First-generation retrosynthetic analysis

The first generation retrosynthetic analysis provides the initial branches of a tree. Similar analysis of each branch, representing a target precursor, is then carried out. A judicious choice of which branches to terminate... 

SCHEME 3 First-generation retrosynthetic analysis of virgatolide B (2). 

Scheme 18.11 Comparison of the first- and second-generation retrosynthetic analysis of the bicyclic [3.1.0]proline core.

Scheme 15. Retrosynthetic analysis of brevetoxin B (1) the first-generation approach.

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-... 

So far we have emphasized the initial steps of a retrosynthetic analysis. The examples shown have also demonstrated that the very first bond selected for disconnection determines the strategy of the entire synthetic scheme. Therefore, this bond should be considered as a strategic bond (SB). Similar analysis aimed at the identification of the strategic bond could be also required for any intermediate structure generated in the course of the subsequent disconnection steps, leading ultimately to simple starting materials. 

In our retrosynthetic analysis (Scheme 19), we envisioned that the penta-cyclic skeleton common to perophoramidine (77) and communesins (78) could be constructed via silver-mediated Diels-Alder reaction of a tryptamine derivative 74 with benzodiene 73 generated in situ from chloroaniline 72. We postulated two stereochemical outcomes for the proposed Diels-Alder reaction (a) exo addition via transition state 75 would generate a perophoramidine-like intermediate 77 with two trans ethylene groups at C7 and C8, or (b) endo addition via transition state 76 would yield a communesin-like pentacyclic intermediate 78 with two cis ethylene groups at C7 and C8. Since the success of our planned DA reaction depended on synthesizing the benzodiene precursor 72, our first task was to prepare this compound from isatin. 

The first problem will prepare 4-bromoaniline (168) from benzene. Syntheses that transform one aromatic compound into another aromatic compound, such as this one, do not lend themselves to the retrosynthetic analysis approach presented in Chapter 25. Most of these syntheses involve functional group transformations. For the sake of continuity, a retrosynthesis is shown in which the amino group is removed to generate bromobenzene, which is obtained directly from benzene. The NH2 unit probably comes from reduction of a nitro group (Section 21.6.2), so the first precursor is 4-bromonitrobenzene (59) and disconnection of the C-N bond leads to the preparation of 59 by reaction of bromobenzene (35) with nitric acid/sulfuric acid. Bromobenzene is prepared directly from benzene as shown in the illustration. 

This is the moment to consider the availability of the TMs of the second-generation TM 2.2a and TM 2.2h. Assuming a Grignard reaction in the synthetic direction, cyclohexyl-bromide is needed. On the first glance this immediate precursor of Grignard reagent TM 2.2b is more easily available than cyclohexyl methyl ketone TM 2.2a (Scheme 2.3). The two-step retrosynthetic analysis of TM 2.2b results in phenol, a commodity from the petrochemical industry. Its hydrogenation produces cyclohexanol, which is brominated under standard conditions. 

The target molecule is now entered and ready for synthetic analysis. The molecule may be saved in a disk file with the WRITE command so the work of input will not be lost in the event of telephone disconnection. It can be read back in by a READF command. To begin analysis with the standard default strategies (which will be described later) the user simply types RUN or pushes light button "PROCESS. This generates the first level of the retrosynthetic tree. Each precursor is shown to the user on his terminal. He is then free to VIEW a precursor and PROCESS it further. Thus the standard usage of SECS is quite simple for the user. 

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