Stereochemistry Michael-type addition

E/Z stereochemistry of a,/ -ethylenic phosphonium derivatives is essentially governed by steric factors apart from when there is extra stabilization, as is the case with betaines87. Z->E isomerization may be performed using sterically crowded amines (so that any Michael-type addition would be prevented)192,193. Spectrometry allows the progress of the reaction to be observed (Section I.C). 

The stereochemistry of nucleophilic 1,4-additions to enones (Michael-type additions) is controlled by stereoelectronic factors. In the absence of compelling steric effects, the nucleophile approaches the [3-carbon of the enone antipamllel to the neighboring (y) pseudoaxial substituent (circled H in the example below). 

Factors controlling the stereochemistry of conjugate additions are not well understood. Mixtures of isomers are often produced, but generally one isomer predominates. Both steric and electronic factors play a role. ° Generally, Michael-type additions have late and hence productlike—and chairlike— transition states. In the example shown below, for stereoelectronic reasons antiparallel attack by the nucleophilic CH3 is favored over parallel attack. 

During the intramolecular Michael-type addition of 151d, the stereochemistry at the two newly produced stereogenic centers (C2 and C7) must be controlled exactly. We obtained four stereoisomers of spiroethers whose stereochemistries were determined through the detailed analysis of NOE difference spectra as well as comparison to other natural products. 

As a reaction mechanism for the strong base-induced cycioaddition reaction of homophthalic anhydrides and dienophiles, two routes are possible (Scheme 4). One is route a via the Diels-Alder reaction, decarboxylation and de-HX. The other is route b via Michael-type addition, intramolecular cycli-zation, decarboxylation and de-HX. Several studies showed that route a was the more preferable. After cycioaddition of the homophthalic anhydrides with dienophiles, the reaction is always accompanied by decarboxylation and aromatization. The stereochemistry of the cycioaddition reaction of the homophthalic anhydride is not considered. 

Michael-type addition of thiols to the dehydroproline double bond of pristinamycin IIa was investigated. Attempted reaction with alkyl thiols, substituted phenyl thiols, ethyl mercaptoacetate or hydroxy-substituted alkyl thiols using standard conditions [128] (but at room temperature) was unsuccessful. Moderate yields (up to 50%) to conjugate addition products from reaction of pristinamycin 11 with these thiols (Scheme 22) were obtained when the reaction was carried out in the presence of N,N-dimethylethanolamine (see below for discussion of the stereochemistry associated with the conjugate addition products). With sterically hindered thiols, for example, 2-mercapto-pyran, no reaction was observed even under catalytic conditions. Similar results to those described above were obtained for reaction of either of the alcohols (60) or (61). 

The standard method of introducing a functionality at the la-position of steroids is to prepare a A -3-ketone and then to carry out an appropriate Michael-type addition reaction which gives the adduct of proper la-stereochemistry. One complication of this method when working toward the preparation of A -sterols is that the usual conditions of the conjugate addition to the unsaturated ketone are sufficient to equilibrate the A -double bond to the more stable A" -3-ketone. Conversely, conditions for deconjugation of the resulting A -3-ketones are unsuitable for retaining substituents at C-1 which can be eliminated by P-elimination. The methods outlined below are adaptations which have been devised to circumvent these difficulties. 

If the carbanion has even a short lifetime, 6 and 7 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each. This will be one of two possible diastereomers, so the reaction will be stereoselective but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific. Unfortunately, this prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases, the reaction has been shown to be stereoselective with syn addition reported in some cases and anti addition in others." When the reaction is performed on a Michael-type substrate, C=C—Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to tra -MeCH=CHCOOEt) predominant anti addition was found there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack. For obvious reasons, additions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, though syn addition and nonstereoselective addition have also been reported. 

The formation of cyclopropanes from 7C-deficient alkenes via an initial Michael-type reaction followed by nucleophilic ring closure of the intermediate anion (Scheme 6.26, see also Section 7.3), is catalysed by the addition of quaternary ammonium phase-transfer catalysts [46,47] which affect the stereochemistry of the ring closure (see Chapter 12). For example, equal amounts of (4) and (5) (X1, X2 = CN) are produced in the presence of benzyltriethylammonium chloride, whereas compound (4) predominates in the absence of the catalyst. In contrast, a,p-unsatu-rated ketones or esters and a-chloroacetic esters [e.g. 48] produce the cyclopropanes (6) (Scheme 6.27) stereoselectively under phase-transfer catalysed conditions and in the absence of the catalyst. Phenyl vinyl sulphone reacts with a-chloroacetonitriles to give the non-cyclized Michael adducts (80%) to the almost complete exclusion of the cyclopropanes. 

Reactions on SP2 Type Unsaturated Systems Very few studies have been carried out on the stereochemistry of the Michael reaction. However, Abramovitch and Struble (36) have found that compound 101 was the main product when diethyl sodiomalonate (free of ethoxide ion and ethanol) was added to 4- t-butyl-1-cyano cyclohexene (99) in boiling toluene. This result can be rationalized by axial attack on 99 to give first 100 having a chair-like conformation which is then transformed into 101 by internal trapping (see arrow). However, when the addition of diethyl malon-ate anion was carried out in ethanol under thermodynamically controlled conditions, product 103 with an equatorial malonate group was obtained, presumably via the twist-boat intermediate 102. 

Next, the mechanism of the Type II reactions is discussed. To discriminate one of the enantiofaces of the acceptor it is desirable to place and to activate the electrophiles in a chiral environment. At the same time, effective activation of the Michael donor is required. In Shibasaki s ALB-catalyzed reaction (Scheme 3), it was proposed that the aluminum cation functioned as a Lewis acid to activate enones at the center of the catalyst, and that the Li-naphthoxide moiety deproton-ated the a-hydrogen of malonate to form the Li enolate (Scheme 9). Such simultaneous activation of both reactants at precisely defined positions became feasible by using multifunctional heterobimetallic complexes the mechanism is reminiscent of that which is operative in the active sites of enzymes. The observed absolute stereochemistry can be understood in terms of the proposed transition state model 19. Importantly, addition of a catalytic amount of KOt-Bu (0.9equiv. to ALB) was effective in acceleration of the reaction rate with no deterioration of the... 

Mechanistically, enamine and Lewis-acid-mediated conjugate additions are complex. The opportunity exists for the product-determining step to occur at a number of points and, without further study, the precise nature of the manifold is not entirely clear. In some enamine cases where the stereoselectivity likely results from the conjugate addition, a synclinal type transition state seems to be involved. With the Mukaiyama-Michael addition, some processes implicate an open-extended pathway. Despite the mechanistic uncertainties that remain, sufficient data are now available so that the stereochemistry in many cases can be anticipated by extrapolation. 

Reversal of the stereochemistry of the Michael addition to PhCH=CHCH=0 has been observed for the MacMillan-type catalysts (257) and (258), which can be rationalized either by yn-addition with respect to the benzylic substituent of an ( )-iminium ion intermediate or by anti-addition to the corresponding (Z)-iminium ion. The issue has not yet been resolved. ... 

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