Diels-Alder reaction retrosynthetic analysis

Tran orm-based or long-range strategies The retrosynthetic analysis is directed toward the application of powerful synthesis transforms. Functional groups are introduced into the target compound in order to establish the retion of a certain goal transform (e.g., the transform for the Diels-Alder reaction, Robinson annulation, Birch reduction, halolactonization, etc.). 

The natural product panepophenanthrin (6/1-170), isolated in 2002 from the fermented broth of the mushroom strain Panus radus IFO 8994 [90], is the first example of an inhibitor of the ubiquitin-activating enzyme [91]. Retrosynthetic analysis based on a biomimetic analysis led to the conjugated diene 6/1-172 by a retro-Diels-Alder reaction via the hemiacetal 6/1-171. Further disconnections of 6/1-172 produces the vinyl stannane 6/1-173 and the vinyl bromide 6/1-174 [92]. 

Ishikawa and coworkers reported a synthesis of ( )-0-methylkinamycin C (54) [32, 33]. Their retrosynthetic analysis is shown in Scheme 3.9. It was envisioned that 54 could be derived from the dihydroindanone 55 by D-ring oxygenation, installation of the diazo substituent, and oxidation of the protected hydroquinone function. The dihydroindanone 55 was envisioned to arise from the enol ether 56, itself formed from an endo Diels-Alder reaction between the indenone 59 and the diene 58. 

Diels-Alder disconnection will have been eliminated, and the retrosynthetic search becomes highly focused. Having selected both the transform and the mapping onto the TGT, it is possible to sharpen the analysis in terms of potentially available dienophile or diene components, variants on the structure of the intermediate for Diels-Alder disconnection, tactics for ensuring stereocontrol and/or position control in the Diels-Alder addition, possible chiral control elements for enantioselective Diels-Alder reaction, etc. 

Retrosynthetic analysis of fumagillol 18 leads to two possible synthetic schemes, (a) and (b), both starting with a Diels-Alder reaction 13... 

In a similar manner, the retrosynthetic analysis of the Diels-Alder reaction is represented below ... 

This stepwise retrosynthetic analysis gives the 1,3-diene and dienophile needed for any Diels-Alder reaction, as shown in the two examples in Figure 16.12. 

The brief report of Jacobsen s total synthesis starts with a detailed retrosynthetic analysis. The compound was broken into four pieces 21a after removal of the phosphate. The unsaturated lactone 24 (M is a metal) could be made by an asymmetric oxo-Diels-Alder reaction from diene 22 and ynal 23. The epoxide 25 provides a second source of asymmetry. One cis alkene comes from an alkyne 26 and the rest from a dienyl tin derivative 27. 

Many Diels-Alder reactions have both stereospecific and stereoselective aspects. It is as important as ever at this point not to confuse perfect stereoselectivity with stereospecificity. So, let s look at a real example. Pumiliotoxin C 11 (a toxin from a tropical frog) contains four chiral centres and in the following synthesis, three of them were controlled by a Diels-Alder reaction.2 The retrosynthetic analysis is quite instructive. 

In many cases, fragmentations corresponding to the retroreaction of a powerful reaction (sec. lO.S.B.vi) can be identified and used retrosynthetically. Retro-mass spectral analysis has been applied to total synthesis by Kametani. The mass spectra of tetrahydroisoquinoline alkaloids show fragmentations by the three major pathways shown in Scheme 10.24.1 Kametani observed that path c (a retro Diels-Alder reaction) was the major fragmentation pathway (sec. ll.S.B). Xylopinene (274) gave this specific fragmentation (to 275 and... 

Retrosynthetic analysis of six-membered ringformation almost always boils down to a Diels-Alder reaction or a Robinson annelation (or variations thereof) as the crucial C—C bond forming step. Both methods have in common that more than one carbon—carbon bond is formed in a one pot reaction which allows a rapid and efficient construction of complex organic molecules from rather simple building blocks. No such general tool exists for the formation of carbocyclic five-membered rings. 

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 development of a silver-mediated Diels-Alder reaction to construct the pentacyclic intermediate 77a in which the two methylene groups were positioned trans to each other paved the way for the asymmetric total synthesis of (+)-perophoramidine. In our retrosynthetic analysis (Scheme 26), we planned to synthesize (+)-perophoramidine via late-stage regioselective N1 -methylation of the hexacycUc intermediate 100. We planned to constmct the B-ring in 100 via intramolecular amination of the imidate functional group in 101, which could be readily synthesized fi-om 77a via a series of functional group transformations. 

Retrosynthetic Analysis and Solution Devising this synthesis will help you see how a Diels-Alder reaction can be used to impart specific stereochemistry in a synthesis. It will also help you review some other reactions you have just learned. Here is our retrosynthetic scheme ... 

Diels-Alder reactions are widely used for making carbon-carbon bonds, and retrosynthetic analysis can reveal opportunities for their application. If a synthetic target contains a cyclohexene ring, start with the double bond and use curved arrows to disconnect the bonds to be formed in the sought-for cycloaddition. For example ... 

Fig. 11. Retrosynthetic analysis of structure 1 As far as the constitution is concerned structure 2 correlates by dehydrogenation with 1 or by retro Diels/Alder reaction with 4 and 5. As far as the configuration is concerned 4 and 5 correlate by Diels/Alder reaction with 3, not with 2.

Through the retrosynthetic analysis of the molecular structure of natural product Maoecrystal V, I found it possesses a 1,4-dicarbonyl unit, therefore proposed a synthetic strategy based on oxidative coupling and Diels-Alder reaction. (Fig. 1.11)... 

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