Enantioselective synthesis of (+)-monobromophakellin and (+)-phakellin: A concise phakellin annulation strategy applicable to palau'amine
Enantioselective synthesis of (+)-monobromophakellin and (+)-phakellin: A concise phakellin annulation strategy applicable to palau'amine
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DOI：
10.1002/anie.200703998
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Romo, Daniel
中科院分区：
文献类型：
--
作者：
Wang, Shaohui;Romo, Daniel
一族天然产物(1a-c)属于吡咯咪唑类海绵生物碱家族，被认为是由oroidin(3)和相关的同系物(方案1)生物合成得到的。[1]这类海洋生物碱因其有趣的结构特征和在某些情况下具有强大的生物活性而引起了合成和生物学方面的极大兴趣。单体吡咯咪唑类化合物(±)-二溴甲壳蛋白(1a)和(±)-单溴甲壳蛋白(1b)是1969年由Burkhold和Sharma从海绵Phakellia flabellata中分离得到的。[2]1985年从圆锥拟黄杆菌中分离到对映体(+)-二溴甲壳蛋白(Et-1a)。[3]Phakellins(1c和Et-1c)没有分离出来，而是通过氢解得到的。二聚吡咯咪唑生物碱Palau amine(4)[5]和相关的同系物[1]在其结构中含有phakellin亚单位，最近提出了对该分子的立体化学修正。[6]Foley和Büchi报道的Rac-dibromophakellin的简明仿生合成为这些生物碱的合成提供了基准。[7A]事实上，大多数后续的外消旋phakellin和phakellstatin生物碱的合成都使用了相关的氧化环化策略。[7]我们以前曾报道过(+)-dibromophakellstatin的对映选择性合成，它同时利用Hoffman重排引入第二个氨基中心(C10；方案2)和环化起始的异氰酸酯来提供环状尿素。[8]结合我们对帕劳胺(4)的合成努力，[9]我们寻求了权宜之计，将法凯林亚基环化到环戊烷核心上。在我们以前的研究中，[9b]我们认识到C6氨基在这些三环体系中的稳定性，这使得我们能够考虑一种不对称策略，包括在N9±C10处关键的C±H胺化断开。这一策略是基于杜波依斯和他的同事最近的研究，[10]，并使用胍5(方案2)作为底物，它可以从已知的L-脯氨酸衍生的卡宾胺6中获得。这一过程将使环胍能够以立体专一性的方式安装，从而给出合成进入帕凯林生物碱的途径。在这里，我们描述了一种简单的氧化过程，该过程产生了胍5的N9±C10键，并导致了海洋生物碱的phakellin家族成员的第一次对映选择性合成，即(+)-monobbroophakellin和(+)-phakellin。这种环化策略可能适用于合成螺环生物碱帕劳胺(4)。最初，我们合成了一种胍类底物，例如5，前提是在随后的分子内胺化反应中，必须获得胍基和相邻的C±H键之间所需的syn排列。因此，L-脯氨酸被分三步转化为已知的化合物6，作为一种无关紧要的(见下文)非对映异构体混合物(DR%3：1；方案3)。
The phakellin group of natural products (1a–c) belong to the pyrrole–imidazole family of marine sponge derived alkaloids and are proposed to be biosynthetically derived from oroidin (3) and related congeners (Scheme 1).[1] This family of marine alkaloids has attracted great interest from both synthetic and biological perspectives because of their intriguing structural features and, in some cases, potent biological activities. The monomeric pyrrole–imidazole members (À)-dibromophakellin (1a) and (À)-monobromophakellin (1b) were isolated in 1969 by Burkholder and Sharma from the marine sponge Phakellia flabellata.[2] Subsequently, enantiomeric (+)-dibromophakellin (ent-1a) was isolated from Pseudoaxinyssa cantharella in 1985.[3] Phakellins (1c and ent-1c) have not been isolated but were obtained by hydrogenolysis of (À)-and (+)-dibromophakellin, respectively.[2b, 3] The phakellstatin (2) group of natural products [4] are related members of this alkaloid family and bear a cyclic urea rather than a cyclic guanidine group. The dimeric pyrrole–imidazole alkaloids palau amine (4)[5] and related congeners [1] contain a phakellin subunit within their structure, and a stereochemical revision of this molecule was recently proposed.[6] The concise biomimetic synthesis of rac-dibromophakellin reported by Foley and Büchi stands as a benchmark for syntheses of these alkaloids.[7a] In fact, most subsequent syntheses of racemic phakellins and phakellstatin alkaloids have used related oxidative cyclization strategies.[7] We have previously reported an enantioselective synthesis of (+)-dibromophakellstatin that employed a Hoffman rearrangement to simultaneously introduce the second aminal center (C10; Scheme 2) and cyclize the incipient isocyanate to deliver the cyclic urea.[8] In connection with our synthetic efforts toward palau amine (4),[9] we have sought expedient strategies to annulate the phakellin substructure onto a cyclopentane core. In our previous studies,[9b] we recognized the stability of C6 aminals in these tricyclic systems and this enabled us to consider an enantioselective strategy involving a key CÀH amination disconnection at N9ÀC10. This strategy was based on recent studies by Du Bois and co-workers,[10] and employed guanidine 5 (Scheme 2) as a substrate, which is accessible from the known carbinolamines 6 derived from l-proline. This procedure would enable installation of the cyclic guanidine in a stereospecific fashion, thus giving synthetic entry to the phakellin alkaloids. Herein we describe a simple oxidative process that generates the N9ÀC10 bond of guanidine 5 and leads to the first enantioselective synthesis of members of the phakellin family of marine alkaloids, namely (+)-monobromophakellin and (+)-phakellin. This annulation strategy is potentially applicable to the preparation of the complex spiro alkaloid palau amine (4). Initially, we set out to synthesize a guanidine substrate, for example 5, with a prerequisite of obtaining the required syn arrangement between the guanidine group and the adjacent CÀH bond for subsequent intramolecular amination. Accordingly, l-proline was converted into the known compound 6 in three steps as an inconsequential (see below) mixture of diastereomers (dr% 3: 1; Scheme 3).[11a] Carbinol-