Bicyclic bromo ketone

G.A. Kraus and co-workers utilized the quasi-Favorskii rearrangement of a bicyclic bridgehead bromide as the key step in their formal total synthesis of ep/-modhephene. The required bicyclo[3.3.1]nonenone bridgehead bromide precursor was prepared by a Robinson annulation reaction between 3-bromo-2-oxocyclohexanecarboxylate and MVK. Upon treatment with lithiated dimethyl methylphosphonate, the bicyclic bromo ketone underwent a facile quasi-Favorskii rearrangement to afford the key intermediate bicyclo[3.3.0]octane derivative. 

Alternatively, l-oxo-l,2,3,4-tetrahydroquinolizinium ion (111 Scheme 73) and its congeners may be converted to derivatives of 1-hydroxyquinolizinium ion (63JCS2203). The bicyclic ketone (111) can be brominated to yield the 2-bromo (112) or the 2,2-dibromo derivative (113). Action of boiling acetic anhydride converts the monobromo ketone (112) to 2-bromoquinolizinium bromide (Table 2). If the same bromo ketone (112) is heated with ion-exchange resin (Amberlite IRA-400) loaded with hydroxyl ions or, alternatively, heated with silver acetate in water, the 1,2-dihydroxyquinolizinium ion is formed and may be recovered as the picrate (Scheme 74). 

As expected, the influence of the halogen in a-halo ketones strongly influences the course of the reaction. At — 10°C, 2-chlorocyclohexanone reacted with pyrrolidine to give the isolable intermediate amino-substituted allylic chloride 6 (X = Cl) in 85% yield, along with 15% of bicyclic aminal. The corresponding a-bromo ketone showed the expected tendency for further ring closure into the cyclopropanone aminal 7, while a-fluorocyclohexanone was completely transformed into the allylic fluoride 6 (X = F). ... 

PROBLEM 19.59 When bromo ketone 1 is treated with potassium fer/-butoxide in / -/-butyl alcohol at room temperature, it gives exclusively the 5,5-fused bicyclic ketone 2. In contrast, when 1 is treated with LDA in tetrahydrofuran (THF) at —72 °C, followed by heating, the product is predominately the 5,7-fused ketone 3. Write arrow formalism mechanisms for these cycloaUgflation reactions and explain why the different reaction conditions favor different products. 

The Woodward synthetic route was initiated with a Diels-Alder reaction between 1,4-benzoquinone (14) and diene 15. The cycloadduct 16 formed in this way underwent Meerwein-Pondorff-Verley reduction to afford tricyclic lactone 17 which was converted to bromoether 18. Treatment of this substance with methoxide gave the methyl ether 19. Conversion of 19 to its halohydrin followed by chromium oxidation provided the a-bromo ketone 20 which upon treatment with zinc in glacial acetic acid afforded the bicyclic enone 21. This substance was transformed to the aldehyde-acid 23 by an osmylation-periodate cleavage sequence. The acid function in 23 was es-terified and the aldehyde moiety was condensed with 6-methoxytryptamine. The Schiff base intermediate obtained in this fashion was reduced to give an amine which provided the lactam 24 upon intramolecular acylation. Bischler-Napieralski cyclization of 24 gave the pentacyclic intermediate 25 in which... 

This hypothesis was supported by the fact that 2-bromo-6,6-diphenylbicyclo[3.1.0]hexan-3-one on treatment with potassium terr-butoxide afforded the same bicyclic ketone 1 in 74% yield." In a study of the migratory aptitudes in the 5-(4-cyanophenyl)-6-phenyIbicyclo[3.1.0]hex-3-en-2-one system 3 it was found that only phenyl migration occurred, contrary to the cyclohex-2-enone systems (see Section 4.3.5.) where 4-cyanophenyl was shown to migrate preferentially. The migratory aptitudes observed here were highly suggestive of phenyl migration to the electron-deficient carbon centers of a zwitterionic intermediate." ... 

Another application of the stereoselective tandem cyelization is the synthesis of isoiri-domyrmecin from an acyclic precursor97. Reductive cyelization of 4-bromo-5-methyl-l-trimethylsilyl-8-decen-l-yne gives a mixture of four bicyclic products in a ratio of 47 44 5 4. Conversion to the bicyclic ketone, an intermediate in the synthesis of isoiridomyrmecin, shows the potential utility of this approach in natural product synthesis. 

The Grob fragmentation is a useful synthetic tool for the construction of rings with six to eight members beginning with a bicyclic structural moiety. One example enables the production of substituted benzenes from readily available bicycles. Khan demonstrated that polyhalogenated (chloro and bromo) phenols (e.g., 36) result from treatment of bicyclic ketones (e.g., 35) with PTSA in toluene. ... 

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