The true structures of the vannusals, part 2: Total synthesis and revised structure of vannusal B.
The true structures of the vannusals, part 2: Total synthesis and revised structure of vannusal B.
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DOI：
10.1002/anie.200902029
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发表时间：
2009
影响因子：
16.6
通讯作者：
Zhang, Hongjun
中科院分区：
文献类型：
--
作者：
Nicolaou, K. C.;Ortiz, Adrian;Zhang, Hongjun
在前面的通信[1]中，我们描述了我们最初试图确定vannusals的真实结构[A（1）和B（2），最初指定的结构（图1）]。在此，我们报告了真实的vannusal B（即图1中的结构4）的全合成，这不仅使其可用于生物学研究，而且还揭开了其真实分子结构及其兄弟姐妹vannusal A的神秘面纱。我们最初的情报收集工作使我们得出结论，a）分子"西南"部分的立体化学细节（即环A和B、C3、C29、C6和C7）最有可能正确，如最初指定的结构1和2中所报告的，和B）最有可能出错的位置是这些结构的"东北"区域的顶部（即环E、C25和C21）。由于我们已经合成了vannusal B最初指定结构的四种可能的C25/C21非对映异构体中的三种（2）[2]，并发现它们是错误的，我们返回到剩余的非对映异构体，结构3（C25-epi-2;图1），作为vannusal B真实结构的可能候选物。由于其在C25/C21处的反式构型，基于在反式取代的C21-epi-2异构体中观察到的H21和H25（J = 8.5 Hz）之间的大偶合常数，结构3早先被放弃（参考文献10中的结构3）。[1]）。这一观察使我们追踪了几种其他的非对映体，正如我们在前面的交流中所看到的，[1]最终证明它们都不能代表vannusal B的真实结构。所有的证据都摆在我们面前，我们现在不得不重新考虑C25-epi-2结构（即3，图1）可能由于特殊的构象而容纳观察到的天然vannusal B（JH 25，21 = 1.6 Hz）的较小耦合常数的可能性。因此，我们决定继续合成3作为可能令人垂涎的vannusal B结构。选择结构3作为我们的下一个优选目标，将化合物5和6（图1）定义为其构建所需的构建单元。在这两个片段中，只有6个需要合成，因为5个已经可以从我们以前的研究中获得对映体纯形式。[2]它的合成开始于外消旋8的还原[通过二酮（CH3）-7（TiCl 4，Et3N）的钛烯醇化物与丙酮（约100%）的反应获得]。第六章：1 dr）][2]，其从分子的α面和两个羰基位点立体选择性地进行，通过色谱法纯化，在两个步骤中以64%的产率得到纯三醇9（方案1）。用NaBH 4对（N）-8进行的非对映选择性还原与其TES保护的对应物的还原相反，后者在C25处得到相反的构型。[2]有趣的是，三醇9在H25和H21之间表现出小的偶联常数（JH25，21 = 1.0 Hz），考虑到其兄弟的相同质子之间的偶联常数，这是相当令人惊讶的，9a（JH25，21 = 10.0 Hz），[1] 9b（JH25，21 = 10.0 Hz），[2] 9c（JH25，21 = 10.0 Hz），[3] 9c（JH25，21 = 10.0 Hz），[4] 9c（JH25，21 = 10.0 Hz），[5] 9c（JH25，21 = 10.0 Hz），[6] 9c（JH25，21 = 10.0 Hz），[7] 9c（JH25，21 = 10.0 Hz），[8] 9c（JH25，21 = 10.0 Hz），[7] 9c
In the preceding communication [1] we described our initial attempts to determine the true structures of the vannusals [A (1) and B (2), originally assigned structures (Figure1)]. Herein, we report the total synthesis of the real vannusal B (ie structure 4 in Figure 1) that served not only to render it available for biological investigations, but also to demystify its true molecular architecture and that of its sibling, vannusal A. Our initial intelligence gathering efforts led us to the conclusion that a) the stereochemical details of the “southwestern” part of the molecule (ie rings A and B, C3, C29, C6, and C7) were most likely correct as reported in the originally assigned structures 1 and 2, and b) the most likely place for an error was the very top of the “northeastern” region of those structures (ie ringE, C25 and C21). As we had already synthesized three of the four possible C25/C21 diastereomers of the originally assigned structure of vannusal B (2)[2] and found them to be erroneous, we returned to the remaining diastereomer, structure 3 (C25-epi-2; Figure 1), as a possible candidate for the true structure of vannusal B. By virtue of its trans configuration at C25/C21, structure 3 was abandoned earlier on the basis of the large coupling constant observed between H21 and H25 (J= 8.5 Hz) in the trans-substituted C21-epi-2 isomer (structure 3 in Ref.[1]). This observation led us to chase several other diastereomers which, as we have seen in the preceding communication,[1] ended by proving that none of them represented the true structure of vannusal B. With all the evidence in front of us, we were now forced to reconsider the possibility that the C25-epi-2 structure (ie 3, Figure 1) may accommodate the observed smaller coupling constant for natural vannusal B (JH25, 21= 1.6 Hz) by virtue of a special conformation. We therefore decided to pursue the synthesis of 3 as the possible coveted structure of vannusal B. The selection of structure 3 as our next favored target defined compounds 5 and 6 (Figure 1) as the required building blocks for its construction. Of these two fragments, only 6 needed to be synthesized, since 5 was already available in enantiopure form from our previous studies.[2] Its synthesis began with reduction of racemic 8 [obtained by reaction of the titanium enolate of diketone (Æ)-7 (TiCl4, Et3N) with acetone (ca. 6: 1 dr)][2] using DIBAL-H, which proceeded stereoselectively from the α face of the molecule and at both carbonyl sites to afford, upon purification by chromatography, pure triol 9 in 64% yield over two steps (Scheme1). The diastereoselective reduction of (Æ)-8 with NaBH4 stands in contrast to the reduction of its TES-protected counterpart, which gave the opposite configuration at C25.[2] Interestingly, triol 9 exhibited a small coupling constant between H25 and H21 (JH25, 21= 1.0 Hz), which was rather surprising given the coupling constants between the same protons of its siblings, 9a (JH25, 21= 10.0 Hz),[1] 9b (JH25, 21=
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影响因子：
16.6
作者：
Nicolaou, K. C.;Zhang, Hongjun;Dagneau, Philippe
通讯作者：
Dagneau, Philippe
影响因子：
16.6
作者：
Nicolaou, K. C.;Zhang, Hongjun;Ortiz, Adrian
通讯作者：
Ortiz, Adrian
影响因子：
15
作者：
Shibuya, Masatoshi;Tomizawa, Masaki;Iwabuchi, Yoshiharu
通讯作者：
Iwabuchi, Yoshiharu
DOI：
10.1002/(sici)1521-3773(19990419)38:8
发表时间：
1999-01-01
影响因子：
16.6
作者：
Guella, G;Dini, F;Pietra, F
通讯作者：
Pietra, F