Theoretical Study on Asymmetric [2 + 2] Cycloaddition of an Alkynone with a Cyclic Enol Silyl Ether Catalyzed by a Chiral N,N′‑Dioxide-Zn(II) Complex

The reaction mechanism and enantioselectivity of the asymmetric [2 + 2] cycloaddition between an alkynone (R1) and a cyclic enol silyl ether (R2) were studied theoretically by the DFT method at the B3LYP-D3­(BJ)/6-311G**­(CH2Cl2,SMD)//B3LYP-D3­(BJ)/def2-SVP­(CH2Cl2,SMD) theoretical level. The noncatalytic reaction occurred via a stepwise mechanism. The first C–C bond was constructed by coupling two pseudo radical centers generated at the most nucleophilic C2 atom in the cyclic enol silyl ether and the most electrophilic terminal Cβ atom in the alkynone, which was responsible for the regioselectivity of the reaction. The counterion NTf2– could stabilize the Zn­(II) complex by coordinating to the center metal, forming a high-reactivity hexacoordinate Zn­(II)-complex intermediate. The bulky CF3 group in the NTf2– ion adjusted the blocking effect of o-iPr in aniline of the ligand toward the reactive site (that is, the Cβ atom in the alkynone) and induced the si face of the cyclic enol silyl ether to approach the alkynone from its less hindered re face, achieving a high enanotioselectivity of products. The Pauli repulsion between the Zn­(II)-associated moiety and cyclic enol silyl ether fragment was the main contributor to the stereodifference of the two competing pathways in chiral N,N′-dioxide-Zn­(II)-catalyzed [2 + 2] cycloaddition. The unfavorable steric repulsion between the o-iPr group of aniline in the ligand and tert-butyldimethylsilyl (TBS) in the cyclic enol silyl ether along the re face path translated into a more destabilizing ΔEPauli value, leading to the predominant cycloaddition product (P-RR) observed in experiments. Variation of the linkage and chiral backbone could affect the repulsion among the o-iPr in the ligand, the counterion NTf2–, and substrates, leading to different stereochemical outcomes. These results are in good agreement with experimental observations.

本研究采用密度泛函理论（DFT）方法，在B3LYP-D3(BJ)/6-311G**(CH2Cl2,SMD)//B3LYP-D3(BJ)/def2-SVP(CH2Cl2,SMD)理论级别下，从理论层面系统研究了炔酮（alkynone, R1）与环状烯醇硅醚（cyclic enol silyl ether, R2）之间的不对称[2+2]环加成反应的反应机理与对映选择性。
非催化反应遵循分步机理进行：环状烯醇硅醚中亲核性最强的C2原子与炔酮中亲电性最强的末端Cβ原子分别生成伪自由基中心，二者通过偶联构筑第一根C–C键，该过程决定了反应的区域选择性。
双三氟甲磺酰亚胺根（NTf2–）可通过与中心金属配位稳定锌(II)配合物，形成高反应活性的六配位锌(II)配合物中间体。配体苯胺结构上的大体积三氟甲基（CF3）可调节配体邻异丙基（o-iPr）对反应位点（即炔酮的Cβ原子）的位阻屏蔽效应，并诱导环状烯醇硅醚的si面从炔酮位阻更小的re面一侧靠近，最终实现产物的高对映选择性。
在手性N,N′-二氧配体-锌(II)催化的[2+2]环加成反应中，与锌(II)结合的基团与环状烯醇硅醚片段之间的泡利排斥（Pauli repulsion）是两条竞争反应途径立体差异的主要贡献因素。沿re面路径发生的配体苯胺邻异丙基与环状烯醇硅醚上的叔丁基二甲基硅基（TBS）之间的不利空间排斥，会转化为更不稳定的ΔEPauli值，最终导致实验中观测到的优势环加成产物为P-RR构型。
配体上的邻异丙基、抗衡离子NTf2–与底物之间的位阻排斥会受连接基团与手性骨架的变化影响，进而产生不同的立体化学结果。上述研究结果与实验观测值吻合良好。