Revisiting [3 + 3] Route to 1,3-Cyclohexanedione Frameworks:  Hidden Aspect of Thermodynamically Controlled Enolates

Abstract

We have revisited the traditional consecutive Michael-Claisen [3 + 3] process (MC-[3 + 3]) promising the synthesis of a cyclohexane-1,3-dione derivatives from nonactivated simple ketones and enoates and evaluated its potential in modern organic synthesis. Twenty to thirty examples were demonstrated to be effective. The reactions exhibited remarkable regioselectivity with the Michael addition proceeding through nucleophilic attack by the more hindered site of the ketones without exception. The subsequent Claisen condensation resulted in the formation of carbon-carbon bonds between less hindered site of the ketones and acyl carbon of the enoates. The MC-[3 + 3] process described is useful for the synthesis of Taxol A-ring synthons in multigram quantities and for the synthesis of other six-membered carbocyclic compounds. A number of control experiments have been conducted to provide strong support for the mechanism of this MC-[3 + 3].

Cyclization of Cyanoethylated Ketones as a Route to 6‐Substituted Indole Derivatives

“…The gem ‐dimethyl derivative 8b is rather insensitive and can even be recrystallized from water. Acidic hydrolysis of 8b gave the known molecule 3‐hydroxy‐6,6‐dimethylcyclohex‐2‐enone . Alkylation of 8a with 3‐chloro‐2‐butanone followed by heating gave the expected and already known indole derivative 9 , whereas treatment of 8b with oxalyl chloride gave an unexpected indole derivative, 11 , as outlined in Scheme .…”

Diastereoselective Synthesis of Spirodihydrobenzofuran Analogues of the Natural Product Filifolinol

“…Our initial point was the synthesis of the cyclic βhydroxyketone 3 by selective reduction of 2,2,4-trimethylcyclohexane-1,3-dione 5 which in turn was synthesized by a combination of a Michael addition and a Claisen condensation reaction in a one pot reaction using 3-pentanone and methyl acrylate as starting materials and methyl iodide as the source of the methyl group in a formal [3 + 3] process (MC- [3 + 3]). [12] In this way, compound 5 was obtained as a colorless oil in 75 % of yield (Scheme 2). We also attempted a stepwise synthesis according to literature reports.…”

Taxol: Synthesis, Bioactive Conformations, and Structure-Activity Relationships in Its Analogs

“…For example, new procedures were proposed for building up ring A [80][81][82], ring B [83][84][85], and BC fragment [86] as intermediates in the Mukaiyama synthesis. Shing et al [87] obtained the CD fragment in 21 steps starting from (S)-(+)-carvone, while Toyota et al [88] synthesized the AB fragment from bicyclo-[3.2.1]octane derivative.…”

“…despite their considerable length, are capable of inhibiting depolymerization of microtubules, though to a lesser extent than the parent compound (83). Taking these data into account, Guenard et al [178] presumed that raising the polarity of the C 7 -substituent should enhance the activity; however, the results obtained for the Me(CH 2 ) n COO series (n = 1-7) do not support this assumption (the opposite views on the effect of lipophilicity of the 7-substituent on the activity will be discussed below).…”