Wichterle reaction

WICHTERLE REACTION, Modification of the Robinson annellation reaction in which 1,3dichloro-ci,r-2-butene is used instead of methyl vinyl ketone... 

Hudlicky, M. The Wichterle reaction. Collect. Czech. Chem. Commun. 1993, 58, 2229-2244. 

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... 

These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of ( )-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4-dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphos-phoric acid, followed by selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90% sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromometh-ane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58... 

This reaction is related to the Aldol Condensation, Michael Addition, and Wichterle Reaction. 

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. 

Perhaps overshadowed by the earlier work of Sir Robert Robinson where methyl vinyl ketone was shown to perform the same annulation, the potential of the Wichterle reaction remained relatively untapped. Despite... 

There is no widely accepted mechanism for the Wichterle reaction and in-depth mechanistic studies have not been performed to fully probe the stepwise sequence. The first step in the Wichterle reaction is the base-mediated alkylation of carbonyl 2 with the allylic chloride 1 to afford the y-chlorocrotyl derivative 3. The alkylation proceeds using stabilized enolates or unstabilized enolates and enamines. The vinylic chloride 3 is then hydrolized with a strong acid, such as H2SO4, to afford the diketone 4. Hydrolysis, which is typically performed at 0 °C, is followed by a rapid dilution during aqueous workup. 

The Wichterle reaction is a closely related variant of the more popular Robinson annulation. The reader is encouraged to read reviews of the Robinson and related annulations that are available for a more comprehensive overview of the variations that can be employed in synthesis. ... 

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. ... 

Various improvements to the Wichterle reaction have been made to enhance the utility of the reaction. One prevalent problem with the Wichterle reaction is the sometimes unpredictable nature of the hydrolysis and cyclization steps. During hydrolysis of the vinylic chloride, premature cyclization can occur in molecules that contain unsaturated ketones. Julia and Marshall both observed this phenomenon during the hydrolysis of 2,2 -dialkylcyclohexanone 17 with cone. H2SO4 to isolate the bicyclo[3.3.1]-nonanone 18 instead of the desired fused ring system. The use of an unsaturated ketone, such as 19, avoids this problem by affording an intermediate 20 that cannot undergo undesired cyclization to the bridged enone. 

Another way to control the unpredictability of the hydrolysis is to use milder acidic conditions. The so-called modified Wichterle reaction was developed by Kobayashi and Matsumoto in the 1970s that changed the hydrolysis conditions from sulfuric acid to a 1 1 mix of formic acid and perchloric acid. This system is compatible with saturated ketones and efficiently combines the hydrolysis and cyclization steps. The use of... 

The Wichterle reaction has found widespread utility in the field of organic chemistry. It has found particular utility in annulation reactions where the use of methyl vinyl ketone is incompatible. Methyl vinyl ketone is susceptible to polymerization and is a relatively reactive Michael acceptor that can participate in undesired side reactions. 

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. 

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. 

Wharton Reaction Whiting Reaction Wichterle Reaction Widman-Stoermer Synthesis... 

Early review R. E. Gawley, Synthesis 1976, 777-794. Improved methodology T. Sato etal, Tetrahedron Letters 31, 1581 (1990). Stereochemical study C. Nussbaumer, Helv. Chim. Acta 73, 1621 (1990). Synthetic applications R. V. Bonnert et al, J. Chem. Soc. Perkin Trans. 11991, 1225 S. Kim, P. L. Fuchs, J. Am. Chem. Soc. 115, 5934 (1993). Cf. Michael Reaction Wichterle Reaction. 

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