Enone. conjugate addition reaction with from aldehydes

First, chemoselective (Chapter 24) conjugate addition of the silyl ketene acetal on the enone is preferred to direct aldol reaction with the aldehyde. Then an aldol reaction of the intermediate silyl enol ether on the benzaldehyde follows. The stereoselectivity results, firstly, from attack of benzalde-hyde on the less hindered face of the intermediate silyl enol ether, which sets the two side chains trans on the cyclohexanone, and, secondly, from the intrinsic diastereoselectivity of the aldol reaction (this is treated in some detail in Chapter 34). This is a summary mechanism. 

Moving forward from 59, six steps were required to convert this compound to 60. Vicinal dihydroxylation of the olefin was followed by oxidative cleavage of the intermediate diol using lead tetraacetate. Reductive amina-tion of the resulting aldehyde with methylamine, followed by acylation of the intermediate secondary amine gave the desired carbamate. Swern oxidation of the secondary alcohol, followed by enol ether formation gave 60. Elimination of -toluenesulfinic acid from 60 provided 61. Oxidation of this dienol ether to dienone 62 was followed by release of the secondary amine, followed by a conjugate addition reaction to establish the critical C-N bond. The remainder of the synthesis followed known chemistry. The mixture of enones 63 was converted to codeinone (35), codeine (3) and then morphine (1). 

An interesting observation from organocuprate chemistry is that the initial step in 1,4-addition to enones may be electron transfer. Thus the relative reactivity of enones toward conjugate addition parallels their ease of reduction. One problem with any reaction between a ketone or aldehyde and a metal alkyl is deprotonation, when a hydrogens are present, to yield an enolate. Given the considerable basicity of metal alkyls, this side reaction should be anticipated. 

Formally, the MBH reaction involves a sequence of Michael addition, aldol reaction and P-elimination. The commonly proposed mechanism consists in a reversible conjugate addition of the nncleophile to the starting enone 237, generating an intermediate enolate 238. This enolate reacts with the electrophilic aldehyde in an aldol-type process, in which two stereogenic centers are formed, to give 239, which suffers an intramolecnlar acid-base eqnilibrinm to give another enolate 240. From this intermediate, the p-elimination of the nncleophile provides the MBH product... 

A metal-free conjugate addition of PhMe Si-BCpin) to o. y -unsaturated carbonyls (137) has been reported to be catalysed by the NHC, generated from (136) and l,8-diazabicycloundec-7-ene (DBU) in HjO/THF (3 1). This new method represents a simpler variant of the NHC-Cu-catalysed reaction and gives rise to (138) with <96% ee. Acyclic enones or lactones and acyclic -unsaturated ketones, esters, and aldehydes can also be used as substrates. ... 

Knoevenagel condensation is the addition of a nucleophile from active methylene compound to a carbonyl group followed by dehydration to form a P-conjugated enone. The Knoevenagel condensation between different aldehydes (15), including various aliphatic, aromatic, and heterocyclic aldehydes with active methylene compounds (119) in the presence of nano-ZnO under solvent-free conditions (Scheme 9.37) has been reported (Hosseini-Sarvari et al. 2008). Most of the aldehydes investigated reacted smoothly to afford the corresponding products in excellent yields (90%-98%) in a reaction time of 5 min to 3 h. 

The next stage of the synthesis required reduction of the Cj-Cs double bond with control over stereochemistry at Cs- The tactics ultimately used to accomplish this transformation involved conjugate addition of thiophenoxide to the enone to provide 58 with Cj stereochemistry that was never established. The critical stereochemistry (Cs), however, was clean and presmnably controlled by kinetic protonation of the intermediate enolate. Reduction of the C9 ketone was followed by esterification to provide acetate 59 as a single stereoisomer (C7 stereochemistry still not defined). Reduction of the C7 thiol was followed by excision of the extra carbon in the usual manner to provide aldehyde 60. The final carbons of the seco- dA were introduced via crossed condensation of the enolate derived from a thioester of propionic acid, with aldehyde 60. This reaction provided the proper stereochemistry at C3, but the undesired stereoisomer at C2. The C2 stereochemistry was corrected by kinetic protonation of the enolate derived from 61 with acetic acid. The structure of the resulting seco-zcid derivative (62) was established by X-ray crystallography. 

In the case of TMEDA, stereoselection in favor of the syn product (98 2) is enhanced over that achieved with Diiso-propylethylamine (94 6). Along with bases sueh as Triethy-lamine and ethylisopropylamine, TMEDA facilitates the preparation of cyanohydrin trimethylsilyl ethers from aldehydes and Cyanotrimethylsilane. It has been suggested that eoordination by nitrogen induces formation of an active hypervalent cyana-tion intermediate from cyanotrimethylsilane. The conjugate addition of thiols to enones has been successfully catalyzed by using TMEDA in methanol at room temperature, as exemplified by the reaction of 10-mercaptoisobomeol and 4-/-butoxycyclopentenone... 

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