Tandem Michael-aldol reaction

T. Arai, H. Sasai, K. Aoe, K. Okamura, T. Date, M. Shibasaki, A New Multifunctional Heterobimetallic Asymmetric Catalyst for Michael Additions and Tandem Michael-Aldol Reactions, Angew. Chem. Int. Ed Engl 1996, 35,104-106. 

Figure 8D.7. Proposed Mechanism for the Catalytic Asymmetric Tandem Michael-Aldol Reaction Promoted by ALB.

A new tandem Michael-aldol reaction of a,ft-unsaturated compounds bearing a chalcogenide or thioamide group with electrophiles has been reviewed.163 The product o -(o -hydroxyalkyl)enones - Morita-Baylis-Hillman (MBH) adducts - can be formed with significant stereocontrol when an optically active thione is used. 

Three-component Tandem Michael-Aldol Reaction I 281... 

Shibasaki and co-workers [19] reported a catalytic asymmetric tandem Michael-aldol reaction wherein cylopentenone 50, diethylmalonate, and 3-phenylpropanal react in the presence of Al-Li-(R)-BINOL complex catalyst 57 forming the corre-... 

Scheme 9.10. Catalytic enantioselective tandem Michael-aldol reaction.

Moderate yields of 3-hydroxyalkylthiochromones 521 result from a tandem Michael-aldol reaction of l-(2-methyl-s111 I d n y I phenv l)propvnone with aldehydes in the presence of two moles of BF3 etherate as a Lewis acid. The process involves a 6-emfo-dig cyclization (Equation 181) <2002TL7039, 2005PS(180)989>. 

A tandem Michael-aldol reaction of ynone selenides with aldehydes provides a convenient route to 3-substituted selenochromen-4-ones 132 (Equation 49) <2002TL7039>. The reaction proceeds via an intermediate zwitterion formed via a 6-/ r/ -r//g-cyclization. 

An intramolecular tandem Michael aldol reaction was described for esters that have an enolizable aldehyde in the molecule. The lithium ester enolate generated through the Michael reaction undergoes an intramolecular aldol reaction. Thus, the reaction of unsaturated esters 153 with lithium benzylthiolate provided the expected cyclization products 156 and 157 via (w-formylenolate 154 in an excellent cis stereoselectivity (Scheme 49)no. 

La-linked-BINOL complex 23 was introduced as a stable, storable, and reuse-able asymmetric catalyst for the Michael reaction [120]. Optimization of the reaction between dibenzyl malonate and 2-cyclohexene-1-one in DME afforded the Michael adduct in 94% yield and >99% ee. The extraordinary versatility of LnLB catalyts is also documented in the highly efficient Michael addition of thiols to a,y9-unsaturated carbonyl compounds [121] and tandem Michael-aldol reactions [122]. 

Ruck-Braun, K., Kunz, H. A new multifunctional heterobimetallic asymmetric catalyst for Michael additions and tandem Michael-aldol reactions. Chemtracts i997, 10, 519-521. 

The first catalytic asymmetric tandem Michael-aldol reactions were also achieved by the Al-Li-binol complex (ALB), which was prepared from LiAlH4 and binol. The ALB catalysts gave the Michael adducts in up to 99% ee (Eq. (12.2)) [12J. Mechanistic and calculation studies on ALB revealed that ALB is a heterobimetallic complex which acts as a multifunctional catalyst. 

Stereoselectivity in Michael additions of organo-copper(I) compounds Trapping the enolate intermediate by silylation Michael Addition followed by Reaction with Electrophiles Tandem Michael/aldol reactions A Double Nucleophile An Interlude without Copper... 

An aluminum-lithiiun catalyst, (R)-ALB, prepared from (R)-BINOL, and lithium aluminium hydride promoted the addition of malonate to 23 giving (R)-44 in 99% ee. X-ray analysis of the ALB catalyst showed an aluminum ate complex structure with li coordination to the oxygen atom. The asymmetric tandem Michael-aldol reaction of 46 was conducted with this catalyst giving a single isomer 47 containing three asymmetric centers. The aluminum enolate under-... 

Furthermore, three-component coupling tandem Michael-aldol reactions were achieved by trapping the aluminium enolate intermediate with an aldehyde (Scheme 19.16a). Initiated by the asymmetric Michael addition of malonic esters to cyclic enones, several natural products were synthesised... 

Lee, S. L, Jang, J. H., Hwang, G.-S., Ryu, D. H. (2013). Asymmetric synthesis of a-aUcylidene-fS-hydroxy-Y-butyrolactones via enantioselective tandem Michael-aldol reaction. Journal of Organic Chemistry, 78, 770-775. 

Treatment of ketone (69) with excess amounts of t-BuMe2SiOTf and bis[(k)-l-phenylethyl]amine ((i )-BPEA) gives tricyclic silyl aldolate (70) with moderate enantioselectivity [104]. The formation of (70) can be explained by the enol silylation to (71) followed by a tandem Michael-aldol reaction. The asymmetric induction by the chiral amine occurs in the enol silylation (Scheme 9.40). The combined use of silyl triflates and amines has been applied to an intramolecular aldol reaction for natural product synthesis [105]. 

The successful achievement of the (/ )-LSB catalyst in asymmetric Michael addition suggested that the metal centers other than rare earths might lead to a novel heterobime-talhc asymmetric catalyst with unique properties. With this foundation, the same group further developed a new heterobimetallic chiral catalyst (/ )-ALB consisting of aluminum, lithium, and (/ )-BINOL in 1996 (Table 9.3). They reported that this type of catalyst could be more efficiently prepared from LiAlH with two equivalents of (/ )-BINOL. When this AlLibis(binaphthoxide) complex (/ )-ALB was employed as catalyst, up to 99% ee and 88% yield of products could be obtained in the reaction of dibenzyl malonate to 2-cyclohexen-l-one. Notably, both dimethyl and diethyl malonates furnished the 1,4-adducts with more than 90% of enantioselectivities. In particular, the catalytic asymmetric tandem Michael-aldol reactions were also achieved in the presence of (/ )-ALB. This protocol provides a usefid method for the catalytic asymmetric synthesis of complex molecules. 

I.4.3. Synthesis of Prostaglandin ll-deoxy-PGFj via Tandem Michael-Aldol Reaction (Scheme 9.14f ... 

Yoshitomi Y, Arai H, Makino K, Hamada Y. Enantioselective synthesis of martineUine chiral core and its diastereomer using asymmetric tandem Michael-aldol reaction. Tetrahedron 2008 64 11568 11579. 

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