CN105541779B - 一种海洋天然产物Haterumadienone的合成方法 - Google Patents

一种海洋天然产物Haterumadienone的合成方法 Download PDF

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CN105541779B
CN105541779B CN201610001069.5A CN201610001069A CN105541779B CN 105541779 B CN105541779 B CN 105541779B CN 201610001069 A CN201610001069 A CN 201610001069A CN 105541779 B CN105541779 B CN 105541779B
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haterumadienone
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王洪双
李惠静
吴彦超
周培林
张振国
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Harbin Institute of Technology Weihai
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Abstract

本发明涉及一种海洋天然产物Haterumadienone的合成方法，属于化学合成领域。本发明以（‑）香紫苏醛和环戊二酮为起始原料，经过（‑）香紫苏醛和烷基保护的环戊二酮的aldol反应制备双环倍半萜的beta‑羟基环戊酮，从而构建出Haterumadienone的骨架；通过酸催化的羟基进攻羰基的亲核反应关环‑消除反应，最终合成海洋天然产物Haterumadienone。本发明具有反应步骤少、操作简便、产物选择性好、适合工业化生产等特点。

Description

一种海洋天然产物Haterumadienone的合成方法
技术领域
本发明涉及一种海洋天然产物Haterumadienone的合成方法。
背景技术
海洋天然产物Haterumadienone属于新型的Puupehenone类天然产物（见附图1）。Puupehenone是1979年夏威夷海绵中分离提取出来的，它的衍生物是重要的海洋代谢物呈现出包括细胞毒性、抗病毒、抗癌、抗真菌、抗疟疾、抗结核和免疫调节等多种生物活性(Pure and Applied Chemistry, 1979, 51(9): 1893-1900; The Journal of Organic Chemistry, 1995, 60(22): 7290-7292; Journal of natural products, 1998, 61(12): 1502-1508)。而本专利中涉及的衍生物的结构与Puupehenone有较大的不同，除了具有共同的倍半萜烯部分和含氧六元吡喃杂环以外，Puupehenone的首端是共轭的六元不饱和烯酮并烯醇的莽草酸类结构，而Haterumadienone的首端则是五元不饱和烯酮环。
Haterumadienone首次于2005年，分离自Dysidea sp.种属的Okinawan 海绵体(Chemistry Letters, 2005, 34(11): 1530-1531), 具有抗细菌，抗真菌，抑制海胆受精卵分裂等生物活性(Heterocycles, 2007, 72: 655-663; Tetrahedron, 2007, 63(6):1380-1384)。鉴于其属于Puupehenone的衍生物，因此，可能还具备潜在的抗病毒、抗癌、抗真菌、抗疟疾、抗结核和免疫调节等生物活性。
鉴于上述论述，开发一种海洋天然产物Haterumadienone的化学合成方法就显得尤为必要。但是，到目前为止关于海洋天然产物Haterumadienone的合成并无报道。本发明是首次报道该天然产物的合成方法，且具备反应步骤少、操作简便、产物选择性好、适合工业化生产等优点。
发明内容
本发明目的在于提供一种海洋天然产物Haterumadienone的合成方法。反应步骤少、产物选择性好、适合工业化生产。
1. 为实现上述目的，本发明包括以下步骤：
a)环戊二酮2经过与脂肪醇反应，合成烷基保护的环戊二酮3；
b)烷基保护的环戊二酮3和（-）香紫苏醛4在碱催化下经aldol反应，合成骨架双环倍半萜的beta-羟基环戊酮5；
c)双环倍半萜的beta-羟基环戊酮5通过酸催化的羟基进攻羰基的亲核反应关环，同时完成半缩醛羟基、烷基保护基、beta-羟基的消除反应，最终合成海洋天然产物Haterumadienone 1。
2.所述步骤a优化方案：环戊二酮与脂肪醇的烷基基保护反应，优先选择对甲苯磺酸、硫酸、盐酸、乙酸、三氟乙酸等为催化剂，甲醇或乙醇或丙醇或异丙醇等醇类为反应保护基，反应温度为0 oC到回流，反应时间为1-12小时条件。
3.所述步骤b优化方案：烷基保护的环戊二酮3和（-）香紫苏醛4在碱催化下的adol反应，优先选择LDA, n-BuLi, KHMDS, LHMDS等有机碱为强碱，四氢呋喃为溶剂，反应温度为-78 °C，反应时间为3-24小时条件。
4.所述步骤c优化方案：双环倍半萜的beta-羟基环戊酮5的关环反应，优先选择对甲苯磺酸为催化剂，苯为溶剂，反应温度为0 oC到回流，反应时间为1-12小时条件。
本发明具有以下特点：
1．本发明为首次报道海洋天然产物Haterumadienone的合成方法；
2．本发明以已知的环戊二酮和（-）香紫苏醛为起始原料，具有反应步骤少, 适合工业化生产；
3．总收率高、产物选择性好。
附图说明
附图1：海洋天然产物Haterumadienone及Puupehenone结构式图；附图2：本发明具体合成路线图。
具体实施方式
实施例1：乙氧基保护的环戊二酮（3，见附图2）的合成
取环戊二酮0.98 克（2，10.0mmol）溶于25毫升无水乙醇中，加入盐酸（1 mmol），室温下搅拌反应3小时，TLC检测反应结束。加入水30毫升，二氯甲烷萃取（30 mL x 3），合并有机相，饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析提纯，得淡黄色油状物乙氧基保护的环戊二酮1.07 克，收率为85%。
实施例2：双环倍半萜的beta-羟基环戊酮（5，见附图2）的合成
取乙氧基保护的环戊二酮126毫克（3，1.0 mmol）溶于2毫升无水四氢呋喃中，反复充排氩气三次，排尽空气，降温至-78 oC。加入LDA（3 mmol），保持在该温度下搅拌反应30分钟。另取（-）香紫苏醛238毫克（4，1.0 mmol）溶于1毫升无水四氢呋喃中，缓慢滴加至上述反应体系中，继续搅拌反应12小时，TLC检测反应结束。向反应体系中滴加饱和氯化铵溶液5毫升，淬灭反应，室温下继续搅拌30 分钟。乙酸乙酯萃取（10 mL x 3），合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析提纯，得白色固体双环二萜的beta-羟基环戊酮273 毫克，收率为75%。
实施例3：Haterumadienone（1，见附图2）的合成
取双环倍半萜的beta-羟基环戊酮182毫克（5，0.5 mmol）溶于2毫升苯中，加入对甲苯磺酸（0.5 mmol），室温下搅拌反应3小时，TLC检测反应结束。加入乙酸乙酯10毫升，饱和食盐水洗涤（10 mL x 3），有机相用无水硫酸钠干燥，过滤，浓缩，柱层析提纯，得淡黄色固体105毫克，收率为70%。旋光[α]D 25-73.6° (c = 0.15, CHCl3); 核磁共振氢谱1H NMR(400 MHz, C6D6) σ5.61 (s, 1H), 5.28 (d, 1H), 2.83 (d, 1H), 2.75 (d, 1H), 1.96(td, 1H), 1.36(m, 1H), 1.31 (m, 2H), 1.26 (m, 1H), 1.25 (m, 2H), 1.03 (dt,1H), 0.95 (s, 3H), 0.80 (s, 3H), 0.74 (s, 3H), 0.5 (s, 3H), 0.67(dt, 1H),0.67(dd, 1H); 核磁共振碳谱13C NMR (75 MHz, C6D6) σ199.2, 177.9, 132.9, 121.2,110.1, 80.1, 53.8, 53.7, 41.8, 39.8, 39.4, 39.4, 37.8, 33.6, 33.1, 28.5,22.0, 18.4, 18.3, 14.5; ;高分辨质谱HRMS (TOF MS ES+) m/z: Calcd forC20H28Cl3O2Na [M+Na]+: 323.1988. Found:323.1776.
本发明涉及环戊二酮烷基保护反应、烷基保护的环戊二酮与香紫苏醛aldol缩合反应、酸催化的双环倍半萜的beta-羟基环戊酮关环-消除3步反应，合成海洋天然产物Haterumadienone。上述具体实施举例仅是本发明的较佳实例而已，并非是对本发明作其它形式的限制。

Claims (4)

1.一种海洋天然产物Haterumadienone的合成方法，其特征在于，包括以下合成步骤：
a)环戊二酮2
Figure FDA0002137861390000011
在酸催化下，经过与醇ROH反应，合成烷基保护的环戊二酮3
Figure FDA0002137861390000012
b)烷基保护的环戊二酮3
Figure FDA0002137861390000013
和(-)香紫苏醛4
Figure FDA0002137861390000014
在碱催化下经aldol反应，合成骨架双环倍半萜的beta-羟基环戊酮5
Figure FDA0002137861390000015
c)双环倍半萜的beta-羟基环戊酮5
Figure FDA0002137861390000016
通过酸催化的羟基进攻羰基的亲核反应关环-消除反应，最终合成海洋天然产物Haterumadienone 1
Figure FDA0002137861390000017
2.根据权利要求1所述的海洋天然产物Haterumadienone的合成方法，步骤a)优先选择对甲苯磺酸、硫酸、盐酸、乙酸、三氟乙酸为催化剂，甲醇、乙醇、丙醇、异丙醇为反应保护基，反应温度为0℃到回流，反应时间为1-12小时的条件。
3.根据权利要求1所述的海洋天然产物Haterumadienone的合成方法，步骤b)优先选择LDA、n-BuLi、KHMDS、LHMDS为碱，四氢呋喃为溶剂，反应温度为-78℃，反应时间为3-24小时的条件。
4.根据权利要求1所述的海洋天然产物Haterumadienone的合成方法，步骤c)优先选择对甲苯磺酸为催化剂，苯为溶剂，反应温度为0℃到回流，反应时间为1-12小时的条件。
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Haterumadienone: A New Puupehenone Congener from an Okinawan Marine Sponge, Dysidea sp.;Katsuhiro Ueda et al.;《Chemistry Letters》;20051015;第34卷(第11期);第1530-1531页 *
Studies on puupehenone-metabolites of a Dysidea sp.:structure and biological activity;M. Letizia Ciavatta et al.;《Tetrahedron》;20061220;第63卷;第1380-1384页 *

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