Retrosynthetic analysis Michael reactions

The structural similarity between claenone (42) and stolonidiol (38) enabled Yamada to exploit an almost identical strategy for the total synthesis of (-)-stolonidiol (38) [40]. A short retrosynthetic analysis is depicted in Fig. 12. An intramolecular HWE reaction of 68 was successfully applied for the macrocyclization. The highly substituted cyclopentanone 69 was made available by a sequence that is highlighted by the sequential Michael-Mi-chael addition between the enolate 53 and the a, -unsaturated ester 70 followed by a retro-aldol addition. However, as is the case for the claenone (42) synthesis, the synthesis of stolonidiol (38) is characterized by numerous functional and protecting group transformations that are a consequence of Yamada s synthetic strategy. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

Our retrosynthetic analysis of generalised pyridine 5.4 commences with an adjustment of the oxidation level to produce dihydropyridine 5.5. This molecule can now be disconnected very readily. Cleavage of the carbon-heteroatom bonds in the usual way leaves dienol 5.6 which exists as diketone 5.7. The 1,5-dicarbonyl relationship can be derived from a Michael reaction of ketone 5.8 and enone 5.9, which in turn can arise from condensation of aldehyde 5.10 and ketone 5.11. 

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. 

Based on the concept of tandem reaction, a series of synthetic routes have been developed, including an intramolecular Aldol/Oxa-Michael/Aldol/Lactonization synthetic strategy (see Fig. 1.17). The retrosynthetic analysis indicated that the synthesis starts from compound 1.7.21, which first undergoes an intramolecular Aldol reaction then immediately intramolecular Oxa-Michael reaction to form the tricyclic system. Finally through the intermolecular Aldol reaction and intramolecular esterification reaction, the tetracyclic skeleton of Maoecrystal V can be constructed. And 1.7.21 can be provided by the relatively simple materials 1.7.22 and 1.7.23 through Suzuki cross-coupling reaction. 

A Robinson annulation is comprised of a Michael reaction, followed by an intramolecular aldol condensation. To determine the starting materials necessary to prepare the desired product via a Robinson aimulation, we draw the following retrosynthetic analysis ... 

---