University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Org Biomol Chem. 2012 Aug 14;10(30):5873-86. doi: 10.1039/c2ob25101a. Epub 2012 Apr 16.
The spirastrellolides are a novel family of structurally unprecedented marine macrolides which show promising anticancer properties due to their potent inhibition of protein phosphatase 2A. In the preceding paper, a modular strategy for the synthesis of spirastellolide A methyl ester which allowed for the initial stereochemical uncertainties was outlined, together with the synthesis of a series of suitably functionalised fragments. In this paper, the realisation of this synthesis is described. Two alternative coupling strategies were explored for elaborating the C26-C40 DEF bis-spiroacetal fragment: a modified Julia olefination of a C26 aldehyde with a C17-C25 sulfone, and a Suzuki coupling of a C25 trialkylborane with a C17-C24 vinyl iodide, which also required the development of a double hydroboration reaction to install the C23/C24 stereocentres. The latter proved a significantly superior strategy, and was fully optimised to provide a C17 aldehyde which was coupled with a C1-C16 alkyne fragment to afford the C1-C40 carbon framework. The BC spiroacetal was then installed within this advanced intermediate by oxidative cleavage of two PMB ethers with spontaneous spiroacetalisation, which also led to unanticipated deprotection of the C23 TES ether. The ensuing truncated seco-acid was cyclised in high yield to construct the 38-membered macrolactone under Yamaguchi macrolactonisation conditions, suggesting favourable conformational pre-organisation. Exhaustive desilylation provided a crystalline macrocyclic pentaol, revealing much about the likely conformation of the macrolactone in solution. Attachment of the remainder of the side chain proved challenging, potentially due to steric hindrance by this macrocycle; an olefin cross-metathesis to install an electrophilic allylic carbonate and subsequent π-allyl Stille coupling with a C43-C47 stannane achieved this goal. Global deprotection completed the first total synthesis of (+)-spirastrellolide A methyl ester which, following detailed NMR correlation with an authentic sample, validated the full configurational assignment. A series of simplified analogues of spirastrellolide incorporating the C26-C47 region were also prepared by π-allyl Stille coupling reactions.
螺旋甾内酯是一类结构新颖的海洋大环内酯，由于其对蛋白磷酸酶 2A 的强烈抑制作用，显示出有希望的抗癌特性。在前一篇论文中，概述了一种用于合成螺旋甾内酯 A 甲酯的模块化策略，该策略允许初始立体化学不确定性，并合成了一系列合适的功能化片段。本文描述了该合成的实现。为了详细阐述 C26-C40 DEF 双螺环缩醛片段，探索了两种替代的偶联策略：C26 醛与 C17-C25 砜的改良 Julia 烯烃化，以及 C25 三烷基硼烷与 C17-C24 乙烯基碘化物的 Suzuki 偶联，这也需要开发双硼氢化反应来安装 C23/C24 立体中心。后者被证明是一种明显优越的策略，并进行了全面优化，以提供 C17 醛，该醛与 C1-C16 炔烃片段偶联，得到 C1-C40 碳骨架。然后，通过用两个 PMB 醚进行氧化裂解和自发螺缩醛化，在这个高级中间体中安装 BC 螺缩醛，这也导致 C23 TES 醚出乎意料的脱保护。随后的截断的仲酸在 Yamaguchi 大环内酯化条件下以高产率环化，构建 38 元大环内酯，表明构象预先组织良好。彻底脱硅得到结晶性的大环戊五醇，这揭示了大环内酯在溶液中的可能构象。连接剩余的侧链证明具有挑战性，这可能是由于这个大环的空间位阻；通过烯烃交叉复分解反应安装亲电烯丙基碳酸酯，然后与 C43-C47 锡烷进行 π-烯丙基 Stille 偶联，实现了这一目标。全保护完成了 (+)-螺旋甾内酯 A 甲酯的首次全合成，通过与真实样品的详细 NMR 相关联，验证了全构型的分配。通过 π-烯丙基 Stille 偶联反应也制备了一系列包含 C26-C47 区域的简化螺旋甾内酯类似物。
