Kravljanac Pavle, Anderson Edward A
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
Molecules. 2023 May 31;28(11):4468. doi: 10.3390/molecules28114468.
Triterpenoid natural products from the family have long presented a significant synthetic challenge. Lancifodilactone I, a member of the family not previously synthesized, was identified as a key natural product target, from which many other members could be synthesized. We envisaged that the core ring system of lancifodilactone I could be accessed by a strategy involving palladium-catalysed cascade cyclisation of a bromoenynamide, via carbopalladation, Suzuki coupling and 8π-electrocyclisation, to synthesize the core 7,8-fused ring system. Exploration of this strategy on model systems resulted in efficient syntheses of 5,6- and 5,8-fused systems in high yields, which represent the first such cyclisation where the ynamide nitrogen atom is 'external' to the forming ring system. The enamide functionality resident in the cascade cyclisation product was found to be less nucleophilic than the accompanying tri-/tetrasubstituted alkene(s), enabling regioselective oxidations. Application of this strategy to 7,6-, and 7,8-fused systems, and ultimately the 'real' substrate, was ultimately thwarted by the difficulty of 7-membered ring closure, leading to side product formation. Nevertheless, a tandem bromoenynamide carbopalladation, Suzuki coupling and 6/8π-electrocyclisation was shown to be a highly efficient tactic for the formation of bicyclic enamides, which may find applications in other synthetic contexts.
该家族的三萜类天然产物长期以来一直是合成领域的重大挑战。披针叶内酯I是该家族中此前未被合成的成员，被确定为关键的天然产物目标，由此可以合成许多其他成员。我们设想披针叶内酯I的核心环系可以通过一种策略来构建，该策略涉及溴代烯基酰胺的钯催化串联环化反应，通过碳钯化、铃木偶联和8π-电环化反应，来合成核心的7,8-稠合环系。在模型体系中对该策略的探索导致高效合成了高产率的5,6-和5,8-稠合体系，这代表了首次在形成环系时烯基酰胺氮原子处于“外部”的此类环化反应。发现串联环化产物中存在的烯酰胺官能团的亲核性低于伴随的三/四取代烯烃，从而实现区域选择性氧化。由于七元环闭合困难导致副产物形成，该策略在7,6-和7,8-稠合体系以及最终的“实际”底物上的应用最终受阻。尽管如此，串联溴代烯基酰胺碳钯化、铃木偶联和6/8π-电环化反应被证明是形成双环烯酰胺的高效策略，可能在其他合成背景中得到应用。
