Weiss-Cook reaction

The reaction mechanism [24, 25] is a double Knoevenagel reaction that gives an a-P-unsaturated y-hydroxycyclopentenone, which reacts with 

When the reaction is carried out under aqueous alkaline conditions, the rate and the yield increase, the side-reactions decrease and the process is a good vehicle for the formation of multicyclic polyquinane systems [27,28]. 

Paquette [29] has recently shown that the (Z)-cyclododec-7-ene-l,2-dione  

Synthesis of cM-bicyclo[3.3.0]octane-3,7-dione. The produet is frequently deear-boxylated. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 265, Springer-Verlag Berlin Heidelberg 2009 

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A regio- and stereospecific synthesis of modhephene has also been achieved beginning with the Weiss-Cook reaction As illustrated in Scheme XCVII, cyclo-pentai -l,2-dione can be readily crait l into a-diazo ketone 8(M), copper-catalyz l decomposition of which delivers tricyclic ketone 801. Following the dimethylation of this intermediate, carbomethoxylation was accomplished to give 802 and provide... 

The most highly unsaturated fenestrane known so far is the [5.5.5.5]fenestra-tetraene 105 (C13H12) which has been synthesized by Cook et al. utilizing the Weiss-Cook reaction (see Scheme 19) [2, 72]. More highly unsaturated fenes-tranes with their expected extremely high strain such as 104 therefore remain a synthetic challenge. 

Galatsis, P. Weiss-Cook Reaction, In Name Reactions for Carbocyclic Ring Formations, Li, J. J., Ed. Wiley Hoboken, NJ, 2010, pp 181-196. (Review). 

The Weiss-Cook reaction entails the formation of c/5-bicyclo[3.3.0]octane ring systems from the condensation of 1,2-dicarbonyl compounds with 3-oxoglutarate diester derivatives. Decarboxylation of the immediate reaction product affords access to the parent carbon scaffold. 

From a mechanistic standpoint, the process involved in the bond formation experienced in the Weiss-Cook reaction is a series of Aldol and Michael reactions. This reaction manifold is initiated by an Aldol reaction of oxoglutarate 2 with dicarbonyl 1. The active species facilitating this bond... 

The Weiss-Cook reaction has seen great utility in the total synthesis of nonnatural as well as natural products. This has resulted from the ability of the reaction to rapidly assemble a highly functionalized, conformationally constrained carbon scaffold that provides rapid access to advanced intermediates that are readily modified for diverse target synthesis. 

A synthesis of the related sesquiterpenoid pentalene, 26, also began with the Weiss-Cook reaction product 12 (R = R" = H). Wittig olefination was carried out on the mono-ketal of 12 followed by hydrolysis of the ketal. The resultant ketone was reduced to the corresponding alcohol and the exocyclic alkene underwent cyclopropanation to produce 23. Oxidation of the alcohol generated a ketone that could be converted to the enone using the... 

Modhephene, 34, was the first isolated propellane natural product. As such, the Weiss-Cook reaction was the perfect method for its construction. The process began with the condensation of 2 with diketone 27. Standard conditions for decarboxylation produced the core scaffold 28. Hydrogenation of the mono-enol phosphate afforded the monoketone 29. The cyclopropyl derivative 30 was prepared by copper-catalyzed decomposition of a diazoketone. gem-Dimethylation to generate 31 preceded carboxylation and esterification to afford the advanced intermediate 32. Cuprate-induced cyclopropane ring opening and methylation of the 3-ketoester introduced the final carbon atoms giving rise to 33. Lithium iodide induced decarboxylation preceded reduction of the ketone followed by dehydration with Martin s sulfurane, thus producing 34. 

The cytotoxic sesquiterpenoid quadrone, 38, has an embedded diquinane carbon framework that allowed the Piers s group to leverage the chemistry of the Weiss-Cook reaction. The monoketal 35 is readily available from 12 (R = R" = H). Several transformations converted this compound into the vinyl cyclopropane 36. Thermal rearrangement of the scaffold employing a Cope process afforded tricyclic 37. This compound was readily elaborated into 38. 

Gymnomitrol, 39, is another sesquiterpenoid that encompasses an embedded diquinane scaffold. This becomes readily apparent when one examines the alternate representation for the compound. Again the use of the output from the Weiss-Cook reaction was found to be a rapid entry to this system in which two groups employed 40 as their foundation for the synthesis of 39. As we have seen, 40 is easily obtained from the reaction of l(R = R" = Me)and2. 

Carboprostacyclin, 43, a stable and biologically active analogue of prostacyclin (PGI2) provides an additional example of the utility of the Weiss-Cook reaction. The Weiss-Cook reaction product 41 was transformed into the advanced intermediate 42. A Wadsworth-Homer-Emmons reaction provided a method to append the alcohol sidechain to the aldehyde moiety and a Wittig reaction, on the deprotected ketone, introduced the carboxy sidechain for the desired target 43. 

The monoterpene glucoside loganin, 46, is a key intermediate in the biosynthesis of several alkaloid families. The cw-fused, bicyclic framework, 41, derived from the Weiss-Cook reaction was exploited for two of its attributes. One of the rings was fragmented as a precursor to the... 

The Weiss-Cook reaction was used to generate the starting material... 

Upon examining the structure of semibullvalene, shown in Figure 1, it becomes obvious how the Weiss-Cook reaction could be implemented in the construction of this framework. The preparation of the substituted semibullvalene 55 began with the Weiss-Cook diketone 11 (R = R" = Me). Bromination followed by cyclizing dehydrobromination gave rise to 54. Reduction of the ketones and conversion to the corresponding mesylates preceded a conjugate 1,4-elimination reaction to afford the substituted derivative 55. 

A more recent approach to 57 began with the Weiss-Cook reaction product 59. Trapping the enol tautomer of this compound with diazomethane preceded alkylation with allyl iodide and hydrolysis/ decarboxylation to generate 60. The final sequence of reactions involved ozonolysis, aldol cyclization, reduction, and dehydration afforded 57. 

The versatility of the Weiss-Cook reaction was leveraged in the synthesis of an isomer of 11 To this end, reaction of 73 with 2 produced 74 after hydrolysis/decarboxylation. Ozonolytic cleavage of the cyclooctene moiety resulted in the formation of 6is-acetal 74 which was able to undergo an acid-catalyzed Aldol reaction to tetracycle 75. Reduction and dehydration converted 75 into the 6i5-angularly fused polyquinene 76. 

There are many more examples of the utility of the Weiss-Cook reaction in synthesis but this limited survey should provide an indication of what has been disclosed and spark new ideas for additional examples. 

While the primary literature provides multiple examples of how the Weiss-Cook reaction can be conducted, general reaction conditions that are able to cover a diverse set of glyoxals has been report with yield ranging from 12 to 94%. ... 

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