Annelation, Robinson

Four ring forming transforms have been considered at length by the LHASA development group - the Diels Alder addition, the Robinson Annelation, the Simmons-Smith reaction, and iodo-lactonization. The first three of these have been fully implemented in LHASA and the fourth is completely flow charted and awaits only coding into the chemistry data base language. 

ACS Symposium Series American Chemical Society Washington, DC, 1977. 

All ring chemistry tables are organized into what is called binary search trees. Queries are posed about the existence of certain structural features. Each of these questions is answerable with a yes or a no. Based on the answer one of two different followup questions is selected. Embedded within the table may be requests for subgoals, either those already in the PGI or PGA table or for special reactions which are needed only for these transforms and are not of general synthetic interest. 

The example below shows some of the synthetic routes generated by the Diels Alder transform for the indicated precursor. It is important to note that while some of the chemistry may look somewhat naive, it can be quite thought provoking. 

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This sequence of Michael reaction and cyclisation is known as tile Robinson annelation since it makes a ring. 

If you don t see why the stereochemistry should be as 1 have drawn it, 1 suggest you make a model of 332A and discover for yourself There is a simple synthesis of 332A (X = OTs) from the Robinson annelation (frame 117) product 332B. 

Cyclizations such as that which underlies the Knorr synthesis have also been successfully used in Robinson annelation sequences [72] (equation 12)... 

Similarly, methyl vinyl ketone has been added to enamines derived from aldehydes (3,321,324-327) and ketones (3,328), providing a useful extension of the Robinson annelation reaetion. Condensations of enamines with other a, 3-unsaturated ketones can give a variety of diketones (329). 

The Robinson annelation reaction has classically been employed for the building up of the six-membered ring components of the steroid nucleus (18). In the original method, the enolate is treated with the methiodide of )9-diethylaminoethyl methyl... 

Two-Group Disconnections III 1,5-Difunctionalised Compounds Michael Addition and Robinson Annelation... 

Example Compound (21) may not look like a Robinson annelation product, but it is certainly an enone so a,B disconnection gives a 1,5-di-carbonyl compound A reverse Michael reaction disconnecting the ring from the chain gives enone (22),... 

Answer Following the Robinson annelation disconnection is simple here. 

Answer The cyclohexenone is a clue to a Robinson annelation disconnection reveals symmetrical amino ketone (26) as starting material (see page T 147 ior its synthesis). An enamine is again the best control. Ana lysis... 

Cyclopropanation from the hydroxyl side of (54) should give (53). Removal of the acetal leaves ketone (55) in which the double bond has been returned to conjugation. The structure remaining is very like ketone (56), the classical product of a Robinson annelation (pT175). Analysls... 

Control is best exercised by forming the enamine of the aldehyde. The reaction goes to (16) in one step and is a Robinson annelation (p T 175 ). 

With the Robinson annelation in mind, we can get back ic a cyclohexadienone (2) by a Wittig disconnection. One of the double bonds could be put in by quinone oxidation leaving cyclohexenonc (3), which we have already made by a Rotjinson annelation and by another route (p 380). 

Select one compound from (37) - (40) for synthesis by each of the methods of this chapter Robinson annelation, Diels-Alder reaction, total reduction of aromatics, and Birch reduction. 

The rest are more difficult to classify, but (39) looks like the Robinson annelation product as the two phenyl groups prevent synthesis from an aromatic compound. 

Aldehyde (41) can be made by rearrangement of epoxide (42) and the Robinson annelation gives (39) in one step. 

Disconnection oX 1), after removal of the kctal. can lead back by allphatio Frlcdcl Crafts reaction to anhydride (24). Bicyclic (22) is clearly derived from Robinson annelation produot (25),... 

Ecologically and economically valuable solvent-free Robinson annelation reactions, which proceed efficiently in a one-pot process at room temperature, have been reported [ 10]. For example, 2-methylcyclohexanone (59), methyl vinyl... 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

A. Bhattacharya, U.-H. Dolling, E. J. J. Grabowski, S. Karady, K. M. Ryan, L M. Weinstock, Enantioselective Robinson Annelations via Phase-Transfer Catalysis , Angew. Chem. Int. Ed. Engl 1986,25, 476-477. 

Syntheses of diastereomerically pure racemates of himachalene derivatives started from cycloheptanone G (Fig. 9). The sequence to I involved dimethyla-tion to yield H followed by bromination/dehydrobromination and conjugate methylation using cuprate chemistry. The sequence furnishing L and M follows a Robinson-annelation type Reaction of I with 3-(trimethylsilyl)but-3-en-2-one yielded K. Refluxing K with potassium hydroxide in ethanol removed the silyl group and cyclized the diketone to form a 97 3 mixture of racemic L and M. Occurring as a volatile in A.flava, L served as a versatile intermediate in the syntheses of other Aphthona compounds. 

The reaction of A2-piperideine (115) with methyl vinyl ketone to give (124) is another example of how initial electrophilic attack on the enamine double bond can be used in heterocyclic synthesis (77ACR193). This overall process is an enamine analog of the Robinson annelation and is a useful approach to the perhydroquinoline ring system. 

By heating the racemic Robinson annelation product (249) with an equimolar amount of (S)-proline pyrrolidide (250), the related dienamine (251) was obtained, which, upon hydrolysis was converted to (S)-(249)248). 

Problem 17.49 The Robinson annelation reaction for synthesizing fused rings uses Michael addition followed by intramolecular aldol condensation. Illustrate with cyclohexanone and methyl vinyl ketone, CHj=CHCOCH,. <... 

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