CN106046028B - 具有组蛋白去甲基化酶抑制活性天然产物的合成 - Google Patents
具有组蛋白去甲基化酶抑制活性天然产物的合成 Download PDFInfo
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- CN106046028B CN106046028B CN201610392119.7A CN201610392119A CN106046028B CN 106046028 B CN106046028 B CN 106046028B CN 201610392119 A CN201610392119 A CN 201610392119A CN 106046028 B CN106046028 B CN 106046028B
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- 229930014626 natural product Natural products 0.000 title claims abstract description 17
- 230000015572 biosynthetic process Effects 0.000 title description 7
- 230000002401 inhibitory effect Effects 0.000 title description 6
- 102000008157 Histone Demethylases Human genes 0.000 title description 4
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- 238000003786 synthesis reaction Methods 0.000 title description 3
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- XHPIWHHLWCZQEF-QQUTXWOLSA-N luteoalbusin A Natural products C1=CC=C2C([C@@]34C[C@]56C(=O)N([C@@](C(=O)N5[C@H]4NC=4C3=CC=CC=4)(CO)SS6)C)=CNC2=C1 XHPIWHHLWCZQEF-QQUTXWOLSA-N 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- AKCLRALPZXLOBG-QQUTXWOLSA-N luteoalbusin B Natural products O=C1[C@@](SSS2)(CO)N(C)C(=O)[C@@]32C[C@]2(C=4C5=CC=CC=C5NC=4)C4=CC=CC=C4N[C@@H]2N31 AKCLRALPZXLOBG-QQUTXWOLSA-N 0.000 claims abstract description 17
- AKCLRALPZXLOBG-PVSGBFIBSA-N luteoalbusin b Chemical compound O=C1[C@@](SSS2)(CO)N(C)C(=O)[C@@]32C[C@@]2(C=4C5=CC=CC=C5NC=4)C4=CC=CC=C4N[C@@H]2N31 AKCLRALPZXLOBG-PVSGBFIBSA-N 0.000 claims abstract description 17
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 14
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- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 4
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 claims description 4
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract
本发明涉及天然产物Luteoalbusin A和B的全合成及其中应用的中间体化合物，利用经典的逆合成分析，成功合成了天然产物Luteoalbusin A和B，合成方法大大提高了收率，具有很强的医药工业的应用前景。
Description
技术领域
本发明涉及具有组蛋白去甲基化酶抑制活性天然产物Luteoalbusin A和B的全合成及其中应用的中间体化合物，属于有机化学领域。
背景技术
组蛋白是真核细胞中核小体的重要组成部分，其折叠区位于核小体的中心，组蛋白的结构和相互作用与DNA复制等密切相关。而组蛋白分子结构中位于核小体核心结构以外的部分常常发生翻译后修饰，例如甲基化、乙酰化、泛素化、磷酸化等。这些修饰是细胞信号通路的重要来源，可以影响组蛋白与DNA的亲和性而改变染色质的状态，也可以影响DNA与转录因子的结合，对基因表达调控起到决定性的作用。因此有“组蛋白密码”的称号。
表观遗传调控主要是针对组蛋白密码的调控。因此针对组蛋白乙酰化和甲基化的调控，是化学生物学和药物化学的研究热点。表观遗传学指的是：“在基因组序列不变的情况下，可以决定基因表达与否并可稳定遗传下去的调控密码”。这些密码包括DNA的“后天性”修饰(如甲基化修饰)、组蛋白的各种修饰等。其中组蛋白的修饰已经成为人们关注的重点，在针对癌症治疗药物开发方面占有越来越重要的地位。正如英国剑桥大学的NessaCarey在近期发表在MedChemComm上的综述文章所指出：表观遗传调控是正在兴起的、非常有前景的新的药物靶标，因为表观遗传调控癌细胞以及一些人类慢性疾病，为药物研发提供了新的契机(Med.Chem.Commun.,2012,3,162)。
而组蛋白赖氨酸和精氨酸上氨基和胍基都可能发生不同程度和形式的甲基化，目前已经发现不但有组蛋白甲基化酶，同样也存在组蛋白去甲基化酶，统称为组蛋白甲基转移酶。其中组蛋白可以发生甲基化的位点共有24个，7个是精氨酸，另外17个属于赖氨酸位点。组蛋白的甲基化过程影响到异染色质的形成、基因印记、X染色体失活和转录调控等多种生理功能，组蛋白甲基化的异常与多种人类疾病，例如肿瘤的发生密切相关。
在靶向组蛋白甲基化的药物研发方面，目前仍然处于起步阶段，例如针对EZH2和DOT1L(二者都是针对组蛋白H3的甲基化转移酶)的抑制剂研究目前仍然处于临床前研究阶段。但是毋庸置疑的是，针对组蛋白的甲基化过程，靶向组蛋白甲基化转移酶的药物研发将是近期研究的热点领域之一。
Luteoalbusin、Leptosin等化合物都是含有硫代哌嗪二酮结构的天然产物。这一类天然产物已经被证实具有靶向组蛋白甲基化转移酶的抑制活性，其抑制活性达到nM级别，对多种癌细胞起到明显的抑制作用。这类结构的天然产物有些目前已经进入临床前研究阶段。
Luteoalbusin A和B是在2012年从海洋真菌中分离得到，这是第一次从Acrostalagmus fungus菌种中分离得到这类结构的天然产物。在所测试的四种肿瘤细胞链中，Luteoalbusin A/B都表现了非常好的细胞毒性活性，相对于参照用药顺铂都要高出10-20倍以上。已经有研究表明含有硫代哌嗪二酮类结构的化合物可以靶向组蛋白甲基化转移酶，抑制肿瘤细胞的生长。
因此，基于上述描述，开发Luteoalbusin A和B全合成的工艺路线将会对于未来实现其工业化规模的制备具有重要的意义和应用价值，其也是目前的研究热点和重点，这也正是本发明得以完成的基础所在和动力所倚。
发明内容
如上所述，为了实现天然产物Luteoalbusin A和B的全合成，本发明人对此进行了深入的研究，在付出大量创造性劳动后，从而完成了本发明。
本发明涉及如下两个方面，更具体而言，第一个方面，本发明涉及Luteoalbusin A和B的合成方法。
1、Luteoalbusin A和B的逆合成分析
以Fisher的吲哚合成方法来构建3位吲哚基时发现这一步产率很低，且条件苛刻，需要160℃高温以50％的收率得到产物(从5到4，PG＝Ts)，且反应规模不能放大。以色氨酸为起始原料经中间体6合成化合物4，可以大大提高了合成效率。进一步的如果采用如下合成路线：
以色氨酸为原料根据已知方法制备溴代物9，再利用已知方法得到化合物10后准备脱除两个Boc保护基时发现所采用的反应条件都不能给出良好的收率：(1)TFA-DCM条件下底物分解；(2)TMSI-MeCN条件下产物产率仅30％；(3)TMSI-MeCN-DIPEA条件下则不发生反应；(4)TMSOTf-DCM-2,6-lutidine条件可以脱除保护基，但产物发生了消旋化。
鉴于此，我们将保护基换成了-Boc和-Cbz，修改的合成路线如下：
顺利得到化合物13后，经过氢化去除Cbz保护基，与N-甲基丝氨酸的偶联反应采用混酐条件，两步总收率达到98％以上获得化合物15。丝氨酸保护基以苄基(Bn)为最佳，采用Cbz保护时得不到目的产物。得到化合物15以后，氢化脱去Bn保护基，在碱性条件下关环得到重要中间体哌嗪二酮类化合物17。此反应中目标产物17与二聚体18的比例为1:1。
为了减小保护基对关哌嗪二酮环的影响，我们将保护基调整为了-Boc和-SO2Ph，修改后路线如下：
将N1位保护基更换为-SO2Ph以后，我们以近乎当量的收率得到了哌嗪二酮化合物24，而几乎没有发生二聚。接下来需要在两个酰胺键的α-位引入羟基，为二硫键的引入奠定基础。得到化合物24以后，我们尝试了一系列的条件对哌嗪二酮进行双羟化，然而都不反应或者痕量反应或者底物直接分解，具体如下表：
在保护基R1＝TBS时不反应。随后又将R1改为-Ac，这样在HMRS中可以看到少量的产物，但我们通过硅胶柱没有分离到产物。我们修改了反应路线，并为了提高反应的可行性，首先将-SO2Ph保护基换为Boc得到化合物26。此时我们采用了全新的氧化哌嗪二酮alpha-位的策略，在THF溶液中，-50度条件下通过氧气氧化的条件得到消除OTBS的中间体27，进一步的双羟基化反应顺利引入所需要的三个羟基，得到三醇化合物28。这两步操作实现了哌嗪二酮化合物alpha-位的官能团化，避免使用高毒性的高价锰盐和银盐等，反应易于操作且收率较高。得到三羟基化合物以后，经两步经典转化得到天然产物LuteoalbusinA(1)，Luteoalbusin A(1)与硫化钠在丙酮中反应则可以转化为Luteoalbusin B(2)。
具体而言，本发明总的合成路线如下：
化合物19与吲哚在三乙基硼、叔丁醇钾的存在下THF溶液中反应从而制备化合物20；
化合物20在三氟乙酸的DCM溶液中制备化合物21；
化合物21在二氯甲烷溶液中，N-甲基吗啡啉和氯甲酸乙酯存在下，与N-Bn-N-Me-OTBS-Ser反应制备化合物22；
化合物22在乙酸乙酯溶液中，氢氧化钯碳-氢气条件下反应制备化合物23；
化合物23在甲醇溶液中与氨水反应制备化合物24；
化合物24在N-甲基吡咯烷酮-叔丁醇(v/v＝1:1)混合溶剂中与二碘化钐反应，制备得到吲哚啉化合物，并进一步在乙腈中，加入DMAP和碳酸叔丁酯，反应得到化合物26；
化合物26在四氢呋喃溶液中，氧气氛围下，加入叔丁醇钾反应，所得粗产物在甲苯中，加入亚磷酸三乙酯反应，制备得到化合物27；
化合物27在丙酮水溶液中，加入N-甲基-N-氧化吗啉和四氧化锇，反应制备得到化合物28；
化合物28在DCM溶液中与三氟化硼乙醚和硫化氢反应，所得产物进一步在碘的乙酸乙酯溶液中反应制备得到Luteoalbusin A(1)；
Luteoalbusin A(1)进一步在硫化钠丙酮溶液中反应制备Luteoalbusin B(2)。
第二个方面，本发明涉及Luteoalbusin A和B的合成方法中的关键中间体化合物，具体如下：
具体实施方式
下面通过具体的实施例对本发明进行详细说明，但这些例举性实施方式的用途和目的仅用来例举本发明，并非对本发明的实际保护范围构成任何形式的任何限定，更非将本发明的保护范围局限于此。
实施例1
将1当量的式19化合物和0.5当量的吲哚溶解在THF中，使吲哚化合物的浓度为0.05M，并冷却到0℃。
然后向其中加入1当量的三乙基硼和1.5当量的叔丁醇钾(其中叔丁醇钾是以溶解在THF中的溶液形式加入的，其浓度为1.0M)，在0℃下搅拌反应2小时，然后加入氯化铵的饱和水溶液淬灭反应，加入足量的乙酸乙酯稀释反应体系，振荡分层，分离出有机相，并用饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物过硅胶柱色谱，以丙酮-正己烷混合溶剂(两者体积比为1:3)进行洗脱、分离纯化，得到式20化合物，产率为98.5％。
[α]D 20＝-23.6(c 1.0,CHCl3)。
1H NMR：(500MHz，CHCl3-d)δ7.76(s,1H),7.58(s,1H),7.48(d,J＝7.9Hz,1H),7.42-7.32(m,3H),7.32-7.28(m,2H),7.26-7.21(m,2H),7.18(s,1H),7.13(t,J＝7.5Hz,1H),7.04-6.97(m,2H),6.60(s,1H),6.03(s,1H),4.85(d,J＝110.0Hz,1H),3.19(s,3H),3.14(d,1H),2.80(d,J＝13.2Hz,1H),1.53(s,9H)。
13C NMR(125MHz,CDCl3)δ171.7,142.3,139.6,137.1,135.3,132.1,129.2,128.1,126.8,125.0,124.8,124.4,123.1,122.6,120.2,119.0,118.2,116.2,111.7,84.7,60.2,52.0,40.3,30.9,28.4。
实施例2
将化合物20溶解在二氯甲烷中，低温下加入三氟乙酸。室温反应2小时，减压除去溶剂和三氟乙酸得到胺基化合物21(三氟乙酸盐)。
将N-Bn-N-Me-OTBS-Ser溶解在二氯甲烷中，低温下加入N-甲基吗啡啉和氯甲酸乙酯，在该温度下反应一个小时。向反应体系中加入上步反应得到的氨基化合物21(溶解在二氯甲烷中)，室温反应8小时，然后加入氯化铵的饱和水溶液淬灭反应，加入足量的乙酸乙酯稀释反应体系，振荡分层，分离出有机相，并用饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物过硅胶柱色谱，以乙酸乙酯-正己烷混合溶剂(两者体积比为1:2)进行洗脱、分离纯化，得到式22化合物，两步产率为87％。
[α]D 20＝-10.4(c 1.0,CHCl3)。
1H NMR(500MHz,CDCl3)δ7.78(d,J＝8.1Hz,1H),7.70(d,J＝2.6Hz,1H),7.51(d,J＝8.1Hz,1H),7.42–7.36(m,1H),7.32(d,J＝8.1Hz,1H),7.26–7.24(m,1H),7.23–7.17(m,6H),7.14–7.09(m,2H),7.04(s,1H),6.99(d,J＝8.0Hz,2H),6.80–6.75(m,2H),6.69(t,J＝7.5Hz,1H),5.61(d,J＝2.5Hz,1H),5.21(d,J＝9.0Hz,1H),5.11(t,J＝6.5Hz,1H),4.33–4.27(m,1H),4.19(dd,J＝10.3,6.1Hz,1H),4.10–4.00(m,2H),3.75(s,1H),3.13(s,3H),3.08(dd,J＝13.3,9.0Hz,1H),2.74(d,J＝13.4Hz,1H),2.57(s,3H),0.98(s,9H),0.19(s,3H),0.15(s,3H)。
13C NMR(125MHz,CDCl3)δ172.3,171.3,142.2,140.2,137.9,136.8,136.4,132.5,129.4,129.2,129.0,128.2,127.9,127.2,126.6,126.0,125.5,124.2,123.0,122.6,120.5,119.9,119.4,111.4,84.5,64.6,59.7,58.8,58.3,57.9,52.0,39.6,38.8,26.0,18.2,-5.3,-5.4。
实施例3
将化合物22溶解在乙酸乙酯中，在氢氧化钯碳-氢气条件下室温反应2小时，过滤除去催化剂氢氧化钯碳，减压浓缩得到粗产品23。
将23溶解在甲醇中(浓度低于0.5％M)，室温加入氨水(30％wt)，然后室温反应12小时。减压除去甲醇，将残渣溶解在足量的乙酸乙酯中，振荡分层，分离出有机相，并用饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物过硅胶柱色谱，以丙酮-二氯甲烷混合溶剂(两者体积比为3:97)进行洗脱、分离纯化，得到式24化合物，两步产率为60％。
[α]D 20＝20.4(c 1.0,CHCl3)；
1H NMR(500MHz,CDCl3)δ7.85(brs,1H),7.74(d,J＝8.2Hz,1H),7.55–7.46(m,2H),7.43–7.33(m,2H),7.34–7.27(m,1H),7.24–7.17(m,1H),7.15–7.03(m,4H),7.01–6.90(m,2H),6.36(s,1H),6.05(d,J＝2.6Hz,1H),5.01(t,J＝9.0Hz,1H),4.25(dd,J＝10.4,2.4Hz,1H),3.98(dd,J＝10.6,2.8Hz,1H),3.91(t,J＝2.5Hz,1H),3.07(dd,J＝14.0,9.1Hz,1H),2.94(s,3H),2.90(dd,J＝14.0,8.9Hz,1H),0.91(s,9H),0.09(s,3H),0.08(s,3H)。
13C NMR(125MHz,CDCl3)δ168.2,167.5,139.6,137.9,137.3,136.9,132.7,128.9,128.37,127.6,125.1,124.7,124.5,123.1,122.7,120.1,118.8,117.1,115.8,111.7,83.8,67.4,62.8,57.4,54.6,37.3,32.0,25.9,18.3,-5.4,-5.6。
实施例4
将24溶解在N-甲基吡咯烷酮-叔丁醇(v/v＝1:1)混合溶剂中，并冷却至0℃，然后缓慢加入二碘化钐溶液。室温反应1.5小时，然后加入碳酸氢钠的饱和水溶液淬灭反应，加入足量的乙酸乙酯稀释反应体系，振荡分层，分离出有机相，并用饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物过硅胶柱色谱，以乙酸乙酯-正己烷混合溶剂(两者体积比为1:1)进行洗脱、分离纯化，得到吲哚啉化合物，产率为95％。
[α]D 20＝62.2(c 1.0,CHCl3)。
1H NMR (400MHz,CDCl3)δ8.31(brs,1H),7.36(d,J＝8.2Hz,1H),7.19–7.08(m,4H),6.96(t,J＝7.4Hz,1H),6.90(d,J＝7.3Hz,1H),6.71(d,J＝7.8Hz,1H),6.67(t,J＝7.4Hz,1H),6.04(d,J＝2.3Hz,1H),5.49(brs,1H),4.78(dd,J＝11.8,6.4Hz,1H),4.05(dd,J＝10.7,2.5Hz,1H),3.93(dd,J＝10.7,2.6Hz,1H),3.87(t,J＝2.6Hz,1H),3.29(dd,J＝13.3,6.4Hz,1H),2.98(s,3H),2.50(dd,J＝13.3,11.8Hz,1H),0.71(s,9H),-0.03(s,3H),-0.11(s,3H)。
13C NMR(100MHz,CDCl3)δ167.9,165.9,147.1,137.4,133.1,128.5,125.8,123.9,122.5,120.9,120.0,119.7,119.5,116.9,111.4,109.4,83.6,67.0,62.6,58.3,54.4,40.8,32.1,25.6,18.1,-5.6,-5.8。
实施例5
将所得到的吲哚啉化合物溶解在乙腈中，然后依次加入DMAP和碳酸叔丁酯。室温反应12小时，加入足量的乙酸乙酯稀释反应体系，依次用氯化铵饱和溶液、饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物过硅胶柱色谱，以乙酸乙酯-正己烷混合溶剂(两者体积比为1:2)进行洗脱、分离纯化，得到式26的化合物，产率为87％。
[α]D 20＝–31.8(c 1.0,CHCl3)。
1H NMR(400MHz,CDCl3)δ8.14(d,J＝8.4Hz,1H),7.70(d,J＝8.0Hz,1H),7.42(d,J＝7.9Hz,1H),7.36–7.30(m,2H),7.29–7.24(m,1H),7.23–7.18(m,1H),7.10–7.05(m,2H),6.30(s,1H),4.83(t,J＝8.9Hz,1H),4.18(dd,J＝10.6,2.5Hz,1H),3.94(dd,J＝10.6,2.7Hz,1H),3.78–3.74(m,1H),3.19(dd,J＝14.1,9.7Hz,1H),3.09(dd,J＝14.1,8.2Hz,1H),2.89(s,3H),1.62(s,9H),1.56(s,9H),0.91(s,9H),0.10(s,3H),0.09(s,3H)。
13C NMR(100MHz,CDCl3)δ167.8,165.5,152.2,149.5,140.4,136.5,135.9,128.8,127.7,124.7,124.6,123.9,123.9,122.7,121.7,119.3,116.8,115.9,84.1,82.1,81.4,67.1,62.9,56.4,52.6,37.3,32.0,28.2,28.1,25.8,18.2,-5.5,-5.5。
实施例6
将化合物26溶解在无水四氢呋喃中，冷却至零下60℃，在氧气氛围下加入叔丁醇钾的四氢呋喃溶液，低温反应半小时，然后加入氯化铵的饱和水溶液淬灭反应，加入足量的乙酸乙酯稀释反应体系，振荡分层，分离出有机相，并用饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物直接投下一步。
将上步反应所得粗产品溶解在甲苯中，然后加入亚磷酸三乙酯，室温反应1小时，加入足量的乙酸乙酯稀释反应体系，依次用水、饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物过硅胶柱色谱，以乙酸乙酯-正己烷混合溶剂(两者体积比为1:3)进行洗脱、分离纯化，得到式27的化合物，产率为80％。
[α]D 20＝5.3(c 0.5,CHCl3)。
1H NMR(500MHz,CDCl3)δ8.12(d,J＝8.1Hz,1H),7.81(d,J＝7.9Hz,1H),7.65(d,J＝8.1Hz,1H),7.31–7.34(m,2H),7.29–7.25(m,1H),7.22(t,J＝7.6Hz,1H),7.16(s,1H),7.07(dd,J＝8.1,7.1Hz,1H),6.74(s,1H),5.90(d,J＝1.5Hz,1H),4.99(d,J＝1.5Hz,1H),3.98(s,1H),3.59(d,J＝15.0Hz,1H),3.23(d,J＝15.1Hz,1H),3.11(s,3H),1.63(s,9H),1.57(s,9H)。
13C NMR(125MHz,CDCl3)δ164.6,158.5,152.0,149.5,140.5,138.4,136.4,136.1,128.9,127.8,124.7,124.4,124.3,124.0,122.9,121.2,119.9,117.3,115.7,105.3,86.7,84.1,82.4,81.8,52.0,46.3,30.3,28.3,28.2。
实施例7
将化合物27溶解在丙酮-水的混合溶剂中，然后依次加入N-甲基-N-氧化吗啉和0.03M的四氧化锇叔丁醇溶液。室温反应5小时，加入足量的乙酸乙酯稀释反应体系，依次用饱和硫代硫酸钠溶液、饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物过硅胶柱色谱，以乙酸乙酯-正己烷混合溶剂(两者体积比为1:2)进行洗脱、分离纯化，得到式28的混合物，产率为90％。
1H NMR(500MHz,CDCl3)δ8.10(7.96)(d,J＝10.0Hz,1H),7.89(7.63)(d,J＝10.0Hz,1H),7.55–7.36(m,1H),7.33–7.28(m,3H),7.24–7.20(m,1H),7.14–7.05(m,2H),6.57(6.55)(s,1H),6.32(5.76)(brs,1H),5.66(5.22)(br-s,1H),4.11–4.15(m,1H),4.01(3.86)(d,J＝10.0Hz,1H),3.79(s,1H),3.62(3.34)(d,J＝15.0Hz,1H),3.29–3.25(m,1H),2.97(2.92)(s,3H),1.63(s,9H),1.58(1.57)(s,9H)。
13C NMR(125MHz,CDCl3)δ168.4,167.1,166.8,166.5,152.7,152.5,149.6,140.0,139.7,136.5,136.4,135.9,129.1,129.0,128.0,127.8,125.0,124.8,124.8,124.7,124.4,124.3,123.0,123.0,121.2,120.8,120.1,120.0,116.9,116.9,115.6,115.5,87.3,86.9,85.3,84.9,84.2,84.1,83.1,82.9,82.12,82.0,77.3,77.0,76.8,63.4,63.3,52.3,51.7,46.1,44.9,29.7,28.4,28.2,27.3,26.9。
实施例8
零下78℃将硫化氢收集到封管中，在该温度下依次向封管中加入化合物28(溶解在无水二氯甲烷中)和三氟化硼乙醚，缓慢升至室温，并室温反应2小时。反应体系冷却至零下78℃，将封管塞子换位橡胶塞，通过双面针头将体系与含有碱液的尾气处理装置连接，缓慢升至室温，硫化氢气体挥发完毕后继续向体系中通入氩气10分钟，加入适量的乙酸乙酯溶解残渣，依次用氯化铵饱和溶液、饱和食盐水洗涤，然后向有机相中加入2当量的碘单质(溶解在乙酸乙酯中)，室温反应5分钟，加入硫代硫酸钠饱和溶液淬灭反应，依次用饱和硫代硫酸钠溶液、饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物过硅胶柱色谱，以乙酸乙酯-正己烷混合溶剂(两者体积比为1:3)进行洗脱、分离纯化，得到天然产物Luteoalbusin A，产率为55％。
1H NMR(500MHz,丙酮-d6)δ10.24(br-s,1H),7.57(d,J＝8.2Hz,1H),7.43(d,J＝8.1Hz,1H),7.34(d,J＝7.5Hz,1H),7.15(d,J＝2.3Hz,1H),7.12(dd,J＝8.0,7.5,1H),7.12(dd,J＝7.9,7.4,1H),7.00(dd,J＝8.0,7.5,1H),6.78(d,J＝8.1,1H),6.77(dd,J＝8.0,7.5,1H),6.21(br-s,1H),5.99(s,1H),4.42(d,J＝12.6Hz,1H),4.35(d,J＝12.7Hz,1H),4.06(d,J＝15.2Hz,1H),3.18(s,3H),3.10(d,J＝15.3Hz,1H)。
13C NMR(125MHz,丙酮-d6)δ168.1,164.4,150.7,139.6,134.5,130.6,127.1,125.9,124.8,123.7,121.1,121.1,120.8,118.4,113.8,111.6,85.1,79.1,76.1,61.8,57.6,45.7,28.7。
实施例9
将Luteoalbusin A溶解在丙酮中，室温加入Na2S，反应一小时后加入足量的乙酸乙酯稀释反应体系，依次用水、饱和食盐水洗涤，然后将有机相用无水硫酸钠干燥、减压浓缩，所得粗产物过硅胶柱色谱，以乙酸乙酯-正己烷混合溶剂(两者体积比为1:2)进行洗脱、分离纯化，得到天然产物Luteoalbusin B，总产率为68％。
1H NMR(500MHz,丙酮-d6)δ10.23(br-s,1H),7.53(d,J＝7.7Hz,1H),7.40(d,J＝7.6Hz,1H),7.22(d,J＝7.8Hz,1H),7.20(d,J＝2.5Hz,1H),7.15(dd,J＝7.8,7.6,1H),7.11(dd,J＝7.6,7.6,1H),6.95(dd,J＝7.6,7.5,1H),6.80(d,J＝7.8,1H),6.69(dd,J＝7.6,7.6,1H),6.41(br-s,1H),5.86(s,1H),4.32(d,J＝11.7Hz,1H),3.97(d,J＝11.7Hz,1H),3.78(d,J＝14.6Hz,1H),3.28(s,3H),3.24(d,J＝14.8Hz,1H)。
13C NMR(125MHz,丙酮-d6)δ170.6,166.3,152.4,139.5,133.5,131.1,126.9,126.3,125.8,123.6,121.1,121.1,120.7,118.5,113.7,111.8,84.3,78.0,81.3,63.2,55.5,51.8,28.8。
综上所述，发明人付出了大量的创造性劳动，完成了天然产物Luteoalbusin A和B的全合成，大大提高了其合成的收率，这对于天然产物Luteoalbusin A和B的工业化生产的研究具有非常重要的意义。
应当理解，这些实施例的用途仅用于说明本发明而非意欲限制本发明的保护范围。此外，也应理解，在阅读了本发明的技术内容之后，本领域技术人员可以对本发明作各种改动、修改和/或变型，所有的这些等价形式同样落于本申请所附权利要求书所限定的保护范围之内。
Claims (5)
1.一种天然产物Luteoalbusin A的合成方法，其特征在于所述方法的合成路线如下：
。
2.如权利要求1所述的合成方法，其特征在于：
化合物19与吲哚在三乙基硼、叔丁醇钾的存在下THF溶液中反应从而制备化合物20；
化合物20在三氟乙酸的DCM溶液中制备化合物21；
化合物21在二氯甲烷溶液中，N-甲基吗啡啉和氯甲酸乙酯存在下，与N-Bn-N-Me-OTBS-Ser反应制备化合物22；
化合物22在乙酸乙酯溶液中，氢氧化钯碳-氢气条件下反应制备化合物23；
化合物23在甲醇溶液中与氨水反应制备化合物24；
化合物24在N-甲基吡咯烷酮-叔丁醇v/v＝1:1混合溶剂中与二碘化钐反应，制备得到吲哚啉化合物，并进一步在乙腈中，加入DMAP和碳酸叔丁酯，反应得到化合物26；
化合物26在四氢呋喃溶液中，氧气氛围下，加入叔丁醇钾反应，所得粗产物在甲苯中，加入亚磷酸三乙酯反应，制备得到化合物27；
化合物27在丙酮水溶液中，加入N-甲基-N-氧化吗啉和四氧化锇，反应制备得到化合物28；
化合物28在DCM溶液中与三氟化硼乙醚和硫化氢反应，所得产物进一步在碘的乙酸乙酯溶液中反应制备得到Luteoalbusin A。
3.一种天然产物Luteoalbusin B的合成方法，其特征在于：根据权利要求1-2中任一项所述的合成方法制备得到Luteoalbusin A，将其在硫化钠丙酮溶液中反应制备Luteoalbusin B。
4.一种用于合成Luteoalbusin A或B的中间体化合物，其特征在于：所述化合物的结构如下
。
5.一种用于合成Luteoalbusin A或B的中间体化合物，其特征在于：所述化合物的结构如下
。
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| Convergent and Biomimetic Enantioselective Total Synthesis of (-)-Communesin F;Stephen P. Lathrop et al.;《J. Am. Chem. Soc.》;20160531;第138卷;第7763-7769页 * |
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