Intramolecular enol ether

The 11,12-carbonate of erythromycin (32) is an older cycHc ester which had greater stabdity and antibiotic activity by diminishing formation of intramolecular enol ether (27) (136,137). A later analogue, the ll-A/-12-0-cychc carbamate of... 

The silyl enol ethers 209 and 212 are considered to be sources of carbanions. and their transmetallation with Pd(OAc)2 forms the Pd enolate 210. or o.w-tt-allylpalladium, which undergoes the intramolecular alkene insertion and. 1-elimination to give 3-methylcyclopentenone (211) and a bicyclic system 213[199], Five- and six-membered rings can be prepared by this reaction[200]. Use of benzoquinone makes the reaction catalytic. The reaction has been used for syntheses of skeletons of natural products, such as the phyllocladine intermediate 214[201], capnellene[202], the stemodin intermediate 215[203] and hir-sutene [204]. 

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I],... 

Pd(II)-catalyzed cyclization of the siloxyhexatriene 34 offers a cyclohexe-none annulation method. The Pd enolate 35, formed by transraetallation of the silyl enol ether with Pd(II), is an intermediate which undergoes intramolecular eWo-alkene insertion. Then Pd(II) is regenerated to give 36, and finally cyclohexenone is formed[38]. 

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). 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

Alkyl aryl ethers and enol ethers are also accessible by the Mitsunobu method. Cyclic ethers can be obtained by an intramolecular variant, which is especially suitable for the synthesis of three- to seven-membered rings ... 

Category 3. Intramolecular Rearrangement. Two examples are the rearrangement of the trimesityl compound (1) to the enol ether (2), " and irradiation of o-nitrobenzaldehydes (3) to give o-nitrosobenzoic acids (4)." ... 

Longifolene has also been synthesized from ( ) Wieland-Miescher ketone by a series of reactions that feature an intramolecular enolate alkylation and ring expansion, as shown in Scheme 13.26. The starting material was converted to a dibromo ketone via the Mr-silyl enol ether in the first sequence of reactions. This intermediate underwent an intramolecular enolate alkylation to form the C(7)—C(10) bond. The ring expansion was then done by conversion of the ketone to a silyl enol ether, cyclopropanation, and treatment of the siloxycyclopropane with FeCl3. 

Under classical Mukaiyama conditions, silyl enol ether 2-372 and the Michael acceptors 2-373 and 2-374 underwent a twofold 1,4-addition to form an enolate in which an ideal set-up exists for an intramolecular aldol reaction. This led to 2-375 with the desired structural core of 2-376 in an overall yield of 42%. 

The mechanism of this transformation is a matter of debate, and may vary with the structure of the heteroanalogous carbonyl compound employed. Although a Diels-Alder-type process is conceivable [246], a Lewis acid-induced addition of the silyl enol ether moiety in 2-453 followed by a cyclizahon through a nucleophilic intramolecular attack of the amine and subsequent elimination of methanol is assumed in this case [247]. 

As the name implies, the first step of this domino process consists of a Knoevenagel condensation of an aldehyde or a ketone 2-742 with a 1,3-dicarbonyl compound 2-743 in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate (Scheme 2.163). In the reaction, a 1,3-oxabutadiene 2-744 is formed as intermediate, which undergoes an inter- or an intramolecular hetero-Diels-Alder reaction either with an enol ether or an alkene to give a dihydropyran 2-745. 

With a less reactive olefin such as isopropenyl acetate, diazoketone 86 gives only a low yield of cyclopropane 90 a-acyl enol ether 92, resulting from an intramolecular rearrangement of the ketocarbenoid, becomes the favored reaction product. If 91... 

Titanium-mediated intramolecular Friedel-Crafts acylation and alkylation are important methods for construction of fused-ring systems (Scheme 29).107 As well as aromatics, olefin units also react in the same way.108 Alkylation of electron-rich olefins such as enol ethers or silyl enol ethers proceeds effectively in the presence of TiCl4.109... 

This reaction is extended to the intramolecular ring closure of the intermediate radical 224 with olefinic or trimethylsilylacetylenic side chains [121]. Cu(BF4)2 is also effective as an oxidant (Scheme 89) [122]. Conjugate addition of Grignard reagents to 2-eyclopenten-l-one followed by cyclopropanation of the resulting silyl enol ethers gives the substituted cyclopropyl silyl ethers, which are oxidized to 4-substituted-2-cyclohexen-l-ones according to the above-mentioned method [123]. (Scheme 88 and 89)... 

An interesting synthesis of enantiopure cu-decahydroquinolines, which involves enol ether hydrolysis, double bond isomerization, and intramolecular 1,4-addition of an amino group across a cyclohexenone has been reported <06T9166>. The process is stereoselective, with the exclusive formation of both cu-isomers 176 (43% over 3 steps) and 177 (17% over 3 steps) of the decahydroquinoline ring. 

A large number of examples of the intramolecular hydroalkoxylation reaction of alkynes bearing pendant alcohols have been reported. In the reactions of enynols, the cyclization process has typically been accompanied by isomerization of the resulting enol ethers to give rise to furan or pyran products. These processes have been achieved using Pd(ll),294-297 Ru(n),298,299 Au(i),300 Au(m)286,300,301 Ir(i)302 Ir(m) 303 and Ag(i) 304 catalysts. Some examples are shown in Equations (83)-(87). 

Judging from these findings, the mechanism of Lewis acid catalysis in water (for example, aldol reactions of aldehydes with silyl enol ethers) can be assumed to be as follows. When metal compounds are added to water, the metals dissodate and hydration occurs immediatdy. At this stage, the intramolecular and intermolecular exchange reactions of water molecules frequently occur. If an aldehyde exists in the system, there is a chance that it will coordinate to the metal cations instead of the water molecules and the aldehyde is then activated. A silyl enol ether attacks this adivated aldehyde to produce the aldol adduct. According to this mechanism, it is expected that many Lewis acid-catalyzed reactions should be successful in aqueous solutions. Although the precise activity as Lewis acids in aqueous media cannot be predicted quantitatively... 

Macrocyclization,3 A new route to cembranolides (3) involves intramolecular coupling of an alkoxyallyltin derivative (1) with an acetylenic aldehyde catalyzed by BF30(C2H5)2 (cf. 12, 513-514). Thus in the presence of BF3 etherate 1 cyclizes to 2 with syn-selectivity. The product is converted to the cembranolide 3 by hydrolysis of the enol ether and oxidation. 

This intramolecular hydrosilylation can be extended to a-hydroxy enol ethers (2-alkoxy-l-alkene-2-ols) to provide access to 2,3-sy -l,2,3-triols.2 In this case a neutral catalyst, Pt(0)-vinylsiloxane,3 is preferred over H2PtCl6. 

Some other ring expansions involving the intramolecular amino Claisen rearrangement of vinylarylaziridine [ 123], the Diels-Alder reaction of indoles with acetylene derivative [124-127] and the dibromocarbene insertion into quinoline enol ethers [ 128] have been used to prepare 1-benzazepines. On the other hand, treatment of 3-chloro-3-phenyl-l,2,3,4,5,6-hexahydro-l-benz-azocin-2-ones with piperidine causes a ring contraction to give 2-phenyl-2-(l-piperidinylcarbonyl)-2,3,4,5-tetrahydro-l//-l-bcnzazepines in an excellent yield [23]. 

Mootoo and co-workers disclosed a procedure for the preparation of C-l substituted galactals based on the intramolecular capture of an oxocarbenium ion by an enol ether residue.79 In their approach, the key intermediate 1 -thio-1,2-O-isopropylidene acetals (TIA) are activated with methyl triflate to generate the crucial annulating synthon (1,2-O-isopropylidenated oxocarbenium ion). 

In the [4 + 2] cycloadditions discussed so far, the enol ether double bond of alkoxyallenes is exclusively attacked by the heterodienes, resulting in products bearing the alkoxy group at C-6of the heterocycles. This regioselective behavior is expected for [4+2] cycloadditions with inverse electron demand considering the HOMO coefficients of methoxyallene 145 [100]. In contrast, all known intramolecular Diels-Alder reactions of allenyl ether intermediates occur at the terminal C=C bond [101], most probably because of geometric restrictions. 

The carbocupration of methoxyallene affords a (Z)- or (E)-enol ether depending on the solvent used [52], In THF, the reaction exhibits Z-selectivity because the coordination ability of THF excludes the intramolecular chelation effect of the methoxy group, which may be responsible for the E-selectivity for the reaction in ether (Scheme 10.49). 

AUenylamine 248 reacts intramolecularly with an enol ether to give the cyclic compound 249 [130]. 

Regio- and Stereoselective Intramolecular Hydrosilation of a-Hydroxy Enol Ethers 2,3-syn-2-Methoxymetnoxy-1,3-nonanediol. 

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