CN110818750A - 一种甜菊苷r的合成方法 - Google Patents
一种甜菊苷r的合成方法 Download PDFInfo
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- CN110818750A CN110818750A CN201911151812.5A CN201911151812A CN110818750A CN 110818750 A CN110818750 A CN 110818750A CN 201911151812 A CN201911151812 A CN 201911151812A CN 110818750 A CN110818750 A CN 110818750A
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- 235000019203 rebaudioside A Nutrition 0.000 description 1
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- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
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- 238000007738 vacuum evaporation Methods 0.000 description 1
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Abstract
本发明首次公开了一种甜菊苷R的制备方法,本发明采用汇聚式合成路线,从原料1和2出发,通过6步反应以19.4%总收率得到甜菊苷R。为该类化合物的高效多样化合成提供了一个简洁可实施的策略。
Description
发明领域
本发明属于有机合成领域,涉及一种甜菊苷R的合成方法。
背景技术
甜菊糖是从甜叶菊(Stevia rebaudiana Bertoni)的叶片中提取的贝壳杉烷型二萜双糖链糖苷混合物,其甜度为蔗糖的150-300倍,为强力甜味剂。和其他甜味剂比较具有使用成本低(和蔗糖相比可降低成本60%以上)、性质稳定(耐高温及酸碱)、使用安全性高(长期毒理、药理研究表明甜菊苷的主要成分在体内不参与代谢、不蓄积、无毒性及遗传性危害,且摄入体内后不会引起血糖升高和胰岛素水平的改变,因此也适用于糖尿病患者等优点。其安全性已通过美国食品药品监督管理局(FDA)的GRAS级别的安全认证,并已经得到FAO及WHO等国际组织的认可。与此同时,研究证实甜菊糖为低热量甜味剂,长期使用不会引起体重的增加,因此受到减肥人士的钟爱。更为重要的是甜菊糖除了甜味剂的作用以外还具有保健功效,适量摄入甜菊糖具有降血糖、降血压、预防龋齿、消炎及抗癌作用,对肥胖病、糖尿病、心脏病、高血压、动脉硬化及龋齿等疾病具有辅助疗效,这必将极大拓展甜菊糖的应用范围。可靠的安全性及重要的保健效果使得甜菊糖在世界范围内得到广泛应用,如可口可乐公司Fanta Still饮料,德国Eches-Granini公司推出的Joker Vital Equilibre品牌的低糖花蜜,法国公司Taillefine保健品牌的果酸乳等都使用了甜菊糖作为甜味剂,从而使得甜菊糖在整个甜味剂领域的市场份额比重迅速攀升至40%以上。而蔗糖这一传统甜味剂则逐年下滑,从2010年的63.9%下降为2011年的58%,逐渐形成了甜味剂市场甜菊糖和蔗糖‘共制’的局面。因此,全球范围内对甜菊糖的需求量也逐年攀升,统计表明,目前全球甜菊糖年需求量为1.5万吨,而目前产能仅为5000吨,因此可以预计甜菊糖产业的未来发展市场前景广阔,经济效益可观。
甜菊糖的生产在我国已有二十多年的历史,经过二十多年的发展,我国已成为世界上最大的甜菊糖生产国和出口国,但总体而言我国甜菊糖产业发展水平还较低,主要以甜叶菊的大面积种植和甜菊糖粗提物的出口为主,不具备深加工的能力,产品附加值低。而我国出口到美国、日本及东南亚的甜菊糖粗产品经过精制后产品附加值获得大幅度提升。
造成我国甜菊糖产业发展滞后的根本原因是针对制约甜菊糖产业发展的因素开展的基础性研究少且研究前瞻性差。目前制约甜菊糖产业发展的不利因素主要包括甜菊糖甜味剂后涩味的口感、甜菊糖的质量控制问题及甜叶菊的大面积种植压缩粮食生产耕地潜在威胁国家粮食安全三大问题。
解决甜菊糖类甜味剂口感不理想的根本途径是新型甜菊糖甜味剂的研发。目前,纯甜菊糖甙的获取高度依赖于与天然来源的直接分离。由于天然甜菊糖甙具有很高的微异质性,因此甜菊糖甙个体与天然来源的直接分离既繁琐又具有挑战性,因此仅适用于获取具有高自然含量的成员。酶促合成确实可以提供甜菊苷衍生物,但是,由于酶促合成的起始原料中存在多个反应位点,因此无法避免复杂的分离过程。只有化学合成是解决含量低甜菊糖苷大量获取的唯一可靠途径。但是,目前为止,甜菊醇糖苷的化学合成仅有少量报到,并且由于使用了常规的糖基化方法,整体效率远远不能令人满意。
天然甜菊糖苷的高度异质性导致迄今已分离和鉴定了50多种甜菊糖苷,例如甜菊苷(Stevioside)、甜菊苷A(Rebaudioside A,简称Reb A),甜菊苷D (Rebaudioside D,简称Reb D)、甜菊苷M(Rebaudioside M,简称Reb M),甜菊苷R(Rebaudioside R,简称Reb R)和甜菊苷S(Rebaudioside S,简称Reb S),而且其数量仍在迅速增加。CN 109021038 A公开一种汇聚式的合成甜菊苷Reb A,Reb D和Reb M的方法。Reb A,Reb D和Reb M三个分子的糖类组成部分全部是葡萄糖,有着相同的苷元部分。本发明人在CN 109021038 A公开了Reb A,Reb D和Reb M的汇聚式合成方法,其中C13糖链的引入方法为:先引入核心位置的葡萄糖,再同时在核心糖的2’,3’位引入两个支链葡萄糖。
2016年,Mc Chesney及其同事分离得到甜菊苷R与同类物显着不同,它具有木糖基部分作为C13糖链的核心糖。本发明人采用CN 109021038A,先引入核心糖木糖,但在同时在核心糖的2’,3’位引入支链葡萄糖时,仅得到12%的3 糖收率。因此,引入甜菊苷R的C13糖链的方法有待优化。
发明内容
本发明要解决的第一个技术问题是,提供一种甜菊苷R的制备方法,以方便在天然物种含量低的甜菊苷R的大量获取。
为解决上述技术问题,本发明采取的技术方案如下:
一种甜菊苷的制备方法,包括以下步骤:
(1)第一溶剂中,TMSOTf催化下,化合物1和化合物2发生糖苷化反应,得到化合物3,
(2)化合物3脱除异头位保护基MP后得到半缩醛中间体,再以ABz保护半缩醛中间体的异头位羟基,得到化合物4,
(3)化合物4和化合物5在乙腈中,金催化剂作用下,发生糖苷化反应,得到化合物6和化合物7,
(4)化合物6在HOAc和TBAF作用下,发生脱保护反应,得到化合物8,
(5)第二溶剂中,K2CO3和TBAB催化下,化合物8和化合物9发生糖苷化反应,得到化合物10,
(6)化合物10脱去所有保护基即可,
步骤(1)中,所述第一溶剂为CH2Cl2,所述糖苷化反应的温度为0~-78℃,化合物1和化合物2的摩尔比为3:1~1:1,TMSOTf和化合物2的摩尔比0.1:1~1:1;
步骤(2)中包括以下步骤:
(2a)将化合物3溶解在乙腈和pH为7的缓冲液的混合溶剂中,添加CAN 搅拌15-30分钟得到半缩醛中间体;
(2b)将步骤(2a)中得到的半缩醛中间体溶于无水CH2Cl 2中,向其中加入ABzOH,iPr2NEt,DMAP,在氮气气氛下,于0℃加入EDCI,然后使反应混合物升温至室温,并在相同温度下继续搅拌6~8小时;
步骤(3)中,所述金催化剂为Ph3PAuNTf2或Ph3PAuOTf,所述金催化剂和化合物4的摩尔比为0.01:1~1:1;化合4和化合物5的摩尔比为3:1~1:1,化合物5在乙腈中的浓度为0.1~0.01mol/L;
步骤(4)中,所述脱保护反应的溶剂为THF,所述脱保护反应的温度为室温,化合物6、HOAc和TBAF的摩尔比为1:2:1~1:4:2;化合物6在所述溶剂中的浓度为0.01~0.1mol/L;
步骤(5)中,所述糖苷化反应的温度为室温~40℃,所述第二溶剂为氯仿和水的混合溶剂,化合物8、K2CO3、TBAB和化合物9的摩尔比为1:3:2:2~1:1:1:1;
步骤(6)中,包括以下步骤:
(6a)第三溶剂中,化合物10,在DDQ作用下脱去NAP保护基,得到C3′-OH 中间体;
(6b)第四溶剂中,步骤(6a)中得到的C3′-OH中间体在NaOMe作用下脱去所有Bz保护基即可。
优选的,步骤(1)中,所述糖苷化反应的温度为-40℃~-78℃,化合物2在 CH2Cl2中的浓度为0.1~0.3mmol/L,TMSOTf和化合物2的摩尔比为0.6:1~0.8:1。
优选的,步骤(2a)中,所述缓冲液为PH=7的磷酸二氢钾/磷酸氢二钠缓冲溶液,乙腈和所述缓冲液的体积比为1:1~5:1,更优选的为4.1:1~5:1,CAN和化合物3的摩尔比为3:1~5:1,化合物3在所述混合溶液中的浓度为0.03~0.1mol/L。
优选的,步骤(2b)中,所述半缩醛中间体、ABzOH、iPr2NEt、DMAP和 EDCI的摩尔比为1:1.5:3:2:3~1:1.5:4:2:4。
优选的,步骤(3)中,所述金催化剂为Ph3PAuNTf2,所述金催化剂和化合物4的摩尔比为0.1:1~0.2:1;化合物4和化合物5的摩尔比为1.5:1~1:1;化合物 5在乙腈中的浓度为0.01~0.02mol/L。
优选的,步骤(5)中,所述氯仿和水的体积比为1:1~1:1.5。
优选的,步骤(6a)中,所述第三溶剂为CH2Cl2和CH3OH的混合溶剂,化合物10和DDQ的摩尔比为1:3~1:5,化合物10在所述混合溶剂中的浓度为 0.01~0.02mol/L,更优选的,CH2Cl2和CH3OH的体积比为3:1~5:1。
优选的,步骤(6b)中,所述第四溶剂为甲醇、所述C3’-OH中间体在第四溶剂中的浓度为0.01~0.25mol/L。
优选的,步骤(1)、步骤(3)或步骤(5)中任一步骤在无水无氧条件下进行。
本发明步骤(3)的反应条件是经过系统研究得到的。
由表1可知,当3糖给体异头位为α-TCA时,以TMSOTf(0.2当量)作为催化,仅检测到化合物7,但在其他条件相同的条件下,将B(C6F5)3用作催化剂,糖基化产物的分离比例为1:1α/β混合物(6:7=1:1)。但是B(C6F5)3-催化与乙腈溶剂的组合,即使在高温下也未观察到反应。但是,在室温下,在Ph3PAuNTf2 的催化下,以化合物4作为供体,在CH2Cl2中获得的3.7:1的α/β比(产率为57%)。通过将反应温度调节至-40℃至rt,可提高收率和α/β的比例(条目5,α/β=2.9:1,86%)。使用Ph3PAuNTf2催化与乙腈溶剂的组合,化合物 6成为主要产物,总收率达到74%。
本发明以容易获得的单糖以及甜菊醇为原料,完成了在C13-OH连接的糖链中具有木糖基核心的甜菊苷R的第一个全合成。本发明通过融合策略引入C13 三糖糖链,在安装甜菊醇糖苷配基之前先制备了支链C13三糖链,并且在随后的糖基化步骤中,通过带有C2-OH支链的三糖供体的糖基化步骤,通过金催化剂和乙腈溶剂的组合作用确保了令人满意的β-立体选择性,从而确保了整体合成效率。该策略相对于线性合成减少了合成步骤,不需要使用过多的保护基操作,增加了整体的合成效率,为大量合成β-立体选择性的三糖提供了高效的方法。
有益效果:
1.本发明采用汇聚式合成路线,从原料1和2出发,通过7步反应以19.4%总收率得到甜菊苷R。
2.本发明简洁高效的合成了甜菊苷R,为该类化合物的高效多样化合成提供了一个有效的策略,同时本发明提供了一种新型的高纯品甜菊苷,可作为一种新型的食品甜味剂。
本发明中缩写的含义如下:
具体实施方式
本发明中未特别指出的试剂、原料或化合物均为市售,或经由市售试剂通过本领域常规方法制备。
本发明中,室温为20~25℃。
本发明中部分化合物的制备方法如下:
(1)化合物1的制备方法
从葡萄糖出发,经过3步反应,以70%的收率得到化合物1。.
(2)化合物2的制备方法
化合物11参考J.Carbohydr.Chem.2007,26,61-82中方法制备,再将4位羟基将化合物11(5.9g,19.9mmol)溶解在无水DMF(25mL),在0℃分批加入NaH(0.96g, 40.0mmol)。N2气氛下,搅拌20分钟后,将NapBr(5.27g,23.8mmol)添加至反应混合物中,再在该温度下搅拌3小时。将反应用水淬灭,用乙酸乙酯稀释,用水和盐水洗涤,然后用无水Na2SO4干燥,过滤,然后减压浓缩,得到粗产物,将其通过硅胶柱色谱法(PE/EA=10∶1)进一步纯化,得到化合物12(8g,92%), [α]D 25=-34.1(c 1.4,CHCl3);1H NMR(400MHz,Acetone-d6)δ7.89(d,J=8.8Hz,4H),7.53– 7.48(m,3H),7.03(d,J=9.2Hz,2H),6.86(d,J=9.2Hz,2H),5.36(d,J=7.2Hz,1H),4.94(d, J=12.0Hz,1H),4.80(d,J=12.4Hz,1H),4.19(dd,J=12.4,4.8Hz,1H),4.00-3.96(m,1H), 3.90(dd,J=9.2,8.4Hz,1H),3.74(s,3H),3.68(dd,J=9.6,7.2Hz,1H),3.62(dd,J=12.4,6.0 Hz,1H),1.48(s,3H),1.47(s,3H);13C NMR(100MHz,Acetone-d6)δ156.2,151.7,137.1,134.3,134.0,128.9,128.8,128.6,127.1(2C),126.8(2C),118.9,115.3,112.4,101.1,81.2,77.5, 77.3,72.2,66.3,55.9,27.3,27.1;HRMS(ESI-TOF)calcd for C26H28O6K[M+K]+ 475.1517,found 475.1514.
室温下,将化合物12(2g,4.6mmol)溶解于在MeOH(10mL)和DCM(10 mL)的混合溶剂中,添加樟脑-10-磺酸(CSA,107mg,0.46mmol)。将反应混合物在相同温度下搅拌2小时,待TLC显示原料完全消失,用Et3N淬灭反应,减压除去溶剂,得到粗产物,将其通过硅胶柱色谱法进一步纯化(PE/EA=2∶ 1),得到化合物2(1.6g,4mmol,89%)。[α]D25=-39.3(c 1.0,CHCl3);1H NMR (400MHz,Acetone-d6)δ7.88-7.85(m,4H),7.53(dd,J=8.4,1.6Hz,1H),7.48-7.45(m,2H),6.99(d,J=9.2Hz,2H),6.81(d,J=9.2Hz,2H),4.96(d,J=12.0 Hz,1H),4.85(d,J=12.4Hz,1H),4.81(d,J=7.6Hz,1H),4.00(ddd,J=11.6,5.2, 2.4Hz,1H),3.70(t,J=8.4,4H),3.62-3.56(m,1H),3.50(dd,J=8.8,7.2Hz,1H), 3.41-3.35(m,1H);13C NMR(100MHz,Acetone-d6)δ206.6,154.7,151.2,136.2, 132.9,132.6,127.5,127.4,127.2,125.8,125.6(2C),125.4,117.8,113.9,102.1,77.1, 75.4,73.1,72.2,63.1,54.6,28.7;HRMS(ESI-TOF)calcd for C23H25O6[M+H]+ 397.1646,found 397.1651.
从市售甜菊醇出发,在碱性条件下,和TBDPSCl反应,通过本领域常规反应条件,即可得到化合物5,谱图数据和CN109021038A一致。
(3)化合物9的制备方法
氮气保护下,将全苯甲酰基保护葡萄糖(58g)溶于干燥的DCM(100mL)中,室温下搅拌溶解,冰浴下加入HBr/HOAc(61mL),缓慢升至室温,室温下搅拌3h, DCM稀释,水洗三次,饱和碳酸氢钠洗三次,饱和氯化钠洗一次,无水硫酸钠干燥有机相,过滤悬干,得化合物9,白色固体51g,收率为:93%。1H NMR (400MHz,Acetone-d6):δ7.35-8.09(m,20H,4×Bz),7.14(d,1H,J=3.98Hz, H-1),6.25(t,1H,J=9.8Hz,H-3),6.03(t,1H,J=9.9Hz,H-4),6.28(dd,1H,J= 3.9,9.8Hz,H-2),4.85-4.90(m,1H,H-5),4.62-4.73(m,2H,H-6a,H-6b).
实施例1:
步骤1:4-甲氧基苯基-2,3-二-O-(2,3,4,6-四-O-苯甲酰基-β-D-葡萄糖吡喃糖基) -4-O-(2-萘甲基)-β-D-木糖吡喃糖苷(3)
室温,氮气气氛下,向1(280mg,0.38mmol)和2(50mg,0.126mmol) 的无水CH2Cl2(1mL)溶液中加入活化的粉末状4A分子筛(80mg)。将得到悬浮液在相同温度下搅拌30分钟,然后冷却至-40℃,向其中加入TMSOTf (14.4μL,0.08mmol)。反应液在-40℃下再搅拌1小时后,添加Et3N以淬灭反应。过滤后,减压浓缩,并将所得残余物通过硅胶柱色谱纯化得到化合物3(150mg, 77%),为无色泡沫。[α]D 25=+70.8(c 0.5,CHCl3);1H NMR(400MHz,CDCl3)δ8.33(d,J=7.2Hz,2H),8.26(d,J=7.2Hz,2H),7.98-7.28(m,47H),6.85(d,J=9.2 Hz,2H),6.58(d,J=8.8Hz,2H),5.87(q,J=9.6Hz,2H),5.66-5.53(m,4H),5.01(d, J=12.4Hz,1H),4.92(d,J=8.0Hz,2H),4.83(dd,J=12.0,7.6Hz,2H),4.44-4.26 (m,3H),4.18(dd,J=12.0,3.6Hz,1H),4.08(t,J=8.8Hz,1H),3.90-3.83(m,2H), 3.67-3.63(m,4H),3.31(dd,J=12.0,9.2Hz,1H),2.81-2.77(m,1H),2.73-2.69(m, 1H);13C NMR(100MHz,CDCl3)δ166.0(2C),165.8,165.2,165.1,165.0(2C), 154.9,151.3,136.0,133.8,133.6(2C),133.5,133.4,133.3,133.1(2C),133.0,130.3, 130.2,129.8(3C),129.7(2C),129.6,129.5(2C),129.4(2C),129.0(2C),128.9, 128.8,128.5(2C),128.4(2C),128.3,128.2,128.0,127.8,126.7,126.1,125.9,125.8, 117.8,114.5,100.7,100.4,100.2,81.1,79.7,77.4,74.7,73.6,73.1,72.8,72.7,72.6, 71.6,71.4,69.7,69.0,63.9,62.7,62.3,55.6;HRMS(ESI-TOF)calcd for C91H80NO24 [M+NH4]+1570.5065,found 1570.5138.
步骤2:2,3-二-O-(2,3,4,6-四-O-苯甲酰基-β-D-吡喃葡萄糖基)-4-O-(2-萘甲基)]-α/β-D-吡喃木糖基-环丙基乙炔基苯甲酸酯(4)
在0℃下,向3(600mg,0.386mmol)在乙腈(10.7mL)和缓冲液(2.7mL, pH 7.0)的混合溶剂中的搅拌溶液中添加CAN(636mg,1.16mmol)。反应液在相同温度下再搅拌15分钟,然后加入乙酸乙酯。得到的溶液依次用饱和 NaHCO3水溶液,水和盐水洗涤,然后用无水Na2SO4干燥。过滤后浓缩,得到的粗产物通过硅胶柱色谱法(PE/EA=2:1)进一步纯化,得到半缩醛中间体 (500mg,89%),未经表征直接用于下一步骤。将上述获得的半缩醛中间体(500 mg,0.34mmol)溶于无水CH2Cl2(3mL)中,向其中加入ABzOH(96.5mg, 0.518mmol),iPr2NEt(0.172mL,1.04mmol),DMAP(84mg,0.69mmol),在氮气气氛下于0℃加入EDCI(198mg,1.04mmol)。然后使反应混合物升温至室温,并在相同温度下继续搅拌6小时。加入乙酸乙酯以稀释反应混合物,所得溶液用水,盐水洗涤,然后经无水Na2SO4干燥。过滤后浓缩,得到残余物,将其进一步通过硅胶色谱法纯化(PE/EA=3:1),以α/β端基异构体的混合物 (α/β)的形式提供4(550mg,88%,2步收率,α/β=3:1)。纯α的-异构体被分离以进行详细表征。[α]D 25=+63(c 2.5,CHCl3);1H NMR(400MHz,CDCl3)δ 8.28(d,J=7.2Hz,4H),8.05(d,J=7.6Hz,1H),7.96-7.70(m,20H),7.66-7.28(m, 24H),7.15(d,J=8.0Hz,2H),6.29(d,J=3.6Hz,1H),5.77(t,J=10.0Hz,1H), 5.67-5.40(m,5H),5.07(d,J=12.0Hz,1H),4.84(d,J=12.0Hz,1H),4.79(d,J= 7.6Hz,1H),4.58(d,J=7.6Hz,1H),4.38(dd,J=12.0,3.6Hz,1H),4.29-4.20(m, 4H),3.79(dd,J=9.2,3.6Hz,1H),3.71-3.58(m,3H),2.71-2.67(m,1H),2.60-2.55 (m,1H),1.59-1.52(m,1H),0.87-0.84(m,4H);13C NMR(100MHz,CDCl3)δ165.0, 164.9(3C),164.2,164.0(2C),163.7,163.5,134.9,133.1,132.8,132.7,132.6,132.4 (2C),132.3,132.2,132.1(2C),130.8,130.7,130.2,129.2,129.1,128.9(2C),128.8, 128.6(2C),128.5(2C),128.1,128.0,127.9,127.8,127.6,127.5(3C),127.3,127.2, 127.0,126.8,126.3,125.8,125.1,124.9(2C),123.9,99.5(2C),98.7,91.6,78.1,76.4, 76.0,73.5,73.4,73.1,72.2,71.7,71.3,71.2,71.1,70.3,68.5(2C),61.7,61.5,61.1, 8.1,8.0,-.012;HRMS(ESI-TOF)calcd for C97H79O26[M+HCOO]-1659.4854,found1659.4876.
步骤3:13-O-[2,3-二-O-(2,3,4,6-四-O-苯甲酰基-β-D-葡萄糖吡喃糖基)-4-O-(2-萘甲基)-α-D-木糖吡喃糖基]-甜菊醇叔丁基二苯甲硅烷基酯(6和7)
在室温下,在N2气氛下,向供体4(44mg,0.027mmol)和受体5(10mg, 0.018mmol)的无水CH3CN(1mL)溶液中加入活化的4A分子筛(100mg)。将悬浮液在相同温度下搅拌30分钟,然后冷却至-40℃。在-40℃加入Ph3PAuNTf2 (4mg,0.005mmol)之后,将混合物温热至室温,并继续搅拌另外10h。过滤后浓缩,得到粗产物,将其通过硅胶柱色谱法(PE/EA=4:1)进一步纯化,得到白色固体6(18.8mg,53%)和7(7.5mg,21%)c。6:[α]D 25=+24.9(c 1.4,CHCl3);1H NMR(400MHz,CDCl3)δ8.28(t,J=7.2Hz 4H),7.93-7.85(m,12H), 7.81-7.64(m,13H),7.57-7.52(m,4H),7.47-7.20(m,28H),5.89-5.80(m,2H),5.62 (dd,J=10.0,8.0Hz,1H),5.56-5.46(m,3H),4.97(s,1H),4.93(d,J=12.8Hz,1H), 4.86(d,J=7.6Hz,1H),4.77(d,J=7.6Hz,1H),4.76(d,J=12.4Hz,1H),4.58(s, 1H),4.49(d,J=6.4Hz,1H),4.24-4.17(m,4H),3.94(t,J=8.8Hz,1H),3.70-3.62 (m,2H),3.54-3.48(m,1H),3.07(dd,J=11.6,9.6Hz,1H),2.64-2.51(m,2H),2.25 (d,J=13.2Hz,1H),2.0(d,J=16.4Hz,1H),1.94(d,J=10.8Hz,1H),1.86-1.76(m, 6H),1.65-1.61(m,3H),1.48-1.40(m,4H),1.35-1.26(m,3H),1.23(s,3H),1.15(s, 9H),1.03-0.76(m,6H),0.74(s,3H);13C NMR(100MHz,CDCl3)δ176.5,165.8 (2C),165.7,165.5,164.9,164.7(2C),153.0,135.9,135.4(2C),133.3(2C),133.2, 133.1,133.0(2C),132.8,132.7,131.9(2C),129.9(2C),129.8,129.7,129.6,129.5 (2C),129.4,129.3,129.2(2C),128.8(2C),128.6,128.2(2C),128.0(2C),127.9, 127.7,127.5,127.4,126.3,125.8,125.6,125.5,104.2,100.1(2C),96.7,84.7,81.9, 79.1,77.0,74.8,73.3,72.8,72.7,72.4(2C),71.2,71.1,69.4,69.3,63.4,62.7,62.4, 56.8,53.7,46.7,45.0,43.2,42.5,41.1,40.4,39.2,38.5,35.9,29.1,26.9,21.9,20.1, 19.2,19.1,16.2;HRMS(ESI-TOF)calcd for C120H116O25SiNa[M+Na]+ 2008.7499,found 2008.7461.7:[α]D 25=+42.0(c 1.0,CHCl3);1H NMR(400MHz, CDCl3)δ8.38-8.34(m,4H),8.00-7.66(m,24H),7.64-7.27(m,29H),5.84(t,J=9.6 Hz,1H),5.78(t,J=9.6Hz,1H),5.65(dd,J=9.6,7.6Hz,1H),5.62-5.57(m,2H), 5.50(t,J=9.6Hz,1H),5.44(s,1H),5.16(d,J=12.0Hz,1H),5.03(s,1H), 4.97-4.92(m,3H),4.63(d,J=8.0Hz,1H),4.44-4.29(m,4H),4.12(dd,J=12.4,4.4 Hz,1H),3.72(t,J=10.4Hz,1H),3.57-3.48(m,3H),2.81-2.77(m,1H),2.60-2.55 (m,1H),2.27(d,J=13.6Hz,1H),1.90-1.78(m,7H),1.66-1.43(m,7H),1.28(s,3H), 1.16(s,9H),1.05-0.91(m,4H),0.74(s,3H);13C NMR(100MHz,CDCl3)δ176.8, 166.0,165.9(2C),165.7,165.1(2C),164.9,164.7,150.1,136.2,135.7,135.6,133.6 (2C),133.5,133.4,133.3,133.1(2C),133.0,132.1,132.0,130.2(2C),130.0,129.9, 129.8(2C),129.7(2C),129.6(2C),129.5(2C),129.4,129.0(2C),128.9,128.8, 128.6,128.4(2C),128.3,128.2,128.1,127.8,127.6,126.9,126.1,126.0,125.8,105.7, 100.5,100.0,93.4,85.6,78.2,78.0,77.3,75.7,74.1,73.5,72.8,72.5,72.1,71.7,71.3, 69.5,69.4,62.8,61.9,59.7,57.1,53.6,47.6,45.2,43.7,41.6,41.3,40.7,39.5,39.2, 38.7,29.8,29.3,27.2(2C),22.2,20.0,19.4,19.3,16.2;HRMS(ESI-TOF)calcd for C120H116O25SiNa[M+Na]+2008.7500,found 2008.7492.
步骤4:13-O-[2,3-二-O-(2,3,4,6-四-O-苯甲酰基-β-D-葡萄糖吡喃糖基)-4-O-(2-萘基甲基)-β-D-木糖吡喃糖基]-甜菊醇(8)
在室温下,向6(128mg,0.064mmol)的无水THF(5mL)溶液中添加HOAc (7.3μL,0.128mmol)和TBAF(1N THF溶液,0.07mL)。在相同温度下搅拌反应30分钟后,加入乙酸乙酯以稀释反应混合物。依次用水和盐水洗涤所得溶液,然后用无水Na2SO4干燥。过滤后真空浓缩,得到粗产物,将其通过硅胶柱色谱法进一步纯化(PE/EA=2:1),得到8(107mg,95%),为无色泡沫。8[α]D 25= +15.8(c 1.0,CHCl3);1H NMR(400MHz,Acetone-d6)δ8.29(dd,J=7.6,2.8Hz, 4H),7.99-7.87(m,16H),7.71-7.65(m,6H),7.61-7.45(m,13H),7.39-7.32(m,8H),6.05-5.96(m,2H),5.81-5.65(m,4H),5.16-5.11(m,3H),4.99(d,J=12.4Hz,1H), 4.86(d,J=12.4Hz,1H),4.69(s,1H),4.60(d,J=6.4Hz,1H),4.44-4.33(m,4H), 4.04(t,J=8.8Hz,1H),3.86-3.77(m,2H),3.62-3.56(m,1H),3.26-3.21(m,1H), 3.15-3.06(m,2H),2.19(t,J=12.0Hz,2H),2.08-1.88(m,6H),1.78(d,J=12.4Hz, 1H),1.67-1.27(m,8H),1.21(s,3H),1.12-0.75(m,8H);13C NMR(100MHz, Acetone-d6)δ178.9,166.5,166.2,166.0,165.8,165.7,165.5,165.4,153.5,137.4, 134.5,134.4,134.3(2C),134.1,133.8(3C),130.7,130.5(4C),130.4(2C),130.3 (2C),130.2,130.1(2C),129.9,129.8(2C),129.7,129.4(2C),129.3(2C),129.1, 128.7(2C),128.5,127.1,126.9(2C),126.5,104.9,101.0,100.8,97.6,86.4,82.5,79.9, 75.3,73.9,73.8,73.7,73.6,73.3,72.3,70.6,70.4,64.0,63.8,63.5,57.3,54.5,48.1, 44.4,44.0,42.7,42.1,41.3,40.1,38.8,38.2,30.5,30.3,30.1,29.9,29.7,29.5,29.3, 29.2,22.7,20.8,19.9,16.4;HRMS(ESI-TOF)calcd for C104H98O25Na[M+Na]+ 1770.6323,found 1770.6304.
步骤5:13-O-[2,3-二-O-(2,3,4,6-四-O-苯甲酰基-β-D-葡萄糖吡喃糖基)-4-O-(2-萘基甲基)-β-D-木糖吡喃糖基]-甜菊醇(2,3,4,6-四-O-苯甲酰基-β-D-吡喃葡萄糖基)酯(10)
室温下,向8(107mg,0.061mmol)的氯仿和水(3mL,v/v=1:1)混合溶液中加入K2CO3(25.3mg,0.18mmol)和TBAB(39.4mg,0.122mmol),搅拌 10分钟后,加入过苯甲酰化的葡糖基溴化物9(80.6mg,0.122mmol)。在40℃下再搅拌14小时后,将反应混合物冷却至室温。加入乙酸乙酯以稀释反应混合物,所得溶液依次用水和盐水洗涤,并用无水Na2SO4干燥。真空过滤并蒸发,得到粗产物,将其通过硅胶柱色谱法进一步纯化(PE/THF=2.5:1),得到9(118mg,83%),为无色泡沫。[α]D 25=+56.6(c 2.0,CHCl3);1H NMR(400MHz,CDCl3) δ8.30(dd,J=7.6,5.2Hz,4H),8.06(d,J=7.6Hz,2H),7.97-7.76(m,22H),7.69(t, J=8.0Hz,4H),7.57-7.21(m,36H),6.17(d,J=8.0Hz,1H),5.97(t,J=9.6Hz,1H), 5.90-5.76(m,4H),5.66(dd,J=9.6,8.0Hz,1H),5.59-5.50(m,3H),5.01(s,1H), 4.95(d,J=12.1Hz,1H),4.90(d,J=7.6Hz,1H),4.83(d,J=7.6Hz,1H),4.79(d,J =12.1Hz,1H),4.66(dd,J=12.3,3.6Hz,2H),4.57-4.53(m,2H),4.30-4.18(m,5H), 3.98(t,J=8.8Hz,1H),3.76(dd,J=11.6,5.6Hz,1H),3.68(dd,J=9.2,6.4Hz,1H), 3.59-3.53(m,1H),3.17(dd,J=11.6,9.2Hz,1H),2.62-2.57(m,2H),2.23(d,J= 13.2Hz,1H),2.06-1.99(m,2H),1.88-1.71(m,7H),1.47-1.26(m,11H),0.99-0.83 (m,5H),0.76(s,3H);13C NMR(100MHz,CDCl3)δ175.2,166.1,166.0(2C),165.9, 165.7(2C),165.2,165.1,165.0,164.8,152.8,136.2,133.6,133.5,133.4(3C),133.3, 133.2,133.0(2C),130.2,129.9,129.8(2C),129.7(3C),129.6(3C),129.4,129.1, 129.0,128.9,128.8(2C),128.7(2C),128.5(2C),128.4(3C),128.3,128.2,128.1, 128.0,127.7,126.5,126.0,125.9,125.7,104.6,100.4,100.2,96.8,91.6,85.4,82.1, 79.2,77.5,75.0,73.5,73.1,73.0,72.8,72.7,72.6,71.5,71.3,71.0,69.6,69.3,63.7, 62.9,62.6,57.2,54.0,47.3,44.1,43.5,42.5,41.3,40.4,39.4,37.8,36.9,32.0,29.7, 28.8,22.8,21.5,20.2,19.3,16.3,14.2;HRMS(ESI-TOF)calcd forC138H124O34Na[M +Na]+2348.7900,found 2348.7875.
步骤6:甜菊苷R
向10(118mg,0.051mmol)的CH2Cl2(2.9mL)和CH3OH(0.9mL)的溶液中添加DDQ(34.7mg,0.153mmol)。将悬浮液在室温下搅拌6小时,然后加入乙酸乙酯以稀释反应混合物。将所得混合物用饱和NaHCO3水溶液和盐水洗涤,用无水Na2SO4干燥。过滤并减压浓缩,得到残余物,将其通过硅胶柱色谱法纯化(PE/EA=1.5∶1),得到C3′-OH中间体(100mg,91%)。直接用于下一步反应。将获得的C3’-OH中间体溶解在无水MeOH(4mL)中,在室温下向其中加入新鲜制备的NaOMe(在1mL无水MeOH中)。将反应混合物在相同温度下搅拌1小时,然后用Amberlite(H+)中和。减压浓缩后进行过滤,得到粗产物,将其通过RP-18硅胶柱纯化(MeOH/H2O=2:1),得到Reb R(41mg, 86%,2步),为白色固体。[α]D 25=-30.3(c 0.2,CH3OH);1HNMR(400MHz, pyridine-d5)δ6.14(d,J=8.0Hz,1H),5.58(s,1H),5.53(d,J=7.6Hz,1H),5.32(d, J=7.6Hz,1H),4.99(s,1H),4.94(d,J=7.2Hz,1H),4.56(dd,J=11.6,2.4Hz,1H), 4.49(dd,J=11.6,2.8Hz,1H),4.42(dd,J=12.0,2.4Hz,1H),4.36-4.31(m,2H),4.29-4.18(m,7H),4.14-4.10(m,4H),4.07-3.89(m,5H),3.45(dd,J=11.6,9.6Hz, 1H),2.53(d,J=11.2Hz,1H),2.35(t,J=12.4Hz,2H),2.18-1.18(m,6H),1.72-1.65 (m,4H),1.43-1.30(m,3H),1.25(s,3H),1.23(s,3H),1.02(d,J=12.4Hz,2H),0.89 (d,J=6.8Hz,1H),0.73(dd,J=15.2,10.8Hz,1H);13C NMR(101MHz, pyridine-d5)δ177.3,154.1,105.4,105.1,105.0,98.7,96.3,87.9,87.2,80.7,79.7, 79.3,79.0,78.9(2C),78.5 76.3,75.8,74.4,72.4,72.1,71.3,70.2,66.3,63.6,62.9, 62.5,57.8,54.7,50.1,48.5,44.7,44.4,42.7,42.2,41.1,40.2,38.9,38.4,29.0,22.6, 20.9,19.9,16.1;HRMS(ESI-TOF)calcdfor C43H72NO22[M+NH4]+954.4540, found 954.4556.
实施例2:
参考实施例的方法制备。所不同的是:
步骤(1)中化合物1和化合物2的摩尔比为1:1,TMSOTf和化合物2的摩尔比为0.7:1;
步骤(2a)中乙腈和所述缓冲液的体积比为1:1,CAN和化合物3的摩尔比为5:1,化合物3在所述混合溶液中的浓度为0.1mol/L;
步骤(2b)中,所述半缩醛中间体、ABzOH、iPr2NEt、DMAP和EDCI的摩尔比为1:1.5:4:2:4;
步骤(3)中,Ph3PAuNTf2和化合物4的摩尔比为0.1:1,化合物4和化合物5 的摩尔比为1:1;化合物5在乙腈中的浓度为0.01mol/L。
步骤(4)中,化合物6、HOAc和TBAF的摩尔比为1:4:2;化合物6在所述溶剂中的浓度为0.02mol/L;
步骤(5)中,氯仿和水的体积比为1:1.5,化合物8、K2CO3、TBAB和化合物9的摩尔比为1:1:1:1;
步骤(6a)中,CH2Cl2和CH3OH的体积比为5:1,化合物10和DDQ的摩尔比为1:5,化合物10在所述混合溶剂中的浓度为0.02mol/L;
步骤(6b)中,所述第四溶剂为甲醇、所述C3’-OH中间体在第四溶剂中的浓度为0.01~0.02mol/L。
对比例1~5:
给体、催化剂和溶剂分别采用表1中对比例1~5的条件,其他反应条件和实施例1,步骤(3)相同,实验结果见表1。
表1:不同给体、催化剂和溶剂对合成化合物6和7的糖苷化反应的影响
当量指和给体的摩尔比。
Claims (10)
2.如权利要求1所述的甜菊苷R的制备方法,其特征在于:
步骤(1)中,所述第一溶剂为CH2Cl2,所述糖苷化反应的温度为0~-78℃,化合物1和化合物2的摩尔比为3:1~1:1,TMSOTf和化合物2的摩尔比0.1:1~1:1;
步骤(2)中包括以下步骤:
(2a)将化合物3溶解在乙腈和pH为7的缓冲液的混合溶剂中,添加CAN搅拌15-30分钟得到半缩醛中间体;
(2b)将步骤(2a)中得到的半缩醛中间体溶于无水CH2Cl2中,向其中加入ABzOH,iPr2NEt,DMAP,在氮气气氛下,于0℃加入EDCI,然后使反应混合物升温至室温,并在相同温度下继续搅拌6~8小时;
步骤(3)中,所述金催化剂为Ph3PAuNTf2或Ph3PAuOTf,所述金催化剂和化合物4的摩尔比为0.01:1~1:1;化合4和化合物5的摩尔比为3:1~1:1,化合物5在乙腈中的浓度为0.1~0.01mol/L;
步骤(4)中,所述脱保护反应的溶剂为THF,所述脱保护反应的温度为室温,化合物6、HOAc和TBAF的摩尔比为1:2:1~1:4:2;化合物6在所述溶剂中的浓度为0.01~0.1mol/L;
步骤(5)中,所述糖苷化反应的温度为室温~40℃,所述第二溶剂为氯仿和水的混合溶剂,化合物8、K2CO3、TBAB和化合物9的摩尔比为1:3:2:2~1:1:1:1;
步骤(6)中,包括以下步骤:
(6a)第三溶剂中,化合物10,在DDQ作用下脱去NAP保护基,得到C3′-OH中间体;
(6b)第四溶剂中,步骤(6a)中得到的C3′-OH中间体在NaOMe作用下脱去所有Bz保护基即可。
3.如权利要求2所述的甜菊苷R的制备方法,其特征在于:步骤(1)中,所述糖苷化反应的温度为-40℃~-78℃,化合物2在CH2Cl2中的浓度为0.1~0.3mmol/L,TMSOTf和化合物2的摩尔比为0.6:1~0.8:1。
4.如权利要求2所述的甜菊苷R的制备方法,其特征在于:步骤(2a)中,所述缓冲液为PH=7的磷酸二氢钾/磷酸氢二钠缓冲溶液,乙腈和所述缓冲液的体积比为1:1~5:1,CAN和化合物3的摩尔比为3:1~5:1,化合物3在所述混合溶液中的浓度为0.03~0.1mol/L。
5.如权利要求2所述的甜菊苷R的制备方法,其特征在于:步骤(2b)中,所述半缩醛中间体、ABzOH、iPr2NEt、DMAP和EDCI的摩尔比为1:1.5:3:2:3~1:1.5:4:2:4。
6.如权利要求2所述的甜菊苷R的制备方法,其特征在于:步骤(3)中,所述金催化剂为Ph3PAuNTf2,所述金催化剂和化合物4的摩尔比为0.1:1~0.2:1;化合物4和化合物5的摩尔比为1.5:1~1:1;化合物5在乙腈中的浓度为0.01~0.02mol/L。
7.如权利要求2所述的甜菊苷R的制备方法,其特征在于:步骤(5)中,所述氯仿和水的体积比为1:1~1:1.5。
8.如权利要求2所述的甜菊苷R的制备方法,其特征在于:步骤(6a)中,所述第三溶剂为CH2Cl2和CH3OH的混合溶剂,化合物10和DDQ的摩尔比为1:3~1:5,化合物10在所述混合溶剂中的浓度为0.01~0.02mol/L。
9.如权利要求2所述的甜菊苷R的制备方法,其特征在于:步骤(6b)中,所述第四溶剂为甲醇、所述C3’-OH中间体在第四溶剂中的浓度为0.01~0.25mol/L。
10.如权利要求1或2所述的甜菊苷R的制备方法,其特征在于:步骤(1)、步骤(3)或步骤(5)中任一步骤在无水无氧条件下进行。
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