聚酮化合物的烯-炔还原交叉耦联合成法：通过高烯丙基醇制备螺缩酮Polyketide Assembly by Alkene-Alkyne Reductive Cross-Coupling:Spiroketals through the Union of Homoallylic Alcohols天然产物螺缩酮是具有强有力和多样化生物特性的一类含量丰富的复杂分 子。例如包括在其令人关注的治疗靶点之中的针对 HIV-1 蛋白酶、 微管蛋白 聚合酶、蛋白磷酸酶和异白氨酰-tRNA合成酶的一些分子。因此，螺缩酮分子 的合成和评价在化学和医学上一直是相当感兴趣的话题。最近的调查表明已经 发现天然产物螺缩酮有抑制细胞微管组装，导致细胞凋亡、 抑制磷酸化、 调 制微管蛋白细胞骨架，并显示潜在疗法 B 细胞慢性淋巴细胞白血病的作用。由 于他们有确定新医药相关的小分子的显著的潜力，所以许多合成立体结构明确 螺缩酮方案的出现并不惊讶。然而最近关注的焦点是控制缩醛的立体化学，几 个通用和灵活的策略已经超越先进的多级羟醛化学，其中涉及目前需要大量羰 基氧化还原和保护基团的操作流程。在这里，我们用一种高度融合和简洁的方 法去合成立体结构明确的螺缩酮，通过烯丙基醇结构单元和三甲基硅烷基乙炔（TMS -乙炔）合成（2 + 3+ 4- 1;图1A）。由于立体选择性烯丙基转移的方 法很多，这里螺缩酮的合成就介绍一种简单的聚合路线，其流程是醛类结构单 元（5或6 ）通过一个序列建立四个C-C键和多达六个新的立体中间体。Spiroketal-containing natural products represent a rich class of complex molecules that are known to possess potent and diverse biological properties. Examples include molecules that target HIV-1 protease, tubulin polymerization, protein phosphatases, and isoleucyl tRNA synthetase among other therapeutically interesting targets.As a result, the synthesis and evaluation of spiroketal-containing molecules has been a topic of considerable interest in chemistry and medicine. Recent investigations along these lines have led to the discovery of natural product-inspired spiroketals that inhibit microtubule assembly, cause apoptosis, inhibit phosphatases, modulate the tubulin cytoskel-eton, and show promise as potential therapeutics for B- cell chronic lymphocytic leukemia.As a result of their significant potential in defining novel medicinally relevant small molecules,it is not surprising that many chemical strategies have emerged for the synthesis of stereodefined spiroketals.While recent interest has focused on methods for controlling the stereochemistry of the acetal,few general and flexible strategies for accessing the carbon skeleton have been advanced beyond multistep aldol chemistry, which involves processes that currently requirenumerous carbonyl redox and protecting-group manipulations. Here we describe a highly convergent and concise entry to substituted and stereodefined spiroketals by the union of homoallylic alcohols with trimethylsilylacetylene (TMS-acetylene) (2+3+4-1; Figure 1A). Because a variety of methods for stereoselective allyl transfer exist,this spiroketal synthesis defines a simple convergent pathway that pro ceeds by the union of aldehydes ( 5 and 6) through a sequence that establishes four C-C bonds and up to six new stereocenters.A. Retrosynthtic plsn：RlReH3斗ailyltransfer chemistryOHOHR1,H5From 日 kjEhj/des:S Chemical transformations targeted:OHOAr51) compl&x spiroketals in 4-5 linear steps2) 4 C-C bonds3) up to 6 new stereocentGrs随着烯丙基转移化学的完善建立，高烯丙醇2和4的结构单元与三甲基硅 乔1 ：:是通过三步完成的，就像图:阳4描述的。用三甲基O5烷基乙炔磁合硅烷基乙炔对高烯丙醇醇2进行区域选择性加氢脱烷基化生成炔烃7。7和第二个 高烯丙醇 4 随后进行立体选择性还原的交叉偶联反应生成二醇 8。最后，烯烃 的中心进行氧化分裂，随后去氢化环合生成螺缩酮 1。图1.通过具有选择性的高烯丙醇結构元聚合组装成螺缩With well-established allyl transfer chemistry in place, the union of homoallylic alcohols 2 and 4 with TMS-acetylene (3) en route to complex spiroketals 1 was targeted through a three-step process, as depicted in Figure 1B. Initial functionalization of homoallylic alcohol 2 by regioselective formal hydroalky- nylation with TMS-acetylene would deliver alkyne 7. Subsequent site- and stereoselective reductive cross-coupling between 7 and the second homoallylic alcohol 4 would then deliver complex diol 8. Finally, oxidative cleavage of the central alkene with subsequent dehydrative cyclization would furnish complex spiroketal 1.初步尝试，以实现通过一个终端烯烃硼氢化形成加氢脱烷基化作用，然后 通过硼代烯丙基和溴代三甲基硅烷基乙炔进行Suzuki偶联，但这种尝试没有成 功。把我们关注的中心转移到炔基硼化学中，我们假设需要的键结构可以通过 图 2A 所描述的顺序进行。2 初始硼氢化预期得到一个三烷基硼中间体，中间虽 然经历所需烷基硼化学反应，但预计将有问题的，因为在随后的 1,2-烷基迁移 中，硼基二环壬烷系统的竞争环扩大是具有选择性的。因此，我们追求结合点 选择性的单氧化合成三烷基硼，接着通过加用锂代三烷基硅基乙炔生成具有一 般结构 9 的中间混合物锂烷基硼。随后碘发起基团选择性 1,2-烷基的迁移和诱 导消除将提供 7， 2 的加氢烷基化产物。Initial attempts to accomplish formal hydroalkynylation via hydroboration of a terminal alkene followed by B-alkyl Suzuki coupling with bromo-TMS-acetylene were met with failure. Turning our attention to classic alkynylborate chemistry, we hypothesized that the desired bond construction could proceed by the sequence depicted in Figure 2A. Initial hydroboration of 2 was anticipated to deliver a trialkylborane intermediate that, although capable of undergoing the desired alkynylborate chemistry, was anticipated to be problematic, as selectivity in subsequent 1,2-alkyl migration is known to proceed with competitive ring expansion of the borabicyclononane system. Thus, we pursued site-selective mono-oxidation of the resulting trialkylborane followed by addition of Li-TMS-acetylide to deliver intermediate mixed lithium alkynylborates having the general structure 9. Subsequent iodine-initiated group-selective 1,2-alkyl migration and base-induced elimination would then deliver 7, the product of formal hydroalkynylation of 2.a= Reaction condilions： i. ?EBN, 7WF;（rr TMANO in CH2CI2 iir.曰dd Li-TMS acelylidg in THF; iv.罩也 b and NaOH.