Disconnection Diels-Alder

TM 19 has a double bond in a six-membered ring and we can use the Diels-Alder disconnection (frames 5-8). 

The most important pericyclic reaction in synthesis, indeed one of the most important of all synthetic methods, is the Diels-Alder reaction. We have seen this many times before. What are the clues for a Diels-Alder disconnection ... 

Analysis We have an obvious Diels-Alder disconnection, some C-S bonds, and a 1,6-dicarbonyl relationship. The only one that gives any rapid simplification is the D-A, so we ll start with that ... 

The information obtained by this preliminary analysis can be used not only to set priorities for the various possible Diels-Alder disconnections, but also to pinpoint obstacles to transform application. Recognition of such obstacles can also serve to guide the search for specific retrosynthetic sequences or for the highest priority disconnections. At this point it is likely that... 

Answer Diels-Alder disconnection (7a) reveals a diene (9), with no stereochemistry, and a dienophile (10) which must be trans to give trans groups in (7). The one-step synthesis is successful. ... 

Diels-Alder disconnection of (S) reveals a cyclic dienophile (11) in which Me and H must be ais since they are also cis in (S), and the one step synthesis duly gi ves c-ir, product. 

Fumaric acid (16) does exist, so the best strategy is to go back to the ring opened diacid (15) before Diels-Alder disconnection. 

Answer Diels-Alder disconnection (23a) reveals maleic anhydride and diene (26) available by a Vfittig reaction from (27) or more conveniently from alcohol (28). Analysis... 

If the ketone group comes from a nitro group, a Diels-Alder disconnection is possible to give a simple condensation product (27), from nltromcthane and aldehyde (28). 

Optically active diacid (16) was needed as a synthetic intermediate. Reconnection gives (17) with no obvious disconnections. The FGA strategy provides a solution as a carbonyl group next to the ring (18) allows a Diels-Alder disconnection. 

The cyclohexene is easy to see so that the Diels-Alder disconnection follows. The stereochemistry of the double bonds comes from two separate arguments the dienophile (a in 5) must be trarjs as the two substituents it produces in (4) are also trans. The diene must be all ain or all trann since the two substituents it produces in (4) are ois (both down). The all tvan, is needed because endo approach (6) is preferred. 

Addition of, say, a C02Et group would allow Diels-Alder disconnection leading eventually to cycloheptanone. A better strategy is to add a carbonyl group to make an enone (31) with Robinson annelatlon as the key reaction. Analysis... 

Scheme 4.4 Diels-Alder disconnections used in the synthesis of strychnine...

Diels-Alder disconnection will have been eliminated, and the rctrosynthetic 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. 

There have been attempts to apply formal methods to the representation of organic compounds [1],[2], some attempts to apply artificial intelligence to organic synthesis [3],[4], and numerous attempts to apply the use of molecular orbital calculations to the verification of the validity of compounds in the synthesis route. This effort was a moderate attempt to examine the representation issues involved in writing production rules for Diels-Alder disconnections. 

The ketone 29 in fact has 1,4-, 1,5- and 1,6-relationships and if we redraw it 29a to see the 1,6-relationship clearly, being careful to get the stereochemistry right, we can reconnect to the cyclohexene 30 and hence, by Diels-Alder disconnection, find the reactive dienophile 31. The methyl and CChH groups are cis in 30 and so must be cis in 31. 

Making the Diels-Alder disconnection by drawing the mechanism of the reverse reaction 31a gives a new enol ether 32 and a quinone 33. The enol ether 32 is a derivative of the simple enone 34 and can be made by trapping the kinetic enolate with a suitable silyl group. 

The guanacastepenes are antibiotics from a rare Costa Rican fungus and have the basic skeleton 35. This has five-, six- and seven-membered carbocyclic rings but there is a hint of Diels-Alder possibilities about it in that ring C is a cyclohexene. In fact Shipe and Sorensen8 chose 36 as a key intermediate but no direct Diels-Alder disconnection looks likely. Does it help if we reconnect to the lactone 37 ... 

Compound 57 looks like a Diels-Alder adduct but the ketone must be changed 60 and it is much simpler if one alkoxy group is removed 61. Diels-Alder disconnection then gives the known dienophile 62 and a functionalised diene 63. 

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