Synthesis reaction workbook

To move data effectively, bidirectional interface between the analytical instruments and the reaction workbook module is needed to provide a mechanism to submit the libraries for analysis and to integrate the resulting data with the synthesis data. The data could be transferred and collected in the reaction workbook module where a chemist can review the data for integrity and forward it to corporate data repositories. A fully automated system that can review the analytical data and identify the library members that pass selection criteria would greatly enhance the throughput of the validation system. 

The Robinson annelation is by no means the only ionic reaction that makes six-membered rings. Six-membered rings form easily so trapping a Nazarov intermediate (chapter 35) makes good sense. The Friedel-Crafts-like disconnection 18 suggests a most unlikely cation 19 until we realise that it would be formed in the Nazarov cyclisation of the dienone 20 whose synthesis is discussed in the workbook. 

An alternative is to put the alkene in another place 84 and discover a different pair of diene 86 and dienophile 85. Again the -isomers will be easier to make and this time we get the right stereochemistry 88 for a-lycorane 71. This strategy was followed in an early synthesis by Hill.9 Another synthesis using the Diels-Alder reaction is by Irie.10 More details appear in the workbook. 

This method has been applied to a synthesis of the alkaloid O-methyljoubertiamine. Reaction of the lithium derivative of 125 with the part-protected diketone 128 gave an enamine 129 that was immediately allylated to create the quaternary centre in 130. Deprotection and cyclisation completed the cyclohexenone28 131. A discussion of the strategy and further details of this synthesis are in the workbook. 

Now that the more nucleophilic alkene is no more, the less nucleophilic one can be oxidised and ring A converted into a lactone 169. The rest of this synthesis is equally interesting but is outside the scope of this chapter. It has to start with some chemoselective reaction on the two lactones in 169 as described in the workbook. 

Both syntheses made the bond between the two alkenes by a Stille coupling. One put the tin on the amide part by a Cu(I) catalysed conjugate addition of Bu3SnLi to the acetylenic ester 212 and Weinreb amide formation. Coupling this vinyl stannane with a single enantiomer of the iodide derived from the rest of the molecule gave crocacin C in good yield. The synthesis of the iodide uses an asymmetric aldol reaction and is described in the workbook.30... 

The other fragment, the alkene 286 originates in an Evans aldol reaction (chapter 27) and is coupled to 285 by hydroboration and Suzuki reaction. The yield is very impressive, as is the stereocontrol over the new centre next to the acetal. The full synthesis appears in the workbook together with some stereochemical explanations. 

The cyclic unsaturated ketone (48) has been used in a synthesis of bullatenone (47) (see Chapter 20 and workbook for Chapter 20) and as a dienophile in Diels-Alder reactions. Disconnection of the enol ether reveals both 1,2- and 1,3-relationships in (49) and one of the 1,3-disconnections... 

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