Tandem Claisen rearrangement

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

For preparation of allyl coumarins and dihydrofuranocoumarins by tandem Claisen rearrangement-cyclization the usual procedures required vigorous reaction conditions, workup procedures were tedious, and long reaction times led to low yields. The rearrangement of allyloxycoumarins 48 to dihydrofuranocoumarins 49 has been optimized in good yields in a sealed Teflon containers with BF3-ether in N-methyl-... 

Tandem Claisen rearrangement/Cope rearrangement equivalent 178... 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone applies a tandem Claisen rearrangement and intramolecular ene-reaction. Most 19-nonsteroid contraceptive agents are produced by total synthesis from nonsteroidal starting materials. 

Claisen condensation equivalent, 10, 174 Claisen rearrangement equivalent, 10, 176 combined G—H activation-Cope rearrangement, 10, 177 as strategic reaction, 10, 178 tandem Claisen rearrangement-Cope equivalent,... 

As shown in Equation (179), a tandem Claisen rearrangement-lactonization involving the C-3 side chain of furan 292 was employed for a concise synthesis of hyperolactone C <2003JNP1039>. Although the product yield was low, the reaction created two contiguous quaternary carhon centers in one step. 

An iridium(lll)-catalyzed tandem Claisen rearrangement-intramolecular hydroaryloxylation protocol has been described that allows the transformation of allyl aryl ethers to dihydrobenzofurans under mild conditions (Scheme 95) <2005TL1237>. An in rl/ -generated PPh3AuOTf complex also proved to be an efficient catalyst for this transformation <2006SL1278>. 

In the laboratory of T. Nakai, the asymmetric tandem Claisen-rearrangement-ene reaction sequence followed by a modified McMurry coupling was used to access (+)-9(11)-dehydroestrone methyl ether. The Claisen-ene product was subjected to ozonolysis and epimerization to the 8,14-anf/ configuration. The C-ring was constructed by treating the tricyclic diketo aldehyde with TiCl3-Zn(Ag) in DME to afford the desired final product in 56% yield. 

Mandai, T., Matsumoto, S., Kohama, M., Kawada, M., Tsuji, J., Saito, S., Moriwake, T. A new, highly efficient method for isocarbacyclin synthesis based on tandem Claisen rearrangement and ene reactions. J. Org. Chem. 1990, 55, 5671-5673. 

Nicolaou, K. C., Li, J. "Biomimetic" cascade reactions in organic synthesis construction of 4-oxatricyclo[4.3.1.0]decan-2-one systems and total synthesis of 1-O-methylforbesione via tandem Claisen rearrangement/Diels-Alder reactions. Angew. Chem.. Int. Ed. Engl. 2001,40, 42644268. 

Eilbracht et al. have developed rhodium- or ruthenium-catalyzed one-pot synthesis of cyclopentanones from allyl vinyl ether via tandem Claisen rearrangement and hydroacylation [109-111]. This protocol requires elevated temperature (140-220°C) and also requires alkyl or aryl substituents at the terminal position of the allylic double bond to prevent undesirable double bond migration in the intermediary formed, unsaturated aldehyde. 

It was found that molybdenum hexacarbonyl effectively catalyzes a tandem Claisen rearrangement—cyclization reaction of allyl aryl ethers 173 to produce the dihydrobenzo-furans 174 in goocl yields (equation 80) . However, the methallyl aryl ethers 175 under the same conditions (40 mol% of catalyst Mo(CO)g in refluxing toluene for 55 hours) gave good yields of the corresponding 2,2-dimethylchromans 176 (equation 81) . 

The original tandem Claisen rearrangement promoted by Et2AlCl and 2-methyl-2-butene was utilized for synthesis of a new type of macrocyclic derivatives 186 from the corresponding macrocyclic polyethers 185 which were formed via 183 and 184 (equations 84 and 85). This very rapid reaction results in good yields of potential host molecules and supramolecular building blocks under mild conditions, instead of the thermal treatment. 

SCHEME 24. Tandem Claisen rearrangement of doubly bridged calix[4]arenes. The intramolecular pathway is indicated by dashed arrows. BTMSU = bistrimethylsilylurea... 

Similarly, the substitution pattern determines the rcgioselectivity in the tandem Claisen rearrangement-intramolecular Diels-Alder reaction 283. The double-bond geometry, however, is still E. 

For an application of this method in the steroid total synthesis by a tandem Claisen rearrangement-ene reaction see ref 523. 

Many other reaction sequences which are referred to as tandem rearrangements are already described in several sections before, c.g.. tandem Claisen rearrangement/aldol reactions, cyclopropanation/Cope rearrangements, etc. Iterative as well as sequential rearrangements have also been discussed. 

A new method has been developed for the preparation of calixarene analogues from macrocyclic polyethers via intramolecular successive carbon-carbon bond formation in a tandem Claisen rearrangement, and a similar tandem Claisen rearrangement promoted by Et2AlCl and 2-methylbut-2-ene, has been used ° to synthesize macrocycles containing phenolic moieties from the corresponding macrocyclic polyether compounds (see Scheme 28). A number of furo[3,2-c 5,4-/]bis[l]benzopyran-3-ones have been synthesized regioselectively by the sequential... 

As mentioned previously, the Chugaev elimination has found particular use in the field of terpenoid chemistry, not only in structural studies, but also in synthesis. For example, a tandem Claisen rearrangement-ene reaction of geraniol derivative 23 gave... 

Di- and trisubstituted furans can be obtained from l,l-dibromo-3-phenyl-l-butene and various aldehydes and ketones (Equation (32)). The reaction proceeds via dehydrobromination, Sn2 -substitution, and a tandem Claisen rearrangement-oyclization <93SL905>. 

Scheme 2. Nicolaou s biomimetic synthesis of 1-0-methylforbesione (9) featuring tandem Claisen rearrangements and an intramolecular Diels-Alder reaction.

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