Michael/aldol reaction, domino

Feringa s group has demonstrated that cyclopentene-3,5-dione monoacetals as 2-47 can also be successfully applied as substrates in an asymmetric three-component domino Michael/aldol reaction with dialkyl zinc reagents 2-48 and aromatic aldehydes 2-49 [17]. In the presence of 2 mol% of the in-sitw-generated enantiomeri-cally pure catalyst Cu(OTf)2/phosphoramidite 2-54, the cyclopentanone derivatives 2-51 were formed nearly exclusively in good yields and with high ee-values (Scheme 2.11). 

Scheme 2.21. Domino Michael/aldol reactions of 7-keto-2-enimides 2-93.

An impressive organocatalytic asymmetric two-component domino Michael/ aldol reaction has been recently published by Jorgensen and coworkers (Scheme 2.23) [38]. 

Scheme 2.23. Domino Michael/aldol reaction of a,(5-unsaturated ketones with (3-ketoesters.

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

The asymmetric conjugate additions with thiol nucleophiles was further expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illustrated the utihty of cyclohexane-diamine bifunctionalized catalysts for the domino... 

Scheme 41 Divergent domino Michael/aldol reaction...

Scheme 6.71 Succinimide-containing substituted thiochromanes obtained from the 12-catalyzed enantio- and diastereoselective domino Michael-aldol reaction between 2-mercaptobenzaldehydes and maleimides.

In 2007, Wang and co-workers published a protocol for an enantio- and diastereoselective domino Michael-aldol reaction using electron-rich and electron-deficient 2-mercaptobenzaldehydes and maleimides as substrates [223]. The conversion was described to proceed smoothly in the presence of bifunctional catalyst 12 (lmol% loading) in xylenes at 0°C reaction temperature producing the desired chiral succinimide-containing substituted thiochromanes 1-5 in high yields (83-96%), in synthetically useful ee values (74—94%), and diastereoselectivities (up to dr 20 1) in 7h reaction time (Scheme 6.71). 

Optically active 4-alkoxycarbonyl-3-hydroxycyclohexanones (formed in highly enantio- and diastereoselective organocatalytic asymmetric domino Michael aldol reaction of / -keto esters and a,/ -unsaturated ketones) are transformed into corresponding chiral oxepanones under the action of urea-hydrogen peroxide and trifluoroacetic anhydride <2004AGE1272>. 

Unusual -branched Baylis-Hillman adducts have been prepared by Li and coworkers by a novel Et2AlCl promoted domino Michael-aldol reaction of propynoates 50 with organo-cuprates and chiral p-toluenesulfinimines 52 (Scheme 10) [42], These condensations proceeded with very good diastereoselectivity to give allylic amines 53. The selectivity can be explained through the chairlike transition state 54. The anion intermediate approaches the sulfinimine from the sterically less hindered side of the lone pair of electrons. The nucleo-... 

Scheme 10. Domino Michael-aldol reaction of propynoates with organocuprates and chiral p-toluenesulfinimines (Li et a .).

Catalytic, enantioselective Michael reactions of cyclopentenones have attracted particular attention in recent years. Ben L. Feringa, Albert S. C. Chan, Andreas Pfaltz and Amir H. Hoveyda described various hgand systems for stereoselective addition of organo-zinc reagents to cyclopentenones. With the aid of a phos-phoramidite derived from BINOL, Feringa developed an enantioselective, catalytic domino-Michael/aldol reaction for the preparation of (+)-PGEi methyl ester. [223]... 

Chiral imidazolidine 106 is also a very effective organocatalyst for the enantio- and diastereoselective domino Michael-aldol reaction of P-diketones [215a], p-ketosulfones [215a], and p-ketoesters [214] with a,P-nnsaturated ketones at rt to afford optically active cyclohexanones having three or four contiguous stereogenic centers (Scheme 2.80). 

The first organocatalyzed domino Michael/aldol reaction was used in the total synthesis of the natural product (—)-huperzine A [12]. This process was catalyzed by (—)-cinchonidine to convert a P-keto ester and methacrolein to a 5,9-methanocycloocta[h]pyridine tricyclic core. Two excellent reviews dealing with these processes have been recently published [8, 11], and in the field of natural products several total syntheses utilize a domino process involving a Michael reaction step [12-24]. This chapter will mainly cover the recent work in the development of novel domino reactions containing a Michael reaction published since the beginning of 2006, as the many such domino reactions were collated prior to this date by Tietze et al. in a comprehensive book [25]. 

Scheme 7.23 Enantioselective domino Michael/aldol reaction by the Rueping group.

Scheme 7.60 Domino Michael/aldol reaction to bispirooxindoles.

Table 8.5 Domino Michael/aldol reaction toward bicyclo[3.2.1]octanes [22].

Organometallic reagents are well known for 1,4-additions and can hence be utilized to catalyze domino Michael/aldol reactions. Based on a methodology published by Noyori et al. [24], the group of Feringa estabhshed a catalytic enantios-elective protocol for the synthesis of (—)-prostaglandin Ej methyl ester [25]. There,... 

Domino Processes with the Aldol Reaction as Subsequent Step 279 Table 8.6 Organocatalytic domino Michael/aldol reaction by Jorgensen et at. [23b]. 

Scheme 8.14 Catalytic enantioselective domino Michael/aldol reaction as developed by Feringa et al. [25].

An intramolecular domino Michael/aldol reaction starting from the chiral Cope products 58 was developed by the group of Schneider [27], After 1,4-addition of... 

Scheme 10.5 Domino Michael/aldol reaction through iminium-enamine activation mode.

Scheme 10.6 Domino Michael/aldol reaction through hydrogen-bonding activation mode.

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