Michael addition disconnections

Nitro compounds also react cleanly in Michael additions. Disconnections of cyclic amide (20) gives a 1,5-relationship if we write NO2 for NH2—the tertiary centre next to NH2in (21) is a strong hint that we should do this. Only one Michael disconnection is then possible. 

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

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

Amide disconnection reveals (18) and FGl (amino to nitro) gives (19) which could be made by Michael addition of nitro compound (16) to an acrylate ester.. lalys-ts... 

The alternative disconnection (25a) requires the Michael addition to a nucleophilic carbene equivalent to an enone. 

The recognition of consonant bifunctional relationships in the target molecule allows their disconnection by a retro-Claisen, a retro-aldol or a retro-Mannich condensation or by retro-Michael addition [equivalent, according to Corey s formalisation, to the application of the corresponding transforms (= operators) to the appropriate retrons]. 

Bifunctional systems In the case of bifunctional systems (or molecules) only two alternatives are possible the bifunctional relationships are either "consonant" or "dissonant" (apart from molecules or systems with functional groups of type A to which we have referred to as "assonant"). In the first case, the synthetic problem will have been solved, in principle, in applying the "heuristic principle" HP-2 that is to say, the molecule will be disconnected according to a retro-Claisen, a retro-aldol or a retro-Mannich condensation, or a retro-Michael addition, proceeding if necessary by a prior adjustment of the heteroatom oxidation level (FGI). 

The first successful synthesis of longifolene was described in detail by E. J. Corey and co-workers in 1964. Scheme 13.19 presents a retrosynthetic analysis corresponding to this route. A key disconnection is made on going from I => II. This transformation simplifies the tricyclic skeleton to a bicyclic one. For this disconnection to correspond to a reasonable synthetic step, the functionality in the intermediate to be cyclized must engender mutual reactivity between C-7 and C-10. This is achieved in diketone II, because an enolate generated by deprotonation at C-10 can undergo an intramolecular Michael addition to C-... 

By bond polarity and resonance, the carbonyl carbon and a carbon (i to the carbonyl carbon can be utilized as electrophilic centers—die carbonyl group by direct nucleophilic addition and die /3 carbon by Michael addition to an a,/3-unsaturated ketone. By resonance interaction, the a position in carbonyl compounds and y positions in o, /3-unsaturated carbonyl compounds can be converted to nucleophilic centers by proton removal. These normal polarities are used frequently in retrosynthetic planning as points of disconnection to establish potential bond-forming steps using carbonyl groups. 

Once the ketone is recognized as a useful intermediate, normal polarities can be used to disconnect it retrosynthetically. For example, a good disconnection could be as shown, where Michael addition to ethyl vinyl ketone by a cyclopentyl anion would give the needed ketone. 

Remember that not all nucleophiles will successfully undergo Michael additions—you must bear this in mind when making a 1,3-disconnection of this type. Most reliable are those based on nitrogen, sulfur, and oxygen (Chapter 10). 

Michael addition of enolates to a,[3-unsaturated compounds is a good way of making 1,5-difunction-alfeed compounds, and you should look for these 1,5-relationships in target molecules with a view to making them in this way, Our example is rogletimide, a sedative that can be disconnected to a 1,5-diester. Further 1,5-diCO disconnection gives a compound we made earlier by ethylation of the ester enolate. 

For the synthesis of the pyrrolizidine fragment (2), we identified maleic anhydride (5, 7 /kg), aminobutyric acid (6, 120 /kg) and trienal 7 as readily available starting materials. In the most ambitious disconnection, the racemic pyrrolizidine carboxylic acid 4a, could be assembled, in principle, in a single step from 4-aminobutyric acid (6) and maleic anhydride (5). A subsequent kinetic resolution via oxa-Michael addition would then generate an enantiomerically enriched enolate equivalent, which could in turn add to the aldehyde 3. However,... 

This disconnection led to the C3 synthon 48 (and hence to its already familiar synthetic equivalent 44) and C9 amino dialdehyde 47. The Michael addition of malonic ester to acrolein was employed for the synthesis of the key starting material 49. The Claisen ester condensation of the latter followed by decarboxylation and reductive aminolysis led to the preparation of amino-bis-acetal 47a. The respective amino dialdehyde 47, generated in situ by a controlled hydrolysis of the acetal groups of 47a, reacted smoothly with acetonedicarboxylic diester and gave the required adduct 46 in a good yield and nearly complete stereoselectivity. 

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. 

Another disconnection outside the enone system is 4e which looks at first sight like a conventional conjugate addition to an a3 Michael acceptor. However we need to get the alkene back again after the Michael addition has occurred. The a3 synthon 14 is unsaturated. 

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... 

The second 119 clearly came from the ketone 121 and this looks like an aldol product from CH20 and a specific enolate of the ketone 121. This ketone is substituted at only one a-atom, so regioselective enolisation would be possible. But there are problems of chemoselectivity (the other CHO group) and stereoselectivity and a Michael addition approach on the enone 122 looked more promising. Aldol disconnection of 122 seems to have uncovered an excellent symmetrical intermediate 123 which can cyclise only to give 122. 

So as to understand the concept of synthon, let us analyse the synthesis of keto ester A in Figure 1.3. There are many different ways to disconnect the C-C bond in A, and eight structural units (a)-(h) are conceivable as possible synthons. Disconnection of a target molecule to possible synthons is called retrosynthetic analysis. If there is a reaction to connect the possible synthons to build up A, then we can select realistic synthons. In the case of A, (d) and (e) are two synthons, which can be connected by employing the Michael addition. 

The Grignard reagent from (41) has been widely used in synthesis. We recognise a bromide and an acetal disconnecting the acetal reveals a j3-bromo aldehyde available by Michael addition of Br" to acrolein (42)... 

The 1,3-disconnection we met in Chapter 6 is also effective for carbon nucleophiles (21). The reaction is the Michael addition of carbanions to a,d-unsaturated carbonyl compounds and we may expect Grignard reagents or RLi to do this reaction. We shall look for this disconnection when there is a branch point at the /3 or 7 carbon atoms, and particularly when the bond to be disconnected joins a ring to a chain. Ketone (22) can clearly be made this way. 

The alternative disconnection (20) requires the Michael addition of an acyl anion equivalent. Cyanide ion, a reagent for COjH and nitro alkane anions (Chapter 22) are both good at Michael additions, so that addition of cyanide ion to (21) is a route to y-keto acids (22). 

With two heteroatoms in the ring, it is again useful to look for a recognisable fragment containing both. Uracil (47), one of the bases in the nucleic adds, can be disconnected to urea and a suitable electrophilic fragment. Michael addition to an electrophilic acetylene is a suitable reaction. 

---