Phosphine-Mediated Tunable Domino Annulation Reactions Involve Morita-Baylis-Hillman Carbonates

Organocatalysts-promoted domino reactions, with the advantages of high efficiency, convenient operation and environmental-friendly manner, could be used to build up powerful platforms for the synthesis of complex and challenging skeletons and has received great attentions. In particular, phosphine-mediated domino cycloaddition reactions have become one of the most important platforms for the construction of cycles. These reactions are significant in the synthesis of many pharmaceutically active products, natural products, perfumes and dyes. After the carefully illustrating and discussing the diversified starting materials and versatile reactive models of phosphine-mediated domino reaction in the first chapter, we detected that the reactive model of Morita-Baylis-Hillman (MBH) carbonates was quite limited (only1,3-dipolar cycloaddition). Based upon the aforementioned illustration and analysis of phosphine-mediated domino reaction, we deem Morita-Baylis-Hillman carbonates have the potential to be a versatile, elastic "building blocks" for the construction of complex, challenging and core skeleton of organic molecule after efficient control and regulation. Therefore, I paid my attention to investigating phosphine-mediated tunable domino annulation involved with Morita-Baylis-Hillman carbonates during the process of pursuing PhD degree.1. The traditional1,3-dipolar cycloaddition model of MBH carbonates was altered by steric hindrance strategy. Instead, the1,1-dipolor synthon was first observed and successfully incorporated into [1+4] cycloaddition reactions for the synthesis of trans-2,3-benzofurans. The2,3-dihydrobenzofuran (DHB) ring-system constitutes not only the core skeletons of a variety of synthetic drugs and biologically active compounds, but also an important skeleton. We successfully developed the efficient method for the construction of trans-2,3-dihydrobenzofurans in high yields and stereoselectivity. Having achieved aforementioned goals, we speculate the reaction might be extended to other1,1-dipolar synthons. Then the steric hinderance strategy-altered [1+4] cycloaddition reactions was successful extended to sulfur ylides for the construction of trans.s-2,3-dihydrofurans and restrained to the kinetic favored acridine derivatives. The method allowed the synthesis of a highly substituted trans-2,3-dihydrobenzofuran skeleton with high yield and excellent chemo-and stereoselectivity. The31P NMR spectroscopy and control experiments indicated that the high diastereoselectivity was controled by the kinetic process rather than thermodynamic equilibrium.2. Based upon the aforementioned investigation, we developed the concept of tunable phosphine-mediated domino reaction.β,γ-unsaturated a-keto esters and MBH carbonates was selected as the starting material. In the presence of phosphine, the MBH carbonates can be selectively used as C1synthon, C2synthon and1,3-dianion C3synthon for the construction of2,3-dihydrofurans, pyrans, benzenes, respectively via tuning substrates, reaction process and reactive models. In terms of the challenges associated with cross-coupling oxidative arylation, we developed a novel domino benzannulation reaction strategy for the construction of multi-aryls in moderate to high yields in chapter4. In these reactions, MBH carbonate firstly served as1,3-dianion C3synthon. Diverse aromatic motifs (including Heck-like products) and functional groups can be assembled in multi-aryls molecules in a metal-free manner, which increases the possibility for the structural modulation. This domino benzannulation reaction strategy is complementary to the traditional cross-coupling methods. Combination of these two methods could provide powerful platform in generating multi-aryl complexity, which is especially true for the construction of unsymmetric multi-aryl skeletons. Moreover, this reaction can be used for the synthesis of biologically active molecular arcaine analogues, which acts as inhibitors of [3H]MK-801binding. In chapter5, we carefully investigated and illustrated the mechanism of the phosophine-mediated benzannulation. We have developed a novel strategy to control the product distribution between2,3-dihydrofurans and biaryls from the same starting materials by tuning the cat-or stoichiometric process. By controlling the loading of PR3, Morita-Baylis-Hillman carbonates can be selectively used as C1or C3synthon respectively. DFT calculation and control experiment indicated that the equilibration resulted in the excellent diastereoselectivity of2,3-dihydrofurans. In chapter6, A novel method was developed for the construction of functionalized (2H)-Pyrans and2-oxabicyclo[2.2.2]oct-5-enes via tuning the catalytic active model. These two molecules were core skeleton of widespread compounds. Especially, the later was core skeleton of anticancer active molecules. In this domino process, the catalysts phosphine and secondary amine worked in a sequential manner. Phosphine initiated this domino process via a [4+1] annulation to give2,3-dihydrofurans, which was followed by secondary amine catalyzed rearrangement process. The mechanism of the novel rearrangement process from2,3-dihydrofurans to (2H)-pyran was investigated by DFT calculations and control experiments. Moreover, this is the first time for the MBH carbonates to be served as C2synthon in organic synthesis.3. The Nazarov reagent and allenoates were similar with β,γ-unsaturated a-keto esters and MBH carbonates in regard to skeletons and reactive manner, respectively. We firstly investigated the reaction between Nazarov reagents and allenoates and successfully synthesized a variety of conjugated2,3-dihydrofurans. Ethanol was essential to this reaction, which served as not only a solvent but also a proton transfer catalyst. DFT calculation indicated that the essential of alcohol was to catalyze the proton transfer. This work could open up new opportunities for mechanism studies concerning phosphine-mediated domino reaction.4. Rauhut-Currier reaction, which is also known as vinylogous Morita-Baylis-Hillman reactions has rarely been investigated due to the lower reactivity of starting materials and lack of selectivity in coupling reaction involving two different activated alkenes. We designed and synthesized a variety of bifunctional phosphine catalyst to incorporate acrolein into cross-rauhut-currier/Michael/Aldol condensation triple domino reaction for the construction of functionalized cyclohexenes. The results proved that the bifunctional phosphine catalysts were efficient to control the RC domino reaction. Asymmetric variant of this reaction was also preliminarily tested with the optically pure bifunctional catalyst. This investigation will shed light on the design of bifunctional catalyst and RC reaction investigation.