Enantioselective total synthesis of 13,14,15-isocrambescidin 800
Enantioselective total synthesis of 13,14,15-isocrambescidin 800
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DOI：
10.1021/ja990992c
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发表时间：
1999-07-28
影响因子：
15
通讯作者：
Stappenbeck, F
中科院分区：
文献类型：
--
作者：
Coffey, DS;McDonald, AI;Stappenbeck, F
海甘蓝是一种鲜红色的硬壳海绵，通常发现于地中海岩石海岸沿着的浅水处，是结构新颖的生物活性生物碱的丰富来源。[2] Rinehart和他的同事[3]以及后来Braekman和他的小组[4]描述了一系列复杂的胍类生物碱，包括13，14，15-isocrambescidin 800（1）、crambescidin 800（2）和crambescidin 816（3），来自C.海甘蓝Kashman、Kakisawa和同事早些时候从加勒比海和红海采集的海绵中报道了相关的生物碱Ptilomycalin A（4）。5 Ptilomycalin A5，6和几种crambescidin 3，4显示出显著的抗肿瘤、抗病毒和抗真菌活性。由于其低丰度，13，14，15-异克拉贝西汀800尚未被广泛筛选，尽管据报道其对L-1210细胞的细胞毒性低于其他克拉贝西汀。3b crambescidin生物碱的定义结构特征是通过直链ω-羟基羧酸间隔基连接到亚精胺或羟基亚精胺单元的五环胍。广泛的NMR研究表明，2-4的五环核的相对立体化学是相同的，3，4，而13，14，15-异红贝西汀800（1）在C13，C14和C15是差向异构的。通过氧化降解这些生物碱的氧杂环庚烯环以产生（S）-2-羟基丁酸（3b）来确定1和3的胍部分的绝对构型，而使用Mosher方法指定3的羟基培脒单元的绝对构型。4 b，7由于1的羟基嘧啶片段中的1H NMR和13 C NMR化学位移与2和3的几乎相同，因此假定所有crambescidin的C43立体化学是相同的。4 b 1995年，我们报道了（-）-ptilomycalin A（4）的对映选择性全合成，这是第一个（也是迄今为止唯一一个）crambescidin生物碱家族成员的全合成。8，9在此，我们公开了13，14，15-异克拉贝西啶800（1）的对映选择性全合成，其首次使克拉贝西啶家族的这一稀有成员可用于详细的药理学筛选。合成的定义反应是胍基缩醛胺14与β-酮酯15的栓系-Biginelli缩合10，11;该反应将1的胍核的所有原子结合在一起，并设定关键的C10-C13立体关系。如方案1所述，由3-丁炔-1-醇（5）制备二烯13，C1-C13胍基缩醛胺的前体。C3立构中心通过Weber和Seebach 12的方法通过在（-）-TADDOL（20摩尔%）和Ti（Oi-Pr）4的存在下使ynal 6与Et 2 Zn缩合来引入，以94%产率和> 98%ee得到（S）-7。以60-70%的产率生成二烯酮10。在Amberlyst-15存在下，10与原酸酯1116和1，3-丙二醇的缩酮化以80%产率提供12。用叠氮化物对仲醇进行Mitsunobu置换，还原成伯胺，并与1H-吡唑-1-甲脒盐酸盐17缩合，以约30%的总收率从6得到胍13。
Crambe crambe, a bright red encrusting sponge commonly found at shallow depths along the rocky coast of the Mediterranean, is a rich source of structurally novel, bioactive alkaloids. 2 Rinehart and co-workers3 and later Braekman and his group, 4 described a series of complex guanidinium alkaloids, including 13, 14, 15-isocrambescidin 800 (1), crambescidin 800 (2), and crambescidin 816 (3), from C. crambe. The related alkaloid, ptilomycalin A (4), was reported earlier by Kashman, Kakisawa, and co-workers from sponges collected in the Caribbean and Red Sea. 5 Ptilomycalin A5, 6 and several of the crambescidins3, 4 show substantial antitumor, antiviral, and antifungal activities. As a result of its low abundance, 13, 14, 15-isocrambescidin 800 has not been extensively screened, although it is reported to be less cytotoxic to L-1210 cells than other crambescidins. 3b The defining structural feature of the crambescidin alkaloids is a pentacyclic guanidine linked by a straight chain ω-hydroxycarboxylic acid spacer to a spermidine or hydroxyspermidine unit. Extensive NMR studies demonstrated that the relative stereochemistry of the pentacyclic cores of 2-4 is identical, 3, 4 while 13, 14, 15-isocrambescidin 800 (1) is epimeric at C13, C14, and C15. 3b, 4b The absolute configuration of the guanidine moieties of 1 and 3 was established by oxidative degradation of the oxepene rings of these alkaloids to yield (S)-2-hydroxybutanoic acid, 3b while the absolute configuration of the hydroxyspermidine unit of 3 was assigned using Mosher’s method. 4b, 7 Since 1H NMR and 13C NMR chemical shifts in the hydroxyspermidine fragments of 1 are nearly identical to those of 2 and 3, it has been assumed that the stereochemistry at C43 is the same for all crambescidins. 4b In 1995 we reported an enantioselective total synthesis of (-)-ptilomycalin A (4), which was the first (and to date only) total synthesis of a member of the crambescidin alkaloid family. 8, 9 Herein, we disclose an enantioselective total synthesis of 13, 14, 15-isocrambescidin 800 (1) which for the first time makes this rare member of the crambescidin family available for detailed pharmacological screening. The defining reaction of the synthesis is a tethered-Biginelli condensation10, 11 of guanidino aminal 14 with β-ketoester 15; this reaction unites all of the atoms of the guanidine core of 1 and sets the pivotal C10-C13 stereorelationship. 10bDiene 13, the precursor of the C1-C13 guanidino aminal, was prepared from 3-butyne-1-ol (5) as summarized in Scheme 1. The C3 stereocenter was introduced by the method of Weber and Seebach12 through condensation of ynal 6 with Et2Zn in the presence of (-)-TADDOL (20 mol%) and Ti (Oi-Pr) 4 to give (S)-7 in 94% yield and> 98% ee. Standard manipulations yielded iodide 8 which was converted to the corresponding lithium reagent and coupled with 913-15 to generate dienone 10 in 60-70% yield. Ketalization of 10 with ortho ester 1116 and 1, 3-propanediol in the presence of Amberlyst-15 provided 12 in 80% yield. Mitsunobu displacement of the secondary alcohol with azide, reduction to the primary amine, and condensation with 1H-pyrazole-1-carboxamidine hydrochloride17 furnished guanidine 13 in∼ 30% overall yield from 6.