Conjugate addition axial attack

Syntlietic cliemists can now work witli tlitee-dlmensional pictures of tlie conjugate addition available on a website [80]. In tlie absence of steric hindrance i5-nietliylcydobexenone, for example), an "axial attack" tlitougb a balf-diait conformation is favored, while in tlie corLisone syntliesis an "equatorial attack" tliroLigli a half-boat conformation is favored because of tlie constraint imposed by tlie bicydic tings [83]. 

Enamines also react with electrophilic alkenes to give conjugate addition products. The addition reactions of enamines of cyclohexanones show a strong preference for attack from the axial direction.319 This is anticipated on stereoelectronic grounds because the tt orbital of the enamine is the site of nucleophilicity. 

As with mechanism, the stereochemical outcome of tandem vicinal difunctionalization is dependent upon the individual bond-forming steps in the sequence. The conjugate addition reaction is quite sensitive to the steric environment of the a,(3-unsaturated substrate, so that the bond-forming process at the 3-carbon adheres to steric approach control factors the 5-methoxycarbonyl substituent of (5) directs axial attack of a bis(dimethylphenylsilyl)copperlithium reagent so that only the 3,5-trans adduct is formed... 

In conclusion, in the case of 1,4-conjugated additions to a,B-unsaturated ketones, some substrates, in order to avoid steric interaction, react through a boat conformation to give an equatorially substituted product, but when there is no steric interaction, the axial attack through a chair conformation is energetically favored. Both processes are however stereoelectroni-cally controlled. 

The stereoselectivity of conjugate addition reaction of 34 can be rationalized as follows. The conformation of 34 is restricted to A by the oxazolizinone ring, and the vinyl anion attacks from stereoelectronically preferred (3-axial direction to give rise to the adduct 35 exclusively. 

The stereoselectivity of the second and key Michael-type conjugate addition reaction can be rationalized as follows. The conformation of 63 will be restricted to 63-A due to A(l 3) strain between the N-methoxycarbonyl and w-propyl groups in 63-B. Attack of the vinyl anion from the stereoelectronically favored a-axial direction provides the adduct 64 exclusively. It is noteworthy that the stereochemical course of the above reaction is controlled by the stereoelectronic effect in spite of severe 1,3-diaxial steric repulsion between the axial ethyl group at the 5-position and the incoming vinyl anion. This remarkable stereoselectivity can be also explained by Cieplak s hypothesis[31]. On the preferred conformation 63-A, the developing a of the transition state is stabilized by the antiperiplanar donor Gc-h at the C-4 position. 

Base-catalysed alkylation [i6 ] of the tricyclic (des-A) compound (9) with methyl vinyl ketone provides another example of stereoselective "axial attack upon an enol anion. Compound (9) is the tricyclic analogue of a 4-methyl-i9-nor-A 3 ketone and the iOj3-alkylation in the tricyclic compound is strictly comparable with 4/ -attack upon the 19-nor system. The alkylation with methyl vinyl ketone is a typical "conjugate addition (see p. 192), and was followed by base-catalysed C5 clisation to form ring A of a loa-steroid (10). 

Exo cycloalkylations have been used to synthesize ct5-1-decalones. For example, treatment of 2-methyl-3(4-tosyloxybutyl)cyclohexanone with sodium t-pentylate in benzene gave c/j-9-methyl-l-deca-lone (50) in 60% yield. Also, as shown in Scheme 28, conjugate addition-cycloalkylation was employed to synthesize a cw-fused decalone related to the sesquiterpene, ( )-valerane. Apparently, in these cases, the enolate intermediate adopts a conformation having the 4-bromobutyl side chain quasi-axial, and C—C bond formation occurs via equatorial attack to give initially a twist-boat conformation of the product. 

The Michael addition of 1-thio-P-D-glucose to this enone proceeded smoothly (6) with the formation of P-(l-5)-4-deoxy-5-C-thiodisaccharide in 94% yield. The proton-proton coupling constants in the H NMR spectrum of the addition product confirmed that only the 5-axial adduct was obtained as a single product. This stereoselectivity, as observed previously in levoglucosenone conjugate additions proceeds by the attack of incoming nucleophile at the top of the alkene face of the enone ring as depicted in Scheme 6. 

A more interesting situation arises with a substituent already on C-5 20. The cuprate then adds anti to that substituent (the intermediate is here trapped as a silyl ether anti-21) and trapping with electrophiles introduces a second anti relationship anti, anti-22. The stereoselectivity arises by axial attack both during the conjugate addition and on the enolate (chapter 21). 

It is known that the 2-cyclohexenone system exists, principally, as two rapidly exchanging envelope (also called sofa) conformations (93, 94). Conjugate addition of a nucleophile can occur to either face of the 2-cyclohexenone. Parallel or anti-parallel (with respect to the axial substituent at C4) attack is possible in principle, however, a nucleophile must approach from an axial direction for satisfying the requirement of the stereoelectronic effect. Anti-parallel attack leads to a favorable chair-like intermediate, whereas parallel attack leads to an unfavorable boat-like intermediate in each case. In an anti-parallel attack, the newly introduced nucleophile forms a frarcs-diaxial arrangement found in a chair conformation. Conversely, parallel attack leads to a syn-diaxial arrangement found in a boat conformation. Therefore, anti-parallel attack is favored as this leads to a lower energy intermediate. 

Nncleophilic Addition and Substitution Reactions. Allylsilane (3) has been shown to undergo conjugate addition to enones in the presence of tetra- -butylammonium fluoride (eq 6). The reaction demonstrates high regioselectivity, as no products arising from 1,2-addition to the enone or attack at the /-position of the allylsilane were isolated. Stereoselective C-glycosidation can be effected by reaction of allylsilane (3) with D-mannopyranoside derivatives in the presence of boron trifluoride etherate (eq 7). The a-C-glycoside arises from axial addition to the pyranoside oxonium ion. 

The Grignard reagent attacks the unsaturated ketones (3) and (6) from the relatively unhindered ot- or jS-side, respectively, perpendicular to the plane of the conjugated system. An analogous transition state (10) leading to axially substituted 1,6-addition products (11) from A -3-ketones (9) with methylmagnesium halide was suggested by Marshall. ... 

Similar to the addition reactions of acceptor-substituted dienes (Scheme 16), the outcome of the transformation depends on the regioselectivity of the nucleophilic attack of the organocopper reagent (1,4- vs. 1,6-addition) and of the electrophilic capture of the enolate formed. The allenyl enolate obtained by 1,6-addition can afford either a conjugated diene or an allene upon reaction with a soft electrophile, and thus opens up the possibility to create axial chirality. The first copper-mediated addition reactions to Michael acceptors of this type, for example, 3-alkynyl-2-cyclopentenone 75,... 

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