖进行三磷酸化修饰，合成了6个新型磷酸化葡萄糖衍生物(Both d-and l-GlucosePolyphosphates Mimic d-myo-Inositol 1,4,5-Trisphosphate:New SyntheticAgonists and Partial Agonists at the Ins(1,4,5)P3 Receptor[J].J Med Chem,2020.63(10):5442-5457)。Fylaktakidou课题组对葡萄糖、半乳糖、甘露糖和二糖的多磷酸化和焦磷酸化，并作为潜在的人血红蛋白变构效应物进行了研究，发现了三种与六磷酸肌醇相比，促使血红蛋白释放氧气效果更好的磷酸化糖(Polyphosphates andpyrophosphates of hexopyranoses as allosteric effectors of human hemoglobin:synthesis,molecular recognition,and effect on oxygen release[J].ChemMedChem,2011.6(1):153-68.)。Kanai课题组以硫酸氢四丁基铵(TBAHS)为催化剂，磷酸烯醇丙酮酸一钾盐(PEP-K)为磷基供体，开发了一种催化化学选择性羟基o-磷酸化方法(CatalyticChemoselective O-Phosphorylation of Alcohols[J].ACS Cent Sci,2020.6(2):283-292.)。
已有文献报道了甘露糖环C-4或C-6位苄基保护的糖砌块14、15、19、20、25、26、32和33的合成方法(Metal Trifluoromethanesulfonate-Catalyzed RegioselectiveReductive Ring Opening of Benzylidene Acetals[J].Journal of the ChineseChemical Society,2009.56(3):510-523.Rapid assembly of gp120 oligosaccharidemoieties via one-pot glycosidation-deprotection sequences[J].Carbohydr Res,2010.345(10):1316-23.A concise synthesis of single components of partiallysulfated oligomannans[J].Org Biomol Chem,2015.13(47):11550-60.Multi-gramscale synthesis of a bleomycin(BLM)carbohydrate moiety:exploring theantitumor beneficial effect of BLM disaccharide attached to 10-hydroxycamptothecine(10-HCPT)[J].New Journal of Chemistry,2019.43(15):6010-6020.Efficient synthesis of Man2,Man3,and Man5 oligosaccharides,usingmannosyl iodide donors[J].J Org Chem,2005.70(22):8772-9.Synthesis ofStandardized Building Blocks as aβ-D-Mannosyl Donors with a TemporaryProtection to be 3,6-Di-O-glycosyl Acceptors,for Constructing the Inner Coreof Glycoproteins and Artificial Antigens[J].Bulletin ofthe Chemical Societyof Japan,1986.59(5):1581-1586.Serine-cis-proline and serine-trans-prolineisosteres:stereoselective synthesis of(Z)-and(E)-alkene mimics by Still-Wittig and Ireland-Claisen rearrangements[J].J Org Chem,2003.68(6):2343-9.)。但这些方法产率低，操作繁琐。根据目前的研究报道，4,6-亚苄基选择性O6、O4开环反应是获得相应C-4或C-6位苄基保护吡喃单糖的有效途径。以DIBAL-H、NaBH3CN、BH3、TMDS、PhSiH3、9-BBN、Me2EtSiH或Et3SiH作为氢源，在路易斯酸的作用下，可完成亚苄基选择性开环，但这种开环的具体原因复杂，机理尚不清楚，溶剂、催化剂、氢源，甚至底物类型都会影响开环效果(Serine-cis-proline and serine-trans-proline isosteres:stereoselective synthesis of(Z)-and(E)-alkene mimics by Still-Wittig andIreland-Claisen rearrangements[J].J Org Chem,2003.68(6):2343-9.)。本研究中，我们探究并优了4,6-亚苄基保护的甘露糖12、13、18以及24的选择性O6、O4开环方法并合成了14、15、19、20、25、26、32和33。
表1化合物12、18、24和13的苄叉缩醛保护基区域选择性O6开环。
糖砌块32、19、25和14分别由底物12、18、24和13选择性O6开环得到。为寻找最佳的开环条件，尽可能提高原料利用率。在二氯甲烷中，我们对12、18、24和13的亚苄基O6开环进行了一系列探究并制备32、19、25和14(表1)。将二醇12溶解在二氯甲烷(DCM)中，使用三氯化铝(AlCl3)和氢源四甲基二硅氧烷(TMDS)组合，低温生成33，产率仅为10％(Entry 1)。尝试金属催化剂三氟甲烷磺酸铜(Cu(OTf)2)和三氟甲烷磺酸镧(La(OTf)3)，以BH3·THF为还原剂，5％mmol Cu(OTf)2为催化剂，室温搅拌5h，以84％的产率得到33，催化效果明显优于15％mmol La(OTf)3(Entry 2-3)。后利用Shipton的方法使用2eq的AlCl3并与BH3·THF组合处理12，室温下搅拌8h能以91％高产率获得三醇33(Entry 4)。之后对13的O6开环方法进行探究，直接使用AlCl3和BH3·THF组合，室温反应8h，只以67％的中等收率得到二醇15(Entry6)；使用TMDS替换BH3·THF，在低温下反应4h，生成的15产率仅为12％(Entry 7)，尝试换用Cu(OTf)2催化，并对比两种催化浓度下的反应差异，15％mmol的浓度能明显缩短反应时间，室温下反应1h后，15的产率能达到78％(Entry 10)。同样，用Cu(OTf)2和BH3·THF组合直接处理18，反应2h后以87％的高产率成功得到20(Entry 11)。后续使用Cu(OTf)2和BH3·THF组合处理24，反应40min也能以较好的产率得到26。
糖砌块32、19、25和14分别由底物12、18、24和13选择性O4开环得到。先前的研究已经证明硅烷试剂在TFA催化下常被用于吡喃糖4,6-亚苄基O4开环。Et3SiH作为有机反应中常用的还原剂，其价格低廉，反应平稳，是一个良好的氢源。因此，我们选择Et3SiH作为O4开环的氢源，对糖砌块12、18，24和13的O6开环进行了一系列探究并制备32，19，25和14(表2)。在合成32时，为了确定最佳反应溶剂和催化剂，进行了一组实验，分别选用DCM、乙腈(MeCN)、THF以及甲苯(PhMe)做溶剂还原12。实验证明，在二氯甲烷中反应相对较好，在消耗了大量原料后，32能以中等产率获得(entry 1-4)。因此，用二氯甲烷作为进一步优化的溶剂。Fairbanks等也描述了用TFA和Et3SiH组合以55％的产率对12进行O4开环得到32。我们发现中等收率是因为TFA使用量较大，它的酸性导致了亚苄基水解，此外，Et3SiH在TFA的作用下表现出的还原性破坏了糖环结构，使体系副产物增多。当TFA用量减少到3eq时，原料耗尽时间明显延长，但TLC检测，观察到生成的副产物仍然较多，体系杂乱，最终导致32的产率只有49％(entry 5)。进一步探究使用TFAA和TFA协同催化，仍观察到较少的32生成(entry6)。然后替换TFA，研究了Et3SiH与其他金属催化剂的组合，只有Cu(OTf)2具有一定的O6开环选择性，但产率却降至29％(entry 7-9)。据Misra报道，MeCN做溶剂，Et3SiH和I2组合可用于呋喃糖亚苄基缩醛区域选择性O6开环。于是，我们尝试了I2作为催化剂，12的O6开环，在MeCN溶液中，0℃下搅拌20min，观察到12转化不完全，产率为41％，且即使延长反应也不能得到理想产率(Entry 10-11)。接下来探究了14的合成，当利用Et3SiH与TFA组合时，观察到14的产率较低(Entry 12)。随后在Et3SiH和I2组合下，在MeCN溶液中反应20min，以中等的收率得到14(Entry 13)。尝试TFA作催化，在二氯甲烷冰浴中，18与Et3SiH共同搅拌1h，能以61％的收率得到19(Entry14)，同样，直接利用TFA和Et3SiH组合处理24进行O4开环，能以56％的中等收率得到25(Entry15)。
表2化合物12、18、24和13的苄叉缩醛保护基团区域选择性O6开环
总之，利用BH3·THF和Et3SiH，建立了一种新的，温和的反应条件，用于甘露糖亚苄基区域选择性O4、O6开环。反应可通过BH3·THF与AlCl3或Cu(OTf)2组合完成O6开环，通过Et3SiH与I2或TFA组合完成O4开环。但Et3SiH作用下的O4开环条件会促使甘露糖中的亚苄基水解或生成其他未确定结构的副产物导致整体反应产率较低，在后续的研究中，仍需优化改进甘露糖环亚苄基O4开环方法。
本发明的优点二，实验证明本发明所述的式(I)其水合物、药学上可接受的盐或药学上可接受的溶剂合物或所述的药物组合物，经过筛选抗胰腺癌活性筛选，发现甲基-α-d-吡喃甘露糖苷-2,4-二磷酸钠离子盐I-f显著提高了甘露糖的抗胰腺癌活性，对胰腺癌细胞增殖具有显著的抑制作用且无明显的肝脏毒性。此外，I-f的抗肿瘤机制可能是抑制癌细胞的糖酵解相关酶(HKs、PGI和G-6-PD)的活性，阻断了细胞能量来源，这将克服目前一线抗癌药物易产生耐药性的缺点。I-f结构简单，易于合成，在抗肿瘤糖类药物的开发上具有潜在的研究价值。
Claims (8)
1.一种甘露糖磷酸化衍生物，其特征在于：磷酸化甘露糖具有通式I或通式II所示化学结构或/和其可药用衍生物：
式中X1和X2其中一个为H时，另一个为C、N、O、S中的一种，R1和R2其中一个为氢原子、氘原子、取代或非取代C1-C8烷基、取代或非取代氘代C1-C8烷基、取代或非取代C2-C8烯烃基、取代或非取代C1-C8烷氧基、卤素、氨基、硝基、羟基、酰基、氰基、取代或非取代的磷酸基、硫代磷酸基、硼磷酸基及其盐中的一种；X3和X4其中一个为H时，另一个为C、N、O、S中的一种，R7和R8其中一个为氢原子、氘原子、取代或非取代C1-C8烷基、取代或非取代氘代C1-C8烷基、取代或非取代C2-C8烯烃基、取代或非取代C1-C8烷氧基、卤素、氨基、硝基、羟基、酰基、氰基、取代或非取代的磷酸酯、膦酸酯、硫代磷(膦)酸酯、硼磷(膦)酸酯、焦磷酸酯及其盐中的一种；R3、R4、R5、R6、R9、R10、R11、R12为氢原子、C1-C8烷基、C2-C8烯烃基、C2-C8炔基、C2-C8卤代烷、C1-C8烷氧基、卤素、氨基、硝基、羟基、酰基、氰基、取代或非取代的磷酸酯、膦酸酯、硫代磷酸酯、硼磷酸酯及其盐中的一种。
2.如权利要求1所述的甘露糖磷酸化衍生物，其特征在于：X1+R1组合和X2+R2组合其中一个为H时，另一个组合为磷酸酯、膦酸酯、硫代磷(膦)酸酯、硼磷(膦)酸酯、焦磷酸酯及其盐中的一种；X3+R7组合和X4+R8组合其中一个为H时，另一个为磷酸酯、膦酸酯、硫代磷(膦)酸酯、硼磷(膦)酸酯、焦磷酸酯及其盐中的一种；R3、R4、R5、R6、R9、R10、R11、R12为氢原子，羟基、磷酸酯、膦酸酯、硫代磷(膦)酸酯、硼磷(膦)酸酯、焦磷酸酯及其盐中的一种。
3.如权利要求2所述的甘露糖磷酸化衍生物，其特征在于：所述磷酸化甘露糖为α-构型或β-构型或D-甘露糖骨架或L-甘露糖骨架。
4.如权利要求3所述的甘露糖磷酸化衍生物，其特征在于：所述通式I、通式II表示的化合物的药学上可接受的盐为无机酸盐、有机酸盐、烷基磺酸盐、芳基磺酸盐中的一种；无机酸盐为钠离子盐、钾离子盐、镁离子盐中的一种；有机酸盐为三乙胺盐、甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐中的一种；烷基磺酸盐为甲基磺酸盐、乙基磺酸盐中的一种；芳基磺酸盐为苯磺酸盐、对甲苯磺酸盐中的一种。
5.如权利要求4所述的甘露糖磷酸化衍生物，其特征在于：所述通式I、通式II表示的化合物的药学上可接受的溶剂合物为通式I、通式II表示的化合物与水、乙醇、异丙醇、乙醚、丙酮的溶剂合物。
6.如权利要求1-5任一所述的甘露糖磷酸化衍生物的制备方法，其特征在于，包括以下步骤：
(1)磷酸化反应：在氮气保护下，将底物糖溶解于超干二氯甲烷中，在搅拌下加入1H-四氮唑，然后加入二苄基-N,N-二异丙基亚磷酰胺，在室温下剧烈搅拌24小时后将反应混合物冷却至-45℃，滴加85％间氯过氧苯甲酸的二氯甲烷溶液，逐渐升温到室温，反应12小时，TLC检测原料反应完全后，将反应液真空旋干，残余物使用乙酸乙酯萃取，用10％的亚硫酸钠溶液洗涤三次，收集有机层，无水硫酸镁干燥，过滤后使用旋转蒸发仪减压浓缩，粗产物使用硅胶柱色谱分离纯化，N,N-二甲基甲酰胺作溶剂用于甲苷和D-甘露糖作底物；
(2)催化氢化：将底物苄基磷酸酯溶于无水甲醇中，配成0.02mmoL/mL的溶液，后加入超纯水使白色浊液返回到反应体系，在搅拌下加入碳酸氢钠粉末，并加入催化剂10％氢氧化钯/碳，在一个大气压的氢气气氛下室温搅拌2天，用聚四氟乙烯滤头滤掉钯催化剂，旋蒸浓缩，粗品使用C18柱纯化，超纯水洗脱，苯酚-硫酸法检测，收集产物冻干，得到白色固体钠盐的甘露糖磷酸化衍生物。
7.一种药物组合物，其特征在于：包括权利要求1-5任一所述的通式I、通式II表示的磷酸化甘露糖衍生物、其药学上可接受的盐或药学上可接受的溶剂合物，和药学上可接受的赋形剂。
8.如权利要求7所述的药物组合物的应用，其特征在于：所述药物组合物用于制备治疗乳腺癌、前列腺癌、肾细胞癌、脑癌、卵巢癌、结肠癌、膀胱癌、胰腺癌、胃癌、食道癌、皮肤黑素瘤、肝癌、肺癌、直肠癌、小肠癌、甲状腺癌、霍奇金淋巴瘤、唇腔癌、皮肤癌、白血病或多发性骨髓瘤药物中的应用。
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