Ketones with DIBALH

With the procedure for constructing the quaternary carbon stereocenter in hand, the conversion of the ris-form to the trans form was explored in accordance with the synthetic plan shown in Scheme 9. The ketone moiety of the 1,4-conjugated adduct 61 was protected by an acetal group, followed by decarboxylation of compound 65 using sodium ethylthiolate to yield lactam trans-62 and cis-62 as an 8 1 diastereomixture [31]. The reason why the lactam trans-62 was obtained as a major product is that the subsequent protonation after decarboxylation proceeded kinetically. This assertion is supported by experimental results in which the trans- and cis-lactam diastereomixture (8 1) in ethanol was refluxed in the presence of potassium hydroxide to afford a 1 5 mixture [15,32,33]. The mixture of the lactam trans-62 and cis-62 was reduced with DIBALH, followed by treatment with sodium hydroxide to give bicyclic enamine 63. The kinetic iminium salt prepared from bicyclic enamine 63 with hydrochloric acid was reduced with sodium cyanoborohydride, leading to the frans-decahydroisoquinoline structure [22], The acetal moiety of the resultant 67 was removed to provide the objective ketones 68a and 2c. This method enabled the construction of the tra s-decahydroisoquinoline structure without an intermediate resembling the neurotoxic MPTP, and in fewer steps. 

Elimination. 1,4-Dienes are prepared from a-(benzothiazol-2-yl)methyl ketones by way of allylation, reduction of the carbonyl group with NaBH, and treatment with DIBALH-MgBr. The newly formed double bond of the major product has a fZj-configuration. 

Oxidation of cyclic enol ether 35 with dimethyl dioxirane (DMDO) followed by in situ reduction of the intermediate epoxide with DIBALH gave secondary alcohol as a 10 1 mixture of diastereom-ers. Oxidation of these alcohols with TPAP/NMO afforded a 10 1 mixture of ketone 37 and its C16 epimer. The isomers were separated and the minor isomer was recycled to a 4 1 mixture of isomers by treatment with imidazole. Subsequent construction of the D-ring was performed by radical reduction of mixed thioacetal in the same way as that adopted by the Sasaki group, leading to octacycle 38. Stereoselective installation of the triene side chain was then carried out via (Z)-vinyl iodide 39... 

Oxidation of 101 with DMDO followed by one-pot reduction with DIBALH provided a 10 1 mixture of alcohols, in which the major isomer possessed the correct stereochemistry at Cl6. Oxidation of the alcohols gave ketone 102 and its C16 epimer, respectively. The minor diastereomer could be isomerized... 

A partial reduction of the nitrile group is possible not only by hydrogenation with DIBALH but also by reaction of O-protected cyanohydrins with Grignard reagents to give the corresponding imino intermediates (Scheme 8). Hydrolysis of the imino compounds under mild conditions results in O-protected optically active hydroxy ketones (i )-14 without any trace of racemization (Scheme 8) [38]. 

The synthesis of the tricyclic core of the cytotoxic marine alkaloid Madangamine required an efficient method to generate the central quaternary carbon function. Weinreb employed an aza-Claisen rearrangement in the presence of a palladium catalyst [21c]. After treatment of ketone 116 subsequently with TOSMIC and DIBALH, the formed carbaldehyde 117 was reacted with diallylamine in the presence of Pd(OCOCFj)2/PPh,. Initially, the enamine 118 was formed, which underwent diastereoselective aza-Claisen rearrangement The unsaturated imine 119 was cleaved with aqueous HCl and the corresponding aldehyde 120 was isolated in 68% yield. Several further steps allowed one to complete the synthesis of the core fragment 121 of the natural product (Scheme 10.27). 

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