Cyclic enol ethers rearrangement

An aluminium-promoted, cobalt-mediated O C rearrangement reaction of cyclic enol ethers has been reported to give functionalized cyclohexanones with good diastereocontrol (Scheme 81).123 The product stereochemistry has been shown to be ( ) dependent on the 7Z-stereochemistry of the starting enol ether. 

The Claisen rearrangement was used in the asymmetric total synthesis of (+)-9(ll)-dehydroestrone methyl ether (5), a versatile intermediate in the synthesis of estrogens5 (Scheme 1. If). The key feature of the synthesis is the successful development of the asymmetric tandem Claisen-ene sequence. Thus, a solution of the cyclic enol ether 6 in toluene was heated in a sealed tube at 180 C for 60 hours to afford the product 9 in 76% isolated yield after deprotection of the silyl enol ether. The Claisen rearrangement of the allyl vinyl ether 6 occurred stereoselectively to give an intermediate (7), in which the 8,14-configuration was 90% syn. The stereoselectivity in the Claisen rearrangement can be explained... 

The oxidation of the cyclobutylcarbinol in equation (52) with buffered PCC proceeds with partial rearrangement a 1 2 ratio of the expected aldehyde (58) to foe ring-expanded cyclic enol ether (59) is ob-... 

The protic reaction on occasion is a useful method of alkene formation, but is far from general because the cation intermediate tends to undergo rearrangements.Further, even for cases in which elimination to an alkene is the predominant pathway, the regioselectivity of the process is often mediocre. A key step in the synthesis of (+)-a-eudesmol and (-)-a-selinene exemplifies this point (Scheme 60). There are, however, isolated examples of excellent selectivity, such as the reaction of a 3-ketotetrahydrofuran tosyl-hydrazone salt to give the corresponding cyclic enol ether as the major product (Scheme 61), the intro-... 

To exploit the whole capacity of the Claisen rearrangement, appropriate methods for the preparation of the allyl vinyl ethers starting from allyl alcohols are necessary. The classical approach involves vinyl-ation with simple vinyl ethers or acetals. Unfortunately these methods fail with more complex systems and do not allow, except in the case of cyclic enol ethers, control of the stereochemistry of the substituted enol ether double bond. Until recently it was only possible to generate such substituted systems with appreciable stereocontrol via ketene N.O-acetals. Their preparation by addition of lyl alcohols to substituted ynamines can lead to adducts of either ( )- or (Z)-geometry, depending upon the conditions used (Scheme 60). 

The first step in this scheme is a Michael addition of the nucleophile to the j5-carbon of the alkynyliodonium salt to give the ylide 102. Loss of iodobenzene from 102 gives alkylidenecarbene 103, which rearranges to alkyne 104 in the absence of external traps. This mechanism is experimentally supported by the isolation of cyclic by-products 108 besides the major products, the alkynyl esters 107 in the reaction of alkynyliodonium salt 105 with nucleophiles (equation 67). These cyclic enol ethers are the result of the insertion of the intermediate carbene 106 into the tertiary-8-carbon-hydrogen bond. 

SCHEME 25 Claisen rearrangement of a cyclic enol ether. 

The Pd(PhCN)2Cl2-catalyzed reaction of cyclic enol ethers with allylic alcohols gave the Claisen rearrangement products a-allylic cyclic ketones (eqs 183 and 184). The same reaction of acyclic vinylic ethers with allyl alcohols afforded the corresponding y,i5-unsaturated enones (eqs 185 and 186).i In most cases, CF3COOH was used as the cocatalyst. 

Harrity exploited the carbocation stabilizing ability of cobalt-alkyne complexes to promote a novel O C rearrangement reaction. Exposure of cyclic enol ether 23 to diethylaluminum chloride promotes ionization of the C-O bond to yield the stabilized carbocation and an enolate. Bond rotation followed by C-C bond formation provides cyclohexanone product 24. ... 

Mikami K, Takahashi K, Nakai T. Diastereocontrol via the phenol- and paUadium(II)-catalyzed Claisen rearrangement with cyclic enol ethers. Tetrahedron Lett. 1987 28(47) 5879-5882. 

Direct treatment of TIPS enol ethers of a variety of cyclic and acyclic ketones with the strong-base combination of n-BuLi/KO-t-Bu leads to /3-ketosilanes (2) after aqueous work-up. In contrast with the earlier method, this rearrangement appears to proceed through allylic, rather than vinylic, metallation, since enol ethers lacking an allylic a-proton are unreactive. 

Cyclization ofsilyl enol ethers of -acetylenic ketones or aldehydes. Reaction of these derivatives of ynones or -als with HgCl2 (1.1 equiv) and hexamethyldisi-lazane (0.2 equiv.) as an acid scavenger in CH2C12 at 30° followed by acidification with aqueous HC1 and Nal (2 equiv. each) results in cyclic 0,y-enones. Thermal cyclization of these substrates requires high temperatures, which lead to decomposition and rearrangements.1... 

Cyclic silyl enol ethers.1 This reagent undergoes 1,2-addition to cyclic a,f3-enones usually in high yield. Brook rearrangement of the adduct results in silyl enol ethers. 

The Claisen rearrangement has been instrumental in the synthesis of a number of natural products.279-289 Many useful derivatives have been prepared using the Claisen-type rearrangement including enol ethers,290 amides,291-293 esters and orthoesters,294-296 acids,297-298 oxazolines,299 ketene acetals,300-301 and thioesters.302 Many of these variants use a cyclic primer to control relative and absolute stereochemistry. The Claisen and oxy Cope provide the best candidates for scale up as a result of the irreversible nature of these reactions. 

Tsai and coworkers89,91,246,247 reported the synthesis of cyclic silyl enol ethers and silyl ethers by using a radical cyclization followed by the radical Brook rearrangement (equation 111). The cyclization of 4-bromo-4-stannylbutyl silyl ketones 188 in benzene with a catalytic amount of tributyltin hydride and AIBN gave cyclic silyl enol ethers 18989 91 247. The whole catalytic cycle proposed is shown in equation 112. 

The quaternary center was constructed stereospecifically by Claisen rearrangement (Scheme 46). The necessary enol ether was obtained by reaction of the secondary alcohol of 399 with ethyl vinyl ether and mercuric acetate. To change the polarity of the endocyclic double bond, the unsaturated ketone was reduced with lithium aluminum hydride to the allylic alcohol, 400, at low temperature. Then, prolonged heating with xylene led to the aldehyde, 401. Protection of the secondary alcohol was achieved by bromoether formation with W-bromosuccinimide in acetonitrile before the aldehyde of 402 was reacted with methyllithium. The epimeric mixture of secondary alcohols was protected as acetates 403. Then, the cyclic ketone... 

Cyclobutenes possessing an angular O-functionality, obtained from a Lewis acid-mediated [2+2] cycloaddition of cyclic silyl enol ethers to ethyl propynoate and subsequent reduction and butenylation, undergo a ring-opening metathesis that produces a substituted dihydropyran that forms part of a c -diene. After desilylation, an oxy-Cope rearrangement leads to the fused tetrahydropyran 4 <03JA14901>. 

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