Chiral auxiliary pumiliotoxin

The pyrrolobenzodiazepine-5,11 -diones II have been utilized in asymmetric syntheses of both the cis- and tra i-decahydro-quinoline alkaloids (Schemes 21 and 22). For example, reduction of 100 with 4.4 equiv. of potassium in the presence of 2 equiv. of t-BuOH, followed by protonation of the resulting enolate with NH4CI at —78 °C gave the cA-fused tetra-hydrobenzene derivative 101.Amide-directed hydrogenation of 101 gave the hexahydrobenzene derivative with diastereo-selectivity greater than 99 1. Removal of the chiral auxiliary and adjustment of the oxidation state provided aldehyde 103 which was efficiently converted to the poison frog alkaloid (+)-pumiliotoxin C. 

Most asymmetric Diels-Alder reactions have the chiral auxiliary attached to the dienophile as in the example we have just seen.14 One of the earliest was the blocked a-hydroxyenone16 136 that cyclises with electron-rich dienes to give adducts such as 139 and was used in a synthesis of pumiliotoxin 143 based on that of Overman.17 The weakness here is the cleavage of the auxiliary requires reduction to a diol and periodate cleavage with the inevitable destruction of the auxiliary. 

A number of Pd-catalyzed carbonylative processes have employed allenes as substrates for the synthesis of nitrogen heterocydes [108], For example, subjection of substituted allene 170 to reaction conditions similar to those employed in related reactions of alkenes led to the formation of pyrrolidine 171 in 68% yield with 2 1 dr (Eq. (1.67)) [108d], Modest asymmetric induction has been achieved in these transformations using simple chiral auxiliaries [108b,d]. This strategy was employed in an asymmetric synthesis of pumiliotoxin 251 D, which involved the aminocarbo-nylation of allene 172 to pyrrolidine 173 as a key step (Eq. (1.68)) [108b]. 

The next synthesis uses a chiral auxiliary approach in which the auxiliary is not sacrificed. The synthesis begins with anthranihc acid derivative 157. A potassium-ammonia reduction provided a mixture of diastereomers 158 and 159. A directed hydrogenation of the major diastereomer (159), using Crabtree s cationic iridium catalyst, provided 160. This material was moved forward to pumiliotoxin-C through intermediates we encountered in the Overman approach (compare the substitution pattern and relative stereochemistry of 160 with 131 on Pumihotoxin-3). 

General Considerations. In addition to its use in peptide chemistry, (S)-proline is often applied as a chiral precursor in the total syntheses of natural products, e.g. odorin, pumiliotoxin, petasinecine," or threonine. Some highly effective pharmaceuticals, such as optically pure ACE inhibitors, are prepared from L-proline. In the last two decades, (S)-proline has attracted much attention as an optically active auxiliary in asymmetric synthesis. 

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