Group path

Fig. 2. Retro synthetic analysis for the dendritic structures FG, FP and X, Y are respectively interconvertible functional groups Path A is the divergent synthesis Path B is the convergent synthesis stands for the core structure Q stands for the branching repeat unit...

In the example shown above, there are two possible ways to disconnect the TM, 2-pentanol. Disconnection close to the functional group (path a) leads to substrates (SE) that are readily available. Moreover, reconnecting these reagents leads directly to the desired TM in high yield using well-known methodologies. Disconnection via path b also leads to readily accessible substrates. However, their reconnection to furnish the TM requires more steps and involves two critical reaction attributes quantitative formation of the enolate ion and control of its monoalkylation by ethyl bromide. 

After rate-determining ionization of a good leaving group, path Dn, the cation is deprotonated by path Dg to produce a pi bond. This elimination is the reverse of the AdgZ addition. As might be expected, the El process competes with the SnI process. If A acts as a base, El occurs if it acts as a nucleophile, SnI occurs. Section 9.5 will discuss such decisions in detail. 

This reaction is the reverse of the hetero Ade2 reaction. The lone-pair-assisted El uses a properly aligned lone pair to expel the leaving group, path Ep. The resultant cation is then deprotonated, path p.t. 

The electrophile is the acylium ion, R-C +, generated by Lewis acid-catalyzed ionization of a leaving group (path Dn) from acyl halides or acid anhydrides (shown in the previous section). The proton that is lost comes from the same carbon that the electrophile attacked. The reaction fails for deactivated rings (Ai wg, meta directors). After the electrophile adds it deactivates the ring toward further attack. No rearrangement of the electrophile occurs. 

The stability of both path Dn product carbocations must be checked the lone-pair-stabilized tertiary cation is much more stable and therefore is favored over the unstabilized primary cation. Ionization of the leaving group (path Dn) creates a somewhat less stable cation than the protonated ketal, so ionization of the leaving group is uphill in energy. 

Five- and six-membered ring enolates with an endocyclic double bond also react to deliver an electrophile from the sterically less hindered face. Enolate 498 was obtained by treatment of 497 with lithium amide. Subsequent reaction with an alkyl halide led to delivery of the halide from the face opposite the alkenyl group (path a) and the trans product shown (499) was isolated in 60% yield.-. Approach via path b would have serious steric consequences, and that transition state is destabilized. Similar effects are observed with 3-alkyl-cyclohexanone derivatives. 

In this step the nucleophile fonns a bond to the carbon by donating an electron pair to the top or bottom face of the carbonyl group [path (a) or (b)]. An electron pair shifts out to the oxygen. 

Addition of the nucleophile can take place by two sterically different pathways. In the first (path (a)), direct attack on the rj -allyl group occurs trans to palladium. This is by far the commoner route and is followed by stabilized carbanions such as CH(C02R)2, CH(C0R)2, PhCHCN and CgHg , and normally also with amines. Aryl and alkyl carbanions (e.g. R CuLi) or hydride however add initially to the metal centre and then migrate to the allyl group (path (b)). The stereochemistry of the product depends on which mechanism is followed (v.i.). 

In this mechanism, a seven-membered ring is formed in the transition state and the (Me0)2P-0 unit serves as a leaving group. Path B is based on nucleophilic substitution at the phosphorus. It commences with the protonation of one methoxy group. This is the precondition for the subsequent positivation of the phosphorus atom. In the transition state, the formation of a thermodynamically stable six-membered ring is realized. 

But let s just complicate slightly the issue by considering another steroidal ketone, compound 4 in Scheme 6.2. Here, a nucleophile (MeO, K2CO3 in MeOH) may behave as such and substitute the leaving group bromide (Scheme 6.2, path a to give product 5), or behave as a base and abstract a proton from the position a to the carbonyl group (path b). 

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