Michael addition/enolate trapping

For the most part, alkynic and allenic ketones have found limited use in conjugate addition-enolate trapping sequences 69,81-83 their analogous esters have been used with far greater frequency (vide infra). Alkynic ketones, in particular, have found use in development of a new anionic polycyclizadon method consisting of intramolecular Michael addition followed by intramolecular alkylation (equation 15).84... 

Few a-ketosulphoxides 123 were prepared by trapping the enolate anions 124, which are generated by the Michael addition of Grignard reagents to easily available a, jS-unsaturated carbonyl compounds 125, with methanesulphinyl chloride174 (equation 65). 

Domino transformations combining two consecutive anionic steps exist in several variants, but the majority of these reactions is initiated by a Michael addition [1]. Due to the attack of a nucleophile at the 4-position of usually an enone, a reactive enolate is formed which can easily be trapped in a second anionic reaction by, for example, another n,(5-urisalurated carbonyl compound, an aldehyde, a ketone, an inline, an ester, or an alkyl halide (Scheme 2.1). Accordingly, numerous examples of Michael/Michael, Michael/aldol, Michael/Dieckmann, as well as Michael/SN-type sequences have been found in the literature. These reactions can be considered as very reliable domino processes, and are undoubtedly of great value to today s synthetic chemist... 

Mechanistically, a-methylenecyclopentenone (2-391) reacts with ester enolate 2-392 in a Michael addition to give the enolate 2-393, which is then trapped with an aldehyde 2-394 generating the alcoholate 2-396. This eventually cyclizes through lactonization to afford 2-397 in good yield. The products 2-397 are obtained as single diastereomer thus, it can be assumed that the aldol reaction proceeds via the six-membered chair-like transition state 2-395. 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

Racemic yatein 43 was obtained by Michael addition of the anion of piperonaldehyde dithiomethyl acetal to 5/7-furan-2-one (butenolide), followed by trapping of the resulting enolate with 3,4,5-trimethoxybenzyl bromide (see section 3.2.2). This process gave 43 with the desired trans stereochemistry at the butyrolactone. Oxidative coupling of the two... 

The reactions in this section cover the conjugate (Michael) addition of various lithiated nucleophiles to activated olefins such as enones and enoates. Lithium enolates are formed as intermediates during the addition process. They can be treated as such and trapped, for instance, by an electrophile to provide ketones or esters substituted both in the a and positions. We will focus only on the most important information relevant to the intermediate enolates, and those are rarely discussed in the literature on the Michael addition. The reader can advantageously consult Chapter 14 of the first part of this volume133, which is entirely dedicated to the organolithium additions to double bonds, for a more extensive coverage of the topic. 

In the total synthesis of (—)-secodaphniphylline, an asymmetric [l,4]-conjugate addition was used to establish relative and absolute stereocontrol.The lithium enolate of a trans-2,5-dimethylpyrrolidine-derived amide adds in a Michael fashion to a cyclic a,p-unsaturated ester, with subsequent enolate trapping, to afford the desired product in 64% yield and 92 8 diastereose-lection (eq 6). 

Sulfides were also involved in a unique three-component, stereospecific Michael addition. The reaction described in Scheme 29 can be explained as follows regiospecific addition of the nucleophile to the exocyclic double bond of the a-methylenecyclopentenone, followed by trapping of the resulting enolate by methyl acrylate, and attack of the anion thus formed on the endocyclic double bond of the cy-clopentenone moiety to result, after protonation, in the bicyclo[2.2.1]heptan-6-one as a single stereoisomer (68% overall yield Scheme 29). 

A unique class of steroidal alkaloids, the batrachotoxinins, is isolated in small quantities from the skins of poison arrow frogs and also from the feather of a New Guinea bird. One of the key steps during the total synthesis of (+)-batrachotoxinin A by Y. Kishi et al. was a Michael addition to form a seven-membered oxazapane ring. The removal of the primary TBS protecting group was achieved by treatment with TASF and the resulting alkoxide attacked the enone at the 3-position to afford an enolate as the Michael adduct. The enolate was trapped with phenyl triflimide as the end triflate. 

A related condensation concerns the reaction of 3-benzyl-l-mesyloxybut-3-en-2-one (38) with lithium dimethylcuprate in tetrahydrofuran/furan which undergoes Michael addition to the enone followed by cyclopropanone formation, the intermediate cyclopropanone 39 being trapped by the enolate derived from the starting material by reduction. The resulting cyclopropanol 40 was isolated as a 5 3 mixture of diastereomers (8% yield), together with an aldol-type product 41. 

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... 

Cuprates react only very slowly with Me3SiCl so it can be present during the Michael addition reaction, enhancing the rate of the reaction and the proportion of 1,4-addition, and trapping the enolate product as the silyl enol ether.18 22 Thus the troublesome enone 42 gives good yields of... 

Ito and Sawamura showed that the use of rhodium and palladium in the presence of the TRAP-type ligand generates an effective catalyst combination for the reaction of an allyl carbonate with a cyanopropionamide [128]. The palladium-TRAP complex is proposed to generate a cationic Jt-allyl species. In addition, a rhodium-TRAP species complexes the cyano group of the nucleophile and induces formation of the enolate. Reaction of the enolate with the Tt-complex in assembly I generates the observed product. Scheme 45. The notion that enoliza-tion is caused by complexation to the cyano group is based on previous results in the enantioselective rhodium-catalyzed Michael addition. 

The first step in this scheme is a Michael addition of the nucleophile to the j5-carbon of the alkynyliodonium salt to give the ylide 102. Loss of iodobenzene from 102 gives alkylidenecarbene 103, which rearranges to alkyne 104 in the absence of external traps. This mechanism is experimentally supported by the isolation of cyclic by-products 108 besides the major products, the alkynyl esters 107 in the reaction of alkynyliodonium salt 105 with nucleophiles (equation 67). These cyclic enol ethers are the result of the insertion of the intermediate carbene 106 into the tertiary-8-carbon-hydrogen bond. 

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