Robinson ring annelation

Despite its drawbacks, the Robinson annelation is still the most widely used cyclohexenone ring annelation. Variants on the... 

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

The synthesis of cyclohexenone derivatives by Michael addition followed by intramolec ular aldol condensation is called the Robinson annulation, after Sir Robert Robinson who popularized its use By annulatwn we mean the building of a ring onto some start mg molecule (The alternative spelling annelation is also often used)... 

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... 

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),... 

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.). 

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. 

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,. <... 

Amplification. See Chirality amplification Anhydrides, ring opening, 331 Anionic polymerization methyl sorbate, 174 trityl acrylate, 181 Annelation, Robinson method, 336 Antibiotics, 8, 44, 80 Antibodies, 12... 

The isoxazole annelation reaction2,3 is a general method for fusing a new cyclohexanone ring onto an existing system and is complementary to the well-known Robinson annelation.4 It has several major advantages ... 

The new ring need not be fused to an old one and simple cyclohexenones can be made by Robinson annelation usually with the addition of a CC Et activating group. In the disconnection of cyclohexenone 78, you could add the CC Et to form 79 before the second disconnection, as we have done, after the second disconnection or while writing out the synthesis. 

The Robinson annelation is by no means the only ionic reaction that makes six-membered rings. Six-membered rings form easily so trapping a Nazarov intermediate (chapter 35) makes good sense. The Friedel-Crafts-like disconnection 18 suggests a most unlikely cation 19 until we realise that it would be formed in the Nazarov cyclisation of the dienone 20 whose synthesis is discussed in the workbook. 

In 1973, Wiesner, Vlahov, and Muzika reported (176) a relatively simple annelation procedure for the construction of ring A as an alternative to the Robinson annelation method. 

The most abundant and widely used monoterpenes, pinenes and their analogues, are often upgraded to more sophisticated structures with a Robinson annelation as the key step. However, as a result of unusual stereochemical constrains imposed by the bicyclic ring, only certain conformational isomers of the pinane skeleton undergo the annelation. Whereas the diketone (41) derived from n. v-inethylnopinone cyclized satisfactorily to the tricyclic ketone under Robinson conditions (Scheme 5.18), the epimeric diketone would not.64... 

This sequential process of Michael-aldol reaction leading to a new six-membered ring is known as the Robinson annelation. It was, in fact, Robinson who invented the idea of using a Mannich product in conjugate additions because he wanted to develop this important reaction. There are now thousands of examples used to make all kinds of compounds, especially steroids (Chapter 49). 

The essential requirement for a Robinson annelation is a Michael addition of an enolate to an enone that has a second enolizable group on the other side of the ketone. The classic enone is butenone (methyl vinyl ketone) and the classic Robinson annelation is the synthesis of rings A and B of the steroid nucleus. 

The second stage is the formation of a new enolate on the other side of the ketone from the first. Note that the original enolate, the intermediate in the conjugate addition, can cyclize to give only an unstable four-membered ring so this cyclization would be reversible, The next intermediate, the aldol product, is often isolated from Robinson annelations, the Robinson annelation mechanism—stage 2 the intramolecular aldol reaction... 

The first enol you saw at the start of Chapter 21 was the stable enol of dimedone , 5,5,-dimethyl-cydohexa-l,3-dione. This six-membered ring is made by a close analogue of the Robinson annelation. The only difference is in the cyclization step, which is a Claisen ester condensation rather than an aldol reaction. 

In Chapter 28 you met the Robinson annelation as a method of making cyclohexenones. The product of the elimination step contains a double bond, but there is no question about its geometry because in a six-membered ring only a cis double bond can exist—a trans one would be far too strained. 

To introduce the topic, an example. It may seem to you that any six-membered ring might show different chemical shifts for axial and equatorial groups. But this doesn t happen. Consider the result of this Robinson annelation reaction. 

This principle is often applied to molecules. If a nucleophile is joined to the carbonyl group it is to attack by a short chain of covalent bonds, it may be able to reach only one side of the carbonyl group. An example from a familiar reaction concerns the Robinson annelation. The first step, Michael addition, creates a stereo genic centre but no relative stereochemistry. It is in the second step—the aldol cyclization—that the stereochemistry of the ring junction is decided. 

EttdaUne sesquiterpenes. Syntheses of eudaicne-type sesquiterpenes commonly utilize the Robinson annelation reaction to construct the bicyclic ring system. However, this annelation reaction often proceeds in low yields and with stereochemical difficulties. Huffman and Mole have recently reported a new stereoselective synthesis. 8-Methoxy-tctralin-2-carboxylic acid (1) is reduced under Birch conditions followed by acid... 

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