Equilibration route, synthesis

As it is well known, the (Si-0) bond in organosiloxanes may be considered to be polar or partially ( 50%) ionic.(12) Therefore, it can be cleaved by the attack of strong acids or bases. This is the main rationale behind the "equilibration" route to the synthesis of a wide variety of functionally terminated siloxane oligomers(12-14) from cyclic siloxanes and a.ordifunctional disiloxanes as shown in Scheme 3. 

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. 

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. 

In addition to dimethylcuprates, various alternate cuprate reagents can be used. As shown in Scheme 11.12, a divinylcuprate was used in a 1,4-addition employed in the total synthesis of meroquinene 42 (Scheme 11.12), a degradation product of cinchonine and also an intermediate en route to cinchona alkaloids such as quinine [52,53]. As illustrated, enone 36, available via acetoxyglucal 35 (Scheme 11.11), was treated with divinylcuprate to exclusively afford the axially substituted 4-vinyl derivative 38. Trapping of this intermediate with methyl bromoacetate gave a mixture of C3 epimers readily equilibrated to 39 in the presence of triethylamine. Further manipulations of 39 gave the 2-deoxy derivative 40 and, in turn, the dialdehyde 41. Cyclization of the latter to enantiomerically pure meroquinene 42 proceeded uneventfully. 

A formal total synthesis of ( )-morphine has been achieved by adopting the above synthetic route (Scheme 18). The tetrahydropyridine 91, prepared from the reaction of A/ -methyl-4-piperidone with 2,3-dimethoxy-phenyllithium, followed by dehydration, was converted to the bicyclic en-amine 92 by treatment with the ylic dibromide. Kinetic protonation of 92 with perchloric acid gave the trans-fused immonium salt, which upon dissolution in methanol equilibrated to the thermodynamically prefered cis isomer 93. Treatment of 93 with diazomethane brought about the formation of the aziridinium salt 94, which was readily transformed into the a-amino aldehyde 95 by its oxidation with dimethyl sulfoxide. It is also worth noting that the Komblum oxidation of aziridinium salts leads to the construction of a-amino aldehydes efficiently. Lewis-acid-catalyzed cyclization of 95 afforded the morphinan carbinol 96 in 80% yield. Successive mesylation and reduction of the mesylate derived from 96 with LiBEtjH afforded morphinan (97) in excellent yield. In this instance, direct conversion of 93 to 97 by treatment with diazomethane gave approximately 1 % of the desired product. Lemieux-Johnson oxidation of 97 under acidic conditions furnished the ketone 98, which was previously transformed into ( )-morphine by Gates. In order to confirm the structure of 98, its conversion to the known... 

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