Robinson disconnection

Analysis the obvious disconnection takes us back to the halide used by Robinson, the one we synthesised in fi ame 27 ... 

Two-Group Disconnections III 1,5-Difunctionalised Compounds Michael Addition and Robinson Annelation... 

Example Compound (21) may not look like a Robinson annelation product, but it is certainly an enone so a,B disconnection gives a 1,5-di-carbonyl compound A reverse Michael reaction disconnecting the ring from the chain gives enone (22),... 

Answer Following the Robinson annelation disconnection is simple here. 

Answer The cyclohexenone is a clue to a Robinson annelation disconnection reveals symmetrical amino ketone (26) as starting material (see page T 147 ior its synthesis). An enamine is again the best control. Ana lysis... 

Example Compound (27) was needed for synthesis of analogues of vernolepin, an anti-tumour compound. Robinson disconnection suggests unsymmetrical ketone (28)... 

With the Robinson annelation in mind, we can get back ic a cyclohexadienone (2) by a Wittig disconnection. One of the double bonds could be put in by quinone oxidation leaving cyclohexenonc (3), which we have already made by a Rotjinson annelation and by another route (p 380). 

Disconnection oX 1), after removal of the kctal. can lead back by allphatio Frlcdcl Crafts reaction to anhydride (24). Bicyclic (22) is clearly derived from Robinson annelation produot (25),... 

Addition of, say, a C02Et group would allow Diels-Alder disconnection leading eventually to cycloheptanone. A better strategy is to add a carbonyl group to make an enone (31) with Robinson annelatlon as the key reaction. Analysis... 

Combining aldol and Michael reactions in one sequence is very powerful, particularly if one of the reactions is a cyclisation. The Robinson annelation9 makes new rings in compounds like 73 that were needed to synthesise steroids. Disconnection of the enone reveals triketone 74 having 1,3- and 1,5-dicarbonyl relationships. The 1,3-disconnection would not remove any carbon atoms but the 1,5-disconnection at the branchpoint gives a symmetrical 3-diketone that should be good at conjugate addition. 

The new ring need not be fused to an old one and simple cyclohexenones can be made by Robinson annelation usually with the addition of a CC Et activating group. In the disconnection of cyclohexenone 78, you could add the CC Et to form 79 before the second disconnection, as we have done, after the second disconnection or while writing out the synthesis. 

Closely related to the Robinson annelation is the sequence of conjugate addition and acylation used to make dimedone 83. Either disconnection of the 1,5-dicarbonyl compound 84 is good but we prefer 84a as the enone 85 is the aldol dimer of acetone (chapter 19) and is readily available. 

The cyclohexenone 13 was needed for a synthesis of the boll weevil hormone grandisol. Disconnection with Robinson annelation (chapter 21) in mind gives the rather unstable looking enone 15. No doubt a Mannich method could be used (16 R = NR2) but any leaving group X in 16 will do. 

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. 

Similar tautomerisation of the enol group gives an actual intermediate 3.13, and disconnection of the amide linkage reveals aminoketone 3.15 and an acylating species 3.14 such as an acid chloride. The forward process, cyclocondensation of amides 3.13 to yield oxazoles 3.10, is known as the Robinson-Gabriel synthesis. 

The advantages of Robinson s concept was confirmed in numerous total syntheses of alkaloids. One of the most illustrative examples is served by Stevens synthesis of the tricyclic compound coccinelline 45 (Scheme 3.10), the pheromone of the ladybug (ladybird). As was acknowledged in Stevens review article, in less time than it took to write this paragraph, we had developed on paper an attractive approach that relies on one of the oldest reactions known in alkaloid synthesis, namely the classical Robinson-Schopf condensation . This approach involved the retrosynthetic transformation of 45 into the ketopiper-idine derivative 46, which is amenable to disconnection in accordance with the same logic as used by Robinson in the analysis of tropinone. 

The structural feature of an a, 3-unsaturated ketone or a (3-hydroxy ketone in a six-member ring suggests a double disconnection coupled with functional group interconversions [Michael addition followed by intramolecular aldol condensation Robinson annulation)]. 

The Robinson annulation consists of a Michael addition followed by aldol cyclization with dehydration. In the retrosynthetic direction, disconnect the alkene formed in the aldol/dehydration, then disconnect the Michael addition to discover the reactants. 

The same strategy, but with the opposite polarity, along with other enone approaches is illustrated by the bicyclic enone 84 needed for the synthesis of the terpene cadinene. Aldol disconnection gives the 1,5-diketone 85 which we expect to make by a Michael addition.18 Hence we require a specific enol equivalent of cyclohexanone to add to the enone 86, and we have rediscovered the Robinson annelation.19... 

Sometimes even the aldol reaction fails to perform with its usual reliability and we must give it some help. The bicyclic enone 33 continues the contrast with Robinson annelation as it resembles the Wieland-Miescher ketone, used as a starting material for steroid syntheses,12 but with two five-membered instead of two six-membered rings. Aldol disconnection reveals the 1,4-diketone 34 but it turns out that closing the second five-membered ring this way works rather badly. 

Simple cyclohexenones can be made by Robinson annelation, if necessary after the addition of an activating group. The a,iS-disconnection on (34) reveals an unsymmetrical open chain 1,5-diketone (35) and so an activating group such as C02Et is necessary to control the Michael reaction leading to... 

Ketone (8) was an intermediate in a synthesis of the boll weevil hormone grandisol (7). This cyclohexenone is a Robinson annelation product disconnection by the method of Chapter 21 leads back to the available aldehyde (9) and the curious enone (10). 

An interesting application of propargyl halides (22) is the formation of cyclopentenones from 1,4-diketones in a five-ring version of the Robinson annelation (Chapter 21). Disconnection of (26) at the a, 8 bond reveals a... 

When Marx wished to investigate whether aikyl groups or C02Et migrated better in rearrangements, he wanted compounds (1) where the R group could be varied easily. One of the double bonds could be put in by oxidation of (2)—an ideal Robinson annelation product. Disconnection reveals 1,3-dicarbonyl compound (3) as the starting material and this can be made from simple esters (4) and ethyl formate. 

Further disconnection of (24) by 1,3-dicarbonyl methods (Chapter 19) gives aldehyde ester (25) as starting material. The aldehyde group will certainly need protection here and probably also during the Robinson annelation so available dichloracetic acid is used. 

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