The asymmetric synthesis of the C<SUB>13</SUB>-C<SUB>27</SUB> moiety <i>44</i> of the polyether antibiotic etheromycin is described. The final step in the synthesis was the formation of the tricyclic fragment <i>44</i> by a biomimetic triepoxide cyclisation cascade. The cyclisation cascade, <i>144</i> to <i>44</i>, is stereospecific and entirely dependent upon the epoxides stereochemistry. The absolute stereochemistry of each of the three epoxides was independently controlled by the Sharpless asymmetric epoxidation methodology. The carbon skeleton of <i>44</i> was constructed from geraniol, (R)-methyl 3-hydroxy-2-methylpropionate <i>117</i>, and two units of t-butyl acetate. Apart from C<SUB>26</SUB>, the chiral centres were all controlled by the Sharpless asymmetric epoxidation. The synthetic strategy was designed to effect the stepwise enantioselective introduction of the three epoxides while building the C<SUB>13</SUB>-C<SUB>27</SUB> carbon skeleton, and directing a subsequent cascade reaction by an internal nucleophile. Two trisubstituted epoxides were introduced stepwise with >20:1 stereoselectivity by asymmetric epoxidation of a geraniol derived segment. The fragment was manipulated between epoxidations to allow stepwise introduction of the epoxides, and to ensure terminal differentiation of the groups. Both hydroxyl groups used to control epoxidation were subsequently and separately utilised, after conversion to the iodide, in alkyation reactions with the lithium enolate of t-butyl acetate to extend the carbon chain. No other conditions investigated to selectively react α to epoxides were satisfactory. Of the two t-butyl ester groups introduced, one (C_24) was reduced to the aldehyde and coupled in a Julia reaction with a sulphone derived from <i>117</i>. The resulting trans olefin was converted into a trans homoallylic alcohol, which was epoxidised by Sharpless methodology with 3 : 1 stereoselectivity. The second of the t-butyl esters (C_13) was used as an internal nucleophile to induce the cascade reaction. The natural ring stereochemistry of <i>44</i> was assumed from the high predictability and stereocontrol of the epoxidation reactions and confirmed by ^1H NMR nOe difference experiments. The synthesis of the sulphone <i>161</i>, in which the three contiguous chiral centres and methyl ketone represents a common polyether terminus, was also demonstrated using a stereocontrolled aldol reaction.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:235930 |
| Date | January 1987 |
| Creators | Mason, Ian |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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