Ring-equilibration synthesis

These results can be interpreted in terms of competition between recombination of the diradical intermediate and conformational equilibration, which would destroy the stereochemical relationships present in the azo compound. The main synthetic application of azo compound decomposition is in the synthesis of cyclopropanes and other strained-ring systems. Some of the required azo compounds can be made by 1,3-dipolar cycloadditions of diazo compounds (see Section 6.2). 

Grubbs applied his ring-closing olefin metathesis reaction to the synthesis of (lS,5R)-44 as shown in Scheme 67 [99]. The key-step was the cyclization of A to give C. The unreacted anti-isomer B could be recovered and equilibrated to a mixture of A and B. 

Another possibility to increase the diastereoselectivity in an asymmetric synthesis can arise from different thermodynamic stabilities of the diasteieoisomeric products. If the thermodynamic stabilities of these are different enough, then, under conditions of equilibrium, a complete conversion of the less stable into the more stable can be achieved. For example, the diastereoselective hydrogenation of naphthalene derivates over Pd/C catalyst leads to a mixture of dihydronaphtalenes in which the cA-isomer predominates. The conversion of this isomer into the tram occurs by changing the properties of the reaction medium, namely by equilibration with a base. For such a purpose, NaOMe in IHF can be used [263], Generally, such an increase in stability in the six-membered rings can result from a rearrangement of the substituents from an axial to an equatorial position. 

Ring-closing metathesis, which has proved to be a popular route to the marine toxins, has found a further application as the key step in the synthesis of the pheromone (-)- and ( )-frontalin <99TL1425>. The precursor in this reaction is a mixture of the syn- and anri-isomers 39. Ring closure in the presence of a ruthenium benzylidene catalyst occurs within minutes at room temperature when only the syn-isomer cyclises to 40. The unreacted anri-isomer can be re-equilibrated for a further cyclisation. 

There are times that it is important to run the Grubbs reaction under equilibrating conditions. In the course of a synthesis of ophirin 12, Michael Crimmins of the University of North Carolina observed (J. Am. Chem. Soc. 2004,126, 10264) that metathesis of 8 under the usual conditions gave mainly the undesired cyclic dimer. At elevated temperature, the dimer re-entered the equilibrium, leading to the desired 9 as the major (15 1) product. The oxonene ring system of 10 then directed the intramolecular Diels-Alder cycloaddition, leading to 12. 

A novel entry to decahydrocyclopentacyclooctene derivatives via the intramolecular photocycloaddition of fused a,/3-unsaturated y-lactones has been developed (80CC1011). Irradiation of the butenolide (153) in acetone solution gave both the fused and bridged photoadducts (154) and (155) (2-3 1). The major adduct was hydrolyzed, oxidized and esterified to afford (156). Reductive cleavage of the unsaturated keto ester (156) with lithium in ammonia afforded a five-component mixture of a,/3- and /3,y-unsaturated esters. Equilibration with 0.1M sodium methoxide in methanol converted the mixture into a single a,j8-unsaturated ester (157 Scheme 34). This annelative two-carbon ring expansion method may find application in the synthesis of ophiobolin and ceroplastol sesterterpenes. 

We envisioned that the B ring of cylindrospermopsin (1) could be prepared by an intramolecular SN2 reaction of the guanidine of 4 on the bro-moketone. Equilibration would provide the desired equatorial side chain. Reduction of the ketone, deprotection and sulfation would complete the synthesis of cylindrospermopsin. Addition of acetylene 5 to pyrimidine... 

The synthesis of cyclic polydimethylsiloxane was first achieved through ring-chain equilibration of siloxane oligomers in the presence of potassium silanolate, as shown in Fig. 51 [163-165]. Cyclics recovered from ring-chain equilibration reactions have been fractionated by preparative GPC, yielding... 

Fig. 51 Synthesis of cyclic polydimethylsiloxane by ring-chain equilibration beginning...

While the original synthesis of 1 features a clever use of the Tebbe olefination reaction, the process routes use elegant methods to set the ring stereochemistry through displacement reactions (and equilibration), followed by reduction, reactions that are much more scalable. This difference reflects the contrasting need for SAR development in the medicinal chemistry work vs. the need for scalability in the process work. 

The synthesis of furoxans has been discussed in a recent review (81AHC(29)25l), and the material summarized in the following sections is cited therein unless otherwise stated. The principal routes comprise oxidative ring closure of a-dioximes dehydration of a-nitro ketone oximes and dimerization of nitrile oxides. In choosing the method the possibility of equilibration between the 2- and 5-oxides of asymmetrically substituted furoxans, which was described in Section 4.22.3.2.1, must be taken into account. There has been no case of direct oxidation of a furazan to a furoxan. 

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