The importance of domino reaction, a consecutive bond forming reaction as a result of previous reaction, has been increasing in view of efficiency in organic syntheses. One of the fundamental nucleophilic domino reactions is the double Michael reaction of the kinetic enolate of cyclohexenone 1 with acrylate 4 leading to endo-bicyclo[2.2.2]octane derivatives 5, which required a stoichiometric amount of amide base 2 in aprotic media. We found for the first time two catalytic processes based on oxophorone derivatives 1 and cyclohexenone derivatives 11, respectively. By employing 0.1 equiv of LDA, reaction of oxophorones 1 with acrylates 4 provided bicyclo[2.2.2]octane-2,4-dione derivatives 7 in high yield. By employing a catalytic amount of bicyclic enolate 9', the reaction afforded bicyclic compound 7 in comparable yield. Based on this finding, autocatalytic cycle is proposed, in which bicyclic enolate 9' generated after second Michael reaction drives the catalytic cycle. The reaction was general with various oxophorone derivatives, acrylates and amide bases. Especially, complete diastereoselection was observed by employing 8-phenylmenthyl acrylate 10. In addition, recylcle use of amine for amide base was realized up to 5 times by using solid amine grafted on silica (NMAP). While, by employing 0.2 equiv of NMAP-Li, domino Michael reaction of trimethylsilylenol ether of cyclohexenone 11 with acrylate furnished bicyclo [2.2.2]octane derivative 5. In this reaction also NMAP was recycled up to 2 times. The reaction is proposed to proceed by Lewis base catalysis via hypervalent silyl intermediates. Utility of this protocol was exemplified by total synthesis of a new sesquiterpenoid, valeriananoid A 22 having a unique tricyclic carbon framework same as that of patchouli alcohol. This compound 22 was isolated by De Quan Yu et al. in 1997 from Valeriana jatamansii Jones which widely distributes in south-western China and the roots of this plant have been utilized as a Chinese folk medicine. Synthesis has started from bicyclo[2.2.2]octane-2,4-dione derivative 7 obtained by autocatalytic domino Michael reaction of oxophorone 1. Conventional ketalization allowed selective protection of the less hindered ketone to provide ketal 16. Treatment of the ketoester 16 with sodium ethoxide in ethanol resulted in complete isomerization of the ester group into the same side as the carbonyl group in 96% yield. Reduction of the ketoester 17 provided diol 18 in 95% yield. Oxidation of the diol 18 followed by addition of MeLi provided alcohol 19 in 72% overall yield (2 steps). PDC oxidation of alcohol 19 provided methylketone in 93% yield. Addition of vinylmagnesium bromide provided allylalcohol 20 as a separable mixture of diastereomers in 99% combined yield. Protection of the tertiary allylalcohol 20 as a MOM ether was successful in 75% yield by employing excess t-BuOK. The 6-endo-Trig-cyclization by single electron transfer process employing sodium provided tricyclic compound 21 in 44% yield. Catalytic hydrogenation of olefin 21 followed by hydrolysis of ketal moiety completed total synthesis of valeriananoid A 22.
