Domino-oxa-Michael aldol reaction

Scheme 14.26 Woggon s synthesis of a-tocopherol (177) via domino aldol/oxa-Michael reaction.

In 2009, a diarylprolinol silyl ether was involved as an organocatalyst in an asymmetric domino aldol-oxa-Michael reaction occurring between salicy-laldehyde and senecialdehyde. As shown in Scheme 2.28, this process generated the corresponding chiral tricyclic systems in good yields and high enantioselectivities of up to 98% ee. One of these products could be further converted into 4-dehydroxydiversonol. 

A catalytic triple domino Michael-aldol-oxa-Michael reaction of acetaldehyde with ( -2-(2-nitrovinyl)phenols catalyzed by (R)-2- diphenyl [(trimethylsilyl)oxy] methyl pyrrolidine followed by a sequential one-pot Wittig, Michael/Wittig-Horner reactions with PPh3=CHC02Et was applied to the asymmetric synthesis of polyfunctionalized chromans (14EJO3076). 

SCHEME 16.28. Enantioselective domino aldol/oxa-Michael/hemiacetalization reaction. 

The reaction of salicylaldehydes with a,P-unsaturated compounds which can lead to chromenes, chromans and other heterocycles has been reviewed <07OBC1499> and details of their reaction with allenic esters and ketones have been published <07CEJ3701>. A proline-catalysed benzoic acid-promoted asymmetric synthesis of chromene-3-carbaldehydes involves a domino oxa-Michael - aldol reaction with a,P-unsaturated aldehydes the ee range is 83-98% (Scheme 11) <07CEJ574>. 

Tetrahydroxanthen-l-ones have been obtained through enantioselective domino oxa-Michael - aldol reactions between salicylaldehydes and cyclohexenones using a chiral pyrrolidine catalyst in the presence of 2-nitrobenzoic acid <07TL2181>. A similar approach using chiral 4-hydroxycyclohexenones and V-methylimidazole as catalyst leads to a diastereomeric mixture of the reduced xanthones (Scheme 40) <07S2175>. Dimeric... 

Chiral cyclohexene derivatives were also constructed by an asymmetric four-component quadruple domino reaction initiated by oxa-Michael addition of alcohols to acrolein. The other two components were another equivalent of acrolein and a nitroalkene. Enders has shown that cyclohexene derivatives can also be assembled by a domino reaction of y-nitroketones and enals. Domino Michael/aldol condensation of 5-oxoalkanals and a,p-unsaturated aldehydes afforded densely functionalised cyclohexenes. Combination of unsaturated aldehydes with unsaturated p-ketoesters resulted in the formation of chiral cyclohexene derivatives via a Michael/ Morita-Baylis-Hillman sequence (Scheme 8.21). ... 

Through a domino oxa-Michael-aldol condensation reaction, a range of 2-substituted 3-formyl-2E/-chromenes were prepared from salicylaldehydes and a,p unsaturated aldehydes catalyzed by a diphenylperhydro indoUnol... 

Ohnemuller UK, (nee Schmid), Nising CF, Nieger M, Erase S (2006) The Domino Oxa-Michael-addition Aldol Reaction - an Access to Variably Substituted Tetrahydroxanthenones. Eur J Org Chem 29 1535... 

Scheme 7.36 Domino oxa-Michael-aldol condensation reactions.

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

A very short synthesis of rac-incarviditone and rac-incarvilleatone was reported in 2012 by Lawrence and co-workers [147], who first prepared on a multigram scale rengyolone in three steps from tyrosol via a DIB-mediated hydroxylative dearomatization into the para-quinol 287 and an oxa-Michael addition. The resulting (zh)-rengyolone was then biomimetically dimerized under mildly basic conditions simply using a catalytic amount of potassium carbonate to furnish ( )-incarviditone in 19% yield via a homochiral oxa-Michael/Michael domino reaction, and ( )-incarvilleatone in 23% yield via a heterochiral oxa-Michael/ Michael/aldol domino reaction (Fig. 70) [147]. 

The reaction follows a highly regulated domino oxa-Michael/Michael/Michael/ aldol condensation sequence through successive iminium ion--enan3ine--iminium... 

The domino reactions can be divided into several categories. The most often reported category is a stereoselective domino-oxa-Michael aldol reaction of a,p-unsaturated ketones with aldehydes. 

In contrast, 2-hydroxybenzaldehydes react with levoglucosenone via stereoselective domino oxa-Michael-aldol reaction as reported by Samet and coworkers [7]. The phenolate-anion attacks from the site opposite to the anhydro-ring of levoglucosenone. The reaction is depicted in Scheme 6.2. 

Later, the cascade three-component organocatalysis was applied in the first enantioselective total synthesis of (-l-)-coni-col (Scheme 21.34). The synthesis was achieved via a key step reaction involving the organocatalytic domino oxa-Michael-Michael-Michael-aldol condensation of 2-( )-2-nitro-vinyl)benzene-l,4-diol 148, 3-methylbut-2-enal 145, and ( )-4,4-dimethoxybut-2-enal 150. The successful synthesis further expands the realm of the reactant of this three-component reaction beyond 3-arylacrylaldehyde to the a, 3-unsaturated aldehydes bearing a y-H. 

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