Proximal cleavage

Interestingly, bicyclopropylidene (7) also reacts with selected electron-deficient open-chain al-kenes, e.g. diethyl fumarate. When tris(2-phenylphenyl) phosphite is employed to modify the nickel catalyst, the yield of the [2 + 2] cycloadduct 10 amounts to 34% and the [3 + 2] cycloadduct 11 is formed as a minor product. Additionally, two diastereomers of the double [3 + 2] cyclo-adduct 12, formally arising from 7 by proximal cleavage of one cyclopropane ring and distal cleavage of the other, are formed in 15.6% yield. ... 

The result of the reaction with MCP and dimethyl bicyclo[2.2.1]hept-2-ene-2,3-dicarboxylate vide supra) is in contrast to the outcome of most nickel-catalyzed [3 + 2] cycloadditions in the absence of phosphanes ( naked nickel catalysts) which employ unsaturated esters as cosubstrates. Normally, products arising from formal proximal cleavage of the three-membcred ring are formed in these cases. All of these reactions proceed readily at slightly above room temperature (20 40°C) and are highly regio- and stereoselective. 

A special case of a transannular cycloisomerization occurs with the ethyl acrylate derivative 22. lO a.b Nickel(O), as well as palladium(O), catalysts effect this reaction in generally high yields, leading to the formation of the [3.3.3]propellane derivative 23. Even in the nickel(0)-catalyzed reaction, no isomeric compound arising from proximal cleavage of the methylenecyelopropane is formed, presumably due to activation of the distal bond arising from the tetrasubstitution of the methylene group. 

Migaki, G. I., J. Kahn, and T. K. Kishimoto. (1995). Mutational analysis of the membrane-proximal cleavage site of L- selectin Relaxed sequence specificity surrounding the cleavage site. J Exp Med. 752 549-557. 

From intermediate 43, the path to monensin would seemingly be straightforward. A significant task which would remain would be the construction of the l,6-dioxaspiro[4.5]decane substructure of monensin. You will note that the oxygen atoms affixed to carbons 5 and 12 in 43 reside in proximity to the ketone carbonyl at C-9. In such a favorable setting, it is conceivable that the action of acid on 43 could induce cleavage of both triethylsilyl ethers to give a keto triol which could then participate in a spontaneous, thermodynamically controlled spiroketalization reaction. Saponification of the C-l methyl ester would then complete the synthesis of monensin. 

The hydrogeh atom bound to the amide nitrogen in 15 is rather acidic and it can be easily removed as a proton in the presence of some competent base. Naturally, such an event would afford a delocalized anion, a nucleophilic species, which could attack the proximal epoxide at position 16 in an intramolecular fashion to give the desired azabicyclo[3.2.1]octanol framework. In the event, when a solution of 15 in benzene is treated with sodium hydride at 100 °C, the processes just outlined do in fact take place and intermediate 14 is obtained after hydrolytic cleavage of the trifluoroacetyl group with potassium hydroxide. The formation of azabi-cyclo[3.2.1]octanol 14 in an overall yield of 43% from enone 16 underscores the efficiency of Overman s route to this heavily functionalized bicycle. 

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