Tandem cyclization based on titanium cascade-Development of short-step synthesis of optically active polycyclic compounds

以光学活性的8-苯基薄荷醇为原料，用(η^2-丙烯)Ti(O-i-Pr)_2(1)与3-烷基-2-烯基-7-吡咯烷酸酯反应，得到相应的钛环戊烯。这些钛环被等摩尔量的质子猝灭，以实现第二个环的闭合，得到光学活性的具有角烷基的双环[3.3.0]Oct-10-3-酮，ee值高达93%。下一步考察了另一种串联环化反应。因此，由内炔、3-丁烯酯和1或3，8-或3，9-烷二烯酯和1生成的钛环戊二烯经历了两个碳-钛键与酯羰基的连续分子内加成，以良好的产率得到单环或双环环戊二烯醇。从5，10-烷基二烯酸酯开始，该串联反应一步得到三环环戊二烯醇。但是，在我们的研究过程中，我们发现1-介导的分子内环化反应很好地与酯或酰胺基团相连，得到了连接到内酯或内酰胺键上的外环、外环双烯。得到的外环、外环双烯与乙酰酮、酯或马来酰亚胺发生Diels-Alder反应，得到具有高区域选择性和/或不对称诱导的(光学活性)双环化合物。从而建立了利用钛环形成和Diels-Alder反应组成的串联反应方便地制备多环化合物的方法。

The following results are summarized according to the order of the initially proposed projects.3-Alkyl-2-alkene-7-ynoates derived from optically active 8-phenylmenthol were treated with (η^2-propene) Ti (O-i-Pr)_2 (1) to give the corresponding titanacyclopentenes. These titanacycles were quenched with an equimolar amount of proton to effect the second ring closure to give optically active bicyclo [3.3.0] oct-ten-3-ones having an angular alkyl group with high ee values of up to 93%.Another tandem cyclization was next examined. Thus, titanacyclopentadienes generated from internal alkyne, 3-butynyl ester, and 1 or, alternatively, from 3, 8- or 3, 9-alkadiynyl ester and 1 underwent the successive intramolecular addition of the two carbon-titanium bonds to the ester carbonyl group to give mono- or bicyclic cyclopentadienols in good yields. Starting from a 5, 10-alkadiynoate, this tandem reaction afforded a tricyclic cyclopentadienol in one step. The extension of this transformation to an asymmetric version and other attempts to use titanacyclopentadienes for the construction of multi-ring products so far did not meet with success.However, during the course of our study, we found that 1-mediated intramolecular cyclization of various diynes tethered with an ester or amide group nicely proceeded to give exo, exo-cyclic dienes attached to the lactone or lactam linkage. The resulting exo, exo-cyclic dienes are very reactive towards Diels-Alder reaction with acetylenic ketones, esters, or maleimides to give (optically active) bicyclic compounds with high regioselectivity and/or asymmetric induction. Thus, the convenient preparation of polycyclic compounds taking advantage of the tandem reaction consisting of the titanacycle formation and Diels-Alder reaction was established.