Intramolecular Michael reactions, aldehydes

Hydroxyalkyl derivatives of seleno- and thio- chromones can be formed by the reaction of aldehydes with appropriate propynones in which an intramolecular Michael reaction is followed by an aldol condensation (Scheme 9) <02TL7039>. 

Hechavarria Fonseca MT, List B (2004) Catalytic asymmetric intramolecular Michael reaction of aldehydes. Angew Chem Int Ed Engl 43 3958-3960... 

The ability of A -heterocyclic carbenes to activate a,p-unsaturated carbonyl compounds via the formation of the corresponding Breslow intermediate, which plays the role of a homoenolate nucleophile, has also been applied to a cascade process involving a formal intramolecular Michael reaction/oxidation/ lactonization, leading to the formation of complex tricyclic carbon frameworks starting from a bifunctional substrate containing an enone and an a,p-unsa-turated aldehyde side chain linked to each other via a benzene tether (Scheme 7.82). The reaction involved a complex multistep mechanism which started with the activation of the enal by the catalyst, forming the Breslow intermediate, which subsequently underwent intramolecular Michael reaction and next the generated enol-type intermediate reacted intramolecularly with the... 

Anilide 2a catalysed asymmetric intramolecular Michael reaction of formyl enones to chiral cyclic keto-aldehydes in excellent yields with good stereoselectivity (eqn. (1) in Scheme 6.3). The intramolecular Michael addition of a ketosulfone to an unsaturated ketone (eqn. (2) in Scheme 6.3) catalysed by 15e has heen used as a key step in the synthesis of the carbon tricyclic framework of Lycopodine. The same sulfonylprolinamide served as catalyst in the construction of all-carhon substituted quaternary stereocentre via Robinson-type annulation process (eqn. (3) in Scheme 6.3). 

Early in 2007, the Scheidt group disclosed a highly diastereo- and enan-tioselective intramolecular Michael reaction via an NHC-enolate intermediate. The addition of the NHC catalyst to an ct,p-unsaturated aldehyde followed by subsequent p-protonation generated a reactive enolate intermediate that underwent addition to a pendant conjugate acceptor. A following intramolecular acylation event released the NHC catalyst to afford the bicy-clic acylated enol that readily gave final products upon treatment with MeOH (up to 80% yield, 99% ee) (Scheme 7.68). 

SCHEME 5.51. Intramolecular Michael reaction of aldehydes and conjugated ketones. 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

The 1,5-anti-aldol reaction was performed with chiral boron enolate of 325 and aldehyde 327, prepared by Evans asymmetric alkylation, cross metathesis, and Wittig homologation (Scheme 72), to afford 324 with a 96 4 diastereoselectivity. Stereoselective reduction of C9-ketone provided the 5y -l,3-diol, which was exposed to catalytic f-BuOK to give 2,6-cis-tetrahyderopyran 333 via an intramolecular Michael reaction. Finally, methyl etherification, deprotection, hydrolysis of ester, and Yamaguchi macrolac-tonization yielded the leucascandrolide macrolide 201 (Scheme 73). 

Non-chiral imidazolium carbenes were also used as Brpnsted bases to directly generate the aldehyde enolates for an intramolecular Michael reaction of 0=CH(CH2)4CH=CXY (X = COPh, CO2R Y = H, CO2R) to produce 1,2-rran5-disubstituted cyclopentanes. ... 

Intramolecular Michael Reaction of Aldehydes. Imidazolidinone catalyst 1 mediates the asymmetric intramolecular Michael addition of simple aldehydes to enones at rt (eq 15). The reaction is thought to proceed via an enamine mechanism but a dual-activation mechanism involving both enamine and iminium catalysis can also be considered. When a catalytic amount of 1 was used, products were obtained in excellent yield although in low enantioselectivity (eq 15). Better selectivity was observed, however, when catalyst 2 was used (eq 15). 

Subsequently, List reported the first organocatalytic intramolecular Michael reaction of multifunctional aldehydes 10. Although this reaction could also be catalyzed by L-proline, both diastereo- and enantioselectivity were low. MacMillan s chiral imidazolidinone 9 gave much better results and the cyclic ketoaldehydes 11 could be obtained efficiently (Scheme 36.3) [8a]. 

Reaction of tryptamine with simple ketones has not been widely explored. Acetone in the presence of benzoyl chloride has been reported to yield 2-benzoyl-1,1 -dimethyl-1,2,3,4-tetrahydro-j8-carbo-line. That the keto group is much less reactive than the aldehyde group is indicated by the fact that j8-keto aldehydes, in the form of their acetals or sodium salts, react with tryptamine at the aldehyde function to yield the conjugated enamine 24, which undergoes ring closure via an intramolecular Michael addition. The potentialities of this interesting modification of the Pictet-Spengler reaction have not yet been fuUy explored. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

Enones with a pendant aldehyde, RC(=0)-CH=CH-(CH2)2-CH0, have been cyclized via an intramolecular MBH reaction in a study of the influence of Michael acceptor stereochemistry on yield.164 Using triphenylphosphine as catalyst, the Z-isomer consistently gave 2.5-8.5 times higher yield of the product (55), using reaction times of 1-3 days. It is unclear whether this is due to the relative accessibility of the /3-positions of the isomers to the nucleophilic catalyst, or differential stability in the enolate intermediates. 

A novel antibody-catalysed intramolecular Michael addition of aldehydes and ketones to enones [(148) -> (149)] has been accomplished. The reaction is enantio- and diastereo-selective with a high ee and cis/trans ratio. Antibody 38C2 is the only catalyst to date capable of generating this selectivity in Michael addition products.177... 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

Earlier syntheses of arylquinolizidine alkaloids mainly utilized the pelletierine condensation to construct the basic skeleton, 4-aryl-2-quinolizidinone (11) (Scheme 1). Two mechanistic pathways, involving (a) initial aldol condensation of pelletierine (8) with an aromatic aldehyde followed by intramolecular Michael-type addition of the resulting enone 9 (6, 7) and (b) a Mannich-type reaction through 10 (8, 9), were proposed without any experimental evidence. Preparation and cyclization studies of the intermediate 9, however, gave conclusive evidence to show that the pelletierine condensation proceeded through pathway a (10). 

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. 

The intramolecular asymmetric Michael reaction of acyclic compounds obtained from chiral alkaloid building blocks using amines and (5)-proline has been investigated. " The Michael addition of dimethyl malonate to a,p-unsaturated aldehydes proceeds... 

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