Wichterle reagent

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

Figure 14. Reaction scheme for the chiral Robinson annulation using the Wichterle reagent.

Water-modified titanium complex, 160 Wichterle reagent, 336 Wieland-Miescher ketone, chromatography, 286... 

Asymmetric Robinson Annulation. 2-Propyl-1-indanone undergoes Robinson annulation with the catalyst and methyl vinyl ketone (eq 6). Higher ee values were achieved using 1,3-dichloro-2-butene (Wichterle Reagent) as an MVK surrogate for the Michael addition and overall Robinson annulation (eq 9)... 

Wacker oxidation, 6, 302,416 Warburganal, 246 Wichterle reagent, 134 Willgerodt-Kindler reaction, 229 Williamson ether synthesis, 92, 194, 395 Wolff-Kishner reaction, 225, 339... 

The Wichterle reaction sequence is the annulation of a ketone to a cyclic enone using l,3-dichloro-2-butene (1), the Wichterle reagent, via a three-step process consisting of an alkylation, hydrolysis, and intramolecular cyclization. 

Due to the vast synthetic utility of annulation reactions, there are numerous analogous sequences that can be performed to reach the same class of products as the Wichterle reaction. The most notable of which is the Robinson annulation, which uses methyl vinyl ketone in place of 1,3-dichloro-2-butene. Later research has elaborated on the Wichterle reagent by constructing an extensive library of methyl vinyl ketone surrogates 9-14 that can be employed in a manner analogous to l,3-dichloro-2-butene. Despite the development of annulation reagents like 9-14, 1,3-dichloro-2-butene retains ample synthetic utility due to both its commercial availability and its ability to be trivially prepared from ethyl acetoacetate or methyl acetoacetate. ... 

Despite the inherent increase in the rate of alkylation employing allyl iodides, such as 9 or 13, or allyl chlorides in the presence of potassium iodide in situ Finkelstein), the regioselectivity of the alkylation can be strongly influenced through the use of sterically hindered enolates. To overcome this sluggish reactivity of the allyl chloride Wichterle reagent, Negishi and coworkers developed a Pd-mediated allylation of enoxyborates that is not... 

A method for the reductive alkylation of enediones was developed by Stork for incorporation in the synthesis of corticosteroids such as ( )-D-homoadrenosterone (48) and ( )-adrenosterone (50). Attempted reductive alkylation of 46 by aprotic Michael addition using silyl enones was found to be ineffective thus equatorial alkylation with the modified Wichterle reagent was found to proceed stereoselectively to afford the dione 47. Subsequent elaboration through a Wichterle sequence and hydrolysis/Jones oxidation of the Cl 7a formate provided ( )-D-homoadrenosterone (48). 

The Wichterle reagent has also been employed in enantioselective Robinson annulations involving the use of phase-transfer catalysis (PTC). Bhattacharya and co-workers had previously investigated the asymmetric alkylation of inadanones, such as 59, using substituted N-benzylcinchoninium salts realizing their ability to produce enantio-enriched... 

Wadsworth-Emmons reaction, 151 Wagner-Meerwein rearrangement, 91, 509 Wichterle reaction, 472 Willgerodt-Kindler reaction, 496 Williamson synthesis, 520 Wittig reactions, 83, 333, 573 Wittig reagents, 83, 549, 573 Wolff-Kishner reduction, 378,414 Wolff rearrangement, 544... 

Fukumoto and co-workers used the Wichterle reaction in their formal synthesis of (+)-estrone The enone 28 was treated with pyrrolidine to form an enamine that was utilized in the alkylation with Wichterle s reagent, which then underwent subsequent hydrolysis and cyclization to afford (+)-dienedione (29). This dione intercepts Danishefsky s earlier total synthesis of ( )-estrone. 

Ireland and co-workers used a Wichterle sequence in their stereoselective syntheses of diterpenoid resin acids when annulations with methyl vinyl ketone resulted in polymeric tars. Stereoselective alkylation of cyclohexanone 34 with Wichterle s reagent afforded 35 as a single stereoisomer. Studies performed on this system determined that alkylation was favored cis to the C2 methyl group. After hydrolysis of the vinylic chloride 35 to the diketone 36, cyclization proved difficult due to the large amount of steric hindrance present in the molecule. Base-catalyzed cyclization resulted in only partial conversion to the desired octalone 37. It was found that a significant portion of the material was cleaved to the starting material for this sequence, monoketone 34, via facile reverse Michael addition when the side chain adopted an equatorial confirmation. 

In their total synthesis of 6-methyl-5-androstene-3,l 1,17-trione 3-ethylene acetal, which is a building block for 6a-methylprednisolone, Daniewski and co-workers used a modified Wichterle reaction to install the A-ring of the natural product/ A racemic mixture of 56 was used in a reductive alkylation with Wichterle s reagent to afford the product 57 as a mixture that could be separated by chromatography. Upon treatment of each diastereomer of 57 with formic acid and perchloric acid to induce cyclization, it was observed that both diastereomers resulted in the same enantiopure product 58. This preferred conformation of the steroidal skeleton was confirmed by comparison to an authentic sample of the product that can be obtained directly from natural cortisone. 

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