10.1021/ja9716160.s001 Hirokazu Urabe Hirokazu Urabe Ken Suzuki Ken Suzuki Fumie Sato Fumie Sato Intramolecular Cyclization of 2,7- or 2,8-Bis-unsaturated Esters Mediated by (η<sup>2</sup>-Propene)Ti(O-<i>i</i>-Pr)<sub>2</sub>. Facile Construction of Mono- and Bicyclic Skeletons with Stereoselective Introduction of a Side Chain. A Synthesis of <i>d</i>-Sabinene American Chemical Society 1997 trimethylsilyl 1.1 equiv allylic bond substituent yield tert Pr BuOH titanabicycle 7 ethyl ethoxycarbonyl D 2 O incorporation PrOD hydrolysis ketone Et 2 CO monodeuterated product 10 Ti cyclization stereochemistry electrophile deuterium butyl bicyclic skeleton octen 1997-10-22 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Intramolecular_Cyclization_of_2_7-_or_2_8-Bis-unsaturated_Esters_Mediated_by_sup_2_sup_-Propene_Ti_O-_i_i_i_-Pr_sub_2_sub_Facile_Construction_of_Mono-_and_Bicyclic_Skeletons_with_Stereoselective_Introduction_of_a_Side_Chain_A_Synthesis_of_i_d_i_-Sabinene/3666156 <i>tert</i>-Butyl 2-en-7-ynoate <b>6</b> was treated with (η<sup>2</sup>-propene)Ti(O-<i>i</i>-Pr)<sub>2</sub> (<b>3</b>), generated <i>in</i> <i>situ</i> from Ti(O-<i>i</i>-Pr)<sub>4</sub> or Ti(O-<i>i</i>-Pr)<sub>3</sub>Cl and <i>i</i>-PrMgCl, in ether at −50 to −20 °C to afford the product <b>8</b> in good yield. The presence of the intermediate titanabicycle <b>7</b> was verified by bis-deuterolysis with excess D<sub>2</sub>O. When the titanabicycle <b>7</b> was treated with 1.1 equiv of <i>i</i>-PrOD and then worked up as usual, the monodeuterated product <b>10</b> was obtained with high site selectivity and stereoselectivity. Other electrophiles such as aldehydes and ketones also reacted with the titanabicycle in a highly stereoselective manner to give cyclopentanes having a stereo-defined side chain. On the contrary, treatment of the corresponding ethyl ester, ethyl 8-(trimethylsilyl)-(<i>E</i>)-2-octen-7-ynoate (<b>28</b>), with <b>3</b> under the same conditions followed by the addition of 1.1 equiv of <i>s</i>-BuOH afforded 2-(trimethylsilyl)-1-bicyclo[3.3.0]octen-3-one (<b>32</b>) in 80% yield. Quenching the same reaction mixture with <i>i</i>-PrOD, EtCHO, and Et<sub>2</sub>CO in place of <i>s</i>-BuOH gave 4-deuterio (with exclusive deuterium incorporation), 4-(1-hydroxypropyl), and 4-(1-ethyl-1-hydroxypropyl) derivatives of the above bicyclic ketone (<b>34</b>, <b>35</b>, and <b>36</b>) in good yields. These electrophiles were always introduced from the convex face of the bicyclic skeleton. The stereochemistry of the cyclization could be controlled by an allylic substituent such as (<i>tert</i>-butyl)dimethylsiloxy or butyl group to a high degree yet with a reversal diastereoselection to give <b>45</b> or <b>47</b>. The reaction of ethyl 7-octen-2-ynoate (<b>56</b>) and <b>3</b> at −50 to 0 °C took place in a quite different way to afford 1-[(ethoxycarbonyl)methyl]bicyclo[3.1.0]hexane (<b>64</b>) in 74% yield after hydrolysis. If the simple hydrolysis is replaced by deuterolysis or the action of diethyl ketone, 1-[(ethoxycarbonyl)dideuteriomethyl] (with 99% deuterium incorporation), or 1-[(ethoxycarbonyl)(3-pentylidene)methyl] derivative of the above product (<b>65</b> or <b>66</b>) was obtained in good yields. A 7-en-2-ynoate having an internal <i>Z</i>-double bond such as <b>80</b> afforded a single stereoisomer <b>82</b> with the substituent at the <i>endo</i> position of the bicyclic skeleton, suggesting that the stereochemical integrity of the <i>Z</i>-double bond of the starting material was retained in the product. An alkyl substituent at the allylic position of the substrates like <b>74</b> and <b>76</b> nicely controlled the stereochemistry of the cyclization to afford single products <b>75</b> and <b>77</b> with the substituent being placed in the <i>exo</i> orientation of the bicyclic structure. This high diastereoselectivity was successfully applied to an enantioselective synthesis of <i>d</i>-sabinene from an optically active enynoate via nearly complete chirality transfer.