Structure-Based Rationale for Selectivity in the Asymmetric Allylic Alkylation of Cycloalkenyl Esters Employing the Trost ‘Standard Ligand’ (TSL): Isolation, Analysis and Alkylation of the Monomeric form of the Cationic η³-Cyclohexenyl Complex [(η³-<i>c</i>-C₆H₉)Pd(TSL)]⁺

The solution-phase structures of the monomeric forms of the cationic Pd-η3-allyl and Pd-η3-cyclohexenyl complexes [Pd(R,R)-1(η3-C3H5)]+ (7+) and [Pd(R,R)-1(η3-C6H9)]+ (8+) bearing the trans-cyclohexylenediamine-based Trost ‘Standard Ligand’ (R,R)-1 have been elucidated by NMR, isotopic labeling and computation. In both complexes, (R,R)-1 is found to adopt a C1-symmetric conformation, leading to a concave shape in the 13-membered chelate in which one amide group in the chiral scaffold projects its NH unit out of the concave surface in close vicinity to one allyl terminus. The adjacent amide has a reversed orientation and projects its carbonyl group out of the concave face in the vicinity of the opposite allyl terminus. Stoichiometric and catalytic asymmetric alkylations of [8+][X−] by MCHE2 (E = ester, M = ‘escort’ counterion, X = Pd allyl counterion) show the same selectivities and trends as have been reported for in situ-generated catalysts, and a new model for the enantioselectivity has been explored computationally. Three factors are found to govern the regioselectivity (pro-S vs pro-R) of attack of nucleophiles on the η3-C6H9 ring in 8+ and thus the ee of the alkylation product: (i) a pro-R torquoselective bias is induced by steric interaction of the η3-C6H9 moiety with one phenyl ring of the ligand; (ii) pro-S delivery of the nucleophile can be facilitated by hydrogen-bonding with the concave orientated amide N−H; and (iii) pro-R delivery of the nucleophile can be facilitated by escort ion (M) binding to the concave orientated amide carbonyl. The latter two opposing interactions lead to the selectivity of the alkylation being sensitive to the identities of X− and M+. The generation of 8+ from cyclohexenyl ester substrate has also been explored computationally. The concave orientated amide N−H is able to activate the leaving group of the allylic ester by hydrogen bonding to its carbonyl group. However, this interaction is only feasible for the (S)-enantiomer of substrate, leading to the prediction of a powerful kinetic resolution (kS ≫ kR), as is found experimentally. This new model involving two regiochemically distinct (NH) and (CO) locations for nucleofuge or nucleophile binding, may prove of broad utility for the interpretation of the selectivity in asymmetric allylic alkylation reactions catalyzed by Pd complexes of (R,R)-1 and related ligands.采用核磁共振波谱法（NMR）、同位素标记法及计算化学手段，阐明了带有反式环己二胺骨架的特罗斯特（Trost）‘标准配体’(R,R)-1的阳离子型单核钯-η³-烯丙基配合物[Pd(R,R)-1(η³-C₃H₅)]⁺ (7⁺)与钯-η³-环己烯基配合物[Pd(R,R)-1(η³-C₆H₉)]⁺ (8⁺)在溶液中的相结构。在两种配合物中，(R,R)-1均呈现C1对称构象，使得13元螯合环呈现凹面结构：手性骨架中的一个酰胺基团将其NH单元伸出凹面，紧邻一个烯丙基端基；相邻的酰胺基团取向相反，将其羰基伸出凹面，靠近另一侧的烯丙基端基。以MCHE₂（其中E为酯基，M为伴随抗衡离子，X为钯烯丙基抗衡离子）对[8⁺][X⁻]进行化学计量及催化不对称烷基化反应，所得选择性规律与原位生成的催化剂报道结果一致；同时通过计算方法探索了一种全新的对映选择性模型。研究发现，影响亲核试剂进攻8⁺中η³-环己烯基环的区域选择性（pro-S vs pro-R）及烷基化产物对映体过量值（ee）的因素有三点：(i) η³-环己烯基片段与配体的一个苯环发生空间位阻相互作用，诱导产生前手性R位的扭转选择性偏向；(ii) 亲核试剂与凹面取向的酰胺N-H形成氢键，可促进前手性S位的亲核进攻；(iii) 伴随抗衡离子M与凹面取向的酰胺羰基结合，可促进前手性R位的亲核进攻。后两种相互作用方向相反，使得烷基化反应的选择性对X⁻与M⁺的种类具有敏感性。此外还通过计算手段探索了由环己烯基酯底物生成8⁺的过程：凹面取向的酰胺N-H可通过与酯基羰基形成氢键，活化烯丙基酯的离去基团。但该相互作用仅对底物的(S)对映体可行，据此可预测存在极强的动力学拆分效应（k_S ≫ k_R），这与实验观测结果一致。这种涉及两个区域化学上不同的（NH）与（CO）位点用于结合离去基团或亲核试剂的全新模型，或可广泛用于解释由(R,R)-1及其相关配体的钯配合物催化的不对称烯丙基烷基化反应的选择性规律。